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NEJM
J. Evan Sadler, M.D., Ph.D. Some patients with aortic stenosis have recurrent bleeding into their skin or gastrointestinal tract. Several studies suggest that this bleeding is caused by an acquired defect in von Willebrand factor and that replacement of the aortic valve restores the normal structure of von Willebrand factor and restores normal hemostasis. However, we know little about the prevalence of symptomatic defects in von Willebrand factor in patients with aortic stenosis. In this issue of the Journal, Vincentelli and colleagues (pages 343�349) address this question and provide new information about the response of such hemostatic abnormalities to valve replacement. Von Willebrand factor circulates in the blood as a gigantic, multimeric protein that may exceed 20,000 kD in size; a single molecule may be longer than 4 �m, or twice the diameter of a platelet. These large multimers mediate the adhesion of platelets to sites of vascular damage, particularly under conditions in which fluid shear stress in the microvasculature is high. Inherited defects in von Willebrand factor that impair its function cause various forms of von Willebrand disease. Acquired disorders are encountered less often but can be equally serious and cause what is referred to as acquired von Willebrand syndrome. The processing of von Willebrand factor multimers provides a framework for understanding the pathology of acquired von Willebrand syndrome (see Figure). Endothelial cells secrete very large von Willebrand factor multimers into the blood, where they may contribute to the formation of platelet plugs. In nascent thrombi, or during normal wear and tear in the circulation, large multimers are cleaved by ADAMTS 13, a plasma metalloprotease that acts on von Willebrand factor preferentially under conditions of high fluid shear stress. The steady-state distribution of multimers reflects an equilibrium between the secretion of large multimers and their proteolysis into smaller, inactive derivatives. Mutations in von Willebrand factor that increase its susceptibility to ADAMTS 13 cause von Willebrand disease type 2A, which is characterized by the selective absence of large multimers. Similar deficits in large multimers occur in acquired von Willebrand syndrome. About half the cases are caused by immune clearance of von Willebrand factor, often in association with lymphoproliferative diseases or autoimmune disorders. Most of the remaining cases are associated with increased proteolysis of von Willebrand factor by ADAMTS 13, often within a stenotic heart valve, a ventricular septal defect, or a patent ductus arteriosus, all of which are sites in which there is pathologically increased fluid shear stress on the blood. Regardless of the pathogenesis, the absence of large multimers of von Willebrand factor can cause bleeding, especially from preexisting lesions such as gastrointestinal angiodysplasia.
The association between aortic stenosis and gastrointestinal bleeding was reported 45 years ago in the Journal1 and has since been confirmed repeatedly, but the prevalence of acquired von Willebrand syndrome in aortic stenosis remains unknown. Now, in their study of 50 consecutive patients, Vincentelli and colleagues report that 21 percent of those with severe aortic stenosis had bleeding from the skin or mucous membranes during the six months before surgery. Most of the bleeding episodes were minor, but one patient required transfusion because of epistaxis. Although serious bleeding symptoms were rare, almost all the patients had abnormalities in the structure and function of von Willebrand factor in vitro. In addition, the mean transvalvular pressure gradient correlated with the decrement in the percentage of large von Willebrand factor multimers, suggesting that shear stress�induced ADAMTS 13 proteolysis has a primary role in the pathogenesis of acquired von Willebrand syndrome. The correlation between the severity of aortic stenosis and the presence of acquired von Willebrand syndrome was reinforced by the results of aortic-valve replacement. Patients with the highest intraoperative blood loss had the greatest preoperative decrease in von Willebrand factor multimers. In every case, the distribution of the multimers and the values for laboratory indexes of von Willebrand factor function became normal on the first postoperative day, a finding that is consistent with the 12-to-20-hour half-life of von Willebrand factor in vivo. Furthermore, the recurrence of aortic stenosis or a mismatch between patient and prosthesis was associated with the recurrence of abnormalities in von Willebrand factor. The authors conclude that acquired von Willebrand syndrome is common in aortic stenosis and may be associated with bleeding symptoms or increased operative blood loss and that the recurrence of the syndrome may indicate persistent or recurrent valvular stenosis. It is possible that shear stress�induced cleavage of von Willebrand factor causes hemostatic defects in other conditions associated with turbulent, high-pressure blood flow. Recognition of this relation has implications for patient care. In general, acquired von Willebrand syndrome associated with cardiovascular lesions does not respond well to desmopressin or to the transfusion of clotting-factor concentrates and requires surgical correction of the flow abnormality.
From the Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis. References
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