Reversible Secondary Myelofibrosis or Clonal Myeloproliferative Disorder

Pulmonary arterial hypertension: Pulmonary arterial hypertension (PAH) is a disease primarily affecting the small precapillary pulmonary vessels. It is characterized by sustained elevation of the pulmonary vascular resistance (PVR). Without therapy, right heart failure and death eventually occur. PAH occurs in an idiopathic form, primary pulmonary hypertension (PPH), and in association with other disorders such as connective tissue diseases or congenital heart disease (CHD). PAH remains a disease of unknown etiology. Until recently, prognosis for PAH was poor, with a median survival of less than 3 years.

Prostacyclin (PGI2) is the main product of arachidonic acid in all vascular endothelium. It is a potent vasodilator in all vascular beds. In addition, it is a potent endogenous inhibitor of platelet aggregation and smooth muscle growth. The prostacyclin receptor (IP) is located on a variety of cell types, enabling prostacyclin to exert a range of biologic actions by means of raising intracellular levels of cAMP through activation of adenylate cyclase. The stable, freeze-dried salt preparation of prostacyclin is known as epoprostenol and is available for IV administration under the brand name Flolan (Glaxo Wellcome, Research Triangle Park, N.C.). The first randomized clinical trial in PPH showed that epoprostenol improved quality of life, hemodynamics, exercise tolerance, and survival over a 12-week period. Epoprostenol has become the standard of care for patients with advanced PPH. Recently, chronic intravenous epoprostenol has been shown to be an effective therapy to improve long-term quality of life and survival in patients with PPH. Epoprostenol also improves hemodynamics, exercise capacity, and quality of life (but not survival) in PAH associated with CHD and connective tissue disease.

Side effects of epoprostenol infusion include rash, headache, jaw pain, leg pain, diarrhea, nausea, catheter infections, chest pain, anxiety dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, tachycardia, flu-like symptoms, and anxiety/nervousness. Thrombocytopenia is commonly seen in patients with PPH treated with PG12. Occasionally, a decrease in other blood cell lines occurs leading to anemia or pancytopenia. Splenomegaly and hypersplenism are observed at times. While thrombocytopenia has been attributed to the antiplatelet effects of prostacyclin, the pathophysiology of pancytopenia is poorly understood. There are no studies that address thrombocytopenia and other hemopoietic abnormalities in people with pulmonary hypertension receiving epoprostenol. The possibility of myelofibrosis causing these hematologic abnormalities has not been investigated.

Primary myelofibrosis is a myeloproliferative disorder, characterized typically by pancytopenia, splenomegaly, a leukoerythroblastic blood smear, fibrosis on the bone marrow examination, and myeloid metaplasia. Like all myeloproliferative disorders, it is due to somatic mutation and clonal proliferation of hematopoietic progenitors. Fibrosis occurs secondary to cytokines secreted by malignant cells. These patients are symptomatic because of cytopenias. Bone marrow failure and transformation to acute myeloid leukemia is the major reason for mortality in these patients. Elevated blood levels of hematopoietic progenitors (identified by positivity for the CD34 antigen) are well documented and correlates with prognosis. Therefore two major identifying features of primary myelofibrosis as opposed to secondary fibrosis of the marrow are: 1) clonal hematopoiesis and 2) high CD 34 positive hematopoietic precursors.

We therefore hypothesize these two will be normal in patients with secondary myelofibrosis and help us distinguish the two entities.