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.     

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.     

Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols

The PVSG was organized in 1967 to establish effective diagnostic criteria for polycythemia vera, to study the natural history of the disease and to define the optimal treatment. Although polycythemia vera and the other myeloproliferative diseases are relatively uncommon, the PVSG was able to accumulate well over 1,000 patients with these various disorders and to study them according to a total of 15 different protocols. PVSG-01, a long-term randomized controlled study of phlebotomy alone compared with the myelosuppressive agents, 32P or chlorambucil supplemented by phlebotomy, continues to receive follow-up data on 93% of surviving patients 18 years after initiation of the study. During its lifetime, PVSG has developed a widely accepted and highly effective set of criteria for the specific diagnosis of polycythemia vera as well as useful criteria for the diagnosis of essential thrombocythemia. It has gathered an enormous volume of data on the natural history of the myeloproliferative diseases and in particular on the nature of the prevalent complications, such as thrombotic events and hematologic and nonhematologic malignancies. With respect to the final question, the optimal treatment for polycythemia vera, it is apparent that the expectation of a single optimal therapy that would apply to all patients at all ages and stages of the disease was naive. Nevertheless considerable progress has been made. Moreover, the group has defined more precisely than ever before the nature of the complications of the disease and the association of the risks of specific complications with specific forms of therapy. It thus has made it possible to pose the next series of therapeutic questions that must be addressed in this disorder with a greater degree of sophistication than was previously possible.     

Thrombocytosis in young people: Evaluation of 57 cases diagnosed before the age of 40

Summary Over the past 13 years 57 cases of primary thrombocytosis in young people have been studied. Only patients with a platelet count over 500×10⁹/liter and a follow-up longer than 2 years were considered. Thrombocytosis in young people represents approximately 25% of total cases referred to our department during this period. The most common causes are essential thrombocythemia (20 cases) and secondary thrombocytosis (22 cases). The highest platelet counts are found in essential thrombocythemia patients. Most of our patients were discovered by a fortuitous hematological examination. In contrast, 5 out of the polycythemic patients were recognized after a thrombosis. The same was true for 2 out of 20 essential thrombocythemia subjects. Four subjects (2 essential thrombocythemia and 2 secondary thrombocytosis) were diagnosed after hemorrhages. The overall survival was very good except for leukemic patients and thrombocytosis secondary to neoplasms. Vascular complications after diagnosis were scarce: 2 polycythemia vera patients showed bleedings during antiaggregating therapy. None of our patients developed epithelial cancer, malignant lymphoma or myelofibrosis. Vascular traumata seem more frequent in polycythemia vera regardless of age. Therefore, it seems useful to treat polycythemic patients, while no therapy seems to be indicated in other forms of thrombocytosis.This study was supported in part by grants from M.P.I., Rome (grant 1592/1988) and from the Veneto Regional Government, Venice, Italy     

Intraventricular thrombosis in polycythemia vera: A cause of intractable cardiac failure

The occurrence of thrombotic events is central to the course of polycythemia vera.^1–5 Myocardial, cerebral, peripheral, and pulmonary infarctions are frequent and are consequences of thromboses in small and medium caliber arteries. Thrombosis in large caliber arteries is a rare event. Thrombosis within the chambers of the heart has not been hitherto reported.This report documents the occurrence of massive left ventricular thrombosis in a patient with polycythemia vera. The thrombus reduced the left ventricular capacity by about 75% and caused intractable congestive heart failure.     

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. © 1994 Wiley-Liss, Inc.     

Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation

The clinical course of polycythemia vera and essential thrombocythemia is potentially associated with long-term severe complications, such as evolution to myelofibrosis or acute myeloid leukemia. Allogeneic stem cell transplantation is currently the only potentially curative treatment for advanced polycythemia vera or essential thrombocythemia. We analyzed 250 consecutive patients with an initial diagnosis of polycythemia vera (n=120) or essential thrombocythemia (n=130), who underwent transplantation due to progression to myelofibrosis (n=193) or acute myeloid leukemia (n=57) and who were reported to the European Group for Blood and Marrow Transplantation registry between 1994 and 2010. Their median age was 56 years (range, 22–75) and in 52% of cases the interval between diagnosis and transplantation was 10 years or more. With a median follow-up from transplantation of 13 months, the 3-year overall survival rate and relapse incidence were 55% and 32%, respectively. In univariate analysis, the main parameters that negatively affected post-transplantation outcomes were older age (>55 years), a diagnosis at transplant of acute myeloid leukemia and the use of an unrelated donor. The overall 3-year cumulative incidence of non-relapse mortality was 28%, but was significantly higher in older patients than in younger ones (>55 years, 35% versus 20%, P=0.032), in those transplanted from an unrelated donor rather than a related donor (34% versus 18%, P=0.034) and in patients with a diagnosis of acute myeloid leukemia compared to myelofibrosis (29% versus 27%, P=0.045). This large retrospective study confirms that transplantation is potentially curative for patients with end-stage polycythemia vera/essential thrombocythemia progressing to myelofibrosis or acute myeloid leukemia. Relapse and non-relapse mortality remain unsolved problems for which innovative treatment approaches need to be assessed.     

Splenic rupture complicating periinterventional glycoprotein IIb/IIIa antagonist therapy for myocardial infarction in polycythemia vera

Polycythemia vera is a myeloproliferative disorder predisposing to thromboembolic and bleeding complications. We report the case of a patient with polyglobuly, leukocytosis, and thrombocytosis, who suffered from acute ST-segment elevation myocardial infarction due to thrombotic high-grade pre-stent stenosis two months after percutaneous coronary intervention for complex coronary one vessel disease. Following re-PTCA and stent implantation in conjunction with periinterventional GP IIb/IIIa antagonist treatment, the patient was initially symptom free for about two hours before rapidly developing signs of a hemorrhagic shock. An abdominal CT scan showed splenic rupture with massive intraabdominal hemorrhage as a consequence of secondary bleeding into multiple pre-existing splenic infarctions. The patient's condition stabilized after emergency splenectomy. Subsequent bone marrow biopsy revealed the presence of polycythemia vera. Post-operatively, the patient was treated with the anti-platelet agents aspirin and clopidogrel to prevent subacute stent thrombosis. Additionally, cyto-reductive therapy with hydroxyurea was initiated because of a further increase in the platelet count. In patients with polycythemia vera, the indication for treatment with GP IIb/IIIa antagonists should be carefully weighed against the potentially serious bleeding complications. Should treatment be established, a risk stratification using abdominal sonography and bleeding time testing is recommended, while during treatment red blood count, platelet count, coagulation tests, and hemodynamic parameters should be closely monitored.     

Polycythemia Vera: Age Relationships and Survival

Study of our first 201 cases of polycythemia vera and of cases reported inthe literature shows a remarkable age distribution for this disease. The ageat onset, age at diagnosis, age at first treatment, and age at death, as well assurvival times, each fits a normal distribution.

In our cases, the median age at onset is 57 years with a standard deviationof 13 years, an entirely different distribution from that for the populationof Oregon. This requires a logarithmic increase in relative age specific incidence from age 20 to 40, when there is little difference in the number ofpersons alive at each age, with a doubling of the proportion occurring ineach 5-year interval every 7.5 years. After age 55, the proportion of newcases developing follows the slope of the number alive in the population.This means that the incidence remains almost constant after the peak ageincidence is reached.

Unfortunately, no data exist to transform these figures to absolute values,but if enough of the population could be studied to give absolute values atany one point, all other points could be determined. The implication is thatpolycythemia vera is due to a single cause which is highly correlated withage.

The normal distribution of survival times means that polycythemia verais not a malignant process since survival times in all malignancies studiedfit a log normal distribution. The constant value of age at death means thatage at first treatment is a most important prognostic factor.

The mean age at death of patients with polycythemia vera, treated withP³², is 69 years ± 1, and treated without radiation therapy is 65 years ± 1.Apparently, if a patient lives to be treated with P³² previous treatment byother modalities or no treatment prior to that, will not affect the years tobe gained by P³² treatment. However, the total survival time is highly correlated with age and the sooner after onset that the patient can be treatedthe more likely it is he will benefit from P³² therapy.

     

Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3

We tested the hypothesis that levels of pentraxin high sensitivity C-reactive protein and pentraxin 3 might be correlated with cardiovascular complications in patients with essential thrombocythemia and polycythemia vera. High sensitivity C-reactive protein and pentraxin 3 were measured in 244 consecutive essential thrombocythemia and polycythemia vera patients in whom, after a median follow up of 5.3 years (range 0-24), 68 cardiovascular events were diagnosed. The highest C-reactive protein tertile was compared with the lowest (>3 vs. <1 mg/L) and correlated with age (P=0.001), phenotype (polycythemia vera vs. essential thrombocythemia, P=0.006), cardiovascular risk factors (P=0.012) and JAK2V617F allele burden greater than 50% (P=0.003). Major thrombosis rate was higher in the highest C-reactive protein tertile (P=0.01) and lower at the highest pentraxin 3 levels (P=0.045). These associations remained significant in multivariate analyses and indicate that blood levels of high sensitivity C-reactive protein and petraxin 3 independently and in opposite ways modulate the intrinsic risk of cardiovascular events in patients with myeloproliferative disorders.     

Aspirin-responsive painful red,blue, black toe,or finger syndrome in polycythemia vera associated with thrombocythemia

Five patients with red, purple blue, or black toes or fingers due to thrombocythemia associated with polycythemia vera (polycythemia and thrombocythemia vera) in four and essential thrombocythemia (thrombocythemia vera) in one are described. The microvascular erythromelalgic syndrome of thrombocythemia was overlooked and progressed to cold blue swollen and painful fingers or black toes in three patients with polycythemia and thrombocythemia vera due to arteriographically documented occlusions of digital or large peripheral arteries with no evidence of preexistent atherosclerotic vascular disease. Concomitant erythromelalgia of the hand palm could be confirmed by the histopathological findings of arteriolar thrombotic lesions in the reticular dermis in two patients with polycythemia and thrombocythemia vera. The increased hematocrit in the presented patients with polycythemia and thrombocythemia vera contributed to the progression of the microvascular syndrome of thrombocythemia to major occlusive ischemic events of the extremities. Standard therapy with oral anticoagulants and reduction of the hematocrit to normal by bloodletting did not affect the platelet-mediated microvascular erythromelalgic, ischemic symptoms in the patients with polycythemia vera because thrombocythemia vera persisted. Complete relief of pain and restoration of the ischemic acral circulation disturbances in patients with thrombocythemia vera or thrombocythemia associated with polycythemia vera in maintained remission by bloodletting could be obtained by long-term treatment with low-dose aspirin.     

Occlusion of the superior mesenteric artery in a patient with Polycythemia vera: Resolution with percutaneous transluminal angioplasty

The case is reported of a 46-year-old male patient with polycythemia vera (PV) treated with phlebotomy who developed an occlusive thrombosis of the superior mesenteric artery 2 years after the diagnosis. He was successfully managed with percutaneous transluminal angioplasty. The patient did not develop any other thrombotic phenomena. To our knowledge, there are no previous reports on the use of percutaneous transluminal angioplasty in the management of arterial thrombotic complications in PV patients.     

Trisomy 1q in polycythemia vera and its relation to disease transition

Clinical and cytogenetic details of 12 patients with polycythemia vera and complete or partial trisomy of the long arm of chromosome 1 are reported. All patients had trisomy for at least the segments 1q22 to 1qter. The 1q or material from 1q was translocated to another chromosome in eight patients. This was chromosome 9 in four patients, and those cases all had trisomy also for 9p. The trisomy 1q was found at the time of diagnosis in three patients, later during the polycythemic phase in five, and in four patients when they were first examined during a late stage of the disease. Acute leukemia or a myelodysplastic syndrome developed in eight of the 12 patients. Signs of advanced disease, eg, myeloid metaplasia or myelofibrosis, preceded the leukemia in four cases and was noted in one more patient. Trisomy 1q was the most frequent structural chromosome abnormality in patients with polycythemia vera. It is thus one of several nonrandom abnormalities that can appear at any stage of the disease. It seems to occur with higher frequency in patients with myelofibrosis and/or leukemia, but it is not a specific characteristic of these complications.     

Hemostatic gene polymorphisms and the prevalence of thrombotic complications in polycythemia vera and essential thrombocythemia.

Patients with polycythemia vera and essential thrombocythemia are at risk for thrombotic and bleeding complications. Currently, no diagnostic test can predict thrombohemorrhagic complications. In a prospective study of 86 patients with polycythemia vera (43 patients) or essential thrombocythemia (43 patients), we examined the possible role of polymorphisms of platelet adhesion receptors [glycoprotein (GP) Ibalpha, GPIa, GPIIIa) and clotting factor II (prothrombin's G20210A mutation) and clotting factor V (Leiden mutation) in determining the risk of thrombotic or bleeding complications. Except for an association between vasomotor symptoms and prothrombin mutation (P < 0.001), no significant correlation between polymorphism of clotting factors and thrombohemorrhagic complications was identified. When the entire patient cohort was considered, the polymorphisms of platelet adhesion receptors were not associated with the risk for thrombotic or bleeding complications. However, among patients with polycythemia vera, the presence of the PlA2 allele of GPIIIa was associated with an increased risk of arterial thrombosis. In view of previous studies linking the presence of the PlA2 allele of GPIIIa to a higher risk for coronary artery thrombosis, our data have physiologic relevance. However, they need to be confirmed in a larger study.     

Anticoagulant-resistant thrombophilia in a patient with polycythemia vera: a case report

Mechanical valve thrombosis is a rare condition in an adequately anticoagulated patient in the absence of underlying thrombophilia. We report a case of a 76-year-old male with mechanical prosthetic mitral valve thrombosis as the presenting feature of polycythemia vera. The patient was treated with thrombolysis at the time of acute presentation and subsequently maintained on low molecular weight heparin, low-dose aspirin, phlebotomy and hydroxyurea. Hemoglobin, leucocytosis and platelet count were controlled for almost 4 years after which the patient suffered a second, fatal episode in the setting of therapeutic anti-Xa level. This case report highlights the thrombotic risks associated with polycythemia vera. The proposed mechanisms of hypercoagulability in polycythemia vera are reviewed. To the best of our knowledge, mechanical valve thromboses as the presenting feature of polycythemia vera has not been reported previously.     

Isolated cerebellar infarction as a presenting symptom of polycythemia vera.

Although polycythemia vera is one of the reported causes for cerebral infarction, isolated cerebellar infarction, a rare disorder, was never reported in combination with polycythemia vera. This is a report of a 72-year-old woman in whom isolated cerebellar infarction was the presenting manifestation of polycythemia vera. The patient was treated with recurrent phlebotomies until the hematocrit decreased to < 45%. This treatment was followed by marked neurological improvement. A better awareness of the possibility of cerebellar infarction in polycythemia vera may disclose additional cases.     

Polycythemia and the Budd-Chiari syndrome: study of serum erythropoietin and bone marrow erythroid progenitors

The mechanism of polycythemia associated with the Budd-Chiari syndrome is unknown. Erythropoiesis in 10 patients with Budd-Chiari syndrome was studied in an attempt to distinguish prior unrecognized polycythemia vera from secondary polycythemia. Serum erythropoietin was assayed using a mouse fetal liver erythroblast assay. High concentrations of serum erythropoietin were observed in 6 of 7 patients with acute primary Budd-Chiari syndrome. Levels were normal in four patients who were investigated during the chronic phase and were increased in one with persisting polycythemia. In one patient, erythropoietin concentration in the hepatic vein was twice the level measured in peripheral, caval and renal venous blood. Bone marrow erythroid progenitors developed in vitro in the absence of exogenous erythropoietin in all polycythemia vera cases studied in acute and chronic phases, whether polycythemia persisted or not. These findings indicate that hepatic erythropoietin production occurs in the acute phase of Budd-Chiari syndrome and suggest that, in some cases of Budd Chiari syndrome, polycythemia which resolves after the acute phase may be secondary to liver disease.     

Leg ulcers in elderly on hydroxyurea: a single center experience in Ph- myeloproliferative disorders and review of literature

Hydroxyurea (HU) is effective in controlling thrombocytosis while reducing the risk of thrombosis in essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). However, HU may carry more or less severe side-effects. Rare cases of patients with painful leg ulcers have been published. We report our experience on such a side-effect in a large cohort of patients with ET and PV treated with HU and review the literature on the topic. Five (4%) out of our 124 patients (69 ET, 51 PV, 4 MF; 49 males, 75 females; mean age at diagnosis 59.1+/-11.8 years) treated with HU developed painful leg ulcers. Sixty-one other patients affected with Phmyeloproliferative disorders (Ph- MPD) developing HU-related painful leg ulcers are described in the English literature. All our five patients were women and developed leg ulcers over the age of 75. Sixty-five percent of all described cases are women; 59% were over 65 years of age and 45% over 70. Most cases received over 1 gr HU per day for at least 1 year. The pathogenesis of HU-induced skin ulcers remains elusive. Treatment is difficult and requires prompt cessation of HU therapy.     

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.     

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.