Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

An Exploratory Study of Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

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.

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.

Inclusion Criteria:

• At least 16 years of age
• Have a confirmed diagnosis of sickle cell anemia (HbSS) or sickle cell beta zero thalassemia
• Have evidence of persistent elevation of pulmonary artery systolic pressure on Doppler echocardiography (TR jet velocity of 2.5 to 2.9 m/s [or estimated pulmonary artery systolic pressure above the upper limit of reference adjusted ranges and up to 45 mm Hg]), but no evidence of moderate or severe diastolic dysfunction on tissue Doppler echocardiography. Mild PHT must be confirmed on repeat evaluation, at least 3 months later
• Have a serum creatinine =/< 1.5 mg/dl
• Have serum transaminase values (ALT) < 2 times upper limits of normal
• Have serum albumin =/> 3.2 g/dl
• Have a platelet count =/< 150,000 cu/mm
• Have normal baseline coagulation profile (PT/PTT)
• Patients on treatment with hydroxyurea should be on a stable dose for at least 6 months. Doses of hydroxyurea may only be adjusted during the course of the study for safety reasons.
• Be able to understand the requirements of the study and be willing to give informed consent.
• Women of childbearing age must be practicing (and will continue to practice for the course of the study) an adequate method of contraception.

Exclusion Criteria:

• Have a baseline hemoglobin < 6.0 gm/dl
• Have congenital heart disease, valvular heart disease, and other identified cause of pulmonary hypertension (including pulmonary fibrosis) unrelated to SCD
• Have an elevated pulmonary capillary wedge pressure, as evidenced by E/Em > 15 by pulsed wave and tissue Doppler imaging
• Have no measurable tricuspid regurgitant velocity on echocardiography
• Have a history of major gastrointestinal bleeding or a bleeding diathesis
• Have sickle cell complications such as recent vaso-occlusive crisis or acute chest syndrome, 4-weeks prior to commencing the study
• Have a history of clinically overt stroke(s) or seizures
• Have a brain magnetic resonance imaging/magnetic resonance angiography scan with evidence of Moya Moya within the preceding year
• Are pregnant or breastfeeding
• Are on chronic anticoagulant therapy
• Have a history of metastatic cancer
• Are chronically on therapy with aspirin or non-steroidal anti-inflammatory agents
• Are on a chronic transfusion program or have received a blood transfusion in the prior 8 weeks
• Have a positive urine toxicology screen for cocaine and amphetamines
• Have a history of alcohol abuse
• Are currently receiving treatment with epoprostenol (or similar prostacyclin analog), sildenafil (or similar phosphodiesterase 5 inhibitor), bosentan or arginine
• Have ingested any investigational drugs within the past 4 weeks.