Adenosine diphosphate (ADP) and ADP receptor play a major role in platelet activation/aggregation induced by sera from heparin-induced thrombocytopenia patients
Adenosine diphosphate (ADP) and ADP receptor play a major role in platelet activation/aggregation induced by sera from heparin-induced thrombocytopenia patients
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DOI：
10.1182/blood.v91.2.549.549_549_554
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发表时间：
1998-01-15
期刊：
影响因子：
20.3
通讯作者：
Clemetson, KJ
中科院分区：
文献类型：
--
作者：
Polgár, J;Eichler, P;Clemetson, KJ
肝素诱导的血小板减少症（HIT）是肝素治疗的一种相对常见的并发症，其分子基础尚未完全了解。我们发现，血小板预处理AR-C66096（以前的FPL 66096），一种特异性的血小板二磷酸腺苷（ADP）受体拮抗剂，在100至200 nmol/L的浓度，阻断ADP依赖性血小板聚集，导致血小板聚集反应完全丧失HIT血清。AR-C66096还完全抑制HIT血清诱导的致密颗粒释放，如通过测量三磷酸腺苷（ATP）释放所判断的。以对凝血酶或花生四烯酸诱导的聚集只有轻微影响的浓度添加到血小板中的腺苷三磷酸双磷酸酶也完全阻断了HIT血清诱导的血小板聚集。此外，AR-C66096抑制由Fc γ RIIA与特异性抗体交联诱导的血小板聚集和ATP释放。这些数据表明，释放的ADP和血小板ADP受体在HIT血清诱导的血小板活化/聚集中起关键作用。血栓素受体抑制剂Daltroban对HIT血清诱导的血小板活化没有影响，而GPIIb-IIIa拮抗剂阻断血小板聚集，但对HIT血清诱导的致密颗粒释放只有中等影响。用软骨素酶而不是肝素酶预处理血小板导致HIT血清诱导的血小板聚集的浓度依赖性抑制。与HIT血清诱导的血小板活化机制相关的这些新数据表明，应检查ADP受体拮抗剂或抑制ADP释放的化合物作为治疗剂有效预防或治疗肝素治疗相关并发症的可能性。(C)1998年，美国血液学会。
The molecular basis for heparin-induced thrombocytopenia (HIT), a relatively common complication of heparin therapy, is not yet fully understood. We found that pretreatment of platelets with AR-C66096 (formerly FPL 66096), a specific platelet adenosine diphosphate (ADP) receptor antagonist, at a concentration of 100 to 200 nmol/L that blocked ADP-dependent platelet aggregation, resulted in complete loss of platelet aggregation responses to HIT sera. AR-C66096 also totally inhibited HIT serum-induced dense granule release, as judged by measurement of adenosine triphosphate (ATP) release. Apyrase, added to platelets at a concentration that had only minor effects on thrombin- or arachidonic acid-induced aggregation, also blocked completely HIT serum-induced platelet aggregation. Furthermore, AR-C66096 inhibited platelet aggregation and ATP release induced by cross-linking Fc gamma RIIA with specific antibodies. These data show that released ADP and the platelet ADP receptor play a pivotal role in HIT serum-induced platelet activation/aggregation. The thromboxane receptor inhibitor, Daltroban, had no effect on HIT serum-induced platelet activation whereas GPIIb-IIIa antagonists blocked platelet aggregation but had only a moderate effect on HIT serum-induced dense granule release. Pretreatment of platelets with chondroitinases but not with heparinases resulted in concentration dependent inhibition of HIT serum-induced platelet aggregation. These novel data relating to the mechanism of platelet activation induced by HIT sera suggest that the possibility should be examined that ADP receptor antagonists or compounds that inhibit ADP release may be effective as therapeutic agents for the prevention or treatment of complications associated with heparin therapy. (C) 1998 by The American Society of Hematology.