Paroxysmal nocturnal hemoglobinuria

Pulmonary arterial hypertension (PAH) and cor pulmonale were found in a patient with paroxysmal nocturnal hemoglobinuria (PNH). Autopsy revealed widespread thromboses in pulmonary microvasculature. Vascular thromboses attributed to hypercoagulability have been found in PNH in many organs, including the lungs. PAH has not been reported, however. This disease should then be considered a rare cause of PAH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by an increased sensitivity of blood cells to complement lysis.[1] Thrombosis is a major complication of this disease.[2] It may be explained by the abnormal interaction of PNH platelets with complement components.[2] Vascular thromboses have been reported in virtually every organ and vascular bed, including pulmonary arteries.[3] However, the occurrence of pulmonary hypertension, to our knowledge, has never been reported. We describe a patient with PNH who developed pulmonary hypertension due to thrombotic occlusion of the pulmonary microvasculature.

CASE REPORT

A 53-year-old woman had the diagnosis of PNH made in 1955. Her disease started at the age of 18 years with hemolytic crises that became more frequent and intense in the following years, requiring periodic transfusions. In 1978, splenectomy was performed and since then, she has been treated intermittently with prednisone at doses ranging from 10 to 40 mg daily.

In 1981, she was first admitted to this hospital because of acute renal failure and she recovered after hemodialysis. In 1983, chest roentgenogram showed prominence of pulmonary arteries (Fig 1). An electrocardiogram revealed incomplete bundle branch block. Doppler echocardiography disclosed systolic pulmonary artery pressure of 60 mm Hg and evidence of tricuspid regurgitation. Right ventricle hypertrophy and enlargement were demonstrated. A perfusion lung scan showed a patchy pattern without segmental perfusion defects. Dicumarol (dicoumarin) anticoagulation was started. In 1988, she developed systemic hypertension and nifedipine at a dose of 40 mg daily was administered. Attempts at vasodilator treatment of pulmonary hypertension with high doses of calcium channel blockers were made, but this treatment had to be discontinued because of severe side effects. Elevated serum aspartate aminotransferase and alanine aminotransferase levels were detected and hepatitis C virus antibody was found to be positive. In 1989, she developed dyspnea on effort, chest pain, and episodes of heart failure. Physical examination revealed 2+ pitting edema. A grade 3 holosystolic murmur was heard along the left sternal border and an intense [S.sub.2] sound was audible. Lungs were clear. Abdominal examination showed mild liver enlargement. Pulmonary function tests showed the following: FVC, 2.42 L (87 percent of predicted); [FEV.sub.1], 1.83 L (82 percent of predicted); and [FEV.sub.1]/FVC, 0.75. Arterial [Po.sub.2] was 65 mm Hg, [Pco.sub.2] was 24 mm Hg, and pH was 7.40. Antinuclear antibodies, rheumatoid factor, and anti-DNA were negative, and total hemolytic complement was normal. In 1990, she developed cryptococcal meningoencephalitis. She died as a consequence of accidental head trauma and rostrocaudal deterioration.

Autopsy revealed the following: enlargement and atherosclerosis of main pulmonary artery and its branches; cardiac enlargement (490 g) with right ventricle hypertrophy (7 mm); diffuse thrombosis of arterial pulmonary vessels smaller than 2 mm in diameter with thrombi of various ages: eccentric fibrosis, old organized and recanalized thrombi, and fresh ones made of platelets and fibrin (Fig 2 and 3); venous thrombosis in accessory spleen, brain, meninges, and superior longitudinal sinus; normal femoral vessels; slight left ventricle hypertrophy (16 mm) with normal coronary arteries; subaracnoid hemorrhage; cryptococcal meningoencephalitis; chronic hepatitis; and mesangial glomerulonephritis.

DISCUSSION

Pulmonary hypertension developed in this patient with a 30-year history of PNH. During lifetime, common causes of pulmonary hypertension were excluded. At autopsy, thrombotic occlusion of the pulmonary microvaculature was demonstrated. Thrombotic pulmonary arteriopathy has been described as a histologic subset of primary pulmonary hypertension.[4] Controversy exists as to whether these lesions arise from an embolic source or develop as a consequence of in situ thrombosis. There is little evidence that they represent repeated microembolism. More than 90,000 emboli would be needed to occlude the pulmonary microvasculature to produce pulmonary hypertension.[4] Also, high levels of fibrinopeptide A are seen in primary pulmonary hypertension, evidence that active intravascular thrombosis is taking place.[4] In this case, no source for emboli was found, as there was no evidence of thrombosis in femoral vessels or cardiac chambers. Some cases of microthromboembolic pulmonary hypertension occur in relation to a recognizable hypercoagulable state[5] such as the antiphospholipid syndrome, antithrombin III deficiency, polycythemia vera, and sickle cell anemia, all of which were excluded in this patient. We raise the hypothesis that the pathogenesis of the microthrombotic occlusion of pulmonary arteries in this patient was related to the hypercoagulable state associated with PNH. Furthermore, venous thromboses in other sites were found in this patient. The mechanism underlying vascular thrombosis in PNH has not been completely elucidated. Procoagulant factors released as a result of red blood cell hemolysis may play a role. Also, abnormal interactions of PNH platelets with complement have been described. There is a defect in the blood cell membrane in PNH that leads to the lack of decay accelerating factor, a complement regulatory protein that normally inhibits the activation of C3 complement component.[6] As a result, there is an increase in platelet aggregation due to the accumulation of C3 on the platelet surface.

It seems that PNH should be added as a rare cause of pulmonary hypertension.

REFERENCES

[1] Beutler E. Paroxysmal nocturnal hemoglobinuria. In: Williams J, Beutler E, Erslev A, Lichtman M. Hematology. 4th ed. New York: McGraw-Hill; 1991:188-92

[2] Devine DV, Siegel RS, Rosse WF. Interaction of the platelets in PNH with complement. J Clin Invest 1987; 79:131-37

[3] Crosby WH. Paroxysmal nocturnal hemoglobinuria: relation of the clinical manifestations to the underlying pathogenic mechanism. Blood 1953; 8:769

[4] Rich S, Levitsky S, Brundage B. Pulmonary hypertension from chronic pulmonary thromboembolism. Ann Intern Med 1988; 108:425-34

[5] Fraser RG, Pare JA, Pare PD, Fraser RS, Genereux GP. Embolic and thrombotic diseases of the lungs. In: Diagnosis of diseases of the chest. 3rd ed. Philadelphia: WB Saunders Co; 1990:1701-1822

[6] Rosse WF. Phosphatidilinositol-linked proteins and PNH. Blood 1990; 75:1595-1601

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