Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: Warfarin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Warfarin<br>Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin | Drug: Warfarin<br>* Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3<br>* Other names: Coumadin;|
| Placebo Comparator: Placebo<br>matching active products | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Anticoagulation on Pulmonary Artery Systolic Pressure Was Obtained by Doppler Echocardiography | We determined the effect of anticoagulation with warfarin on estimated pulmonary artery systolic pressure obtained by Doppler echocardiography. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward. | Measurements were obtained at Screening, and at Months 3, 6, 9, and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-minute Walk Test | We evaluated the distance walked over 6 minutes. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward. | Measurements were obtained at Screening, Months 3, 6, 9, and 12 | 
| Thrombin Generation | We evaluated the effect of warfarin on a plasma measure of thrombin generation (thrombin-antithrombin complex) | Measurements were obtained at Screening, and at Months 3, 6, 9, and 12 | 
| Platelet Activation | We evaluated the effect of anticoagulation with warfarin on platelet activation assessed by measuring plasma levels of soluble CD40 ligand | Measurements were obtained at Screening, Prior to Run-in, and at Months 3, 6, 9, and 12 | 
| Endothelial Activation | We assessed the effect of warfarin on plasma measures of endothelial activation (soluble vascular cell adhesion molecule-1) | Measurements were obtained at Screening, and at Months 3, 6, 9, and 12 | 
| All-cause Mortality | We assessed the effect of warfarin on mortality in the study subjects | Assessment was obtained until completion of study at 12 months | 
| Major and Minor Bleeding Complications | We evaluated the safety of warfarin by evaluating for major and minor bleeding complications in study subjects | Evaluations were obtained at Screening, and at Months 3, 6, 9, and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell disease, pulmonary hypertension, coagulation activation, platelet activation, endothelial activation