The function of von Willebrand factor (VWF) is regulated by proteolysis, which limits its multimeric size and ability to tether platelets. The importance of ADAMTS13 metalloprotease in VWF regulation is demonstrated by the association between severe deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura (TTP). However, ADAMTS13 activity levels do not always correlate with the clinical course of TTP, suggesting that other proteases could be important in regulating VWF. We identified 4 leukocyte IntroductionThe hemostatic activity of von Willebrand factor (VWF) is regulated in blood by the metalloprotease ADAMTS13, which cleaves VWF in the A2 domain. 1 The importance of VWF regulation by ADAMTS13 is demonstrated by the close association between severe deficiency of ADAMTS13 activity and thrombotic thrombocytopenic purpura (TTP). 2,3 However, the association between ADAMTS13 activity and TTP is imperfect. Patients with inhibitor-mediated ADAMTS13 deficiency can achieve clinical remission despite persistent severe deficiency of ADAMTS13 activity, 2,4 and not all patients with congenital deficiency of ADAMTS13 develop TTP. 5 Moreover, VWF proteolysis can be paradoxically increased in TTP patients during acute episodes. 6 These observations suggest the existence of other important disease-modifying factors in TTP, in addition to ADAMTS13.Disease-modifying factors in TTP may include other VWFcleaving proteases. Before the discovery of ADAMTS13, the proteases calpain, neutrophil elastase, and cathepsin G were known to cleave VWF. [7][8][9][10][11][12] However, the exact cleavage sites were not determined, and the physiologic relevance of these proteases was unknown. It was known that normal plasma contained proteolytic fragments of VWF having masses of approximately 176 kDa and 140 kDa. The primary cleavage site that gave rise to these fragments was identified as the Y1605-M1606 peptide bond. 13 In studies seeking to identify the responsible protease, Tsai et al 8,9,14 observed that neutrophil proteases cleaved high-molecular-weight VWF into a series of multimers indistinguishable from those found in normal plasma. By contrast, Berkowitz et al 10 concluded that VWF cleavage fragments generated by neutrophil elastase were different from the 176-kDa and 140-kDa fragments found in plasma. The role of leukocyte proteases in VWF regulation remained unresolved, and was later overshadowed by the discovery of ADAMTS13.In this study, we demonstrate that under denaturing and fluid shear stress conditions multiple leukocyte proteases cleave VWF predominantly in the central A2 domain. We also show that activated neutrophils, but not normal neutrophils, retain VWF cleaving activity in the presence of plasma inhibitors, suggesting that leukocyte proteases may regulate VWF function under physiologic conditions. Methods Patients and plasmaBlood samples were obtained from volunteer subjects after informed consent, in accordance with the Declaration of Helsinki, sanctioned by the institutional human research subject committees o...
The PBL curricular changes implemented with the graduating class of 1997 resulted in higher performances on USMLEs and improved evaluations from residency program directors. These changes better prepare graduates with knowledge and skills needed to practice within a complex health care system. Outcomes reported here support the investment of financial and human resources in our PBL curriculum.
Clinical Pharmacology and Therapeutics (1988) 43, 345–353; doi:
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