Abstract
Von Willebrand factor (VWF) is a pro-hemostatic multimeric plasma protein that promotes platelet aggregation and stabilizes coagulation factor VIII (FVIII) in plasma. The metalloproteinase ADAMTS13 regulates the platelet aggregation function of VWF via proteolysis. Severe deficiency of ADAMTS13 is associated with thrombotic thrombocytopenic purpura, but does not always correlate with its clinical course. Therefore, other proteases could also be important in regulating VWF activity. In the present study, we demonstrate that VWF is cleaved by the cytotoxic lymphocyte granule component granzyme M (GrM). GrM cleaved both denaturated and soluble plasma-derived VWF after Leu at position 276 in the D3 domain. GrM is unique in that it did not affect the multimeric size and pro-hemostatic platelet aggregation ability of VWF, but instead destroyed the binding of VWF to FVIII in vitro. In meningococcal sepsis patients, we found increased plasma GrM levels that positively correlated with an increased plasma VWF/FVIII ratio in vivo. We conclude that, next to its intracellular role in triggering apoptosis, GrM also exists extracellularly in plasma where it could play a physiological role in controlling blood coagulation by determining plasma FVIII levels via proteolytic processing of its carrier VWF.
Highlights
Von Willebrand factor (VWF) is a pro-hemostatic multimeric plasma protein that promotes platelet adhesion by bridging injured subendothelium and platelet receptors [1]
granzyme M (GrM) cleaves VWF ADAMTS13 and granzyme B (GrB) cleave VWF only when the specific cleavage sites are exposed in the VWF A2 domain [27,28,29]
GrM cleaved both soluble and immobilized VWF with the concomitant appearance of a similar VWF cleavage fragment that differs from those induced by GrB (Fig. 1A,B)
Summary
Von Willebrand factor (VWF) is a pro-hemostatic multimeric plasma protein that promotes platelet adhesion by bridging injured subendothelium and platelet receptors [1]. Low ADAMTS13 levels are observed in TTP patients in remission [6,7], not all patients with congenital ADAMTS13 deficiency develop TTP [8], and increased VWF proteolysis has been identified in acute TTP patients without loss of larger multimers [9]. These findings strongly suggest the existence of other important proteases that regulate VWF activity, in addition to ADAMTS13. Buzza et al have shown that VWF activity in vitro could be regulated via cleavage by a serine protease from the granules of cytotoxic lymphocytes, i.e. granzyme B (GrB) [12]
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