Elevated factor VIII levels and risk of venous thrombosis P. Vince Jenkins, 1 Orla Rawley, 1 Owen P. Smith 2 and James S. O’Donnell 1,3 1 Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James’s Hospital, Trinity College Dublin, Dublin, 2 Department of Haematology, Our Lady’s Children’s Hospital, Dublin, and 3 National Centre for Hereditary Coagulation Disorders, St James’s Hospital, Dublin, Ireland Summary Modern thrombophilia testing fails to identify any underly- ing prothrombotic tendency in a significant number of patients presenting with objectively confirmed venous throm- boemboembolism (VTE). This observation has led to a search for other novel inherited or acquired human throm- bophilias. Although a number of putative mechanisms have been described, the evidence behind many of these candi- dates remains weak. In contrast, an increasing body of work supports the hypothesis that increased plasma factor VIII (FVIII) levels may be important in this context. An associa- tion between elevated plasma FVIII levels and VTE was first described in the Leiden Thrombophilia Study (LETS). Subse- quently, these conclusions have been supported by an increasing number of independent case–control studies. Cumulatively, these studies have clearly demonstrated that high FVIII levels constitute a prevalent, dose-dependent risk factor for VTE. Furthermore, more recent studies have shown that the risk of recurrent venous thrombosis is also significantly increased in patients with high FVIII levels. In this review, we present the evidence supporting the hypothe- sis that elevated FVIII levels constitute a clinically important thrombophilia. In addition, we examine the biological mech- anisms that may underlie persistently elevated FVIII levels, and the pathways through which high FVIII may serve to increase thrombotic risk. Keywords: factor VIII, von Willebrand factor, ABO blood group, venous thrombosis. Despite significant advances in the field, current state-of-the- art thrombophilia testing still fails to identify an underlying inherited or acquired prothrombotic tendency in up to 50% of patients presenting with an objectively confirmed venous thromboembolism (VTE) (Dahlba ¨ck, 2008). This observation has prompted the search for other novel pathological pro- thrombotic mechanisms. Bearing in mind the complexity of the coagulation and fibrinolytic systems, it is clear that many other candidate proteins could be important in this context. Moreover, it may seem self-evident that elevation of specific procoagulant factors could increase risk of thrombosis. How- ever, although this relationship appears to be true for some coagulation factors (e.g. factor XI and prothrombin) (Meijers et al, 2000; Poort et al, 1996), it does not apply for all factors (e.g. factor V) (Kamphuisen et al, 2000a). Factor VIII (FVIII) is a plasma sialoglycoprotein that plays an essential role in normal haemostasis by acting as a critical cofactor for the serine protease, activated factor IX (FIXa). For many years, it has been recognized that FVIII deficiency in patients with haemophilia A results in a significant bleed- ing diathesis. Over more recent years, increasing evidence suggests that the converse is also true, in that high plasma levels of FVIII may constitute a clinically important risk fac- tor for thrombosis. In this review, we examine the evidence supporting the hypothesis that elevated plasma FVIII levels constitute a common and dose-dependent risk factor for venous thrombosis. Elevated FVIII levels and venous thrombosis The Leiden Thrombophilia Study (LETS) was the first to report an association between high plasma levels of FVIII and VTE (Koster et al, 1995). This case–control study enrolled 301 patients with first objectively confirmed VTE, together with a similar number of healthy controls matched for age and sex. Although the median time interval between acute thrombosis and FVIII coagulant activity (FVIII:C) mea- surement was 18 months (minimum 6 months) elevated FVIII:C levels (>150 iu/dl) were present in 25% of the patient cohort, compared to 11% of controls. Univariate analysis demonstrated that FVIII:C, von Willebranf factor antigen (VWF:Ag) and non-O blood group were all associ- ated with increased risk for VTE. However, on subsequent multivariate analysis, only FVIII:C levels remained a signifi- cant independent risk factor. These data suggest that plasma VWF:Ag and ABO blood group are only risk factors for VTE by virtue of their influence on plasma FVIII:C levels. When adjusted for ABO blood group, an odds ratio of 4·8 [95% confidence interval (CI) 2·3–10·0] was determined for Correspondence: Professor James O’Donnell, Haemostasis Research Group, Institute of Molecular Medicine, St James’s Hospital, Dublin 8, Ireland. E-mail jodonne@tcd.ie ª 2012 Blackwell Publishing Ltd First published online 25 April 2012 British Journal of Haematology, 2012, 157, 653–663 doi:10.1111/j.1365-2141.2012.09134.x review