Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
| Status: | Completed |
|---|---|
| Conditions: | High Blood Pressure (Hypertension), Anemia |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Hematology |
| Healthy: | No |
| Age Range: | 16 - 65 |
| Updated: | 3/1/2014 |
| Start Date: | December 2009 |
| End Date: | December 2013 |
| Contact: | Kenneth I Ataga, MD |
| Email: | kataga@med.unc.edu |
| Phone: | 919-966-0178 |
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.
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.
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 PASP on Doppler echocardiography (TR jet
velocity of 2.5 to 2.9 m/s [or estimated PASP 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/INR, 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 PCWP, 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 MRI/MRA 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.
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