Exercise-induced Changes in Microclotting and Cytokine Levels Point to Vascular Injury and Inflammation in People with Long COVID

Exercise-induced Changes in Microclotting and Cytokine Levels Point to Vascular Injury and Inflammation in People with Long COVID | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exercise-induced Changes in Microclotting and Cytokine Levels Point to Vascular Injury and Inflammation in People with Long COVID Callum Thomas, Massimo Nunes, Jan H. Pretorius, Ruth EM. Ashton, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6717727/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Long COVID is a persistent and episodic multi-system condition that impacts quality of life and functional status. Underlying pathologies include viral persistence, endothelial dysfunction, platelet hyperactivation/dysregulation, and the presence of anomalous deposits, also referred to as fibrinaloid complexes or microclots. Exercise is sometimes suggested to be beneficial for people with Long COVID despite minimal exertion being shown to exacerbate symptoms in many cases. To date, changes in microclot dynamics, inflammation, and biomarker profile in response to exercise remain unstudied in people living with Long COVID. Methods: 46 people living with Long COVID with a low risk of experiencing post-exertional malaise (PEM) completed two submaximal cardiopulmonary exercise tests, separated by 24 hours. Thirteen individuals were ineligible for participation for the following reasons: high-risk of PEM (n=9), a severe orthopaedic condition (n=1), a severe cardiac issue (n=1) or were unable to commit to the study requirements (n=2). Venous blood was collected pre- and post-exercise for cytokine profiling and for imaging flow cytometry analysis of microclots. Changes in large and small microclot populations and their association with inflammatory and vascular injury markers were assessed using fixed-effects and instrumental variable statistical models. Results: No adverse events were reported in this study on either CPET day. At the first ventilatory threshold (VT1), O 2 was 9.7 ± 1.9 ml•kg•min -1 and decreased on day 2 (8.9 ± 1.9 ml•kg•min -1 ; p=0.003). O 2 pulse at VT1 was lower on day 2 (day 1 vs. day 2; 8.3 ± 2.4 vs. 7.5 ± 1.9 mL/b; p<0.001). CPET induced the fragmentation of large microclots (100–3000 µm²) and caused an increase in small microclots (<30 µm²) after repeated exertion. Fragmentation correlated with increases in cytokines associated with pro- and anti-inflammation, as well as vascular injury. Conclusion : This study provides the first evidence of a biological basis that might explain exercise-induced symptom exacerbation in people with Long COVID through microclot fragmentation, which may contribute to systemic inflammation. This has important implications for Long COVID rehabilitation practices that seek to improve health outcomes through exercise therapies that may have the capacity to be harmful for people living with Long COVID and underscores the need for targeted therapeutic strategies that consider microclot clearance and endothelial repair. Physiology Infectious Diseases Long COVID Blood Biomarkers Inflammation Vascular Injury COVID-19 Microclots Figures Figure 1 Figure 2 INTRODUCTION Long COVID describes a continuation and/or development of symptoms that can manifest into a chronic disease state 3-months following a SARS-CoV-2 infection that cannot be explained by an alternative diagnosis but instead encapsulate multiple diagnosable conditions [ 1 , 2 ]. Long COVID is recognised as a chronic and episodic condition associated with over 200 established symptoms that are categorised more broadly into physical, cognitive, and psychosocial symptom domains [ 3 ]. The Long COVID presentation is heterogenous and ranges from a modest decrease in everyday activities to a disabling condition associated with a broad reduction in quality of life and functional status [ 4 – 6 ]. It has been estimated that Long COVID affects 65–150 million people globally [ 7 , 8 ], but these figures are dependent on the definition and likely conservative with less restrictive criteria; other analyses report that this figure could be more than 400 million cases [ 9 ]. To date, there are no established curative treatments, and preventing acute infections with SARS-CoV-2 remains the best way to prevent Long COVID. Recent studies have provided important insights into the multi-system nature of Long COVID, implicating endothelial dysfunction, platelet hyperactivation, autoimmune dysfunction, perturbed blood flow and perfusion, and viral persistence as pathologies that could contribute mechanistic explanations of the prolonged symptoms [ 10 – 13 ]. Biomarkers of Long COVID have been widely discussed as an important gateway to understanding the pathophysiology, and candidate markers have been identified (i.e. interleukin-6 [IL-6], vascular endothelial growth factor [VEGF], and CD8 + T-cell concentrations) [ 14 – 16 ]. Due to the multi-system and simultaneous pathologies of Long COVID, these markers, in isolation, mean very little as many will be influenced by intrinsic and extrinsic factors; for example, IL-6 concentrations can be influenced by cardiovascular disease, medication, and habitual exercise status [ 17 , 18 ]. However, diagnostic tests using blood biomarker profiles have demonstrated laudable accuracy. Patterson et al. [ 19 ] were able to correctly identify 118/121 people living with Long COVID using a mathematical equation that involved inflammatory and immunological blood biomarkers. Similarly, Patel et al. [ 20 ] were able to use two vascular blood biomarkers (ANG-1/P-SEL) to identify correctly 96% of people living with Long COVID. Thus, these studies highlight multiple domains of biomarkers that can identify people living with Long COVID. Endothelial dysfunction and damage, increased platelet activation, formation of microthrombi, and damage to the microcirculatory circulation are further consequences of acute SARS-CoV-2 infection [ 21 – 23 ]. Specifically, persistent endothelial inflammation and platelet hyperactivation, and the presence of anomalous deposits (also known as fibrinaloid microclots), which are resistant to normal fibrinolytic processes, have been linked to Long COVID [ 10 , 24 – 26 ]. Microclots are heterogeneous in content and morphology, and are composed of inflammatory proteins, fibrinogen chains, and other biomolecules, and are positively stained with amyloid markers. The adoption of an amyloid state by fibrinogen and other proteins, as well as the possible presence of antifibrinolytic molecules entrapped in microclots, render these aggregates more resistant to proteolysis [ 27 ] and hence enables their persistence in circulation [ 28 ]. Collectively, these properties impede microvascular function, impairing gas transfer, and could be driving hypoxia-related symptoms observed in people living with Long COVID [ 25 , 26 ]. Inflammatory molecules in circulation are associated with microclots and perpetuate systemic inflammation [ 26 ]. Notably, neutrophil extracellular traps (NETs) are structurally associated with microclots, potentially amplifying thrombo-inflammatory responses. Cardiopulmonary exercise testing (CPET) [ 29 ] has prognostic and diagnostic capabilities that can increase the understanding of Long COVID pathology [ 30 , 31 ]. Coupled with a detailed blood biomarker assessment, it could also increase the understanding of the disease pathology driving symptom presentation. CPET can be performed using either submaximal or maximal protocols, in which the integrative response to incremental exercise enables the assessment of the cardiorespiratory system and identification of any physical impairments [ 32 ]. Studies that involve CPETs have demonstrated multi-system impairment in response to both maximal [ 33 , 34 ] and sub-maximal [ 35 ] protocols in people living with Long COVID. Two-day exercise approaches enable assessment of restorative function and may help create new knowledge of symptom exacerbation following physical exertion, commonly known as post-exertional malaise (PEM) or post-exertion symptom exacerbation (PESE) [ 36 ]. Gattoni et al. [ 37 ] utilised this approach with fifteen people living with Long COVID but found a reduction in VE/V̇CO 2 at the gas exchange threshold only on day 2 compared with day 1. By contrast, our previous work utilising a submaximal approach with a larger sample size (N = 68) found reductions in oxygen consumption ( \(\:\dot{\text{V}}\) O 2 ) and pulse, end-tidal carbon dioxide, and workload at the ventilatory threshold on day 2 compared with day 1 [35]. In healthy people, there is an assumption that exercise facilitates clot clearance [38]; however, no study has assessed how microclots and other blood biomarkers associated with Long COVID respond to submaximal two-day CPET. We hypothesized that submaximal exercise would exacerbate markers of inflammation and vascular injury, and this would align with a high microclot count as opposed to an elimination from circulation, and a worsening of submaximal CPET parameters on the second day of exercise. Accordingly, we aimed to explore the dynamic relationship between exercise-induced physiological changes, microclot count, and inflammatory, vascular injury, and immunological blood biomarker fluctuations, offering novel insights into the mechanisms of persistent symptoms in individuals with Long COVID. METHODS Study Design and Ethical Approval This single-centre, retrospective, observational study was conducted at the University of Derby, United Kingdom, and was prospectively registered with clinicaltrials.gov (NCT06394921). The study received both NHS (IRAS ID: 313936) and institutional (ETH2324-1808) research ethics approval. All participants provided written informed consent prior to their involvement in the study and the study conformed to the standards set by Good Clinical Practice (GCP) and by the Declaration of Helsinki (Version 2024). Participants Screening and Eligibility All participants were screened via telephone consultation to determine eligibility. Eligibility included having a confirmed history of SARS-CoV-2 infection, a clinical diagnosis of Long COVID and the presence of PESE with a low risk of experiencing PEM, determined by the severity and frequency function of the De-Paul Symptom Questionnaire [ 39 ]. Additional inclusion criteria included having sufficient English language comprehension and cognitive ability to provide informed consent and be able to complete all study assessments as per the study protocol. Due to the exercise component of the study, standard CPET safety criteria were applied [ 40 ], which excluded individuals with conditions such as unstable angina, uncontrolled hypertension (resting systolic blood pressure [SBP] > 180mmHg, or resting diastolic blood pressure [DBP] > 110mmHg), severe orthopaedic conditions, recent embolism, and other significant metabolic or cardiovascular conditions. Participant eligibility was recorded by CT, and a second reviewer (MF) was consulted to determine suitability and appropriateness for participation in the study. Thirteen individuals were ineligible for participation for the following reasons: high-risk of PEM (n = 9), a severe orthopaedic condition (n = 1), a severe cardiac issue (n = 1) and (n = 2) were unable to commit to the study requirements. Following confirmation of eligibility, 46 individuals (n = 32 female) were invited to complete a series of three face-to-face visits over ten days. Study Procedure Patient Profiling COVID-19/Long COVID During the first visit (1 of 3), baseline data collection involved recording demographic information, medical history, details regarding pre-COVID-19 health status, suspected and confirmed COVID-19 infections, vaccination status and a comprehensive review of Long COVID history, including index infection, referral to support systems, ongoing interventions for Long COVID and symptom profile. Functional impairment of Long COVID symptoms was assessed using the PCFS scale [ 41 ]. Physiological assessments were conducted, including measurements of heart rate (HR), blood pressure, peripheral oxygen saturation (SpO 2 ), respiratory rate, lung function assessment, respiratory muscle strength and tympanic body temperature. Functional status was assessed via the 6-minute walk test (6MWT) and was conducted according to American Thoracic Society guidelines [ 42 ]. Data from the 6WMT were subsequently used to determine the starting work rate for an adapted CPET test (strata outline below): Strata I: 6MWT distance 400 m (starting WR of 30 W with subsequent increments of 5W) Patient-Reported Outcome Measures Patient-reported outcome measures (PROMs) were completed at all study visits and questionnaire information is detailed elsewhere [ 35 ]. Symptoms were measured using an 18-item, 5-point likert scale (0 symptom not present – 5 very severe) and a single item, 10-point likert scale (0 no impact – 10 large impact) to determine severity and impact within the previous 24 hours. Quality of Life (QoL) was assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) [ 43 ]. Participants completed two separate measures of fatigue: 1) the Fatigue Assessment Scale (FAS) [ 44 ]; and 2) the modified fatigue impact scale (MFIS) [ 45 ]. The Medical Research Council (MRC) Dyspnoea Scale was administered to grade the effect of breathlessness on the person’s daily activities [ 46 ]. Cardiopulmonary Exercise Tests (CPET) The protocol for the CPET session is detailed fully elsewhere [ 35 ]. Briefly, participants completed two submaximal CPET sessions, separated by 24 hours, using an incremental exercise ramp test on a friction-loaded cycle ergometer (Monark 894E Ergomedic Peak Bike, Monark, Varberg, Sweden) following the American Thoracic Society guidelines [ 29 ]. The protocol began with a 3-minute rest period, followed by a maximum of 12 minutes of cycle exercise at ~ 60 revolutions per minute (rpm) delivered via a stepwise incremental protocol. Test termination criteria included a consistent drop in cadence below 60 revolutions per minute despite encouragement and participant volition, whereby symptom exacerbation was beyond the tolerable limits of the participant. Adverse Event Reporting Patients were asked at every study visit to report any adverse events following study visits; this included contacting the study team directly in the seven days post completion of study activities. Adverse events were investigated by appropriate clinical personnel (TB). Sample Collection Venous blood samples were collected into sodium citrate and serum-separating tube vacutainers from participants at four time points, including both before and after submaximal exercise on two days separated by 24 hours to assess changes in microclot formation and blood biomarker levels. Plasma and serum separation was performed within 1–2 hours of collection by centrifuging the blood samples at 2,500 rpm (1048 g ) for 10 minutes at room temperature. The upper layer was collected into 0.5mL aliquots and these were stored at -80°C until analysis. CPET Data Processing and Analysis CPET data were reviewed for completeness by the test site coordinator (CT). Raw gas analysis data were transformed from breath-by-breath to 30-second moving average and middle 5-of-7 breath averages to reduce variability and identify data outliers or missing data. The ventilatory threshold (VT1) describes the point where energy contribution from primarily aerobic metabolism changes to a greater involvement from anaerobic energy sources. The respiratory compensation point (VT2) reflects the upper limit of aerobic energy contribution and primarily indicates that oxidative metabolism is no longer sufficient to meet energy demands; anaerobic energy contribution continues to increase beyond this point until volitional exhaustion or test cessation [ 47 ]. Middle 5-of-7 breaths data were used to determine VT1 and VT2 using the V-slope method. Exercise threshold decisions were made according to the standardised ACSM guidelines [ 40 ] by the test site coordinator (CT) with 10% checked by an additional author (RA). The chief investigator (MF) resolved any uncertainty on exercise threshold decisions through discussion with CT and RA where consensus originally had not been reached. A more detailed account of CPET data processing and analysis can be found in our previous work [ 35 ]. Data are presented as mean ± standard deviation. Normal distribution was assessed using Shapiro-Wilks tests. Parametric data were assessed using paired samples t-tests; nonparametric data were assessed using Wilcoxon Signed Rank tests in GraphPad Prism (Version 10) with a set α level of 0.050 (two-tailed; Bonferroni corrected 0.013). Uncorrected p values are presented within text and tables and the Bonferroni corrected alpha level for significance was applied for all comparisons. Cohen’s D was used to calculate the effect size of parametric paired samples t-tests with thresholds set at 0.2 = Small, 0.5 = Medium, and 0.8 = Large. To calculate the effect size value of Wilcoxon Signed Rank t-tests, the formula Difference between sums of ranks / Total of sums of ranks was implemented with thresholds set at 0.1 = Small, 0.3 = Medium, and 0.5 = Large. In accordance with the literature, multiple imputation (MI) was applied in cases where 5–10% of data were missing [ 48 ]. MI was not used to create data where VT1 and VT2 decisions could not be obtained due to the participant having not reached or exceeded the threshold. Microclot Analysis Sample preparation For microclot analysis, platelet poor plasma (PPP) samples were stored at − 80°C until analysis. Thioflavin T (ThT) is a fluorogenic dye that binds to various types of amyloid proteins [ 49 ]. On the day of testing, each sample was thawed to room temperature, PPP was incubated with 0.3 µM final ThT exposure concentration, for 30 minutes. Imaging flow cytometry was then performed using an Amnis® FlowSight® Imaging Flow Cytometer (Luminex Corporation). A 405 nm laser was used for excitation, and ThT-positive events were detected using channel 7, which covered the 435–505 nm wavelength range. A standardized acquisition template was applied across all samples. Each sample was analyzed for five minutes at a flow rate of 0.043 µL/s, resulting in a total volume of 12.9 µL analyzed per run. Microclots were characterized based on size (measured as µm 2 from two-dimensional micrographs), morphology, and fluorescence intensity. Negative controls, including water with and without ThT, and unstained Long COVID PPP samples, were used to establish both an acquisition and analysis gate ( Supplementary Fig. 1 ), and to validate the reliability of the data. Sample analysis IDEAS 6.3 software developed for the Amnis® FlowSight® Imaging Flow Cytometer was used to perform all flow cytometry analyses. Statistical analyses were performed using R version 4.4.3. Descriptive statistics, including the mean and standard deviation (SD), were used to summarize continuous variables. Comparisons between pre-exercise and post-exercise measurements were conducted using paired t-tests or non-parametric equivalents, depending on the data distribution. Correlations between microclot counts, size, and cytokine levels were assessed using Pearson’s or Spearman’s correlation coefficients. Cytokine Panel Analysis Serum samples were analysed using a cytokine 30-plex human panel from Thermo Fisher Scientific (catalogue number: LHC6003M), designed for Luminex™ platforms. This experiment was performed on the Flexmap 3D platform (software: xPONENT 4.2). This panel measures immune biomarkers including various interleukins, both interferon-α (IFN-α) and interferon-γ (IFN-γ), both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumour necrosis factor-α (TNF-α). All analyses followed the manufacturer’s guidelines, and cytokine concentrations were compared across pre-exercise and post-exercise samples to investigate changes in systemic inflammation. The laboratory staff were blinded to the severity or clinical details of the participants in this project. Data are presented as mean ± standard deviation. Normal distribution was assessed using Shapiro-Wilks tests. Parametric data were assessed using one-way repeated measures ANOVA; meanwhile, nonparametric data were assessed using Friedman’s tests in Graphpad Prism (Version 10) with a set α level of 0.050. Data were corrected for multiple comparisons using Tukey tests for one-way repeated measures ANOVA and Dunn’s tests for Friedman’s tests. Statistical Inference We investigated the relationship between treatment-induced microclot changes and inflammation using a three-step empirical strategy. First, we tested whether CPET leads to the breakdown of larger microclots (100–3000 µm²). Secondly, we assessed whether this breakdown causes elevated levels of circulating small microclots (< 30 µm²). Finally, we examined whether a higher burden of small microclots is associated with an inflammatory cytokine response. To do this, we estimated a sequence of models incorporating fixed effects, first differences, and instrumental variable regressions. Logarithmic Transformation and Microclot Size Definitions All count variables were log-transformed to address skewness and enhance comparability across individuals. Raw distributions for large microclots, small microclots, and objects/mL showed substantial skew (1.67–2.74) and kurtosis (2.00–8.11), with Shapiro-Wilk tests indicating strong non-normality (p < 10⁻¹⁴). After transformation, distributions were markedly more symmetric, with skewness reduced to near zero and normality substantially improved. These adjustments supported the use of log-transformed variables in our regression analyses. Fixed Effects Model of Microclot Breakdown To test whether CPET induced the breakdown of large into small microclots, we estimated a fixed effects model at the individual level. The dependent variable was the change in log small microclot count, modelled as a function of changes in log large microclots and log objects/mL (a proxy for overall burden). Time was defined by treatment stages: Pre- and Post-CPET 1 and 2. Formally, we estimated: $$\:\varDelta\:{\text{log}\left(SmallMicroclots\right)}_{it}={\beta\:}_{1}\varDelta\:{\text{log}\left(LargeMicroclots\right)}_{it}+{\beta\:}_{2}\varDelta\:{\text{log}\left(Objects\right)}_{it}+{\epsilon\:}_{it}$$ This fixed-effects specification controlled for all time-invariant individual heterogeneity, such as baseline coagulation profile or immune reactivity. Instrumental Variables Estimation We used two-stage least squares (2SLS), treating treatment phase (t) as an instrument for large microclot counts. We assumed t influences small microclots only via its effect on large microclot breakdown. First stage: \(\:\text{l}\text{o}\text{g}{\left(\text{L}\text{a}\text{r}\text{g}\text{e}\text{M}\text{i}\text{c}\text{r}\text{o}\text{c}\text{l}\text{o}\text{t}\text{s}\right)}_{\text{i}\text{t}}\:=\:{\pi\:}₀\:+\:{\pi\:}₁{\text{t}}_{\text{i}\text{t}}\:+\:{\pi\:}₂\text{l}\text{o}\text{g}{\left(\text{O}\text{b}\text{j}\text{e}\text{c}\text{t}\text{s}\right)}_{\text{i}\text{t}}\:+\:{{\eta\:}}_{\text{i}\text{t}}\) Second stage: \(\:\text{l}\text{o}\text{g}{\left(\text{S}\text{m}\text{a}\text{l}\text{l}\text{M}\text{i}\text{c}\text{r}\text{o}\text{c}\text{l}\text{o}\text{t}\text{s}\right)}_{\text{i}\text{t}}\:=\:{\alpha\:}₀\:+\:{\alpha\:}₁\text{l}\text{o}\text{g}{\left(\text{L}\text{a}\text{r}\text{g}\text{e}\text{M}\text{i}\text{c}\text{r}\text{o}\text{c}\text{l}\text{o}\text{t}\text{s}\right)}_{\text{i}\text{t}}\:+\:{\alpha\:}₂\text{l}\text{o}\text{g}\left(\text{O}\text{b}\text{j}\text{e}\text{c}\text{t}\text{s}\right)\_\text{i}\text{t}\:+\:{{\nu\:}}_{\text{i}\text{t}}\) This approach identified the causal effect of large microclots on small microclots, assuming exogeneity of the treatment instrument. Cytokine Response Due to suspected non-linearity in the relationship between microclots and cytokines, we used non-parametric methods rather than linear models. Spearman rank correlations (ρ) were calculated between microclot counts (small and large) and cytokine levels, providing robustness to outliers and distributional assumptions. Results are summarised using a tile plot with significance stars. RESULTS Patient profiling and functional assessments Table 1 and Supplementary Figure 2 contains a detailed demographic description of the study participants. Briefly, 2 ± 1 SARS-CoV-2 infections were recorded (range: 1-5 infections from 2020-2023), and the mean number of vaccinations was 4 ± 1 vaccines (range 1-7). One or more comorbidities were reported by 76% (n=35) of participants. Table 1 . Participant demographics, vaccination status and comorbidities. Participant Characteristics (n=46) Age (years) 52 ± 11 Sex n (%) Male Female 14 (30%) 32 (70%) Height (cm) Weight (kg) Body mass index (kg/m 2 ) 167 ± 10 78 ± 17 28 ± 6 Vaccinated n (%) Yes No One dose Two doses Three doses > Three doses Unknown 46 (100%) 0 (0%) 2 (4%) 3 (7%) 16 (35%) 24 (52%) 1*(2%) Comorbidities n (%) Yes No Endocrine/diabetes Renal Cardiovascular Gastrointestinal/Liver Neurological/cerebrovascular Malignancy including haematological Respiratory Rheumatological Psychological Other 35 (76%) 11 (24%) 6 (13%) 4 (9%) 19 (41%) 13 (28%) 17 (37%) 2 (4%) 15 (33%) 7 (15%) 5 (9%) 9 (20%) PROMs* PCFS (AU) EQ-5D-5L utility score (AU) EQ-5D-5L VAS (AU) Symptom Score (AU) FAS (AU) MFIS (AU) MRC dyspnoea (AU) Cognitive function (AU) Baseline physiological measures Systolic blood pressure (mmHg) Diastolic blood pressure ( mmHg) Heart rate (bpm) SpO 2 (%) Baseline functional status* FEV1 (Litres) FVC (Litres) FEV1/FVC (AU) PEF ( L•min -1 ) MIP cmH 2 O MEP cmH 2 O 3 ± 1 0.74 ± 0.15 57 ± 15 21 ± 9 31 ± 7 52 ± 13 3 ± 1 27 ± 2 130 ± 19 86 ± 11 74 ± 13 98 ± 1 2.78 ± 0.77 3.49 ± 0.99 81 ± 6 449 ± 114 94 ± 33 130 ± 43 *Denotes data available for 45 participants. PROMs denote patient reported outcomes. FEV1 denotes forced expiratory volume in one second. FVC denotes forced vital capacity. PEF denotes peak expiratory flow. MIP and MEP denote maximal inspiratory and expiratory pressure, respectively. The most prevalent symptoms were fatigue (94%), headaches (72%), concentration issues (70%), joint pain (61%), difficulty sleeping (65%), and dizziness (41%). The impact of symptoms on daily life was self-reported as moderate (6 ± 2 out of 10). Mean distance covered by participants on the 6MWT was 407 ± 80 m (range: 270-600m). Accordingly, 13 (28%), 10 (22%), and 23 (50%) participants were assigned to strata 1, 2, and 3 of the CPET protocol, respectively. Further PROMs, physiological, and functional measures are described in Table 1 and Supplementary Figure 3. Protocol Safety and Tolerability No severe adverse or adverse events were reported following the completion of CPET on either day 1 or day 2. Six participants (13%) were unable to complete the full 12-minute protocol. Reasons for test termination were due to symptom exacerbation (breathlessness (n=7), fatigue/heaviness in legs (n=4), and dizziness (n=1). Summary of CPET Outcomes Workload at iso-time peak, defined as work rates that were matched within participants for total duration of cycle exercise (comparison of the shortest duration reached of the two datasets) [50], was 73 ± 15 W. Cardiopulmonary measures at rest, iso-time peak, and VT1 for CPET day 1 and day 2 are presented in Table 2 . Compared with day 1, on day 2 heart rate (mean increase 4 ± 5%, 73 ± 14 bpm; p=0.005), minute ventilation (mean increase 6 ± 4%, 10.4 ± 2.3 L•min -1 ; p=0.010), breathing frequency (mean increase 8 ± 10%, 16 ± 4 breaths/min; p=0.007), and P ET O 2 (mean increase 2 ± 8%, 110 ± 4 mmHg; p=0.005) were all increased at rest. At VT1, O 2 (mean reduction 9 ± 20%, 0.65 ± 0.11 L•min -1 ; p=0.002), O 2 pulse (mean reduction 9 ± 22%, 7.5 ± 1.9 mL/b; p<0.001) and V̇CO 2 (mean reduction 9 ± 17%,0.51 ± 0.10 L•min -1 ; p=0.006) were all reduced on Day 2. Baseline blood lactate on Day 1 was 1.3 ± 0.5 mmol/L and increased to 3.5 ± 1.6 mmol/L post-test (p<0.001) and was 1.4 ± 0.6 mmol/L at baseline on Day 2 which increased to 3.3 ± 1.7 mmol/L post exercise (p<0.001). There were no between-day differences in peak blood lactate at baseline (p=0.451) or post-exercise (p=0.087). Table 2. Cardiopulmonary measures at rest, VT1, and iso-time peak for CPET day one and two. n=46 people living with Long COVID (Mean ± Standard Deviation) Rest VT1 Iso-time peak Day 1 Day 2 p value ES Day 1 Day 2 p value ES Day 1 Day 2 p value ES V̇O 2 (L•min -1 ) 0.31 ± 0.06 0.32 ± 0.06 0.143 -0.220 0.71 ± 0.14 0.65 ± 0.11 0.002 † 0.737 1.33 ± 0.25 1.33 ± 0.22 0.864 0.025 V̇O 2 (mL•kg -1 •min -1 ) 3.93 ± 0.87 4.03 ± 0.96 0.219 0.210 9.7 ± 1.9 8.9 ± 1.9 0.003 † -0.680 17.4 ± 3.8 17.4 ± 4.0 0.509 -0.114 V̇O 2 _HR (mL/b) 4.49 ± 1.14 4.51 ± 1.12 0.820 -0.040 8.3 ± 2.4 7.5 ± 1.9 <0.001 † -0.747 11.1 ± 2.8 11.0 ± 3.0 0.302 -0.177 HR (bpm) 71 ± 13 73 ± 14 0.005 † 0.471 88 ± 12 89 ± 13 0.828 0.054 125 ± 25 125 ± 25 0.952 -0.011 Workload (Watts) - - - - 27 ± 12 21 ± 13 0.038* -0.680 73 ± 15 73 ± 15 1.000 0.000 VE/V̇O 2 (AU) 24.6 ± 3.8 25.2 ± 3.0 0.192 0.223 22.0 ± 1.9 22.1 ± 1.8 0.584 0.133 30.5 ± 6.0 30.5 ± 4.9 0.880 -0.027 VE/V̇CO 2 (AU) 29.3 ± 4.2 29.7 ± 4.0 0.488 0.119 28.1 ± 2.7 28.2 ± 2.6 0.877 0.040 30.8 ± 5.1 30.9 ± 4.4 0.880 0.027 RER (AU) 0.84 ± 0.06 0.85 ± 0.05 0.099 0.280 0.78 ± 0.04 0.79 ± 0.05 0.833 0.053 0.99 ± 0.06 0.99 ± 0.06 0.745 -0.056 VE (L•min -1 ) 9.8 ± 2.4 10.4 ± 2.3 0.010 † 0.434 18.4 ± 2.6 17.4 ± 3.0 0.018* -0.547 45.0 ± 13.4 44.7 ± 10.8 0.737 -0.058 BF (breaths/min) 15 ± 4 16 ± 4 0.007 † 0.454 19 ± 5 20 ± 6 0.040* 0.480 28 ± 9 28 ± 9 0.983 0.005 V̇CO 2 (L•min -1 ) 0.26 ± 0.05 0.27 ± 0.05 0.036* -0.319 0.56 ± 0.12 0.51 ± 0.10 0.006 † 0.623 1.32 ± 0.28 1.31 ± 0.25 0.750 0.047 P ET O 2 (mmHg) 109 ± 5 110 ± 4 0.005 † 0.469 101 ± 5 102 ± 5 0.037* 0.487 111 ± 6 111 ± 5 0.483 0.120 P ET CO 2 (mmHg) 33.2 ± 3.3 32.5 ± 3.2 0.023* 0.348 37.6 ± 4.4 36.5 ± 3.2 0.015* 0.535 36.4 ± 5.3 36.0 ± 4.3 0.214 0.186 ES denotes the effect size. O 2 denotes oxygen uptake. V̇O 2 _HR denotes oxygen pulse. VE/V̇O 2 denotes the ventilatory equivalent for oxygen. VE/V̇CO 2 denotes the ventilatory equivalent for carbon dioxide. RER denotes respiratory exchange ratio. VE denotes minute ventilation. BF denotes breathing frequency. V̇CO 2 denotes carbon dioxide production. P ET O 2 and P ET CO 2 denote end-tidal oxygen and carbon dioxide, respectively. *denotes significant with 0.05 alpha level. † denotes significant with Bonferroni correction (alpha level 0.013). Microclot burden in people living with Long COVID Participants with Long COVID were found to have substantially greater microclot burden pre-CPET day 1 within the greater size ranges (>400 µm²) when compared with previously collected control data [51]. Long COVID participants in the present study were found to have a microclot burden that was greater in the 900-1600 µm² microclot range pre-CPET day 1 compared with controls (Median [Q1-Q3]: 31 [2-256] vs. 2 [1-4]) (See representative micrographs of microclots captured using imaging flow cytometry in Supplementary Figure 4 ). Microclot dynamics across CPET sessions (Fixed Effects Model of Microclot Breakdown) Analyses of microclot size distributions revealed distinct time trends across size bins (Figure 1). De-meaned trends (individual microclot counts minus each person’s average) with standard error bands for each size category showing clear reductions in large microclots (100–3000 µm²) post-CPET, with increased frequency of small microclots (< 30 µm²). Microclot Breakdown Causal Inference First-difference regressions showed strong associations: during CPET 1: a 1% drop in the number of large microclots was linked to a 0.49% rise in the number of small microclots (p<0.001); these percentage changes observed were relative to the number of microclots within the size ranges, meaning that we observed a disappearance of material contained in microclots. CPET 2 showed the same directional effect, with a smaller but still statistically significant relationship between the decrease in large microclots and the increase in small ones (β = −0.26, p < 0.001). This suggests that, even during the second CPET, the breakdown of large microclots continued to yield more small microclots, albeit to a lesser extent, potentially due to a delayed or reduced formation of large microclots before the test. To address endogeneity (the concern that unobserved factors may influence both large and small microclot levels, making it difficult to isolate the true effect [52]), we instrumented large microclot counts using CPET session timing in a fixed effects 2SLS model. The instrument was statistically strong (F = 84.3), meaning that the timing of the CPET sessions was highly predictive of changes in large microclot counts, a key requirement for drawing valid causal inferences in this type of analysis. The second-stage results then confirmed a significant negative relationship of large on the number of small microclots (β = −0.46, p < 0.001), supporting a causal interpretation. See Table 3 for details. Table 3. Effect of large microclot breakdown on small microclots (Fixed-Effects OLS and 2SLS Models). All models include individual fixed effects. Robust standard errors are clustered at the group level. Cytokine Profile Cytokine differences pre-post CPET are presented in Supplementary Table 1. Within-day changes were observed on both days. On day 1, pre-and post-test levels of interlukin-6 (IL-6; mean increase 13%, 121 ± 432 pg/ml; p=0.018), and interferon-gamma-inducible protein 10 (IP-10; mean increase 18%, 8.6 ± 9.0 pg/ml; p<0.001) were increased. Whilst epidermal growth factor (EGF; mean reduction 22%, 133 ± 172 pg/ml; p<0.001) was reduced. On day 2, EGF (mean reduction 27%, 25 ±155 pg/ml; p<0.001) and CCL5/Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) were decreased (mean reduction 10%, 2069 ± 604 pg/ml; p=0.010). Between-day changes (post-CPET 1 and pre-CPET day 2) saw EGF was increased (mean increase 21%, 167 ± 141 pg/ml; p<0.001), whereas IL-6 (mean reduction 12%, 107 ± 383 pg/ml; p<0.0001), and IP-10 (mean reduction 16%, 7.2 ± 8.1 pg/ml; p=0.0002) were reduced. Furthermore (post-CPET 1, post-CPET day 2) RANTES (mean reduction 12%, 2069 ± 604 pg/ml; p<0.0001), interleukin-13 (IL-13; mean reduction 12%, 41 ± 79 pg/ml; p<0.001), and basic fibroblast growth factor (bFGF; mean reduction 3%, 42 ± 32 pg/ml; p=0.005) were all decreased. F igure 2 shows Spearman correlations between cytokine levels and microclot size. Several cytokines are significantly associated with clot burden, but the relationships are time sensitive. Notably, large microclots show negative correlations with pro-inflammatory cytokines (e.g. IFN-α, IL-15, IL-17A), likely reflecting CPET-induced breakdown: as large clots degrade, cytokine levels rise, suggesting that clot degradation (rather than cytokine-driven clot formation) may trigger inflammation through the release of embedded mediators. IL-4, an anti-inflammatory cytokine, show positive correlations with small microclots and negative correlations with large microclots. Other anti-inflammatory cytokines (e.g. IL-10 & IL-13) showed no significant correlation with either microclot sizes although both were significantly decreased post-CPET day 2 when compared with post-CPET day 1. These data imply that that the immune system may attempt to regulate the inflammatory response triggered by microclot fragmentation following physical exertion, but compensatory mechanisms appear insufficient or failing ( Supplementary Table 1). DISCUSSION The data presented here reinforce evidence of distinct physiological and multi-system impairment in individuals with Long COVID. Furthermore, we demonstrate a novel insight into the behaviour of microclots in response to a safe sub-maximal exercise protocol. Whilst it is documented that graded exercise therapy can prompt a worsening of symptoms for people with Long COVID [ 53 ], our focus was not to assess whether exercise resolves microclots, but rather to examine how microclot profiles dynamically respond to repeated exertion across consecutive days. Our findings reveal that submaximal exercise induces a shift in microclot size distribution: specifically, a decrease in the proportion of larger microclots (100–3000 µm²) is accompanied by a relative increase in smaller microclots (> 0–30 µm²) post-exercise. This change corresponds with a reduction in \(\:\dot{\text{V}}\) O 2 at submaximal thresholds combined with reduced O 2 pulse which highlights impaired O 2 transport and/or utilisation. The patterns demonstrated here suggest that larger microclots undergo fragmentation rather than clearance during exercise, revealing an important mechanistic insight into how microclots behave under physiological stress that may be at least in-part responsible for reductions in O 2 transport and utilisation during physical exertion in people living with Long COVID. Previously published microclot count data across multiple size ranges (0-1600 µm²) were found using imaging flow cytometry to be much higher in people living with Long COVID when compared with a healthy comparator cohort [ 51 , 54 ]. Data from the present study also assessed multiple microclot size ranges and indicated that microclot burden prior to the first CPET was higher across the bigger size ranges when compared with previous data [ 51 ]. We also demonstrate an increased prevalence of smaller microclots post-exercise, which could indicate that mechanical or biochemical stress during exercise disrupts larger microclot structures. This may break them into smaller components that persist in the circulation and possibly limit blood flow and O 2 uptake and/or transport in the vasculature. The reduction in overall clot size distribution post-exercise, as indicated by the decrease in total object count per mL, further supports this hypothesis. Although the percentage increase in small microclots is less than the percentage decrease in large ones (e.g., a 1% drop in large microclots corresponds to a ~ 0.49% rise in small ones), this does not imply full accounting of all microclots. This discrepancy may be partly explained by limitations in the size-based detection range of our imaging methodology. Microclots below the lower limit of detection in this study (1 µm²) may not be captured, despite being biologically present. Moreover, the conversion of a single large microclot into multiple smaller fragments does not necessarily translate to a proportional increase in countable events, due to possible aggregation below detection thresholds or morphological changes that challenge automated segmentation. While some microclots in this small range may have resulted from the breakdown of larger ones (100–3000 µm²), it is equally plausible that the small ones subsequently fragmented into even smaller sizes. Taken together, these data support the interpretation that microclot fragmentation, not clearance, is occurring during exertion, contributing to a redistribution of clot sizes and potentially impairing oxygen transport and/or utilization, as suggested by concurrent reductions in V̇O₂ and O₂ pulse. Furthermore, these data are important and challenge the assumption that exercise necessarily promotes clot clearance, at least in healthy people [38]. Instead, our data suggest that, at least in individuals with fibrinaloid microclots, exercise alters microclot morphology and sizes and potentially changes the way these microclots interact with the vasculature, rather than eliminating them from circulation. Several previous studies have shown a reduction in exercise capacity in people living with Long COVID and impaired O 2 consumption has been implicated within these findings [ 33 , 34 ]. Breaking down and reforming of microclot deposits, alongside the exposure of inflammatory cytokines into the circulation, might affect O 2 transport to the working muscles and therefore increase the reliance on anaerobic processes, which is associated with broad intra-muscular/systemic disruption and perturbations. Symptoms related to muscle pathologies and PESE & PEM may be explained by microclots moving into tissues, especially into muscle and surrounding connective tissues via damaged vasculature where the disease has degraded the physiological barrier function. Appelman et al. found a greater concentration of amyloid-containing deposits in those living with Long COVID compared with healthy controls at baseline and observed a marked increase one-day following maximal CPET [ 33 ]. However, they stated that they did not find substantial amyloid-containing deposits in the capillaries but did find them in the extracellular matrix although the limited depth of field could not permit the former conclusion. The authors did not observe skeletal muscle tissue hypoxia and concluded that PEM in Long COVID could not be explained directly by blocked vessel perfusion. It may be possible that the origin of these amyloid-containing deposits is not within circulation, but instead within tissues, and further structural analysis using transmission electron microscopy is ongoing to determine the exact position of the amyloid-containing deposits. The correlation heatmaps (Fig. 2) provide further insight into the interplay between microclot fragmentation and systemic inflammation. The positive correlations between smaller microclots (< 30 µm 2 ) and pro-inflammatory cytokines, such as G-CSF, IFN-γ and IFN-α, suggest that microclot fragmentation is linked to a post-exercise inflammatory response. Previous research has observed entrapment of several pro-inflammatory markers within microclots that may also contribute to a failed fibrinolytic system (e.g. increased platelet factor 4 and von Willebrand factor and decreased plasma Kallikrein) [ 28 ]. However, it is unclear whether the breakdown of larger microclots into smaller microclots is responsible for the release of various entrapped inflammatory molecules or whether the release of these cytokines and interferons from immune and vascular cells is causally linked to the increased burden of small microclots in response to exertion. Exercise can also lead to an increase in shear stress and inflammation [ 55 ], which in turn increases the risk of chronic ischaemic-reperfusion injury if smaller vasculature is impeded by the larger microclots, which could be responsible for inducing PESE [ 56 ]. Our data (post-CPET 1 and pre-CPET 2, Fig. 1 ) suggest that larger microclots may reform after exertion which may potentially again entrap other inflammatory markers and perpetuate this process until an appropriate treatment or intervention is given. Impact for People Living with Long COVID The results highlight the dynamic nature of microclots and their interaction with systemic inflammation during exercise. The observed increase in EGF between CPET days, which plays a significant role in angiogenesis [ 57 ], may possibly implicate the breakdown of larger microclots into smaller ones causing vascular injury and promoting the formation of new blood vessels. The increase in smaller microclots post-exercise suggests that microclots do not behave as static entities but can rather undergo structural changes in response to physical exertion. This has critical implications for the development and recommendation of exercise-based rehabilitation strategies in Long COVID. If exercise does increase microclot fragmentation without promoting clearance, these smaller clots, as well as the larger microclots, could contribute to persistent microvascular dysfunction and endothelial damage, impaired O 2 delivery, and increased PESE. The worsening of symptoms reported by some Long COVID patients following physical exertion may, at least in part, be explained by these shifts in microclot size distribution and the resultant inflammatory interactions. The evidence presented here indicates that exposure to submaximal physical exercise may pose additional consequences for individuals with Long COVID where microclots are a contributing pathology and the risk of PEM is low, but PESE is reported. This underscores the importance of thorough clinical evaluation and careful screening for PESE and PEM before recommending and encouraging physical activity. Future Research Future research should prioritise the development of more sensitive and specific tools to evaluate PESE and PEM in individuals with Long COVID. While Gattoni et al. [ 37 ] employed the DePaul Symptom Questionnaire in a two-day CPET protocol, the current study used this questionnaire as a screening tool and repurposed other symptom-specific and functional scales to assess PESE. Whilst this questionnaire is valuable to ensure those with a higher risk of PEM are protected against the possible deleterious impact of exercise in our study, these approaches may lack the resolution to capture the delayed and heterogeneous nature of symptom exacerbation, particularly given that PESE & PEM can emerge up to 72 hours post-exertion [ 58 ]. Moreover, while this study suggests a possible association between microclot fragmentation and inflammatory responses following exercise, we acknowledge that further direct evidence linking this to exact clinical symptom manifestations is needed. It remains speculative to suggest that microclot fragmentation is pathological or causally related to symptoms without further mechanistic data. It is equally plausible that such fragmentation may reflect some beneficial physiological cytokine clearing process, similar to post-exercise increases in anti-inflammatory cytokines observed in healthy populations and other disease groups [ 59 – 61 ]. These responses, although associated with symptom provocation in Long COVID, are not inherently pathological. Therefore, expanding the post-CPET cytokine sampling window and developing more refined assessment tools for PESE & PEM may help elucidate the nuanced interplay between coagulation, inflammation, and symptom exacerbation. In future, therapeutic strategies might be tailored at targeting microclot fragmentation post-exercise, once the clinical significance of these events is better understood. The lack of a healthy comparator group in this study is a limitation that meant comparisons with ‘normal’ response were only made with previously collected data, and further research is needed to include comparator/control groups documenting comorbidities and clinical information so that the findings in this study can be better understood. Conclusion This study is the first to provide evidence of a biological basis that might explain exercise-induced symptom exacerbation in people with Long COVID through microclot fragmentation. Our findings demonstrate that exercise does not eliminate microclots but instead alters their size distribution, with larger microclots breaking down into smaller microclots post-exercise. These changes are associated with inflammatory pathways, suggesting that microclot fragmentation is not a passive process but rather an active interaction with systemic inflammation. Understanding these mechanisms is essential and has importance when recommending exercise interventions for people with Long COVID as part of their rehabilitation, which may have the capacity to be harmful if appropriate clinical evaluations and treatments are absent. These findings underscore the need to develop targeted approaches to mitigate the vascular and inflammatory consequences of microclot persistence. Declarations Additional Information Funding: This work received a funding grant from Gilead Sciences (IN-UK-983-6080). Ethics approval: The study received both NHS (IRAS ID: 313936) and institutional (ETH2324-1808) research ethics approval. Competing interest: There is potential Competing Interest. EP holds a patent for the detection of microclots in Long COVID and is the founding director of Biocode Technologies. The rest of the authors have no competing interests to declare Authors’ contributions: MAF, REMA, TB and EP conceived the idea and design of the study. CT led data collection at the test site. REMA & MAF both contributed to data collection. Data analysis was performed by CT, MN, JHP, EP and IS. CT, MF, and EP led the write-up of the submitted manuscript. All partners contributed to the development of the submitted manuscript. Data availability statement: Anonymised data can be made available on request. References WHO. A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021 . 2021 22/07/2022]; Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1. Ely, E.W., Brown, L. M., & Fineberg, H. V., Long Covid Defined. New England Journal of Medicine, 2024. 391 (18): p. 1746-1753. Davis, H.E., et al., Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine, 2021. 38 : p. 101019. O'Brien, K.K., et al., Conceptualising the episodic nature of disability among adults living with Long COVID: a qualitative study. BMJ Glob Health, 2023. 8 (3). Owen, R., et al., Profiling the persistent and episodic nature of long COVID symptoms and the impact on quality of life and functional status: a cohort observation study. J Glob Health, 2025. 15 : p. 04006. Thomas, C., et al., Lived experience of patients with Long COVID: a qualitative study in the UK. BMJ Open, 2023. 13 (4): p. e068481. Graham, F., Daily briefing: At least 65 million people have long COVID. Nature 2023. Wulf Hanson, S., et al., A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021. medRxiv, 2022. Al-Aly, Z., et al., Long COVID science, research and policy. Nat Med, 2024. 30 (8): p. 2148-2164. Davis, H.E., et al., Long COVID: major findings, mechanisms and recommendations. Nature Reviews Microbiology, 2023. Proal, A.D., et al., Targeting the SARS-CoV-2 reservoir in long COVID. Lancet Infect Dis, 2025. Campen, C.M.C.V., P.C. Rowe, and F.C. Visser, Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Medicina, 2021. 58 (1): p. 28. Wang, Y., et al., Cerebral blood flow alterations and host genetic association in individuals with long COVID: A transcriptomic-neuroimaging study. J Cereb Blood Flow Metab, 2025. 45 (3): p. 431-442. Espin, E., et al., Cellular and molecular biomarkers of long COVID: a scoping review. EBioMedicine, 2023. 91 : p. 104552. Lai, Y.J., et al., Biomarkers in long COVID-19: A systematic review. Front Med (Lausanne), 2023. 10 : p. 1085988. Thomas, C., et al., Blood Biomarkers of Long COVID: A Systematic Review. Mol Diagn Ther, 2024. 28 (5): p. 537-574. Del Giudice, M. and S.W. Gangestad, Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain, Behavior, and Immunity, 2018. 70 : p. 61-75. Nash, D., et al., IL‐6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance. Scandinavian Journal of Medicine & Science in Sports, 2023. 33 (1): p. 4-19. Patterson, B.K., et al., Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning. Front Immunol, 2021. 12 : p. 700782. Patel, M.A., et al., Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Molecular Medicine, 2022. 28 (1). Ackermann, M., et al., Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med, 2020. 383 (2): p. 120-128. Jing, H., et al., Pathophysiological mechanisms of thrombosis in acute and long COVID-19. Front Immunol, 2022. 13 : p. 992384. Østergaard, L., SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: Consequences of capillary transit-time changes, tissue hypoxia and inflammation. Physiological Reports, 2021. 9 (3). Altmann, D.M., et al., The immunology of long COVID. Nat Rev Immunol, 2023. 23 (10): p. 618-634. Kell, D.B., G.J. Laubscher, and E. Pretorius, A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochem J, 2022. 479 (4): p. 537-559. Pretorius, E., et al., Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol, 2021. 20 (1): p. 172. Kell, D.B. and E. Pretorius, Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. Prog Biophys Mol Biol, 2017. 123 : p. 16-41. Kruger, A., et al., Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system. Cardiovascular Diabetology, 2022. 21 (1). Christle, J.W., & Arena, R. , Cardiopulmonary Exercise Testing and Prescription of Exercise , in Textbook of Sports and Exercise Cardiology , A. Pressler, & Niebauer, J., Editor. 2020. p. 897–912. Faghy, M.A., et al., Using cardiorespiratory fitness assessment to identify pathophysiology in long COVID – Best practice approaches. Progress in Cardiovascular Diseases, 2024. Faghy, M.A., et al., Cardiopulmonary exercise testing in the COVID-19 endemic phase. Br J Anaesth, 2020. 125 (4): p. 447-449. Faghy, M.A., et al., Integrated sports and respiratory medicine in the aftermath of COVID-19. The Lancet Respiratory Medicine, 2020. 8 (9): p. 852. Appelman, B., et al., Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications, 2024. 15 (1). Durstenfeld, M.S., et al., Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults. JAMA Network Open, 2022. 5 (10): p. e2236057. Thomas, C., Kudiersky, N., Ansdell, P., Ashton, R. E., Brown, C., Bewick, T., Carr, J., Hume, E., Spillane, P., Pastorio, E., Owen, R., Maden-Wilkinson, T., McNeil-Angopa, E., Parkington, T., Arena, R., Ozemek, C., Formenti, F., Veluswamy, S.K., Gururaj, R., & Faghy, M. A., Submaximal 2-day cardiopulmonary exercise testing to assess exercise capacity and post-exertional symptom exacerbation in people with Long COVID. Experimental Physiology, In Press. Thaweethai, T., Jolley, S. E., Karlson, E. W., Levitan, E. B., Levy, B., McComsey, G. A., ... & Donohue, S. E., Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA, 2023. 329 (22): p. 1934–1946. Gattoni, C., et al., Two-day cardiopulmonary exercise testing in long COVID post-exertional malaise diagnosis. Respir Physiol Neurobiol, 2025. 331 : p. 104362. Kupchak, B.R., et al., Beneficial effects of habitual resistance exercise training on coagulation and fibrinolytic responses. Thromb Res, 2013. 131 (6): p. e227-34. Cotler, J., et al., A Brief Questionnaire to Assess Post-Exertional Malaise. Diagnostics (Basel), 2018. 8 (3). Liguori, G., & American College of Sports Medicine., ACSM's guidelines for exercise testing and prescription. 11th ed, ed. L.W. Wilkins. 2020. Klok, F.A., et al., The Post-COVID-19 Functional Status scale: a tool to measure functional status over time after COVID-19. Eur Respir J, 2020. 56 (1). Holland, A.E., et al., An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J, 2014. 44 (6): p. 1428-46. Herdman, M., et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of Life Research, 2011. 20 (10): p. 1727-1736. Michielsen, H.J., J. De Vries, and G.L. Van Heck, Psychometric qualities of a brief self-rated fatigue measure: The Fatigue Assessment Scale. J Psychosom Res, 2003. 54 (4): p. 345-52. Larson, R.D., Psychometric Properties of the Modified Fatigue Impact Scale. International Journal of MS Care, 2013. 15 (1): p. 15-20. Bestall, J.C., Paul, E. A., Garrod, R., Garnham, R., Jones, P. W., & Wedzicha, J. , Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax, 1999. 54 (7): p. 581-586. Ozmek, C.A.C.o.S.M., ACSM's Guidelines for Exercise Testing and Prescription . 12th ed. 2025: Wolters Kluwer Health. 688. Lee, J.H., & Huber Jr, J., Evaluation of Multiple Imputation with Large Proportions of Missing Data: How Much Is Too Much? . Iran J Public Health, 2021: p. 1372-80. Gade Malmos, K., et al., ThT 101: a primer on the use of thioflavin T to investigate amyloid formation. Amyloid, 2017. 24 (1): p. 1-16. Nicolò, A., et al., Comparing Continuous and Intermittent Exercise: An “Isoeffort” and “Isotime” Approach. PLoS ONE, 2014. 9 (4): p. e94990. Turner, S., et al., Accelerating discovery: A novel flow cytometric method for detecting fibrin(ogen) amyloid microclots using long COVID as a model. Heliyon, 2023. 9 (9): p. e19605. Wooldridge, J.M., Econometric analysis of cross section and panel data. 2010: MIT press. Eckey, M., et al., Patient-Reported Treatment Outcomes in ME/CFS and Long COVID . 2024, Cold Spring Harbor Laboratory. Pretorius, E., et al., Flow Clotometry: Measuring Amyloid Microclots in ME/CFS, Long COVID, and Healthy Samples with Imaging Flow Cytometry. 2024. Sallam, N. and I. Laher, Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases. Oxid Med Cell Longev, 2016. 2016 : p. 7239639. Kell, D.B. and E. Pretorius, The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications. Biochemical Journal, 2022. 479 (16): p. 1653-1708. Assal, Y., M. Mie, and E. Kobatake, The promotion of angiogenesis by growth factors integrated with ECM proteins through coiled-coil structures. Biomaterials, 2013. 34 (13): p. 3315-23. An, Y., et al., Prevalence and measurement of post-exertional malaise in post-acute COVID-19 syndrome: A systematic review and meta-analysis. Gen Hosp Psychiatry, 2024. 91 : p. 130-142. Ostapiuk-Karolczuk, J., Zembron-Lacny, A., Naczk, M., Gajewski, M., Kasperska, A., Dziewiecka, H., & Szyszka, K., Cytokines and cellular inflammatory sequence in non-athletes after prolonged exercise. Journal of sports medicine and physical fitness, 2012. 52 (5): p. 563. Petersen, A.M. and B.K. Pedersen, The anti-inflammatory effect of exercise. J Appl Physiol (1985), 2005. 98 (4): p. 1154-62. Ploeger, H.E., Takken, T., De Greef, M. H., & Timmons, B. W., The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review. Exerc Immunol Rev., 2009. 15 (1): p. 6-41. Additional Declarations The authors declare potential competing interests as follows: There is potential Competing Interest. EP holds a patent for the detection of microclots in Long COVID and is the founding director of Biocode Technologies. The rest of the authors have no competing interests to declare Supplementary Files SupplementaryFigure1.docx Supplementary Figure 1. SupplementaryFigure2.docx Supplementary Figure 2. SupplementaryFigure3.docx Supplementary Figure 3. SupplementaryFigure4.docx Supplementary Figure 4. SupplementaryFigure5.docx Supplementary Figure 5. SupplementaryTable1.docx Supplementary Table 1. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6717727","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":459985008,"identity":"6784adba-39a1-4b8b-9950-61be61b07410","order_by":0,"name":"Callum Thomas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBAC/gb+bxAGQwIDM1SQGbd6IJA4wNgGZkg2EKvFwAGqxeAA0VoYGNsefMyxszc+nnzsc2Ebgzx/A4+xAQEt7YYztyUnbjvzLHn2zDYGwxkHeIwTCNkizbuNOcHsRo4xM28bA+MGBh7jA0Roqbc3npH/GaTFnrAWB7CWw4wbJHKYQVoSQVrwOkziMGOb5MxtxxNnnHlmzDzjnETyjMNsxXi9z9/e2CbxcVu1PX978mPmgjIb2/725s0S+LSgxgEjmwShWMEAf0hTPgpGwSgYBSMDAAACfEEu8B7wtQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8608-8231","institution":"University of Derby","correspondingAuthor":true,"prefix":"","firstName":"Callum","middleName":"","lastName":"Thomas","suffix":""},{"id":459985009,"identity":"2a7577fd-0239-4b70-8cf4-755a76b742c4","order_by":1,"name":"Massimo Nunes","email":"","orcid":"","institution":"Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"","lastName":"Nunes","suffix":""},{"id":459985010,"identity":"fbead009-6175-4660-9f13-d2da9f1f223b","order_by":2,"name":"Jan H. Pretorius","email":"","orcid":"","institution":"Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"H.","lastName":"Pretorius","suffix":""},{"id":459985011,"identity":"194416ea-60eb-4850-9460-9a948f66a1c3","order_by":3,"name":"Ruth EM. Ashton","email":"","orcid":"","institution":"Coventry University","correspondingAuthor":false,"prefix":"","firstName":"Ruth","middleName":"EM.","lastName":"Ashton","suffix":""},{"id":459985012,"identity":"624b46b3-e4b8-4a30-a1c8-41a17d54114f","order_by":4,"name":"Isaac T. Shawa","email":"","orcid":"","institution":"University of Derby","correspondingAuthor":false,"prefix":"","firstName":"Isaac","middleName":"T.","lastName":"Shawa","suffix":""},{"id":459985013,"identity":"360fcac5-40b9-4973-b119-46826d4d758d","order_by":5,"name":"Tom Bewick","email":"","orcid":"","institution":"University Hospitals of Derby and Burton NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Tom","middleName":"","lastName":"Bewick","suffix":""},{"id":459985014,"identity":"e9634554-6b8f-4a85-9bba-0065bdaa02f4","order_by":6,"name":"Etheresia Pretorius","email":"","orcid":"https://orcid.org/0000-0002-9108-2384","institution":"Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Etheresia","middleName":"","lastName":"Pretorius","suffix":""},{"id":459985015,"identity":"c8f44db5-bccf-46be-b54c-ad7e42ca262a","order_by":7,"name":"Douglas B. Kell","email":"","orcid":"https://orcid.org/0000-0001-5838-7963","institution":"University of Liverpool","correspondingAuthor":false,"prefix":"","firstName":"Douglas","middleName":"B.","lastName":"Kell","suffix":""},{"id":459985016,"identity":"fd960b38-8f21-4bf1-b6ae-d9d0e44180f7","order_by":8,"name":"Mark A. Faghy","email":"","orcid":"","institution":"University of Derby","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"A.","lastName":"Faghy","suffix":""}],"badges":[],"createdAt":"2025-05-21 15:05:47","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6717727/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6717727/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83439451,"identity":"59fb2e0f-b106-4ce1-88d9-911db6286d4a","added_by":"auto","created_at":"2025-05-26 09:12:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":83067,"visible":true,"origin":"","legend":"\u003cp\u003eDemeaned microclot counts by size bin and CPET stage. Each panel represents a different microclot size bin. \u003cstrong\u003eA\u003c/strong\u003e. \u0026lt; 30 µm²; \u003cstrong\u003eB.\u003c/strong\u003e 30-100 µm²; \u003cstrong\u003eC. \u003c/strong\u003e100-400 µm²; \u003cstrong\u003eD. \u003c/strong\u003e400-900 µm²; \u003cstrong\u003eE. \u003c/strong\u003e900-1600 µm²; \u003cstrong\u003eF. \u003c/strong\u003e1600-3000 µm².\u003c/p\u003e","description":"","filename":"Figure1..png","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/b5bedacaccb21d6c9b5bb43d.png"},{"id":83438604,"identity":"6f9973ac-2d9a-4fcd-bded-938d9e399d11","added_by":"auto","created_at":"2025-05-26 09:04:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":85378,"visible":true,"origin":"","legend":"\u003cp\u003eSpearman correlations between demeaned microclot size and cytokine levels. Large and small microclots correspond with the size ranges of 100–3000 µm² and \u0026lt; 30 µm², respectively. *denotes p\u0026lt;0.05. **denotes p\u0026lt;0.01. ***denotes p\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"Figure2..png","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/8b9166997865015a8f113cb7.png"},{"id":83439957,"identity":"5a7813ba-237e-42de-8809-d2ac53bba53c","added_by":"auto","created_at":"2025-05-26 09:20:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1733416,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/a734a2aa-8a05-4eee-bfbd-e3b9bda4ccfe.pdf"},{"id":83438602,"identity":"d5e4ec5b-04e7-4a11-8f25-90e9d07824e3","added_by":"auto","created_at":"2025-05-26 09:04:05","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":254081,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFigure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/0ff72bede42c919368035412.docx"},{"id":83439452,"identity":"289ef943-5858-4c21-aa08-7ea638288ba9","added_by":"auto","created_at":"2025-05-26 09:12:05","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":141359,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 2.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFigure2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/e0b51273e0320f0a2b5ad982.docx"},{"id":83438607,"identity":"9378c26f-408f-4d08-9967-0ed16ff6d7f7","added_by":"auto","created_at":"2025-05-26 09:04:05","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":324992,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 3.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFigure3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/4d22e0e005f3824c32281d21.docx"},{"id":83438606,"identity":"5bc5f49d-6c30-4c50-9a22-83829a347561","added_by":"auto","created_at":"2025-05-26 09:04:05","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1160273,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 4.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFigure4.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/e8b1e5a07fa88986cb1860a1.docx"},{"id":83438608,"identity":"1ef416ad-41d7-4cd4-9911-1bb7afa9233b","added_by":"auto","created_at":"2025-05-26 09:04:05","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":383895,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 5.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFigure5.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/a5be6ab358a91dba260417c2.docx"},{"id":83438610,"identity":"42ad2715-f63b-4ef2-bfba-9eb13b1195d3","added_by":"auto","created_at":"2025-05-26 09:04:05","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":18733,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 1.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717727/v1/5e015f8db064df0d6b815605.docx"}],"financialInterests":"The authors declare potential competing interests as follows: There is potential Competing Interest. EP holds a patent for the detection of microclots in Long COVID and is the founding director of Biocode Technologies. The rest of the authors have no competing interests to declare","formattedTitle":"\u003cp\u003e\u003cstrong\u003eExercise-induced Changes in Microclotting and Cytokine Levels Point to Vascular Injury and Inflammation in People with Long COVID\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eLong COVID describes a continuation and/or development of symptoms that can manifest into a chronic disease state 3-months following a SARS-CoV-2 infection that cannot be explained by an alternative diagnosis but instead encapsulate multiple diagnosable conditions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Long COVID is recognised as a chronic and episodic condition associated with over 200 established symptoms that are categorised more broadly into physical, cognitive, and psychosocial symptom domains [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The Long COVID presentation is heterogenous and ranges from a modest decrease in everyday activities to a disabling condition associated with a broad reduction in quality of life and functional status [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. It has been estimated that Long COVID affects 65\u0026ndash;150\u0026nbsp;million people globally [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], but these figures are dependent on the definition and likely conservative with less restrictive criteria; other analyses report that this figure could be more than 400\u0026nbsp;million cases [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, there are no established curative treatments, and preventing acute infections with SARS-CoV-2 remains the best way to prevent Long COVID. Recent studies have provided important insights into the multi-system nature of Long COVID, implicating endothelial dysfunction, platelet hyperactivation, autoimmune dysfunction, perturbed blood flow and perfusion, and viral persistence as pathologies that could contribute mechanistic explanations of the prolonged symptoms [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Biomarkers of Long COVID have been widely discussed as an important gateway to understanding the pathophysiology, and candidate markers have been identified (i.e. interleukin-6 [IL-6], vascular endothelial growth factor [VEGF], and CD8\u0026thinsp;+\u0026thinsp;T-cell concentrations) [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Due to the multi-system and simultaneous pathologies of Long COVID, these markers, in isolation, mean very little as many will be influenced by intrinsic and extrinsic factors; for example, IL-6 concentrations can be influenced by cardiovascular disease, medication, and habitual exercise status [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, diagnostic tests using blood biomarker profiles have demonstrated laudable accuracy. Patterson et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] were able to correctly identify 118/121 people living with Long COVID using a mathematical equation that involved inflammatory and immunological blood biomarkers. Similarly, Patel et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] were able to use two vascular blood biomarkers (ANG-1/P-SEL) to identify correctly 96% of people living with Long COVID. Thus, these studies highlight multiple domains of biomarkers that can identify people living with Long COVID.\u003c/p\u003e \u003cp\u003eEndothelial dysfunction and damage, increased platelet activation, formation of microthrombi, and damage to the microcirculatory circulation are further consequences of acute SARS-CoV-2 infection [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Specifically, persistent endothelial inflammation and platelet hyperactivation, and the presence of anomalous deposits (also known as fibrinaloid microclots), which are resistant to normal fibrinolytic processes, have been linked to Long COVID [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Microclots are heterogeneous in content and morphology, and are composed of inflammatory proteins, fibrinogen chains, and other biomolecules, and are positively stained with amyloid markers. The adoption of an amyloid state by fibrinogen and other proteins, as well as the possible presence of antifibrinolytic molecules entrapped in microclots, render these aggregates more resistant to proteolysis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and hence enables their persistence in circulation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Collectively, these properties impede microvascular function, impairing gas transfer, and could be driving hypoxia-related symptoms observed in people living with Long COVID [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Inflammatory molecules in circulation are associated with microclots and perpetuate systemic inflammation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Notably, neutrophil extracellular traps (NETs) are structurally associated with microclots, potentially amplifying thrombo-inflammatory responses.\u003c/p\u003e \u003cp\u003eCardiopulmonary exercise testing (CPET) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] has prognostic and diagnostic capabilities that can increase the understanding of Long COVID pathology [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Coupled with a detailed blood biomarker assessment, it could also increase the understanding of the disease pathology driving symptom presentation. CPET can be performed using either submaximal or maximal protocols, in which the integrative response to incremental exercise enables the assessment of the cardiorespiratory system and identification of any physical impairments [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Studies that involve CPETs have demonstrated multi-system impairment in response to both maximal [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] and sub-maximal [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] protocols in people living with Long COVID. Two-day exercise approaches enable assessment of restorative function and may help create new knowledge of symptom exacerbation following physical exertion, commonly known as post-exertional malaise (PEM) or post-exertion symptom exacerbation (PESE) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Gattoni \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] utilised this approach with fifteen people living with Long COVID but found a reduction in VE/V̇CO\u003csub\u003e2\u003c/sub\u003e at the gas exchange threshold only on day 2 compared with day 1. By contrast, our previous work utilising a submaximal approach with a larger sample size (N\u0026thinsp;=\u0026thinsp;68) found reductions in oxygen consumption (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\dot{\\text{V}}\\)\u003c/span\u003e\u003c/span\u003eO\u003csub\u003e2\u003c/sub\u003e) and pulse, end-tidal carbon dioxide, and workload at the ventilatory threshold on day 2 compared with day 1 [35]. In healthy people, there is an assumption that exercise facilitates clot clearance [38]; however, no study has assessed how microclots and other blood biomarkers associated with Long COVID respond to submaximal two-day CPET.\u003c/p\u003e \u003cp\u003eWe hypothesized that submaximal exercise would exacerbate markers of inflammation and vascular injury, and this would align with a high microclot count as opposed to an elimination from circulation, and a worsening of submaximal CPET parameters on the second day of exercise. Accordingly, we aimed to explore the dynamic relationship between exercise-induced physiological changes, microclot count, and inflammatory, vascular injury, and immunological blood biomarker fluctuations, offering novel insights into the mechanisms of persistent symptoms in individuals with Long COVID.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Design and Ethical Approval\u003c/h2\u003e\n \u003cp\u003eThis single-centre, retrospective, observational study was conducted at the University of Derby, United Kingdom, and was prospectively registered with clinicaltrials.gov (NCT06394921). The study received both NHS (IRAS ID: 313936) and institutional (ETH2324-1808) research ethics approval. All participants provided written informed consent prior to their involvement in the study and the study conformed to the standards set by Good Clinical Practice (GCP) and by the Declaration of Helsinki (Version 2024).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eScreening and Eligibility\u003c/h2\u003e\n \u003cp\u003eAll participants were screened via telephone consultation to determine eligibility. Eligibility included having a confirmed history of SARS-CoV-2 infection, a clinical diagnosis of Long COVID and the presence of PESE with a low risk of experiencing PEM, determined by the severity and frequency function of the De-Paul Symptom Questionnaire [\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]. Additional inclusion criteria included having sufficient English language comprehension and cognitive ability to provide informed consent and be able to complete all study assessments as per the study protocol. Due to the exercise component of the study, standard CPET safety criteria were applied [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e], which excluded individuals with conditions such as unstable angina, uncontrolled hypertension (resting systolic blood pressure [SBP]\u0026thinsp;\u0026gt;\u0026thinsp;180mmHg, or resting diastolic blood pressure [DBP]\u0026thinsp;\u0026gt;\u0026thinsp;110mmHg), severe orthopaedic conditions, recent embolism, and other significant metabolic or cardiovascular conditions.\u003c/p\u003e\n \u003cp\u003eParticipant eligibility was recorded by CT, and a second reviewer (MF) was consulted to determine suitability and appropriateness for participation in the study. Thirteen individuals were ineligible for participation for the following reasons: high-risk of PEM (n\u0026thinsp;=\u0026thinsp;9), a severe orthopaedic condition (n\u0026thinsp;=\u0026thinsp;1), a severe cardiac issue (n\u0026thinsp;=\u0026thinsp;1) and (n\u0026thinsp;=\u0026thinsp;2) were unable to commit to the study requirements. Following confirmation of eligibility, 46 individuals (n\u0026thinsp;=\u0026thinsp;32 female) were invited to complete a series of three face-to-face visits over ten days.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eStudy Procedure\u003c/h3\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient Profiling COVID-19/Long COVID\u003c/h2\u003e\n \u003cp\u003eDuring the first visit (1 of 3), baseline data collection involved recording demographic information, medical history, details regarding pre-COVID-19 health status, suspected and confirmed COVID-19 infections, vaccination status and a comprehensive review of Long COVID history, including index infection, referral to support systems, ongoing interventions for Long COVID and symptom profile. Functional impairment of Long COVID symptoms was assessed using the PCFS scale [\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]. Physiological assessments were conducted, including measurements of heart rate (HR), blood pressure, peripheral oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e), respiratory rate, lung function assessment, respiratory muscle strength and tympanic body temperature. Functional status was assessed via the 6-minute walk test (6MWT) and was conducted according to American Thoracic Society guidelines [\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e]. Data from the 6WMT were subsequently used to determine the starting work rate for an adapted CPET test (strata outline below):\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eStrata I: 6MWT distance\u0026thinsp;\u0026lt;\u0026thinsp;350 m (metres) (starting WR of 10 watts (W); with subsequent increments of 5 W)\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eStrata II: 6MWT distance 350\u0026ndash;400 m (starting WR of 20 W with subsequent increments of 5 W).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eStrata III: 6MWT distance\u0026thinsp;\u0026gt;\u0026thinsp;400 m (starting WR of 30 W with subsequent increments of 5W)\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient-Reported Outcome Measures\u003c/h2\u003e\n \u003cp\u003ePatient-reported outcome measures (PROMs) were completed at all study visits and questionnaire information is detailed elsewhere [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Symptoms were measured using an 18-item, 5-point likert scale (0 symptom not present \u0026ndash; 5 very severe) and a single item, 10-point likert scale (0 no impact \u0026ndash; 10 large impact) to determine severity and impact within the previous 24 hours. Quality of Life (QoL) was assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) [\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]. Participants completed two separate measures of fatigue: 1) the Fatigue Assessment Scale (FAS) [\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e]; and 2) the modified fatigue impact scale (MFIS) [\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]. The Medical Research Council (MRC) Dyspnoea Scale was administered to grade the effect of breathlessness on the person\u0026rsquo;s daily activities [\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eCardiopulmonary Exercise Tests (CPET)\u003c/h3\u003e\n\u003cp\u003eThe protocol for the CPET session is detailed fully elsewhere [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Briefly, participants completed two submaximal CPET sessions, separated by 24 hours, using an incremental exercise ramp test on a friction-loaded cycle ergometer (Monark 894E Ergomedic Peak Bike, Monark, Varberg, Sweden) following the American Thoracic Society guidelines [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. The protocol began with a 3-minute rest period, followed by a maximum of 12 minutes of cycle exercise at ~\u0026thinsp;60 revolutions per minute (rpm) delivered via a stepwise incremental protocol. Test termination criteria included a consistent drop in cadence below 60 revolutions per minute despite encouragement and participant volition, whereby symptom exacerbation was beyond the tolerable limits of the participant.\u003c/p\u003e\n\u003ch3\u003eAdverse Event Reporting\u003c/h3\u003e\n\u003cp\u003ePatients were asked at every study visit to report any adverse events following study visits; this included contacting the study team directly in the seven days post completion of study activities. Adverse events were investigated by appropriate clinical personnel (TB).\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eSample Collection\u003c/h2\u003e\n \u003cp\u003eVenous blood samples were collected into sodium citrate and serum-separating tube vacutainers from participants at four time points, including both before and after submaximal exercise on two days separated by 24 hours to assess changes in microclot formation and blood biomarker levels. Plasma and serum separation was performed within 1\u0026ndash;2 hours of collection by centrifuging the blood samples at 2,500 rpm (1048 \u003cem\u003eg\u003c/em\u003e) for 10 minutes at room temperature. The upper layer was collected into 0.5mL aliquots and these were stored at -80\u0026deg;C until analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eCPET Data Processing and Analysis\u003c/h2\u003e\n \u003cp\u003eCPET data were reviewed for completeness by the test site coordinator (CT). Raw gas analysis data were transformed from breath-by-breath to 30-second moving average and middle 5-of-7 breath averages to reduce variability and identify data outliers or missing data. The ventilatory threshold (VT1) describes the point where energy contribution from primarily aerobic metabolism changes to a greater involvement from anaerobic energy sources. The respiratory compensation point (VT2) reflects the upper limit of aerobic energy contribution and primarily indicates that oxidative metabolism is no longer sufficient to meet energy demands; anaerobic energy contribution continues to increase beyond this point until volitional exhaustion or test cessation [\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]. Middle 5-of-7 breaths data were used to determine VT1 and VT2 using the V-slope method. Exercise threshold decisions were made according to the standardised ACSM guidelines [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e] by the test site coordinator (CT) with 10% checked by an additional author (RA). The chief investigator (MF) resolved any uncertainty on exercise threshold decisions through discussion with CT and RA where consensus originally had not been reached. A more detailed account of CPET data processing and analysis can be found in our previous work [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Normal distribution was assessed using Shapiro-Wilks tests. Parametric data were assessed using paired samples t-tests; nonparametric data were assessed using Wilcoxon Signed Rank tests in GraphPad Prism (Version 10) with a set \u0026alpha; level of 0.050 (two-tailed; Bonferroni corrected 0.013). Uncorrected p values are presented within text and tables and the Bonferroni corrected alpha level for significance was applied for all comparisons. Cohen\u0026rsquo;s D was used to calculate the effect size of parametric paired samples t-tests with thresholds set at 0.2\u0026thinsp;=\u0026thinsp;Small, 0.5\u0026thinsp;=\u0026thinsp;Medium, and 0.8\u0026thinsp;=\u0026thinsp;Large. To calculate the effect size value of Wilcoxon Signed Rank t-tests, the formula \u003cem\u003eDifference between sums of ranks / Total of sums of ranks\u003c/em\u003e was implemented with thresholds set at 0.1\u0026thinsp;=\u0026thinsp;Small, 0.3\u0026thinsp;=\u0026thinsp;Medium, and 0.5\u0026thinsp;=\u0026thinsp;Large. In accordance with the literature, multiple imputation (MI) was applied in cases where 5\u0026ndash;10% of data were missing [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]. MI was not used to create data where VT1 and VT2 decisions could not be obtained due to the participant having not reached or exceeded the threshold.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eMicroclot Analysis\u003c/h2\u003e\n \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\n \u003ch2\u003eSample preparation\u003c/h2\u003e\n \u003cp\u003eFor microclot analysis, platelet poor plasma (PPP) samples were stored at \u0026minus;\u0026thinsp;80\u0026deg;C until analysis. Thioflavin T (ThT) is a fluorogenic dye that binds to various types of amyloid proteins [\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e]. On the day of testing, each sample was thawed to room temperature, PPP was incubated with 0.3 \u0026micro;M final ThT exposure concentration, for 30 minutes. Imaging flow cytometry was then performed using an Amnis\u0026reg; FlowSight\u0026reg; Imaging Flow Cytometer (Luminex Corporation). A 405 nm laser was used for excitation, and ThT-positive events were detected using channel 7, which covered the 435\u0026ndash;505 nm wavelength range. A standardized acquisition template was applied across all samples. Each sample was analyzed for five minutes at a flow rate of 0.043 \u0026micro;L/s, resulting in a total volume of 12.9 \u0026micro;L analyzed per run. Microclots were characterized based on size (measured as \u0026micro;m\u003csup\u003e2\u003c/sup\u003e from two-dimensional micrographs), morphology, and fluorescence intensity. Negative controls, including water with and without ThT, and unstained Long COVID PPP samples, were used to establish both an acquisition and analysis gate (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;1\u003c/strong\u003e), and to validate the reliability of the data.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSample analysis\u003c/h2\u003e\n \u003cp\u003eIDEAS 6.3 software developed for the Amnis\u0026reg; FlowSight\u0026reg; Imaging Flow Cytometer was used to perform all flow cytometry analyses. Statistical analyses were performed using R version 4.4.3. Descriptive statistics, including the mean and standard deviation (SD), were used to summarize continuous variables. Comparisons between pre-exercise and post-exercise measurements were conducted using paired t-tests or non-parametric equivalents, depending on the data distribution. Correlations between microclot counts, size, and cytokine levels were assessed using Pearson\u0026rsquo;s or Spearman\u0026rsquo;s correlation coefficients.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eCytokine Panel Analysis\u003c/h2\u003e\n \u003cp\u003eSerum samples were analysed using a cytokine 30-plex human panel from Thermo Fisher Scientific (catalogue number: LHC6003M), designed for Luminex\u0026trade; platforms. This experiment was performed on the Flexmap 3D platform (software: xPONENT 4.2). This panel measures immune biomarkers including various interleukins, both interferon-\u0026alpha; (IFN-\u0026alpha;) and interferon-\u0026gamma; (IFN-\u0026gamma;), both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumour necrosis factor-\u0026alpha; (TNF-\u0026alpha;). All analyses followed the manufacturer\u0026rsquo;s guidelines, and cytokine concentrations were compared across pre-exercise and post-exercise samples to investigate changes in systemic inflammation. The laboratory staff were blinded to the severity or clinical details of the participants in this project.\u003c/p\u003e\n \u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Normal distribution was assessed using Shapiro-Wilks tests. Parametric data were assessed using one-way repeated measures ANOVA; meanwhile, nonparametric data were assessed using Friedman\u0026rsquo;s tests in Graphpad Prism (Version 10) with a set \u0026alpha; level of 0.050. Data were corrected for multiple comparisons using Tukey tests for one-way repeated measures ANOVA and Dunn\u0026rsquo;s tests for Friedman\u0026rsquo;s tests.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Inference\u003c/h2\u003e\n \u003cp\u003eWe investigated the relationship between treatment-induced microclot changes and inflammation using a three-step empirical strategy. First, we tested whether CPET leads to the breakdown of larger microclots (100\u0026ndash;3000 \u0026micro;m\u0026sup2;). Secondly, we assessed whether this breakdown causes elevated levels of circulating small microclots (\u0026lt;\u0026thinsp;30 \u0026micro;m\u0026sup2;). Finally, we examined whether a higher burden of small microclots is associated with an inflammatory cytokine response. To do this, we estimated a sequence of models incorporating fixed effects, first differences, and instrumental variable regressions.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eLogarithmic Transformation and Microclot Size Definitions\u003c/h2\u003e\n \u003cp\u003eAll count variables were log-transformed to address skewness and enhance comparability across individuals. Raw distributions for large microclots, small microclots, and objects/mL showed substantial skew (1.67\u0026ndash;2.74) and kurtosis (2.00\u0026ndash;8.11), with Shapiro-Wilk tests indicating strong non-normality (p\u0026thinsp;\u0026lt;\u0026thinsp;10⁻\u0026sup1;⁴). After transformation, distributions were markedly more symmetric, with skewness reduced to near zero and normality substantially improved. These adjustments supported the use of log-transformed variables in our regression analyses.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eFixed Effects Model of Microclot Breakdown\u003c/h2\u003e\n \u003cp\u003eTo test whether CPET induced the breakdown of large into small microclots, we estimated a fixed effects model at the individual level. The dependent variable was the change in log small microclot count, modelled as a function of changes in log large microclots and log objects/mL (a proxy for overall burden). Time was defined by treatment stages: Pre- and Post-CPET 1 and 2.\u003c/p\u003e\n \u003cp\u003eFormally, we estimated:\u003c/p\u003e\n \u003cdiv id=\"Equa\" class=\"Equation\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e$$\\:\\varDelta\\:{\\text{log}\\left(SmallMicroclots\\right)}_{it}={\\beta\\:}_{1}\\varDelta\\:{\\text{log}\\left(LargeMicroclots\\right)}_{it}+{\\beta\\:}_{2}\\varDelta\\:{\\text{log}\\left(Objects\\right)}_{it}+{\\epsilon\\:}_{it}$$\u003c/div\u003e\n \u003c/div\u003e\n \u003cp\u003eThis fixed-effects specification controlled for all time-invariant individual heterogeneity, such as baseline coagulation profile or immune reactivity.\u003c/p\u003e\n \u003cp\u003eInstrumental Variables Estimation\u003c/p\u003e\n \u003cp\u003eWe used two-stage least squares (2SLS), treating treatment phase (t) as an instrument for large microclot counts. We assumed t influences small microclots only via its effect on large microclot breakdown.\u003c/p\u003e\n \u003cp\u003eFirst stage:\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\text{l}\\text{o}\\text{g}{\\left(\\text{L}\\text{a}\\text{r}\\text{g}\\text{e}\\text{M}\\text{i}\\text{c}\\text{r}\\text{o}\\text{c}\\text{l}\\text{o}\\text{t}\\text{s}\\right)}_{\\text{i}\\text{t}}\\:=\\:{\\pi\\:}₀\\:+\\:{\\pi\\:}₁{\\text{t}}_{\\text{i}\\text{t}}\\:+\\:{\\pi\\:}₂\\text{l}\\text{o}\\text{g}{\\left(\\text{O}\\text{b}\\text{j}\\text{e}\\text{c}\\text{t}\\text{s}\\right)}_{\\text{i}\\text{t}}\\:+\\:{{\\eta\\:}}_{\\text{i}\\text{t}}\\)\u003c/span\u003e\u003c/span\u003e\u003cbr\u003e\u003cbr\u003eSecond stage:\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\text{l}\\text{o}\\text{g}{\\left(\\text{S}\\text{m}\\text{a}\\text{l}\\text{l}\\text{M}\\text{i}\\text{c}\\text{r}\\text{o}\\text{c}\\text{l}\\text{o}\\text{t}\\text{s}\\right)}_{\\text{i}\\text{t}}\\:=\\:{\\alpha\\:}₀\\:+\\:{\\alpha\\:}₁\\text{l}\\text{o}\\text{g}{\\left(\\text{L}\\text{a}\\text{r}\\text{g}\\text{e}\\text{M}\\text{i}\\text{c}\\text{r}\\text{o}\\text{c}\\text{l}\\text{o}\\text{t}\\text{s}\\right)}_{\\text{i}\\text{t}}\\:+\\:{\\alpha\\:}₂\\text{l}\\text{o}\\text{g}\\left(\\text{O}\\text{b}\\text{j}\\text{e}\\text{c}\\text{t}\\text{s}\\right)\\_\\text{i}\\text{t}\\:+\\:{{\\nu\\:}}_{\\text{i}\\text{t}}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003eThis approach identified the causal effect of large microclots on small microclots, assuming exogeneity of the treatment instrument.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eCytokine Response\u003c/h2\u003e\n \u003cp\u003eDue to suspected non-linearity in the relationship between microclots and cytokines, we used non-parametric methods rather than linear models. Spearman rank correlations (\u0026rho;) were calculated between microclot counts (small and large) and cytokine levels, providing robustness to outliers and distributional assumptions. Results are summarised using a tile plot with significance stars.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003ePatient profiling and functional assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e and \u003cstrong\u003eSupplementary Figure 2\u003c/strong\u003e contains a detailed demographic description of the study participants. \u0026nbsp;Briefly, 2 \u0026plusmn; 1 SARS-CoV-2 infections were recorded (range: 1-5 infections from 2020-2023), and the mean number of vaccinations was 4 \u0026plusmn; 1 vaccines (range 1-7). One or more comorbidities were reported by 76% (n=35) of participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Participant demographics, vaccination status and comorbidities.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 567px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant Characteristics (n=46)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e52 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (30%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e32 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight (cm)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eWeight (kg)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e167 \u0026plusmn; 10\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;78 \u0026plusmn; 17\u003c/p\u003e\n \u003cp\u003e28 \u0026plusmn; 6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVaccinated n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; One dose\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Two doses\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Three doses\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026gt; Three doses\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e46 (100%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e2 (4%)\u003c/p\u003e\n \u003cp\u003e3 (7%)\u003c/p\u003e\n \u003cp\u003e16 (35%)\u003c/p\u003e\n \u003cp\u003e24 (52%)\u003c/p\u003e\n \u003cp\u003e1*(2%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Endocrine/diabetes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Renal\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Cardiovascular\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Gastrointestinal/Liver\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Neurological/cerebrovascular\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Malignancy including haematological\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eRespiratory\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Rheumatological\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePsychological\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e35 (76%)\u003c/p\u003e\n \u003cp\u003e11 (24%)\u003c/p\u003e\n \u003cp\u003e6 (13%)\u003c/p\u003e\n \u003cp\u003e4 (9%)\u003c/p\u003e\n \u003cp\u003e19 (41%)\u003c/p\u003e\n \u003cp\u003e13 (28%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;17 (37%)\u003c/p\u003e\n \u003cp\u003e2 (4%)\u003c/p\u003e\n \u003cp\u003e15 (33%)\u003c/p\u003e\n \u003cp\u003e7 (15%)\u003c/p\u003e\n \u003cp\u003e5 (9%)\u003c/p\u003e\n \u003cp\u003e9 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePROMs*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;PCFS (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;EQ-5D-5L utility score (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;EQ-5D-5L VAS (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Symptom Score (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;FAS (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;MFIS (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;MRC dyspnoea (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCognitive function (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline physiological measures\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Systolic blood pressure (mmHg)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Diastolic blood pressure\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003emmHg)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Heart rate (bpm)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; SpO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(%)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline functional status*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003cstrong\u003eFEV1 (Litres)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;FVC (Litres)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;FEV1/FVC (AU)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePEF (\u003c/strong\u003e\u003cstrong\u003eL\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;MIP\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ecmH\u003csub\u003e2\u003c/sub\u003eO\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;MEP\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ecmH\u003csub\u003e2\u003c/sub\u003eO\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 \u0026plusmn; 1\u003c/p\u003e\n \u003cp\u003e0.74 \u0026plusmn; 0.15\u003c/p\u003e\n \u003cp\u003e57 \u0026plusmn; 15\u003c/p\u003e\n \u003cp\u003e21 \u0026plusmn; 9\u003c/p\u003e\n \u003cp\u003e31 \u0026plusmn; 7\u003c/p\u003e\n \u003cp\u003e52 \u0026plusmn; 13\u003c/p\u003e\n \u003cp\u003e3 \u0026plusmn; 1\u003c/p\u003e\n \u003cp\u003e27 \u0026plusmn; 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e130 \u0026plusmn; 19\u003c/p\u003e\n \u003cp\u003e86 \u0026plusmn; 11\u003c/p\u003e\n \u003cp\u003e74 \u0026plusmn; 13\u003c/p\u003e\n \u003cp\u003e98 \u0026plusmn; 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.78 \u0026plusmn; 0.77\u003c/p\u003e\n \u003cp\u003e3.49 \u0026plusmn; 0.99\u003c/p\u003e\n \u003cp\u003e81 \u0026plusmn; 6\u003c/p\u003e\n \u003cp\u003e449 \u0026plusmn; 114\u003c/p\u003e\n \u003cp\u003e94 \u0026plusmn; 33\u003c/p\u003e\n \u003cp\u003e130 \u0026plusmn; 43\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Denotes data available for 45 participants. PROMs denote patient reported outcomes. FEV1 denotes forced expiratory volume in one second. FVC denotes forced vital capacity. PEF denotes peak expiratory flow. MIP and MEP denote maximal inspiratory and expiratory pressure, respectively.\u003c/p\u003e\n\u003cp\u003eThe most prevalent symptoms were fatigue (94%), headaches (72%), concentration issues (70%), joint pain (61%), difficulty sleeping (65%), and dizziness (41%). The impact of symptoms on daily life was self-reported as moderate (6 \u0026plusmn; 2 out of 10). Mean distance covered by participants on the 6MWT was 407 \u0026plusmn; 80 m (range: 270-600m). Accordingly, 13 (28%), 10 (22%), and 23 (50%) participants were assigned to strata 1, 2, and 3 of the CPET protocol, respectively. Further PROMs, physiological, and functional measures are described in \u003cstrong\u003eTable 1\u003c/strong\u003e and \u003cstrong\u003eSupplementary Figure 3.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol Safety and Tolerability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo severe adverse or adverse events were reported following the completion of CPET on either day 1 or day 2. Six participants (13%) were unable to complete the full 12-minute protocol. Reasons for test termination were due to symptom exacerbation (breathlessness (n=7), fatigue/heaviness in legs (n=4), and dizziness (n=1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary of CPET Outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWorkload at iso-time peak, defined as work rates that were matched within participants for total duration of cycle exercise (comparison of the shortest duration reached of the two datasets) [50], was 73 \u0026plusmn; 15 W. Cardiopulmonary measures at rest, iso-time peak, and VT1 for CPET day 1 and day 2 are presented in \u003cstrong\u003eTable 2\u003c/strong\u003e. Compared with day 1, on day 2 heart rate (mean increase 4 \u0026plusmn; 5%, 73 \u0026plusmn; 14 bpm; p=0.005), minute ventilation (mean increase 6 \u0026plusmn; 4%, 10.4 \u0026plusmn; 2.3 L\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e; p=0.010), breathing frequency (mean increase 8 \u0026plusmn; 10%, 16 \u0026plusmn; 4 breaths/min; p=0.007), and P\u003csub\u003eET\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (mean increase 2 \u0026plusmn; 8%, 110 \u0026plusmn; 4 mmHg; p=0.005) were all increased at rest. At VT1, \u003cimg width=\"10\" height=\"20\" src=\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAA8AAAAeCAMAAADEgrRGAAAAAXNSR0IArs4c6QAAAEVQTFRFAAAAAAAAAAA6AABmADqQAGa2OgAAOpDbZgAAZjoAZrb/kDoAkLZmkNv/tmYAtv//25A62/+22////7Zm/9uQ//+2///b9BnCYAAAAAF0Uk5TAEDm2GYAAAAJcEhZcwAAFiUAABYlAUlSJPAAAAAZdEVYdFNvZnR3YXJlAE1pY3Jvc29mdCBPZmZpY2V/7TVxAAAAgUlEQVQoU7VQyRaAIAiUNm1fzP7/U2NRsg69Ls0BB4EZ1JgvCG215X0eyjnPn/UXzQlqrS7IM6ngoDNHj0HggVypSTCBxbg30Ts4JjrgY2M89T64YuS59AbRWTgSuHL03EVgujf5nhbN01o8sIp52qwYVE02B1WjHF92/8Br9Gd2Atg9BJ0pFRG6AAAAAElFTkSuQmCC\" alt=\"image\"\u003eO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(mean\u003csub\u003e\u0026nbsp;\u003c/sub\u003ereduction 9 \u0026plusmn; 20%,\u0026nbsp;0.65 \u0026plusmn; 0.11\u0026nbsp;L\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e; p=0.002), O\u003csub\u003e2\u003c/sub\u003e pulse (mean\u003csub\u003e\u0026nbsp;\u003c/sub\u003ereduction 9 \u0026plusmn; 22%,\u0026nbsp;7.5 \u0026plusmn; 1.9 mL/b; p\u0026lt;0.001) and\u0026nbsp;V̇CO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(mean reduction 9 \u0026plusmn; 17%,0.51 \u0026plusmn; 0.10 L\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e; p=0.006) were all reduced on Day 2. Baseline blood lactate on Day 1 was 1.3 \u0026plusmn; 0.5 mmol/L and increased to 3.5 \u0026plusmn; 1.6 mmol/L post-test (p\u0026lt;0.001) and was 1.4 \u0026plusmn; 0.6 mmol/L at baseline on Day 2 which increased to 3.3 \u0026plusmn; 1.7 mmol/L post exercise (p\u0026lt;0.001). There were no between-day differences in peak blood lactate at baseline (p=0.451) or post-exercise (p=0.087).\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1037\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"22\" valign=\"top\" style=\"width: 1037px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Cardiopulmonary measures at rest, VT1, and iso-time peak for CPET day one and two.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 466px;\"\u003e\n \u003cp\u003en=46 people living with Long COVID (Mean \u0026plusmn; Standard Deviation)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 306px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRest\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 290px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVT1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 290px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIso-time peak\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eES\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003eES\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eV̇O\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(L\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.31 \u0026plusmn; 0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.32 \u0026plusmn; 0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-0.220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.71 \u0026plusmn; 0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e0.65 \u0026plusmn; 0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.002\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.737\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1.33 \u0026plusmn; 0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1.33 \u0026plusmn; 0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.864\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eV̇O\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(mL\u0026bull;kg\u003csup\u003e-1\u003c/sup\u003e\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e3.93 \u0026plusmn; 0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e4.03 \u0026plusmn; 0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.210\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e9.7 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e8.9 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.003\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e-0.680\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e17.4 \u0026plusmn; 3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e17.4 \u0026plusmn; 4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.509\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e-0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eV̇O\u003csub\u003e2\u003c/sub\u003e_HR (mL/b)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e4.49 \u0026plusmn; 1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e4.51 \u0026plusmn; 1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.820\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e8.3 \u0026plusmn; 2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e7.5 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e-0.747\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e11.1 \u0026plusmn; 2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e11.0 \u0026plusmn; 3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.302\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e-0.177\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eHR (bpm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e71 \u0026plusmn; 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e73 \u0026plusmn; 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.005\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.471\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e88 \u0026plusmn; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e89 \u0026plusmn; 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.828\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.054\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e125 \u0026plusmn; 25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e125 \u0026plusmn; 25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.952\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e-0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eWorkload (Watts)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e27 \u0026plusmn; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e21 \u0026plusmn; 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.038*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e-0.680\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e73 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e73 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eVE/V̇O\u003csub\u003e2\u003c/sub\u003e (AU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e24.6 \u0026plusmn; 3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e25.2 \u0026plusmn; 3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.223\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e22.0 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e22.1 \u0026plusmn; 1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.584\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e30.5 \u0026plusmn; 6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e30.5 \u0026plusmn; 4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e-0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eVE/V̇CO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(AU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e29.3 \u0026plusmn; 4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e29.7 \u0026plusmn; 4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.488\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e28.1 \u0026plusmn; 2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e28.2 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.877\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e30.8 \u0026plusmn; 5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e30.9 \u0026plusmn; 4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eRER (AU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.84 \u0026plusmn; 0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.85 \u0026plusmn; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.78 \u0026plusmn; 0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e0.79 \u0026plusmn; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.833\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e0.99 \u0026plusmn; 0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e0.99 \u0026plusmn; 0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.745\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e-0.056\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eVE (L\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e9.8 \u0026plusmn; 2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e10.4 \u0026plusmn; 2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.010\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.434\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e18.4 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e17.4 \u0026plusmn; 3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.018*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e-0.547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e45.0 \u0026plusmn; 13.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e44.7 \u0026plusmn; 10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.737\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e-0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eBF (breaths/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e15 \u0026plusmn; 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e16 \u0026plusmn; 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.007\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e19 \u0026plusmn; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e20 \u0026plusmn; 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.040*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.480\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e28 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e28 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.983\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eV̇CO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(L\u0026bull;min\u003csup\u003e-1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.26 \u0026plusmn; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.27 \u0026plusmn; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.036*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-0.319\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.56 \u0026plusmn; 0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e0.51 \u0026plusmn; 0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.006\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1.32 \u0026plusmn; 0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1.31 \u0026plusmn; 0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eP\u003csub\u003eET\u003c/sub\u003eO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e109 \u0026plusmn; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e110 \u0026plusmn; 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.005\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.469\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e101 \u0026plusmn; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e102 \u0026plusmn; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.037*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e111 \u0026plusmn; 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e111 \u0026plusmn; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.483\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eP\u003csub\u003eET\u003c/sub\u003eCO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e33.2 \u0026plusmn; 3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e32.5 \u0026plusmn; 3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.023*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 71px;\"\u003e\n \u003cp\u003e37.6 \u0026plusmn; 4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e36.5 \u0026plusmn; 3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.015*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.535\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e36.4 \u0026plusmn; 5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e36.0 \u0026plusmn; 4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.214\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"22\" valign=\"top\" style=\"width: 1037px;\"\u003e\n \u003cp\u003eES denotes the effect size. O\u003csub\u003e2\u003c/sub\u003e denotes oxygen uptake. V̇O\u003csub\u003e2\u003c/sub\u003e_HR denotes oxygen pulse. VE/V̇O\u003csub\u003e2\u0026nbsp;\u003c/sub\u003edenotes the ventilatory equivalent for oxygen. VE/V̇CO\u003csub\u003e2\u003c/sub\u003e denotes the ventilatory equivalent for carbon dioxide. RER denotes respiratory exchange ratio. VE denotes minute ventilation. BF denotes breathing frequency. V̇CO\u003csub\u003e2\u003c/sub\u003e denotes carbon dioxide production. P\u003csub\u003eET\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e and P\u003csub\u003eET\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003e denote end-tidal oxygen and carbon dioxide, respectively. *denotes significant with 0.05 alpha level. \u003csup\u003e\u0026dagger;\u003c/sup\u003edenotes significant with Bonferroni correction (alpha level 0.013).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eMicroclot burden in people living with Long COVID\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants with Long COVID were found to have substantially greater microclot burden pre-CPET day 1 within the greater size ranges (\u0026gt;400\u0026nbsp;\u003c/strong\u003e\u0026micro;m\u0026sup2;) when compared with previously collected control data [51]. Long COVID participants in the present study were found to have a microclot burden that was greater in the 900-1600 \u0026micro;m\u0026sup2; microclot range pre-CPET day 1 compared with controls (Median [Q1-Q3]: 31 [2-256] vs. 2 [1-4]) (See representative micrographs of microclots captured using imaging flow cytometry in \u003cstrong\u003eSupplementary Figure 4\u003c/strong\u003e).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eMicroclot dynamics across CPET sessions (Fixed Effects Model of Microclot Breakdown)\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eAnalyses of microclot size distributions revealed distinct time trends across size bins\u003cstrong\u003e\u0026nbsp;(Figure 1).\u003c/strong\u003e De-meaned trends (individual microclot counts minus each person\u0026rsquo;s average) with standard error bands for each size category showing clear reductions in large microclots (100\u0026ndash;3000 \u0026micro;m\u0026sup2;) post-CPET, with increased frequency of small microclots (\u0026lt; 30 \u0026micro;m\u0026sup2;).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eMicroclot Breakdown Causal Inference\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eFirst-difference regressions showed strong associations: during CPET 1: a 1% drop in the number of large microclots was linked to a 0.49% rise in the number of small microclots (p\u0026lt;0.001); these percentage changes observed were relative to the number of microclots within the size ranges, meaning that we observed a disappearance of material contained in microclots. CPET 2 showed the same directional effect, with a smaller but still statistically significant relationship between the decrease in large microclots and the increase in small ones (\u0026beta; = \u0026minus;0.26, p \u0026lt; 0.001). This suggests that, even during the second CPET, the breakdown of large microclots continued to yield more small microclots, albeit to a lesser extent, potentially due to a delayed or reduced formation of large microclots before the test. To address endogeneity (the concern that unobserved factors may influence both large and small microclot levels, making it difficult to isolate the true effect [52]), we instrumented large microclot counts using CPET session timing in a fixed effects 2SLS model. The instrument was statistically strong (F = 84.3), meaning that the timing of the CPET sessions was highly predictive of changes in large microclot counts, a key requirement for drawing valid causal inferences in this type of analysis. The second-stage results then confirmed a significant negative relationship of large on the number of small microclots (\u0026beta; = \u0026minus;0.46, p \u0026lt; 0.001), supporting a causal interpretation. See \u003cstrong\u003eTable 3\u003c/strong\u003e for details.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eEffect of large microclot breakdown on small microclots (Fixed-Effects OLS and 2SLS Models).\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"623\" height=\"397\" 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\" alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll models include individual fixed effects. Robust standard errors are clustered at the group level.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCytokine Profile\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCytokine differences pre-post CPET are presented in \u003cstrong\u003eSupplementary Table 1.\u0026nbsp;\u003c/strong\u003eWithin-day changes were observed on both days. On day 1, pre-and post-test levels of interlukin-6 (IL-6; mean increase 13%, 121 \u0026plusmn; 432 pg/ml; p=0.018), and interferon-gamma-inducible protein 10 (IP-10; mean increase 18%, 8.6 \u0026plusmn; 9.0 pg/ml; p\u0026lt;0.001) were increased. Whilst epidermal growth factor (EGF; mean reduction 22%, 133 \u0026plusmn; 172 pg/ml; p\u0026lt;0.001) was reduced. On day 2, EGF (mean reduction 27%, 25 \u0026plusmn;155 pg/ml; p\u0026lt;0.001) and CCL5/Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) were decreased (mean reduction 10%, 2069 \u0026plusmn; 604 pg/ml; p=0.010). Between-day changes (post-CPET 1 and pre-CPET day 2) saw EGF was increased (mean increase 21%, 167 \u0026plusmn; 141 pg/ml; p\u0026lt;0.001), whereas IL-6 (mean reduction 12%, 107 \u0026plusmn; 383 pg/ml; p\u0026lt;0.0001), and IP-10 (mean reduction 16%, 7.2 \u0026plusmn; 8.1 pg/ml; p=0.0002) were reduced. Furthermore (post-CPET 1, post-CPET day 2) RANTES (mean reduction 12%, 2069 \u0026plusmn; 604 pg/ml; p\u0026lt;0.0001), interleukin-13 (IL-13; mean reduction 12%, 41 \u0026plusmn; 79 pg/ml; p\u0026lt;0.001), and basic fibroblast growth factor (bFGF; mean reduction 3%, 42 \u0026plusmn; 32 pg/ml; p=0.005) were all decreased.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003cstrong\u003eigure 2\u003c/strong\u003e shows Spearman correlations between cytokine levels and microclot size. Several cytokines are significantly associated with clot burden, but the relationships are time sensitive. Notably, large microclots show negative correlations with pro-inflammatory cytokines (e.g. IFN-\u0026alpha;, IL-15, IL-17A), likely reflecting CPET-induced breakdown: as large clots degrade, cytokine levels rise, suggesting that clot degradation (rather than cytokine-driven clot formation) may trigger inflammation through the release of embedded mediators. IL-4, an anti-inflammatory cytokine, show positive correlations with small microclots and negative correlations with large microclots. Other anti-inflammatory cytokines (e.g. IL-10 \u0026amp; IL-13) showed no significant correlation with either microclot sizes although both were significantly decreased post-CPET day 2 when compared with post-CPET day 1. These data imply that that the immune system may attempt to regulate the inflammatory response triggered by microclot fragmentation following physical exertion, but compensatory mechanisms appear insufficient or failing (\u003cstrong\u003eSupplementary Table 1).\u003c/strong\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe data presented here reinforce evidence of distinct physiological and multi-system impairment in individuals with Long COVID. Furthermore, we demonstrate a novel insight into the behaviour of microclots in response to a safe sub-maximal exercise protocol. Whilst it is documented that graded exercise therapy can prompt a worsening of symptoms for people with Long COVID [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], our focus was not to assess whether exercise resolves microclots, but rather to examine how microclot profiles dynamically respond to repeated exertion across consecutive days. Our findings reveal that submaximal exercise induces a shift in microclot size distribution: specifically, a decrease in the proportion of larger microclots (100\u0026ndash;3000 \u0026micro;m\u0026sup2;) is accompanied by a relative increase in smaller microclots (\u0026gt;\u0026thinsp;0\u0026ndash;30 \u0026micro;m\u0026sup2;) post-exercise. This change corresponds with a reduction in \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\dot{\\text{V}}\\)\u003c/span\u003e\u003c/span\u003eO\u003csub\u003e2\u003c/sub\u003e at submaximal thresholds combined with reduced O\u003csub\u003e2\u003c/sub\u003e pulse which highlights impaired O\u003csub\u003e2\u003c/sub\u003e transport and/or utilisation. The patterns demonstrated here suggest that larger microclots undergo fragmentation rather than clearance during exercise, revealing an important mechanistic insight into how microclots behave under physiological stress that may be at least in-part responsible for reductions in O\u003csub\u003e2\u003c/sub\u003e transport and utilisation during physical exertion in people living with Long COVID.\u003c/p\u003e \u003cp\u003ePreviously published microclot count data across multiple size ranges (0-1600 \u0026micro;m\u0026sup2;) were found using imaging flow cytometry to be much higher in people living with Long COVID when compared with a healthy comparator cohort [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Data from the present study also assessed multiple microclot size ranges and indicated that microclot burden prior to the first CPET was higher across the bigger size ranges when compared with previous data [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. We also demonstrate an increased prevalence of smaller microclots post-exercise, which could indicate that mechanical or biochemical stress during exercise disrupts larger microclot structures. This may break them into smaller components that persist in the circulation and possibly limit blood flow and O\u003csub\u003e2\u003c/sub\u003e uptake and/or transport in the vasculature. The reduction in overall clot size distribution post-exercise, as indicated by the decrease in total object count per mL, further supports this hypothesis. Although the percentage increase in small microclots is less than the percentage decrease in large ones (e.g., a 1% drop in large microclots corresponds to a\u0026thinsp;~\u0026thinsp;0.49% rise in small ones), this does not imply full accounting of all microclots. This discrepancy may be partly explained by limitations in the size-based detection range of our imaging methodology. Microclots below the lower limit of detection in this study (1 \u0026micro;m\u0026sup2;) may not be captured, despite being biologically present. Moreover, the conversion of a single large microclot into multiple smaller fragments does not necessarily translate to a proportional increase in countable events, due to possible aggregation below detection thresholds or morphological changes that challenge automated segmentation. While some microclots in this small range may have resulted from the breakdown of larger ones (100\u0026ndash;3000 \u0026micro;m\u0026sup2;), it is equally plausible that the small ones subsequently fragmented into even smaller sizes. Taken together, these data support the interpretation that microclot fragmentation, not clearance, is occurring during exertion, contributing to a redistribution of clot sizes and potentially impairing oxygen transport and/or utilization, as suggested by concurrent reductions in V̇O₂ and O₂ pulse. Furthermore, these data are important and challenge the assumption that exercise necessarily promotes clot clearance, at least in healthy people [38]. Instead, our data suggest that, at least in individuals with fibrinaloid microclots, exercise alters microclot morphology and sizes and potentially changes the way these microclots interact with the vasculature, rather than eliminating them from circulation.\u003c/p\u003e \u003cp\u003eSeveral previous studies have shown a reduction in exercise capacity in people living with Long COVID and impaired O\u003csub\u003e2\u003c/sub\u003e consumption has been implicated within these findings [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Breaking down and reforming of microclot deposits, alongside the exposure of inflammatory cytokines into the circulation, might affect O\u003csub\u003e2\u003c/sub\u003e transport to the working muscles and therefore increase the reliance on anaerobic processes, which is associated with broad intra-muscular/systemic disruption and perturbations. Symptoms related to muscle pathologies and PESE \u0026amp; PEM may be explained by microclots moving into tissues, especially into muscle and surrounding connective tissues via damaged vasculature where the disease has degraded the physiological barrier function. Appelman \u003cem\u003eet al.\u003c/em\u003e found a greater concentration of amyloid-containing deposits in those living with Long COVID compared with healthy controls at baseline and observed a marked increase one-day following maximal CPET [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, they stated that they did not find substantial amyloid-containing deposits in the capillaries but did find them in the extracellular matrix although the limited depth of field could not permit the former conclusion. The authors did not observe skeletal muscle tissue hypoxia and concluded that PEM in Long COVID could not be explained directly by blocked vessel perfusion. It may be possible that the origin of these amyloid-containing deposits is not within circulation, but instead within tissues, and further structural analysis using transmission electron microscopy is ongoing to determine the exact position of the amyloid-containing deposits.\u003c/p\u003e \u003cp\u003eThe correlation heatmaps (Fig.\u0026nbsp;2) provide further insight into the interplay between microclot fragmentation and systemic inflammation. The positive correlations between smaller microclots (\u0026lt;\u0026thinsp;30 \u0026micro;m\u003csup\u003e2\u003c/sup\u003e) and pro-inflammatory cytokines, such as G-CSF, IFN-γ and IFN-α, suggest that microclot fragmentation is linked to a post-exercise inflammatory response. Previous research has observed entrapment of several pro-inflammatory markers within microclots that may also contribute to a failed fibrinolytic system (e.g. increased platelet factor 4 and von Willebrand factor and decreased plasma Kallikrein) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, it is unclear whether the breakdown of larger microclots into smaller microclots is responsible for the release of various entrapped inflammatory molecules or whether the release of these cytokines and interferons from immune and vascular cells is causally linked to the increased burden of small microclots in response to exertion. Exercise can also lead to an increase in shear stress and inflammation [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e], which in turn increases the risk of chronic ischaemic-reperfusion injury if smaller vasculature is impeded by the larger microclots, which could be responsible for inducing PESE [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Our data (post-CPET 1 and pre-CPET 2, \u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e) suggest that larger microclots may reform after exertion which may potentially again entrap other inflammatory markers and perpetuate this process until an appropriate treatment or intervention is given.\u003c/p\u003e\n\u003ch3\u003eImpact for People Living with Long COVID\u003c/h3\u003e\n\u003cp\u003eThe results highlight the dynamic nature of microclots and their interaction with systemic inflammation during exercise. The observed increase in EGF between CPET days, which plays a significant role in angiogenesis [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e], may possibly implicate the breakdown of larger microclots into smaller ones causing vascular injury and promoting the formation of new blood vessels. The increase in smaller microclots post-exercise suggests that microclots do not behave as static entities but can rather undergo structural changes in response to physical exertion. This has critical implications for the development and recommendation of exercise-based rehabilitation strategies in Long COVID. If exercise does increase microclot fragmentation without promoting clearance, these smaller clots, as well as the larger microclots, could contribute to persistent microvascular dysfunction and endothelial damage, impaired O\u003csub\u003e2\u003c/sub\u003e delivery, and increased PESE. The worsening of symptoms reported by some Long COVID patients following physical exertion may, at least in part, be explained by these shifts in microclot size distribution and the resultant inflammatory interactions. The evidence presented here indicates that exposure to submaximal physical exercise may pose additional consequences for individuals with Long COVID where microclots are a contributing pathology and the risk of PEM is low, but PESE is reported. This underscores the importance of thorough clinical evaluation and careful screening for PESE and PEM before recommending and encouraging physical activity.\u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eFuture Research\u003c/h2\u003e \u003cp\u003eFuture research should prioritise the development of more sensitive and specific tools to evaluate PESE and PEM in individuals with Long COVID. While Gattoni et al. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] employed the DePaul Symptom Questionnaire in a two-day CPET protocol, the current study used this questionnaire as a screening tool and repurposed other symptom-specific and functional scales to assess PESE. Whilst this questionnaire is valuable to ensure those with a higher risk of PEM are protected against the possible deleterious impact of exercise in our study, these approaches may lack the resolution to capture the delayed and heterogeneous nature of symptom exacerbation, particularly given that PESE \u0026amp; PEM can emerge up to 72 hours post-exertion [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Moreover, while this study suggests a possible association between microclot fragmentation and inflammatory responses following exercise, we acknowledge that further direct evidence linking this to exact clinical symptom manifestations is needed. It remains speculative to suggest that microclot fragmentation is pathological or causally related to symptoms without further mechanistic data. It is equally plausible that such fragmentation may reflect some beneficial physiological cytokine clearing process, similar to post-exercise increases in anti-inflammatory cytokines observed in healthy populations and other disease groups [\u003cspan additionalcitationids=\"CR60\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. These responses, although associated with symptom provocation in Long COVID, are not inherently pathological. Therefore, expanding the post-CPET cytokine sampling window and developing more refined assessment tools for PESE \u0026amp; PEM may help elucidate the nuanced interplay between coagulation, inflammation, and symptom exacerbation. In future, therapeutic strategies might be tailored at targeting microclot fragmentation post-exercise, once the clinical significance of these events is better understood. The lack of a healthy comparator group in this study is a limitation that meant comparisons with \u0026lsquo;normal\u0026rsquo; response were only made with previously collected data, and further research is needed to include comparator/control groups documenting comorbidities and clinical information so that the findings in this study can be better understood.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study is the first to provide evidence of a biological basis that might explain exercise-induced symptom exacerbation in people with Long COVID through microclot fragmentation. Our findings demonstrate that exercise does not eliminate microclots but instead alters their size distribution, with larger microclots breaking down into smaller microclots post-exercise. These changes are associated with inflammatory pathways, suggesting that microclot fragmentation is not a passive process but rather an active interaction with systemic inflammation. Understanding these mechanisms is essential and has importance when recommending exercise interventions for people with Long COVID as part of their rehabilitation, which may have the capacity to be harmful if appropriate clinical evaluations and treatments are absent. These findings underscore the need to develop targeted approaches to mitigate the vascular and inflammatory consequences of microclot persistence.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAdditional Information\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work received a funding grant from Gilead Sciences (IN-UK-983-6080).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e The study received both NHS (IRAS ID: 313936) and institutional (ETH2324-1808) research ethics approval.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest:\u003c/strong\u003e There is potential Competing Interest. EP holds a patent for the detection of microclots in Long COVID and is the founding director of Biocode Technologies. The rest of the authors have no competing interests to declare\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eMAF, REMA, TB and EP conceived the idea and design of the study. CT led data collection at the test site. REMA \u0026amp; MAF both contributed to data collection. Data analysis was performed by CT, MN, JHP, EP and IS. CT, MF, and EP led the write-up of the submitted manuscript. All partners contributed to the development of the submitted manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e Anonymised data can be made available on request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eWHO. \u003cem\u003eA clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021\u003c/em\u003e. 2021 22/07/2022]; Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1.\u003c/li\u003e\n \u003cli\u003eEly, E.W., Brown, L. M., \u0026amp; Fineberg, H. V., \u003cem\u003eLong Covid Defined.\u003c/em\u003e New England Journal of Medicine, 2024. \u003cstrong\u003e391\u003c/strong\u003e(18): p. 1746-1753.\u003c/li\u003e\n \u003cli\u003eDavis, H.E., et al., \u003cem\u003eCharacterizing long COVID in an international cohort: 7 months of symptoms and their impact.\u003c/em\u003e EClinicalMedicine, 2021. \u003cstrong\u003e38\u003c/strong\u003e: p. 101019.\u003c/li\u003e\n \u003cli\u003eO\u0026apos;Brien, K.K., et al., \u003cem\u003eConceptualising the episodic nature of disability among adults living with Long COVID: a qualitative study.\u003c/em\u003e BMJ Glob Health, 2023. \u003cstrong\u003e8\u003c/strong\u003e(3).\u003c/li\u003e\n \u003cli\u003eOwen, R., et al., \u003cem\u003eProfiling the persistent and episodic nature of long COVID symptoms and the impact on quality of life and functional status: a cohort observation study.\u003c/em\u003e J Glob Health, 2025. \u003cstrong\u003e15\u003c/strong\u003e: p. 04006.\u003c/li\u003e\n \u003cli\u003eThomas, C., et al., \u003cem\u003eLived experience of patients with Long COVID: a qualitative study in the UK.\u003c/em\u003e BMJ Open, 2023. \u003cstrong\u003e13\u003c/strong\u003e(4): p. e068481.\u003c/li\u003e\n \u003cli\u003eGraham, F., \u003cem\u003eDaily briefing: At least 65 million people have long COVID.\u003c/em\u003e Nature 2023.\u003c/li\u003e\n \u003cli\u003eWulf Hanson, S., et al., \u003cem\u003eA global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021.\u003c/em\u003e medRxiv, 2022.\u003c/li\u003e\n \u003cli\u003eAl-Aly, Z., et al., \u003cem\u003eLong COVID science, research and policy.\u003c/em\u003e Nat Med, 2024. \u003cstrong\u003e30\u003c/strong\u003e(8): p. 2148-2164.\u003c/li\u003e\n \u003cli\u003eDavis, H.E., et al., \u003cem\u003eLong COVID: major findings, mechanisms and recommendations.\u003c/em\u003e Nature Reviews Microbiology, 2023.\u003c/li\u003e\n \u003cli\u003eProal, A.D., et al., \u003cem\u003eTargeting the SARS-CoV-2 reservoir in long COVID.\u003c/em\u003e Lancet Infect Dis, 2025.\u003c/li\u003e\n \u003cli\u003eCampen, C.M.C.V., P.C. Rowe, and F.C. Visser, \u003cem\u003eOrthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.\u003c/em\u003e Medicina, 2021. \u003cstrong\u003e58\u003c/strong\u003e(1): p. 28.\u003c/li\u003e\n \u003cli\u003eWang, Y., et al., \u003cem\u003eCerebral blood flow alterations and host genetic association in individuals with long COVID: A transcriptomic-neuroimaging study.\u003c/em\u003e J Cereb Blood Flow Metab, 2025. \u003cstrong\u003e45\u003c/strong\u003e(3): p. 431-442.\u003c/li\u003e\n \u003cli\u003eEspin, E., et al., \u003cem\u003eCellular and molecular biomarkers of long COVID: a scoping review.\u003c/em\u003e EBioMedicine, 2023. \u003cstrong\u003e91\u003c/strong\u003e: p. 104552.\u003c/li\u003e\n \u003cli\u003eLai, Y.J., et al., \u003cem\u003eBiomarkers in long COVID-19: A systematic review.\u003c/em\u003e Front Med (Lausanne), 2023. \u003cstrong\u003e10\u003c/strong\u003e: p. 1085988.\u003c/li\u003e\n \u003cli\u003eThomas, C., et al., \u003cem\u003eBlood Biomarkers of Long COVID: A Systematic Review.\u003c/em\u003e Mol Diagn Ther, 2024. \u003cstrong\u003e28\u003c/strong\u003e(5): p. 537-574.\u003c/li\u003e\n \u003cli\u003eDel Giudice, M. and S.W. Gangestad, \u003cem\u003eRethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters.\u003c/em\u003e Brain, Behavior, and Immunity, 2018. \u003cstrong\u003e70\u003c/strong\u003e: p. 61-75.\u003c/li\u003e\n \u003cli\u003eNash, D., et al., \u003cem\u003eIL‐6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance.\u003c/em\u003e Scandinavian Journal of Medicine \u0026amp;amp; Science in Sports, 2023. \u003cstrong\u003e33\u003c/strong\u003e(1): p. 4-19.\u003c/li\u003e\n \u003cli\u003ePatterson, B.K., et al., \u003cem\u003eImmune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning.\u003c/em\u003e Front Immunol, 2021. \u003cstrong\u003e12\u003c/strong\u003e: p. 700782.\u003c/li\u003e\n \u003cli\u003ePatel, M.A., et al., \u003cem\u003eElevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism.\u003c/em\u003e Molecular Medicine, 2022. \u003cstrong\u003e28\u003c/strong\u003e(1).\u003c/li\u003e\n \u003cli\u003eAckermann, M., et al., \u003cem\u003ePulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.\u003c/em\u003e N Engl J Med, 2020. \u003cstrong\u003e383\u003c/strong\u003e(2): p. 120-128.\u003c/li\u003e\n \u003cli\u003eJing, H., et al., \u003cem\u003ePathophysiological mechanisms of thrombosis in acute and long COVID-19.\u003c/em\u003e Front Immunol, 2022. \u003cstrong\u003e13\u003c/strong\u003e: p. 992384.\u003c/li\u003e\n \u003cli\u003e\u0026Oslash;stergaard, L., \u003cem\u003eSARS CoV-2 related microvascular damage and symptoms during and after COVID-19: Consequences of capillary transit-time changes, tissue hypoxia and inflammation.\u003c/em\u003e Physiological Reports, 2021. \u003cstrong\u003e9\u003c/strong\u003e(3).\u003c/li\u003e\n \u003cli\u003eAltmann, D.M., et al., \u003cem\u003eThe immunology of long COVID.\u003c/em\u003e Nat Rev Immunol, 2023. \u003cstrong\u003e23\u003c/strong\u003e(10): p. 618-634.\u003c/li\u003e\n \u003cli\u003eKell, D.B., G.J. Laubscher, and E. Pretorius, \u003cem\u003eA central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications.\u003c/em\u003e Biochem J, 2022. \u003cstrong\u003e479\u003c/strong\u003e(4): p. 537-559.\u003c/li\u003e\n \u003cli\u003ePretorius, E., et al., \u003cem\u003ePersistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin.\u003c/em\u003e Cardiovasc Diabetol, 2021. \u003cstrong\u003e20\u003c/strong\u003e(1): p. 172.\u003c/li\u003e\n \u003cli\u003eKell, D.B. and E. Pretorius, \u003cem\u003eProteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting.\u003c/em\u003e Prog Biophys Mol Biol, 2017. \u003cstrong\u003e123\u003c/strong\u003e: p. 16-41.\u003c/li\u003e\n \u003cli\u003eKruger, A., et al., \u003cem\u003eProteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system.\u003c/em\u003e Cardiovascular Diabetology, 2022. \u003cstrong\u003e21\u003c/strong\u003e(1).\u003c/li\u003e\n \u003cli\u003eChristle, J.W., \u0026amp; Arena, R. , \u003cem\u003eCardiopulmonary Exercise Testing and Prescription of Exercise\u003c/em\u003e, in \u003cem\u003eTextbook of Sports and Exercise Cardiology\u003c/em\u003e, A. Pressler, \u0026amp; Niebauer, J., Editor. 2020. p. 897\u0026ndash;912.\u003c/li\u003e\n \u003cli\u003eFaghy, M.A., et al., \u003cem\u003eUsing cardiorespiratory fitness assessment to identify pathophysiology in long COVID \u0026ndash; Best practice approaches.\u003c/em\u003e Progress in Cardiovascular Diseases, 2024.\u003c/li\u003e\n \u003cli\u003eFaghy, M.A., et al., \u003cem\u003eCardiopulmonary exercise testing in the COVID-19 endemic phase.\u003c/em\u003e Br J Anaesth, 2020. \u003cstrong\u003e125\u003c/strong\u003e(4): p. 447-449.\u003c/li\u003e\n \u003cli\u003eFaghy, M.A., et al., \u003cem\u003eIntegrated sports and respiratory medicine in the aftermath of COVID-19.\u003c/em\u003e The Lancet Respiratory Medicine, 2020. \u003cstrong\u003e8\u003c/strong\u003e(9): p. 852.\u003c/li\u003e\n \u003cli\u003eAppelman, B., et al., \u003cem\u003eMuscle abnormalities worsen after post-exertional malaise in long COVID.\u003c/em\u003e Nature Communications, 2024. \u003cstrong\u003e15\u003c/strong\u003e(1).\u003c/li\u003e\n \u003cli\u003eDurstenfeld, M.S., et al., \u003cem\u003eUse of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults.\u003c/em\u003e JAMA Network Open, 2022. \u003cstrong\u003e5\u003c/strong\u003e(10): p. e2236057.\u003c/li\u003e\n \u003cli\u003eThomas, C., Kudiersky, N., Ansdell, P., Ashton, R. E., Brown, C., Bewick, T., Carr, J., Hume, E., Spillane, P., Pastorio, E., Owen, R., Maden-Wilkinson, T., McNeil-Angopa, E., Parkington, T., Arena, R., Ozemek, C., Formenti, F., Veluswamy, S.K., Gururaj, R., \u0026amp; Faghy, M. A., \u003cem\u003eSubmaximal 2-day cardiopulmonary exercise testing to assess exercise capacity and post-exertional symptom exacerbation in people with Long COVID.\u003c/em\u003e Experimental Physiology, In Press.\u003c/li\u003e\n \u003cli\u003eThaweethai, T., Jolley, S. E., Karlson, E. W., Levitan, E. B., Levy, B., McComsey, G. A., ... \u0026amp; Donohue, S. E., \u003cem\u003eDevelopment of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.\u003c/em\u003e JAMA, 2023. \u003cstrong\u003e329\u003c/strong\u003e(22): p. 1934\u0026ndash;1946.\u003c/li\u003e\n \u003cli\u003eGattoni, C., et al., \u003cem\u003eTwo-day cardiopulmonary exercise testing in long COVID post-exertional malaise diagnosis.\u003c/em\u003e Respir Physiol Neurobiol, 2025. \u003cstrong\u003e331\u003c/strong\u003e: p. 104362.\u003c/li\u003e\n \u003cli\u003eKupchak, B.R., et al., \u003cem\u003eBeneficial effects of habitual resistance exercise training on coagulation and fibrinolytic responses.\u003c/em\u003e Thromb Res, 2013. \u003cstrong\u003e131\u003c/strong\u003e(6): p. e227-34.\u003c/li\u003e\n \u003cli\u003eCotler, J., et al., \u003cem\u003eA Brief Questionnaire to Assess Post-Exertional Malaise.\u003c/em\u003e Diagnostics (Basel), 2018. \u003cstrong\u003e8\u003c/strong\u003e(3).\u003c/li\u003e\n \u003cli\u003eLiguori, G., \u0026amp; American College of Sports Medicine., \u003cem\u003eACSM\u0026apos;s guidelines for exercise testing and prescription.\u003c/em\u003e 11th ed, ed. L.W. Wilkins. 2020.\u003c/li\u003e\n \u003cli\u003eKlok, F.A., et al., \u003cem\u003eThe Post-COVID-19 Functional Status scale: a tool to measure functional status over time after COVID-19.\u003c/em\u003e Eur Respir J, 2020. \u003cstrong\u003e56\u003c/strong\u003e(1).\u003c/li\u003e\n \u003cli\u003eHolland, A.E., et al., \u003cem\u003eAn official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease.\u003c/em\u003e Eur Respir J, 2014. \u003cstrong\u003e44\u003c/strong\u003e(6): p. 1428-46.\u003c/li\u003e\n \u003cli\u003eHerdman, M., et al., \u003cem\u003eDevelopment and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).\u003c/em\u003e Quality of Life Research, 2011. \u003cstrong\u003e20\u003c/strong\u003e(10): p. 1727-1736.\u003c/li\u003e\n \u003cli\u003eMichielsen, H.J., J. De Vries, and G.L. Van Heck, \u003cem\u003ePsychometric qualities of a brief self-rated fatigue measure: The Fatigue Assessment Scale.\u003c/em\u003e J Psychosom Res, 2003. \u003cstrong\u003e54\u003c/strong\u003e(4): p. 345-52.\u003c/li\u003e\n \u003cli\u003eLarson, R.D., \u003cem\u003ePsychometric Properties of the Modified Fatigue Impact Scale.\u003c/em\u003e International Journal of MS Care, 2013. \u003cstrong\u003e15\u003c/strong\u003e(1): p. 15-20.\u003c/li\u003e\n \u003cli\u003eBestall, J.C., Paul, E. A., Garrod, R., Garnham, R., Jones, P. W., \u0026amp; Wedzicha, J. , \u003cem\u003eUsefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease.\u003c/em\u003e Thorax, 1999. \u003cstrong\u003e54\u003c/strong\u003e(7): p. 581-586.\u003c/li\u003e\n \u003cli\u003eOzmek, C.A.C.o.S.M., \u003cem\u003eACSM\u0026apos;s Guidelines for Exercise Testing and Prescription\u003c/em\u003e. 12th ed. 2025: Wolters Kluwer Health. 688.\u003c/li\u003e\n \u003cli\u003eLee, J.H., \u0026amp; Huber Jr, J., \u003cem\u003eEvaluation of Multiple Imputation with Large Proportions of Missing Data: How Much Is Too Much? .\u003c/em\u003e Iran J Public Health, 2021: p. 1372-80.\u003c/li\u003e\n \u003cli\u003eGade Malmos, K., et al., \u003cem\u003eThT 101: a primer on the use of thioflavin T to investigate amyloid formation.\u003c/em\u003e Amyloid, 2017. \u003cstrong\u003e24\u003c/strong\u003e(1): p. 1-16.\u003c/li\u003e\n \u003cli\u003eNicol\u0026ograve;, A., et al., \u003cem\u003eComparing Continuous and Intermittent Exercise: An \u0026ldquo;Isoeffort\u0026rdquo; and \u0026ldquo;Isotime\u0026rdquo; Approach.\u003c/em\u003e PLoS ONE, 2014. \u003cstrong\u003e9\u003c/strong\u003e(4): p. e94990.\u003c/li\u003e\n \u003cli\u003eTurner, S., et al., \u003cem\u003eAccelerating discovery: A novel flow cytometric method for detecting fibrin(ogen) amyloid microclots using long COVID as a model.\u003c/em\u003e Heliyon, 2023. \u003cstrong\u003e9\u003c/strong\u003e(9): p. e19605.\u003c/li\u003e\n \u003cli\u003eWooldridge, J.M., \u003cem\u003eEconometric analysis of cross section and panel data.\u003c/em\u003e 2010: MIT press.\u003c/li\u003e\n \u003cli\u003eEckey, M., et al., \u003cem\u003ePatient-Reported Treatment Outcomes in ME/CFS and Long COVID\u003c/em\u003e. 2024, Cold Spring Harbor Laboratory.\u003c/li\u003e\n \u003cli\u003ePretorius, E., et al., \u003cem\u003eFlow Clotometry: Measuring Amyloid Microclots in ME/CFS, Long COVID, and Healthy Samples with Imaging Flow Cytometry.\u003c/em\u003e 2024.\u003c/li\u003e\n \u003cli\u003eSallam, N. and I. Laher, \u003cem\u003eExercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases.\u003c/em\u003e Oxid Med Cell Longev, 2016. \u003cstrong\u003e2016\u003c/strong\u003e: p. 7239639.\u003c/li\u003e\n \u003cli\u003eKell, D.B. and E. Pretorius, \u003cem\u003eThe potential role of ischaemia\u0026ndash;reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications.\u003c/em\u003e Biochemical Journal, 2022. \u003cstrong\u003e479\u003c/strong\u003e(16): p. 1653-1708.\u003c/li\u003e\n \u003cli\u003eAssal, Y., M. Mie, and E. Kobatake, \u003cem\u003eThe promotion of angiogenesis by growth factors integrated with ECM proteins through coiled-coil structures.\u003c/em\u003e Biomaterials, 2013. \u003cstrong\u003e34\u003c/strong\u003e(13): p. 3315-23.\u003c/li\u003e\n \u003cli\u003eAn, Y., et al., \u003cem\u003ePrevalence and measurement of post-exertional malaise in post-acute COVID-19 syndrome: A systematic review and meta-analysis.\u003c/em\u003e Gen Hosp Psychiatry, 2024. \u003cstrong\u003e91\u003c/strong\u003e: p. 130-142.\u003c/li\u003e\n \u003cli\u003eOstapiuk-Karolczuk, J., Zembron-Lacny, A., Naczk, M., Gajewski, M., Kasperska, A., Dziewiecka, H., \u0026amp; Szyszka, K., \u003cem\u003eCytokines and cellular inflammatory sequence in non-athletes after prolonged exercise.\u003c/em\u003e Journal of sports medicine and physical fitness, 2012. \u003cstrong\u003e52\u003c/strong\u003e(5): p. 563.\u003c/li\u003e\n \u003cli\u003ePetersen, A.M. and B.K. Pedersen, \u003cem\u003eThe anti-inflammatory effect of exercise.\u003c/em\u003e J Appl Physiol (1985), 2005. \u003cstrong\u003e98\u003c/strong\u003e(4): p. 1154-62.\u003c/li\u003e\n \u003cli\u003ePloeger, H.E., Takken, T., De Greef, M. H., \u0026amp; Timmons, B. W., \u003cem\u003eThe effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review.\u003c/em\u003e Exerc Immunol Rev., 2009. \u003cstrong\u003e15\u003c/strong\u003e(1): p. 6-41.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"27642659-d02e-47fe-b277-a225cc1e7549","identifier":"10.13039/100005564","name":"Gilead Sciences","awardNumber":"IN-UK-983-6080","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Derby","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Long COVID, Blood Biomarkers, Inflammation, Vascular Injury, COVID-19, Microclots","lastPublishedDoi":"10.21203/rs.3.rs-6717727/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6717727/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eLong COVID is a persistent and episodic multi-system condition that impacts quality of life and functional status. Underlying pathologies include viral persistence, endothelial dysfunction, platelet hyperactivation/dysregulation, and the presence of anomalous deposits, also referred to as fibrinaloid complexes or microclots. Exercise is sometimes suggested to be beneficial for people with Long COVID despite minimal exertion being shown to exacerbate symptoms in many cases. To date, changes in microclot dynamics, inflammation, and biomarker profile in response to exercise remain unstudied in people living with Long COVID.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e46 people living with Long COVID with a low risk of experiencing post-exertional malaise (PEM) completed two submaximal cardiopulmonary exercise tests, separated by 24 hours. Thirteen individuals were ineligible for participation for the following reasons: high-risk of PEM (n=9), a severe orthopaedic condition (n=1), a severe cardiac issue (n=1) or were unable to commit to the study requirements (n=2). Venous blood was collected pre- and post-exercise for cytokine profiling and for imaging flow cytometry analysis of microclots. Changes in large and small microclot populations and their association with inflammatory and vascular injury markers were assessed using fixed-effects and instrumental variable statistical models.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eNo adverse events were reported in this study on either CPET day. At the first ventilatory threshold (VT1), \u003cimg width=\"10\" height=\"20\" src=\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAA8AAAAeCAMAAADEgrRGAAAAAXNSR0IArs4c6QAAAEVQTFRFAAAAAAAAAAA6AABmADqQAGa2OgAAOpDbZgAAZjoAZrb/kDoAkLZmkNv/tmYAtv//25A62/+22////7Zm/9uQ//+2///b9BnCYAAAAAF0Uk5TAEDm2GYAAAAJcEhZcwAAFiUAABYlAUlSJPAAAAAZdEVYdFNvZnR3YXJlAE1pY3Jvc29mdCBPZmZpY2V/7TVxAAAAgUlEQVQoU7VQyRaAIAiUNm1fzP7/U2NRsg69Ls0BB4EZ1JgvCG215X0eyjnPn/UXzQlqrS7IM6ngoDNHj0HggVypSTCBxbg30Ts4JjrgY2M89T64YuS59AbRWTgSuHL03EVgujf5nhbN01o8sIp52qwYVE02B1WjHF92/8Br9Gd2Atg9BJ0pFRG6AAAAAElFTkSuQmCC\"/\u003eO\u003csub\u003e2 \u003c/sub\u003ewas 9.7 ± 1.9 ml•kg•min\u003csup\u003e-1\u003c/sup\u003e and decreased on day 2 (8.9 ± 1.9 ml•kg•min\u003csup\u003e-1\u003c/sup\u003e; p=0.003). O\u003csub\u003e2\u003c/sub\u003e pulse at VT1 was lower on day 2 (day 1 vs. day 2; 8.3 ± 2.4 vs. 7.5 ± 1.9 mL/b; p\u0026lt;0.001). CPET induced the fragmentation of large microclots (100–3000 µm²) and caused an increase in small microclots (\u0026lt;30 µm²) after repeated exertion. Fragmentation correlated with increases in cytokines associated with pro- and anti-inflammation, as well as vascular injury.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: This study provides the first evidence of a biological basis that might explain exercise-induced symptom exacerbation in people with Long COVID through microclot fragmentation, which may contribute to systemic inflammation. This has important implications for Long COVID rehabilitation practices that seek to improve health outcomes through exercise therapies that may have the capacity to be harmful for people living with Long COVID and underscores the need for targeted therapeutic strategies that consider microclot clearance and endothelial repair.\u003c/p\u003e","manuscriptTitle":"Exercise-induced Changes in Microclotting and Cytokine Levels Point to Vascular Injury and Inflammation in People with Long COVID","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-26 09:04:00","doi":"10.21203/rs.3.rs-6717727/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e8988486-ff83-4e81-9c85-4b1992a95660","owner":[],"postedDate":"May 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48945846,"name":"Physiology"},{"id":48945847,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2025-05-26T09:04:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-26 09:04:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6717727","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6717727","identity":"rs-6717727","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}