Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis.
The behavior of plasma von Willebrand factor (vWF) in patients with acute leukemia (n = 5), decompensated cirrhosis (n = 10), and acute pancreatitis (n = 5) was investigated to evaluate whether the systemic proteolytic states associated with these diseases had affected the structure and function of the molecule. vWF antigen and, to a lesser degree, ristocetin cofactor activity in patient plasma were high. Multimeric analysis of plasma vWF revealed loss of high molecular weight multimers. The subunit composition and proteolytic pattern of vWF immunopurified from patient plasmas and reduced were studied by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis followed by transblotting and probing with monoclonal antibodies that distinguish cleavages caused by plasmin from those caused by other proteases. There was marked reduction of the relative concentration of the native vWF subunit of 225 Kd in all patient groups, indicating heightened cleavage of the protein. The concentrations of 189- and 140-Kd vWF fragments, normally present in plasma, were increased in cirrhosis and pancreatitis but not in leukemia. Novel fragments, ranging in size from less than 225 to approximately 120 Kd were present in leukemia and cirrhosis, including plasmin-generated fragments of 176 and 145 Kd. These data indicate that in clinical conditions in which there is heightened proteolysis vWF is degraded in vivo by plasmin and other proteases. Degraded vWF may be less effective than native vWF in supporting primary hemostasis, thereby being a cofactor in the multifactorial bleeding diathesis accompanying systemic proteolytic states.
Federici
A B
AB
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, RCSS Maggiore Hospital, Milan, Italy.
Berkowitz
S D
SD
Lattuada
A
A
Mannucci
P M
PM
D000208:Acute Disease; D000911:Antibodies, Monoclonal; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000097:blood*; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000097:blood*; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood*; D008103:Liver Cirrhosis / Q000097:blood*; D046911:Macromolecular Substances; D010195:Pancreatitis / Q000097:blood*; D010976:Platelet Count; D012016:Reference Values; D014841:von Willebrand Factor / Q000302:isolation & purification / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D046911:Macromolecular Substances; D014841:von Willebrand Factor; D010450:Endopeptidases; D005341:Fibrinolysin