Coagulation factor VIII levels and the risk of cardiovascular events: Systematic review and Meta-analysis

Coagulation factor VIII levels and the risk of cardiovascular events: Systematic review and Meta-analysis | 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 Coagulation factor VIII levels and the risk of cardiovascular events: Systematic review and Meta-analysis feifei wang, Wenchi Li, Yiqing lin, yunhe Zhang, Chun Wang, feng zhu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8021341/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background Numerous epidemiological studies have explored the association between coagulation Factor VIII (FVIII) and cardiovascular event risk; however, the overall results are still inconsistent. Objectives The aim of this systematic review and meta-analysis was to evaluate the relationship between FVIII and the risk of various cardiovascular events. Methods Two independent reviewers screened all available literature to identify studies that met the inclusion criteria. Heterogeneity was evaluated quantitatively via the I² statistic, and corresponding analyses were conducted using random-effects model. Results A total of 22 original studies were included in the quantitative meta-analysis. The meta-analysis results of both case-control and cohort studies showed a positive correlation between FVIII levels and the risk of cardiovascular events (OR = 2.69, 95%CI 2.06–3.49, heterogeneity I 2 = 0%; HR = 1.22, 95%CI 1.14–1.30; heterogeneity I 2 = 64%). In the cohort studies, subgroup analysis revealed a positive correlation between FVIII levels and the risk of myocardial infarction (HR = 1.18, 95% CI 1.06–1.32; heterogeneity I²=55%), ischemic stroke (HR = 1.21, 95%CI 1.11–1.32; heterogeneity I 2 = 11%), heart failure (HR 1.23, 95% CI 1.07–1.42; heterogeneity I²=30%), and composite outcome of cardiovascular disease (HR = 1.39, 95%CI 1.05–1.84; heterogeneity I² = 86%). In the case-control studies, subgroup analysis revealed a positive correlation between FVIII levels and the risk of myocardial infarction (OR = 2.56, 95% CI 1.74–3.77; heterogeneity I² = 0%) and ischemic stroke (OR = 2.80, 95% CI 1.95–4.01; heterogeneity I 2 = 0%). Conclusion The results of this study demonstrate a positive association between elevated FVIII levels and an increased risk of cardiovascular events, particularly myocardial infarction and stroke. factor VIII ischemic stroke myocardial infarction cardiovascular events heart failure Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Cardiovascular events refer to any occurrence that affects the cardiovascular system that included the heart, brain, and blood vessels. The most common types of cardiovascular events include acute coronary syndrome, strokes, and cardiac arrests leading cause of morbidity and mortality worldwide [ 1 ]. One of its major pathological features is systemic thrombotic propensity related to abnormal coagulation function [ 2 ]. Coagulation Factor VIII (FVIII) is a key non-enzymatic cofactor in the intrinsic coagulation pathway, playing a critical role in physiological hemostasis and thrombus formation [ 3 ]. FVIII circulates in an inactive state bound to von Willebrand factor (vWF), which both stabilizes it and may facilitate its delivery to sites of vascular injury. Activation of FVIII, factor VIIIa, is proteolytically activated by thrombin or factor Xa. Factor VIIIa, in conjunction with activated coagulation factor IXa, assembles into the tenase complex on an anionic phospholipid surface. This complex critically catalyzes the conversion of factor X to its activated form, factor Xa, a reaction essential for the propagation phase of coagulation [ 4 ]. Thus, the role of FVIII is to markedly increase the catalytic efficiency of factor IXa toward factor X by several orders of magnitude, leading to thrombin generation. Abnormally elevated FVIII levels can disrupt the balance of the coagulation system and promote thrombus formation, making its role in thrombotic diseases an increasing focus of research. Multiple studies have shown that elevated levels of FVIII are independently associated with an increased risk of venous and arterial thrombotic events [ 5 – 7 ]. Kraaijenhagen [ 8 ] found that an elevated plasma level of FVIII is a significant, prevalent, independent and dose-dependent risk factor for venous thromboembolism. For each 10 IU/dl increment of FVIII activity, the risk for a single and recurrent episode of venous thrombosis increased by 10% and 24%, respectively. So far, the relation between FVIII levels and cardiovascular events also has been extensively studied. The Progetto Lombardo Atero-Trombosi (PLAT) Study, a prospective, multicenter, multidisciplinary study, found that FVIII activity may be involved in the multifactorial mechanism of atherothrombotic phenomena in patients with preexisting coronary or cerebrovascular disease. But there have different association between FVIII activity and vascular events, including myocardial infarction, angina pectoris, transient ischemic attacks and peripheral vascular disease. Multivariate analysis showed that only the myocardial infarction group was independently associated with elevated FVIII levels [ 9 ]. A recent study estimated the effect of FVIII activity levels on risk for secondary vascular events among ischemic stroke patients. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR = 2.05, 95%CI 1.28–3.29), including first of either recurrent stroke, myocardial infarction, or death attributable to any cause, within three years [ 10 ]. These findings suggest that FVIII may not only serve as a biomarker for thrombosis, but could also represent an independent risk factor for cardiovascular diseases. Although existing studies have provided preliminary evidence linking FVIII to cardiovascular events, significant heterogeneity exists across studies regarding population characteristics, timing and methods of FVIII measurement, control of confounding factors, and subtypes of cardiovascular events [ 11 – 14 ]. Therefore, this systematic review and meta-analysis aim to synthesize current evidence to quantify the relationship between FVIII levels and the risk of cardiovascular events, identify potential sources of heterogeneity and influencing factors, and provide evidence for future clinical practice and research directions. Methods Search strategy and study selection The methodology of this study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [ 15 ] and complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [ 16 ] for the design, implementation, and reporting of this systematic review and meta-analysis. This study and the corresponding search protocol were registered in the Prospective Register of Systematic Reviews registry ( https://www.crd.york.ac.uk/PROSPERO ) with registration number CRD420251139996. Up until July 19, 2025, a thorough English-language literature search was carried out in the PubMed, Embase, Web of Science, and Cochrane Library. The search strategy is detailed in Supplementary material. Inclusion criteria and study selection The inclusion criteria were as follows: (1) published in English; (2) utilizing case-control or cohort study designs in adults (age ≥ 18 years); (3) reporting on estimates of associations of plasma levels of FVIII with risks of cardiovascular events (myocardial infarction, angina pectoris, heart failure, stroke, transient ischemic attack). Studies were excluded for the following reasons: (1) studies with the smallest sample size or the shortest follow-up period, when there are multiple published articles in overlapping groups and the same outcome indicators; (2) case reports, letters, reviews, conference abstracts, and animal model studies. The titles and abstracts were screened by two independent reviewers (Wang and Lin) based on the inclusion criteria. For any study deemed to meet the criteria, the full text was retrieved to perform a more in-depth analysis. Data extraction and quality assessment Two independent reviewers (Wang and Lin) performed parallel data extraction encompassing the following variables: study name, study design, age, country, number of participants, cardiovascular events, publication year, follow-up, and FVIII monitoring method and assay. Any discrepancies identified during this process were resolved through discussion until a consensus was reached. The quality of the included studies was assessed using the Newcastle–Ottawa Scale score, which ranges from 0 to 9 points; a higher score indicated greater study quality. The evaluation was performed independently by two authors (Wang and Lin). Statistical analysis Data analysis was performed using RevMan 5.4 (The Cochrane Collaboration, The Nordic Cochrane Centre) and STATA 14.0 (StataCorp) software. Random-effects models were employed to pool the natural logarithm-transformed OR, HR, and 95% CI comparing the highest versus lowest categories of FVIII levels. Heterogeneity among the studies was assessed using the I² statistic. To control for potential confounders including age, sex, ethnicity, antihypertensive medications, and diabetes, we extracted data from multivariate Cox regression analyses adjusted for these factors. Sensitivity analysis was conducted using the leave-one-out method. Publication bias was evaluated with Egger’s and Begg’s tests, and when present, was adjusted using the trim and fill method. Results Study characteristics Following a manual search and an initial search in the PubMed, Embase, Web of Science, and Cochrane Library databases, 3515 items were found after duplicates were eliminated. Based on the abstract and title information, 3428 articles were removed according to the exclusion requirements. As a result, 87 articles were used for additional assessment. Lastly, the quantitative comprehensive meta-analysis included 22 publications in total (Fig. 1 ). The analysis included 16 cohort studies (a total of 109330 participants, including 7877 patients) and 6 case-control studies (comprising 1,191 cases and 694 controls). In the cohort studies, subgroup analyses were conducted for patients with composite outcome of cardiovascular disease, myocardial infarction, stroke, and heart failure; the case-control studies included subgroups of patients with myocardial infarction and stroke. Tables 1 and 2 display the pertinent data for each study, people from various nations worldwide were included in this meta-analysis: 10 from the United States, 4 from the UK, 2 from the Netherlands, and one each from Italy, France, Germany, Scotland, Finland, and China. The follow-up duration of the prospective cohort studies ranged from 2 to 20.6 years. The vast majority of the included studies assessed FVIII activity. Quality assessment results showed that 4 studies were rated as “moderate” (4–6 points), 18 studies were rated as “high quality” (≥ 7 points), and none were assessed as "low quality" (< 4 points). Table 1 Research characteristics of cohort studies in this systematic review and meta-analysis. Study Country Age (years) a Total population (M/F) Cardiovascular events Incident cases (M/F) FVIII status Assay Follow-up (years) Quality Cortellaro, 1992[ 9 ] Italy 56.1 ± 8.2 953(862/91) myocardial infarction 335(319/16) Continuous variable Activity 2 8/9 Folsom, 1993[ 17 ] USA 45–64 14357(6281/8076) myocardial infarction 1802(790/1012) Continuous variable Activity 3 5/9 Meade, 1994[ 18 ] UK 40–64 1393(M) myocardial infarction 178 Continuous variable Activity 16.1 7/9 Folsom, 1997[ 11 ] USA 45–64 14477(6297/8180) myocardial infarction 349(238/110) Continuous variable Activity 5.2(4–7) 8/9 Folsom, 1999[ 19 ] USA 45–64 14713 ischemic stroke 191(94/97) Continuous variable Activity 7.2(6–9) 8/9 Rumley, 1999[ 20 ] UK 49–65 2223(M) myocardial infarction 129 Q5 vs Q1 b Activity 5.1 8/9 Tracy, 1999[ 21 ] USA ≥ 65 5888 ischemic stroke — Q5 vs Q1 Activity 5 8/9 Zakai, 2007[ 12 ] USA 68 ± 3.8 4510(1759/2751) cardiovascular disease c 1700 Q5 vs Q1 Activity 9.2 9/9 Garcias, 2011[ 22 ] France 69 ± 14 160(83/77) cardiovascular disease d 61 Q4 vs Q1 - 2.5 ± 1.7 5/9 Wannamethee, 2017[ 23 ] UK 60–79 3366 heart failure 203 Q4 vs Q1 Activity 13 8/9 Zakai, 2018[ 7 ] USA ≥ 45 30239 ischemic stroke 646(308/338) Continuous variable Antigen 5.8(4.1-7) 8/9 Raffield, 2020[ 24 ] USA 21–93 3493(1327/2166) heart failure 2755 Continuous variable Antigen 10 8/9 Rohmann, 2020[ 10 ] Germany ≥ 18 621(379/242) cardiovascular disease e 94 Q4 vs Q1 Activity 3 8/9 Singleton, 2021[ 25 ] USA 66 ± 9 1748(647/1101) ischemic stroke 81(42/39) Q4 vs Q1 Antigen 5.2 8/9 Lowe, 2022[ 26 ] Scottish 30–74 3523(1677/1846) cardiovascular disease f 562(97/465) Continuous variable Activity 17.5–20.6 8/9 Abdelsayed, 2025[ 27 ] USA ≥ 18 7666(2392/5274) heart failure — Continuous variable Activity 5 8/9 F, female; M, male; FVIII, factor VIII; Q, quartile. a The age of this study is represented by mean ± SD or range. b This study used concentration intervals to represent FVIII. FVIII levels were divided into 5 quartile intervals according to numerical ranges to characterize the characteristics of participants in different intervals and to examine the relationship between FVIII and other parameters. c The cardiovascular diseases include myocardial infarction, coronary artery angioplasty, angina, stroke, transient ischemic attack, and cardiovascular death. d The cardiovascular diseases include cardiovascular death, stroke, acute coronary syndrome, and heart failure. e The cardiovascular diseases include stroke, myocardial infarction, and cardiovascular death. f The cardiovascular diseases include coronary heart disease and stroke. Table 2 Research characteristics of case-control studies in this systematic review and meta-analysis. Study Country Age (years) a Controls (M/F) Cardiovascular events Cases (M/F) FVIII status Assay Quality Rice, 1998[ 13 ] UK 59.24(51.63–65.27) 313(217/96) myocardial infarction 288(193/95) Q4 vs Q1 b Antigen 8/9 Karttunen, 2002[ 28 ] Finland 18–60 104(59/45) ischemic stroke 46(27/19) Q4 vs Q1 Activity 8/9 Tanis, 2006[ 29 ] Netherlands 48.7 ± 76.1 626(F) myocardial infarction 200 Q4 vs Q1 Activity 8/9 Chang, 2014[ 30 ] USA 53 32(18/14) ischemic stroke 84(35/49) Continuous variable Activity 5/9 Dooren, 2015[ 31 ] Netherlands 18–50 — ischemic stroke — Q4 vs Q1 Activity 6/9 Kuo, 2015[ 32 ] China — 116(66/50) ischemic stroke 76(37/39) Continuous variable Activity 7/9 F, female; M, male; FVIII, factor VIII; Q, quartile. a The age of this study is represented by mean ± SD or median or mean or range. b This study used concentration intervals to represent FVIII. FVIII levels were divided into 5 quartile intervals according to numerical ranges to characterize the characteristics of participants in different intervals and to examine the relationship between FVIII and other parameters. Meta-analysis of case-control and cohort studies Among the 16 cohort studies, five studies examined the correlation between FVIII levels and myocardial infarction, four between FVIII levels and the composite outcome of cardiovascular events, four between FVIII levels and stroke, and three between FVIII levels and heart failure. There are 13 cohort studies of community-based populations, while others are patient cohorts that include populations with established cardiovascular disease. FVIII levels and the risk of cardiovascular events were positively correlated according to the overall effect size (HR 1.22, 95%CI 1.14–1.30; heterogeneity I 2 = 64%; Fig. 2 A). Of the six case-control studies, four explored the relationship between FVIII levels and stroke, and two explored the relationship between FVIII levels and myocardial infarction. The elevated FVIII levels are significantly associated with an increased risk of cardiovascular events based on the overall effect size (OR 2.69, 95%CI 2.06–3.49, heterogeneity I 2 = 0%; Fig. 2 B). FVIII levels and myocardial infarction Regarding the relationship between FVIII levels and myocardial infarction, five cohort studies revealed a significant positive association (HR = 1.18, 95% CI 1.06–1.32; heterogeneity I²=55%, Fig. 3 ), while two case-control studies yielded analogous results (OR = 2.56, 95% CI 1.74–3.77; heterogeneity I² = 0%, Fig. 4 ). FVIII levels and stroke An analysis of four cohort studies demonstrated that the risk of stroke was positively correlated with increasing FVIII levels (HR = 1.21, 95%CI 1.11–1.32; heterogeneity I 2 = 11%, Fig. 3 ). Results of four case-control studies showed that the odds of having elevated FVIII levels were 2.80 times higher in the stroke group than in the control group (OR = 2.80, 95% CI 1.95–4.01; heterogeneity I 2 = 0%, Fig. 4 ). FVIII levels and heart failure Results from three cohort studies demonstrated a significant association between elevated FVIII levels and increased risk of heart failure (HR 1.23, 95% CI 1.07–1.42; heterogeneity I² = 30%, Fig. 3 ). FVIII levels and composite outcome of cardiovascular disease The composite outcome of cardiovascular disease is the occurrence of two or more cardiovascular events, including myocardial infarction, angina, stroke, transient ischemic attack, acute coronary syndrome, heart failure, and cardiovascular death. The definitions of composite outcome of cardiovascular disease in each included study are presented in Table 1 . A total of four cohort studies were conducted to evaluate the prognostic association between FVIII levels and the risk of a composite outcome of cardiovascular disease. The pooled results confirmed a statistically significant positive association between elevated FVIII levels and the risk of a composite outcome of cardiovascular disease (HR = 1.39, 95%CI 1.05–1.84; heterogeneity I² = 86%, Fig. 3 ). Sensitivity Analysis The leave-one-out sensitivity analysis was conducted to assess the stability of these studies outcomes. As presented in Fig. 5 , the effect sizes obtained after sequentially excluding each study all fell within the confidence interval of the preliminary results, indicating strong robustness of the findings in this study. Publication bias Table 3 presents the results of Egger's test for cohort studies and Begg's test for case-control studies regarding the correlation between FVIII levels and cardiovascular events. No evidence of publication bias was detected in case-control studies (p > 0.05), whereas a certain degree of publication bias was observed in cohort studies. Therefore, we applied the trim-and-fill method to further analysis (Fig. 6 ). Seven estimated missing virtual studies were included after three iterations of the linear method. The reanalyzed pooled effect values showed that there was a significantly positive correlation between FVIII levels and the risk of cardiovascular events (HR = 1.13, 95% CI 1.06–1.20). Table 3 Egger’s test results Study design Egger‘s Test Begg’s Test Intercept p z P case-control study —— 0.00 1.00 cohort study 5.93 0.00 —— Discussion In this systematic review and meta-analysis, we observed that elevated FVIII levels were associated with an increased risk of cardiovascular events across both case-control and cohort studies. Subgroup analysis revealed a positive correlation between FVIII levels and the risk of myocardial infarction and stroke. The finding that patients with FVIII deficiency, haemophilic A, have an 80% reduction in coronary heart disease mortality than in the general population provides indirect evidence supporting a role for FVIII in the pathogenesis of ischaemic heart disease [ 33 ]. Rosendaal [ 34 ] considered that raised FVIII levels may predispose to ischaemic heart disease by increasing thrombogenic potential. Recently, instrumental variable or Mendelian randomization analyses of FVIII using results of recent FVIII GWAS in Europeans have suggested FVIII levels may be causally related to coronary heart disease risk [ 35 ]. Arterial thromboembolism is most commonly triggered by platelet aggregation following the rupture of the atherosclerotic plaques in the arteries, in contrast, coagulation factor dysregulation is more likely to cause venous clots. Conventional cardiovascular risk factors can explain only about 50% of cases of arterial thrombosis [ 36 ]. Thus, the role of clotting factors in the development of arterial thrombosis is also considered. The PLAT study showed that FVIII activity was significantly higher in myocardial infarction survivors than in patients with coronary disease only [ 37 ], and FVIII activity were found to have an independent association with myocardial infarction after 2 years follow-up of this cohort [ 9 ]. A case-control study assessed whether high FVIII, factor IX, and factor XI activity levels are associated with an increased myocardial infarction risk in young women [ 29 ], and found that high levels of FVIII and factor IX were associated with a more than twofold increased risk of myocardial infarction in contrast with high levels of factor XI. This suggests that FVIII is a role for secondary haemostasis in the aetiology of coronary thrombosis. Ischemic stroke is a heterogeneous disease that is caused by several underlying pathologic processes, of the role played by hemostasis in the pathogenesis is still controversial. The etiology of many ischemic stroke risk factors is still not well understood. Hemostatic factors constitute another plausible risk factor, since disturbance of the hemostatic balance is central to the pathogenesis of thrombosis. Findings indicate that high FVIII levels were significantly associated with acute stroke, stroke subtype (cardioembolic stroke), and neurological worsening after acute stroke [ 32 ]. Previous research has demonstrated that the rs688 genotype may determine levels of FVIII, which may explain its association with different stroke subtypes, including cerebral infarction and intracerebral hemorrhage [ 38 ]. Regarding ischemic stroke patients who underwent thrombolysis, a study found that having elevated FVIII activity, both immediately and 24 hours after thrombolysis, led to a higher risk for poor functional outcome at 90 days [ 39 ]. In addition, evidence indicates a positive association between elevated FVIII levels and carotid atherosclerosis, a common causes of acute cerebral infarction, in a Chinese population [ 40 ]. The results of the present meta-analysis further confirm the positive association between FVIII and ischemic stroke, with a low degree of heterogeneity across studies. Despite modest heterogeneity, the results from all three cohort studies consistently showed a significant positive association between high FVIII levels and incident heart failure (HR 1.23, 95% CI 1.07–1.42; heterogeneity I²=30%). Hypercoagulability, systemic activation of blood coagulation, is a general feature of heart failure [ 41 ], and arterial and venous thrombotic events are a common complication of patients with heart failure [ 42 ]. Abdelsayed [ 27 ] observed a graded concentration response relationship between serum vWF levels and new-onset heart failure, with higher vWF concentrations associated with an increased likelihood of incident heart failure. It is plausible that chronic inflammation mediated by vWF in patients with elevated FVIII levels may contribute to endothelial dysfunction, vascular injury, and the progression of coronary therosclerosis or vasculopathy, ultimately leading to heart failure. There are relatively few studies on the relationship between FVIII and heart failure, and more research is needed to verify this in the future. The meta-analysis revealed a significant association between elevated FVIII levels and an increased risk of composite cardiovascular disease (HR = 1.39, 95%CI 1.05–1.84). However, substantial heterogeneity was observed across the included studies (I² = 86%), which may be ascribed to variations in population characteristics, differences in laboratory methodologies for FVIII measurement, inconsistencies in the adjustment of confounding factors, and, most importantly, discrepancies in the definitions of cardiovascular events. The definitions of the composite cardiovascular disease outcome varied across the included studies in the present study. Heterogeneity in the definitions of cardiovascular events in cardiovascular research may have an important impact on the results of clinical trials, which in turn influence guidelines and practice. For instance, in the trial of evaluation of percutaneous coronary intervention versus coronary artery bypass surgery for effectiveness of left main revascularization, the conclusions of the EXCEL trial and the NOBLE trial are completely contradictory due to differences in the definitions of major adverse cardiac or cerebrovascular events [ 43 ]. Therefore, there is a pressing need to reach consensus on the standardized variables and their definitions across the whole of cardiology for use in cardiovascular research. The association between FVIII and composite outcome of cardiovascular disease was hence assessed as an exploratory analysis due to methodological limitations, specifically the limited number of included studies and the absence of standardized definitions of composite outcome of cardiovascular disease. The FVIII are required for continued thrombin generation and maintenance of fibrin formation [ 44 ]. The FVIII biological function is to act as a cofactor in the conversion of factor X to factor Xa by factor IXa in the presence of phospholipid and calcium, as an integral part of the intrinsic coagulation cascade [ 4 ]. The potential mechanism by which elevated FVIII promotes thrombosis may involve a direct enhancement of basal thrombin generation mediated by high FVIII levels, leading to increased levels of thrombin–antithrombin complex and prothrombin fragments. This disrupts the balance between coagulation and fibrinolysis, particularly in the context of endothelial injury or stasis, thereby increasing the risk of thrombus formation [ 45 , 46 ]. Studies evaluating the effect of elevated FVIII on arterial thrombosis in mice, found that the rate of thrombin-antithrombin complex formation, and the final concentration of thrombin-antithrombin complexes, significantly increased as FVIII levels were elevated from 100% to 400% FVIII activity [ 37 ]. In addition, the acute elevation of circulating FVIII to 400% FVIII activity resulted in significantly decreased times to vessel occlusion. Another possibility is that high plasma FVIII levels induce resistance to the action of activated protein C, which exerts its anticoagulant effect by inactivating activated factor V and FVIII [ 47 ]. Currently, the available evidence tends to support that FVIII is a causal factor for thrombosis; however, the present study merely establishes an association between FVIII and cardiovascular events, without substantiating a causal relationship between them. FVIII levels and the risk of cardiovascular events were positively correlated according to the overall effect size (HR 1.22, 95%CI 1.14–1.30; heterogeneity I 2 = 64%), but our meta-analysis revealed substantial heterogeneity across cohort studies, particularly within subgroups of composite cardiovascular disease (I² = 86%). The heterogeneity may be attributable to variations in study design, population characteristics, FVIII measurement methodologies and critical confounder (namely, vWF), as well as differences in follow-up duration and endpoint definitions. In contrast, case-control studies demonstrated negligible heterogeneity, indicating consistent findings among these studies. FVIII levels have been observed to be influenced by multifactorial and driven by genetic processes, environmental factors, and biological variations, including age [ 48 ], sex [ 49 ], race [ 50 ], acute phase reactants [ 49 ], diabetes mellitus [ 48 ], and blood groups [ 51 ]. Furthermore, vWF level may be the driver of the association of FVIII with risk of thrombosis, since plasma levels of FVIII and vWF are highly correlated due to their circulate as a high-affinity non-covalent complex. The FVIII-vWF complex, is essential for platelet adhesion to the arterial subendothelium, raises the concentration of FVIII at sites of vascular damage by preventing rapid removal of this procoagulant protein from the circulation [ 52 ]. Increased vWF levels therefore may augment platelet adhesion, enhance shear stress-induced platelet aggregation, and increase plasma FVIII levels, thereby increasing risk of cerebral thrombosis when atherosclerotic plaques rupture. A study reported that FVIII and vWF showed independent associations with cardiovascular disease risk, and may be involved together with some conventional risk factors in the multifactorial mechanism of atherothrombotic phenomena in patients with preexisting coronary or cerebrovascular disease [ 9 , 17 ]. Finaly, the confounding factors adjusted for vary across studies. Unfortunately, nearly none of the 22 included studies adjusted for vWF-an important confounding factor that should not be overlooked. If the adjusting factors were merely confounding variables, then the multivariate relative risks are the most informative. However, if several risk factors operate through hemostatic mechanisms, then the relative risks adjusted only for age, race, and field center represent the mechanistic aspects of these hemostatic variables on coronary heart disease. It should be noted that a certain degree of publication bias was detected in cohort studies. After adjustment using the trim-and-fill method, the results consistent with the original findings, indicating a persistently significant positive association between FVIII levels and the risk of cardiovascular events. It is important to note that, owing to the limited number of included studies, the Egger's and Begg's tests exhibited insufficient statistical power, and the findings of the trim-and-fill analysis should be construed merely as exploratory. Consequently, the potential existence of publication bias cannot be ruled out in the present study. There are several limitations to our study. First, in the cohort studies, a high I² value indicates substantial heterogeneity in our meta-analysis, with the subgroup of composite cardiovascular disease identified as the primary source of this heterogeneity. The observed heterogeneity may primarily stem from variations in the adjustment of multiple confounding variables and inconsistencies in the definition of composite cardiovascular disease outcomes. Second, despite adjustments for multiple confounding variables, including age, race, sex, blood group, hypertension, diabetes, and cholesterol, residual confounding may persist due to limitations across studies, with vWF being a particularly critical confounder that is insufficiently addressed in the 22 studies included in this study. Third, considerable heterogeneity existed in FVIII measurement. While the vast majority of studies quantified FVIII activity, a minority employed FVIII antigen assays, with methodology further compounded by inter-assay variability. Finally, as a meta-analysis of observational studies, the present research can only indicate an association between FVIII levels and cardiovascular events, but does not demonstrate causality. Further studies are warranted to explore this relationship. Conclusion In summary, these findings suggest that elevated FVIII levels are correlated with an increased risk of various cardiovascular events, particularly myocardial infarction and stroke. In the future, prospective studies are needed to explore the potential value of FVIII in the prevention and treatment of cardiovascular diseases. Additionally, genetic approaches can be combined to verify the causal relationship between FVIII and cardiovascular diseases, providing a crucial foundation for developing FVIII-focused anticoagulation for the primary prevention of cardiovascular disease. Abbreviations FVIII coagulation Factor VIII vWF von Willebrand factor MOOSE Meta-analysis of Observational Studies in Epidemiology PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Declarations Ethics approval and consent to participate This article does not contain any studies with human participants or animals performed by any of the authors. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the National Key R & D Program of China [grant numbers 2024YFC3505700] and the National Natural Science Foundation of China [grant number 82102288]. Author Contribution Feng Zhu (FZ) was responsible for the study design, resolution of disagreements, and critical appraisal of the study. Feifei Wang (FFW), Yunhe Zhang (YHZ) and Chun Wang (CW) performed literature search. WFF, Wenchi Li (WCL) and Yiqing Lin (YQL) performed study selection and data extraction. WFF and LYQ performed bias assessment. WFF performed review writing. LWC performed statistical analysis. WFF are considered the first authors. All authors read and approved the final manuscript. Acknowledgements Not applicable. Data Availability All data used in the current study are available from the corresponding author on reasonable request. References Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596–646. Falk E, Fernández-Ortiz A. Role of thrombosis in atherosclerosis and its complications. Am J Cardiol. 1995;75(6):B3–11. Kiouptsi K, Reinhardt C. Physiological Roles of the von Willebrand Factor-Factor VIII Interaction. Subcell Biochem. 2020;94:437–64. Fay PJ. Activation of factor VIII and mechanisms of cofactor action. Blood Rev. 2004;18(1):1–15. Koster T, Blann AD, Briët E, et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995;345(8943):152–5. Martinelli I. von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis. Semin Hematol. 2005;42(1):49–55. Zakai NA, Judd SE, Kissela B, et al. Factor VIII, Protein C and Cardiovascular Disease Risk: The REasons for Geographic and Racial Differences in Stroke Study (REGARDS). Thromb Haemost. 2018;118(7):1305–15. Kraaijenhagen RA, in't Anker PS, Koopman MM, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost. 2000;83(1):5–9. Cortellaro M, Boschetti C, Cofrancesco E, et al. The PLAT study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients. Arterioscler Thromb. 1992;12:1063–70. Rohmann JL, Huo SF, Sperber PS, et al. Coagulation factor XII, XI, and VIII activity levels and secondary events after first ischemic stroke. J Thromb Haemost. 2020;18(12):3316–24. Folsom AR, Wu KK, Rosamond WD, et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 1997;96(4):1102–8. Zakai NA, Katz R, Jenny NS, et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. J Thromb Haemost. 2007;5(6):1128–35. Rice GI, Grant PJ. FVIII coagulant activity and antigen in subjects with ischaemic heart disease. Thromb Haemost. 1998;80(5):757–62. Harshfield EL, Sims MC, Traylor M, et al. The role of haematological traits in risk of ischaemic stroke and its subtypes. Brain. 2020;143(1):210–21. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Rev Esp Cardiol (Engl Ed). 2021;74(9):790–9. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12. Folsom AR, Wu KK, Shahar E, et al. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Arterioscler Thromb. 1993;13(12):1829–36. Meade TW, Cooper JA, Stirling Y, et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol. 1994;88(3):601–7. Folsom AR, Rosamond WD, Shahar E, et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation. 1999;100(7):736–42. Rumley A, Lowe GD, Sweetnam PM, et al. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study. Br J Haematol. 1999;105(1):110–6. Tracy RP, Arnold AM, Ettinger W, et al. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol. 1999;19(7):1776–83. Garcias EB, Ederhy S, Lang S, et al. Are von willebrand factor and factor 8 associated with cardiovascular events including heart failure in non-valvular atrial fibrillation? J Am Coll Cardiol. 2011;57(14):E67. Wannamethee SG, Whincup PH, Papacosta O, et al. Associations between blood coagulation markers, NT-proBNP and risk of incident heart failure in older men: The British Regional Heart Study. Int J Cardiol. 2017;230:567–71. Raffield LM, Lu AT, Szeto MD, et al. Coagulation factor VIII: Relationship to cardiovascular disease risk and whole genome sequence and epigenome-wide analysis in African Americans. J Thromb Haemost. 2020;18(6):1335–47. Singleton MJ, Yuan Y, Dawood FZ, et al. Multiple Blood Biomarkers and Stroke Risk in Atrial Fibrillation: The REGARDS Study. J Am Heart Assoc. 2021;10(15):e020157. Lowe G, Peters S, Rumley A, et al. Associations of Hemostatic Variables with Cardiovascular Disease and Total Mortality: The Glasgow MONICA Study. TH Open. 2022;6(2):e107–13. Abdelsayed K, Najah Q, Mohamed AA et al. Prognostic implications of factor VIII levels in African Americans: insights from a propensity-matched US-based multicenter retrospective analysis. J Thromb Thrombolysis. 2025. Karttunen V, Alfthan G, Hiltunen L, et al. Risk factors for cryptogenic ischaemic stroke. Eur J Neurol. 2002;9(6):625–32. Tanis B, Algra A, Graaf Y, et al. Procoagulant factors and the risk of myocardial infarction in young women. Eur J Haematol. 2006;77(1):67–73. Chang TR, Albright KC, Boehme AK, et al. Factor VIII in the setting of acute ischemic stroke among patients with suspected hypercoagulable state. Clin Appl Thromb Hemost. 2014;20(2):124–8. Van Dooren D, Rosendaal F, Algra A, et al. Increased risk of ischaemic stroke with high levels of coagulation factor VIII activity in combination with oral contraceptives. Int J stroke. 2015;10:216–7. Kuo CY, Lin CH, Kuo YW, et al. Factor VIII levels are associated with ischemic stroke, stroke subtypes and neurological worsening. Curr Neurovasc Res. 2015;12(1):85–90. Triemstra M, Rosendaal FR, Smit C, et al. Mortality in Patients with Hemophilia. Changes in a Dutch Population from 1986 to 1992 and 1973 to 1986. Ann Intern Med. 1995;123:823–7. Rosendaal FR, Brie¨t E, Stibbe J, et al. Haemophilia protects against ischaemic heart disease: a study of risk factors. Br J Haematol. 1990;75:525–30. Sabater-Lleal M, Huffman JE, de Vries PS, et al. Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. Circulation. 2019;139:620–35. Małecki R, Adamiec R. Factor VIII and the risk of arterial thrombosis. Postepy igieny i medycyny doświadczalnej (Online). 2006;60:602–8. Cortellaro M, Boschetti C, Cofrancesco E, et al. The PLAT Study: a multidisciplinary study of hemostatic function and conventional risk factors in vascular disease patients. Atherosclerosis. 1991;90:109–18. Lee JD, Hsiao KM, Lee TH, et al. Genetic polymorphism of LDLR (rs688) is associated with primary intracerebral hemorrhage. Curr Neurovasc Res. 2014;11(1):10–5. Toth NK, Szekely EG, Czuriga-Kovacs KR, et al. Elevated Factor VIII and von Willebrand Factor Levels Predict Unfavorable Outcome in Stroke Patients Treated with Intravenous Thrombolysis. Front Neurol. 2017;8:721. Pan WH, Bai CH, Chen JR, et al. Associations between carotid atherosclerosis and high factor VIII activity, dyslipidemia, and hypertension. Stroke. 1997;28(1):88–94. Kim JH, Shah P, Tantry US, et al. Coagulation Abnormalities in Heart Failure: Pathophysiology and Therapeutic Implications. Curr Heart Fail Rep. 2016;13:319–28. Zannad F, Stough WG, Regnault V, et al. Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges. Int J Cardiol. 2013;167:1772–82. Bhatty A, Wilkinson C, Sydes M, et al. Defining the need for cardiovascular event definitions. Eur Heart J Qual Care Clin Outcomes. 2024;10(2):105–7. Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991;30:10363–70. Ryland JK, Lawrie AS, Mackie IJ, et al. Persistent high factor VIII activity leading to increased thrombin generation - a prospective cohort study. Thromb Res. 2012;129(4):447–52. Szlam F, Sreeram G, Solomon C, et al. Elevated factor VIII enhances thrombin generation in the presence of factor VIII-deficiency, factor XI-deficiency or fondaparinux. Thromb Res. 2011;127(2):135–40. De Mitrio V, Marino R, Scaraggi FA, et al. Influence of factor VIII/von Willebrand complex on the activated protein C-resistance phenotype and on the risk for venous thromboembolism in heterozygous carriers of the factor V Leiden mutation. Blood Coagul Fibrinolysis. 1999;10(7):409–16. Conlan MG, Folsom AR, Finch A, et al. Associations of Factor VIII and von Willebrand Factor with Age,Race, Sex, and Risk Factors for Atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost. 1993;70:380–5. Haverkate F, Thompson SG, Duckert F. Haemostasis Factors in Angina Pectoris; Relation to Gender, Age and Acute-phase Reaction. Results of the ECAT Angina Pectoris Study Group. Thromb Haemost. 1995;73:561–7. Folsom AR, Basu S, Hong CP, et al. Reasons for differences in the incidence of venous thromboembolism in black versus white Americans. Am J Med. 2019;132(8):970–6. Preston AE, Barr A. The Plasma Concentration of Factor VIII in the Normal Population. II. The Effects of Age, Sex, and Blood Group. Br J Haematol. 1964;10:238–45. Ruggeri ZM, Zimmerman T. von Willebrand factor and von Willebrand disease. Blood. 1987;70:895–904. Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":102762,"visible":true,"origin":"","legend":"\u003cp\u003eLiterature screening flowchart.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/1c5b6fa423111573aa57bdfd.png"},{"id":97689151,"identity":"8ca20caa-9d7a-4b03-b4e7-5817e2bedfa1","added_by":"auto","created_at":"2025-12-08 10:43:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":186598,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between coagulation factor VIII levels and the risk of cardiovascular events. (A) cohort studies and (B) Case-control studies.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/184ab745e3f8f73d556b55d4.png"},{"id":97689153,"identity":"d34bf756-b7cb-4408-b199-51de3006d7d8","added_by":"auto","created_at":"2025-12-08 10:43:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":176191,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of subgroup analysis of the cohort studies.\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/f522e23060510823ca6ce075.png"},{"id":97893804,"identity":"b51550d8-e51d-448d-bd14-9dc9326d7f35","added_by":"auto","created_at":"2025-12-10 15:31:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1102968,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of subgroup analysis of the case-control studies.\u003c/p\u003e","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/835841fa3f90c2602586d254.png"},{"id":97689161,"identity":"5b0fc8e3-9926-43cd-aa25-236f55e3eee7","added_by":"auto","created_at":"2025-12-08 10:43:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":245437,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analyses for cohort studies (A) and case-control studies (B).\u003c/p\u003e","description":"","filename":"OnlineFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/d92ff251ef62fdaaf2b426f9.png"},{"id":97892484,"identity":"15300024-b156-47ed-b3d3-e96b16c63658","added_by":"auto","created_at":"2025-12-10 15:06:44","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":108092,"visible":true,"origin":"","legend":"\u003cp\u003eEgger’s Test results for cohort studies (A) and Filled funnel plot with pseudo 95% confidence limits (B).\u003c/p\u003e","description":"","filename":"OnlineFigure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/62fa34dd2a624153c457d5dc.png"},{"id":97902508,"identity":"736ba401-c4e2-4054-8513-77ca2572c902","added_by":"auto","created_at":"2025-12-10 15:52:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2447407,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/14e4d956-9c80-4809-8f10-006a8e884df9.pdf"},{"id":97893369,"identity":"160ff6f5-f7be-40d2-98b8-49c0ca4a077f","added_by":"auto","created_at":"2025-12-10 15:30:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17745,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile1searchstrategy.docx","url":"https://assets-eu.researchsquare.com/files/rs-8021341/v1/b547e32329152bab7fb098e2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Coagulation factor VIII levels and the risk of cardiovascular events: Systematic review and Meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiovascular events refer to any occurrence that affects the cardiovascular system that included the heart, brain, and blood vessels. The most common types of cardiovascular events include acute coronary syndrome, strokes, and cardiac arrests leading cause of morbidity and mortality worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. One of its major pathological features is systemic thrombotic propensity related to abnormal coagulation function [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Coagulation Factor VIII (FVIII) is a key non-enzymatic cofactor in the intrinsic coagulation pathway, playing a critical role in physiological hemostasis and thrombus formation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. FVIII circulates in an inactive state bound to von Willebrand factor (vWF), which both stabilizes it and may facilitate its delivery to sites of vascular injury. Activation of FVIII, factor VIIIa, is proteolytically activated by thrombin or factor Xa. Factor VIIIa, in conjunction with activated coagulation factor IXa, assembles into the tenase complex on an anionic phospholipid surface. This complex critically catalyzes the conversion of factor X to its activated form, factor Xa, a reaction essential for the propagation phase of coagulation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Thus, the role of FVIII is to markedly increase the catalytic efficiency of factor IXa toward factor X by several orders of magnitude, leading to thrombin generation.\u003c/p\u003e\u003cp\u003eAbnormally elevated FVIII levels can disrupt the balance of the coagulation system and promote thrombus formation, making its role in thrombotic diseases an increasing focus of research. Multiple studies have shown that elevated levels of FVIII are independently associated with an increased risk of venous and arterial thrombotic events [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Kraaijenhagen [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] found that an elevated plasma level of FVIII is a significant, prevalent, independent and dose-dependent risk factor for venous thromboembolism. For each 10 IU/dl increment of FVIII activity, the risk for a single and recurrent episode of venous thrombosis increased by 10% and 24%, respectively. So far, the relation between FVIII levels and cardiovascular events also has been extensively studied. The Progetto Lombardo Atero-Trombosi (PLAT) Study, a prospective, multicenter, multidisciplinary study, found that FVIII activity may be involved in the multifactorial mechanism of atherothrombotic phenomena in patients with preexisting coronary or cerebrovascular disease. But there have different association between FVIII activity and vascular events, including myocardial infarction, angina pectoris, transient ischemic attacks and peripheral vascular disease. Multivariate analysis showed that only the myocardial infarction group was independently associated with elevated FVIII levels [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A recent study estimated the effect of FVIII activity levels on risk for secondary vascular events among ischemic stroke patients. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR\u0026thinsp;=\u0026thinsp;2.05, 95%CI 1.28\u0026ndash;3.29), including first of either recurrent stroke, myocardial infarction, or death attributable to any cause, within three years [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These findings suggest that FVIII may not only serve as a biomarker for thrombosis, but could also represent an independent risk factor for cardiovascular diseases.\u003c/p\u003e\u003cp\u003eAlthough existing studies have provided preliminary evidence linking FVIII to cardiovascular events, significant heterogeneity exists across studies regarding population characteristics, timing and methods of FVIII measurement, control of confounding factors, and subtypes of cardiovascular events [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, this systematic review and meta-analysis aim to synthesize current evidence to quantify the relationship between FVIII levels and the risk of cardiovascular events, identify potential sources of heterogeneity and influencing factors, and provide evidence for future clinical practice and research directions.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSearch strategy and study selection\u003c/h2\u003e\u003cp\u003eThe methodology of this study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] for the design, implementation, and reporting of this systematic review and meta-analysis. This study and the corresponding search protocol were registered in the Prospective Register of Systematic Reviews registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/PROSPERO\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/PROSPERO\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) with registration number CRD420251139996.\u003c/p\u003e\u003cp\u003eUp until July 19, 2025, a thorough English-language literature search was carried out in the PubMed, Embase, Web of Science, and Cochrane Library. The search strategy is detailed in Supplementary material.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInclusion criteria and study selection\u003c/h3\u003e\n\u003cp\u003eThe inclusion criteria were as follows: (1) published in English; (2) utilizing case-control or cohort study designs in adults (age\u0026thinsp;\u0026ge;\u0026thinsp;18 years); (3) reporting on estimates of associations of plasma levels of FVIII with risks of cardiovascular events (myocardial infarction, angina pectoris, heart failure, stroke, transient ischemic attack). Studies were excluded for the following reasons: (1) studies with the smallest sample size or the shortest follow-up period, when there are multiple published articles in overlapping groups and the same outcome indicators; (2) case reports, letters, reviews, conference abstracts, and animal model studies.\u003c/p\u003e\u003cp\u003eThe titles and abstracts were screened by two independent reviewers (Wang and Lin) based on the inclusion criteria. For any study deemed to meet the criteria, the full text was retrieved to perform a more in-depth analysis.\u003c/p\u003e\n\u003ch3\u003eData extraction and quality assessment\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers (Wang and Lin) performed parallel data extraction encompassing the following variables: study name, study design, age, country, number of participants, cardiovascular events, publication year, follow-up, and FVIII monitoring method and assay. Any discrepancies identified during this process were resolved through discussion until a consensus was reached. The quality of the included studies was assessed using the Newcastle\u0026ndash;Ottawa Scale score, which ranges from 0 to 9 points; a higher score indicated greater study quality. The evaluation was performed independently by two authors (Wang and Lin).\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData analysis was performed using RevMan 5.4 (The Cochrane Collaboration, The Nordic Cochrane Centre) and STATA 14.0 (StataCorp) software. Random-effects models were employed to pool the natural logarithm-transformed OR, HR, and 95% CI comparing the highest versus lowest categories of FVIII levels. Heterogeneity among the studies was assessed using the I\u0026sup2; statistic. To control for potential confounders including age, sex, ethnicity, antihypertensive medications, and diabetes, we extracted data from multivariate Cox regression analyses adjusted for these factors. Sensitivity analysis was conducted using the leave-one-out method. Publication bias was evaluated with Egger\u0026rsquo;s and Begg\u0026rsquo;s tests, and when present, was adjusted using the trim and fill method.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStudy characteristics\u003c/h2\u003e\u003cp\u003eFollowing a manual search and an initial search in the PubMed, Embase, Web of Science, and Cochrane Library databases, 3515 items were found after duplicates were eliminated. Based on the abstract and title information, 3428 articles were removed according to the exclusion requirements. As a result, 87 articles were used for additional assessment. Lastly, the quantitative comprehensive meta-analysis included 22 publications in total (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The analysis included 16 cohort studies (a total of 109330 participants, including 7877 patients) and 6 case-control studies (comprising 1,191 cases and 694 controls). In the cohort studies, subgroup analyses were conducted for patients with composite outcome of cardiovascular disease, myocardial infarction, stroke, and heart failure; the case-control studies included subgroups of patients with myocardial infarction and stroke.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e display the pertinent data for each study, people from various nations worldwide were included in this meta-analysis: 10 from the United States, 4 from the UK, 2 from the Netherlands, and one each from Italy, France, Germany, Scotland, Finland, and China. The follow-up duration of the prospective cohort studies ranged from 2 to 20.6 years. The vast majority of the included studies assessed FVIII activity. Quality assessment results showed that 4 studies were rated as \u0026ldquo;moderate\u0026rdquo; (4\u0026ndash;6 points), 18 studies were rated as \u0026ldquo;high quality\u0026rdquo; (\u0026ge;\u0026thinsp;7 points), and none were assessed as \"low quality\" (\u0026lt;\u0026thinsp;4 points).\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\u003eResearch characteristics of cohort studies in this systematic review and meta-analysis.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003cp\u003e(years)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTotal population (M/F)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCardiovascular events\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncident cases (M/F)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFVIII status\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAssay\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFollow-up (years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eQuality\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCortellaro, 1992[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eItaly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e953(862/91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emyocardial infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e335(319/16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFolsom, 1993[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14357(6281/8076)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emyocardial infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1802(790/1012)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeade, 1994[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1393(M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emyocardial infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e178\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e16.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFolsom, 1997[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14477(6297/8180)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emyocardial infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e349(238/110)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5.2(4\u0026ndash;7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFolsom, 1999[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14713\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e191(94/97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e7.2(6\u0026ndash;9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRumley, 1999[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49\u0026ndash;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2223(M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emyocardial infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ5 vs Q1\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTracy, 1999[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5888\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ5 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZakai, 2007[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4510(1759/2751)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ecardiovascular disease\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1700\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ5 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e9.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e9/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGarcias, 2011[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFrance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e160(83/77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ecardiovascular disease\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWannamethee, 2017[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60\u0026ndash;79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3366\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eheart failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e203\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZakai, 2018[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30239\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e646(308/338)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAntigen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5.8(4.1-7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRaffield, 2020[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21\u0026ndash;93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3493(1327/2166)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eheart failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2755\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAntigen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRohmann, 2020[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e621(379/242)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ecardiovascular disease\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSingleton, 2021[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e66\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1748(647/1101)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e81(42/39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAntigen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLowe, 2022[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScottish\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u0026ndash;74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3523(1677/1846)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ecardiovascular disease\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e562(97/465)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17.5\u0026ndash;20.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdelsayed, 2025[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7666(2392/5274)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eheart failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eF, female; M, male; FVIII, factor VIII; Q, quartile.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ea\u003c/sup\u003eThe age of this study is represented by mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or range.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003eb\u003c/sup\u003eThis study used concentration intervals to represent FVIII. FVIII levels were divided into 5 quartile intervals according to numerical ranges to characterize the characteristics of participants in different intervals and to examine the relationship between FVIII and other parameters.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ec\u003c/sup\u003eThe cardiovascular diseases include myocardial infarction, coronary artery angioplasty, angina, stroke, transient ischemic attack, and cardiovascular death.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ed\u003c/sup\u003eThe cardiovascular diseases include cardiovascular death, stroke, acute coronary syndrome, and heart failure.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ee\u003c/sup\u003eThe cardiovascular diseases include stroke, myocardial infarction, and cardiovascular death.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ef\u003c/sup\u003eThe cardiovascular diseases include coronary heart disease and stroke.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\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\u003eResearch characteristics of case-control studies in this systematic review and meta-analysis.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAge (years)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eControls (M/F)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCardiovascular events\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases (M/F)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFVIII status\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAssay\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eQuality\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRice, 1998[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59.24(51.63\u0026ndash;65.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e313(217/96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emyocardial infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e288(193/95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAntigen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKarttunen, 2002[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFinland\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18\u0026ndash;60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104(59/45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e46(27/19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTanis, 2006[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNetherlands\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48.7\u0026thinsp;\u0026plusmn;\u0026thinsp;76.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e626(F)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emyocardial infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e8/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChang, 2014[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32(18/14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e84(35/49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDooren, 2015[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNetherlands\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18\u0026ndash;50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4 vs Q1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e6/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKuo, 2015[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e116(66/50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eischemic stroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e76(37/39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eContinuous variable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e7/9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eF, female; M, male; FVIII, factor VIII; Q, quartile.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003ea\u003c/sup\u003eThe age of this study is represented by mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median or mean or range.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003eb\u003c/sup\u003eThis study used concentration intervals to represent FVIII. FVIII levels were divided into 5 quartile intervals according to numerical ranges to characterize the characteristics of participants in different intervals and to examine the relationship between FVIII and other parameters.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMeta-analysis of case-control and cohort studies\u003c/h3\u003e\n\u003cp\u003eAmong the 16 cohort studies, five studies examined the correlation between FVIII levels and myocardial infarction, four between FVIII levels and the composite outcome of cardiovascular events, four between FVIII levels and stroke, and three between FVIII levels and heart failure. There are 13 cohort studies of community-based populations, while others are patient cohorts that include populations with established cardiovascular disease. FVIII levels and the risk of cardiovascular events were positively correlated according to the overall effect size (HR 1.22, 95%CI 1.14\u0026ndash;1.30; heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;64%; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOf the six case-control studies, four explored the relationship between FVIII levels and stroke, and two explored the relationship between FVIII levels and myocardial infarction. The elevated FVIII levels are significantly associated with an increased risk of cardiovascular events based on the overall effect size (OR 2.69, 95%CI 2.06\u0026ndash;3.49, heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\n\u003ch3\u003eFVIII levels and myocardial infarction\u003c/h3\u003e\n\u003cp\u003eRegarding the relationship between FVIII levels and myocardial infarction, five cohort studies revealed a significant positive association (HR\u0026thinsp;=\u0026thinsp;1.18, 95% CI 1.06\u0026ndash;1.32; heterogeneity I\u0026sup2;=55%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), while two case-control studies yielded analogous results (OR\u0026thinsp;=\u0026thinsp;2.56, 95% CI 1.74\u0026ndash;3.77; heterogeneity I\u0026sup2; = 0%, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eFVIII levels and stroke\u003c/h2\u003e\u003cp\u003eAn analysis of four cohort studies demonstrated that the risk of stroke was positively correlated with increasing FVIII levels (HR\u0026thinsp;=\u0026thinsp;1.21, 95%CI 1.11\u0026ndash;1.32; heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;11%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Results of four case-control studies showed that the odds of having elevated FVIII levels were 2.80 times higher in the stroke group than in the control group (OR\u0026thinsp;=\u0026thinsp;2.80, 95% CI 1.95\u0026ndash;4.01; heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eFVIII levels and heart failure\u003c/h2\u003e\u003cp\u003eResults from three cohort studies demonstrated a significant association between elevated FVIII levels and increased risk of heart failure (HR 1.23, 95% CI 1.07\u0026ndash;1.42; heterogeneity I\u0026sup2; = 30%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eFVIII levels and composite outcome of cardiovascular disease\u003c/h2\u003e\u003cp\u003eThe composite outcome of cardiovascular disease is the occurrence of two or more cardiovascular events, including myocardial infarction, angina, stroke, transient ischemic attack, acute coronary syndrome, heart failure, and cardiovascular death. The definitions of composite outcome of cardiovascular disease in each included study are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of four cohort studies were conducted to evaluate the prognostic association between FVIII levels and the risk of a composite outcome of cardiovascular disease. The pooled results confirmed a statistically significant positive association between elevated FVIII levels and the risk of a composite outcome of cardiovascular disease (HR\u0026thinsp;=\u0026thinsp;1.39, 95%CI 1.05\u0026ndash;1.84; heterogeneity I\u0026sup2; = 86%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eSensitivity Analysis\u003c/h2\u003e\u003cp\u003eThe leave-one-out sensitivity analysis was conducted to assess the stability of these studies outcomes. As presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the effect sizes obtained after sequentially excluding each study all fell within the confidence interval of the preliminary results, indicating strong robustness of the findings in this study.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003ePublication bias\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the results of Egger's test for cohort studies and Begg's test for case-control studies regarding the correlation between FVIII levels and cardiovascular events. No evidence of publication bias was detected in case-control studies (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), whereas a certain degree of publication bias was observed in cohort studies. Therefore, we applied the trim-and-fill method to further analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Seven estimated missing virtual studies were included after three iterations of the linear method. The reanalyzed pooled effect values showed that there was a significantly positive correlation between FVIII levels and the risk of cardiovascular events (HR\u0026thinsp;=\u0026thinsp;1.13, 95% CI 1.06\u0026ndash;1.20).\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\u003eEgger\u0026rsquo;s test results\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eEgger\u0026lsquo;s Test\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eBegg\u0026rsquo;s Test\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntercept\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ez\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecase-control study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u0026mdash;\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecohort study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u0026mdash;\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\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this systematic review and meta-analysis, we observed that elevated FVIII levels were associated with an increased risk of cardiovascular events across both case-control and cohort studies. Subgroup analysis revealed a positive correlation between FVIII levels and the risk of myocardial infarction and stroke.\u003c/p\u003e\u003cp\u003eThe finding that patients with FVIII deficiency, haemophilic A, have an 80% reduction in coronary heart disease mortality than in the general population provides indirect evidence supporting a role for FVIII in the pathogenesis of ischaemic heart disease [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Rosendaal [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] considered that raised FVIII levels may predispose to ischaemic heart disease by increasing thrombogenic potential. Recently, instrumental variable or Mendelian randomization analyses of FVIII using results of recent FVIII GWAS in Europeans have suggested FVIII levels may be causally related to coronary heart disease risk [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Arterial thromboembolism is most commonly triggered by platelet aggregation following the rupture of the atherosclerotic plaques in the arteries, in contrast, coagulation factor dysregulation is more likely to cause venous clots. Conventional cardiovascular risk factors can explain only about 50% of cases of arterial thrombosis [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Thus, the role of clotting factors in the development of arterial thrombosis is also considered. The PLAT study showed that FVIII activity was significantly higher in myocardial infarction survivors than in patients with coronary disease only [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], and FVIII activity were found to have an independent association with myocardial infarction after 2 years follow-up of this cohort [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A case-control study assessed whether high FVIII, factor IX, and factor XI activity levels are associated with an increased myocardial infarction risk in young women [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], and found that high levels of FVIII and factor IX were associated with a more than twofold increased risk of myocardial infarction in contrast with high levels of factor XI. This suggests that FVIII is a role for secondary haemostasis in the aetiology of coronary thrombosis.\u003c/p\u003e\u003cp\u003eIschemic stroke is a heterogeneous disease that is caused by several underlying pathologic processes, of the role played by hemostasis in the pathogenesis is still controversial. The etiology of many ischemic stroke risk factors is still not well understood. Hemostatic factors constitute another plausible risk factor, since disturbance of the hemostatic balance is central to the pathogenesis of thrombosis. Findings indicate that high FVIII levels were significantly associated with acute stroke, stroke subtype (cardioembolic stroke), and neurological worsening after acute stroke [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Previous research has demonstrated that the rs688 genotype may determine levels of FVIII, which may explain its association with different stroke subtypes, including cerebral infarction and intracerebral hemorrhage [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Regarding ischemic stroke patients who underwent thrombolysis, a study found that having elevated FVIII activity, both immediately and 24 hours after thrombolysis, led to a higher risk for poor functional outcome at 90 days [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In addition, evidence indicates a positive association between elevated FVIII levels and carotid atherosclerosis, a common causes of acute cerebral infarction, in a Chinese population [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The results of the present meta-analysis further confirm the positive association between FVIII and ischemic stroke, with a low degree of heterogeneity across studies.\u003c/p\u003e\u003cp\u003eDespite modest heterogeneity, the results from all three cohort studies consistently showed a significant positive association between high FVIII levels and incident heart failure (HR 1.23, 95% CI 1.07\u0026ndash;1.42; heterogeneity I\u0026sup2;=30%). Hypercoagulability, systemic activation of blood coagulation, is a general feature of heart failure [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], and arterial and venous thrombotic events are a common complication of patients with heart failure [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Abdelsayed [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] observed a graded concentration response relationship between serum vWF levels and new-onset heart failure, with higher vWF concentrations associated with an increased likelihood of incident heart failure. It is plausible that chronic inflammation mediated by vWF in patients with elevated FVIII levels may contribute to endothelial dysfunction, vascular injury, and the progression of coronary therosclerosis or vasculopathy, ultimately leading to heart failure. There are relatively few studies on the relationship between FVIII and heart failure, and more research is needed to verify this in the future.\u003c/p\u003e\u003cp\u003eThe meta-analysis revealed a significant association between elevated FVIII levels and an increased risk of composite cardiovascular disease (HR\u0026thinsp;=\u0026thinsp;1.39, 95%CI 1.05\u0026ndash;1.84). However, substantial heterogeneity was observed across the included studies (I\u0026sup2; = 86%), which may be ascribed to variations in population characteristics, differences in laboratory methodologies for FVIII measurement, inconsistencies in the adjustment of confounding factors, and, most importantly, discrepancies in the definitions of cardiovascular events. The definitions of the composite cardiovascular disease outcome varied across the included studies in the present study. Heterogeneity in the definitions of cardiovascular events in cardiovascular research may have an important impact on the results of clinical trials, which in turn influence guidelines and practice. For instance, in the trial of evaluation of percutaneous coronary intervention versus coronary artery bypass surgery for effectiveness of left main revascularization, the conclusions of the EXCEL trial and the NOBLE trial are completely contradictory due to differences in the definitions of major adverse cardiac or cerebrovascular events [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Therefore, there is a pressing need to reach consensus on the standardized variables and their definitions across the whole of cardiology for use in cardiovascular research. The association between FVIII and composite outcome of cardiovascular disease was hence assessed as an exploratory analysis due to methodological limitations, specifically the limited number of included studies and the absence of standardized definitions of composite outcome of cardiovascular disease.\u003c/p\u003e\u003cp\u003eThe FVIII are required for continued thrombin generation and maintenance of fibrin formation [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The FVIII biological function is to act as a cofactor in the conversion of factor X to factor Xa by factor IXa in the presence of phospholipid and calcium, as an integral part of the intrinsic coagulation cascade [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The potential mechanism by which elevated FVIII promotes thrombosis may involve a direct enhancement of basal thrombin generation mediated by high FVIII levels, leading to increased levels of thrombin\u0026ndash;antithrombin complex and prothrombin fragments. This disrupts the balance between coagulation and fibrinolysis, particularly in the context of endothelial injury or stasis, thereby increasing the risk of thrombus formation [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Studies evaluating the effect of elevated FVIII on arterial thrombosis in mice, found that the rate of thrombin-antithrombin complex formation, and the final concentration of thrombin-antithrombin complexes, significantly increased as FVIII levels were elevated from 100% to 400% FVIII activity [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In addition, the acute elevation of circulating FVIII to 400% FVIII activity resulted in significantly decreased times to vessel occlusion. Another possibility is that high plasma FVIII levels induce resistance to the action of activated protein C, which exerts its anticoagulant effect by inactivating activated factor V and FVIII [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Currently, the available evidence tends to support that FVIII is a causal factor for thrombosis; however, the present study merely establishes an association between FVIII and cardiovascular events, without substantiating a causal relationship between them.\u003c/p\u003e\u003cp\u003eFVIII levels and the risk of cardiovascular events were positively correlated according to the overall effect size (HR 1.22, 95%CI 1.14\u0026ndash;1.30; heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;64%), but our meta-analysis revealed substantial heterogeneity across cohort studies, particularly within subgroups of composite cardiovascular disease (I\u0026sup2; = 86%). The heterogeneity may be attributable to variations in study design, population characteristics, FVIII measurement methodologies and critical confounder (namely, vWF), as well as differences in follow-up duration and endpoint definitions. In contrast, case-control studies demonstrated negligible heterogeneity, indicating consistent findings among these studies. FVIII levels have been observed to be influenced by multifactorial and driven by genetic processes, environmental factors, and biological variations, including age [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], sex [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], race [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], acute phase reactants [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], diabetes mellitus [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], and blood groups [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Furthermore, vWF level may be the driver of the association of FVIII with risk of thrombosis, since plasma levels of FVIII and vWF are highly correlated due to their circulate as a high-affinity non-covalent complex. The FVIII-vWF complex, is essential for platelet adhesion to the arterial subendothelium, raises the concentration of FVIII at sites of vascular damage by preventing rapid removal of this procoagulant protein from the circulation [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Increased vWF levels therefore may augment platelet adhesion, enhance shear stress-induced platelet aggregation, and increase plasma FVIII levels, thereby increasing risk of cerebral thrombosis when atherosclerotic plaques rupture. A study reported that FVIII and vWF showed independent associations with cardiovascular disease risk, and may be involved together with some conventional risk factors in the multifactorial mechanism of atherothrombotic phenomena in patients with preexisting coronary or cerebrovascular disease [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Finaly, the confounding factors adjusted for vary across studies. Unfortunately, nearly none of the 22 included studies adjusted for vWF-an important confounding factor that should not be overlooked. If the adjusting factors were merely confounding variables, then the multivariate relative risks are the most informative. However, if several risk factors operate through hemostatic mechanisms, then the relative risks adjusted only for age, race, and field center represent the mechanistic aspects of these hemostatic variables on coronary heart disease.\u003c/p\u003e\u003cp\u003eIt should be noted that a certain degree of publication bias was detected in cohort studies. After adjustment using the trim-and-fill method, the results consistent with the original findings, indicating a persistently significant positive association between FVIII levels and the risk of cardiovascular events. It is important to note that, owing to the limited number of included studies, the Egger's and Begg's tests exhibited insufficient statistical power, and the findings of the trim-and-fill analysis should be construed merely as exploratory. Consequently, the potential existence of publication bias cannot be ruled out in the present study.\u003c/p\u003e\u003cp\u003eThere are several limitations to our study. First, in the cohort studies, a high I\u0026sup2; value indicates substantial heterogeneity in our meta-analysis, with the subgroup of composite cardiovascular disease identified as the primary source of this heterogeneity. The observed heterogeneity may primarily stem from variations in the adjustment of multiple confounding variables and inconsistencies in the definition of composite cardiovascular disease outcomes. Second, despite adjustments for multiple confounding variables, including age, race, sex, blood group, hypertension, diabetes, and cholesterol, residual confounding may persist due to limitations across studies, with vWF being a particularly critical confounder that is insufficiently addressed in the 22 studies included in this study. Third, considerable heterogeneity existed in FVIII measurement. While the vast majority of studies quantified FVIII activity, a minority employed FVIII antigen assays, with methodology further compounded by inter-assay variability. Finally, as a meta-analysis of observational studies, the present research can only indicate an association between FVIII levels and cardiovascular events, but does not demonstrate causality. Further studies are warranted to explore this relationship.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, these findings suggest that elevated FVIII levels are correlated with an increased risk of various cardiovascular events, particularly myocardial infarction and stroke. In the future, prospective studies are needed to explore the potential value of FVIII in the prevention and treatment of cardiovascular diseases. Additionally, genetic approaches can be combined to verify the causal relationship between FVIII and cardiovascular diseases, providing a crucial foundation for developing FVIII-focused anticoagulation for the primary prevention of cardiovascular disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFVIII\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecoagulation Factor VIII\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003evWF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003evon Willebrand factor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMOOSE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMeta-analysis of Observational Studies in Epidemiology\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePRISMA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analyses.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eThis article does not contain any studies with human participants or animals performed by any of the authors.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was supported by the National Key R \u0026amp; D Program of China [grant numbers 2024YFC3505700] and the National Natural Science Foundation of China [grant number 82102288].\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eFeng Zhu (FZ) was responsible for the study design, resolution of disagreements, and critical appraisal of the study. Feifei Wang (FFW), Yunhe Zhang (YHZ) and Chun Wang (CW) performed literature search. WFF, Wenchi Li (WCL) and Yiqing Lin (YQL) performed study selection and data extraction. WFF and LYQ performed bias assessment. WFF performed review writing. LWC performed statistical analysis. WFF are considered the first authors. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data used in the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eArnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596\u0026ndash;646.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFalk E, Fern\u0026aacute;ndez-Ortiz A. Role of thrombosis in atherosclerosis and its complications. Am J Cardiol. 1995;75(6):B3\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKiouptsi K, Reinhardt C. Physiological Roles of the von Willebrand Factor-Factor VIII Interaction. Subcell Biochem. 2020;94:437\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFay PJ. Activation of factor VIII and mechanisms of cofactor action. Blood Rev. 2004;18(1):1\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoster T, Blann AD, Bri\u0026euml;t E, et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995;345(8943):152\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartinelli I. von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis. Semin Hematol. 2005;42(1):49\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZakai NA, Judd SE, Kissela B, et al. Factor VIII, Protein C and Cardiovascular Disease Risk: The REasons for Geographic and Racial Differences in Stroke Study (REGARDS). Thromb Haemost. 2018;118(7):1305\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKraaijenhagen RA, in't Anker PS, Koopman MM, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost. 2000;83(1):5\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCortellaro M, Boschetti C, Cofrancesco E, et al. The PLAT study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients. Arterioscler Thromb. 1992;12:1063\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRohmann JL, Huo SF, Sperber PS, et al. Coagulation factor XII, XI, and VIII activity levels and secondary events after first ischemic stroke. J Thromb Haemost. 2020;18(12):3316\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFolsom AR, Wu KK, Rosamond WD, et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 1997;96(4):1102\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZakai NA, Katz R, Jenny NS, et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. J Thromb Haemost. 2007;5(6):1128\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRice GI, Grant PJ. FVIII coagulant activity and antigen in subjects with ischaemic heart disease. Thromb Haemost. 1998;80(5):757\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarshfield EL, Sims MC, Traylor M, et al. The role of haematological traits in risk of ischaemic stroke and its subtypes. Brain. 2020;143(1):210\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Rev Esp Cardiol (Engl Ed). 2021;74(9):790\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFolsom AR, Wu KK, Shahar E, et al. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Arterioscler Thromb. 1993;13(12):1829\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeade TW, Cooper JA, Stirling Y, et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol. 1994;88(3):601\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFolsom AR, Rosamond WD, Shahar E, et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation. 1999;100(7):736\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRumley A, Lowe GD, Sweetnam PM, et al. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study. Br J Haematol. 1999;105(1):110\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTracy RP, Arnold AM, Ettinger W, et al. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol. 1999;19(7):1776\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarcias EB, Ederhy S, Lang S, et al. Are von willebrand factor and factor 8 associated with cardiovascular events including heart failure in non-valvular atrial fibrillation? J Am Coll Cardiol. 2011;57(14):E67.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWannamethee SG, Whincup PH, Papacosta O, et al. Associations between blood coagulation markers, NT-proBNP and risk of incident heart failure in older men: The British Regional Heart Study. Int J Cardiol. 2017;230:567\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaffield LM, Lu AT, Szeto MD, et al. Coagulation factor VIII: Relationship to cardiovascular disease risk and whole genome sequence and epigenome-wide analysis in African Americans. J Thromb Haemost. 2020;18(6):1335\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingleton MJ, Yuan Y, Dawood FZ, et al. Multiple Blood Biomarkers and Stroke Risk in Atrial Fibrillation: The REGARDS Study. J Am Heart Assoc. 2021;10(15):e020157.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLowe G, Peters S, Rumley A, et al. Associations of Hemostatic Variables with Cardiovascular Disease and Total Mortality: The Glasgow MONICA Study. TH Open. 2022;6(2):e107\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdelsayed K, Najah Q, Mohamed AA et al. Prognostic implications of factor VIII levels in African Americans: insights from a propensity-matched US-based multicenter retrospective analysis. J Thromb Thrombolysis. 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKarttunen V, Alfthan G, Hiltunen L, et al. Risk factors for cryptogenic ischaemic stroke. Eur J Neurol. 2002;9(6):625\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTanis B, Algra A, Graaf Y, et al. Procoagulant factors and the risk of myocardial infarction in young women. Eur J Haematol. 2006;77(1):67\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChang TR, Albright KC, Boehme AK, et al. Factor VIII in the setting of acute ischemic stroke among patients with suspected hypercoagulable state. Clin Appl Thromb Hemost. 2014;20(2):124\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVan Dooren D, Rosendaal F, Algra A, et al. Increased risk of ischaemic stroke with high levels of coagulation factor VIII activity in combination with oral contraceptives. Int J stroke. 2015;10:216\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKuo CY, Lin CH, Kuo YW, et al. Factor VIII levels are associated with ischemic stroke, stroke subtypes and neurological worsening. Curr Neurovasc Res. 2015;12(1):85\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTriemstra M, Rosendaal FR, Smit C, et al. Mortality in Patients with Hemophilia. Changes in a Dutch Population from 1986 to 1992 and 1973 to 1986. Ann Intern Med. 1995;123:823\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosendaal FR, Brie\u0026uml;t E, Stibbe J, et al. Haemophilia protects against ischaemic heart disease: a study of risk factors. Br J Haematol. 1990;75:525\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSabater-Lleal M, Huffman JE, de Vries PS, et al. Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. Circulation. 2019;139:620\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMałecki R, Adamiec R. Factor VIII and the risk of arterial thrombosis. Postepy igieny i medycyny doświadczalnej (Online). 2006;60:602\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCortellaro M, Boschetti C, Cofrancesco E, et al. The PLAT Study: a multidisciplinary study of hemostatic function and conventional risk factors in vascular disease patients. Atherosclerosis. 1991;90:109\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee JD, Hsiao KM, Lee TH, et al. Genetic polymorphism of LDLR (rs688) is associated with primary intracerebral hemorrhage. Curr Neurovasc Res. 2014;11(1):10\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eToth NK, Szekely EG, Czuriga-Kovacs KR, et al. Elevated Factor VIII and von Willebrand Factor Levels Predict Unfavorable Outcome in Stroke Patients Treated with Intravenous Thrombolysis. Front Neurol. 2017;8:721.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePan WH, Bai CH, Chen JR, et al. Associations between carotid atherosclerosis and high factor VIII activity, dyslipidemia, and hypertension. Stroke. 1997;28(1):88\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim JH, Shah P, Tantry US, et al. Coagulation Abnormalities in Heart Failure: Pathophysiology and Therapeutic Implications. Curr Heart Fail Rep. 2016;13:319\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZannad F, Stough WG, Regnault V, et al. Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges. Int J Cardiol. 2013;167:1772\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBhatty A, Wilkinson C, Sydes M, et al. Defining the need for cardiovascular event definitions. Eur Heart J Qual Care Clin Outcomes. 2024;10(2):105\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991;30:10363\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRyland JK, Lawrie AS, Mackie IJ, et al. Persistent high factor VIII activity leading to increased thrombin generation - a prospective cohort study. Thromb Res. 2012;129(4):447\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSzlam F, Sreeram G, Solomon C, et al. Elevated factor VIII enhances thrombin generation in the presence of factor VIII-deficiency, factor XI-deficiency or fondaparinux. Thromb Res. 2011;127(2):135\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDe Mitrio V, Marino R, Scaraggi FA, et al. Influence of factor VIII/von Willebrand complex on the activated protein C-resistance phenotype and on the risk for venous thromboembolism in heterozygous carriers of the factor V Leiden mutation. Blood Coagul Fibrinolysis. 1999;10(7):409\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eConlan MG, Folsom AR, Finch A, et al. Associations of Factor VIII and von Willebrand Factor with Age,Race, Sex, and Risk Factors for Atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost. 1993;70:380\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHaverkate F, Thompson SG, Duckert F. Haemostasis Factors in Angina Pectoris; Relation to Gender, Age and Acute-phase Reaction. Results of the ECAT Angina Pectoris Study Group. Thromb Haemost. 1995;73:561\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFolsom AR, Basu S, Hong CP, et al. Reasons for differences in the incidence of venous thromboembolism in black versus white Americans. Am J Med. 2019;132(8):970\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePreston AE, Barr A. The Plasma Concentration of Factor VIII in the Normal Population. II. The Effects of Age, Sex, and Blood Group. Br J Haematol. 1964;10:238\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRuggeri ZM, Zimmerman T. von Willebrand factor and von Willebrand disease. Blood. 1987;70:895\u0026ndash;904.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"factor VIII, ischemic stroke, myocardial infarction, cardiovascular events, heart failure","lastPublishedDoi":"10.21203/rs.3.rs-8021341/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8021341/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eNumerous epidemiological studies have explored the association between coagulation Factor VIII (FVIII) and cardiovascular event risk; however, the overall results are still inconsistent.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eThe aim of this systematic review and meta-analysis was to evaluate the relationship between FVIII and the risk of various cardiovascular events.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eTwo independent reviewers screened all available literature to identify studies that met the inclusion criteria. Heterogeneity was evaluated quantitatively via the I\u0026sup2; statistic, and corresponding analyses were conducted using random-effects model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 22 original studies were included in the quantitative meta-analysis. The meta-analysis results of both case-control and cohort studies showed a positive correlation between FVIII levels and the risk of cardiovascular events (OR\u0026thinsp;=\u0026thinsp;2.69, 95%CI 2.06\u0026ndash;3.49, heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; HR\u0026thinsp;=\u0026thinsp;1.22, 95%CI 1.14\u0026ndash;1.30; heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;64%). In the cohort studies, subgroup analysis revealed a positive correlation between FVIII levels and the risk of myocardial infarction (HR\u0026thinsp;=\u0026thinsp;1.18, 95% CI 1.06\u0026ndash;1.32; heterogeneity I\u0026sup2;=55%), ischemic stroke (HR\u0026thinsp;=\u0026thinsp;1.21, 95%CI 1.11\u0026ndash;1.32; heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;11%), heart failure (HR 1.23, 95% CI 1.07\u0026ndash;1.42; heterogeneity I\u0026sup2;=30%), and composite outcome of cardiovascular disease (HR\u0026thinsp;=\u0026thinsp;1.39, 95%CI 1.05\u0026ndash;1.84; heterogeneity I\u0026sup2; = 86%). In the case-control studies, subgroup analysis revealed a positive correlation between FVIII levels and the risk of myocardial infarction (OR\u0026thinsp;=\u0026thinsp;2.56, 95% CI 1.74\u0026ndash;3.77; heterogeneity I\u0026sup2; = 0%) and ischemic stroke (OR\u0026thinsp;=\u0026thinsp;2.80, 95% CI 1.95\u0026ndash;4.01; heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe results of this study demonstrate a positive association between elevated FVIII levels and an increased risk of cardiovascular events, particularly myocardial infarction and stroke.\u003c/p\u003e","manuscriptTitle":"Coagulation factor VIII levels and the risk of cardiovascular events: Systematic review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 10:43:30","doi":"10.21203/rs.3.rs-8021341/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-20T00:03:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-19T20:20:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"171841600665768264457435316625441896322","date":"2026-04-18T18:57:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-18T22:13:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"101459821796500003692578775703113543567","date":"2025-12-04T11:30:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-03T17:14:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-05T06:15:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-05T06:15:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thrombosis Journal","date":"2025-11-03T16:30:56+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":"bead4cd2-64fd-4b54-ac68-c123fb3417f2","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T00:08:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 10:43:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8021341","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8021341","identity":"rs-8021341","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}