Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin
Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin
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DOI：
10.1182/blood-2003-11-3994
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发表时间：
2004-11-15
期刊：
影响因子：
20.3
通讯作者：
Kowalska, MA
中科院分区：
文献类型：
--
作者：
Eslin, DE;Zhang, CY;Kowalska, MA
血小板特异性趋化因子血小板因子4（PF4）在血管损伤部位大量释放。 PF4与具有高亲和力的肝素结合，但尚未定义其体内生物学作用。我们使用杂合子和纯合子PF4敲除小鼠（分别为MPF4（+/-）和MPF4（ - / - ）（分别为MPF4（+/-））和过度表达人PF4（HPF4（+））的PF4在血栓形成中的作用。这些线都没有明显的出血性透性，但是在FECL3颈动脉血栓形成模型中，均显示出血栓形成受损。通过在狭窄的浓度范围内注入HPF4，可以纠正MPF4（ - / - ）动物中血栓形成的这种缺陷。 MPF4（+/-）和MPF4（ - / - ）动物中的血栓缺陷对负电荷抗凝肝素的输注特别敏感。然而，尽管这些动物是全身抗凝的，但在HPF4（+）动物中矛盾的肝素矛盾的归一化血栓形成。在注入正电蛋白质硫酸质蛋白质时，使用MPF4（+/-）和MPF4（ - / - ）动物观察到具有改善血栓形成的动物，而HPF4（+）动物的血栓形成恶化。这些研究支持PF4在血栓形成中的重要作用，并表明PF4的中和是肝素抗凝作用的重要组成部分。这些观察到PF4生物学及其临床意义的基础的机制尚待确定。 （c）2004年美国血液学学会。
The platelet-specific chemokine platelet factor 4 (PF4) is released in large amounts at sites of vascular injury. PF4 binds to heparin with high affinity, but its in vivo biologic role has not been defined. We studied the role of PF4 in thrombosis using heterozygote and homozygote PF4 knock-out mice (mPF4(+/-) and mPF4(-/-), respectively) and transgenic mice overexpressing human PF4 (hPF4(+)). None of these lines had an overt bleeding diathesis, but in a FeCl3 carotid artery thrombosis model, all showed impaired thrombus formation. This defect in thrombus formation in the mPF4(-/-) animals was corrected by infusing hPF4 over a narrow concentration range. The thrombotic defect in the mPF4(+/-) and mPF4(-/-) animals was particularly sensitive to infusions of the negatively charged anticoagulant heparin. However, the same amount of heparin paradoxically normalized thrombus formation in the hPF4(+) animals, although these animals were anticoagulated systemically. Upon infusion of the positively charged protein, protamine sulfate, the reverse was observed with mPF4(+/-) and mPF4(-/-) animals having improved thrombosis, with the hPF4(+) animals having worsened thrombus formation. These studies support an important role for PF4 in thrombosis, and show that neutralization of PF4 is an important component of heparin's anticoagulant effect. The mechanisms underlying these observations of PF4 biology and their clinical implications remain to be determined. (C) 2004 by The American Society of Hematology.