The Role of LDL in Hemostasis

Abstract Hemophilia A is a hereditary bleeding disorder that results from deficiency of clotting factor VIII and affects more than 400,000 individuals worldwide. Severity levels of hemophilia (mild, moderate, or severe) are classified based on remaining clotting factor. However, bleeding risk varies considerably within the same classification, and different levels of blood clot lysis could be a crucial contributor to that variation. Severe hemophilia patients have shown increased fibrinolysis with higher concentrations of tissue-type plasminogen activator (tPA), the primary initiator of lysis but the mechanism is unknown. Furthermore, compared to age-matched general population, hemophilia patients have lower overall cardiovascular risk with lower atherogenic low-density lipoprotein (LDL)-cholesterol levels, and the lowest LDL cholesterol levels were observed in hemophilia patients with the severest bleeding symptoms. Plasma tPA activity is negatively associated with atherogenic LDL cholesterol levels in patients with cardiovascular and metabolic diseases. Our new preliminary data showed that 1) hemophilia A patients have lower LDL-cholesterol and apoB with the lowest level in the severe group. 2) Lower apoB levels correlate with lower resistance to fibrinolysis by recombinant tPA (rtPA)-induced turbidity assay in hemophilia patients (n=16, r=0.62, p=0.01). 3) LDL particles isolated from healthy volunteers or from wild-type mice accelerate clotting time in the whole blood of hemophilia A mice measured by ROTEM. 4) LDL is a major carrier of circulating FVIII proteins. 5) Tranexamic acid (TXA) partially blocks the interaction between tPA and apoB. Based on these compelling preliminary data, the overarching objective of this proposal is to test the central hypothesis that LDL improves hemostasis by accelerating clotting time and inhibiting fibrinolysis. We propose the following three specific aims to test our central hypothesis using established methods, hemophilia murine models, and access to hemophilia patient plasma and whole blood samples from Versiti CCBD.