Venous thromboembolism (VTE) the third most frequent cause of vascular mortality after myocardial infarction and stroke, occurs more frequently among Americans of African descent compared with other ethnic minorities in the US. VTEs are provoked by diverse risk factors but can be unprovoked in individuals with a hypercoagulable state, in whom there is a predisposition for thrombosis. Patients with Sickle Cell Disease (SCD) have added risk of VTE as the disease itself is a hypercoagulable state. VTE frequency is increased across the entire spectrum of SCD severity, in those experiencing both mild (HbSC patients) and severe sickling symptoms (HbSS/HbSbeta0 thalassemia patients). Studies show that up to 12% of patients with SCD have VTE events \[deep vein thrombus (DVT) or pulmonary embolism (PE) or both\] early in life by age 40, most of which are unprovoked. Moreover, owing to a persistent hypercoagulable state, SCD patients are at an unacceptably high risk for recurrence, particularly those in whom VTE was unprovoked. SCD patients who develop a VTE have a 24.1% risk of recurrence over 5 years. A history of a VTE in SCD is associated with greater mortality risk (Odd Ratio, OR = 2.88; Confidence Interval, CI = 2.35 - 3.52).

Our overall hypothesis is that the proinflammatory state associated with SCD perturbs the coagulation system and contributes to the thrombotic vascular pathobiology of SCD. Abnormal intravascular tissue factor expressed on monocytes and endothelial cells and circulating tissue factor positive extracellular vesicles released by these cells drive coagulation activation in SCD. Specifically, intravascular tissue factor forms the tenase complex (TF:VIIa) which converts factor X to factor Xa, generating the initial thrombin burst that possibly triggers intravascular thrombosis. Besides, heightened tissue factor exposure during acute sickling crises, increased release of tissue factor positive extracellular vesicles and inadequate clearance of the latter favors thrombin generation, fibrin deposition and thrombosis in the venous vasculature. SCD patients with VTE and/or recurrent VTE are therefore more likely to have more tissue factor positive extracellular vesicles and plasma tissue factor procoagulant activity compared with SCD patients without VTE.

Prospective cohort studies of extended duration/indefinite anticoagulation in non-SCD patients with an underlying hypercoagulable state have effectively reduced recurrence rates. However, similar studies of extended duration anticoagulation in SCD patients are lacking. Besides, whether exposing SCD patients to extended/indefinite anticoagulation increases bleeding risk to unacceptably high levels is unknown. Studying thrombogenic risk and specifically identifying those SCD patients who are at greatest risk for VTE recurrence therefore becomes a high priority. In addition, individuals with sickle cell trait are prone to thrombosis but few studies evaluate markers of thrombotic risk in these individuals. Such studies could provide a rationale for targeted primary or secondary VTE prophylaxis.

In the current proposal we will test the hypothesis that plasma tissue factor positive extracellular vesicles and tissue factor activity are elevated among SCD patients with VTE compared with SCD patients without VTE and in individuals with Sickle Cell Trait compared with ethnically matched controls.