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年里以恒定的速度发生，每年至少有25万例。据估计，深静脉血栓和肺栓塞每年造成约30万至60万人住院，多达5万人死亡。慢性静脉功能不全是静脉血栓形成的后遗症，大约影响40万至50万皮肤溃疡患者，600万至700万皮肤瘀血改变患者，高达28%的显著髂股深静脉血栓患者随着时间的推移会出现严重水肿和皮肤变化，这可能导致静脉溃疡。简而言之，VT花费了医疗系统数十亿美元。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-白细胞相互作用的粘蛋白类糖蛋白细胞粘附分子。初步研究结果表明，p -选择素与室性室炎症和血栓形成反应的启动和维持具有暂时性的相关性。我们的研究假设包括：p -选择素与室性室炎症和血栓形成放大具有偶发性；单独抑制p -选择素或与其他药物联合抑制p -选择素可减少炎症和血栓形成，无全身抗凝并发症；p -选择素的抑制会刺激血栓的溶栓，增加其他纤溶剂的作用。我们将以三个特定目的来解决这些假设：特定目的1：确定与静脉血栓形成相关的炎症机制是否与p选择素有关。研究人员将使用表达高水平循环可溶性p选择素的转基因小鼠，以及阻断过量可溶性p选择素的效果。然后将它们与给予可溶性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。特异性目的2：评估p -选择素的抑制作用，并测试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Xa因子和直接抑制凝血酶。此外，联合用药以确定哪种或哪种药物对无抗凝血活性的室速治疗效果最好。特异性目的3：确定直接p -选择素抑制是否增强自发溶栓和药理学诱导溶栓，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.