Pulmonary Hypertension in Thalassemia

January 19, 2010 – Pulmonary hypertension is a complication that occurs in some individuals with thalassemia. (Although it can occur in both thalassemia major and thalassemia intermedia, it is considered by CAF Medical Advisory Board Chair Ellis Neufeld to be a big problem in adults with intermedia and of possible rising significance in adults with major as they age.) Below, CAF speaks with Claudia R. Morris, MD, of Children’s Hospital and Research Center Oakland about pulmonary hypertension and thalassemia and about some current clinical trials in this area. These trials, which include a multi-center Thalassemia Clinical Research Network trial, are ongoing and are currently recruiting subjects.

CAF: Pulmonary hypertension is high blood pressure occurring in the arteries in the lungs. Why is this something which occurs in people with thalassemia, especially people with thalassemia intermedia? Is blood pressure in the lungs measured in a different method than “typical” blood pressure?

Claudis Morris, MD
Claudia Morris, MD
Dr. Morris’ presentation on pulmonary hypertension at the 9th Cooley’s Anemia Symposium is online. Click here to view.

Dr. Morris: Pulmonary hypertension is a serious medical condition that can contribute to early death. There are many reasons why a patient with thalassemia may be at increased risk for developing pulmonary hypertension. Mechanisms that include:

• a history of splenectomy,
• the biological consequences of hemolysis (the breaking down of red blood cells),
• abnormal coagulation (the way that blood forms clots),
• iron overload from chronic blood transfusions with subsequent damage to the heart,
• inflammation and
• the effects of advancing age that deplete an individual’s ability to counterbalance oxidative stress

all contribute to this increased risk.

During hemolysis, molecules are released from the ruptured red blood cell that consume an important vasodilator called “nitric oxide.” (A vasodilator widens the blood vessels, allowing blood to travel more


“As nitric oxide levels decrease, vessels constrict, contributing to high blood pressures in the artery that connects the heart to the lungs. “


easily.) As nitric oxide levels decrease, vessels constrict, contributing to high blood pressures in the artery that connects the heart to the lungs. Sticky platelets and other clumping cells can lead to blood clots in these vessels called “pulmonary emboli,” which also cause increased blood pressure in the pulmonary arteries. It turns out that most medical conditions associated with hemolysis also have a high frequency of pulmonary hypertension. (Hemolysis is more of an issue in thalassemia intermedia, which is one reason why pulmonary hypertension tends to be more often associated with intermedia than major. -Ed.)

Blood pressure in the lungs is measured differently than a typical “blood pressure” performed on your arm. The gold standard test for pulmonary hypertension is a procedure called a right-side cardiac catheterization. This involves passing a thin flexible tube (catheter) into the right side of the heart, usually passing through vessels in the groin or arm. This study is done by a trained cardiologist. A Doppler echocardiogram (a non-invasive test to estimate pulmonary artery pressures that is functionally an ultrasound of your heart and lung vessels) is then conducted and used to identify patients who are at risk for having pulmonary hypertension.

Sildenafil is used to treat pulmonary hypertension in the non-thalassemic population. Is it used to treat other conditions as well? Are there any typical side effects that are currently thought to be associated with its use (in the non-thalassemic population)? Why can’t we just assume that sildenafil will be as safe for people with thalassemia as it is for other patients?

Sildenafil is one of over 10 medications that is FDA-approved to treat pulmonary hypertension. Although sildenafil is effective in treating pulmonary hypertension, it has not specifically been studied in patients with thalassemia. Thalassemia patients are different from patients with other forms of pulmonary hypertension (and thalassemia major is different from thalassemia intermedia), and these differences may affect the way they respond to certain medications. This is why studies determining the best way to treat pulmonary hypertension in patients with thalassemia are needed. (Since sildenafil does not at this point have a label indication for use in thalassemia, an organized clinical trial can provide a good, safe setting for a thalassemia patient to try sildenafil as a possible treatment option for pulmonary hypertension. – Ed.)


“Sildenafil has not (yet) specifically been studied in patients with thalassemia.”


Also known as Viagra, sildenafil has gotten its reputation as a successful treatment for erectile dysfunction in addition to its role as a therapy for pulmonary hypertension. It is also used to treat high altitude sickness.

As with any medication, there are several side-effects that can occur with sildenafil use, although it is generally considered safe and well-tolerated. In clinical trials (which were not focused on the thalassemia population), the most common side effects included headache, flushing, dyspepsia (indigestion), nasal congestion and impaired vision, including photophobia (light sensitivity) and blurred vision. Rare cases of vision loss have been reported. Other rare but serious side effects include severe hypotension (abnormally low blood pressure),
heart attack, stroke, heart arrhythmia and sudden hearing loss. It should not be taken with other nitric oxide donating medications (organic nitrites and nitrates, such as nitroglycerine, sodium nitroprusside, amyl nitrite).

Sildenafil is an oral medication. How is it ingested – as a pill or as a solution?

Sildenafil comes in both a pill and liquid form.

What are the reasons that a person with thalassemia might want to enroll a study for pulmonary hypertension?

There are several reasons why a patient might be interested in participating in clinical trials. Research is very important in order to advance science, contribute to the greater good, and improve medical insight into diseases like thalassemia in order to improve therapies in the future. In particular, if a patient has pulmonary hypertension, it would be of benefit to the patient to have the condition studied further.

Ongoing studies utilize several procedures as part of the study to help determine the most significant contributing factors causing pulmonary hypertension. Pulmonary hypertension is associated with a number of risk factors. It is likely the result of a combination of factors, including coagulation issues, iron overload and the long-term consequences of hemolysis.

Clinical trials help guide future therapy for patients with thalassemia dealing with pulmonary hypertension. It is possible that sildenafil or other FDA approved stud


“Clinical trials help guide future therapy for patients with thalassemia dealing with pulmonary hypertension.”


ies may help improve pulmonary hypertension, although we do not yet know if this therapy will work in patients with thalassemia. Control arms are often included in studies in order to determine the differences between patients who develop a complication like pulmonary hypertension from those who do not.

Researchers hope that this information gained from clinical trials will lead to improved therapies for patients with thalassemia in the future. Participation in clinical trials will insure that progress is made in both our understanding of this complication, and the best alternatives for treatment.

If you or someone you know has thalassemia and pulmonary hypertension, even if they are not interested in participation in a clinical trial, it is important that they see a cardiopulmonary specialist for further evaluation. Although guidelines for the treatment of pulmonary hypertension in thalassemia do not yet exist, specialists in pulmonary hypertension can help provide you with the best options to address this condition.

One pulmonary hypertension study currently under way is a multi-center trial run through the Thalassemia Clinical Research Network (TCRN) evaluating the safety and efficacy of sildenafil for pulmonary hypertension in Thalassemia. In addition to taking sildenafil 3 times a day, patients with pulmonary hypertension will undergo a series of tests during weeks 1, 2, 4, 8 and 12. Can you explain what is involved in these tests? Can all be completed on one day of each visit? Can you estimate the amount of time involved for the tests? And are there any special requirements (e.g., fasting, etc.) required by the tests?


What are a 6 Minute Walk Test and a Doppler Echo?

6-Minute Walk Test:

The object of this test is to walk for as far as possible for 6 minutes. You will walk back and forth on a flat surface such as a hallway. Six minutes is a long time to walk, so you will be exerting yourself. You will be asked to familiarize yourself with the Modified Borg Scale. This scale is way of rating your degree of breathlessness and/or difficult, uncomfortable or labored breathing as well as fatigue level. You will be asked to use the Borg Scale before, during and after your walk.

(Above information from YourLungHealth.org)

Doppler echo:

Doppler is a special part of the ultrasound examination that assess blood flow (direction and velocity). During the Doppler examination, the ultrasound beams will evaluate the flow of blood as it makes it way though and out of the heart. This information is presented visually on the monitor (as color images or grayscale tracings and also as a series of audible signals with a swishing or pulsating sound). It provides information on the size of the heart and pumping function.

(Above information from HeartSite.org)


The TCRN sildenafil study, is currently enrolling patients. The main goal of the sildenafil trial is to determine whether sildenafil improves exercise tolerance and walking distance in patients with an abnormal Doppler echo suggesting pulmonary hypertension.

Since you asked about the sildenafil trial, a summary of the procedures follows:

There are many procedures and blood tests that will be done as part of the sildenafil study. It can take 1-2 days to complete all the tests for baseline and final evaluations, while the 2 week evaluation will take several hours. No fasting is required for these tests. The tests and procedures are commonly performed as part of the clinical work-up for pulmonary hypertensi

Tests and Procedures:
• Medical history, review of symptoms and physical exam (performed at every visit)
• 6 minute walk test (performed at every visit): Involves walking around a predetermined path at a comfortable pace for 6 minutes to the distance walked in 6 minutes, which reflects exercise capacity.
• Doppler echocardiograph (week 0 and 12): Noninvasive ultrasound of heart and lung vessels
• Pulmonary Function Tests (week 0 and 12)
• Cardiac MRI (week 0 and 12)
• Chest CT (week 0)
• Blood tests (performed at every visit): Up to 2 tablespoons of blood will be drawn for multiple analyses

• Pregnancy test (in females, performed at every visit)

Another study focusing on pulmonary hypertension and thalassemia evaluates the safety and efficacy of a nutritional supplement called glutamine. It is an 8 week open-label study in patients with thalassemia and echocardiogram evidence of pulmonary hypertension, and involves study visits every 2 weeks, a blood draw and exercise tolerance test (6 minute walk test) at each visit, pulmonary function tests and a Doppler echo pre and post therapy.

The goal of this study is to determine if glutamine therapy replenishes the glutamine deficiency that occurs in the red blood cells of patients with pulmonary hypertension. This is a single center trial enrolling patients at Children’s Hospital & Research Center Oakland. More information on both studies and others targeting thalassemia can be found on


or specifically forthe sildenafil trial:


and for the glutamine trial:


I’m a little confused concerning what patients without pulmonary hypertension will be required to do in the TCRN sildenafil trial.


“We are hoping to generate data that will guide future therapy for pulmonary hypertension in thalassemia.”


The listing states that the control group will attend one to three study visits at baseline; does that mean they will have all the same tests as the pulmonary hypertension group (plus lung function test, chest MRI, CAT, exhaled NO test), but that they might be spread out over two or three visits, rather than all performed at the same visit? And that they will not need to repeat the tests?

The baseline tests performed in patients with pulmonary hypertension will also be performed on control patients without pulmonary hypertension. If planned carefully these tests can all be done in one very busy day. Often it is spread over 2 days given scheduling challenges and the time it takes to have a Chest CT, heart MRI, Doppler echocardiogram, blood draw and 6 minute walk test preformed.

If a person wishes to participate, at what centers is the study being conducted? Who should s/he contact to learn more? Is there any funding available for people who might have transportation/location obstacles?

This is an NIH, NHLBI sponsored study run through the Thalassemia Clinical Research Network. Participating sites are in Boston, MA, New York City, NY, Philadelphia, PA Dallas, TX, Oakland, CA, and Toronto, Canada. Our London, UK and Beirut, Lebanon sites will hopefully be enrolling soon. Please contact Lisa Virzi, the Project Director, for information on the site nearest you, and possible availability of funding for travel if interested in participation.

Lisa Virzi
Project Director/TCRN Network Manager
New England Research Institutes
9 Galen Street
Watertown, MA 02472
Tel: 617- 923-7747 x258
email: lvirzi@neriscience.com

Again, more information on these and other studies relevant to thalassemia can be found on clinicaltrials.gov.

I know this is hard to predict, but can you give a general idea of what would happen AFTER the TCRN study is completed, in a best case scenario?

This is a small pilot study. We are hoping to generate data that will lead to larger trials and guide future therapy for pulmonary hypertension in thalassemia. The results of this study will also provide new insight into the causes of pulmonary hypertension in patients with thalassemia. This information is vital in order to design specific therapies that target these specific mechanisms of disease. Best case scenario, this is the first step to better treatment options for patients with pulmonary hypertension and thalassemia.

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