The relationships between disseminated intravascular coagulation and time series change of von Willebrand factor in patients with out-of-hospital cardiac arrest: a retrospective observational study

The relationships between disseminated intravascular coagulation and time series change of von Willebrand factor in patients with out-of-hospital cardiac arrest: a retrospective observational study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The relationships between disseminated intravascular coagulation and time series change of von Willebrand factor in patients with out-of-hospital cardiac arrest: a retrospective observational study Yuki Itagaki, Yuki Chiba, Misako Suzuki, Mariko Hayamizu, Hisanori Horiuchi, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7604080/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Feb, 2026 Read the published version in Thrombosis Journal → Version 1 posted 9 You are reading this latest preprint version Abstract Background Out-of-hospital cardiac arrest (OHCA) is frequently complicated by disseminated intravascular coagulation (DIC), which is associated with poor outcomes. The von Willebrand factor (VWF) plays a central role in haemostasis, and its multimeric size and activity are regulated by ADAMTS13. In thrombotic thrombocytopenic purpura, decreased ADAMTS13 activity leads to the accumulation of ultralarge VWF multimers and microvascular thrombosis. Elevated VWF antigen (VWF Ag) levels and reduced ADAMTS13 activity have also been observed after OHCAand are correlated with poor outcomes. However, the relationships among VWF activity, VWF multimer size, and ADAMTS13 activity in DIC after OHCA remain unclear. Methods This single-centre retrospective cohort study included adult patients with witnessed cardiogenic OHCA admitted to the Hokkaido University Hospital between September 2019 and January 2023. Patients treated with extracorporeal membrane oxygenation were excluded. Plasma samples were collected from day 0 (upon arrival at the emergency department) to Day4. Plasma VWF antigen (VWF Ag), VWF ristocetin cofactor activity (VWF RCo), VWF large multimer index (VWF LMI), and ADAMTS13 activity were measured, and patients were classified into DIC and non-DIC groups. Temporal changes in these biomarkers were compared between the two groups, and their associations with DIC scores were assessed. Results Among 28 patients with witnessed cardiogenic OHCA, 16 fulfilled the DIC criteria upon admission. VWF-Ag and VWF-RCo were markedly elevated in both groups upon arrival at the emergency department and increased further during the observational period, without significant group differences. The VWF RCo/vWF Ag ratio was decreased in the DIC group. VWF LMI tended to be lower, and ADAMTS13 activity was consistently reduced in the DIC group compared to the non-DIC group. As the DIC score increased, VWF Ag content also increased. Furthermore, the VWF LMI and ADAMTS13 activity decreased as the DIC score increased. Conclusion In patients with OHCA, VWF antigen levels and functional activity are markedly elevated immediately after cardiac arrest. However, despite reduced ADAMTS13 activity in patients with DIC, the VWF multimer size and functional activity did not differ between the DIC and non-DIC groups. Therefore, VWF does not play a major role in platelet activation and DIC pathogenesis in this context and may be cleaved through alternative pathways independent of ADAMTS13. Trial Registration Retrospectively registered. out-of-hospital cardiac arrest Von Willebrand factor ADAMTS13 Figures Figure 1 Figure 2 Figure 3 Background Out-of-hospital cardiac arrest (OHCA) is a major cause of mortality worldwide [ 1 ]. Ischaemia-reperfusion injury following cardiac arrest induces systemic inflammation and coagulopathy, including disseminated intravascular coagulation (DIC) [ 2 ]. DIC is defined by widespread activation of coagulation pathways, leading to microvascular thrombosis and multi-organ dysfunction. Elevated DIC scores shortly after OHCA have been associated with worse neurological outcomes and increased early mortality [ 3 , 4 ]. Von Willebrand factor (VWF) is a multimeric glycoprotein synthesised and stored in vascular endothelial cells and released in response to physiological and pathological stimuli such as sepsis or trauma [ 5 , 6 ]. VWF plays a central role in haemostasis by facilitating platelet adhesion at sites of vascular injury [ 5 ]. Consequently, elevated plasma VWF levels are frequently observed in critically ill patients. VWF multimers are cleaved by the metalloprotease A disintegrin-like metalloproteinase with thrombospondin type I motif 13 (ADAMTS13), which regulates their size and activity. Larger multimers exhibit greater platelet-binding capacity and stronger procoagulant activity [ 7 ]. A significant decrease in ADAMTS13 activity has been reported [ 8 , 9 ]. ADAMTS13 deficiency impairs VWF cleavage, leading to accumulation of ultra-large VWF multimers in the circulation [ 9 ]. These multimers bind to platelet glycoprotein Ib-IX-V complex and promote platelet aggregation [ 6 , 10 ]. Thus, ultra-large VWF multimers promote widespread microvascular thrombosis, causing organ ischaemia and infarction that may manifest as neurological dysfunction, renal impairment, or cutaneous hemorrhage [ 11 ]. Several biomarkers have been reported as prognostic indicators of neurological outcomes after OHCA. Previous studies demonstrated that VWF antigen (VWF-Ag) levels exceed the normal range following cardiac arrest [ 12 ] and correlate with poor neurological outcomes after resuscitation [ 13 ]. Decreased ADAMTS13 activity has also been observed in OHCA patients and correlated with poor outcomes [ 14 ]. We hypothesise that increased VWF Ag and decreased ADAMTS13 activity induce enlargement of the VWF multimer, similar to that observed in thrombotic thrombocytopenic purpura (TTP), which may enhance VWF activity and contribute to platelet activation and DIC after OHCA. Furthermore, DIC has been reported to be associated with poor outcomes in patients with OHCA [ 15 ]. However, no studies have investigated the relationships between VWF activity, VWF multimer size, and ADAMTS13 activity in the context of DIC after OHCA. To address this gap, we conducted a single-centre observational study to characterise the temporal dynamics of VWF-related markers and ADAMTS13 activity during the acute phase after witnessed cardiogenic OHCA, with particular focus on their association with DIC status. Methods Setting This single-centre retrospective cohort study investigated the relationship between VWF-related markers and ADAMTS13 activity in patients with OHCA admitted to the Emergency and Critical Care Centre at Hokkaido University Hospital between September 2019 and January 2023 [ 16 ]. This study was approved by the Institutional Review Board of Hokkaido University Hospital (approval number: 022–0122) and conducted in accordance with the Declaration of Helsinki. Inclusion criteria were cardiac aetiology, witnessed cardiac arrest, and age > 18 years. Patients treated by extracorporeal membrane oxygenation were excluded, as this intervention affects VWF multimer size. The need for written informed consent was waived due to the retrospective design. Laboratory measurements and data collection Plasma samples were collected from day 0 (on arrival at emergency department) to day 4 and stored at − 80℃ until analysis. VWF ristocetin cofactor activity (VWF RCo) was measured using BC Von Willebrand Reagent® (Siemens Healthcare Diagnostics, Marburg, Germany) [ 17 ], and VWF antigen (VWF Ag) using VWF Ag Reagent® (Siemens Healthcare Diagnostics)[ 18 ]. All assays were performed using an automated coagulation analyzer CN-6000™ (Sysmex, Kobe, Japan) according to the manufacturer instructions. ADAMTS13 activity was measured using the ADAMTS13-act ELISA KINOS (KAINOS Laboratories, Inc., Tokyo, Japan) according to the manufacturer’s instructions. The VWF multimer assay was performed using 1.0% agarose gel electrophoresis. Equal amounts of VWF Ag from each sample were analysed under non-reducing conditions by western blotting with a primary anti-VWF antibody (DAKO, Glostrup, Denmark). Multimer bands were categorised as small (5th band to bottom), medium (6th − 10th ), or large (11th or above). Quantitative evaluation of large VWF multimers was performed by densitometry (ImageJ, NIH, USA). The VWF large multimer ratio was defined as the proportion of large multimer bands to total multimer bands. The VWF large multimer index (VWF LMI) was calculated as the ratio of the patient’s large multimer ratio to that of the control (Siemens Standard Plasma) [ 19 – 21 ]. Clinical Data Collection Demographic and clinical data, including conventional laboratory parameters, were retrospectively collected from electronic medical records and prehospital emergency service reports. Definition of DIC DIC was defined using the modified diagnostic criteria of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria [ 22 ]. Ptients were classified into the DIC and non-DIC groups based on whether they met these criteria upon admission to the emergency department. Statistical analysis Linearised mixed models were used to evaluate time-dependent changes in coagulation markers, including VWF Ag, VWF RCo, VWF RCo/VWF Ag ratio, VWF LMI, and ADAMTS13 activity. Each model included fixed effects for DIC status, days since hospital admission (categorical, days 0–4), and their interaction, with a random intercept for each patient to account for repeated measures. To evaluate monotonic trends in biomarker levels across increasing DIC scores, the Jonckheere–Terpstra test was applied for ordered independent groups. All statistical analyses were performed using R version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Two-tailed p-values were reported and statistical significance was defined as P < 0.05. Results A total of 28 patients with witnessed cardiogenic OHCA were enrolled. Of these, 16 met the DIC diagnostic criteria upon arrival at the ED and were assigned to the DIC group, while the remaining 12 patients formed the non-DIC group. Baseline characteristics are summarized in Table 1 (Characteristics of the patients of DIC group and None-DIC group). Patients in the DIC group were older and had higher body mass index (BMI). Although they showed longer low-flow times, received higher doses of adrenaline (both pre- and in-hospital), and had higher mortality rates, these differences were not statistically significant. Similarly, pH and lactate levels, indicators of systemic hypoperfusion, did not differ significantly between the two groups. Temporal trends in VWF-related markers in the DIC and non-DIC groups are shown in Figures 1 and 2. Von Willebrand factor antigen (VWF Ag) VWF Ag levels were markedly elevated in both groups (normal range: 50–155%). In both groups, levels increased further during the observation period (P = 0.007), but there was no significant group difference (P = 0.362) or time-group interaction (P = 0.665). Von Willebrand factor r istocetin cofactor activity (VWF RCo) VWF RCo levels were also elevated by approximately 150% in both groups (normal range: 50–150%). No significant group differences were observed (P = 0.378), although modest time-dependent changes were detected (P = 0.016 ). Von Willebrand factor r istocetin cofactor activity to von Willebrand factor antigen ratio (VWF RCo/ VWF Ag) The VWF RCo/vWF Ag ratio remained stable over time in both groups (normal range: 0.7). However, the DIC group showed declining trend compared to the non-DIC group, with significant time-group interaction (P = 0.004). Overall levels did not differ significantly between groups (P = 0.837). Von Willebrand factor large multimer index (VWF LMI) The VWF LMI tended to be lower in the DIC group than in the non-DIC group (normal range: 80%) throughout the observation period, with a significant time-group interaction (P = 0.027), despite no overall difference between the groups (P = 0.888). ADAMTS13 The median ADAMTS13 activity was consistently lower in the DIC group than in the non-DIC group throughout the observation period (normal range: 0.5-1.5 IU/mL). The group effect was statistically significant (P = 0.003), indicating persistently reduced ADAMTS13 activity in DIC patients. Figure 3 shows the association between DIC score and VWF-related markers. As the DIC score increased, VWF Ag also increased (P = 0.006). Furthermore, VWD LMI and ADAMTS13 activity decreased as DIC score increased (P = 0.001 and <0.001, respectively). However, VWF RCo was not associated with an increase in DIC score (P = 0.794). Discussion In this study, ADAMTS13 activity was lower in the DIC group than in the non-DIC group, whereas VWF LMI was also reduced in the DIC group. VWF antigen and VWF RCo levels did not differ between groups during the observation period. Notably, despite reduced ADAMTS13 activity in patients with DIC, VWF LMI was paradoxically decreased, suggesting that VWF multimers were cleaved. As illustrated in Fig. 3 , both LMI and ADAMTS13 activity decreased with increasing DIC score. These findings suggest that VWF and ADAMTS13 may not play major roles in the pathogenesis of DIC after OHCA. Instead, VWF may be cleaved by proteases other than ADAMTS13. Although ADAMTS13 activity was reduced in DIC patients, the expected accumulation of large VWF multimers was not observed. This discrepancy suggests that ADAMTS13 deficiency alone does not fully regulate VWF multimer size. Alternative mechanisms, such as cleavage by plasmin or neutrophil elastase, may contribute to VWF degradation independently of ADAMTS13 [ 23 – 25 ]. Levels of these proteases increase following whole-body ischaemia-reperfusion injury, such as cardiac arrest, potentially contributing to VWF degradation [ 25 , 26 ]. Furthermore, plasmin and neutrophil elastase levels are particularly elevated in OHCA patients with DIC [ 25 ]. It is therefore plausible that VWF cleavage via plasmin or neutrophil elastase compensates for reduced ADAMTS13 activity, leading to lower-than-expected VWF multimer size. Further studies are warranted to clarify the relative contributions of these mechanisms to VWF regulation. We initially speculated that platelet activation via VWF may contribute to the development of DIC [ 27 ]. In this cohort, VWF antigen and VWF RCo levels were markedly elevated above the normal range in both DIC and non-DIC groups. However, despite lower ADAMTS13 activity in DIC group, neither VWF RCo nor LMI differed between the two groups. These findings suggest that dynamic changes in VWF do not play a major role in the occurrence of DIC in OHCA patients. This study has several limitations. First, this was a single-centre, retrospective observational study. Second, the sample size was small, although patients with cardiogenic OHCA studied for VWF and ADAMTS13 remain rare. Third, biomarker measurements were limited to the first 5 days after admission. Conclusion In patients with OHCA, VWF antigen levels and functional activity were markedly elevated immediately after cardiac arrest. However, despite reduced ADAMTS13 activity in patients with DIC, VWF multimer size and functional activity did not differ between the DIC and non-DIC groups. These findings suggest that VWF does not play a major role in DIC pathogenesis in this setting and may instead be cleaved through alternative pathways independent of ADAMTS13. Abbreviations OHCA; out-of-hospital cardiac arrest, DIC; disseminated intravascular coagulation, VWF; von Willebrand factor, FⅧ; Factor Ⅷ, PT-INR; the international normalised ratio of PT, ADAMTS13; a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, VWF RCo; von Willebrand factor ristocetin cofactor activity, RCoAg; von Willebrand factor Ristocetin Cofactor Antigen, VWF Ag; von Willebrand factor antigen, Rco/VWF Ag; Ristocetin cofactor to von Willebrand factor antigen ratio, VWF LMI; Von Willebrand factor large multimer index Declarations Availability of data and materials The data supporting the findings of this study are available from the corresponding author, on reasonable request. Acknowledgment A part of this study was supported by Sysmex Corporation. We would like to thank Editage (www. editage. com) for English language editing. Author contribution Hayakawa M was guarantor and contributed to the conception of the study. The manuscript was drafted by YI and revised by Hayamizu M, YC, and Hayakawa M. YC collected the clinical data. MS and HH performed measurements related to VWF-related parameters. All authors read and approved the final manuscript. Funding Not applicable. Human Ethics and Consent to Participate declarations Not applicable. Ethics approval and consent to participate This study was approved by the Institutional Review Boards of the Ethics Committees of Hokkaido University Hospital (approval number: 022–0122). The study was conducted following the Helsinki Declaration, and the need for additional written informed consent was waived because of the retrospective design. Consent for publication Not applicable. Conflict of interest The authors declare no conflict of interest. References Berdowski J, Berg RA, Tijssen JG, Koster RW: Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies . Resuscitation 2010, 81 (11):1479-1487. 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Tati R, Kristoffersson AC, Manea Hedstrom M, Morgelin M, Wieslander J, van Kooten C, Karpman D: Neutrophil Protease Cleavage of Von Willebrand Factor in Glomeruli - An Anti-thrombotic Mechanism in the Kidney . EBioMedicine 2017, 16 :302-311. van der Vorm LN, Remijn JA, de Laat B, Huskens D: Effects of Plasmin on von Willebrand Factor and Platelets: A Narrative Review . TH Open 2018, 2 (2):e218-e228. Wada T, Gando S, Mizugaki A, Yanagida Y, Jesmin S, Yokota H, Ieko M: Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome--fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction . Thromb Res 2013, 132 (1):e64-69. Gando S, Nanzaki, S., Morimoto, Y. et al.: Out-of-hospital cardiac arrest increases soluble vascular endothelial adhesion molecules and neutrophil elastase associated with endothelial injury. Intensive Care Med 2000, 26, 38–44 . Schwameis M, Schorgenhofer C, Assinger A, Steiner MM, Jilma B: VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP . Thromb Haemost 2015, 113 (4):708-718. Table Table 1 is available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Table202508.xlsx Cite Share Download PDF Status: Published Journal Publication published 14 Feb, 2026 Read the published version in Thrombosis Journal → Version 1 posted Editorial decision: Revision requested 10 Nov, 2025 Reviews received at journal 10 Nov, 2025 Reviewers agreed at journal 21 Oct, 2025 Reviews received at journal 09 Oct, 2025 Reviewers agreed at journal 24 Sep, 2025 Reviewers invited by journal 24 Sep, 2025 Editor assigned by journal 22 Sep, 2025 Submission checks completed at journal 22 Sep, 2025 First submitted to journal 12 Sep, 2025 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-7604080","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":524776646,"identity":"9a7758c3-baa2-4f42-8c8d-790d374bf00d","order_by":0,"name":"Yuki Itagaki","email":"","orcid":"","institution":"Hokkaido University Hospital, Hokkaido University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Itagaki","suffix":""},{"id":524776648,"identity":"c63fabe4-16cd-45e2-be3a-bf0c2c561d32","order_by":1,"name":"Yuki Chiba","email":"","orcid":"","institution":"Hokkaido University 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07:32:17","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":78835,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7604080/v1/902a2ba1d090cf452c82cf86.html"},{"id":93013248,"identity":"45609877-24cf-44d4-ae1c-68d68770b7b9","added_by":"auto","created_at":"2025-10-08 07:24:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85338,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTemporal changes in VWF-related markers in DIC and non-DIC groups.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBox plots show the levels of (A) VWF antigen (vWF Ag), (B) VWF ristocetin cofactor activity (VWF RCo), (C) VWF RCo to VWF Ag ratio (VWF RCo/VWF Ag) from Day 0 (on arrival at emergency department) to Day 4 in patients with and without disseminated intravascular coagulation (DIC).\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-7604080/v1/7de04ac25454687973671153.png"},{"id":93013896,"identity":"46be9018-bed3-458b-8611-f3a359aec80a","added_by":"auto","created_at":"2025-10-08 07:32:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57474,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTemporal changes in VWF large multimer index and \u003c/strong\u003eADAMTS13\u003cstrong\u003ein DIC and non-DIC groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBox plots show the levels of (A) \u003cstrong\u003eVWF large multimer index (VWF LMI)\u003c/strong\u003e, (B) ADAMTS13 activity from Day 0 (on arrival at emergency department) to Day 4 in patients with and without disseminated intravascular coagulation (DIC).\u003c/p\u003e\n\u003cp\u003eADAMTS13, A disintegrin-like and metalloproteinase with thrombospondin type Ⅰ motifs 13\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-7604080/v1/83b1ee49499040b05edb67f8.png"},{"id":93013244,"identity":"1390bb2f-1cad-4528-bfb2-00d2df5d0af7","added_by":"auto","created_at":"2025-10-08 07:24:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":74010,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation between DIC score and VWF-related markers. \u003c/strong\u003eBox plots display levels of (A) VWF antigen (VWF Ag), (B) VWF ristocetin cofactor activity (VWF Rco), (C) VWF large multimer index (VWF LMI), and (D) ADAMTS13 activity across increasing disseminated intravascular coagulation (DIC) scores.\u003c/p\u003e\n\u003cp\u003eADAMTS13, A disintegrin-like and metalloproteinase with thrombospondin type Ⅰ motifs 13.\u003c/p\u003e\n\u003cp\u003eAs no patient had a DIC score of 6 and one patient had a score of 7, we consolidated score of 5 or higher into a single category for statistical analysis. The data include all patients in the cohort.\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-7604080/v1/dc646148a859aa00248369c1.png"},{"id":102785823,"identity":"1eb9ca26-a15d-425d-bf82-8a1e4e98414b","added_by":"auto","created_at":"2026-02-16 16:10:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2070285,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7604080/v1/91db564c-1b8d-4d11-9205-93a055d09b47.pdf"},{"id":93013245,"identity":"a423b945-3f65-4969-acb7-1ac93d2e93d9","added_by":"auto","created_at":"2025-10-08 07:24:16","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13848,"visible":true,"origin":"","legend":"","description":"","filename":"Table202508.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7604080/v1/cb12c42240673bd0bc8c177a.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The relationships between disseminated intravascular coagulation and time series change of von Willebrand factor in patients with out-of-hospital cardiac arrest: a retrospective observational study","fulltext":[{"header":"Background","content":"\u003cp\u003eOut-of-hospital cardiac arrest (OHCA) is a major cause of mortality worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Ischaemia-reperfusion injury following cardiac arrest induces systemic inflammation and coagulopathy, including disseminated intravascular coagulation (DIC) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. DIC is defined by widespread activation of coagulation pathways, leading to microvascular thrombosis and multi-organ dysfunction. Elevated DIC scores shortly after OHCA have been associated with worse neurological outcomes and increased early mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eVon Willebrand factor (VWF) is a multimeric glycoprotein synthesised and stored in vascular endothelial cells and released in response to physiological and pathological stimuli such as sepsis or trauma [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. VWF plays a central role in haemostasis by facilitating platelet adhesion at sites of vascular injury [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Consequently, elevated plasma VWF levels are frequently observed in critically ill patients. VWF multimers are cleaved by the metalloprotease A disintegrin-like metalloproteinase with thrombospondin type I motif 13 (ADAMTS13), which regulates their size and activity. Larger multimers exhibit greater platelet-binding capacity and stronger procoagulant activity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA significant decrease in ADAMTS13 activity has been reported [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. ADAMTS13 deficiency impairs VWF cleavage, leading to accumulation of ultra-large VWF multimers in the circulation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These multimers bind to platelet glycoprotein Ib-IX-V complex and promote platelet aggregation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Thus, ultra-large VWF multimers promote widespread microvascular thrombosis, causing organ ischaemia and infarction that may manifest as neurological dysfunction, renal impairment, or cutaneous hemorrhage [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral biomarkers have been reported as prognostic indicators of neurological outcomes after OHCA. Previous studies demonstrated that VWF antigen (VWF-Ag) levels exceed the normal range following cardiac arrest [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and correlate with poor neurological outcomes after resuscitation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Decreased ADAMTS13 activity has also been observed in OHCA patients and correlated with poor outcomes [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. We hypothesise that increased VWF Ag and decreased ADAMTS13 activity induce enlargement of the VWF multimer, similar to that observed in thrombotic thrombocytopenic purpura (TTP), which may enhance VWF activity and contribute to platelet activation and DIC after OHCA. Furthermore, DIC has been reported to be associated with poor outcomes in patients with OHCA [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, no studies have investigated the relationships between VWF activity, VWF multimer size, and ADAMTS13 activity in the context of DIC after OHCA.\u003c/p\u003e\u003cp\u003eTo address this gap, we conducted a single-centre observational study to characterise the temporal dynamics of VWF-related markers and ADAMTS13 activity during the acute phase after witnessed cardiogenic OHCA, with particular focus on their association with DIC status.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSetting\u003c/h2\u003e\u003cp\u003eThis single-centre retrospective cohort study investigated the relationship between VWF-related markers and ADAMTS13 activity in patients with OHCA admitted to the Emergency and Critical Care Centre at Hokkaido University Hospital between September 2019 and January 2023 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This study was approved by the Institutional Review Board of Hokkaido University Hospital (approval number: 022\u0026ndash;0122) and conducted in accordance with the Declaration of Helsinki. Inclusion criteria were cardiac aetiology, witnessed cardiac arrest, and age\u0026thinsp;\u0026gt;\u0026thinsp;18 years. Patients treated by extracorporeal membrane oxygenation were excluded, as this intervention affects VWF multimer size. The need for written informed consent was waived due to the retrospective design.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eLaboratory measurements and data collection\u003c/h3\u003e\n\u003cp\u003ePlasma samples were collected from day 0 (on arrival at emergency department) to day 4 and stored at \u0026minus;\u0026thinsp;80℃ until analysis. VWF ristocetin cofactor activity (VWF RCo) was measured using BC Von Willebrand Reagent\u0026reg; (Siemens Healthcare Diagnostics, Marburg, Germany) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and VWF antigen (VWF Ag) using VWF Ag Reagent\u0026reg; (Siemens Healthcare Diagnostics)[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. All assays were performed using an automated coagulation analyzer CN-6000\u0026trade; (Sysmex, Kobe, Japan) according to the manufacturer instructions. ADAMTS13 activity was measured using the ADAMTS13-act ELISA KINOS (KAINOS Laboratories, Inc., Tokyo, Japan) according to the manufacturer\u0026rsquo;s instructions.\u003c/p\u003e\u003cp\u003eThe VWF multimer assay was performed using 1.0% agarose gel electrophoresis. Equal amounts of VWF Ag from each sample were analysed under non-reducing conditions by western blotting with a primary anti-VWF antibody (DAKO, Glostrup, Denmark). Multimer bands were categorised as small (5th band to bottom), medium (6th \u0026minus;\u0026thinsp;10th ), or large (11th or above). Quantitative evaluation of large VWF multimers was performed by densitometry (ImageJ, NIH, USA). The VWF large multimer ratio was defined as the proportion of large multimer bands to total multimer bands. The VWF large multimer index (VWF LMI) was calculated as the ratio of the patient\u0026rsquo;s large multimer ratio to that of the control (Siemens Standard Plasma) [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eClinical Data Collection\u003c/h3\u003e\n\u003cp\u003eDemographic and clinical data, including conventional laboratory parameters, were retrospectively collected from electronic medical records and prehospital emergency service reports.\u003c/p\u003e\n\u003ch3\u003eDefinition of DIC\u003c/h3\u003e\n\u003cp\u003eDIC was defined using the modified diagnostic criteria of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Ptients were classified into the DIC and non-DIC groups based on whether they met these criteria upon admission to the emergency department.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eLinearised mixed models were used to evaluate time-dependent changes in coagulation markers, including VWF Ag, VWF RCo, VWF RCo/VWF Ag ratio, VWF LMI, and ADAMTS13 activity. Each model included fixed effects for DIC status, days since hospital admission (categorical, days 0\u0026ndash;4), and their interaction, with a random intercept for each patient to account for repeated measures. To evaluate monotonic trends in biomarker levels across increasing DIC scores, the Jonckheere\u0026ndash;Terpstra test was applied for ordered independent groups.\u003c/p\u003e\u003cp\u003eAll statistical analyses were performed using R version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Two-tailed p-values were reported and statistical significance was defined as P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 28 patients with witnessed cardiogenic OHCA were enrolled. Of these, 16 met the DIC diagnostic criteria upon arrival at the ED and were assigned to the DIC group, while the remaining 12 patients formed the non-DIC group. Baseline characteristics are summarized in Table 1 (Characteristics of the patients of DIC group and None-DIC group). Patients in the DIC group were older and had higher body mass index (BMI). Although they showed longer low-flow times, received higher doses of adrenaline (both pre- and in-hospital), and had higher mortality rates, these differences were not statistically significant. Similarly, pH and lactate levels, indicators of systemic hypoperfusion,\u0026nbsp;did not differ significantly between the two groups. Temporal trends\u0026nbsp;in\u0026nbsp;VWF-related markers in\u0026nbsp;the\u0026nbsp;DIC and non-DIC groups\u0026nbsp;are\u0026nbsp;shown\u0026nbsp;in Figures 1 and 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVon Willebrand factor antigen (VWF Ag)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eVWF Ag levels were markedly elevated in both groups (normal range: 50–155%). In both groups, levels increased further during the observation period (P = 0.007), but there was no significant group difference (P = 0.362) or time-group interaction (P = 0.665).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVon Willebrand factor r\u003c/em\u003e\u003cem\u003eistocetin cofactor activity\u0026nbsp;(VWF RCo)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eVWF RCo levels were also elevated by approximately 150% in both groups (normal range: 50–150%). No significant group differences were observed (P = 0.378), although modest\u0026nbsp;time-dependent changes were detected (P = 0.016\u0026nbsp;).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVon Willebrand factor r\u003c/em\u003e\u003cem\u003eistocetin cofactor activity to von Willebrand factor antigen ratio (VWF RCo/ VWF Ag)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe VWF RCo/vWF Ag ratio remained stable over time in both groups (normal range: 0.7). However, the DIC group showed declining trend compared to the non-DIC group, with significant time-group interaction (P = 0.004). Overall levels did not differ significantly between groups (P = 0.837).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVon Willebrand factor large multimer index (VWF LMI)\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe VWF LMI tended to be lower in the DIC group than in the non-DIC group (normal range: 80%) throughout the observation period, with a significant time-group interaction (P = 0.027), despite no overall difference between the groups (P = 0.888).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eADAMTS13\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe median ADAMTS13 activity was consistently lower in the DIC group than in the non-DIC group throughout the observation period (normal range: 0.5-1.5 IU/mL). The group effect was statistically significant (P = 0.003), indicating persistently reduced ADAMTS13 activity in DIC patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure 3 shows the\u0026nbsp;\u003cstrong\u003eassociation between\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eDIC score and\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;VWF-related markers.\u003c/strong\u003e As the DIC score increased, VWF Ag also increased (P = 0.006). Furthermore, VWD LMI and ADAMTS13 activity decreased as DIC score increased (P = 0.001 and \u0026lt;0.001, respectively). However, VWF RCo was not associated with an increase in DIC score (P = 0.794).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, ADAMTS13 activity was lower in the DIC group than in the non-DIC group, whereas VWF LMI was also reduced in the DIC group. VWF antigen and VWF RCo levels did not differ between groups during the observation period. Notably, despite reduced ADAMTS13 activity in patients with DIC, VWF LMI was paradoxically decreased, suggesting that VWF multimers were cleaved. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, both LMI and ADAMTS13 activity decreased with increasing DIC score. These findings suggest that VWF and ADAMTS13 may not play major roles in the pathogenesis of DIC after OHCA. Instead, VWF may be cleaved by proteases other than ADAMTS13.\u003c/p\u003e\u003cp\u003eAlthough ADAMTS13 activity was reduced in DIC patients, the expected accumulation of large VWF multimers was not observed. This discrepancy suggests that ADAMTS13 deficiency alone does not fully regulate VWF multimer size. Alternative mechanisms, such as cleavage by plasmin or neutrophil elastase, may contribute to VWF degradation independently of ADAMTS13 [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Levels of these proteases increase following whole-body ischaemia-reperfusion injury, such as cardiac arrest, potentially contributing to VWF degradation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Furthermore, plasmin and neutrophil elastase levels are particularly elevated in OHCA patients with DIC [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. It is therefore plausible that VWF cleavage via plasmin or neutrophil elastase compensates for reduced ADAMTS13 activity, leading to lower-than-expected VWF multimer size. Further studies are warranted to clarify the relative contributions of these mechanisms to VWF regulation.\u003c/p\u003e\u003cp\u003eWe initially speculated that platelet activation via VWF may contribute to the development of DIC [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In this cohort, VWF antigen and VWF RCo levels were markedly elevated above the normal range in both DIC and non-DIC groups. However, despite lower ADAMTS13 activity in DIC group, neither VWF RCo nor LMI differed between the two groups. These findings suggest that dynamic changes in VWF do not play a major role in the occurrence of DIC in OHCA patients.\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, this was a single-centre, retrospective observational study. Second, the sample size was small, although patients with cardiogenic OHCA studied for VWF and ADAMTS13 remain rare. Third, biomarker measurements were limited to the first 5 days after admission.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with OHCA, VWF antigen levels and functional activity were markedly elevated immediately after cardiac arrest. However, despite reduced ADAMTS13 activity in patients with DIC, VWF multimer size and functional activity did not differ between the DIC and non-DIC groups. These findings suggest that VWF does not play a major role in DIC pathogenesis in this setting and may instead be cleaved through alternative pathways independent of ADAMTS13.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eOHCA; out-of-hospital cardiac arrest, DIC; disseminated intravascular coagulation, VWF; von Willebrand factor, FⅧ; Factor Ⅷ, PT-INR; the international normalised ratio of PT, ADAMTS13; a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, VWF RCo; von Willebrand factor ristocetin cofactor activity, RCoAg; von Willebrand factor Ristocetin Cofactor Antigen, VWF Ag; von Willebrand factor antigen, Rco/VWF Ag; Ristocetin cofactor to von Willebrand factor antigen ratio, VWF LMI; Von Willebrand factor large multimer index\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author, on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA part of this study was supported by Sysmex Corporation. We would like to thank Editage (www. editage. com) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHayakawa M was guarantor and contributed to the conception of the study. The manuscript was drafted by YI and revised by Hayamizu M, YC, and Hayakawa M. YC collected the clinical data. MS and HH performed measurements related to VWF-related parameters. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Boards of the Ethics Committees of Hokkaido University Hospital (approval number:\u0026nbsp; 022–0122). The study was conducted following the Helsinki Declaration, and the need for additional written informed consent was waived because of the retrospective design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBerdowski J, Berg RA, Tijssen JG, Koster RW: \u003cstrong\u003eGlobal incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies\u003c/strong\u003e. \u003cem\u003eResuscitation \u003c/em\u003e2010, \u003cstrong\u003e81\u003c/strong\u003e(11):1479-1487.\u003c/li\u003e\n\u003cli\u003eGando S, Wada T: \u003cstrong\u003eDisseminated intravascular coagulation in cardiac arrest and resuscitation\u003c/strong\u003e. 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platelet hyperfunction in patients with cardiac arrest achieving restoration of spontaneous circulation\u003c/strong\u003e. \u003cem\u003eCrit Care Med \u003c/em\u003e2009, \u003cstrong\u003e37\u003c/strong\u003e(3):975-979.\u003c/li\u003e\n\u003cli\u003eGeppert A, Zorn G, Delle-Karth G, Koreny M, Siostrzonek P, Heinz G, Huber K: \u003cstrong\u003ePlasma concentrations of von Willebrand factor and intracellular adhesion molecule-1 for prediction of outcome after successful cardiopulmonary resuscitation\u003c/strong\u003e. \u003cem\u003eCrit Care Med \u003c/em\u003e2003, \u003cstrong\u003e31\u003c/strong\u003e(3):805-811.\u003c/li\u003e\n\u003cli\u003eOhbe H, Kudo D, Yamanouchi S, Kushimoto S: \u003cstrong\u003eDecreased a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 activity and neurologic outcome in patients with successful resuscitation of out-of-hospital cardiac arrest: A prospective observational study\u003c/strong\u003e. \u003cem\u003eJ Crit Care \u003c/em\u003e2017, \u003cstrong\u003e37\u003c/strong\u003e:13-18.\u003c/li\u003e\n\u003cli\u003eWada T, Gando S, Ono Y, Maekawa K, Katabami K, Hayakawa M, Sawamura A: \u003cstrong\u003eDisseminated intravascular coagulation with the fibrinolytic phenotype predicts the outcome of patients with out-of-hospital cardiac arrest\u003c/strong\u003e. \u003cem\u003eThromb J \u003c/em\u003e2016, \u003cstrong\u003e14\u003c/strong\u003e:43.\u003c/li\u003e\n\u003cli\u003eChiba Y, Goto K, Suzuki M, Horiuchi H, Hayakawa M: \u003cstrong\u003eImpact of extracorporeal membrane oxygenation treatments on acquired von Willebrand syndrome in patients with out-of-hospital cardiac arrest: a retrospective observational study\u003c/strong\u003e. \u003cem\u003eThromb J \u003c/em\u003e2024, \u003cstrong\u003e22\u003c/strong\u003e(1):46.\u003c/li\u003e\n\u003cli\u003eMohammed S FE: \u003cstrong\u003eLaboratory Testing for Von Willebrand factor Ristocetin Cofactor (VWF:RCo). \u003c/strong\u003e. \u003cem\u003eMethods Mol Biol \u003c/em\u003e2017, \u003cstrong\u003e1646:435\u0026ndash;51.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003eFavaloro EJ MS, Patzke J.: \u003cstrong\u003eLaboratory Testing for Von Willebrand Factor Antigen (VWF:Ag).\u003c/strong\u003e \u003cem\u003eMethods Mol Biol \u003c/em\u003e2017, \u003cstrong\u003e1646\u003c/strong\u003e:1646:1403\u0026ndash;1616.\u003c/li\u003e\n\u003cli\u003eTamura T HH, Imai M, Tada T, Shiomi H, Kuroda M, et al.: \u003cstrong\u003eUnexpectedly high prevalence of acquired von Willebrand syndrome in patients with severe aortic stenosis as evaluated with a novel large multimer index.\u003c/strong\u003e \u003cem\u003eJournal of Atherosclerosis and Thrombosis \u003c/em\u003e2015, \u003cstrong\u003e22.11 (2015): 1115-1123.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003eSakatsume K, Saito K, Akiyama M, Sasaki K, Kawatsu S, Takahashi G, Adachi O, Kawamoto S, Horiuchi H, Saiki Y: \u003cstrong\u003eAssociation between the severity of acquired von Willebrand syndrome and gastrointestinal bleeding after continuous-flow left ventricular assist device implantation\u003c/strong\u003e. \u003cem\u003eEur J Cardiothorac Surg \u003c/em\u003e2018, \u003cstrong\u003e54\u003c/strong\u003e(5):841-846.\u003c/li\u003e\n\u003cli\u003eHoriuchi H, Doman T, Kokame K, Saiki Y, Matsumoto M: \u003cstrong\u003eAcquired von Willebrand Syndrome Associated with Cardiovascular Diseases\u003c/strong\u003e. \u003cem\u003eJ Atheroscler Thromb \u003c/em\u003e2019, \u003cstrong\u003e26\u003c/strong\u003e(4):303-314.\u003c/li\u003e\n\u003cli\u003eYamakawa K, Umemura Y, Mochizuki K, Matsuoka T, Wada T, Hayakawa M, Iba T, Ohtomo Y, Okamoto K, Mayumi T\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eProposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis\u003c/strong\u003e. \u003cem\u003eThromb Haemost \u003c/em\u003e2024.\u003c/li\u003e\n\u003cli\u003eTati R, Kristoffersson AC, Manea Hedstrom M, Morgelin M, Wieslander J, van Kooten C, Karpman D: \u003cstrong\u003eNeutrophil Protease Cleavage of Von Willebrand Factor in Glomeruli - An Anti-thrombotic Mechanism in the Kidney\u003c/strong\u003e. \u003cem\u003eEBioMedicine \u003c/em\u003e2017, \u003cstrong\u003e16\u003c/strong\u003e:302-311.\u003c/li\u003e\n\u003cli\u003evan der Vorm LN, Remijn JA, de Laat B, Huskens D: \u003cstrong\u003eEffects of Plasmin on von Willebrand Factor and Platelets: A Narrative Review\u003c/strong\u003e. \u003cem\u003eTH Open \u003c/em\u003e2018, \u003cstrong\u003e2\u003c/strong\u003e(2):e218-e228.\u003c/li\u003e\n\u003cli\u003eWada T, Gando S, Mizugaki A, Yanagida Y, Jesmin S, Yokota H, Ieko M: \u003cstrong\u003eCoagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome--fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction\u003c/strong\u003e. \u003cem\u003eThromb Res \u003c/em\u003e2013, \u003cstrong\u003e132\u003c/strong\u003e(1):e64-69.\u003c/li\u003e\n\u003cli\u003eGando S, Nanzaki, S., Morimoto, Y. et al.: \u003cstrong\u003eOut-of-hospital cardiac arrest increases soluble vascular endothelial adhesion molecules and neutrophil elastase associated with endothelial injury.\u003c/strong\u003e \u003cem\u003eIntensive Care Med \u003c/em\u003e2000, \u003cstrong\u003e26, 38\u0026ndash;44\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eSchwameis M, Schorgenhofer C, Assinger A, Steiner MM, Jilma B: \u003cstrong\u003eVWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP\u003c/strong\u003e. \u003cem\u003eThromb Haemost \u003c/em\u003e2015, \u003cstrong\u003e113\u003c/strong\u003e(4):708-718.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section\u003c/p\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":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"out-of-hospital cardiac arrest, Von Willebrand factor, ADAMTS13","lastPublishedDoi":"10.21203/rs.3.rs-7604080/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7604080/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOut-of-hospital cardiac arrest (OHCA) is frequently complicated by disseminated intravascular coagulation (DIC), which is associated with poor outcomes. \u0026nbsp;The von Willebrand factor (VWF) plays a central role in haemostasis, and its multimeric size and activity are regulated by ADAMTS13. In thrombotic thrombocytopenic purpura, decreased ADAMTS13 activity leads to the accumulation of ultralarge VWF multimers and microvascular thrombosis. Elevated VWF antigen (VWF Ag) levels and reduced ADAMTS13 activity have also been observed after OHCAand are correlated with poor outcomes. However, the relationships among VWF activity, VWF multimer size, and ADAMTS13 activity in DIC after OHCA remain unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis single-centre retrospective cohort study included adult patients with witnessed cardiogenic OHCA admitted to the Hokkaido University Hospital between September 2019 and January 2023. Patients treated with extracorporeal membrane oxygenation were excluded. Plasma samples were collected from day 0 (upon arrival at the emergency department) to Day4. Plasma VWF antigen (VWF Ag), VWF ristocetin cofactor activity (VWF RCo), VWF large multimer index (VWF LMI), and ADAMTS13 activity were measured, and patients were classified into DIC and non-DIC groups. Temporal changes in these biomarkers were compared between the two groups, and their associations with DIC scores were assessed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 28 patients with witnessed cardiogenic OHCA, 16 fulfilled the DIC criteria upon admission. VWF-Ag and VWF-RCo were markedly elevated in both groups upon arrival at the emergency department and increased further during the observational period, without significant group differences. The VWF RCo/vWF Ag ratio was decreased in the DIC group. VWF LMI tended to be lower, and ADAMTS13 activity was consistently reduced in the DIC group compared to the non-DIC group. As the DIC score increased, VWF Ag content also increased. Furthermore, the VWF LMI and ADAMTS13 activity decreased as the DIC score increased.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn patients with OHCA, VWF antigen levels and functional activity are markedly elevated immediately after cardiac arrest. However, despite reduced ADAMTS13 activity in patients with DIC, the VWF multimer size and functional activity did not differ between the DIC and non-DIC groups. Therefore, VWF does not play a major role in platelet activation and DIC pathogenesis in this context and may be cleaved through alternative pathways independent of ADAMTS13.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRetrospectively registered.\u003c/p\u003e","manuscriptTitle":"The relationships between disseminated intravascular coagulation and time series change of von Willebrand factor in patients with out-of-hospital cardiac arrest: a retrospective observational study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 07:24:12","doi":"10.21203/rs.3.rs-7604080/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-11T02:36:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-10T15:47:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"116021924514367905458445304476482205776","date":"2025-10-21T05:25:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-09T05:11:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"173014061628070050912358544497767718004","date":"2025-09-25T03:48:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-25T00:39:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-23T03:50:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-23T03:49:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thrombosis Journal","date":"2025-09-13T02:19:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"04e10f72-4c36-441a-b56f-5e6e59f861ce","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:08:12+00:00","versionOfRecord":{"articleIdentity":"rs-7604080","link":"https://doi.org/10.1186/s12959-026-00842-z","journal":{"identity":"thrombosis-journal","isVorOnly":false,"title":"Thrombosis Journal"},"publishedOn":"2026-02-14 15:58:02","publishedOnDateReadable":"February 14th, 2026"},"versionCreatedAt":"2025-10-08 07:24:12","video":"","vorDoi":"10.1186/s12959-026-00842-z","vorDoiUrl":"https://doi.org/10.1186/s12959-026-00842-z","workflowStages":[]},"version":"v1","identity":"rs-7604080","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7604080","identity":"rs-7604080","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}