Plasma von Willebrand factor and stroke risk

BIRMINGHAM, UNITED KINGDOM. Platelet activation and aggregation is a crucial first step in the formation of blood clots (thrombi) that may cause an ischemic stroke. Platelets, like red and white blood cells, are an integral part of normal blood. In spite of their small size they contain an amazing variety of enzymes that interact with other plasma components crucial to the formation of blood clots. Among the more significant of these components are thromboxane A2, ADP (adenosine diphosphate) and von Willebrand factor (vWF). The first step in the platelet aggregation process involves the adherence of platelets to sub-endothelial tissue or a foreign object. Von Willebrand factor is the main “glue” involved in platelet sticking to each other and to the vessel wall.

There is evidence that thrombosis in the left atrial appendage (LAA) may be related to elevated levels of vWF. There is also evidence that a high plasma level of vWF increases the risk of stroke and cardiovascular events in non-anticoagulated atrial fibrillation (AF) patients. Now a group of researchers from the University of Birmingham and the University of Murcia in Spain reports that high vWF levels are also associated with an increased risk of stroke, cardiovascular events, bleeding, and death in AF patients on warfarin therapy.

The study included 829 older patients with permanent (long-standing persistent) AF (50% male with a median age of 76 years) who were on warfarin therapy and had maintained an INR between 2.0 and 3.0 for at least 6 months prior to having their medical history recorded and blood samples drawn for the measurement of plasma concentration of vWF and D-dimer. The study participants were, not unexpectedly, an unhealthy lot. Eighty-two percent had hypertension, 37% had heart failure, 31% had high cholesterol levels, 25% had diabetes, and 18% had a history of stroke or TIA (transient ischemic attack).

The patients were followed for an average of 2 years. During this time, 32 (1.7% per year) suffered a stroke or TIA, 36 (1.9% per year) experienced acute coronary syndrome events (heart attack, unstable angina, etc), 27 (1.5% per year) had acute heart failure, and 68 (3.6% per year) suffered a major bleeding event. Sixty-nine patients (3.7% per year) died during follow-up of which 25 deaths (1.13% per year) were related to cardiovascular causes. Multivariate Cox regression analysis showed that patients 75 years and older had a two-fold increase in risk of an adverse cardiovascular event (stroke/TIA, acute coronary syndrome, acute heart failure, peripheral embolism, and cardiac death). A history of stroke or heart failure was associated with an 80% increased risk of an adverse cardiovascular event, while a vWF level at or above 221 IU/dL was associated with an almost three-fold (HR = 2.71) increase in risk. The association between stroke risk and vWF level was particularly pronounced with a level at 221 IU/dL or above associated with a five-fold increase in stroke risk.

A high vWF level was also associated with a four-fold (HR = 4.47) increase in the risk of major bleeding, a three-fold increase in the risk of cardiovascular death and a doubling of all-cause mortality. Age of 75 years or older, current smoking, and diabetes were also major risk factors for increased overall mortality. High cholesterol levels, on the other hand, were associated with a significantly lower risk of cardiovascular death (HR = 0.27) and overall mortality (HR = 0.46). Somewhat surprisingly, vWF level was significantly more predictive of the risk of cardiovascular events, bleeding and death than were the commonly used risk scores of CHADS2, CHA2DS2VASc, and HAS-BLED . The authors of the study conclude that the addition of vWF level to these risk scores will materially increase their predictive ability.

Roldan, V, Lip, GYH, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. Journal of the American College of Cardiology, Vol. 57, No. 25, June 21, 2011

Editor’s comment: Although the patient population in the study bears no resemblance to a group of otherwise healthy lone afibbers, it may nevertheless be a good idea to have a vWF measurement and take steps to reduce it if necessary. It is surprising, or maybe not, that the authors do not suggest that it may be a good idea for afibbers with a high vWF level to take steps to reduce it. There is ample evidence that this can be accomplished by supplementation with vitamin C and vitamin E[1,2,3]
[1] Antoniades, C., et al. Effects of antioxidant vitamins C and E on endothelial function and thrombosis/fibrinolysis system in smokers. Thromb Haemost, Vol. 89, June 2003, pp. 990-95
[2] Tousoulis, D, et al. Vitamin C affects thrombosis/fibrinolysis system and reactive hyperemia in patients with type 2 diabetes and coronary artery disease. Diabetes Care, Vol. 26, October 2003, pp. 2749-53
[3] Huang, N, et al. Alpha-tocopherol, a potent modulator of endothelial cell function. Thromb Res, Vol. 50, No. 4, May 1988, pp. 547-57