People with low levels of von Willebrand factor (VWF) had a lower risk of incident cardiovascular disease (CVD), according to a study published in Research & Practice in Thrombosis & Haematosis. Henri M.H. Spronk, PhD, of Cardiovascular Research Institute Maastricht (CARIM) at Maastricht University Medical Center in the Netherlands, and colleagues conducted a study to test the hypothesis that the lower risk for CVD seen in patients with von Willebrand disease (VWD) might also occur in people at the lower end of VWF activity and antigen range.
In prior studies, “higher levels of VWF were repeatedly associated with [CVD], in particular arterial thrombosis; thus, SNPs [single-nucleotide polymorphisms] affecting the VWF may be directly linked to the incidence of arterial thrombosis,” researchers wrote. “Studies investigating the effect of VWD on CVD in humans demonstrated a significantly lower prevalence of CVD in [patients with VWD].”
This study included 5,000 individuals ages 35 to 74 who were enrolled from April 2007 to October 2008 in the prospective Gutenberg Health Study. Dr. Spronk and colleagues assessed VWF antigen and VWF activity using an enzyme-linked immunosorbent assay and an immunologic-based assay. The primary outcomes were incidence of myocardial infarction (MI) and death related to CVD.
The researchers set a threshold considered to be “low VWF” as a VWF antigen level of 83% and a VWF activity level of 76.2%.
After adjusting for age and sex, VWF activity levels below 76.2% were associated with a 40% decreased relative risk (RR) for CVD (RR=0.57; 95% CI 0.35-0.90). The association remained after adjusting for traditional cardiovascular risk factors (RR=0.59; 95% CI 0.37-0.95) and for levels of factor VIII (FVIII; RR=0.60; 95% CI 0.36-0.99).
VWF antigen levels below 83% were associated with a 40% decreased risk for all-cause mortality (RR=0.61; 95% CI 0.41-0.91). The researchers noted, however, that the association was lost after adjusting for FVIII levels.
Cumulative incidence plots showed that low levels of VWF antigen and VWF activity were significantly associated with fewer deaths related to CVD.
As a potential explanation for these associations, the researchers pointed out that VWF “affects hemostasis by mediating platelet adhesion to the damaged vascular wall on the one hand, as well as by binding to FVIII, thereby limiting its degradation on the other hand.”
Hemostasis also plays a role in atherosclerosis development, eventually manifesting as CVD.
“Hence, physiologically low VWF antigen and activity could reduce platelet adhesion and activation, reducing not only procoagulant effects of platelets but potentially also their inflammatory role,” the researchers wrote.
Of the 5,000 enrolled participants, 741 were lost to follow-up. The researchers pointed out that the rate of prevalent CVD was 20.8% in this group of patients compared to 11.4% in the study population, which could be considered a potential bias. In addition, the study could be limited by unknown confounders that were not measured as part of the Gutenberg Health Study.
Finally, the researchers questioned whether the findings from this study – that VWF could be a target for therapeutic prevention of CVD – could lead to any action.
“On the one side, reducing levels of VWF will also diminish FVIII levels, thereby inducing a bleeding tendency,” they wrote. “On the other side, reducing FVIII levels to approximately 50% in those with levels above 100% and high CVD risk could be beneficial without apparent bleeding risk.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Van Paridon PCS, Panova-Noeva M, can Oerle R, et al. Lower levels of vWF are associated with lower risk of cardiovascular disease. Res Pract Thromb Haemost. 2022;6(7):e12797.
Perspectives
VWF has been studied as a biomarker across a spectrum of disorders, particularly CVD. VWF is a multimeric glycoprotein synthesized by endothelial cells and megakaryocytes, and it is stored in endothelial Weibel-Palade bodies and platelet alpha granules. Release of VWF is induced by inflammatory agonists, and VWF is a commonly used biomarker for endothelial activation and thrombogenesis1 with prognostic value in venous thromboembolic disease, and ischemic heart and peripheral vascular diseases.
The study by van Paridon and colleagues expands existing evidence for VWF as a biomarker of CVD. Building upon data showing that patients with VWD demonstrate relative protection against CVD, the authors assessed the relationship between low-normal VWF antigen and activity levels and CVD. They show that VWF antigen and activity correlates with traditional cardiovascular risk factors, and that VWF activity below the 20th percentile of the reference group (i.e., below 76.2%) was associated with a decreased relative risk for CVD independent of age, sex, traditional cardiovascular risk factors, and FVIII levels.
Challenges in VWF testing and physiologic fluctuations in individual levels may present logistical considerations in the clinical application of VWF as a biomarker. For example, the ristocetin cofactor assay, a surrogate for VWF activity, may display variation of up to 50% between laboratories, as well as a false positive rate related to a VWF domain A1 variant.2 Moreover, individual levels are influenced by the acute phase response and other factors, notably ABO blood type.
It remains uncertain whether VWF is causal in the progression of vascular disease and if measures aimed at reducing VWF levels will be beneficial therapeutically. The role of FVIII is a potential confounder and may be difficult to tease out; FVIII and VWF circulate in plasma as a tightly bound complex, and VWF is a key functional partner for FVIII with significant roles in FVIII production, stabilization, conformation, and immunogenicity.3
CVD remains the leading cause of death in the U.S.4 VWF may be a useful biomarker for incorporation into CVD risk assessment models and a potential target for reducing cardiovascular risk.
Anne Hubben, MD
Taussig Cancer Institute, Cleveland Clinic Foundation
Cleveland, OH
Keith McCrae, MD
Taussig Cancer Institute, Cleveland Clinic Foundation and
Department of Cardiovascular and Metabolic Sciences,
Cleveland Clinic
Cleveland, OH
References
- Lip GYH, Blann A. von Willebrand factor: a marker of endothelial dysfunction in vascular disorders? Cardiovasc Res. 1997;34(2):255-265.
- Roberts JC, Morateck PA, Christopherson PA. Rapid discrimination of the phenotypic variants of von Willebrand disease. Blood. 2016;127(20):2472-2480.
- Federici AB. The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica. 2003;88(6):EREP02.
- Murphy SL, Kochanek KD, Xu JQ, Arias E. Mortality in the United States, 2020. NCHS Data Brief, no 427. Hyattsville, MD: National Center for Health Statistics; December 22, 2021.