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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.
Clonality Studies: Clonality is based on the principal of X-chromosome inactivation and thus, for clonality studies only females can be used as subjects. It is based on the principal that while female cells have two X-chromosomes, one is randomly inactivated during early embryonic development and thus female tissue is a mixture of cells expressing either paternal or maternal inherited x-chromosome genes. In the first step, DNA analysis will study 5 exonic polymorphisms for the X-chromosome genes which have previously been shown to be useful for these purposes. If any of the five loci is heterozygous then the subject is said to be informative for clonality. Studies which will proceed as follows: The fresh blood platelets and granulocytes will be isolated and the RNA isolated and used later for reverse transcription to cDNA which will then be analyzed for X-chromosome allelic usage ratio by single-stranded conformational polymorphisms (SSCP). If only one allele is expressed in platelets or granulocytes the patient is said to be clonal and favors a diagnosis of myeloproliferative disorder (such as AMM), while polyclonal blood (both X-chromosome alleles expressed in platelets and granulocytes) is compatible with secondary myelofibrosis.
A three-color direct immunofluorescent staining method will be used in the evaluation of CD34+ cells. In our preliminary experience we observed four Flolan treated patients with PPH who had splenomegaly, anemia and/or thrombocytopenia. All of these patients had severe marrow fibrosis. The purpose of this study is to determine whether the incidence of the bone marrow fibrosis in this patient population is primary or secondary, and whether a secondary effect is a fibrosis that would be expected to be transient and resolve after discontinuation of Flolan.
Participating subjects will Patients will undergo the following studies:
1. History and Physical examination
2. Peripheral blood smear
3. Bone marrow examination to determine the presence and severity of fibrosis. The bone marrow specimen taken for diagnostic purposes will be examined by three independent hematologists/hematopathologists in a masked fashion for the presence of fibrosis using routine methods.
4. Blood: 30 cc of blood will be collected for
1. Clonality studies (female subjects only),
2. CD34 quantitation.
3. Further studies will be done to monitor the aberrant trafficking of hemopoietic stem cells, the adhesion molecules, and any disease related genes, such as JAK2V617F and cMPL, if indicated.
4. The above studies will be repeated in patients undergoing lung transplants at 3 months, 6 months and 1 year after transplantation.
Observational Model: Cohort, Time Perspective: Prospective
University of Utah
Salt Lake City
University of Utah
Published on BioPortfolio: 2014-08-27T03:28:49-0400
Male or female individuals, aged 18 years or older who have been diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-E...
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A de novo myeloproliferation arising from an abnormal stem cell. It is characterized by the replacement of bone marrow by fibrous tissue, a process that is mediated by CYTOKINES arising from the abnormal clone.
An acute myeloid leukemia in which 20-30% of the bone marrow or peripheral blood cells are of megakaryocyte lineage. MYELOFIBROSIS or increased bone marrow RETICULIN is common.
A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs.
The primary responsibility of one nurse for the planning, evaluation, and care of a patient throughout the course of illness, convalescence, and recovery.
Techniques or methods of patient care used by nurses as primary careproviders.
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Cardiology is a specialty of internal medicine. Cardiac electrophysiology : Study of the electrical properties and conduction diseases of the heart. Echocardiography : The use of ultrasound to study the mechanical function/physics of the h...
Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of affected individuals. Symptoms can range from mild breathles...