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

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 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.