Streptokinase-induced platelet activation involves antistreptokinase antibodies and cleavage of protease-activated receptor-1.
Streptokinase activates platelets, limiting its effectiveness as a thrombolytic agent. The role of antistreptokinase antibodies and proteases in streptokinase-induced platelet activation was investigated. Streptokinase induced localization of human IgG to the platelet surface, platelet aggregation, and thromboxane A(2) production. These effects were inhibited by a monoclonal antibody to the platelet Fc receptor, IV.3. The platelet response to streptokinase was also blocked by an antibody directed against the cleavage site of the platelet thrombin receptor, protease-activated receptor-1 (PAR-1), but not by hirudin or an active site thrombin inhibitor, Ro46-6240. In plasma depleted of plasminogen, exogenous wild-type plasminogen, but not an inactive mutant protein, S(741)A plasminogen, supported platelet aggregation, suggesting that the protease cleaving PAR-1 was streptokinase-plasminogen. Streptokinase-plasminogen cleaved a synthetic peptide corresponding to PAR-1, resulting in generation of PAR-1 tethered ligand sequence and selectively reduced binding of a cleavage-sensitive PAR-1 antibody in intact cells. A combination of streptokinase, plasminogen, and antistreptokinase antibodies activated human erythroleukemic cells and was inhibited by pretreatment with IV.3 or pretreating the cells with the PAR-1 agonist SFLLRN, suggesting Fc receptor and PAR-1 interactions are necessary for cell activation in this system also. Streptokinase-induced platelet activation is dependent on both antistreptokinase-Fc receptor interactions and cleavage of PAR-1. (Blood. 2000;95:1301-1308)
McRedmond
J P
JP
Centre for Cardiovascular Science, Department of Clinical Pharmacology, The Royal College of Surgeons in Ireland, Dublin, Ireland.
Harriott
P
P
Walker
B
B
Fitzgerald
D J
DJ
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000906:Antibodies / Q000494:pharmacology; D000907:Antibodies, Bacterial / Q000494:pharmacology / Q000502:physiology*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D004915:Leukemia, Erythroblastic, Acute; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D044463:Receptor, PAR-1; D011961:Receptors, Fc / Q000502:physiology*; D018179:Receptors, Thrombin / Q000276:immunology / Q000502:physiology*; D013300:Streptokinase / Q000276:immunology / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000907:Antibodies, Bacterial; D006629:Hirudins; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D011961:Receptors, Fc; D018179:Receptors, Thrombin; D000244:Adenosine Diphosphate; D013300:Streptokinase; D002118:Calcium