Castelli R, Cassinerio E, Cappellini M D, Porro F, Graziadei G, Fabris F
Department of Medicine and Medical Specialities Division of Internal Medicine, IRCCS Fondazione Ospedale Maggiore Policlinico of Milan, Via Pace 9 Milan, Italy. Castelli39@interfree
Cardiovasc Hematol Disord Drug Targets. 2007 Sep;7(3):153-62. doi: 10.2174/187152907781745251.
Heparin induced thrombocytopenia (HIT) in addition to bleeding complications are the most serious and dangerous side effects of heparin treatment. HIT remains the most common antibody-mediated, drug-induced thrombocytopenic disorder and a leading cause of morbidity and mortality. Two types of HIT are described: Type I is a transitory, slight and asymptomatic reduction of platelet count occurring during 1-2 days of therapy. HIT type II, which has an immunologic origin, is characterized by a thrombocytopenia that generally onset after the fifth day of therapy. Despite thrombocytopenia, haemorrhagic complications are very rare and HIT type II is characterized by thromboembolic complications consisting in venous and arterial thrombosis. The aim of this paper is to review new aspects of epidemiology, pathophysiology, clinical features, diagnosis and therapy of HIT type II. There is increasing evidence that platelet factor 4 (PF4) displaced from endothelial cells, heparan sulphate or directly from the platelets, binds to heparin molecule to form an immunogenic complex. The anti-heparin/PF4 IgG immune-complexes activates platelets through binding with the Fcgamma RIIa (CD32) receptor inducing endothelial lesions with thrombocytopenia and thrombosis. Cytokines are generated during this process and inflammation could play an additional role in the pathogenesis of thromboembolic manifestations. The onset of HIT type II is independent from dosage, schedule, and route of administration of heparin. A platelet count must be carried out prior to heparin therapy. Starting from the fourth day, platelet count must be carried out daily or every two days for at least 20 days of any heparin therapy regardless of the route of the drug administration. Patients undergoing orthopaedic or cardiac surgery are at higher risk for HIT type II. The diagnosis of HIT type II should be formulated on basis of clinical criteria and confirmed by in vitro demonstration of heparin-dependent antibodies detected by functional and antigen methods. However, the introduction of sensitive ELISA tests to measure anti-heparin/PF4 antibodies has showed the immuno-conversion in an higher number of patients treated with heparin such as the incidence of anti-heparin/PF4 exceeds the incidence of the disease. If HIT type II is likely, heparin must be immediately discontinued, even in absence of certain diagnosis of HIT type II, and an alternative anticoagulant therapy must be started followed by oral dicumaroids, preferably after resolution of thrombocytopenia. Further studies are required in order to elucidate the pathogenetic mechanism of thrombosis and its relation with inflammation; on the other hand large clinical trials are needed to confirm the best therapeutic strategies for HIT Type II.
肝素诱导的血小板减少症（HIT）以及出血并发症是肝素治疗最严重且危险的副作用。HIT仍然是最常见的抗体介导的药物性血小板减少症，也是发病和死亡的主要原因。HIT分为两种类型：I型是在治疗1 - 2天内出现的短暂、轻微且无症状的血小板计数减少。II型HIT具有免疫源性，其特征是血小板减少症通常在治疗第五天后开始出现。尽管存在血小板减少症，但出血并发症非常罕见，II型HIT的特征是血栓栓塞并发症，包括静脉和动脉血栓形成。本文旨在综述II型HIT在流行病学、病理生理学、临床特征、诊断和治疗方面的新进展。越来越多的证据表明，从内皮细胞、硫酸乙酰肝素或直接从血小板上置换下来的血小板因子4（PF4）与肝素分子结合形成免疫原性复合物。抗肝素/PF4 IgG免疫复合物通过与FcγRIIa（CD32）受体结合激活血小板，导致内皮损伤并伴有血小板减少和血栓形成。在此过程中会产生细胞因子，炎症可能在血栓栓塞表现的发病机制中起额外作用。II型HIT的发病与肝素的剂量、给药方案和给药途径无关。在肝素治疗前必须进行血小板计数。从第四天开始，无论药物给药途径如何，在任何肝素治疗的至少20天内，必须每天或每两天进行一次血小板计数。接受骨科或心脏手术的患者发生II型HIT的风险更高。II型HIT的诊断应基于临床标准，并通过功能和抗原方法检测到的肝素依赖性抗体的体外证实来确认。然而，引入敏感的ELISA试验来测量抗肝素/PF4抗体后发现，在接受肝素治疗的更多患者中出现了免疫转化，例如抗肝素/PF4的发生率超过了疾病的发生率。如果可能是II型HIT，即使没有确诊II型HIT，也必须立即停用肝素，并开始替代抗凝治疗，随后使用口服双香豆素类药物，最好在血小板减少症缓解后使用。需要进一步研究以阐明血栓形成的发病机制及其与炎症的关系；另一方面，需要大型临床试验来确认II型HIT的最佳治疗策略。
