von Willebrand Factor and Venous Thromboembolism: Pathogenic Link and Therapeutic Implications

Abstract

Venous thromboembolism (VTE) is a frequent cause of disability and mortality worldwide. Von Willebrand factor (VWF) is a major determinant of hemostasis and clot formation, in both arteries and veins. Although VWF is mainly known for its role in arterial thrombosis, several studies suggest a pathogenic role for VWF and its regulator ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in venous thrombosis. Nongenetic and genetic factors, including gene mutations and polymorphisms, aging, hormone status, ABO blood groups, and systemic inflammation, have been involved in the modulation of both VTE predisposition and plasma levels of VWF. In several clinical settings, including inflammatory disease and cancer, VWF and ADAMTS-13 are currently investigated as possible determinants of vein thrombosis. These data indicate VWF as a potential therapeutic target in the management of VTE. Several studies report unselective antagonism of VWF for drugs used in daily clinical practice, including heparin and statins. Selective inhibition of VWF pathway has recently been tested in animal models of arterial and venous thrombosis as a novel therapeutic strategy to prevent platelet aggregation and thrombosis, promote vein lumen recanalization, and improve vein valve competency with excellent safety profile. In this review, we summarize the role of VWF in VTE, focusing on clinical and potential therapeutic implications.

Prothrombotic State Induced by Middle-Distance Endurance Exercise in Middle-Aged Athletes

“…The remarkable increase in VWF:Ag, FVIII, and D-dimer values observed after the run was quite predictable. VWF is an acute phase protein, 28 and its concentration in blood is highly correlated with that of FVIII, as also shown in our study both at baseline and at the end of the half marathon. Although its plasma concentration is also dependent on the ABO blood group (i.e., subjects with blood group O have lower concentration than those with non-O blood groups), 25,26 emerging evidence suggests that this protein may play a pivotal role in the pathogenesis of VTE, 28 alone or in combination with enhanced plasma activity of FVIII.…”

“…The most important changes involve a substantial increase in the values of VWF:Ag and FVIII, which otherwise are considered highly associated prothrombotic risk factors. 28,29 Likewise, we found a concomitant enhancement of D-dimer values, which is a well-established biomarker of blood coagulation activation, 30 compounded by a significant reduction of APTT, which is also considered a risk factor for VTE. 31,32 The concomitant reduction of thrombin generation (both TGA-AUC and TGA-PK) recorded immediately after the run is also suggestive of a blood coagulation activation during the prolonged physical effort, reflected by the relative exhaustion of thrombin generation potential immediately after the run.…”

The impact of ABO blood type on the prevalence of portal vein thrombosis in patients with advanced chronic liver disease

“…Accordingly, with a mean age of 54.1 ± 11.4, we would have expected a profound impact of ABO blood type in our second cohort (“Vienna cohort”). In adjusted analysis, the non‐O blood type‐related increase in VWF antigen levels was about 24%, which, in absolute terms, was comparable to the differences reported in the general population 15 . However, the median VWF level in our series of patients with portal hypertension was 313 (167)%, and thus, the relative difference was less then 10%.…”

“…Moreover, VWF levels are determined by ABO blood type. VWF and factor VIII levels are about 25% higher in non‐O individuals, as compared to O individuals, 15 which translates into a clinically significantly increased risk of VTE (eg, incidence rate ratio of 1.8 and population attributable risk of 32%), 15,16 and to a smaller extent, arterial thrombosis (in particular, myocardial infarction: incidence rate ratio of 1.1 and population attributable risk of 6%) 16,17 . Moreover, some evidence links VWF/factor VIII levels with incident PVT in patients with cirrhosis 18 …”

Venöz tromboembolizm tanımı ve fizyopatolojisi

“…Bu özelleşmiş endotel bölgesindeki hipoksi ve sonrasında gelişen inflamasyon sonucu, bu bölgeden salgılanan antikoagülan proteinler "aşağı-regüle" (downregulated) olurken doku faktörü (TF) ve von Willebrand faktör (vWF) gibi prokoagülanlar "yukarı-regüle" (upregulated) olur. [15][16][17] Sonuç olarak, lokal prokoagülan-antikoagülan dengesi bozulur ve trombogenezis aktive edilir.…”