Proteolysis of von Willebrand Factor and Shear Stress–Induced Platelet Aggregation in Patients With Aortic Valve Stenosis

Abstract

Background-Excessive bleeding may complicate congenital cardiac defects. To explain the pathogenesis of this abnormality, we evaluated selected parameters of primary hemostasis in patients with aortic valve stenosis before and after corrective surgery. Methods and Results-We examined shear-induced platelet aggregation with the filter aggregometer test and von Willebrand factor (vWF) structure by evaluating the multimeric distribution and extent of subunit proteolysis. The platelet count was reduced before corrective surgery, and shear-induced platelet aggregation was impaired. Moreover, vWF multimers of higher molecular mass were decreased, and proteolytic subunit fragments were increased. After correction of the cardiac defect, all of these parameters returned to normal. Conclusions-Alterations of vWF and platelet function may contribute to the bleeding diathesis in patients with aortic valve stenosis. Improvement after corrective surgery suggests that the passage of blood through a stenosed aortic valve may result in shear forces that induce vWF interaction with platelets in the circulation and, in turn, trigger platelet clearance, vWF degradation, and the impairment of primary hemostasis.

Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis

“…[31][32][33] Aortic stenosis is sometimes associated with loss of high molecular von Willebrand multimers and with a greater tendency to bleed. 34,35 Although these issues are of clinical significance only in cases of severe anemia requiring transfusion, mild anemia in our subjects may exist in part because of these mechanisms. If so, the low hemoglobin level may also indicate that aortic valve injury was more severe at the earlier echocardiographic examination in subjects with progression.…”

Acquired von Willebrand Syndrome

“…In patients with aortic valve stenosis, vWF multimers can be subject to mechanical damage or proteolysis with ADAMTS-13 metalloproteinase [26][27][28]. Proteolysis of HMW vWF during the course of essential thrombocythemia may be triggered by platelet-released calcium ions, causing the activation of proteases and elastases.…”

Acquired von Willebrand syndrome: An update

“…A similar mechanism has been postulated in aortic valve stenosis, where high shear rates may activate platelets, leading to adsorption of VWF multimers onto their surface [84]. However, other mechanisms have also been proposed to explain aVWS in patients with aortic valve stenosis, such as an increased proteolysis of VWF by the metalloprotease ADAMTS-13 [123,124] or the mechanical destruction of large VWF multimers [80,85]. The plasma volume expander hydroxyethyl starch (HES) also induces aVWS, which may be related to the adsorption of large multimers of VWF onto macromolecules of HES [92].…”

“…Direct evidence of VWF proteolysis includes the finding of elevated levels of proteolytic VWF fragments in patients with essential thrombocythemia [45]. As reported earlier, the proteolytic degradation of VWF by plasmin or ADAMTS-13 has also been suggested as a possible mechanism of aVWS in patients with cardiac valve diseases [123,124]. An abnormal proteolysis of VWF has also been postulated to explain the occurrence of aVWS associated with uremia [98] and the antibiotic ciprofloxacin [90].…”