Acquired von Willebrand Syndrome Associated with Cardiovascular Diseases

Abstract

The blood glycoprotein von Willebrand factor (VWF) plays an important role in hemostasis and thrombosis. VWF is produced and secreted as large multimers by endothelial cells and megakaryocytes. It is then cleaved in a sheer-stress dependent manner by a specific protease, ADAMTS13, into multimers consisting of 2–80 subunits. Among VWF multimers, high molecular weight (HMW) multimers play important roles in platelet aggregation. Therefore, their loss induces a hemostatic disorder known as von Willebrand disease (VWD) type 2A. Various cardiovascular diseases, such as aortic stenosis, hypertrophic obstructive cardiomyopathy (HOCM), and several congenital structural diseases, as well as mechanical circulatory support systems, generate excessive high shear stress in the bloodstream. These cause excessive cleavage of VWF multimers resulting in a loss of HMW multimers, known as acquired von Willebrand syndrome (AVWS), a hemostatic disorder similar to VWD type 2A. Bleeding often occurs in the gastrointestinal tract since a fragile angiodysplasia develops associated with these diseases. Radical treatment for AVWS is to remove the pathological high shear causing AVWS.

Pathophysiology of atherothrombosis: Mechanisms of thrombus formation on disrupted atherosclerotic plaques

“…von Willebrand factor is essential for platelet adhesion and aggregation, and it assumes a multimeric form (MW range, 50–20 000 kDa) in circulating blood 16 . This factor is synthesized and stored in Weibel–Palade bodies of endothelial cells and upon release, is rich in ultra‐large (UL) multimeric forms that hyperactively bind platelet GP Ib and can induce platelet aggregation 31,32 . Under high shear conditions, UL‐VWF multimers are rapidly cleaved by the plasma protease, ADAMTS‐13, to smaller and less active multimeric forms 32 .…”

“…This factor is synthesized and stored in Weibel–Palade bodies of endothelial cells and upon release, is rich in ultra‐large (UL) multimeric forms that hyperactively bind platelet GP Ib and can induce platelet aggregation 31,32 . Under high shear conditions, UL‐VWF multimers are rapidly cleaved by the plasma protease, ADAMTS‐13, to smaller and less active multimeric forms 32 . Since ADAMTS‐13 cleaves VWF multimers under high shear conditions, it is considered to protect against platelet aggregation and thrombotic occlusion in stenotic atherosclerotic arteries 33 .…”

Anticoagulation after Transcatheter Aortic Valve Implantation: Current Status

“…9,10,12 In addition, bleeds may be augmented by coexisting conditions, such as older age, frailty, fall risk, renal failure, liver disease, malignancy, anaemia and coagulation disorders, as well as by AF and antithrombotic therapy. [59][60][61][62][63][64] Finally, a periprocedural thrombo-inflammatory state and reduced platelet turnover in the older patient may act synergistically, resulting in transient thrombocytopenia in 69-87% of TAVI patients, signalling severe impairment of general homeostasis. [65][66][67] Gastrointestinal bleeding associated with aortic stenosis is due to the shear stress and flow turbulence across the stenotic aortic valve, which may cause the cleavage of high-molecular-weight multimers of von Willebrand factor, a coagulation protein responsible for haemostasis.…”

Commentary: Alive without a pulse and bleeding

“…These conditions have also been described in patients with valvular heart disease (aortic and mitral stenosis, regurgitant valve lesions, and structural and nonstructural valve deterioration), congenital heart disease, and pulmonary hypertension. [7][8][9] The severity of acquired vWF deficiency increases as these lesions progress and usually reverses after treatment either by surgery or by transcatheter procedures. [7][8][9] Similar to the conditions in valvular heart disease, preventing the development of acquired vWF deficiency by restoring pulse pressure and decreasing shear stress may lead to lower rates of gastrointestinal bleeding.…”

“…[7][8][9] The severity of acquired vWF deficiency increases as these lesions progress and usually reverses after treatment either by surgery or by transcatheter procedures. [7][8][9] Similar to the conditions in valvular heart disease, preventing the development of acquired vWF deficiency by restoring pulse pressure and decreasing shear stress may lead to lower rates of gastrointestinal bleeding. 5 Furthermore, advances in hemocompatibility, pump design and management may similarly achieve this goal.…”