McRedmond J P, Harriott P, Walker B, Fitzgerald D J
Centre for Cardiovascular Science, Department of Clinical Pharmacology, The Royal College of Surgeons in Ireland, Dublin, Ireland.
Blood. 2000 Feb 15;95(4):1301-8.
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)
链激酶可激活血小板，限制了其作为溶栓剂的有效性。研究了抗链激酶抗体和蛋白酶在链激酶诱导的血小板激活中的作用。链激酶可诱导人IgG定位于血小板表面、血小板聚集以及血栓素A2的产生。这些效应可被抗血小板Fc受体的单克隆抗体IV.3抑制。针对血小板凝血酶受体裂解位点的抗体，即蛋白酶激活受体-1（PAR-1），也可阻断血小板对链激酶的反应，但水蛭素或活性位点凝血酶抑制剂Ro46-6240则不能。在缺乏纤溶酶原的血浆中，外源性野生型纤溶酶原而非无活性的突变蛋白S(741)A纤溶酶原可支持血小板聚集，这表明裂解PAR-1的蛋白酶是链激酶-纤溶酶原。链激酶-纤溶酶原可裂解与PAR-1对应的合成肽，导致PAR-1拴系配体序列的产生，并选择性降低完整细胞中对裂解敏感的PAR-1抗体的结合。链激酶、纤溶酶原和抗链激酶抗体的组合可激活人红白血病细胞，且可被IV.3预处理或用PAR-1激动剂SFLLRN预处理细胞所抑制，这表明Fc受体和PAR-1相互作用在该系统中对细胞激活也是必需的。链激酶诱导的血小板激活既依赖于抗链激酶-Fc受体相互作用，也依赖于PAR-1的裂解。（《血液》。2000年；95:1301 - 1308）
