An active woman slowed by the effects of sickle cell anemia

 In July 2004, I saw Ms. T, a 47-year-old African American who had sickle cell anemia. Once bright and bouncy, she had become increasingly ill despite medical care at a sickle cell clinic. Understandably, she had grown discouraged with the care she was receiving. Despite her health problems, she  continued to work her usual hours, but it was increasingly difficult to keep up with the responsibilities of her job in city government. Her initial complaints included excessive weakness, shortness of breath on minimal exertion (e.g., walking one city block), light-headedness, anorexia, bouts of heart racing, and some ankle edema. She had a long history of ulcers on the lower extremities. Her situation was further complicated by a history of bronchial asthma. Medications included hydroxyurea, cetirizine (Zyrtec), fluticasone/salmeterol (Advair), and albuterol. She also took folic acid and vitamins.

PHYSICAL EXAMINATION

Ms. T was 5 ft 5 in tall and weighed 125 lb. BP was 105/70 mm Hg. There was a suggestive systolic heave just to the left of the sternum. A grade 2 ejection systolic murmur was heard from the second right interspace to the fourth left interspace. The second sound at the base was split, with a loud second component. Her arterial pulses were of good quality and equal bilaterally. Auscultation revealed that her chest was clear. Her liver was mildly pulsatile. An ECG showed a sinus rhythm, evidence of right atrial enlargement (tall P wave in lead V₁) (Figure 1), and findings consistent with right ventricular hypertrophy.

Figure 1. ECG shows tall P waves in lead V1, an indication of right atrial enlargement.

Initial diagnoses included sickle cell anemia, bronchial asthma, and pulmonary hypertension. Laboratory studies showed a hemoglobin of 7.5 g/dL and a hematocrit of 21.1%. Reticulocytes were elevated at 5.8%. Creatinine measured 1.6 mg/dL. Other blood studies were unremarkable. Echocardiography showed changes consistent with right ventricular hypertrophy, a pulmonary artery pressure of 73 mm Hg, and severe tricuspid insufficiency. No evidence of deep venous thrombosis was found on duplex ultrasonography. Pulmonary function testing demonstrated decreased diffusing capacity for carbon monoxide. A helical CT scan of the chest with IV contrast revealed changes consistent with chronic thromboembolic disease and secondary arterial hypertension. Ms. T was started on chronic warfarin therapy, verapamil, and furosemide for her fluid retention.

In January 2005, Ms. T returned to our office complaining of marked fatigue, chills, cough, and fever. She was hospitalized after developing nausea and vomiting. The clinical picture was consistent with an acute infectious bronchitis. Her hemoglobin was 5.9. Antibiotics, bronchodilators, and blood transfusions brought about marked improvement. The hematologist suggested instituting serial transfusions and stopping the hydroxyurea.

THERAPEUTIC APPROACH

Two weeks after being discharged from the hospital, Ms. T was feeling better but still complained of markedly decreased energy and strength. She was started on tadalafil (Cialis) 10 mg every third day. Two weeks later, she felt better and said her breathing was more comfortable. Her BP was 105/70. Chest exam was clear. The heart murmur and sounds were unchanged.

At her next appointment, Ms. T weighed  in at 123 lb and noted that her leg ulcers were healing. She had received four blood transfusions since being discharged from the hospital. Her medications included irbesartan/hydrochlorothiazide (Avalide) 150/12.5 mg every morning; furosemide 20 mg every morning; vitamin C 500 mg daily; tadalafil; warfarin; folacin, pyridoxine, and cyanocobalamin tablets (Foltx); and pantoprazole (Protonix) 40 mg every other day.

When last seen, Ms. T reported improvement. She was working regularly and more effectively. Her energy level was improved, and she had less fatigue. She was planning on resuming her swimming exercise. Her ankle ulcers were almost completely healed. At that point, she had received a total of six transfusions.

DISCUSSION

Pulmonary hypertension and chronic lung disease are two of the most common causes of death in patients with sickle cell disease. Treatment of the pulmonary hypertension, undoubtedly due in large part to an obliterative vasculopathy, is difficult. Prostacyclin reduces pulmonary artery pressure, but this agent must be given by continuous IV infusion and has significant side effects. Endothelin-1-receptor antagonists (e.g., bosentan) have been used effectively in pulmonary hypertension, though there is limited knowledge about bosentan's use in sickle cell pulmonary hypertension; it does have the potential for serious liver injury. Other agents that have been used with varying success include the calcium channel blockers, anticoagulants, and thromboxane inhibitors.

The phosphodiesterase inhibitor sildenafil has been shown to have a salutary effect in pulmonary hypertension and is now being marketed for that indication as Revatio. It has been theorized that longer-acting phosphodiesterase inhibitors may prove even more useful. This potential effect had prompted us to start Ms. T on tadalafil, which has a duration of action of about three days. Our patient would not have been able to afford sildenafil t.i.d., but she has been able to use the tadalafil every three days.

Ms. T's treatment regimen for pulmonary hypertension includes blood transfusions, tadalafil, verapamil, and warfarin. Her bronchial asthma has been quiescent and will be treated as necessary. We have considered adding montelukast (Singulair). The present regimen has yielded a clinical improvement. Depending on her liver function, it may be possible to add bosentan. Only time will tell whether the obliterative vasculopathy that afflicts these patients is significantly slowed by the newer treatments. Obviously, studies are needed to evaluate the longer-acting phosphodiesterase inhibitors in the treatment of pulmonary hypertension. Meanwhile, we hope for beneficial effects beyond those seen in patients with erectile dysfunction.

Dr. Miller is professor of clinical medicine (cardiology) at the Feinberg Schoolof Medicine, Northwestern University in Chicago.

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Vichinsky EP. Pulmonary hypertension in sickle cell disease. N Engl J Med. 2004;350:857-859.