PROPERTIES OF FIBRINOGEN CLEAVED BY JARARHAGIN, A METALLOPROTEINASE FROM THE VENOM OF BOTHROPS-JARARACA

Haemorrhagic metalloproteinases from Bothrops jararaca and other venom s degrade vessel-wall and plasma proteins involved in platelet plug an d fibrin clot formation. These enzymes also cause proteolytic digestio n of fibrinogen which has been suggested to cause defective platelet f unction. Fibrinogen degradation by jararhagin, a metalloproteinase fro m B. jararaca, and the effect of jararhagin fibrinogenolysis on both p latelet aggregation and fibrin clot formation were investigated. Jarar hagin was found to cleave human fibrinogen in the C-terminal region of the A alpha-chain giving rise to a 285-290 kDa fibrinogen molecule la cking the A alpha-chain RGD 572-574 platelet-binding site. Platelet bi nding and aggregation of ADP-activated platelets is unaffected by this modification. This indicates that the lost site is not essential for platelet aggregation, and that the remaining platelet binding sites lo cated in the N-terminal portion of Aa: chains (RGD 95-97) and the C-te rminal of gamma chains (dodecapeptide 400-411) are unaffected by jarar hagin-digestion of fibrinogen. Fibrin clot formation with thrombin of this remnant fibrinogen molecule was defective, with poor polymer izat ion of fibrin monomers but normal release of FPA. The abnormal polymer ization could be explained by the loss of one of the two complementary polymerization sites required for side-by-side association of fibrin protofibrils. Jararhagin-induced inhibition of platelet function, an i mportant cause of haemorrhage in envenomed patients, is not caused by proteolysis of fibrinogen, as had been thought, and the mechanism rema ins to be elucidated.