Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
Condition: Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Hypertension; Anemia, Sickle Cell
Intervention: Warfarin; Placebo
Intervention description: Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3
Intervention MeSH terms: Warfarin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 3.0
Sex: All
Minimum age: 16 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: sickle cell disease; pulmonary hypertension; coagulation activation; platelet activation; endothelial activation

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.
    

Eligibility criteria:

        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.