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PubMed1997

Erythromelalgia and vascular complications in polycythemia vera.

The vascular complications in patients with polycythemia vera are microvascular circulatory disturbances typical of thrombocythemia including erythromelalgia, peripheral ischemia, atypical cerebral ischemic attacks, and major arterial and venous thrombotic events. These are positively related to hematocrits due to the increased red cell mass and its concomitant increased whole blood viscosity. Phlebotomy does not prevent the aspirin-responsive microcirculatory circulation disturbances in polycythemia vera because thrombocythemia (platelet count > 400 x 10(9)/L) persists. The risk of major vascular ischemic episodes in poorly controlled polycythemia vera at hematocrits between 0.45 and 0.50 is rather high. The risk of vascular complications in polycythemia vera is best controlled by maintaining the hematocrit at less than 0.45 and the platelet count below 400 x 10(9)/L. The microvascular syndrome associated with thrombocythemia in early stage polycythemia vera in remission by phlebotomy is easily and best controlled by low-dose aspirin (50 to 100 mg) or by selective reduction of platelet count to normal with low-dose myelosuppressive agents. The potential leukemogenic myelosuppressive agents busulfan and hydroxyurea and the nonleukemogenic cytosine interferon-alpha have proven to be effective in the control of the proliferative phase of polycythemia vera. However, data on the natural history of polycythemia vera and the best treatment modality of the various stages of myeloproliferative disease are still lacking.

Aspirin↗
PubMed2000

Congenital and inherited polycythemia.

Absolute polycythemia is a condition with increased red blood cell mass. There are a number of primary and secondary polycythemic disorders leading to absolute polycythemia. Primary polycythemias are caused by a defect intrinsic to the erythroid progenitor cells. The best characterized primary polycythemia is the autosomal dominant primary familial and congenital polycythemia (PFCP). Familial or childhood occurrence of the myeloproliferative disorder polycythemia vera are also discussed, emphasizing the importance of distinction between polycythemia vera and PFCP. Congenital or familial secondary polycythemic conditions are characterized by increased red cell mass, which is caused by circulating serum factors, typically erythropoietin.

2,3-Diphosphoglycerate↗
PubMed1995

Primary polycythemias.

In this review, primary polycythemic states are discussed in the context of other polycythemic disorders. Primary polycythemias result from an acquired or inborn mutation affecting hematopoietic and erythroid cells. The best-known type of primary polycythemia is polycythemia vera, which is caused by an acquired somatic mutation of a hematopoietic stem cell with exaggerated myeloid proliferation; the molecular events leading to this disease are not understood. In contrast, primary familial and congenital polycythemias result from inborn mutation affecting hematopoietic and erythroid cells. The molecular mechanisms causing primary familial and congenital polycythemias may be different in different families; some have already been defined. Progress in defining the molecular defect of primary polycythemias and the better understanding of altered signal transduction leading to excessive erythrocyte production should provide important insights into the pathogenesis of primary polycythemias, other leukemic disorders, as well as normal hematopoiesis. Such information should contribute to better understanding of and more effective therapeutic interventions in myeloproliferative and leukemic disorders.

Erythropoiesis↗
PubMed1999

Molecular basis for polycythemia.

This overview concentrates on familial and congenital polycythemias in the context of other polycythemic disorders, with emphasis on those with established molecular lesions. Recent advances in the regulation of erythropoiesis, as they may relate to polycythemic states, are discussed as a background for those well-defined polycythemic states wherein the molecular defect has not yet been elucidated. Primary familial congenital polycythemias and congenital and familial secondary polycythemias, including hemoglobin mutants, methemoglobinemias and congenital 2,3-bisphosphoglycerate deficiency, are discussed. The most common primary polycythemia, polycythemia vera, as well as the only likely endemic congenital secondary polycythemia, known as Chuvash polycythemia, are discussed.

Animals↗
PubMed1994

What clinical and laboratory data are indicative of polycythemia and when are blood volume studies needed?

An increased hematocrit can be caused by primary proliferative polycythemia (PPP), by secondary polycythemia, by relative polycythemia (reduced plasma volume with a normal red cell mass), or by modifications of the red cell mass and the plasma volume within their normal ranges. As an increased hematocrit by itself is a risk factor for thrombosis, it is important to diagnose not only polycythemia, but also its possible cause, in order to offer optimal therapy. Smoking is the most frequent cause of an increased hematocrit. Splenomegaly, aquagenic pruritus, and erythromelalgia often exist in PPP, whereas other symptoms such as dyspnea are more likely to be associated with secondary polycythemia. Smokers with an increased hematocrit will be asked to stop smoking before ordering blood volume studies. These studies are not indicated in patients with obvious pulmonary disease. Male patients with an hematocrit over 60% and female patients with an hematocrit over 55% always have absolute polycythemia. The associations of an increased hematocrit with splenomegaly, a raised white blood cell count or thrombocytosis are indicators for PPP. The necessity for blood volume studies is questionable in these patients. However, blood volume studies are useful in patients with an increased hematocrit and no other clinical or biological signs suggestive of any form of polycythemia.

Blood Cell Count↗
PubMed1993

[Secondary polycythemias: the role of erythropoietin].

The discovery of high hemoglobin and hematocrit values in a patient necessitates the determination of the red blood cell mass in order to confirm the absolute character of the polycythemia. If a true polycythemia is confirmed, its etiology must then be established. The diagnostic approach of polycythemia is presented in this paper. It is illustrated by a case presentation in which a polycythemia secondary to a renal carcinoma is discussed. Erythrocytosis is a classical, albeit rare manifestation of this type of tumor, and has the advantage of allowing early detection. Thus, it permits a prompt treatment plan, thereby improving the prognosis of such a neoplasia. The usefulness of a serum level of erythropoietin (EPO) is subsequently discussed. The diagnostic value of EPO remains controversial because of the overlapping values recorded amongst healthy patients, patients with polycythemia vera and others with secondary polycythemia. Finally, we discuss the presence of substances in paraneoplastic polycythemias whose biological activity is close to that of EPO. However, this molecules of a different structure would not be detected by the radioimmunoassay used to measure erythropoietin level.

Algorithms↗
PubMed1987

Intracellular growth factors in polycythemia vera and other myeloproliferative disorders.

In polycythemia vera, idiopathic myelofibrosis, and essential thrombocytosis, hematopoietic cell proliferation is increased in the absence of a recognizable stimulus, suggesting the autonomous production of growth factors in these disorders. Sonicates of peripheral blood mononuclear cells (PBMNC) from patients with polycythemia vera, idiopathic myelofibrosis, and essential thrombocytosis contained soluble factors that stimulated the proliferation of quiescent-confluent 3T3 cells. PBMNC sonicates from normal individuals; from patients with secondary erythrocytosis, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, and acute myelogenous leukemia; and from K-562 and HL-60 cells did not stimulate proliferation. Polycythemia vera PBMNC sonicates also induced anchorage-independent colony formation in soft agar by normal rat kidney fibroblasts. Both the mitogenic and transforming activities of the polycythemia vera PBMNC sonicates resided in the T-lymphocyte-depleted mononuclear fraction of the PBMNC and were not secreted. By gel filtration, reversed-phase HPLC and NaDodSO4/PAGE, the mitogenic and transforming activities in the polycythemia vera PBMNC were localized to three proteins with molecular masses of 13-, 17-, and 65-kDa. The 13-kDa protein was only mitogenic, and the 17-kDa protein was only transforming, whereas the 65-kDa protein had both mitogenic and transforming activity. These proteins may be involved in the autonomous hematopoiesis that characterizes polycythemia vera, idiopathic myelofibrosis, and essential thrombocytosis.

Animals↗
PubMed1993

[Polycythemia: primary or secondary? The differential diagnostic value of stem cell cultures].

Cultures of hematopoietic precursor cells can be helpful in differentiating between primary polycythemia (polycythaemia vera, PV) and reactive secondary polycythemia: in PV erythroid precursors form hemoglobinized colonies in the absence of added erythropoietin (epo) (= endogenous erythroid colonies), whereas in normals and in patients with secondary polycythemia, formation of erythroid colonies is dependent on added epo. We have performed cultures of peripheral blood precursors from 132 patients with elevated hemoglobin in the presence/absence of added epo. In 48/132 patients we assumed that PV was the cause of polycythemia. In 80/132 patients no endogenous colonies appeared and the polycythemia was judged secondary. 23 PV patients were examined repeatedly. In 18 of them the first diagnosis was confirmed by subsequent cultures; in 5 cases endogenous colonies, which had been present in the first cultures, were no longer detectable. A questionnaire on the subsequent clinical course was sent to 108 treating physicians. 77 questionnaires were answered correctly and returned. In 86% of these patients, our culture diagnosis of PV was either confirmed or another myeloproliferative disorder had been found as a cause of endogenous colonies. In 14% our diagnosis of PV had been false positive. On the other hand, our diagnosis of secondary polycythemia was confirmed in 85% of the patients; its most frequent cause was cigarette smoking and chronic bronchitis and only rarely was it associated with heart or kidney disease. 5/77 patients had persistently elevated Hb without an evident cause, and in 3/77 the Hb normalized spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Colony-Forming Units Assay↗
PubMed1983

Increased bone marrow blood flow in polycythemia vera.

Bone marrow blood flow was measured in polycythemia vera, in compensatory and in relative polycythemia with a 133Xe washout method. In the treated polycythemia vera bone marrow blood flow was significantly increased compared with the age-matched controls. The fraction of blood flow entering the bone and flowing through the hematopoietic marrow was markedly increased in both the untreated and the treated polycythemia vera. Although the number of observations in compensatory and relative polycythemia was small, the results suggest that bone marrow blood flow is not markedly increased in these diseases. The results also suggest that in older patients the simple 133Xe method may support the diagnosis of polycythemia vera.

Adult↗
PubMed2004

Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.

PURPOSE: To assess life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. METHODS: The study sample consisted of 831 consecutive patients with polycythemia vera (n = 396; 4184 person-years of follow-up) or essential thrombocythemia (n = 435; 4304 person-years of follow-up). Mortality in each group was compared with the Italian population using the standardized mortality ratio (SMR) based on life expectancy data obtained from the Italian Institute of Statistics. RESULTS: The 15-year survival was 65% in patients with polycythemia and 73% in those with thrombocythemia. By Cox regression analysis, the independent predictors of death were a history of thrombosis for polycythemia (hazard ratio [HR] = 2.2; P = 0.0002) and thrombocythemia (HR = 2; P = 0.01), and male sex (HR = 1.8; P = 0.03) for thrombocythemia. Mortality compared with the general population was 1.6-fold higher (P <0.001) in patients with polycythemia but was not increased in those with thrombocythemia (SMR = 1; P = 0.8). CONCLUSION: Life expectancy of patients with polycythemia vera (especially if younger than 50 years) was reduced compared with the general population, whereas life expectancy of patients with essential thrombocythemia was not affected significantly by the disease, reflecting the more indolent nature of the proliferation. History of thrombosis was the main predictor of death in both diseases.

Female↗
PubMed1997

Inapparent polycythemia vera: an unrecognized diagnosis.

PURPOSE: The Polycythemia Vera Study Group (PVSG) has established useful criteria for the diagnosis of polycythemia vera. In some circumstances, an increase of plasma volume (PV) masks that of red cell mass (RCM), with hemoglobin (Hb) and hematocrit (Ht) remaining normal. This defines the concept of inapparent polycythemia. PATIENTS AND METHODS: One hundred and three patients seen in the hematology unit with the diagnosis of polycythemia vera were studied. There were 55 males and 48 females with a median age of 59 years. Ninety-five patients fulfilled the PVSG criteria. Spontaneous erythroid colonies and low serum erythropoietin level confirmed the diagnosis in the 8 other cases. Patients were classified according to Hb and Ht level. RESULTS: Group A consisted of 85 patients with increased Hb and Ht defined, respectively, by Hb > 18 g/dl, Ht > 0.52 in males and Hb > 16 g/dL, Ht>0.47 in females. Group B included 18 patients (17%) with inapparent polycythemia vera (IPV) defined by a normal Hb and Ht value at diagnosis. In this group, the reasons to perform RCM were as follows: splenomegaly associated with increased platelets and/or leucocytes counts (n = 8), portal vein thrombosis (n = 5), increased platelets or leucocytes counts without splenomegaly (n = 3), and isolated splenomegaly (n = 2). The two groups were balanced in terms of age, sex, leucocyte, serum iron, and platelet level. Hemoglobin and Ht levels were significantly different between the two groups. The difference between the PV was indeed highly significant. The mean PV increase was + 9.5% (nL < +20%) in group A versus + 36.3% in group B (P < 0.00005). Red cell mass was not different between the two groups. CONCLUSIONS: Increased Hb or Ht should constitute the sole criteria for RCM determination. In the context of portal vein thrombosis, isolated hyperleucocytosis, thrombocytosis, or splenomegaly, a RCM should be performed. The frequency of IPV remains to be specified but the diagnosis of polycythemia vera is probably underestimated.

Adult↗
PubMed1997

New drugs in essential thrombocythemia and polycythemia vera.

Among the chronic myeloproliferative disorders, polycythemia vera and essential thrombocythemia are unique because of their association with thrombohemorrhagic manifestations and their relatively indolent clinical course. Patients with essential thrombocythemia may not have a significant shortening of life-expectancy and most may not require specific therapy. However, patients with polycythemia vera have a significant risk of transformation of polycythemia vera into acute leukemia or postpolycythemic myelofibrosis (or both). 'High-risk-for-thrombosis' patients with either polycythemia vera or essential thrombocythemia require specific therapy with a platelet-lowering agent to prevent thrombotic complications. Currently, the standard agent used for this is hydroxyurea. However, its tetratogenic and leukemogenic potential has been of concern. As a result, new platelet-lowering agents are being evaluated in the treatment of polycythemia vera and essential thrombocythemia. Anagrelide and interferon alfa are two such agents and have been shown to be effective in reducing platelet counts in patients with chronic myeloproliferative disorders. The putative mechanism of action of these drugs, their specific activity in polycythemia vera and essential thrombocythemia, side-effect profile, and current indications are discussed herein.

Antineoplastic Agents↗
PubMed1999

Defective expression of the SHP-1 phosphatase in polycythemia vera.

The SHP-1 phosphatase associates with the receptors for erythropoietin, stem cell factor, and interleukin-3, and negatively regulates the mitogenic signals generated during engagement by their respective ligands. The erythroid progenitors of patients with polycythemia vera are hypersensitive to the mitogenic effects of these growth factors despite the fact that the numbers and binding affinities for their receptors are not increased. To determine whether post-receptor signaling defects may account for growth factor-hypersensitivity in polycythemia vera, we determined the expression of SHP-1 in highly purified erythroid progenitors from polycythemia vera patients. Our data demonstrate that in approximately 60% of the patients, expression of SHP-1 in the colony forming unit-erythroid population is diminished. The decreased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid progenitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference between the two at early colony forming unit-erythroid stage of differentiation although polycythemia vera cells showed retarded differentiation kinetics at late colony forming unit-erythroid stage of differentiation. Furthermore, SHP-1 expression in normal colony forming unit-erythroid demonstrated downregulation of mRNA and protein levels during terminal differentiation, suggesting that its function is required for growth control during the early stages of erythropoiesis. These results indicate an important role for SHP-1 in the regulation of normal human erythroid progenitors and suggest that defective expression of the protein may contribute to the pathogenesis of polycythemia vera.

Cell Differentiation↗
PubMed2001

Comparison of four serum-free, cytokine-free media for analysis of endogenous erythroid colony growth in polycythemia vera and essential thrombocythemia.

INTRODUCTION: The assay of endogenous erythroid colony formation (EEC), a characteristic of polycythemia vera and essential thrombocythemia, is not standardized. In this multicentric study, we tested four semisolid, serum-free, cytokine-free media based on either methylcellulose (M1, M2) or collagen (C1, C2) commercialized for the EEC assay. MATERIALS AND METHODS: Bone marrow mononuclear cells (BMMC) from 73 individuals (62 patients with either polycythemia vera (26), essential thrombocythemia (19), secondary polyglobuly (17) or chronic myeloid leukemia (2) and 11 healthy donors) were grown in parallel in the four media without, or with 0.01 U/ml erythropoietin (EPo). RESULTS: In all four media EEC formation was specific, as it was not observed in cultures of patients with secondary polyglobuly or chronic myeloid leukemia, nor of healthy donors. Analysis of fresh or MGG-stained collagen gel cultures allowed detection of EEC formation significantly more frequently than methylcellulose-based media; addition of 0.01 U/ml of EPo had little or no effect on EEC formation. Collagen-based medium C1 gave better results than the other media tested: the 'C1' EEC assay was positive for 68.2% of polycythemia vera cultures with significantly higher median EEC numbers (6.5/10(5) BMMC for patients with one major criteria of polycythemia vera and 19 and 21/10(5) BMMC for patients with two or three major criteria, respectively). Medium C1 was also better for essential thrombocythemia cultures with 47.4% of positive results but with a low median EEC number (6.7/10(5) BMMC). When associated with the ELISA dosage of serum EPo, the 'C1' EEC assay allowed confirmation or elimination of the diagnosis of polycythemia vera for 91% (20/22) of polyglobulic patients. CONCLUSION: We propose that serum-free collagen-based culture systems be considered to standardize the EEC assay, now part of the new criteria of polycythemia vera.

Bone Marrow Cells↗
PubMed2003

Familial polycythemia vera with Budd-Chiari syndrome in childhood.

Polycythemia vera is a myeloproliferative disorder that, in most cases, occurs sporadically with a median age at presentation of 60 years. Familial cases are very rare and usually manifest in elderly family members. The Budd-Chiari syndrome, characterized by the obstruction and occlusion of the suprahepatic veins, is a rare typical complication in polycythemia vera patients. To date, only two children or adolescents with polycythemia vera and Budd-Chiari syndrome have been described. Here, we report an 11-year-old girl with Budd-Chiari syndrome as the initial symptom of familial polycythemia vera, which was also found in the girl's grandmother. Details of the diagnostic procedures used and the clinical course are reported. The patient underwent orthotopic liver transplantation and is being treated with hydroxyurea. The available literature on familial polycythemia vera and polycythemia vera in childhood with and without Budd-Chiari syndrome is reviewed.

Bone Marrow↗
PubMed1998

Expression of Bcl-x in erythroid precursors from patients with polycythemia vera.

BACKGROUND: Deregulating the expression of Bcl-xL, an inhibitor of apoptosis, in an erythropoietin-dependent erythroblast cell line averts apoptosis induced by the withdrawal of erythropoietin. Since in polycythemia vera an abnormal clone of erythroid progenitors is independent of erythropoietin, we investigated whether the endogenous expression of Bcl-xL was deregulated in these cells. METHODS: Erythroid colonies from patients with polycythemia vera and normal subjects were cultured in the presence and absence of erythropoietin and assessed by immunocytochemical and flow-cytometric analysis with anti-Bcl-x antibodies that recognize the two species of Bcl-x (Bcl-xL and Bcl-xS). Reverse-transcriptase-polymerase-chain-reaction analysis was used to determine which one of the two species was responsible for anti-Bcl-x staining. Bone marrow mononuclear cells from 8 healthy bone marrow donors, 14 patients with polycythemia vera, 19 patients with other myeloproliferative syndromes, and 12 patients with secondary erythrocytosis were analyzed by flow cytometry with antibodies against Bcl-x and glycophorin A, an erythroid marker. RESULTS: Erythroid cells from patients with polycythemia vera survived in vitro without erythropoietin, and this finding correlated with the expression of Bcl-x protein (Bcl-xL messenger RNA was the main species of Bcl-x found), even in mature erythroblasts that normally do not express Bcl-x. The mean (+/-SD) percentage of cells positive for both glycophorin A and Bcl-x in the 14 patients with polycythemia vera (21.8+/-3.6 percent) was significantly higher than that in 8 normal donors (6.62+/-1.58 percent), 12 patients with secondary erythrocytosis (6.87+/-1.95 percent), 9 patients with essential thrombocythemia (3.81+/-0.97 percent), and 10 patients with chronic myeloid leukemia (2.7+/-0.41 percent). CONCLUSIONS: Deregulated expression of Bcl-x may contribute to the erythropoietin-independent survival of erythroid-lineage cells in polycythemia vera and thereby contribute to the pathogenesis of this disease.

Adolescent↗
PubMed2005

Enhanced erythropoietin production during hypobaric hypoxia in mice under treatments to keep the erythrocyte mass from rising: implications for the adaptive role of polycythemia.

Stress erythropoiesis is usually considered as a compensatory effort to counteract tissue hypoxia. Its homeostatic importance in anemic hypoxia has not been questioned, but researchers, clinicians, and mountain climbers have had second thoughts on polycythemia as to its appropriateness for hypoxic or altitude hypoxia (HA). Therefore, polycythemia, one of the responses to HA seen in nongenetically adapted mammals, could or could not be considered beneficial. The present study was thus performed to obtain further information on the importance of HA polycythemia on acclimation of mice to HA. To this end, the development of polycythemia was prevented by experimental manipulations (administration of 20 mg/kg/d of the hemolytic drug phenylhydrazine or removal of 0.225 mL/d of blood), and the degree of tissue hypoxia was evaluated from plasma erythropoietin (pEPO) concentration, as determined by immunoassay, in adult female mice exposed to air maintained at 506 mbar (380 mmHg) in a simulated HA (SHA) chamber during at least 23.5 h/d for 9 d. Plasma EPO concentration in those treated hypoxic mice whose hematocrit values remained almost unchanged was between 5.55 and 7.89 times higher (depending on the experimental designs) than in control hypoxic mice allowed to develop HA polycythemia. These results, plus the finding of an inverse relationship between the hematocrit value and pEPO concentration in both the polycythemic and normocythemic SHA-exposed mice indicate that HA polycythemia is highly effective in ameliorating tissue hypoxia under SHA conditions, thus giving support to the concept of the important role of the increased hemoglobin mass in nongenetically adapted animals, whereas a left-shifted oxyhemoglobin dissociation curve confers a good degree of adaptation to HA in genetically adapted animals.

Altitude Sickness↗
PubMedDate not supplied

Wilms tumor associated with polycythemia: case report and review of the literature.

PURPOSE AND METHODS: A case of polycythemia with a normal serum erythropoietin is described, which led to the diagnosis of Wilms tumor. The clinical features of the reported cases of Wilms tumor associated with polycythemia are reviewed. RESULTS: An asymptomatic 6-year-old boy with polycythemia, a normal serum erythropoietin, and no evidence of erythroid colony forming activity in his serum was found to have a Wilms tumor. After resection and chemotherapy, he has had no recurrence of either the polycythemia or the Wilms tumor. There have now been 10 cases of Wilms tumor reported: 7 patients were more than 16 years of age, 8 were boys, and 9 were clinical stage I with a favorable histology. CONCLUSIONS: Polycythemia is a rare manifestation of Wilms tumor that can occur in the absence of an elevated serum erythropoietin and has an association with male gender, older patient age, and low clinical stage. Children with unexplained polycythemia should be investigated for Wilms tumor, even if the serum erythropoietin level is normal.

Child↗