Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies
Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies
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DOI：
10.1182/blood-2011-05-353391
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发表时间：
2012-02-02
期刊：
影响因子：
20.3
通讯作者：
Greinacher, Andreas
中科院分区：
文献类型：
--
作者：
Krauel, Krystin;Hackbarth, Christine;Greinacher, Andreas
肝素是一种广泛使用的抗凝剂。由于其带负电荷，它与带正电荷的血小板因子4（PF 4）形成复合物。这可以诱导抗PF 4/肝素IgG抗体。产生的免疫复合物激活血小板，导致血栓前不良药物反应肝素诱导的血小板减少症（HIT）。HIT需要使用替代抗凝剂治疗。批准用于HIT的有2种直接凝血酶抑制剂（DTI;来匹卢定、阿加曲班）和达那肝素。它们是有局限性的利基产品。我们评估了DTI达比加群、Xa因子直接抑制剂利伐沙班和2-O，3-O双酯肝素（ODSH;一种具有最小抗凝作用的部分双酯肝素）对PF 4/肝素复合物的影响以及抗PF 4/肝素Ab与血小板的相互作用。达比加群或利伐沙班对PF 4或抗PF 4/肝素抗体与血小板的相互作用均无任何影响。相反，ODSH抑制PF 4结合到凝胶过滤的血小板，从PF 4转染的细胞系中置换PF 4，从血小板表面置换PF 4/肝素复合物，并抑制抗PF 4/肝素Ab结合到PF 4/肝素复合物和随后的血小板活化。达比加群和利伐沙班似乎是有HIT病史患者的替代抗凝治疗选择。ODSH可防止免疫原性PF 4/肝素复合物的形成，并且当与肝素一起给药时，可能具有降低肝素治疗期间HIT风险的潜力。（血。2012;119（5）：1248-1255）
Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti-PF4/heparin Abs with platelets. In contrast, ODSH inhibited PF4 binding to gel-filtered platelets, displaced PF4 from a PF4-transfected cell line, displaced PF4/heparin complexes from platelet surfaces, and inhibited anti-PF4/heparin Ab binding to PF4/heparin complexes and subsequent platelet activation. Dabigatran and rivaroxaban seem to be options for alternative anticoagulation in patients with a history of HIT. ODSH prevents formation of immunogenic PF4/heparin complexes, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin. (Blood. 2012;119(5):1248-1255)