Fibrin clot permeability (Ks) in patients on left ventricular assist device

Fibrin clot permeability (Ks) in patients on left ventricular assist device | 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 Article Fibrin clot permeability (Ks) in patients on left ventricular assist device Agnieszka Kuczaj, Michał Skrzypek, Bartosz Hudzik, Jacek Kaczmarski, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3954363/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Aug, 2024 Read the published version in Scientific Reports → Version 1 posted 13 You are reading this latest preprint version Abstract Background Patients on left ventricular assist devices (LVAD) are prone to excessive hemostasis disturbances due to permanent contact of artificial pump surfaces with blood components. Aims We aimed to investigate if fibrin clot permeability is altered in patients on long-term continuous flow LVAD therapy and if the clot permeability is associated with clinical characteristics and adverse events. Methods We investigated 85 end-stage heart failure patients (90.6% men, age 48.6–63.8 years) scheduled for continuous flow long-term LVAD support according to current clinical indications. The patients were assessed periodically: prior to LVAD implantation (T1), 3–6 months (T2) after LVAD implantation, 6–12 months after (T3) and then every 6 months. We tested the first three blood samples (T1-T3) and the last available blood sample (T4), but no longer than 5 years after LVAD implantation. We assessed hemostasis parameters changes during the study period. Results MACCE occurred in 36.5% patients, bleeding events in 25.9%, NACE in 62.4%; 31.7% patients died, and 17.6% underwent transplantation. We observed a decrease in fibrin clot permeability (Ks) between T1, T2, T3 and T4 time periods; P < 0.01 for each comparison. Fibrin clot permeability was negatively correlated with fibrinogen concentration: r = 0.51, P < 0.001, factor VIII activity r=-0.42, P < 0.001. Discrepancies in Ks were observed between patients with MACCE, bleeding, and NACE, and patients without adverse events. Ks showed a constant trend towards normalization (P < 0.01) only in patients without adverse events. Conclusions Adverse events such as MACCE, NACE, and bleeding may be associated with inappropriate fibrin clot structure. heart failure left ventricular assist device fibrin clot permeability Ks Figures Figure 1 Figure 2 Summary In our study, we observed that patients with advanced heart failure have strongly disturbed clot structure. Despite a high rate of thromboembolic complications associated with LVAD devices, there is a beneficial effect on fibrin clot structure. We confirmed that the fibrin clot structure is connected with factor VIII activity and fibrinogen concentration. Positive changes (trend directed to normalization of the Ks values) in fibrin clot structure were associated with fewer thromboembolic and bleeding complications in this group of patients. Introduction The management of advanced heart failure patients (HF) includes, among long-term therapeutic options, continuous-flow left ventricular assist devices (LVADs) 1 . With organ shortages and a growing number of heart failure cases, there’s an increasing demand for durable circulatory support systems. Long-term mechanical circulatory support raises major concerns regarding driveline issues, comprising primarily of driveline infections at the exit site, right ventricular heart failure, and thromboembolic and bleeding complications 2 . In contrast to heart transplantation (HTx), where the most challenging period occurs within the first year following HTx by a relative stabilization thereafter 3 , LVAD patients seem to accumulate complications over time. The most detrimental complications in continuous flow LVAD therapy are bleeding and thromboembolic events, with ischemic strokes and intracranial bleeding being particularly disabling. Demographic trends in Europe indicate an increasing predicted lifespan coupled with ageing population 4 . Heart failure prevalence rises with age, and older patients with HF often have a higher rate of comorbidities 5 . Efforts are being made not only to extend life expectancy but also optimize the quality of life in HF patients. Complications such as ischemic and hemorrhagic strokes significantly impact both life expectancy and quality of life in LVAD patients. Complications associated with comorbidities and advanced age 6 substantially increase healthcare and caregiver burden. Consequently, efforts are underway to identify significant risk factors to prevent these complications. Optimal medication, including heart failure treatment, appropriate anticoagulation, antiplatelet therapy, and blood pressure control, can impact the risk of bleeding and thromboembolic complications 7 . Despite optimal management, complications remain high at 14% in the first year and 20% within the first two years of the long-term continuous-flow LVAD support. The incidence of hemorrhagic and ischemic strokes is nearly equal, and both contribute to increased mortality 8 . Efforts are ongoing to mitigate their effects and prevent their occurrence. We hypothesize that prothrombotic conditions may precede these adverse events. Fibrin clot permeability is a parameter describing functional fibrin clot properties, defined by the Darcy constant (Ks). The parameter characterizes the density of the fibrin net and its porosity. Denser and more compact fibrin clots appear to be more resistant to lysis and are correlated with thromboembolic events. Previous studies have indicated diminished fibrin clot permeability in patients with prothrombotic conditions like venous thromboembolism in women receiving hormonal contraception 9 . Denser fibrin clot structures have been reported in anticoagulated patients with ischemic stroke. Lower permeability values (Ks) are observed in patients with cardiovascular disease and thromboembolism. Altered fibrin clot permeability is also noticed in patients with dysfibrinogenemia 10–12 . An international study on standardizing fibrin clot permeability measurements suggests its potential in characterizing thromboembolic diseases 13 . Aligned with these findings, our study aimed to investigate the role of changes in fibrin clot permeability (Ks) in patients on long-term LVAD support. Materials/Patients and Methods We recruited 85 consecutive adult patients (over 18 years old) diagnosed with advanced heart failure, meeting at least one of the following inclusion criteria: a history of at least 3 hospitalizations due to HF decompensations in the preceding 12 months, dependence on inotropes or temporary mechanical circulatory support, progressive end-organ dysfunction attributed to the low cardiac output, very limited exercise capacity (VO2 peak < 12ml/kg/min), or an inability to exercise. Exclusion criteria encompassed current pregnancy, ongiong infections, recurrent malignant arrhythmias, severe right ventricular failure, phenotypes of hypertrophic or restrictive cardiomyopathy hindering safe LVAD implantation, known contraindications to antiplatelet or anticoagulation therapies, life-limiting severe comorbidities or cancer (with an expected survival of less than two years), severe renal or liver failure, absence of social support or unstable psychosocial background. Implantation was performed either as a bridge to transplantation or bridge to candidacy. The study was conducted at a single high-volume heart transplantation center between May 10, 2017 and September 10, 2021. All patients provided informed consent before participation in and underwent assessment adhering to the inclusion and exclusion criteria preimplantation. The study adheres to the principles of the Declaration of Helsinki and received approval from the Medical University of Silesia Bioethics Committee (PCN/CBN/0022/KB1/144/21/22). Two available continuous-flow LVAD systems (HeartWare, Medtronic or HeartMate 3, Abbot) were used. The choice between two types and surgical approach (full sternotomy vs. mini- sternotomy) was at the operator’s discretion. Both devices had national health insurance approval at the time of implantation. Both pumps consisted of an inflow cannula inserted into the left ventricle connected to a continuous-flow centrifugal pump placed in the chest. The outflow cannula transported blood from the pump to the ascending aorta. Both pumps were externally powered, connected to an external energy source via the driveline tunneled in abdominal tissues and exiting on the skin surface. Pump flow was regulated by altering the rotation speed in the external controller 14 . Pump speed adjustment was performed by an experienced transplant physician based on echocardiography and patient’ clinical condition 15 . Subsequent to acquiring informed consent for participation in the study, patients were regularly followed up at scheduled visits: prior to LVAD implantation, 3–4 months post-implantation, 6–12 months post-implantation, and thereafter every 6 months post the first year (for a maximum follow-up of 5 years). The last available blood sample was analyzed We (median 21 months; IQR:10–29 months). The anticoagulation regimen comprised titrated warfarin (vitamin K antagonist) to achieve a target international normalized ratio (INR) of 2–3. Patients underwent INR home tests for all-day self-monitoring. In instances of vitamin K antagonist cessation, patients were bridged with therapeutic doses of low molecular weight or unfractionated heparin. Acetylsalicylic acid at a daily dose of 75mg was the preferred an antiplatelet therapy. We monitored ASPI to assess aspirin response. If the ASPI test fell below 745AU × min, we maintained the dose; if it exceeded 745AU × min, we increased the dosage to 150 mg daily. Should ASPI test levels remain elevated, we switched antiplatelet medication to clopidogrel 75mg daily and monitored the response using ADP tests. If the ADP test resulted below 534 AU × min, we maintained the dosage; otherwise, we doubled the dosage. Detail of the anticoagulation and antiplatelet regimen are described elsewhere 16 . Heart failure guideline-directed medical therapy included angiotensin-convertingenzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), angiotensin receptor- neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRA), sodium-glucose contransporter-2 (SGLT-2), beta-blockers, diuretics, and optionally, depending on etiology, statins. Comorbidities were managed based on individual indications. Major adverse cardiac and cerebrovascular events (MACCE) encompassed all-cause mortality, ischemic stroke, transient ischemic attack, peripheral embolism, pulmonary embolism, and pump thrombosis. We documented all symptomatic events during follow-ups and outpatient visits. Bleeding complications were classified based on criteria established by the International Society on Thrombosis and Hemostasis 17 .Net adverse clinical events (NACE) comprised a composite of MACCE and bleeding complications. Transplantations were calculated separately and were not included in MACCE or NACE assessments. Laboratory investigations Assessment timeline : Basic clinical and laboratory parameters were analyzed at four time points: directly before to LVAD implantation (T1), 3–4 months post-implantation (T2), 6–12 months post-implantation (T3), and the last available blood sample (T4). Fasting venous blood samples were collected between 7:30 and 09:00 AM. Routine laboratory tests were used to evaluate basic biochemical parameters and complete blood count. Coagulation profile : Citrated venous blood samples were collected using S—Monovettes: Citrate 9NC/2.9 mL (9NC:0.106 mol/L) to assess Prothrombin Time, Activated Partial Thromboplastin Time, Fibrinogen, D-dimer, Antithrombin, Thrombin Time, Factor VIII, and von Willebrand Factor. Assay Details Prothrombin time (PT) and INR we evaluated using STA Neoptimal reagent, Diagnostica Stago, Canada, with a reference range of 70–120%. Activated Partial Thromboplastin Time (APTT) was assessed with STA Cephascreen reagent, Diagnostica Stago, Canada, with a normal range of 24–35 s. Thrombin Time (TT) was evaluated with STA Thrombin, Diagnostica Stago, Canada with a reference range of 14–21 s. Fibrinogen levels were determined using STA Liquid Fib reagent, Diagnostica Stago, Canada, with a normal range of 200–400 mg/dL. D-dimer assessment employed an immunoturbidimetric method (TA Liatest D-DI Plus reagent, Diagnostica Stago, Canada) with a reference range of 0-0.5 ug/mL FEU. Antithrombin time (AT) utilized a colorimetric method with the STA Stachrom AT III reagent, Diagnostica Stago, Canada, and reference range of 80–120%. Factor VIII assessment involved STA Immunodef VIII, Diagnostica Stago, Canada, with a reference range of 60–150%. Von Willebrand factor assessment used an immunoturbidimetric method (STA Liatest VWF: Ag reagent, Diagnostica Stago, Canada) with aormal range was 50–160%. Platelet Function Assessment ASPI Test Platelet function in response to acetylsalicylic acid was evaluated using impedance aggregation in a Multiplate analyzer (Roche Diagnostics, Mannheim, Germany), with a reference range from 745 to 1361 AU × min. ADP test Platelet function in response to clopidogrel was assessed via impedance aggregation in a Multiplate analyzer (Roche, Diagnostics, Mannheim, Germany), with a reference range of 534 to 1220 AU × min. Fibrin Clot Permeability Assessment Fibrin clot permeability was evaluated using a pressure system 18 . Clots were obtained from citrated plasma by applying 1 IU/mL of human thrombin and 20mM CaCl 2 according to established standards 13 . The volume and mass of the buffer flowing through the clot was measured over a specified time period. Permeability Coefficient (Ks) Calculation : The Ks (×10 − 9 cm 2 ) was calculated using the following formula: Ks (×10 − 9 cm 2 ) = Q × L × η/t × A × ∆P, Where: Q (cm 3 ) represents the flow rate at time t (s), L (cm) signifies the length of the fibrin gel, η (dyne × s/cm 2 ) denotes the viscosity of the liquid, A (cm 2 ) signifies the cross-sectional area, and ∆P (dyne/cm 2 ) represents the pressure gradient. Statistical Analysis Continuous variables were presented as means and standard deviations for normally distributed data or medians with lower and upper quartiles (IQR: 25th to 75th) for data with non-normal distribution. Categorical variables were presented as percentages. Normal distribution was verified using the Shapiro-Wilk test. Statistical tests included the chi-squared test for categorical variables and the Student’s t-test or Mann-Whitney U test for continuous variables. Friedman rank sum test and exact all-pairs comparisons tests of Friedman-type ranked data 19 [ and Mann-Whitney U test with Holm-Bonferroni correction for multiple comparisons were used. To assess a monotonic trend the Page's ordered aligned rank sum test was used. Repeated measures correlation was also calculated 20 . A P value < 0.05 was considered statistically significant. All analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 4.3.1 (R Core Team, 2023). Results As depicted in Table 1 , the study involved 85 patients, with a mean age of 54.9 ± 11.9 years (median age: 58.2 years, range: 48.6–63.8); 77 patients (90.6%) were male. The most frequent cause of heart failure among these patients was ischemic etiology. At baseline, the medication was as follows: 38 patients (44.7%) received vitamin K antagonists, 24 patients (28.2%) were prescribed acetylsalicylic acid, 5 patients (5.9%) received clopidogrel, 44 patients (51.8%) were on ACE inhibitors, 12 patients (14.1%) used ARB or combinations, 74 patients (87.1%) were administered aldosterone antagonists, 65 patients (76.5%) were on beta blockers, and 51 patients (60%) were prescribed statins. Table 1 Baseline characteristics of LVAD patients (prior to LVAD implantation). Variable Age at the time of implantation, years 58 [49–64] NYHA class , median [IQR] 4[3.5-4] NYHA III 21 (24.7) NYHA III advanced 5 (5.9) NYHA IV 59 (69.4) INTERMACS median [IQR] 3[ 2 – 4 ] INTERMACS 1 0 INTERMACS 2 27 (31.8) INTERMACS 3 33 (38.8) INTERMACS 4 24 (28.2) INTERMACS 5 1 (1.2) LVEF, % 15[ 11 – 17 ] NTproBNP [pg/mL] 7222 [4537–14054] LVEDD, mm 75[70–82] HF etiology : Ischemic HF 49 (57.6) Dilated CM 29 (34) Inflammatory 6 (7.1) Non-compaction 1 (1.2) Anthracycline 1 (1.2) Toxic 1 (1.2) Comorbidities : Prior stroke 13 (17.6) Hypertension 38 (44.7) Diabetes mellitus 35 (41.2) CAD 49 (57.6) Impaired glucose tolerance 3 (3.5) CKD stage ≥ 3 37 (45.1) Type of LVAD support, HM3 72 (84.7) Implanted HW 13 (15.3) Data are shown as numbers (%), mean ± standard deviation or median [interquartile range]. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers, CAD, coronary artery disease, CKD, chronic kidney disease CM, cardiomyopathy, INTERMACS Interagency Registry for Mechanically Assisted Circulatory Support, HM3, HeartMate 3, HW, HeartWare, IQR, interquartile range, NYHA New York Heart Association class, LVEDD left ventricle end diastolic dimension, LVEF left ventricular ejection fraction, NACE encompassed MACCE and bleeding complications. Throughout the entire follow-up, MACCE occurred in 31 (36.5%) patients, bleeding events in 22 (25.9%) patients, and NACE in 53 (62.4%) patients. The cumulative incidence of adverse events and transplantations is presented in Table 2 . Table 2 Major adverse cardiac and cerebrovascular events (MACCE), bleeding events, Net Adverse Clinical Events (NACE), deaths and transplantations. Cumulative incidence. Events Cumulative incidence MACCE, No of events 34 Bleeding events, No. of events 23 NACE, No. of events 55 Heart transplantation, No. (%) 15 (17.6) Death No. (%) 27 (31.8) We observed a trend toward normalization of the Ks values in the entire patient cohort (two-sided probability: P < 0.001, Page’s test). Figure 1 illustrates the timeline of Ks values in the entirety of LVAD patients. We observed differences in Ks values based on HF etiology. Patients with ischemic etiology of heart failure exhibited significantly lower Ks values (P = 0.037) compared to patients with other HF etiologies. Nevertheless, these values changed over time in a similar manner (Fig. 2 ) History of stroke prior to implantation did not affect the Ks values. However, the favorable trend in Ks improvement was exclusively observed in patients with no prior ischemic stroke (significant differences observed in: T1 vs. T2, T1 vs. T3, T3 vs. T4, T2 vs. T3, T2 vs. T4 and T3 vs. T4; P < 0.001). We did not identify significant differences in Ks concerning medication (antiplatelet therapy, statins, angiotensin receptor blocker, ARB/ angiotensin converting enzyme inhibitors, ACEI, mineraloid receptor antagonists, MRA). While no significant correlations were found with ASPI and ADP, correlations were observed with fibrinogen, D-dimer, antithrombin, and factor VIII activity. Further details are presented in Table 3 . Table 3 Correlation between repeated measurements of Ks with selected clotting parameters. Laboratory parameter Mean/median value, SD/ IQR Repeated measures correlation, r, [95% CI] P value ASPI [AU × min] T1: 556.5 [352.8–850] T2: 462 [273–766] T3: 440 [232–766] T4: 464.5 [271.5–870] -0.177; 95% CI: [-0.32 -0.031] 0.039 ADP [AU × min] T1: 401 [285.8-630.8] T2: 355 [229.8-591.2] T3: 445 [264–601] T4: 460 [307–671] -0.0034; 95% CI: [-0.166 0.138] 0.97 Fibrinogen [mg/dL] T1:431 [334.8-496.8] T2: 432 [374-474.5] T3: 394 [333.5-458.5] T4: 379 [329–444] -0.51; 95% CI: [-0.62 -0.398] P < 0.001 D-dimer [µg/mL] T1: 1.48 [0.56–3.57] T2: 1.94 [1.42–2.55] T3: 1.295 [0.95–2.02] T4: 1.23 [0.71–1.94] -0.18; 95% CI: - [0.29–0.065] 0.038 Antithrombin [%] T1:79 [67–90] T2: 91 [85–102] T3: 94.5 [85-103.75] T4: 90.5 [80.5–104] 0.22; 95% CI: 0.12 0.41 0.012 Factor VIII activity T1:266.5 [221-341.8] T2: 202.5 [170-240.5] T3: 166 [128–214] T4: 182 [135.5–236] -0.42; 95% CI: [-0.58 -0.31] P < 0.001 vWF [%] T1: 252 [165–341] T2: 168 [126–223] T3: 173.5 [129.2-215.8] T4: 197.5 [146.8-306.8] -0.22; 95% CI: [-0.38 -0.074] 0.015 Ks values did not differ with respect to survival status during follow-up. Regarding to survival within the observation period, differences in Ks significantly improved only in the group of survivors (P < 0.001) at each timepoint. In contrast, among deceased patients, a significant difference was observed only between T1 and T4 time points. No differences were found in Ks values concerning bleedings, MACCE, and NACE (Table 4 ). Table 4 The Ks values (×10 − 9 cm 2 ) concerning bleedings, MACCE and NACE, shown median [IQR] Bleedings patients with bleedings patients without bleedings P value T1 4.09 [3.07–4.57] 4.12 [3.05–4.71] 0.81 T2 3.88 [3.11–6.41] 4.63 [3.98–6.12] 0.77 T3 4.49 [4.05–6.05] 5.97 [4.73–7.3] 0.75 T4 6.91 [5.6–7.9] 7.55 [5.86–8.57] 0.75 MACCE patients with MACCE patients without MACCE P value T1 4.13 [3.05–5.01] 3.98 [3.05–4.55] 1 T2 4.54 [3.75–7.1] 4.68 [3.93–6.08] 1 T3 4.36 [3.55–6.51] 5.46 [4.89–7.3] 0.37 T4 7.51 [5.96–7.93] 7.15 [5.68–8.85] 1 NACE patients with NACE patients without NACE P value T1 4.11 [3.05–4.85] 4.13 [3.15–4.64] 1 T2 4.54 [3.71–6.97] 4.68 [3.94–6.03] 1 T3 4.49 [4.05–6.05] 6.12 [4.96–7.3] 0.33 T4 7.14 [5.77–7.99] 7.63 [5.81–8.89] 0.62 Patients without MACCE, NACE, and bleedings exhibited significant differences (P < 0.001) between all-time points. In the NACE group, differences (P < 0.05) were only observed between T1 vs. T3, T1 vs. T4, T2 vs. T4 and T3 vs. T4. Among patients with MACCE, differences were significant (P < 0.05) only at T1 vs. T4 and T2 vs. T4. Conversely, in patients experiencing bleedings, no differences were observed among these time points. Discussion Fibrin clot permeability is a measure of pore size in a fibrin clot. Dense fibers are more resistant to lysis, and some studies suggest that they are associated with adverse cardiovascular events. Our study is the first to demonstrate that in the group of patients with left ventricular assist devices (LVAD) implanted due to advanced heart failure, fibrin clot permeability changes over time. Studies and available standards present, that in healthy volunteers the Ks is shorter than in patients with adverse cardiovascular events 13 . According to this fact it may be supposed, that the LVAD support may have beneficial effect on clotting hemostasis in patients with end stage heart failure. It seems surprising, considering the fact that current generation LVAD devices is still connected with high incidence of ischemic and hemorrhagic strokes 21 . However according to results presented in healthy volunteers, our patients with end stage HF scheduled for LVAD therapy had strongly disturbed clotting hemostasis 13 . We demonstrated, based on repeated measures correlation, that in this group of patients, the Ks was connected with known risk factors of thromboembolic complications such as fibrinogen concentration, factor VIII activity, vWF activity, D-dimer, and antithrombin. In our study, we confirmed a moderate negative correlation of Ks with fibrinogen and factor VIII activity and a weak positive correlation with antithrombin. The negative correlation with vVF factor activity can be assessed as a weak. Our results are concordant with patients with type 1 diabetes, where fibrin clot structure was correlated with fibrin concentration. Fibrin clot permeability in this group of patients was correlated with clinical microangiopathy, microalbuminuria and glycemic control defined by HbA1c 11 . In previous studies involving patients on vitamin K antagonists with atrial fibrillation, it was shown that patients with lower Ks are more prone to transient ischemic attacks or ischemic strokes 22 . Ks was also found to be valuable in predicting recurrent venous thromboembolic complications 11 . Similarly, reduced fibrin clot permeability on admission in acute pulmonary embolism patients seemed to predict future residual obstruction of pulmonary arteries. The Ks value was significantly lower at baseline and at 6–7 days after the incident in patients who developed residual pulmonary arteries obstruction. The authors created predictive model based on Ks showing that the baseline Ks level ≤ 6.55 x 10 − 9 had area under the ROC curve of 0.91 in predicting the future residual pulmonary vascular obstruction. It was also demonstrated that fibrin clot structure is associated with markers of endothelial injury and liver function. Patients with Fontan circulation had lower Ks values than controls, and a low Ks value was associated with lower levels of protein C, protein S, and albumin. As in the group of LVAD patients the Ks correlated negatively with fibrinogen concentration and factor VIII activity 23 . The etiology of heart failure seems to have an important influence on clot structure. In our study, we observed that patients with ischemic etiology and patients with diabetes had shortened baseline Ks. This is concordant with other studies where Ks was negatively correlated with hypo- or hyperglycemia in type 2 diabetes patients 24 . Duration of diabetes exceeding 5 years and HbA1c level over 6.5% in a study comprising 156 consecutive patients with type 2 diabetes was also associated with shortened Ks values 25 . In patients diagnosed with atrial fibrillation factors such as age 65–74 years, presence of heart failure and hypertension was independently associated with lower Ks. In the context of the CHA2DS2-VASc score, the difference between CHA2DS2-VASc scores of 0 and 1 was also linked to a decrease in Ks 26 . Cross-sectional studies showed that atherosclerotic diseases have an impact on altered fibrin clot structure. Factors such as oxidative stress, chronic inflammation, endothelial dysfunction and increased platelet activation are common pathway for cardiovascular risk factors and clotting disturbances 27,28 . Despite observations from previous studies indicating that interventions influencing cardiovascular risk factors such as administration of statins or ACE inhibitors administration increased the clot permeability 29,30 we did not observe differences based on the heart failure medication. However, our finding might stem from the relatively limited sample size. Of important value is not only the Ks value itself, which is strongly disturbed at baseline in these HF patients, but also changes in fibrin clot structure may be of significant value for future prognosis. The beneficial changes were clearly visible only in patients without adverse events such as bleeding, MACCE and NACE. Both types of complications, as shown in the literature, are often connected, and bleedings in this group of patients may precede ischemic complications 31 . Declarations Disclosure None declared Financial conflict of interest : none declared. The study was supported by the National Center for Research and Development grant within the quest STRATEGMED as a part of RH ROT (WP 3.7) program. Author contributions: AK: study design, data analysis, writing of manuscript, MS: statistical analysis, writing of manuscript, BH: writing of manuscript, JK: writing of manuscript, TH writing of manuscript, SP: writing of manuscript, PP acquisition of funding. 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J Clin Med . 2022;11(13):3712. doi:10.3390/jcm11133712 Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients. J Thromb Haemost . 2005;3(4):692-694. doi:10.1111/j.1538-7836.2005.01204.x Ząbczyk M, Piłat A, Awsiuk M, Undas A. An automated method for fibrin clot permeability assessment. Blood Coagul Fibrinolysis Int J Haemost Thromb . 2015;26(1):104-109. doi:10.1097/MBC.0000000000000232 Eisinga R, Heskes T, Pelzer B, Te Grotenhuis M. Exact p-values for pairwise comparison of Friedman rank sums, with application to comparing classifiers. BMC Bioinformatics . 2017;18:68. doi:10.1186/s12859-017-1486-2 Bakdash JZ, Marusich LR. Repeated Measures Correlation. Front Psychol . 2017;8. Accessed December 22, 2023. https://www.frontiersin.org/articles/10.3389/fpsyg.2017.00456 Chiang YP, Cox D, Schroder JN, et al. Stroke risk following implantation of current generation centrifugal flow left ventricular assist devices. J Card Surg . 2020;35(2):383-389. doi:10.1111/jocs.14397 Drabik L, Wołkow P, Undas A. Fibrin Clot Permeability as a Predictor of Stroke and Bleeding in Anticoagulated Patients With Atrial Fibrillation. Stroke . 2017;48(10):2716-2722. doi:10.1161/STROKEAHA.117.018143 Skubera M, Gołąb A, Plicner D, et al. Properties of Plasma Clots in Adult Patients Following Fontan Procedure: Relation to Clot Permeability and Lysis Time—Multicenter Study. J Clin Med . 2021;10(24):5976. doi:10.3390/jcm10245976 Dunn EJ, Ariëns R a. S, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologia . 2005;48(6):1198-1206. doi:10.1007/s00125-005-1742-2 Konieczynska M, Fil K, Bazanek M, Undas A. Prolonged duration of type 2 diabetes is associated with increased thrombin generation, prothrombotic fibrin clot phenotype and impaired fibrinolysis. Thromb Haemost . 2014;111(4):685-693. doi:10.1160/TH13-07-0566 Głowicki B, Matusik PT, Plens K, Undas A. Prothrombotic State in Atrial Fibrillation Patients With One Additional Risk Factor of the CHA2DS2-VASc Score (Beyond Sex). Can J Cardiol . 2019;35(5):634-643. doi:10.1016/j.cjca.2019.01.014 Ząbczyk M, Ariëns RAS, Undas A. Fibrin clot properties in cardiovascular disease: from basic mechanisms to clinical practice. Cardiovasc Res . 2023;119(1):94-111. doi:10.1093/cvr/cvad017 Ząbczyk M, Natorska J, Undas A. Fibrin Clot Properties in Atherosclerotic Vascular Disease: From Pathophysiology to Clinical Outcomes. J Clin Med . 2021;10(13):2999. doi:10.3390/jcm10132999 Undas A, Celinska-Löwenhoff M, Löwenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost JTH . 2006;4(5):1029-1036. doi:10.1111/j.1538-7836.2006.01882.x Siudut J, Ząbczyk M, Wołkow P, Polak M, Undas A, Jawień J. Intensive low-density lipoprotein cholesterol lowering improves fibrin clot properties: Association with lipoproteins and C-reactive protein. Vascul Pharmacol . 2022;144:106977. doi:10.1016/j.vph.2022.106977 Szymanski TW, Weeks PA, Patel CJ, et al. Risk of pump thrombosis and stroke in patients with continuous-flow left ventricular assist devices and gastrointestinal bleeding. Artif Organs . 2020;44(11):1171-1175. doi:10.1111/aor.13751 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 30 Aug, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 19 Jun, 2024 Reviews received at journal 14 Jun, 2024 Reviews received at journal 12 Jun, 2024 Reviewers agreed at journal 03 Jun, 2024 Reviewers agreed at journal 03 Jun, 2024 Reviewers agreed at journal 27 Mar, 2024 Reviews received at journal 12 Mar, 2024 Reviewers agreed at journal 12 Mar, 2024 Reviewers invited by journal 12 Mar, 2024 Editor assigned by journal 11 Mar, 2024 Editor invited by journal 25 Feb, 2024 Submission checks completed at journal 25 Feb, 2024 First submitted to journal 13 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-3954363","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":274796107,"identity":"1324b36f-7ec4-436d-801a-6ebae6c6a888","order_by":0,"name":"Agnieszka Kuczaj","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDACHjDJJgfhsQExO5FajBFamInTwpDYQLQW/p4zhh9/1PClz5+RncDwoewwgzkhLRJne4wlJI6x5W64kbuBcca5wwyWzYQcdp7HjMGADahFIncDM2/bYQaDwwR0yIO0JPxjS5efAdTylxgtBmd7zBgOtrElMAAdxsxIjBbDM8eKJRv72Aw3nHm74WDPuXQegn6RO5O88eOPb8fk5dtzNz74UWYtZ87eQEAPBBwDkweAmMeAKA0MDDUIJrFaRsEoGAWjYOQAAK5XP9ksPx5mAAAAAElFTkSuQmCC","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":true,"prefix":"","firstName":"Agnieszka","middleName":"","lastName":"Kuczaj","suffix":""},{"id":274796108,"identity":"429c5818-9d91-4dcd-9699-b03a2336530c","order_by":1,"name":"Michał Skrzypek","email":"","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":false,"prefix":"","firstName":"Michał","middleName":"","lastName":"Skrzypek","suffix":""},{"id":274796109,"identity":"c43ea909-869a-4b7f-b014-f2ffd3ffcd24","order_by":2,"name":"Bartosz Hudzik","email":"","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":false,"prefix":"","firstName":"Bartosz","middleName":"","lastName":"Hudzik","suffix":""},{"id":274796110,"identity":"3bc272bc-bbb8-4c11-83ae-16b42978b715","order_by":3,"name":"Jacek Kaczmarski","email":"","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":false,"prefix":"","firstName":"Jacek","middleName":"","lastName":"Kaczmarski","suffix":""},{"id":274796111,"identity":"bc1178c1-2304-4660-86b0-42f028eb82cc","order_by":4,"name":"Szymon Pawlak","email":"","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":false,"prefix":"","firstName":"Szymon","middleName":"","lastName":"Pawlak","suffix":""},{"id":274796112,"identity":"cda8f5ee-6ead-48dd-9c9b-f49599ff3211","order_by":5,"name":"Tomasz Hrapkowicz","email":"","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":false,"prefix":"","firstName":"Tomasz","middleName":"","lastName":"Hrapkowicz","suffix":""},{"id":274796113,"identity":"5a35f134-3b6e-4cc9-9d98-255354356ed3","order_by":6,"name":"Piotr Przybyłowski","email":"","orcid":"","institution":"Medical University of Silesia","correspondingAuthor":false,"prefix":"","firstName":"Piotr","middleName":"","lastName":"Przybyłowski","suffix":""}],"badges":[],"createdAt":"2024-02-13 20:14:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3954363/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3954363/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-69665-0","type":"published","date":"2024-08-30T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51767961,"identity":"e4519575-6240-452e-82a9-e5a24e0d19fd","added_by":"auto","created_at":"2024-02-28 19:03:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":155445,"visible":true,"origin":"","legend":"\u003cp\u003eClot permeability values (Ks) in the whole group of patients during LVAD support. Significant differences (P\u0026lt;0.001) were observed between T1 vs. T3, T1 vs. T4 and T2 vs. T4 timepoints. In the box-whisker plot, the box represents the interquartile range (lover and upper quartiles), with the horizontal line inside the box indicating the median value. Whiskers illustrate the minimum and maximum values.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3954363/v1/b6a9d1130d9cc8a93d4b4eb4.png"},{"id":51767960,"identity":"c7aa0a59-cf6f-43fb-b02b-54bbc50a50b1","added_by":"auto","created_at":"2024-02-28 19:03:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31489,"visible":true,"origin":"","legend":"\u003cp\u003eKs changes over time in regard to HF etiology.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3954363/v1/129682fd40a982708dabbc4a.png"},{"id":63820940,"identity":"4d91c1fe-caf9-42cd-9416-0a2b4c40e991","added_by":"auto","created_at":"2024-09-02 16:10:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":827287,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3954363/v1/507c770d-0f8e-4dfa-ac19-c81b5b121656.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Fibrin clot permeability (Ks) in patients on left ventricular assist device","fulltext":[{"header":"Summary","content":"\u003cp\u003eIn our study, we observed that patients with advanced heart failure have strongly disturbed clot structure. Despite a high rate of thromboembolic complications associated with LVAD devices, there is a beneficial effect on fibrin clot structure. We confirmed that the fibrin clot structure is connected with factor VIII activity and fibrinogen concentration. Positive changes (trend directed to normalization of the Ks values) in fibrin clot structure were associated with fewer thromboembolic and bleeding complications in this group of patients.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe management of advanced heart failure patients (HF) includes, among long-term therapeutic options, continuous-flow left ventricular assist devices (LVADs) \u003csup\u003e1\u003c/sup\u003e. With organ shortages and a growing number of heart failure cases, there\u0026rsquo;s an increasing demand for durable circulatory support systems. Long-term mechanical circulatory support raises major concerns regarding driveline issues, comprising primarily of driveline infections at the exit site, right ventricular heart failure, and thromboembolic and bleeding complications \u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn contrast to heart transplantation (HTx), where the most challenging period occurs within the first year following HTx by a relative stabilization thereafter \u003csup\u003e3\u003c/sup\u003e, LVAD patients seem to accumulate complications over time.\u003c/p\u003e \u003cp\u003eThe most detrimental complications in continuous flow LVAD therapy are bleeding and thromboembolic events, with ischemic strokes and intracranial bleeding being particularly disabling. Demographic trends in Europe indicate an increasing predicted lifespan coupled with ageing population \u003csup\u003e4\u003c/sup\u003e. Heart failure prevalence rises with age, and older patients with HF often have a higher rate of comorbidities \u003csup\u003e5\u003c/sup\u003e. Efforts are being made not only to extend life expectancy but also optimize the quality of life in HF patients. Complications such as ischemic and hemorrhagic strokes significantly impact both life expectancy and quality of life in LVAD patients. Complications associated with comorbidities and advanced age \u003csup\u003e6\u003c/sup\u003e substantially increase healthcare and caregiver burden. Consequently, efforts are underway to identify significant risk factors to prevent these complications.\u003c/p\u003e \u003cp\u003eOptimal medication, including heart failure treatment, appropriate anticoagulation, antiplatelet therapy, and blood pressure control, can impact the risk of bleeding and thromboembolic complications \u003csup\u003e7\u003c/sup\u003e. Despite optimal management, complications remain high at 14% in the first year and 20% within the first two years of the long-term continuous-flow LVAD support. The incidence of hemorrhagic and ischemic strokes is nearly equal, and both contribute to increased mortality \u003csup\u003e8\u003c/sup\u003e. Efforts are ongoing to mitigate their effects and prevent their occurrence. We hypothesize that prothrombotic conditions may precede these adverse events.\u003c/p\u003e \u003cp\u003eFibrin clot permeability is a parameter describing functional fibrin clot properties, defined by the Darcy constant (Ks). The parameter characterizes the density of the fibrin net and its porosity. Denser and more compact fibrin clots appear to be more resistant to lysis and are correlated with thromboembolic events.\u003c/p\u003e \u003cp\u003ePrevious studies have indicated diminished fibrin clot permeability in patients with prothrombotic conditions like venous thromboembolism in women receiving hormonal contraception \u003csup\u003e9\u003c/sup\u003e. Denser fibrin clot structures have been reported in anticoagulated patients with ischemic stroke. Lower permeability values (Ks) are observed in patients with cardiovascular disease and thromboembolism. Altered fibrin clot permeability is also noticed in patients with dysfibrinogenemia\u003csup\u003e10\u0026ndash;12\u003c/sup\u003e. An international study on standardizing fibrin clot permeability measurements suggests its potential in characterizing thromboembolic diseases \u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAligned with these findings, our study aimed to investigate the role of changes in fibrin clot permeability (Ks) in patients on long-term LVAD support.\u003c/p\u003e"},{"header":"Materials/Patients and Methods","content":"\u003cp\u003eWe recruited 85 consecutive adult patients (over 18 years old) diagnosed with advanced heart failure, meeting at least one of the following inclusion criteria: a history of at least 3 hospitalizations due to HF decompensations in the preceding 12 months, dependence on inotropes or temporary mechanical circulatory support, progressive end-organ dysfunction attributed to the low cardiac output, very limited exercise capacity (VO2 peak\u0026thinsp;\u0026lt;\u0026thinsp;12ml/kg/min), or an inability to exercise. Exclusion criteria encompassed current pregnancy, ongiong infections, recurrent malignant arrhythmias, severe right ventricular failure, phenotypes of hypertrophic or restrictive cardiomyopathy hindering safe LVAD implantation, known contraindications to antiplatelet or anticoagulation therapies, life-limiting severe comorbidities or cancer (with an expected survival of less than two years), severe renal or liver failure, absence of social support or unstable psychosocial background.\u003c/p\u003e \u003cp\u003eImplantation was performed either as a bridge to transplantation or bridge to candidacy. The study was conducted at a single high-volume heart transplantation center between May 10, 2017 and September 10, 2021. All patients provided informed consent before participation in and underwent assessment adhering to the inclusion and exclusion criteria preimplantation.\u003c/p\u003e \u003cp\u003e The study adheres to the principles of the Declaration of Helsinki and received approval from the Medical University of Silesia Bioethics Committee (PCN/CBN/0022/KB1/144/21/22).\u003c/p\u003e \u003cp\u003eTwo available continuous-flow LVAD systems (HeartWare, Medtronic or HeartMate 3, Abbot) were used. The choice between two types and surgical approach (full sternotomy vs. mini- sternotomy) was at the operator\u0026rsquo;s discretion. Both devices had national health insurance approval at the time of implantation. Both pumps consisted of an inflow cannula inserted into the left ventricle connected to a continuous-flow centrifugal pump placed in the chest. The outflow cannula transported blood from the pump to the ascending aorta. Both pumps were externally powered, connected to an external energy source via the driveline tunneled in abdominal tissues and exiting on the skin surface. Pump flow was regulated by altering the rotation speed in the external controller \u003csup\u003e14\u003c/sup\u003e. Pump speed adjustment was performed by an experienced transplant physician based on echocardiography and patient\u0026rsquo; clinical condition \u003csup\u003e15\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSubsequent to acquiring informed consent for participation in the study, patients were regularly followed up at scheduled visits: prior to LVAD implantation, 3\u0026ndash;4 months post-implantation, 6\u0026ndash;12 months post-implantation, and thereafter every 6 months post the first year (for a maximum follow-up of 5 years). The last available blood sample was analyzed We (median 21 months; IQR:10\u0026ndash;29 months).\u003c/p\u003e \u003cp\u003eThe anticoagulation regimen comprised titrated warfarin (vitamin K antagonist) to achieve a target international normalized ratio (INR) of 2\u0026ndash;3. Patients underwent INR home tests for all-day self-monitoring. In instances of vitamin K antagonist cessation, patients were bridged with therapeutic doses of low molecular weight or unfractionated heparin.\u003c/p\u003e \u003cp\u003eAcetylsalicylic acid at a daily dose of 75mg was the preferred an antiplatelet therapy. We monitored ASPI to assess aspirin response. If the ASPI test fell below 745AU \u0026times; min, we maintained the dose; if it exceeded 745AU \u0026times; min, we increased the dosage to 150 mg daily. Should ASPI test levels remain elevated, we switched antiplatelet medication to clopidogrel 75mg daily and monitored the response using ADP tests. If the ADP test resulted below 534 AU \u0026times; min, we maintained the dosage; otherwise, we doubled the dosage. Detail of the anticoagulation and antiplatelet regimen are described elsewhere \u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e Heart failure guideline-directed medical therapy included angiotensin-convertingenzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), angiotensin receptor- neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRA), sodium-glucose contransporter-2 (SGLT-2), beta-blockers, diuretics, and optionally, depending on etiology, statins. Comorbidities were managed based on individual indications.\u003c/p\u003e \u003cp\u003eMajor adverse cardiac and cerebrovascular events (MACCE) encompassed all-cause mortality, ischemic stroke, transient ischemic attack, peripheral embolism, pulmonary embolism, and pump thrombosis. We documented all symptomatic events during follow-ups and outpatient visits. Bleeding complications were classified based on criteria established by the International Society on Thrombosis and Hemostasis \u003csup\u003e17\u003c/sup\u003e.Net adverse clinical events (NACE) comprised a composite of MACCE and bleeding complications. Transplantations were calculated separately and were not included in MACCE or NACE assessments.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eLaboratory investigations\u003c/h2\u003e \u003cp\u003e \u003cb\u003eAssessment timeline\u003c/b\u003e: Basic clinical and laboratory parameters were analyzed at four time points: directly before to LVAD implantation (T1), 3\u0026ndash;4 months post-implantation (T2), 6\u0026ndash;12 months post-implantation (T3), and the last available blood sample (T4). Fasting venous blood samples were collected between 7:30 and 09:00 AM. Routine laboratory tests were used to evaluate basic biochemical parameters and complete blood count.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCoagulation profile\u003c/b\u003e: Citrated venous blood samples were collected using S\u0026mdash;Monovettes: Citrate 9NC/2.9 mL (9NC:0.106 mol/L) to assess Prothrombin Time, Activated Partial Thromboplastin Time, Fibrinogen, D-dimer, Antithrombin, Thrombin Time, Factor VIII, and von Willebrand Factor.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eAssay Details\u003c/strong\u003e \u003cp\u003eProthrombin time (PT) and INR we evaluated using STA Neoptimal reagent, Diagnostica Stago, Canada, with a reference range of 70\u0026ndash;120%.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eActivated Partial Thromboplastin Time (APTT) was assessed with STA Cephascreen reagent, Diagnostica Stago, Canada, with a normal range of 24\u0026ndash;35 s.\u003c/p\u003e \u003cp\u003eThrombin Time (TT) was evaluated with STA Thrombin, Diagnostica Stago, Canada with a reference range of 14\u0026ndash;21 s.\u003c/p\u003e \u003cp\u003eFibrinogen levels were determined using STA Liquid Fib reagent, Diagnostica Stago, Canada, with a normal range of 200\u0026ndash;400 mg/dL.\u003c/p\u003e \u003cp\u003eD-dimer assessment employed an immunoturbidimetric method (TA Liatest D-DI Plus reagent, Diagnostica Stago, Canada) with a reference range of 0-0.5 ug/mL FEU.\u003c/p\u003e \u003cp\u003eAntithrombin time (AT) utilized a colorimetric method with the STA Stachrom AT III reagent, Diagnostica Stago, Canada, and reference range of 80\u0026ndash;120%.\u003c/p\u003e \u003cp\u003eFactor VIII assessment involved STA Immunodef VIII, Diagnostica Stago, Canada, with a reference range of 60\u0026ndash;150%.\u003c/p\u003e \u003cp\u003eVon Willebrand factor assessment used an immunoturbidimetric method (STA Liatest VWF: Ag reagent, Diagnostica Stago, Canada) with aormal range was 50\u0026ndash;160%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePlatelet Function Assessment\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eASPI Test\u003c/strong\u003e \u003cp\u003ePlatelet function in response to acetylsalicylic acid was evaluated using impedance aggregation in a Multiplate analyzer (Roche Diagnostics, Mannheim, Germany), with a reference range from 745 to 1361 AU \u0026times; min.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eADP test\u003c/strong\u003e \u003cp\u003ePlatelet function in response to clopidogrel was assessed via impedance aggregation in a Multiplate analyzer (Roche, Diagnostics, Mannheim, Germany), with a reference range of 534 to 1220 AU \u0026times; min.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFibrin Clot Permeability Assessment\u003c/strong\u003e \u003cp\u003eFibrin clot permeability was evaluated using a pressure system \u003csup\u003e18\u003c/sup\u003e. Clots were obtained from citrated plasma by applying 1 IU/mL of human thrombin and 20mM CaCl\u003csub\u003e2\u003c/sub\u003e according to established standards \u003csup\u003e13\u003c/sup\u003e. The volume and mass of the buffer flowing through the clot was measured over a specified time period.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePermeability Coefficient (Ks) Calculation\u003c/b\u003e: The Ks (\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;9\u003c/sup\u003ecm\u003csup\u003e2\u003c/sup\u003e) was calculated using the following formula: Ks (\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;9\u003c/sup\u003ecm\u003csup\u003e2\u003c/sup\u003e)\u0026thinsp;=\u0026thinsp;Q \u0026times; L\u0026thinsp;\u0026times;\u0026thinsp;η/t \u0026times; A \u0026times; ∆P, Where:\u003c/p\u003e \u003cp\u003eQ (cm\u003csup\u003e3\u003c/sup\u003e) represents the flow rate at time t (s),\u003c/p\u003e \u003cp\u003eL (cm) signifies the length of the fibrin gel,\u003c/p\u003e \u003cp\u003eη (dyne \u0026times; s/cm\u003csup\u003e2\u003c/sup\u003e) denotes the viscosity of the liquid,\u003c/p\u003e \u003cp\u003eA (cm\u003csup\u003e2\u003c/sup\u003e) signifies the cross-sectional area, and\u003c/p\u003e \u003cp\u003e∆P (dyne/cm\u003csup\u003e2\u003c/sup\u003e) represents the pressure gradient.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were presented as means and standard deviations for normally distributed data or medians with lower and upper quartiles (IQR: 25th to 75th) for data with non-normal distribution. Categorical variables were presented as percentages. Normal distribution was verified using the Shapiro-Wilk test. Statistical tests included the chi-squared test for categorical variables and the Student\u0026rsquo;s t-test or Mann-Whitney U test for continuous variables. Friedman rank sum test and exact all-pairs comparisons tests of Friedman-type ranked data \u003csup\u003e19\u003c/sup\u003e[ and Mann-Whitney U test with Holm-Bonferroni correction for multiple comparisons were used. To assess a monotonic trend the Page's ordered aligned rank sum test was used. Repeated measures correlation was also calculated \u003csup\u003e20\u003c/sup\u003e. A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 4.3.1 (R Core Team, 2023).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAs depicted in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the study involved 85 patients, with a mean age of 54.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.9 years (median age: 58.2 years, range: 48.6\u0026ndash;63.8); 77 patients (90.6%) were male. The most frequent cause of heart failure among these patients was ischemic etiology. At baseline, the medication was as follows: 38 patients (44.7%) received vitamin K antagonists, 24 patients (28.2%) were prescribed acetylsalicylic acid, 5 patients (5.9%) received clopidogrel, 44 patients (51.8%) were on ACE inhibitors, 12 patients (14.1%) used ARB or combinations, 74 patients (87.1%) were administered aldosterone antagonists, 65 patients (76.5%) were on beta blockers, and 51 patients (60%) were prescribed statins.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of LVAD patients (prior to LVAD implantation).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at the time of implantation, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 [49\u0026ndash;64]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNYHA class\u003c/b\u003e, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4[3.5-4]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNYHA III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (24.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNYHA III advanced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNYHA IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (69.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eINTERMACS\u003c/b\u003e median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINTERMACS 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINTERMACS 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (31.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINTERMACS 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (38.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINTERMACS 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (28.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINTERMACS 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15[\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNTproBNP [pg/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7222 [4537\u0026ndash;14054]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEDD, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75[70\u0026ndash;82]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHF etiology\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIschemic HF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (57.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDilated CM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInflammatory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (7.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-compaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnthracycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToxic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (44.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (41.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (57.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImpaired glucose tolerance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD stage\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (45.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of LVAD support,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHM3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (84.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImplanted HW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (15.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are shown as numbers (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median [interquartile range]. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers, CAD, coronary artery disease, CKD, chronic kidney disease CM, cardiomyopathy, INTERMACS Interagency Registry for Mechanically Assisted Circulatory Support, HM3, HeartMate 3, HW, HeartWare, IQR, interquartile range, NYHA New York Heart Association class, LVEDD left ventricle end diastolic dimension, LVEF left ventricular ejection fraction,\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNACE encompassed MACCE and bleeding complications. Throughout the entire follow-up, MACCE occurred in 31 (36.5%) patients, bleeding events in 22 (25.9%) patients, and NACE in 53 (62.4%) patients. The cumulative incidence of adverse events and transplantations is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMajor adverse cardiac and cerebrovascular events (MACCE), bleeding events, Net Adverse Clinical Events (NACE), deaths and transplantations. Cumulative incidence.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvents\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCumulative incidence\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMACCE, No of events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding events, No. of events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNACE, No. of events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart transplantation, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (31.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe observed a trend toward normalization of the Ks values in the entire patient cohort (two-sided probability: P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Page\u0026rsquo;s test). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the timeline of Ks values in the entirety of LVAD patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe observed differences in Ks values based on HF etiology. Patients with ischemic etiology of heart failure exhibited significantly lower Ks values (P\u0026thinsp;=\u0026thinsp;0.037) compared to patients with other HF etiologies. Nevertheless, these values changed over time in a similar manner (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHistory of stroke prior to implantation did not affect the Ks values.\u003c/p\u003e \u003cp\u003eHowever, the favorable trend in Ks improvement was exclusively observed in patients with no prior ischemic stroke (significant differences observed in: T1 vs. T2, T1 vs. T3, T3 vs. T4, T2 vs. T3, T2 vs. T4 and T3 vs. T4; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eWe did not identify significant differences in Ks concerning medication (antiplatelet therapy, statins, angiotensin receptor blocker, ARB/ angiotensin converting enzyme inhibitors, ACEI, mineraloid receptor antagonists, MRA). While no significant correlations were found with ASPI and ADP, correlations were observed with fibrinogen, D-dimer, antithrombin, and factor VIII activity. Further details are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation between repeated measurements of Ks with selected clotting parameters.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory parameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean/median value,\u003c/p\u003e \u003cp\u003eSD/ IQR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRepeated measures correlation, r, [95% CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASPI [AU \u0026times; min]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1:\u003c/p\u003e \u003cp\u003e556.5 [352.8\u0026ndash;850]\u003c/p\u003e \u003cp\u003eT2:\u003c/p\u003e \u003cp\u003e462 [273\u0026ndash;766]\u003c/p\u003e \u003cp\u003eT3:\u003c/p\u003e \u003cp\u003e440 [232\u0026ndash;766]\u003c/p\u003e \u003cp\u003eT4: 464.5 [271.5\u0026ndash;870]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.177; 95% CI: [-0.32 -0.031]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADP [AU \u0026times; min]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1:\u003c/p\u003e \u003cp\u003e401 [285.8-630.8]\u003c/p\u003e \u003cp\u003eT2: 355\u003c/p\u003e \u003cp\u003e[229.8-591.2]\u003c/p\u003e \u003cp\u003eT3: 445\u003c/p\u003e \u003cp\u003e[264\u0026ndash;601]\u003c/p\u003e \u003cp\u003eT4: 460 [307\u0026ndash;671]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.0034; 95% CI:\u003c/p\u003e \u003cp\u003e[-0.166 0.138]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrinogen [mg/dL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1:431\u003c/p\u003e \u003cp\u003e[334.8-496.8]\u003c/p\u003e \u003cp\u003eT2: 432\u003c/p\u003e \u003cp\u003e[374-474.5]\u003c/p\u003e \u003cp\u003eT3: 394\u003c/p\u003e \u003cp\u003e[333.5-458.5]\u003c/p\u003e \u003cp\u003eT4: 379 [329\u0026ndash;444]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.51; 95% CI:\u003c/p\u003e \u003cp\u003e[-0.62 -0.398]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-dimer [\u0026micro;g/mL]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1: 1.48 [0.56\u0026ndash;3.57]\u003c/p\u003e \u003cp\u003eT2: 1.94 [1.42\u0026ndash;2.55]\u003c/p\u003e \u003cp\u003eT3: 1.295 [0.95\u0026ndash;2.02]\u003c/p\u003e \u003cp\u003eT4: 1.23 [0.71\u0026ndash;1.94]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18; 95% CI: - [0.29\u0026ndash;0.065]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntithrombin [%]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1:79 [67\u0026ndash;90]\u003c/p\u003e \u003cp\u003eT2: 91 [85\u0026ndash;102]\u003c/p\u003e \u003cp\u003eT3: 94.5 [85-103.75]\u003c/p\u003e \u003cp\u003eT4: 90.5 [80.5\u0026ndash;104]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.22; 95% CI: 0.12 0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor VIII activity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1:266.5 [221-341.8]\u003c/p\u003e \u003cp\u003eT2: 202.5 [170-240.5]\u003c/p\u003e \u003cp\u003eT3: 166 [128\u0026ndash;214]\u003c/p\u003e \u003cp\u003eT4: 182 [135.5\u0026ndash;236]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.42; 95% CI: [-0.58 -0.31]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evWF [%]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1: 252 [165\u0026ndash;341]\u003c/p\u003e \u003cp\u003eT2: 168 [126\u0026ndash;223]\u003c/p\u003e \u003cp\u003eT3: 173.5 [129.2-215.8]\u003c/p\u003e \u003cp\u003eT4: 197.5 [146.8-306.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.22; 95% CI: [-0.38 -0.074]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eKs values did not differ with respect to survival status during follow-up. Regarding to survival within the observation period, differences in Ks significantly improved only in the group of survivors (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) at each timepoint. In contrast, among deceased patients, a significant difference was observed only between T1 and T4 time points.\u003c/p\u003e \u003cp\u003eNo differences were found in Ks values concerning bleedings, MACCE, and NACE (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe Ks values (\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;9\u003c/sup\u003ecm\u003csup\u003e2\u003c/sup\u003e) concerning bleedings, MACCE and NACE, shown median [IQR]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleedings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003epatients with bleedings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003epatients without bleedings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.09 [3.07\u0026ndash;4.57]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.12 [3.05\u0026ndash;4.71]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.88 [3.11\u0026ndash;6.41]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.63 [3.98\u0026ndash;6.12]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.49 [4.05\u0026ndash;6.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.97 [4.73\u0026ndash;7.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.91 [5.6\u0026ndash;7.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.55 [5.86\u0026ndash;8.57]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMACCE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003epatients with MACCE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003epatients without MACCE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.13 [3.05\u0026ndash;5.01]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.98 [3.05\u0026ndash;4.55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.54 [3.75\u0026ndash;7.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.68 [3.93\u0026ndash;6.08]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.36 [3.55\u0026ndash;6.51]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.46 [4.89\u0026ndash;7.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.51 [5.96\u0026ndash;7.93]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.15 [5.68\u0026ndash;8.85]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNACE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003epatients with NACE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003epatients without NACE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.11 [3.05\u0026ndash;4.85]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.13 [3.15\u0026ndash;4.64]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.54 [3.71\u0026ndash;6.97]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.68 [3.94\u0026ndash;6.03]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.49 [4.05\u0026ndash;6.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.12 [4.96\u0026ndash;7.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.14 [5.77\u0026ndash;7.99]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.63 [5.81\u0026ndash;8.89]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatients without MACCE, NACE, and bleedings exhibited significant differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) between all-time points. In the NACE group, differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were only observed between T1 vs. T3, T1 vs. T4, T2 vs. T4 and T3 vs. T4. Among patients with MACCE, differences were significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) only at T1 vs. T4 and T2 vs. T4. Conversely, in patients experiencing bleedings, no differences were observed among these time points.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFibrin clot permeability is a measure of pore size in a fibrin clot. Dense fibers are more resistant to lysis, and some studies suggest that they are associated with adverse cardiovascular events. Our study is the first to demonstrate that in the group of patients with left ventricular assist devices (LVAD) implanted due to advanced heart failure, fibrin clot permeability changes over time.\u003c/p\u003e \u003cp\u003eStudies and available standards present, that in healthy volunteers the Ks is shorter than in patients with adverse cardiovascular events \u003csup\u003e13\u003c/sup\u003e. According to this fact it may be supposed, that the LVAD support may have beneficial effect on clotting hemostasis in patients with end stage heart failure.\u003c/p\u003e \u003cp\u003eIt seems surprising, considering the fact that current generation LVAD devices is still connected with high incidence of ischemic and hemorrhagic strokes \u003csup\u003e21\u003c/sup\u003e. However according to results presented in healthy volunteers, our patients with end stage HF scheduled for LVAD therapy had strongly disturbed clotting hemostasis \u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe demonstrated, based on repeated measures correlation, that in this group of patients, the Ks was connected with known risk factors of thromboembolic complications such as fibrinogen concentration, factor VIII activity, vWF activity, D-dimer, and antithrombin. In our study, we confirmed a moderate negative correlation of Ks with fibrinogen and factor VIII activity and a weak positive correlation with antithrombin. The negative correlation with vVF factor activity can be assessed as a weak. Our results are concordant with patients with type 1 diabetes, where fibrin clot structure was correlated with fibrin concentration. Fibrin clot permeability in this group of patients was correlated with clinical microangiopathy, microalbuminuria and glycemic control defined by HbA1c \u003csup\u003e11\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn previous studies involving patients on vitamin K antagonists with atrial fibrillation, it was shown that patients with lower Ks are more prone to transient ischemic attacks or ischemic strokes \u003csup\u003e22\u003c/sup\u003e. Ks was also found to be valuable in predicting recurrent venous thromboembolic complications \u003csup\u003e11\u003c/sup\u003e. Similarly, reduced fibrin clot permeability on admission in acute pulmonary embolism patients seemed to predict future residual obstruction of pulmonary arteries. The Ks value was significantly lower at baseline and at 6\u0026ndash;7 days after the incident in patients who developed residual pulmonary arteries obstruction. The authors created predictive model based on Ks showing that the baseline Ks level\u0026thinsp;\u0026le;\u0026thinsp;6.55 x 10\u003csup\u003e\u0026minus;\u0026thinsp;9\u003c/sup\u003e had area under the ROC curve of 0.91 in predicting the future residual pulmonary vascular obstruction.\u003c/p\u003e \u003cp\u003eIt was also demonstrated that fibrin clot structure is associated with markers of endothelial injury and liver function. Patients with Fontan circulation had lower Ks values than controls, and a low Ks value was associated with lower levels of protein C, protein S, and albumin. As in the group of LVAD patients the Ks correlated negatively with fibrinogen concentration and factor VIII activity \u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe etiology of heart failure seems to have an important influence on clot structure. In our study, we observed that patients with ischemic etiology and patients with diabetes had shortened baseline Ks. This is concordant with other studies where Ks was negatively correlated with hypo- or hyperglycemia in type 2 diabetes patients \u003csup\u003e24\u003c/sup\u003e. Duration of diabetes exceeding 5 years and HbA1c level over 6.5% in a study comprising 156 consecutive patients with type 2 diabetes was also associated with shortened Ks values \u003csup\u003e25\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn patients diagnosed with atrial fibrillation factors such as age 65\u0026ndash;74 years, presence of heart failure and hypertension was independently associated with lower Ks. In the context of the CHA2DS2-VASc score, the difference between CHA2DS2-VASc scores of 0 and 1 was also linked to a decrease in Ks \u003csup\u003e26\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCross-sectional studies showed that atherosclerotic diseases have an impact on altered fibrin clot structure. Factors such as oxidative stress, chronic inflammation, endothelial dysfunction and increased platelet activation are common pathway for cardiovascular risk factors and clotting disturbances \u003csup\u003e27,28\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite observations from previous studies indicating that interventions influencing cardiovascular risk factors such as administration of statins or ACE inhibitors administration increased the clot permeability \u003csup\u003e29,30\u003c/sup\u003e we did not observe differences based on the heart failure medication. However, our finding might stem from the relatively limited sample size.\u003c/p\u003e \u003cp\u003eOf important value is not only the Ks value itself, which is strongly disturbed at baseline in these HF patients, but also changes in fibrin clot structure may be of significant value for future prognosis. The beneficial changes were clearly visible only in patients without adverse events such as bleeding, MACCE and NACE. Both types of complications, as shown in the literature, are often connected, and bleedings in this group of patients may precede ischemic complications \u003csup\u003e31\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial conflict of interest\u003c/strong\u003e:\u0026nbsp;none declared.\u003c/p\u003e\n\u003cp\u003eThe study was supported by the National Center for Research and Development grant within the quest STRATEGMED as a part of RH ROT (WP 3.7) program.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAK: study design, data analysis, writing of manuscript,\u003c/p\u003e\n\u003cp\u003eMS: statistical analysis, writing of manuscript,\u003c/p\u003e\n\u003cp\u003eBH: writing of manuscript,\u003c/p\u003e\n\u003cp\u003eJK: writing of manuscript,\u003c/p\u003e\n\u003cp\u003eTH writing of manuscript,\u003c/p\u003e\n\u003cp\u003eSP: writing of manuscript,\u003c/p\u003e\n\u003cp\u003ePP acquisition of funding.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Professor Anetta Undas for valuable comments.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMembers AF, McDonagh TA, Metra M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. \u003cem\u003eEur J Heart Fail\u003c/em\u003e. 2022;24(1):4-131. doi:10.1002/ejhf.2333\u003c/li\u003e\n\u003cli\u003eSaeed D, Feldman D, Banayosy AE, et al. The 2023 International Society for Heart and Lung Transplantation Guidelines for Mechanical Circulatory Support: A 10- Year Update. \u003cem\u003eJ Heart Lung Transplant\u003c/em\u003e. 2023;42(7):e1-e222. doi:10.1016/j.healun.2022.12.004\u003c/li\u003e\n\u003cli\u003eVelleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. \u003cem\u003eJ Heart Lung Transplant\u003c/em\u003e. 2023;42(5):e1-e141. doi:10.1016/j.healun.2022.10.015\u003c/li\u003e\n\u003cli\u003eAgeing EURO. Accessed November 15, 2023. https://www.who.int/europe/health-topics/ageing\u003c/li\u003e\n\u003cli\u003eBosch L, Assmann P, de Grauw WJC, Schalk BWM, Biermans MCJ. Heart failure in primary care: prevalence related to age and comorbidity. \u003cem\u003ePrim Health Care Res Dev\u003c/em\u003e. 2019;20:e79. doi:10.1017/S1463423618000889\u003c/li\u003e\n\u003cli\u003eShahreyar M, Bob-Manuel T, Khouzam RN, et al. 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Fibrin clot properties and haemostatic function in men and women with type 1 diabetes. \u003cem\u003eThromb Haemost\u003c/em\u003e. 2015;113(02):312-318. doi:10.1160/TH14-05-0404\u003c/li\u003e\n\u003cli\u003eLim BCB, Ari\u0026euml;ns RAS, Carter AM, Weisel JW, Grant PJ. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. \u003cem\u003eLancet Lond Engl\u003c/em\u003e. 2003;361(9367):1424-1431. doi:10.1016/S0140-6736(03)13135-2\u003c/li\u003e\n\u003cli\u003ePieters M, Undas A, Marchi R, Maat MPMD, Weisel JW, Ari\u0026euml;ns R a. S. An international study on the standardization of fibrin clot permeability measurement: methodological considerations and implications for healthy control values. \u003cem\u003eJ Thromb Haemost\u003c/em\u003e. 2012;10(10):2179-2181. doi:10.1111/j.1538-7836.2012.04883.x\u003c/li\u003e\n\u003cli\u003eLoforte A, Botta L, Boschi S, et al. 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Accessed December 22, 2023. https://www.frontiersin.org/articles/10.3389/fpsyg.2017.00456\u003c/li\u003e\n\u003cli\u003eChiang YP, Cox D, Schroder JN, et al. Stroke risk following implantation of current generation centrifugal flow left ventricular assist devices. \u003cem\u003eJ Card Surg\u003c/em\u003e. 2020;35(2):383-389. doi:10.1111/jocs.14397\u003c/li\u003e\n\u003cli\u003eDrabik L, Wołkow P, Undas A. Fibrin Clot Permeability as a Predictor of Stroke and Bleeding in Anticoagulated Patients With Atrial Fibrillation. \u003cem\u003eStroke\u003c/em\u003e. 2017;48(10):2716-2722. doi:10.1161/STROKEAHA.117.018143\u003c/li\u003e\n\u003cli\u003eSkubera M, Gołąb A, Plicner D, et al. Properties of Plasma Clots in Adult Patients Following Fontan Procedure: Relation to Clot Permeability and Lysis Time\u0026mdash;Multicenter Study. \u003cem\u003eJ Clin Med\u003c/em\u003e. 2021;10(24):5976. doi:10.3390/jcm10245976\u003c/li\u003e\n\u003cli\u003eDunn EJ, Ari\u0026euml;ns R a. S, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. \u003cem\u003eDiabetologia\u003c/em\u003e. 2005;48(6):1198-1206. doi:10.1007/s00125-005-1742-2\u003c/li\u003e\n\u003cli\u003eKonieczynska M, Fil K, Bazanek M, Undas A. Prolonged duration of type 2 diabetes is associated with increased thrombin generation, prothrombotic fibrin clot phenotype and impaired fibrinolysis. \u003cem\u003eThromb Haemost\u003c/em\u003e. 2014;111(4):685-693. doi:10.1160/TH13-07-0566\u003c/li\u003e\n\u003cli\u003eGłowicki B, Matusik PT, Plens K, Undas A. Prothrombotic State in Atrial Fibrillation Patients With One Additional Risk Factor of the CHA2DS2-VASc Score (Beyond Sex). \u003cem\u003eCan J Cardiol\u003c/em\u003e. 2019;35(5):634-643. doi:10.1016/j.cjca.2019.01.014\u003c/li\u003e\n\u003cli\u003eZąbczyk M, Ari\u0026euml;ns RAS, Undas A. Fibrin clot properties in cardiovascular disease: from basic mechanisms to clinical practice. \u003cem\u003eCardiovasc Res\u003c/em\u003e. 2023;119(1):94-111. doi:10.1093/cvr/cvad017\u003c/li\u003e\n\u003cli\u003eZąbczyk M, Natorska J, Undas A. Fibrin Clot Properties in Atherosclerotic Vascular Disease: From Pathophysiology to Clinical Outcomes. \u003cem\u003eJ Clin Med\u003c/em\u003e. 2021;10(13):2999. doi:10.3390/jcm10132999\u003c/li\u003e\n\u003cli\u003eUndas A, Celinska-L\u0026ouml;wenhoff M, L\u0026ouml;wenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. \u003cem\u003eJ Thromb Haemost JTH\u003c/em\u003e. 2006;4(5):1029-1036. doi:10.1111/j.1538-7836.2006.01882.x\u003c/li\u003e\n\u003cli\u003eSiudut J, Ząbczyk M, Wołkow P, Polak M, Undas A, Jawień J. Intensive low-density lipoprotein cholesterol lowering improves fibrin clot properties: Association with lipoproteins and C-reactive protein. \u003cem\u003eVascul Pharmacol\u003c/em\u003e. 2022;144:106977. doi:10.1016/j.vph.2022.106977\u003c/li\u003e\n\u003cli\u003eSzymanski TW, Weeks PA, Patel CJ, et al. Risk of pump thrombosis and stroke in patients with continuous-flow left ventricular assist devices and gastrointestinal bleeding. \u003cem\u003eArtif Organs\u003c/em\u003e. 2020;44(11):1171-1175. doi:10.1111/aor.13751\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"heart failure, left ventricular assist device, fibrin clot permeability, Ks","lastPublishedDoi":"10.21203/rs.3.rs-3954363/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3954363/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePatients on left ventricular assist devices (LVAD) are prone to excessive hemostasis disturbances due to permanent contact of artificial pump surfaces with blood components.\u003c/p\u003e\u003ch2\u003eAims\u003c/h2\u003e \u003cp\u003eWe aimed to investigate if fibrin clot permeability is altered in patients on long-term continuous flow LVAD therapy and if the clot permeability is associated with clinical characteristics and adverse events.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe investigated 85 end-stage heart failure patients (90.6% men, age 48.6\u0026ndash;63.8 years) scheduled for continuous flow long-term LVAD support according to current clinical indications. The patients were assessed periodically: prior to LVAD implantation (T1), 3\u0026ndash;6 months (T2) after LVAD implantation, 6\u0026ndash;12 months after (T3) and then every 6 months. We tested the first three blood samples (T1-T3) and the last available blood sample (T4), but no longer than 5 years after LVAD implantation. We assessed hemostasis parameters changes during the study period.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMACCE occurred in 36.5% patients, bleeding events in 25.9%, NACE in 62.4%; 31.7% patients died, and 17.6% underwent transplantation. We observed a decrease in fibrin clot permeability (Ks) between T1, T2, T3 and T4 time periods; P\u0026thinsp;\u0026lt;\u0026thinsp;0.01 for each comparison. Fibrin clot permeability was negatively correlated with fibrinogen concentration: r\u0026thinsp;=\u0026thinsp;0.51, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, factor VIII activity r=-0.42, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001. Discrepancies in Ks were observed between patients with MACCE, bleeding, and NACE, and patients without adverse events. Ks showed a constant trend towards normalization (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) only in patients without adverse events.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAdverse events such as MACCE, NACE, and bleeding may be associated with inappropriate fibrin clot structure.\u003c/p\u003e","manuscriptTitle":"Fibrin clot permeability (Ks) in patients on left ventricular assist device","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-28 19:03:24","doi":"10.21203/rs.3.rs-3954363/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-19T05:30:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-14T16:06:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-12T11:22:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"16164915416369152821020211721065130314","date":"2024-06-03T13:15:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271046948077702287954526256721207456209","date":"2024-06-03T06:08:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58d21a08-8def-4313-8797-bd35aa57941a","date":"2024-03-27T14:43:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-12T08:01:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"1b8f684f-d7ad-4138-b766-d7c9c470b6cd","date":"2024-03-12T06:52:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-12T04:03:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-12T00:25:38+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-02-25T14:51:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-25T14:49:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-02-13T19:59:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"69a3ef26-57ae-43f0-be70-977b2bcb1b4f","owner":[],"postedDate":"February 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-02T16:02:14+00:00","versionOfRecord":{"articleIdentity":"rs-3954363","link":"https://doi.org/10.1038/s41598-024-69665-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-08-30 15:57:38","publishedOnDateReadable":"August 30th, 2024"},"versionCreatedAt":"2024-02-28 19:03:24","video":"","vorDoi":"10.1038/s41598-024-69665-0","vorDoiUrl":"https://doi.org/10.1038/s41598-024-69665-0","workflowStages":[]},"version":"v1","identity":"rs-3954363","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3954363","identity":"rs-3954363","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}