Preleukemia and leukemia in polycythemia vera.

A group of 76 polycythemia vera patients was followed prospectively with bone marrow examinations at regular intervals. Six terminated in acute leukemia, preceded by an indolent preleukemic phase succeeded by a very fulminant leukemia. At autopsy, all patients had extramedullary hematopoiesis. In one of them, only the bone marrow was leukemic, suggesting that it was the primary site of this transformation. In three with leukemic involvement of nonhematopoietic organs, the infiltrate consisted of myelo- or myelomonoblasts and normoblasts. The preleukemic phase was characterized by a rapidly evolving spontaneous pancytopenia, with a drop from polycythemic blood counts within 2 mo. In the bone marrow, megaloblastoid erythropoiesis with ring sideroblasts was prominent. A similar preleukemic phase evolving in other potentially leukemic conditions, has been described. Therefore, in patients at risk, the appearance of ring sideroblasts may be regarded as an early indicator of imminent acute leukemic transformation.     

The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera

Model for the role exerted by CALR in the modulation of the stress response in normal erythroid cells and how impairment of CALR function may contribute to erythrocytosis in JAK2⁺-PV. Under steady-state conditions, EPO/EPO-R interactions control erythropoiesis by activating JAK2, which induces proErys to mature. Under stress, GRα activation “switches” JAK2 signaling to a proliferation mode, rapidly increasing the number of erythroblasts available to differentiate. However, for this increase of erythroblast numbers to be effective in recovering from anemia, an unidentified mechanism must switch the JAK2 signaling in these cells back to the maturation mode. The data presented here suggest that this switch is CALR. In fact, Ca²⁺-induced conformation changes of this protein, which may be induced in vivo by EPO-R activation, promoted nuclear export of GRα, resetting the stress responsiveness of normal erythroid cells. In contrast, in JAK2⁺-PV, hyperactivation of JAK2, possibly by increasing intracellular Ca²⁺ levels even further, impairs the nuclear export functions of CALR, retaining GRα in the nucleus and erythroblasts in proliferation and contributing to erythrocytosis. Ruxolitinib, by suppressing JAK2V717F activity, restores the GRα nuclear export activity of CALR, increasing the Dex responsiveness of these cells and reducing erythrocytosis. The cellular diagram of erythroid maturation is modified from Palis, 2014.

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Activation of the coagulation system in polycythemia vera.

Thrombosis is one of the major complications of polycythemia vera. Seventeen patients with polycythemia vera in good hematologic control were evaluated for abnormalities of the coagulation system. Activation of the intrinsic coagulation cascade was suggested by low levels of factor XII, prekallikrein, and kallikrein inhibitors in 12 of 17 patients. The group also demonstrated a significant increase in soluble fibrin complexes using plasma gel filtration on 4% agarose. Fibrin degradation products were normal and antithrombin III levels were slightly elevated. It appears that patients with polycythemia vera have chronic activation of the coagulation system, probably initiated by activation of factor XII. No correlation between the degree of coagulation abnormalities and thromboembolic complications was evident in this group of patients.     

Pulmonary hypertension in polycythemia vera

Thromboembolic events occur in about 27% of the patients with polycythemia vera and account for 31% of the deaths. These include cerebrovascular accidents, myocardial infarction, peripheral vascular occlusions, pulmonary infarctions, and venous thrombosis. We report two cases with polycythemia vera who presented with pulmonary hypertension in the absence of previous thromboembolic complications of any kind. One patient died suddenly, with evidence of extensive bilateral thrombosis of prelobular pulmonary arteries at autopsy. In the second patient, local thrombosis in the pulmonary vasculature or recurrent silent pulmonary emboli appear to be responsible for the development of pulmonary hypertension. After institution of anticoagulant therapy, he is able to maintain his functional status. The purpose of this report is to alert clinicians to the development of this insidious, but potentially fatal complication in patients with polycythemia vera. © 1994 Wiley-Liss, Inc.     

Cytogenetic studies in polycythemia vera

A group of 54 patients with the original diagnosis of polycythemia vera were subjected to cytogenetic examination. Six (17.6%) of the 34 cases examined in the period of the advanced phase of the polycythemia vera had a chromosomal change. Thirteen (65%) of the 20 patients undergoing the cytogenetic examination in the period when the polycythemia vera turned into another myeloproliferative disease showed chromosomal aberration. This suggests a relationship between the number of chromosomal changes and the transformation of the disease. No connection between the cytogenetic changes and myelosuppressive cures could be confirmed in our material. The chromosomal change 20q- considered to be the most frequent kind in the polycythemia vera was not discovered until in patients with the polycythemia vera transformed into a different myeloproliferative disease.