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PubMed2002

Biochemical characterization of PRV-1, a novel hematopoietic cell surface receptor, which is overexpressed in polycythemia rubra vera.

The cDNA for polycythemia rubra vera 1 (PRV-1), a novel hematopoietic receptor, was recently cloned by virtue of its overexpression in patients with polycythemia vera. PRV-1 is a member of the uPAR/CD59/Ly6 family of cell surface receptors, which share a common cysteine-rich domain and are tethered to the cell surface via a glycosylphosphatidylinositol (GPI) link. We have determined the intron-exon structure of the PRV1 gene and show that the locus is structurally intact in patients with polycythemia vera. Thus, PRV-1 overexpression in these patients is not due to rearrangement or structural alteration of the gene. Northern blot analysis detects multiple PRV-1 transcripts. Here we show that these transcripts arise from alternative polyadenylation and encode the same protein. Biochemical analysis reveals that PRV-1 is N-glycosylated and embedded in the cell membrane by a lipid anchor, like other members of this family. Moreover, PRV-1 is shed from the cell surface because soluble protein can be detected in cell supernatants. Fluorescence-activated cell sorting analysis of stably transfected cells revealed that PRV-1 is recognized by antibodies directed against the neutrophil antigen NB1/CD177. Flow cytometry of bone marrow and peripheral blood of both healthy donors and patients with polycythemia vera showed that PRV-1 protein is expressed on myeloid cells of the granulocytic lineage. However, unlike the significant difference in PRV-1 expression observed on the mRNA level, the amount of PRV-1 protein on the cell surface is not consistently elevated in patients with polycythemia vera compared with healthy controls. Therefore, quantification of PRV-1 surface expression cannot be used for the diagnosis of polycythemia vera.

3' Untranslated Regions↗
PubMed2006

Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F.

BACKGROUND: A somatic activating mutation (V617F) in the JAK2 tyrosine kinase was recently discovered in the majority of patients with polycythemia vera (PV), and some with essential thrombocythemia (ET) and chronic idiopathic myelofibrosis. However, the role of mutant JAK2 in disease pathogenesis is unclear. METHODS AND FINDINGS: We expressed murine JAK2 WT or V617F via retroviral bone marrow transduction/transplantation in the hematopoietic system of two different inbred mouse strains, Balb/c and C57Bl/6 (B6). In both strains, JAK2 V617F, but not JAK2 WT, induced non-fatal polycythemia characterized by increased hematocrit and hemoglobin, reticulocytosis, splenomegaly, low plasma erythropoietin (Epo), and Epo-independent erythroid colonies. JAK2 V617F also induced leukocytosis and neutrophilia that was much more prominent in Balb/c mice than in B6. Platelet counts were not affected in either strain despite expression of JAK2 V617F in megakaryocytes and markedly prolonged tail bleeding times. The polycythemia tended to resolve after several months, coincident with increased spleen and marrow fibrosis, but was resurrected by transplantation to secondary recipients. Using donor mice with mutations in Lyn, Hck, and Fgr, we demonstrated that the polycythemia was independent of Src kinases. Polycythemia and reticulocytosis responded to treatment with imatinib or a JAK2 inhibitor, but were unresponsive to the Src inhibitor dasatinib. CONCLUSIONS: These findings demonstrate that JAK2 V617F induces Epo-independent expansion of the erythroid lineage in vivo. The fact that the central erythroid features of PV are recapitulated by expression of JAK2 V617F argues that it is the primary and direct cause of human PV. The lack of thrombocytosis suggests that additional events may be required for JAK2 V617F to cause ET, but qualitative platelet abnormalities induced by JAK2 V617F may contribute to the hemostatic complications of PV. Despite the role of Src kinases in Epo signaling, our studies predict that Src inhibitors will be ineffective for therapy of PV. However, we provide proof-of-principle that a JAK2 inhibitor should have therapeutic effects on the polycythemia, and perhaps myelofibrosis and hemostatic abnormalities, suffered by MPD patients carrying the JAK2 V617F mutation.

Amino Acid Substitution↗
PubMed1992

Familial and congenital polycythemia in three unrelated families.

Three families with polycythemia inherited through apparently different modes are described. Secondary causes of polycythemia were ruled out. Erythropoietin (EPO) levels were normal or low, even after phlebotomy. In vitro erythroid colony growth in standard assay cultures containing EPO was normal; however, in the absence of added EPO, a few progenitors from most of the affected individuals were able to generate recognizable colonies of mature erythroblasts, although these were smaller and proportionately less numerous than seen in polycythemia vera (PV). To search for EPO-receptor changes as a possible pathophysiologic mechanism, we examined, by Southern blot analysis, genomic DNA samples from affected and nonaffected family members, as well as three patients with PV. Two different probes, derived from the human EPO-receptor, were used. We found no evidence for chromosomal rearrangements or gene amplification in hereditary polycythemia or PV patients. Further, no nucleotide sequences were found that were homologous to the Friend spleen focus-forming virus glycoprotein gp55, which has been shown to bind to and activate the murine EPO-receptor. Functional studies examining number and binding affinity of the EPO-receptor on erythroid progenitors from three hereditary polycythemia patients demonstrated no abnormalities. We conclude that the mechanism(s) for the erythrocytosis in familial and congenital polycythemia and in PV may not involve the EPO-receptor and, therefore, may result from alterations of postreceptor responses.

2,3-Diphosphoglycerate↗
PubMed1991

Polycythemia in diabetic patients on CAPD.

Polycythemia in CAPD patients has been rarely described. Over an eight year period, 4 out of 123 CAPD patients (3%) were identified as having Hct values exceeding 50% for 1 month or longer. All of the 4 patients were insulin dependent diabetics (4/47 diabetic patients, 8.5%). Charts were reviewed on 3 of these 4 patients. Polycythemia developed after a mean of 21 +/- 7 months on peritoneal dialysis. Prior to the development of polycythemia, ferritin levels were low and ferrous sulfate therapy was begun at a time the Hct values were 36 to 40%. Erythropoietin levels were obtained in 2 patients, and were 22 U/L (Hct 51%) and less than 5 U/L (Hct 55%). Renal ultrasound failed to show renal masses or cysts. One patient had a plasma volume of 2.1 L (normal 2.4-3.2 L); another patient was clinically volume depleted. Complications during the period of polycythemia included gangrenous feet requiring amputation in 2 patients, CVA in 2 patients, and splenic infarct in 1 patient. One patient died of cerebral thrombosis. We conclude that polycythemia is uncommon in CAPD patients and occurs most often in diabetic patients. Volume depletion and iron therapy may play a role in its etiology. In this high risk group of patients polycythemia may contribute to vascular complications and should be avoided.

Adult↗
PubMed1993

[Study of pathophysiology of pulmonary circulation in polycythemia using scintigraphy].

In order to evaluate the pathophysiology of pulmonary circulation in polycythemia, Tl-201 myocardial scintigraphy and perfusion lung scintigraphy with 99m-Tc MAA were performed in 19 cases with polycythemia including polycythemia rubra vera and in 11 cases with secondary polycythemia due to pulmonary diseases. Tl-201 lung uptake, right ventricular visualization and pulmonary perfusion impairment were studied. In the 19 cases, Tl-201 lung uptake was observed in all cases and 54.5% of them showed moderate lung uptake. The grade of right ventricular visualization was moderate in one case and slight in 16 cases; right ventricular hypertrophy was shown in 89.5% of all cases by Tl-201 scintigraphy, only one of which showed right ventricular hypertrophy on electrocardiography. Abnormalities of lung perfusion consisted of scattered small areas of hypoperfusion in 36.8%, peripheral hypoperfusion in 78.9% and uneven distribution of pulmonary perfusion in 94.7%. The degree of hypoperfusion was slightly related to decrease in FEV1.0%, V25 and PaO2 and increase in circulating blood volume and peripheral red blood cell counts. Abnormalities of pulmonary function consisted of increased RV/TLC in 50.0%, increased CV/VC in 35.7% and decreased V25 in 36.8%. Arterial blood gases showed hypoxemia in 57.1%, the degree of which was slightly related to increase in RV/TLC and CV/VC and decrease in V25. Cases of secondary polycythemia due to pulmonary diseases showed more marked right ventricular visualization, pulmonary perfusion impairment and abnormalities of various kinds of pulmonary function than polycythemia rubra vera cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

[Value of analyzing reticulocyte subpopulations in polycythemia].

OBJECTIVE: The evaluation of the RNA content in reticulocytes by means of flow cytometry allows us to differentiate three reticulocyte populations by their degree of maturity: LFR, MFR and HFR. We have studied the value of those reticulocyte subpopulations for the differential diagnosis in polycythemia. PATIENTS AND METHODS: We have studied 25 polycythemia patients, 12 of these were diagnosed of polycythemia vera (PV) and 13 of secondary polycythemia (PS). Reticulocytes and their different reticulocyte populations were automatically analyzed by flow cytometry using the Sysmex R-2000 analyzer (TOA Corp. Japan). We calculated the reticulocyte maturity index (RMI) which is the percentage of the equation (MFR + HFR) x 100/LFR (9). We have also studied hemogram parameters (Hct, Hb, VCM, HCM, RDW, leukocytes and platelets), iron metabolism (serum iron, ferritin, transferrin and transferrin saturation index), and erythropoietin levels. The findings were statistically analyzed using the Pearson correlation test and the comparison tests of averages of independent samples (Student's t). RESULTS: Patients with PV present high RMI and MFR + HFR (medium and high fluorescence reticulocytes) as compared with secondary polycythemia . We did not find any correlation between RMI and other analytical parameters (erythropoietin, ferritin, serum iron, transferrin), except for the transferrin saturation index (TSI), with a correlation factor r: 0.5486 for p < 0.05. CONCLUSION: This higher proportion of younger reticulocytes in PV might be explained because they are a parameter that would reflect the expansion of erythropoietic bone progenitor cells, which would be more increased in PV than in PS. However, another possible explanation would consist in the existence of associated ferropenia in PVs, which lead to an increase in cytoplasmic levels of transferrin receptor mRNA.

Adult↗
PubMed1997

Enhanced generation of monocyte tissue factor and increased plasma prothrombin fragment1+2 levels in patients with polycythemia vera: mechanism of activation of blood coagulation.

Polycythemia vera (PV) is associated with a high incidence of thrombosis. The association of apparent and secondary polycythemia with thrombosis is not clear. It was suggested that activation of the coagulation system contributes to thrombus formation in PV. However, the mechanism of activation is unknown. Monocytes generate a potent tissue factor (TF) upon stimulation with various substances, which is involved in thrombus formation in various disorders. Therefore, we studied the possibility that the factor is involved in the activation of coagulation and thrombus formation also in PV. Unstimulated peripheral blood mononuclear cells (PBMC) from each of the different types of polycythemia expressed weak TF activity (2 U) and antigen (41.4 to 52.9 pg/ml), which were similar to normal controls. Following stimulation with endotoxin, PBMC from normal controls and from apparent and secondary polycythemia showed a 3.9- to 4.5-fold increase in TF, while cells from PV showed a 21-fold increase (P<0.001). Similar levels were generated by PBMC after treatment of PV and at the spent phase. TF was generated by monocytes but not by lymphocytes. Plasma prothrombin fragment1+2 (F1+2) levels, assayed at the same time, were significantly higher in PV (2.46 nm) compared to normals and apparent and secondary polycythemia (0.22 to 0.32 nm), and were in a significant correlation with monocyte TF activity and antigen levels (r = 0.77, 0.87). The high levels of F1+2 confirm that the coagulation system is activated in PV. The increased capacity of monocytes to generate TF may be responsible for the activation of the coagulation system and thrombus formation. The hypercoagulability state that is induced by this mechanism suggests that long-life oral anticoagulation should be considered once thrombosis has been developed in PV.

Adult↗
PubMed1987

Differentiation between essential thrombocythemia and polycythemia vera with marked thrombocytosis.

Accurate distinction between essential thrombocythemia and thrombocytotic polycythemia vera requires determination of the red cell mass in the presence of adequate iron stores, but this is not always possible. We therefore compared the clinical and laboratory features at the time of presentation of 50 patients with unequivocal essential thrombocythemia and 27 patients with thrombocytotic polycythemia vera. Univariate analysis failed to identify any single parameter capable of reliably separating the groups. A logistic regression algorithm incorporating hematocrit, white cell count, and spleen size markedly increased the diagnostic accuracy (92%) compared with predictions based on the hematocrit alone (52%). The algorithm's usefulness for patients with intermediate hematocrits was confirmed by analysis of independent samples of essential thrombocythemia and thrombocytotic polycythemia vera patients, and also by analysis of patients with probable essential thrombocythemia in whom the diagnosis could not be confirmed because of inadequate exclusion of polycythemia vera. Furthermore, comparison of survival data suggests that differentiating these disorders is prognostically important. The algorithm is recommended as an alternate method for differentiating essential thrombocythemia from thrombocytotic polycythemia vera whenever the red cell mass is unavailable or iron deficiency cannot be excluded.

Adult↗
PubMed1994

Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989.

To investigate the suggestion that the incidence of polycythemia vera has increased in recent decades, we ascertained secular trends in the incidence of polycythemia vera in Olmsted County, Minnesota, over the 55-year period, 1935-1989. The inpatient and outpatient medical records of all potential cases of polycythemia vera in Olmsted County residents were reviewed and the diagnostic criteria of the Polycythemia Vera Study Group were applied. We found no indication of an increase in the age- and sex-adjusted incidence of polycythemia vera, which averaged 1.9 per 100,000 person-years (95% C.I., 1.4-2.5) over the study period. Incidence rates increased with age, and age-adjusted incidence rates were greater for men (2.8 per 100,000 person-years; 95% C.I., 1.8-3.9) than for women (1.3 per 100,000 person-years; 95% C.I., 0.7-1.9), with the highest incidence rate (23.5 per 100,000 person-years) among men aged 70-79 years. Survival was reduced in this inception cohort of 50 cases, compared to that expected for individuals of like age and sex (P < 0.0001); median survival following diagnosis was 7.2 years.

Adult↗
PubMed1982

Polycythemia vera: studies of hemopoiesis in continuous long-term culture of human marrow.

Long-term cultures of marrow cells from ten normal subjects and three patients with polycythemia vera were established to compare normal and neoplastic hemopoiesis in vitro. Suspended cells were removed periodically from the cultures and assayed from their content of various colony-forming cells, including erythroid colony- and burst-forming cells (CFU-E and BFU-E), granulocyte/macrophage colony-forming (CFU-C), and "mixed cell" colony progenitors (CFU-GEMM). To determine if mixed cell colonies arise from a single progenitor, we used the cellular mosaicism conferred by X-chromosome inactivation. The isoenzymes of glucose-6-phosphate dehydrogenase (G-6-PD) were used as markers of the mosaicism. Preliminary results suggest that these colonies are clonal only at low plating densities. The G-6-PD system was also used to determine whether selection or "drift" occurs in continuous long-term cultures. The ratios of G-6-PD isoenzyme types in pooled colonies from cultures of two normal heterozygotes remained similar, indicating stable cultures. Long-term cultures of normal marrow and marrow from the patients with polycythemia vera maintained BFU-E for a mean of 8.7 (+/- 0.6) and 12.5 (+/- 0.5) weeks (P = 0.03), respectively. The fractions of total BFU-E detected as endogenous erythroid colonies remained similar over the culture period. These results demonstrate that 1) hemopoiesis in polycythemia vera can be analyzed in long-term culture; 2) polycythemia vera marrow grows as well or better than normal in long-term culture; and 3) the proportion of the neoplastic clone in polycythemia vera represented by endogenous erythroid colony growth is unchanged over time, suggesting no reemergence of normal stem cell progeny in this system.

Bone Marrow↗
PubMedDate not supplied

Neonatal polycythemia.

461 consecutive inborn babies, delivered during the period September 1993-March 1994 were subjected to a microhematocrit assessment at 6 hours of age to determine the incidence of polycythemia. 47 babies (inborn and out born), admitted to the neonatal unit with confirmed polycythemia were studied for clinical and laboratory abnormalities. These 47 babies were then randomly assigned to receive partial exchange transfusion with either normal saline or fresh plasma. The incidence of polycythemia was 27 of 461 (5.8%). 23 of 27 (85.1%) were term babies and 15 of 27 (55.5%) were small for gestational age. 14 of 27 (51.1%) babies had mothers who had pregnancy induced hypertension. Feeding problems (16/47) and lethargy (25/47) were the commonest symptoms (34% and 51% respectively). 25 of 47 (51%) babies had hypoglycemia and 5 of 47 (10.6%) had hypocalcemia. Thrombocytopenia was seen in 13/47 (27.65%) of cases. 24 babies received normal saline and 23 received fresh plasma for partial exchange transfusion. The immediate post-exchange fall in hematocrit was significant in both groups and this was well sustained over the following 48 hours. However, improvement in clinical and laboratory parameters was more remarkable with fresh plasma. Polycythemia appears to be a real clinical entity in neonates in India and babies with known risk factors should be actively screened for this condition. Once diagnosis is established special attempts should be made to rule out hypoglycemia. For treatment of polycythemia fresh plasma is preferable for partial exchange transfusion but normal saline appears to be an adequate substitute.

Exchange Transfusion, Whole Blood↗
PubMed1975

Decreased (Ca2+ + Mg2+)-stimulated ATPase activity in erythrocyte membranes from polycythemia vera patients.

Erythrocytes were hemolyzed in hypotonic phospate buffer containing 0.5 mmol/l Ca2+ and the membranes subsequently washed twice in hypotonic tris buffer. The centrifugation was performed in a continuous flow system, which was necessary to obtain maximal ATPase activity. The Mg2+-dependent Ca2+-stimulated ATPase activity of 14 patients with polycythemia vera was only 67 per cent (P less than 0.001) of the activity of a control material consisting of 10 donors and 11 bank blood specimens. Five patients with secondary polycythemia and four patients with an increased erythrocyte fraction did not differ significantly from the controls. The polycythemia vera patients with the highest leukocyte count showed the lowest ATPase activity. The apparent calcium dissociation constant of the ATPase in polycythemia vera was about 10(-6) mol/l, as in controls. The relation between the reduced ATPase activity and the abnormal hemopoiesis of polycythemia vera patients is discussed.

Adenosine Triphosphatases↗
PubMed2003

Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.

The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1 alpha (HIF-1 alpha) and serves as a recognition component of an E3-ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1 alpha forms a heterodimer with HIF-beta and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO). The autosomal dominant cancer-predisposition von Hippel-Lindau (VHL) syndrome is due to inheritance of a single mutated allele of VHL. In contrast, we recently showed that homozygous germline 598C-->T VHL mutation leads to Chuvash polycythemia (CP). We subsequently found VHL mutations in three unrelated individuals unaffected with CP, one of whom was compound heterozygous for the 598C-->T mutation and another VHL mutation. We now report seven additional polycythemic patients with VHL mutations in both alleles. Two Danish siblings and another American boy were homozygous for the VHL 598C-->T mutation. Three unrelated white Americans were compound heterozygotes for 598C-->T and another VHL mutation, 562C-->G in two and 574C-->T in the third. Additionally, a Croatian boy was homozygous for a 571C-->G VHL mutation, the first example of homozygous VHL germline mutation causing polycythemia, other than the VHL 598C-->T mutation. We have not observed VHL syndrome-associated tumors in polycythemic subjects or their heterozygous relatives; however, this will need to be evaluated by longitudinal studies. Over all, we found that up to half of the consecutive patients with apparent congenital polycythemia and increased serum Epo we have examined have mutations of both VHL alleles. Those findings, along with reports of CP, underscore that VHL mutations are the most frequent cause of congenital polycythemia and define a new class of polycythemic disorder, polycythemias due to augmented hypoxia sensing.

Adolescent↗
PubMedDate not supplied

Hyperlipidemia and myocardial infarction among 118 patients with polycythemia vera.

Hyperlipidemia was reported among 46 of 118 polycythemia vera patients as compared to a control group of 115 healthy subjects in whom hyperlipidemia was reported in 20. Among the 46 hyperlipidemic patients with polycythemia vera 14 had a myocardial infarction, while among the other 72 nonhyperlipidemic polycythemia vera patients myocardial infarction occurred amont 17. Since repeated phlebotomies may induce hyperlipidemia, this form of treatment of polycythemia vera may be potentially dangerous in already hyperlipidemic polycythemia vera patients.

Female↗
PubMedDate not supplied

Polycythemia in the newborn.

Neonatal polycythemia, a venous hematocrit >65%, occurs in 1% to 5% of the total newborn population. Polycythemia can result from an excess production of red blood cells (active form) or from an increase in fetal blood volume (passive form). Clinical manifestations of polycythemia are caused by an increase in whole blood viscosity with a subsequent decrease in blood flow to organ systems. However, little information exists in the nursing literature concerning neonatal polycythemia. This article addresses the two categories of polycythemia and their etiologies; the involved pathophysiology; clinical manifestations of affected organ systems; supportive and specific therapies that can be used to treat polycythemic infants; the prognosis for polycythemic infants; and the difficulty healthcare providers face in deciding whether to treat this disorder. In addition, a case of a symptomatic infant who was treated with a partial exchange transfusion is presented.

Adolescent↗
PubMed1992

Neonatal polycythemia in appropriately grown infants of hypertensive mothers.

Neonatal polycythemia is a frequent finding after pregnancies complicated by diabetes and by maternal hypertension with intrauterine growth retardation (IUGR). It is still unclear if the association of polycythemia with hypertension is the result of IUGR or of hypertension per se. To establish the incidence of neonatal polycythemia in populations at risk, we analyzed the results of hematocrit values obtained from 1592 neonates born consecutively at the Hospital de Clinicas, Buenos Aires. Capillary hematocrit values were obtained by heel stick before 6 h of age. When the values were 65% or greater, new samples were obtained from an antecubital vein. The risk of polycythemia in appropriately grown infants of hypertensive mothers was 12.6-fold greater than the risk in the general population. These data show that maternal hypertension poses a significant risk for polycythemia, regardless of fetal growth. We suggest that, to prevent possible sequela, hematocrit is measured routinely in all infants of hypertensive mothers for prompt diagnosis and treatment.

Chi-Square Distribution↗
PubMed1973

Granulocyte alkaline phosphatase. Studies of purified enzymes from normal subjects and patients with polycythemia vera.

To characterize the biological changes which result in increased granulocyte alkaline p-nitrophenyl phosphatase activity in patients with polycythemia vera, the enzyme was purified from granule fractions of sucrose homogenates made from dextran-sedimented leukocytes of normal subjects and patients with polycythemia vera. Polycythemic blood yielded 3-10 times as much granulocyte alkaline phosphatase per 10(9) leukocytes as did normal blood. Sodium dodecyl sulfate extracts of granules were purified by DEAE-cellulose chromatography and sucrose gradient centrifugation to apparent homogeneity as judged by polycarylamide disk gel electrophoresis. Granulocyte alkaline phosphatase from normal subjects was purified 6910-fold with a 60% yield and a specific activity of 47 U/mg. Granulocyte alkaline phosphatase from polycythemic patients was purified 1.166-fold with a 50% yield and a specific activity of 70 U/mg. The two enzymes did not differ in molecular weight; both appeared to be about 160,000 daltons by sucrose gradient centrifugation. Both appeared to be zinc metalloenzymes, in that they were specifically inhibited by o-phenanthroline. Their elution requirements when adsorbed to DEAE-cellulose suggested they were lipoproteins although the content of phosphorus was below the threshold of detection. The identity of the two enzymes was suggested by immunological studies in which antibody prepared against purified polycythemia vera enzyme gave a precipitation reaction of identity with another polycythemia vera enzyme and two pools of normal enzyme. It is possible to account for the difference in alkaline phosphatase activity between the granulocytes of patients with polycythemia vera and normal subjects by differences in the quantity of enzyme synthesized.

Alkaline Phosphatase↗
PubMed2002

Paradoxical secondary polycythemia in von Hippel-Lindau patients treated with anti-vascular endothelial growth factor receptor therapy.

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by germline mutations in the VHL tumor-suppressor gene. Central nervous system (CNS) and retinal hemangioblastomas are highly vascular tumors that are hallmarks of the disease. These tumors overexpress vascular endothelial growth factor (VEGF) and represent a potential target for anti-angiogenic drugs. We observed, after 3 to 4 months of treatment, secondary paradoxical polycythemia in 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416. Hematocrit was normal before the beginning of the trial, and no progression of hemangioblastomas was observed. Polycythemia vera and all known causes of secondary polycythemia were also ruled out. Polycythemia has never been reported in current SU5416 trials for advanced malignancies and could express a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene. These findings could also affect the inclusion of VHL patients with pre-existing polycythemia in future anti-VEGF receptor trials.

Adult↗