Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia
Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia
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HIT 抗原的动态细胞间重新分布调节肝素诱导的血小板减少症
DOI：
10.1182/blood-2018-02-830737
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发表时间：
2018-08-16
期刊：
影响因子：
20.3
通讯作者：
Rauova, Lubica
中科院分区：
文献类型：
--
作者：
Dai, Jing;Madeeva, Dana;Rauova, Lubica
肝素诱导的血小板减少症（HIT）是一种由血小板因子4（PF 4）/肝素复合物抗体引发的血栓前疾病。从血小板释放的PF 4与造血细胞和血管细胞上的表面糖胺聚糖结合，这些细胞在组成上是异质的，并且对PF 4的亲和力不同。PF 4与单核细胞的结合亲和力高于与血小板的结合亲和力，在小鼠HIT模型中，单核细胞的耗竭加剧了血小板减少症。在这里，我们表明，血小板上的PF 4的表达和血小板减少症的发展是由PF 4的造血和内皮细胞表面之间的（重新）分布调制。在体外，PF 4与全血中血小板的结合与白色细胞计数成反比，这可能是因为单核细胞对PF 4的亲和力更大。在小鼠中，单核细胞耗竭使PF 4与血小板的结合增加了2 - 3倍。在小鼠中诱导HIT引起HIT抗体与单核细胞的结合瞬时增加> 80倍，而与血小板的结合瞬时增加3.5倍，并引起快速瞬时单核细胞减少症。单核细胞计数的正常化先于血小板计数的恢复。血液暴露于内皮细胞也会消耗血小板表面的PF 4。这些研究表明，造血细胞和血管细胞之间的表面结合的PF 4的动态交换，可能会限制血小板减少症的代价，促进血栓形成前的过程中HIT。
Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder initiated by antibodies to platelet factor 4 (PF4)/heparin complexes. PF4 released from platelets binds to surface glycosaminoglycans on hematopoietic and vascular cells that are heterogenous in composition and differ in affinity for PF4. PF4 binds to monocytes with higher affinity than to platelets, and depletion of monocytes exacerbates thrombocytopenia in a murine HIT model. Here we show that the expression of PF4 on platelets and development of thrombocytopenia are modulated by the (re) distribution of PF4 among hematopoietic and endothelial cell surfaces. Binding of PF4 to platelets in whole blood in vitro varies inversely with the white cell count, likely because of the greater affinity of monocytes for PF4. In mice, monocyte depletion increased binding of PF4 to platelets by two-to three-fold. Induction of HIT in mice caused a transient > 80-fold increase in binding of HIT antibody to monocytes vs 3.5-fold increase to platelets and rapid transient monocytopenia. Normalization of monocyte counts preceded the return in platelet counts. Exposure of blood to endothelial cells also depletes PF4 from platelet surfaces. These studies demonstrate a dynamic interchange of surface-bound PF4 among hematopoetic and vascular cells that may limit thrombocytopenia at the expense of promoting prothrombotic processes in HIT.