Pulmonary Hypertension a Major Risk for Adults with Sickle Cell

Nearly one third of adults with sickle cell disease develop high blood pressure in arteries that supply the lungs - a condition referred to as pulmonary hypertension - which causes a much higher death rate in sickle cell patients with the complication than in those without it, according to a study published in The New England Journal of Medicine (Feb. 26, 2004).

Pulmonary hypertension can cause fatigue, dizziness and shortness of breath as blood vessels that supply the lungs narrow, forcing the heart to work harder to push blood through. (Pulmonary hypertension is not related to the "systemic" blood pressure that is commonly measured with a cuff on the arm.)

Researchers at the National Institutes of Health, who collaborated on the study with the Howard University Center for Sickle Cell Disease, said that the new data supports universal screening for pulmonary hypertension in sickle cell disease patients and the need for more clinical trials to further investigate therapies to combat high blood pressure in the lungs.

"What they show is that there's a strong association between pulmonary hypertension and the risk of death, in that sickle cell disease patients with pulmonary hypertension seem to die much more frequently," said J. Paul Scott, MD, Medical College of Wisconsin Professor of Pediatrics.

"Causation is not proven; what you have is evidence that the blood pressure is increased in the lungs, which can be associated with problems with the heart. The mechanism causing the increased blood pressure in the lungs isn't clear. If an individual were to suddenly have a marked increase in pulmonary blood pressure, it could markedly reduce the blood flow through the lungs and potentially trigger acute decompensation." People experiencing decompensation, in which the heart can't maintain adequate circulation, usually have problems like edema - foot or leg swelling from excess fluid backup - and trouble breathing.

"An alternative hypothesis," says Dr. Scott, "is that pulmonary hypertension is associated with other things, like accelerated hemolysis (destruction of red blood cells), kidney disease or systemic hypertension - the blood pressure that your doctor usually measures. Together, maybe these conditions mark a group of patients who have particularly bad sickle cell disease. Pulmonary hypertension seems very clearly linked with an increased risk of death, but linking all the arrows to explain 'why' has not been done."

Dr. Scott, an attending hematologist at Children's Hospital of Wisconsin and Medical Director of the Wisconsin Sickle Cell Center, is part of the team at the Medical College-affiliated Blood Research Institute, the research arm of the Blood Center of Southeastern Wisconsin.

More Study and Collaboration
Several aspects of research within the sickle cell program at the Blood Research Institute relate to pulmonary hypertension.

"My colleague Cheryl Hillery (MD, Medical College Associate Professor of Pediatrics) is working specifically on cell adhesion in sickle cell disease, meaning the red cells' 'stickiness,'" said Dr. Scott.

"Dr. Hillery's was the first lab to demonstrate that inhibition of nitric oxide synthesis causes stroke in sickle cell disease. There's been a longstanding interest in nitric oxide and nitric oxide metabolites and its influence on sickling and other phenomena by her and her research group.

"We also want to look at adolescents. The patients who were studied had an average age of about 36 - they were all adults. So the questions are, 'is this an evolving process that begins in childhood? And if you see it evolving in childhood, are there things that you can do to prevent this from getting worse?'"

"We were the first group to publish on the use of hydroxyurea in children," Dr. Scott continues. "If hydroxyurea were effective in children like it is in adults, and it appears to be, then it would reduce the episodes of acute chest syndrome, and if you prevent lung damage then in theory you prevent pulmonary hypertension.

Finally, since 1992, we've been major contributors to the field of bone marrow transplantation in sickle cell disease. That, ultimately, is a way to prevent this pulmonary hypertension because we cure patients of sickle cell disease with a bone marrow transplant." (The most discouraging aspect of the recent study, Dr. Scott said, is that the researchers could not definitively link hydroxyurea therapy to a better outcome. Hydroxyurea is the only approved drug for treatment of sickle cell disease.)

Another area of study in the treatment of sickle cell disease involves blood transfusions, says Dr. Scott. "It may be useful to give blood transfusions to reduce the amount of sickle hemoglobin and increase the amount of normal hemoglobin by transfusing those red cells and thereby see if you can reduce pulmonary hypertension. There is some evidence that that occurs, both observationally by others and by me; we've seen this."

Certain medications might also prove useful, he notes. "The newest agent on the horizon, recently recorded as an abstract in Sickle Cell News, is Viagra (sildenafil). Oral sildenafil seems to lower pulmonary blood pressure and there are ongoing clinical studies and research using Viagra for pulmonary hypertension, both in adults and children. This is really the newest advance, potentially, but the safety and efficacy data are not complete."

While the use of sildenafil to treat pulmonary hypertension shows promise in general, there are concerns about potential side effects. "The big question right now is whether Viagra is going to play a role in treatment and prevention of pulmonary hypertension in sickle cell disease," said Dr. Scott. "There are a lot of people who are excited about it."

Dan Ullrich
HealthLink Contributing Writer

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.