ANTIBODIES FROM PATIENTS WITH HEPARIN-INDUCED THROMBOCYTOPENIA/THROMBOSIS ARE SPECIFIC FOR PLATELET FACTOR-4 COMPLEXED WITH HEPARIN OR BOUND TO ENDOTHELIAL-CELLS
ANTIBODIES FROM PATIENTS WITH HEPARIN-INDUCED THROMBOCYTOPENIA/THROMBOSIS ARE SPECIFIC FOR PLATELET FACTOR-4 COMPLEXED WITH HEPARIN OR BOUND TO ENDOTHELIAL-CELLS
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DOI：
10.1172/jci116987
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发表时间：
1994-01-01
影响因子：
15.9
通讯作者：
ASTER, RH
中科院分区：
文献类型：
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作者：
VISENTIN, GP;FORD, SE;ASTER, RH
肝素诱导的血小板减少/血栓形成(HITP)被认为是由免疫球蛋白介导的，在药物浓度的肝素存在下，免疫球蛋白激活血小板，但这种相对常见且往往是严重的肝素治疗并发症的分子基础尚未建立。我们发现，12例HITP患者的血浆均含有效价高(大于或等于1：200)的抗体，该抗体可与凝血素和血小板α颗粒中的肝素结合蛋白4(PF4)的固定化复合体反应。在该检测系统中，重组人PP4的行为与从血小板中分离的PF4相似。当表观肝素/PF4分子比接近1：2(新鲜肝素)和接近1：12(过期肝素)时，形成的复合体最有效地结合抗体。由PF4、肝素和抗体组成的免疫复合体与静息的血小板反应；这种相互作用被针对Fc-Gamma RII受体的单抗和过量的肝素抑制。已知的人脐静脉内皮细胞表面表达类肝素糖胺聚糖分子，在PF4单独存在时可被抗体识别；这一反应可被过量的肝素抑制，但不能被抗Fc-Gamma RII抑制。在50例其他类型的免疫性血小板减少症患者中，3例(6%)在1：10(Ig G)和1：50(Ig M)稀释度检测到与肝素/PF4反应的抗体。这些发现表明，与HITP相关的抗体与溶液中与肝素络合的PF4或与内皮细胞表面的糖胺聚糖分子反应，为解释对肝素敏感的患者发生血小板减少并血栓形成或弥漫性血管内凝血的新假说提供了基础。
Heparin-induced thrombocytopenia/thrombosis (HITP) is thought to be mediated by immunoglobulins that activate platelets in the presence of pharmacologic concentrations of heparin, but the molecular basis for this relatively common and often serious complication of heparin therapy has not been established. We found that plasma from each of 12 patients with HITP contained high titer (greater than or equal to 1:200) antibodies that reacted with immobilized complexes of heparin and platelet factor 4 (PF4), a heparin-binding protein contained in platelet alpha-granules. Recombinant human PP4 behaved similarly to PF4 isolated from platelets in this assay system. Complexes formed at an apparent heparin/PF4 molecular ratio of similar to 1:2 (fresh heparin) and similar to 1:12 (outdated heparin) were most effective in binding antibody. Immune complexes consisting of PF4, heparin, and antibody reacted with resting platelets; this interaction was inhibited by a monoclonal antibody specific for the Fc gamma RII receptor and by excess heparin. Human umbilical vein endothelial cells, known to express heparin-like glycosaminoglycan molecules on their surface, were recognized by antibody in the presence of PF4 alone; this reaction was inhibited by excess heparin, but not by anti-Fc gamma RII. Antibodies reactive with heparin/PF4 were not found in normal plasma, but IgG and IgM antibodies were detected at dilutions of 1:10 (IgG) and 1:50 (IgM) in 3 of 50 patients (6%) with other types of immune thrombocytopenia. These findings indicate that antibodies associated with HITP react with PF4 complexed with heparin in solution or with glycosaminoglycan molecules on the surface of endothelial cells and provide the basis for a new hypothesis to explain the development of thrombocytopenia with thrombosis or disseminated intravascular coagulation in patients sensitive to heparin.