Factor XIII and Fibrinogen: Mechanisms of Genetic Risk in SCD-Related Priapism

 描述(由申请人提供)：异常勃起影响30-40%患有镰状细胞病(SCD)的男性。阴茎异常勃起涉及阴茎血管充血和这些血管的瘀血，但其发病机制尚不清楚。因此，对急性和复发性异常勃起的治疗仍然非常不令人满意。最近探索SCD异常勃起的遗传易感性的努力导致了几个与异常勃起风险相关的基因多态的鉴定。凝血级联反应中两个最相关的多态存在于蛋白质中：凝血因子XIIIA A链(FXIIIA)和纤维蛋白原B链。值得注意的是，超过90%的异常勃起患者至少有一种危险基因，这表明纤维蛋白形成和纤维蛋白(原)交联在异常勃起中起关键作用。 异常勃起的病理生理学研究。我们推测，FXIII和纤维蛋白原的这些多态性通过改变纤维蛋白的交联性(或其他蛋白质，如纤维连接蛋白与纤维蛋白的交联性)以及镰刀状红细胞与纤维蛋白凝块或与其他细胞成分(即其他血细胞)的相互作用来影响SCD异常勃起的风险。为了了解SCD中这些多态与异常勃起相关的机制，我们提出了两个特定的目标。目的1：比较具有与异常勃起相关的FXIIIA和纤维蛋白原？链基因多态的个体的凝血活性、纤维蛋白交联度、红细胞在凝块中的捕获和凝块稳定性。我们假设，具有FXIII和纤维蛋白原风险等位基因的SCD患者将有更快或更明显的纤维蛋白交联度，增加红细胞在血栓中的滞留，并增加血栓稳定性。我们还将描述异常勃起期间这些指标的变化。目的：研究FXIIIA基因和纤维蛋白原B链基因多态性对稳态SCD患者外周血中异种血细胞聚集体频率和组成的影响。我们假设，具有FXIII和纤维蛋白原风险等位基因的SCD患者将有更多的循环异细胞聚集和增加的FXIII底物(例如，纤维蛋白、纤维连接蛋白或层粘连蛋白)在细胞聚集中交叉连接。我们期望阐明FXIII和纤维蛋白原基因多态性与SCD异常勃起风险相关的机制将揭示导致这一毁灭性并发症的病理生理过程。我们预计，这些信息将确定并允许研究新的治疗靶点。

 DESCRIPTION (provided by applicant): Priapism affects between 30-40% of males with sickle cell disease (SCD). Priapism involves engorgement of penile vessels and blood stasis in these vessels, but the process underlying its pathogenesis remains unclear. Consequently, treatment for acute and recurrent priapism remains highly unsatisfactory. Recent efforts to explore genetic predisposition to priapism in SCD has resulted in the identification of several genetic polymorphisms associated with risk for priapism. Two of the most strongly associated polymorphisms reside in proteins in the coagulation cascade: the Factor XIII A-chain (FXIIIA) and the fibrinogen ß-chain. Notably, over 90% of SCD subjects with priapism have at least one risk genotype, suggesting that fibrin formation and fibrin(ogen) crosslinking play key roles in the pathophysiology of priapism in SCD. We hypothesize that these polymorphisms in FXIII and fibrinogen affect the risk for priapism in SCD by altering crosslinking of fibrin (or crosslinking f other proteins, such as fibronectin, to fibrin) and interactions of sickle RBCs with fibrin clots o with other cellular elements (i.e., other blood cells). To understand the mechanism responsible for the association of these polymorphisms with priapism in SCD, we propose two Specific Aims. Aim 1: Compare coagulation activation, fibrin crosslinking, capture of RBCs in clots and clot stability, in individuals with and without the FXIIIA and fibrinogen ß-chain polymorphisms associated with priapism. We hypothesize that SCD patients with FXIII and fibrinogen risk alleles will have a more rapid or pronounced degree of fibrin crosslinking, increased RBC retention in clots, and increased clot stability. We will also characterize changes in these measures during priapic episodes. Aim 2: Determine the effects of FXIIIA and fibrinogen ß-chain polymorphisms on the frequency and composition of circulating heterologous blood cell aggregates in SCD patients during steady state. We hypothesize that SCD patients with FXIII and fibrinogen risk alleles will have increased circulating heterocellular aggregates and increased FXIII substrates (e.g., fibrin, fibronectin or laminin) cross-linked in cellular aggregats. We expect that elucidating the mechanisms associating FXIII and fibrinogen polymorphisms with priapism risk in SCD will reveal pathophysiological processes leading to this devastating complication. We anticipate that this information will identify and allow investigation of new therapeutic targets.