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.

Keywords: Acquired von Willebrand’s syndrome; Aortic stenosis; ECMO; Heyde’s syndrome; Left ventricular assist device; von Willebrand factor.

Fig. 1.

The structure of von Willebrand factor (VWF) A) Schematic structure of VWF monomer with its functional domains. Binding sites are indicated for FVIII (D' and D3 domains), GPIb (A1 domain), collagen (A3 domain) and GPIIb/IIIa (C1 domain). An ADAMTS13 cleavage site is located in the A2 domain. B) The VWF multimer structure. The subunits of pro-VWF is initially dimerized by disulfide bonds between C-terminal cysteine knot (CK) domains of each subunit in endoplasmic reticulum and then multimerized by at least two disulfide bonds in D'D3 domains concomitantly with the removal of short peptide in the C-terminal region in the Golgi apparatus.

Fig. 2.

Quantification method for the calculation of the von Willebrand factor (VWF) large multimer index This is defined as the ratio of the patient's HMW multimer ratio to the healthy subject's ratio analyzed in the same gel. With the index, a patient's high molecular weight (HMW) multimers are expressed as a percentage of those of a healthy control. The patient's plasma in this figure was from the patient with severe aortic stenosis with mean aortic pressure of 68 mmHg and peak blood flow of 5.24 m/sec.

Fig. 3.

Pathogenesis of gastrointestinal bleeding associated in patients treated with an left ventricular assist device (LVAD). The gastrointestinal bleeding is caused by mucosal damage, platelet dysfunction, antithrombotic therapy, a reduction of von Willebrand factor (VWF) high molecular weight (HMW) multimers and angiodysplasia as possible causes. In an early phase, bleeding could be caused mainly by mucosal damage. In a late phase, bleeding could be caused mainly by angiodysplasia formed after LVAD implantation.

Fig. 4.

Typical angiodysplasia in the small intestine. The photo is adopted from Tamura et al.⁴⁴⁾.