P-selectin is Central to Venous Thrombosis Pathogenesis

静脉血栓形成（VT）是一个全国性的健康问题，在过去的20年中以恒定的速度发生，每年至少有250，000例发病。 据估计，深静脉血栓形成和肺栓塞与每年约300，000至600，000例住院治疗和多达50，000例死亡相关。 慢性静脉功能不全，静脉血栓形成的后遗症，影响大约40万至50万皮肤溃疡患者，600万至700万皮肤瘀滞变化患者，并且随着时间的推移，高达28%的显著髂股DVT患者将发展严重水肿和皮肤变化，这可能导致静脉溃疡。 简言之，VT花费了卫生系统数十亿美元。 选择素是由活化的内皮细胞和血小板表达的粘蛋白样糖蛋白细胞粘附分子，并介导白细胞-血小板、白细胞-内皮细胞和白细胞-白细胞相互作用。 初步数据表明，P-选择素与VT相关的炎症和血栓反应的启动和维持存在时间相关性。 我们的研究假设包括：P-选择素与VT炎症和血栓形成放大偶然相关;单独抑制P-选择素或与其他药物一起增强将减少炎症和血栓形成而没有全身抗凝并发症;并且P-选择素抑制将刺激形成的血栓的血栓溶解，增强其他纤维蛋白溶解剂。 我们将解决这些假设与三个具体目标：具体目标1：以确定是否与静脉血栓形成相关的炎症机制涉及P-选择素。 这将使用表达高水平循环可溶性P-选择素的遗传改变的小鼠以及阻断过量可溶性P-选择素的效果来研究。 然后将它们与施用可溶性P-选择素的野生型小鼠和遗传上缺乏P-选择素的小鼠进行对比。 具体目标二：评估P-选择素抑制作用并检测其他抗血栓药物治疗VT的疗效，这些药物具有不同的作用机制，包括抑制因子Xa和直接抑制凝血酶。此外，联合收割机药物，以确定哪种或哪几种药物可为无抗凝活性的VT提供最佳治疗。 具体目标3：确定直接P-选择素抑制是否增强自发性和非自发性诱导的血栓溶解，特别是确定P-选择素抑制是否损害纤维蛋白沉积或增加纤维蛋白溶解。这些研究将明确P-选择素在VT发病机制、治疗和溶栓中的作用。

Venous thrombosis (VT) is a national health concern, occurring at a constant rate over the past 20 years, with an annual incidence of at least 250,000 cases. It is estimated that deep venous thrombosis and pulmonary embolism are associated with approximately 300,000 to 600,000 hospitalizations and as many as 50,000 deaths per year. Chronic venous insufficiency, the sequela of venous thrombosis, affects approximately 400,000 to 500,000 patients with skin ulceration, 6 to 7 million patients with skin stasis changes, and up to 28 percent of patients with significant iliofemoral DVT over time will develop severe edema and skin changes which may lead to venous ulceration. VT in short costs the health system billions of dollars. Selectins are mucin like glycoprotein cell adhesion molecules that are expressed by activated endothelial cells and platelets and mediate leukocyte-platelet, leukocyte-endothelial cell, and leukocyte-leukocyte interactions. Preliminary data suggest that P-selectin is temporally related to the initiation and maintenance of the inflammatory and thrombotic response associated with VT. Our research hypotheses include: P-selectin is casually related to VT inflammation and thrombosis amplification; inhibition of P-selectin alone or augmented with other agents will decrease inflammation and thrombosis without systemic anticoagulant complications; and P-selectin inhibition will stimulate thrombolysis of thrombus that does form, augmenting other fibrinolytic agents. We will address these hypotheses with three specific aims: Specific Aim 1: To determine if the mechanism of inflammation associated with venous thrombosis involves P-selectin. This will be investigated using genetically altered mice which express high levels of circulating soluble P-selectin, and the effect of blocking the excess soluble P-selectin. They will then be contrasted to wild type mice administered soluble P-selectin, and mice genetically lacking P- selectin. Specific Aim 2: To assess P-selectin inhibition and to test the efficacy of other antithrombotic agents for VT treatment, agents with different mechanisms of action including inhibition of factor Xa and direct thrombin inhibition. Additionally, to combine agents to determine which agent or agents offer the best treatment for VT without anticoagulant activity. Specific Aim 3: To determine if direct P-selectin inhibition augments both spontaneous and pharmacologically induced thrombolysis and specifically to determine if P-selectin inhibition impairs fibrin deposition or increases fibrinolysis. These studies will define the role of P-selectin in VT pathogenesis, treatment and thrombolysis.