Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Blood. 2012 May 31;119(22):5285-93. doi: 10.1182/blood-2011-06-359430. Epub 2012 Mar 6.
Heparin-induced thrombocytopenia (HIT) is a potentially devastating form of drug-induced thrombocytopenia that occurs in patients receiving heparin for prevention or treatment of thrombosis. Patients with HIT develop autoantibodies to the platelet factor 4 (PF4)/heparin complex, which is termed the HIT Ab complex. Despite a decrease in the platelet count, the most feared complication of HIT is thrombosis. The mechanism of thrombosis in HIT remains poorly understood. We investigated the effects of the HIT Ab complex on tissue factor (TF) expression and release of TF-positive microparticles in peripheral blood mononuclear cells and monocytes. To model these effects ex vivo, we used a murine mAb specific for the PF4/heparin complex (KKO), as well as plasma from patients with HIT. We found that the HIT Ab complex induced TF expression in monocytes and the release of TF-positive microparticles. Further, we found that induction of TF is mediated via engagement of the FcγRI receptor and activation of the MEK1-ERK1/2 signaling pathway. Our data suggest that monocyte TF may contribute to the development of thrombosis in patients with HIT.
肝素诱导的血小板减少症（HIT）是一种潜在的破坏性药物诱导的血小板减少症，发生在接受肝素预防或治疗血栓形成的患者中。患有 HIT 的患者会产生针对血小板因子 4（PF4）/肝素复合物的自身抗体，称为 HIT Ab 复合物。尽管血小板计数下降，但 HIT 最可怕的并发症是血栓形成。HIT 中血栓形成的机制仍不清楚。我们研究了 HIT Ab 复合物对组织因子（TF）在外周血单核细胞和单核细胞中表达和释放 TF 阳性微粒的影响。为了在体外模拟这些作用，我们使用了一种针对 PF4/肝素复合物的鼠单克隆抗体（KKO）以及来自 HIT 患者的血浆。我们发现 HIT Ab 复合物诱导单核细胞中 TF 的表达和 TF 阳性微粒的释放。此外，我们发现 TF 的诱导是通过 FcγRI 受体的结合和 MEK1-ERK1/2 信号通路的激活来介导的。我们的数据表明，单核细胞 TF 可能有助于 HIT 患者血栓形成的发展。
