title: Cleavage of von Willebrand factor by granzyme M destroys its factor VIII binding capacity.
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.
authors: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands. M.J.Hollestelle@umcutrecht.nl
authors: Martine J
authors: MJ
authors: Hollestelle
authors: Ka Wai
authors: KW
authors: Lai
authors: Marcel
authors: M
authors: van Deuren
authors: Peter J
authors: PJ
authors: Lenting
authors: Philip G
authors: PG
authors: de Groot
authors: Tom
authors: T
authors: Sprong
authors: Niels
authors: N
authors: Bovenschen
mesh_terms: D001792:Blood Platelets / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism*; D053804:Granzymes / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008589:Meningococcal Infections / Q000097:blood / Q000150:complications / Q000382:microbiology; D009345:Neisseria meningitidis / Q000502:physiology; D010974:Platelet Aggregation; D011485:Protein Binding; D055503:Protein Multimerization; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000382:microbiology; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D005169:Factor VIII; D003094:Collagen; D053804:Granzymes