Essential thrombocytosis

A 72-year-old physician with myeloid metaplasia developed marked thrombocytosis, pulmonary hypertension, and right heart failure following splenectomy. No cause for the pulmonary hypertension could be found. The pulmonary hypertension and right heart failure returned to normal when hydroxyurea therapy corrected the thrombocythemia. It is concluded that thrombocytosis may cause pulmonary hypertension, mediated by pulmobary capillary obstruction from cellular components, involving platelet aggregation, microthrombosis, and stasis, and possible vasoconstrictor effects.

Thrombocytosis in the absence of thromboembolic disease has only rarely been suspect as the etiology of pulmonary hypertension. We herewith report a case of right heart failure and pulmonary hypertension developing coincident with remarkable thrombocythemia and the resolution of both simultaneously.

CASE REPORT

A 72-year-old white male physician presented with clinical evidence of profound right heart failure. A diagnosis of myeloid

Thrombocytosis in the absence of thromboembolic disease has only rarely been suspect as the etiology of pulmonary hypertension. We herewith report a case of right heart failure and pulmonary hypertension developing coincident with remarkable thrombocythemia and the resolution of both simultaneously.

Case Report

A 72-year-old white male physician presented with clinical evidence of profound right heart failure. A diagnosis of myeloid metaplasia was established approximately two years earlier. Three months prior to this current evaluation, a splenectomy had been performed for suspect subcapsular hematoma which was not found. The spleen, at the time of surgery, was massively enlarged, with abundant hematopoietic tissue. Subsequent to the splenectomy, a rising platelet count and progressive evidence of heart failure was noted.

On physical examination, the patient was pale, thin, and mildly short of breath. Marked jugular venous distention was noted, and there was bilateral pitting lower extremity edema and hepatomegaly. A fourth heart sound was present at the apex and right sternal border. The chest was clear to examination. The platelet count was 1,494 x [10.sup.3]/ml with 9 percent of the platelets reported as micromegakaryocytes. Previous platelet counts had always been in the high normal range. The white blood cell count was 34 x [10.sup.3]/ml with 46 percent neutrophils, 3 percent band cells, 35 percent lymphocytes, 12 percent monocytes, and 1 percent each eosinophils, basophils, metamyelocytes, and myelocytes.

An echocardiogram revealed right atrial enlargement and 2 + tricuspid regurgiation with an estimated pulmonary artery systolic pressure of 50 mm Hg. Left ventricular function was normal. An echocardiogram performed several years earlier had been normal. A chest roentgenogram was normal. Noninvasive studies of the lower extremities were normal. A complete rheumatologic blood screen was negative. Fibrinogen, FSP, thrombin time, and bleeding times were normal. A ventilation/perfusion scan of the lungs was reported as low probability for pulmonary embolism.

Right heart catheterization and pulmonary arteriography were performed. Systemic oxygen saturation was 98 percent. There was no left-to-right or right-to-left shunt. Mean right atrial pressure was 20 mm Hg, right ventricle 62/15, pulmonary artery 62/15 (39), and pulmonary capillary wedge pressure was 2 mm Hg, mean. Pulmonary and systemic vascular resistance was 554 and 1,359 dynes.s. [cm.sup.5]/[m.sup.2], respectively. Pulmonary arteriograms revealed normal pulmonary vascularity without evidence of pulmonary emboli or occlusive disease. Symptomatic treatment for right heart failure was instituted with diuretics and cardiac glycosides. A regimen of aspirin, 325 mg a day and specific antiplatelet therapy (anagrelide) was instituted. Following one month of such therapy, little improvement in right heart failure or in the patient's platelet count (1,831 x [10.sup.3]/ml with 10 percent giant platelets) was noted. Megakaryoblasts were also seen in the peripheral smear and the white blood cell count was 27,000 x [10.sup.3] ml (Fig 1). The patient's therapy was changed to hydroxyurea, 3 g per day. Aspirin was continued.

The patient subsequently had a hematologic response to the hydroxurea with a fall in his platelet and white blood cell counts and a dramatic clinical improvement in his right heart failure (Fig 1). Serial echocardiographic evaluations revealed improvement in tricuspid regurgitation and a gradual fall in the pulmonary artery systolic pressure. One year after institution of hydroxyurea therapy, the patient had no evidence of right heart failure, he was not receiving diuretic therapy, and he was completely asymptomatic. The platelet count had returned to normal.

DISCUSSION

It is generally accepted that megakaryocytes (10 to 150 [mu]) continually migrate from the bone marrow and are trapped within the pulmonary capillaries (7 to 10 [mu] in diameter) where transformation to platelets normally occurs.[1] Megakaryocytes have been demonstrated to be plentiful in the pulmonary capillary bed.[2] We postulate that the cause of pulmonary hypertension in our patient was pulmonary capillary obstruction by megakaryocytes with stasis and secondary microthrombosis. Subsequent correction of the thrombocytosis resulted in relief of the capillary obstruction and resolution of the right heart failure.

Blachly and associates[3] have previously reported a patient with chronic myelogenous leukemia and marked thrombocytosis with pulmonary hypertension who at post-mortem demonstrated right ventricular dilatation and whose pulmonary arterioles and capillaries were filled and distended with platelets and megakaryocytes. Hepatic sinusoids also revealed similar infiltration with platelets and megakaryocytes. Rostagno et al[4] recently reported a patient with "primary pulmonary hypertension" with marked thrombocytosis and no defects on ventilation/perfusion lung scan whose symptoms improved while receiving antiplatelet treatment. Evidence for platelet "aggressiveness" also resolved while receiving this treatment. Shimoto and co-workers[5] described a patient with marked thrombocytosis and pulmonary hypertension in whom the pulmonary hypertension was felt to be secondary to the elevated platelet count.

The assumption that large circulating cells can cause pulmonary hypertension by microcirculatory obstruction is supported by reports of pulmonary hypertension and cor pulmonale secondary to tumor microemboli.[6,7] These cases are subacute in onset with a paucity of clinical or roentgenographic pulmonary findings and can be differentiated from those patients with lymphangitic carcinomatosis. Several cases of portal hypertension have been ascribed to infiltration of liver sinusoids by megakaryocytes and platelets in patients with thrombocytosis.[8] In an autopsy series of 100 randomly selected cases, Chyczewski et al[9] documented enhanced microthombosis in the pulmonary vessels of lungs containing a large number of megakaryocytes. It is possible that microthrombosis and "hyperfunctional" platelets and vasoconstrictor influences along with obstruction of the pulmonary microcirculation by increased megakaryocytes and platelets are necessary to produce pulmonary hypertension in patients with marked thrombocytosis. It would appear, however, that the pulmonary hypertension is potentially reversible by decreasing the platelet count and perhaps decreasing platelet "aggressiveness" as evidenced by the successful treatment in our patient.

REFERENCES

[1] Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987; 2:1434-35

[2] Masson RG, Ruggieri J. Pulmonary microvascular cytology: a new diagnostic application of the pulmonary artery catheter. Chest 1985; 88:908-14

[3] Blachly RJ, Herring GF, Mansouri A. Chronic myelocytic leukemia with near total pulmonary microvascular obstruction by platelets. South Med J 1988; 81:521-24

[4] Rostagno C, Prisco D, Abbate R, Poggesi L. Pulmonary hypertension associated with longstanding thrombocytosis. Chest 1991; 99:1305-06

[5] Shimoto H, Imaizumi K, Mizoguchi K, Ikeda T. A case of essential thrombocythemia with pulmonary hypertension and bilateral effusions. Jpn J Thorac Dis 1990; 28:504-10

[6] Durham JR, Ashley PF, Dorencamp D. Cor pulmonale due to tumor emboli. JAMA 1961; 175:757-60

[7] Scully RE, Mark JE, McNeely WF, McNeely UP. Case records of the Massachusetts General Hospital. N Engl J Med 1987; 317:225-34

[8] Roux D, Bioulac-Sage P, Merlio JP, Lamouliatte H, Quinton A, Balaboud C. Liver sinusoids and sinusoidal cells in patients with agnogenic myeloid metaplasia. Clin Gastroenterol 1987; 9:483-87

[9] Chyczewski L, Chyczewska E, Tasi V. Megakaryocytes in human lungs in nonselected autopsy specimens--topography of their occurrence and correlation with pulmonary thrombosis. Patol Pol 1989; 40:17-27

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