von Willebrand Factor and Aging Barbara A. Konkle, MD1,2 1 Puget Sound Blood Center, Seattle, Washington 2 Division of Hematology, Department of Medicine, University of

Washington, Seattle, Washington

Address for correspondence Barbara A. Konkle, MD, Puget Sound Blood Center, 921 Terry Avenue, Seattle, WA 98104 (e-mail: [email protected]).



► von Willebrand factor ► von Willebrand disease ► factor VIII ► hemorrhage ► thrombosis ► aging

von Willebrand factor (VWF) plays critical roles in initiating primary hemostasis and extending the half-life of coagulation factor VIII in circulation. VWF levels increase with age and elevated levels are associated with an increased risk of venous thromboembolism and cardiovascular disease (CVD). Patients with von Willebrand disease (VWD) due to a deficiency or dysfunction of VWF may have symptoms that ameliorate with aging or may have exacerbation of their disease. Bleeding sites of particular challenge in the aging patient include gastrointestinal bleeding and hematuria. Some medications used to treat VWD should be used with special precaution in older patients, including desmopressin and VWF-containing factor concentrates. Patients with VWD may have some protection from CVD, but in those patients who develop CVD, management is very challenging, given the role of antiplatelet therapy as the mainstay of treatment.

von Willebrand factor (VWF) is a large multimeric glycoprotein with two primary functions.1 VWF binds to both platelets and subendothelial structures, acting as a bridging molecule for initial reactions during primary hemostasis. The largest multimers are created by the polymerization of subunits that all contain the same binding sites, and the repeated binding sites make VWF a molecule that is particularly well suited to act as a bridge between cells and other structures of the vasculature. VWF also binds factor VIII (FVIII), protecting FVIII from proteolysis in the circulation. This noncovalent interaction of VWF with FVIII prolongs the half-life of FVIII in the circulation fivefold. In plasma, FVIII is present in an approximate 1:50 molar ratio with VWF; however, in vitro binding can occur at a 1:1 ratio.

von Willebrand Factor Levels and Aging in the General Population In addition to a broad statistical normal range of VWF in plasma (50–200%), there are physiological and pathological conditions which alter the level of VWF in the circulation, including aging. Both VWF and FVIII levels increase with age. In adults, VWF increases approximately 1 to 2% per year.2

published online August 24, 2014

Issue Theme Age-Related Changes in Thrombosis and Hemostasis; Guest Editors: Hau C. Kwaan, MD, FRCP, Brandon J. McMahon, MD, and Elaine M. Hylek, MD, MPH.

However, the absolute increase is greater as individuals age.3 Overall, the increase is similar in women and men, although, in a study of blood donors in South Wales, there was a significant difference between men and women, with women having a higher rate of increase in middle age,3 which could reflect changes in hormonal status. Hormones affect VWF levels, although changes with menopause are minor compared with those observed in pregnancy.4,5 VWF levels are controlled by both genetic and environmental factors. In a study of older Danish (aged 73–94 years) monozygotic and dizygotic twins, Bladbjerg et al found that, for VWF, environment had an increasing influence on levels over genetics with aging.6 As an acute phase reactant, VWF (and FVIII) levels are increased during physiologic changes that occur with inflammation.7 Increases in VWF with aging are postulated to be secondary to endothelial activation, although that process likely accounts for only a portion of the variation seen.

Elevated VWF Levels and Thrombosis Elevated VWF levels are associated with increased risk of venous thromboembolism (VTE), cardiovascular disease

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DOI http://dx.doi.org/ 10.1055/s-0034-1389079. ISSN 0094-6176.

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Semin Thromb Hemost 2014;40:640–644.

(CVD), and ischemic stroke.8–11 In the Multiple Environmental and Genetic Assessment of risk factor for venous thrombosis study of patients followed in outpatient anticoagulation clinics in the Netherlands, elevated VWF levels (>80th percentile of control population) were associated with an approximate 4-fold increase risk of VTE, and when combined with a major illness and immobilization, the risk increased to 88-fold (95% CI: 33.9–228.3).9 The Rotterdam study of CVD in participants 55 years of age found an association between increasing quartile of VWF antigen level and coronary heart disease.10 Elevated FVIII levels are also well-established risk factors for VTE and CVD. While VWF and FVIII levels are generally concordant, there is evidence for independent regulation. In an analysis of the Atherosclerosis in Community database, FVIII activity was mismatched with VWF antigen in up to 27% of subjects.12 The role of VWF in atherosclerosis and coronary artery syndromes is still being defined. Although markedly decreased levels of VWF play a protective role in preventing the development of coronary atherosclerosis in an animal model with Type 3 von Willebrand disease (VWD), studies in humans have not shown that low VWF levels protect against atherosclerosis.13,14 However, protection from CVD was found in a study of 635 patients (VWF antigen < 30% and FVIII < 40%) in the Netherlands, where the combined prevalence of acute myocardial infarction, ischemic stroke, and coronary heart disease was 39 and 63% lower than reported in two reference Dutch populations.15 Studies have identified variants within the VWF gene that are associated with VWF levels, VTE, and cardiovascular risk.16,17 Future findings should provide insight into VWF levels and influences related to genetics and aging.

The Impact of Aging on von Willebrand Disease VWD is due to a partial or complete, or near complete, quantitative deficiency, termed types 1 and 3, respectively, or qualitative deficiencies, termed types 2A, 2B, 2M, and 2N, of VWF (see ►Table 1). Given the quantitative deficiency in


type 1 VWD, one could expect an increase in levels as a natural consequence of aging. This has not been systematically studied, but clinical experience suggests that some patients have an increase in levels and some do not. The underlying causative mutation likely impacts whether an increase with aging is seen in patients with type 1 VWD. While some patients are heterozygous for a null mutation, we now know that type 1 VWD frequently results from mutations that affect synthesis, processing, and secretion.18 It would follow that some defects in processing would not allow expression of age-related increases. In addition, low levels of VWF with a diagnosis of mild type 1 VWD may be due to genetic and environmental influences outside of the VWF locus, including ABO blood type. These patients may be the most likely to have levels normalize with age.

VWD and Cardiovascular Disease While VWD may provide some protection from CVD, patients with VWD still develop CVD and require management. Patients with VWD usually have worsening bleeding symptoms with ingestion of antiplatelet agents. This makes standard treatment of CVD challenging. In patients with mild VWD, a trial of low-dose aspirin can be undertaken, but is unlikely to be tolerated in those with more severe disease. If such patients have CVD, the approach to therapy should be carefully considered. Antiplatelet treatment, particularly dual therapy, may require treatment for bleeding to counter the drug effect, so medicated cardiac stents, where extended antiplatelet therapy is needed, should be avoided. Coronary artery bypass surgery, albeit requiring hemostatic support during surgery and postoperatively, may be a better option overall. Anticoagulation may be tolerated, particularly in patients with milder disease. Patients with lower FVIII activity may be more at risk of bleeding in this setting. Before prescribing anticoagulation, the severity of disease and underlying bleeding and thrombotic risks will need to be taken into consideration and decisions for therapy made on an individual patient basis. The challenges in managing CVD in patients with VWD call for more emphasis on prevention. Patients with VWD should

Table 1 von Willebrand disease classification




Frequency of typea

VWF antigen

VWF activity

FVIII activity

Multimer pattern


Autosomal dominant


Uniform ↓ All multimers present


Autosomal dominant (and recessive)



↓ Large and intermediate multimers


Autosomal dominant



↓ Large multimers


Autosomal dominant (and recessive)

Von Willebrand factor and aging.

von Willebrand factor (VWF) plays critical roles in initiating primary hemostasis and extending the half-life of coagulation factor VIII in circulatio...
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