Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet derived cofactor
Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet derived cofactor
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DOI：
10.1111/j.1538-7836.2005.01157.x
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发表时间：
2005-03-01
影响因子：
10.4
通讯作者：
Tracy, PB
中科院分区：
文献类型：
--
作者：
Gould, WR;Simioni, P;Tracy, PB
来自血浆或从刺激的血小板释放的因子Va（FVa）是由凝血酶原酶复合物催化的凝血酶产生中的必需辅因子。血浆衍生因子V（FV）在肝脏中合成。血小板衍生辅因子的来源仍有疑问。我们确定了一例FVLeiden突变的纯合子患者，他接受了来自纯合子野生型FV供体的肝移植。移植后18天，患者血小板衍生的FV的表型分析表明血小板正在获得野生型FV。与巨核细胞的暂时分化和随后的血小板产生一致。移植后9个月，血小板衍生的FV库完全由野生型FV组成。因此，巨核细胞内吞的血浆衍生的FV必须占整个血小板衍生的池，因为血源性血小板不能结合或内吞FV。在该内吞过程之后，患者的血小板衍生的FV被切割成部分活性辅因子。并使其对血小板相关激酶催化的磷酸化具有抗性，因此对活化的蛋白C催化的失活较不敏感。这些数据提供了第一个在体内证明内吞血浆蛋白进行细胞内修饰，改变其功能。该过程导致活性FVa在血小板隔室内的隔离。在损伤部位从血小板释放后立即发挥作用。
Factor Va (FVa), derived from plasma or released from stimulated platelets, is the essential cofactor in thrombin production catalyzed by the prothrombinase complex. Plasma-derived factor V (FV) is synthesized in the liver. The source(s) of the platelet-derived cofactor remains in question. We identified a patient homozygous for the FVLeiden mutation, who received a liver transplant from a homozygous wildtype FV donor. Eighteen days post-transplant, phenotypic analysis of the patient's platelet-derived FV indicated that the platelets were acquiring wild-type FV. consistent with the temporal differentiation of megakaryocytes and subsequent platelet production. Nine months post-transplant, the platelet-derived FV pool consisted entirely of wild-type FV. Consequently, megakaryocyle endocytosis of plasma-derived FV must account for the entire platelet-derived pool, because blood-borne platelets cannot bind or endocytose FV. subsequent to this endocytic process, the patient's platelet-derived FV was cleaved to a partially active cofactor. and rendered resistant to phosphorylation catalyzed by a platelet-associated kinase, and hence less susceptible to activated protein C-catalyzed inactivation. These data provide the first in vivo demonstration of an endocytosed Plasma protein undergoing intracellular modifications that alter its function. This process results in the sequestration of active FVa within the platelet compartment., poised for immediate action subsequent to release from platelets at a site of injury.