High concentrations of coagulation factor VIII and thrombosis: is the factor VIII‐binding domain of von Willebrand factor implicated?

Bowen, Derrick John; Maclean, Rhona; Pellard, S.; Collins, Peter William

doi:10.1046/j.1365-2141.2001.02830.x

Cited by 14 publications

(6 citation statements)

References 10 publications

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“…No relationship with VWF levels, factor VIII:Ag levels or an increased risk of venous thrombosis was found. These results are in agreement with recent data of Bowen et al (2001) who did not find gain‐of‐function mutations in the factor VIII‐binding domain of VWF that could explain elevated factor VIII levels.…”

Section: Discussionsupporting

confidence: 93%

High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene

et al. 2001

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High factor VIII levels increase the risk of venous thromboembolism, but the mechanisms that cause high factor VIII levels are unclear. In 301 thrombosis patients and 301 matched healthy controls, factor VIII antigen (VIII:Ag) levels > or = 150 IU/dl increased the thrombosis risk more than fivefold. We investigated whether high factor VIII:Ag levels result from a genetic variation in the factor VIII or von Willebrand factor (VWF) genes. Six polymorphisms in the VWF gene and two CA-repeats in the factor VIII gene were not associated with plasma VWF levels, factor VIII:Ag levels, or thrombosis risk. Our data do not support the hypothesis that a single functional sequence variation in the factor VIII or VWF gene explains the majority of high factor VIII levels and thrombotic risk.

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Section: Discussionsupporting

confidence: 93%

High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene

et al. 2001

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“…In theory, a gain of function mutation in the FVIII‐binding domain of VWF may lead to high FVIII levels. However, sequence analysis in 13 thrombosis patients with high FVIII levels did not show any novel mutations in this binding domain [44]. Also no association of FVIII levels with two polymorphisms in the region coding for the FVIII‐binding domain of VWF was found [23].…”

Section: Discussionmentioning

confidence: 99%

Linkage analysis of factor VIII and von Willebrand factor loci as quantitative trait loci

Visser

Sandkuijl²,

Lensen

et al. 2003

Journal of Thrombosis and Haemostasis

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Summary. Elevated factor (F)VIII levels contribute to venous thrombotic risk. FVIII levels are determined to a large extent by levels of von Willebrand factor (VWF), its carrier protein which protects FVIII against proteolysis. VWF levels are largely dependent on ABO blood group. Subjects with blood group non-O have higher VWF and FVIII levels than individuals with blood group O. Apart from ABO blood group no genetic determinants of high FVIII levels have been identified, whereas clustering of FVIII levels has been reported within families even after adjustment for ABO blood group and VWF levels. We investigated the FVIII and VWF loci as possible quantitative trait loci (QTL) influencing FVIII and VWF levels. Two sequence repeats in the FVIII gene and three repeats in the VWF gene were typed in 52 FV Leiden families. Multipoint sibpair linkage analysis was performed with the MAPMAKER/ SIBS program. FVIII levels adjusted for VWF levels and age, and VWF levels adjusted for ABO blood group and age, were used for this linkage analysis. No linkage of FVIII levels to the FVIII locus was found, whereas we found evidence that the VWF locus contains a QTL for VWF levels [maximum likelihood no dominance variance lod score ¼ 0.70 (P ¼ 0.04) and non-parametric Z-score ¼ 1.92 (P ¼ 0.03)]. About 20% of the total variation in VWF levels may be attributed to this VWF locus.

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“…In this context, several groups have sought to investigate whether VWF gene variation may be important in some patients with elevated FVIII levels. In a study of 13 patients with VTE and high FVIII:C, Bowen et al () failed to identify any sequence mutations within exons 18–24 of the VWF gene that encode the FVIII‐binding domain. Moreover, two polymorphisms in this same region of the VWF gene (2365 A/G; exon 18 and 2555 G/A; exon 20) were not associated with any variation in plasma FVIII:Ag levels, or thrombotic risk (Kamphuisen et al , ).…”

Section: Fviii and Vwf Gene Analysis In Patients With High Fviii:cmentioning

confidence: 99%

Elevated factor VIII levels and risk of venous thrombosis

et al. 2012

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SummaryModern thrombophilia testing fails to identify any underlying prothrombotic tendency in a significant number of patients presenting with objectively confirmed venous thromboemboembolism (VTE). This observation has led to a search for other novel inherited or acquired human thrombophilias. Although a number of putative mechanisms have been described, the evidence behind many of these candidates 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 association between elevated plasma FVIII levels and VTE was first described in the Leiden Thrombophilia Study (LETS). Subsequently, 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 hypothesis that elevated FVIII levels constitute a clinically important thrombophilia. In addition, we examine the biological mechanisms that may underlie persistently elevated FVIII levels, and the pathways through which high FVIII may serve to increase thrombotic risk.

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High concentrations of coagulation factor VIII and thrombosis: is the factor VIII‐binding domain of von Willebrand factor implicated?

Cited by 14 publications

References 10 publications

High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene

High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene

Linkage analysis of factor VIII and von Willebrand factor loci as quantitative trait loci

Elevated factor VIII levels and risk of venous thrombosis

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