Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.
Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.
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DOI：
10.1182/blood-2010-03-276964
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发表时间：
2010-12
期刊：
影响因子：
20.3
通讯作者：
L. Rauova;J. Hirsch;T. Greene;Li Zhai;V. Hayes;M. Kowalska;D. Cines;M. Poncz
中科院分区：
文献类型：
--
作者：
L. Rauova;J. Hirsch;T. Greene;Li Zhai;V. Hayes;M. Kowalska;D. Cines;M. Poncz
肝素诱发的血小板减少症（HIT）是一种危及生命和肢体的血栓性疾病，在暴露于肝素后发展，通常在炎症的背景下。我们之前已经证明HIT与血小板因子4和血小板表面的糖胺聚糖（GAG）侧链之间形成的复合物的抗体相关。然而，血栓形成可以发生在没有血小板减少症。我们现在发现，血小板因子4与单核细胞结合，并与它们的表面GAG侧链形成抗原复合物，比血小板更有效，这可能是由于GAG组成的差异。当细胞被内毒素激活时，与单核细胞的结合增强。原位显微镜观察单核细胞在动脉血栓形成过程中的聚集情况。在改良的小鼠HIT模型中，体内单核细胞耗尽或失活可减轻颈动脉光化学损伤引起的血栓形成，同时矛盾地加剧血小板减少症。这些研究证明了单核细胞在HIT动脉血栓形成的发病机制中以前未被认识到的作用，并表明针对这些细胞的治疗可能提供一种替代方法来帮助限制这种以及可能发生在炎症背景下的其他血栓性疾病的血栓形成。
Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia. We now show that platelet factor 4 binds to monocytes and forms antigenic complexes with their surface GAG side chains more efficiently than on platelets likely due to differences in GAG composition. Binding to monocytes is enhanced when the cells are activated by endotoxin. Monocyte accumulation within developing arteriolar thrombi was visualized by situ microscopy. Monocyte depletion or inactivation in vivo attenuates thrombus formation induced by photochemical injury of the carotid artery in a modified murine model of HIT while paradoxically exacerbating thrombocytopenia. These studies demonstrate a previously unappreciated role for monocytes in the pathogenesis of arterial thrombosis in HIT and suggest that therapies targeting these cells might provide an alternative approach to help limit thrombosis in this and possibly other thrombotic disorders that occur in the setting of inflammation.