Conditions: Pulmonary Hypertension
Keywords: sickle cell disease pulmonary hypertension coagulation activation platelet activation endothelial activation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
Sickle cell disease (SCD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. Pulmonary hypertension (PHT) is a common complication associated with significant morbidity and mortality. Autopsy studies of SCD patients with PHT show evidence of in situ thrombosis involving pulmonary vessels, similar to findings in non-sickle cell patients with PHT. Anticoagulation has been reported to be of benefit in non-sickle cell patients with PHT. With the evidence of increased coagulation activation in SCD, PHT represents a clinical endpoint that may be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. The investigators hypothesize that increased thrombin generation, as well as platelet activation are central to the pathophysiology of SCD and contribute to the occurrence of several SCD-related complications, including PHT. As a consequence, treatment modalities that down-regulate thrombin generation would be expected to delay the progression of PHT and result in improved survival in patients with SCD.

Detailed description:
As a result of the presence of large vessel thrombotic complications, as well as the biochemical evidence of ongoing coagulation activation, sickle cell disease (SCD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. While the majority of clinical studies using anticoagulants have shown no convincing benefit in the prevention or treatment of acute pain episodes, most of these studies were small and poorly controlled. Furthermore, because the acute pain episode appears to result from the occlusion of postcapillary venules by the interaction of red blood cells and other cellular elements with the vascular endothelium and subendothelial matrix proteins, it may not be the ideal clinical endpoint for assessing the effect of anticoagulation in SCD patients. Pulmonary hypertension (PHT), a common complication associated with significant morbidity and mortality, and with histopathologic findings of in situ thrombosis involving pulmonary vessels, represents a clinical endpoint that is likely due, at least in part, to increased thrombin generation, and may therefore be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. Twenty patients with sickle cell anemia (HbSS) or sickle beta zero thalassemia (Sickle beta zero thalassemia) and mild PHT who meet the eligibility requirements will be enrolled, 10 patients to receive anticoagulation with warfarin and 10 to receive placebo rfor 12 months of treatment.

Arms:
arm 1: Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin arm 2: matching active products

Interventions: intervention 1: Warfarin intervention 2: Placebo
Intervention descriptions: intervention 1: Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3 intervention 2: None

Protocol document: