Association of monoclonal gammopathy and polycythemia vera or essential thrombocythemia: study of a large cohort of patients

Concomitant cases of monoclonal gammopathies with polycythemia vera (PV) and essential thrombocythemia (ET) have been described. We report our experience in a large cohort of patients with ET and PV and the occurrence of M protein in such a population. Retrospective evaluation of clinical and laboratory records of 164 patients with PV and 218 with ET was performed, and 500 subjects matched for sex and age were used as controls. The patients were divided into group A (younger than 55 years), group B (55-70 years), and group C (over 70 years), and the presence of M protein was sought at the time of diagnosis and later during follow-up. M protein was found in 14 patients with myeloproliferative disorders (MPDs), representing 3.6% of patients both with ET and PV, and in 10 subjects of the control group (2%). M protein was detected in 2.1% of MPD patients of group A, in 4.8% of group B, and in 5.7% of group C and in 1.6% of controls of group A, 2.7% of group B, and 2% of group C. No significant statistical difference was observed. The occurrence of M protein in PV and ET does not seem to differ from that observed in the control group. A more relevant increase in the incidence of M protein in MPDs than in the controls was observed by dividing patients and controls by age. However, no statistical significant difference was documented.     

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.     

Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera

OBJECTIVE: Circulating polymorphonuclear leukocyte (PMN) activation occurs in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We want to define whether this phenomenon plays a role in the formation of circulating PMN-platelet aggregates in these conditions. METHODS: In 80 patients (46 ET and 34 PV) and 50 control subjects, we conducted a flow cytometric analysis to evaluate the levels of PMN-platelet aggregates (defined as the percentage of CD11b-positive PMN coexpressing a platelet-specific marker, i.e., CD42b or CD62P) and the levels of activated PMN and activated platelets. In addition, the in vitro PMN-platelet aggregate formation in response to N-formyl-methionyl-leucyl-phenylalanine (f-MLP)-induced activation of PMN was studied. RESULTS: Significantly high PMN-platelet aggregates in ET and PV patients were found and were associated with increased PMN surface CD11b and surface platelet CD62P expression. In vitro f-MLP stimulation upregulated PMN-CD11b expression and simultaneously increased CD11b/CD42b and CD11b/CD62P aggregates, without affecting platelet surface antigens. In ET patients receiving aspirin, the increments in f-MLP-induced PMN-CD11b and in PMN-platelet aggregates were significantly lower versus ET subjects not treated with aspirin. CONCLUSION: Our data show that in ET and PV patients PMN activation plays an important role in increasing circulating PMN-platelet aggregates and suggest that aspirin treatment may decrease their formation.     

Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea

Therapeutic options for patients with polycythemia vera (PV) and essential thrombocythemia (ET) resistant or intolerant to hydroxyurea are limited. Busulfan is effective as first-line therapy, but there is scarce information on this drug as second-line treatment. The efficacy of busulfan in patients with advanced PV or ET refractory or intolerant to hydroxyurea was assessed in 36 patients (PV n?=?15, ET n?=?21) treated for a median of 256 days. Complete hematological response (CHR) was achieved in 83 % of patients, after a median time of 203 days (range 92–313). The probability of sustained CHR at 1 and 2 years was 87 and 62 %, respectively. Time to CHR was shorter in patients treated with ≥14 mg of busulfan per week than with lower doses (141 versus 336 days, p?=?0.01). Partial molecular response was achieved in three out of nine (33 %) patients. Busulfan was stopped in 27 patients (75 %) due to CHR achievement in 18 cases (67 %), hematological toxicity in 8 cases (30 %), and disease transformation in 1 case. With a median follow-up of 721 days, six patients have died, with the probability of survival at 2 years being 85 %. The probability of thrombosis at 2 years was 11 %. Transformation into acute leukemia or myelodysplastic syndrome was observed in three cases, all of them in a JAK2V617F-negative clone carrying additional mutations. Busulfan, at a dose of 2 mg/day, is an effective option for elderly patients with PV or ET who fail to hydroxyurea, but a significant rate of transformation was observed.     

Alpha-interferon in polycythemia vera and essential thrombocythemia

Twenty-one patients with chronic myeloproliferative disorders, eleven with polycythemia vera (PV) and ten with essential thrombocythemia (ET), were treated with small doses of alpha-2a interferon (IFN). The median follow-up was, respectively, 10.8 months (range 4-22) for PV and 8.11 months (range 4-16) for ET. Six patients with PV and five with ET had been previously treated with conventional cytotoxic drugs, while the remaining patients were newly diagnosed. In four patients with PV we observed a durable normal hematocrit level (PCV less than 0.48) and a reduction of platelet count and spleen size within 4-8 weeks of treatment. Three patients achieved moderate disease control. In the others the disease remained substantially unchanged. Five out of nine evaluable patients with ET showed complete response (CR) within six weeks, one patient had a partial response (PR) and three no response (NR). In one patient with ET the IFN therapy was stopped after twelve days because neurological side effects were observed. All the other patients tolerated long-term treatment very well.     

Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey

A multicenter retrospective analysis was performed to estimate the frequency of thrombosis and hemorrhage after surgical procedures in patients with polycythemia vera (PV) and patients with essential thrombocythemia (ET). Data from 105 patients with PV and 150 patients with ET were analyzed, for a total of 311 surgical interventions. An emergency procedure was performed in 25 (8.1%) patients; 194 surgeries were done under general anesthesia, and 21 (23%) of 91 abdominal interventions were done under laparoscopy; 155 (50.1%) were major surgeries. Subcutaneous heparin was administered in 169 (54.3%) of 311 cases and antiplatelet therapy in 48 (15.4%) of 311 case interventions. One hundred eighty-eight (74%) of 255 patients were on cytoreductive therapy before surgery. No events were observed in 259 (83.2%) of 311 procedures during 3 months of follow-up; there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages, and 5 deaths. Arterial thromboses were more frequent in ET (5.3% vs 1.5%; P=.08), venous events were more frequent in PV (7.7% vs 1.1%; P=.002). There was not a correlation between bleeding episodes and the type of diagnosis, use of antithrombotic prophylaxis, or type of surgery. A high proportion of PV and ET surgeries was complicated by vascular occlusion (7.7%) or by a major hemorrhage (7.3%). Prospective investigations analyzing the optimal prophylaxis in these patients are suggested.     

Prevalence of polycythemia vera and essential thrombocythemia

Polycythemia vera (PV) and essential thrombocythemia (ET) are common types of myeloproliferative disorders (MPD), the prevalence of which has not been well documented in the United States. Recent breakthroughs in the molecular etiology of these disorders and the accelerated development of targeted pharmacotherapeutics to treat them underscore the need to define the affected population. In this study, we obtained health claims data from major commercial insurance payers in Connecticut and the Center for Medicare and Medicaid Services to estimate the prevalence of PV and ET. Specifically, logistic regression was utilized to develop algorithms to predict the probability that an individual with claims suggestive of MPD truly has PV or ET, and the algorithms were then applied to health claims to estimate the number of PV and ET patients in Connecticut. As of 2003, the age-standardized prevalence was 22 per 100,000 and 24 per 100,000 for PV and ET, respectively, in Connecticut. Applying the age-specific prevalence of PV and ET to the entire US population resulted in an estimated total of 65,243 patients with PV and 71,078 patients with ET in the United States in 2003. This study is the first to assess the prevalence of PV and ET in a large US population. Given the large number of individuals afflicted with these diseases and the fact that demographic changes alone will further increase the burden of     

The rate of progression to polycythemia vera or essential thrombocythemia in patients with erythrocytosis or thrombocytosis

The clinical relevance of mild erythrocytosis (hematocrit > 0.48 in women or > 0.51 in men) or thrombocytosis (platelet count > 400 x 10(9) cells/L) in asymptomatic persons is uncertain.     

Front-line therapy in polycythemia vera and essential thrombocythemia

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a "high-risk" or "low-risk" category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.     

Anagrelide-associated cardiomyopathy in polycythemia vera and essential thrombocythemia

A comprehensive database inquiry at our institutions identified 11 patients with echocardiogram-documented idiopathic cardiomyopathy that post-dated a diagnosis of either polycythemia vera or essential thrombocythemia. Anagrelide therapy was temporally associated with the particular complication in 6 patients, all of whom experienced symptomatic and/or objective improvement after drug discontinuation.     

Risk-adapted therapy in essential thrombocythemia and polycythemia vera

The clinical course of Polycythemia vera (PV) and Essential Thrombocythemia (ET) is marked by an high incidence of thrombotic complications, which represent the main cause of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use raises the risk of PV and ET transformation into acute leukemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients with PV should be treated with phlebotomy and low-dose aspirin, whereas those with ET can be left untreated. Cytotoxic therapy is indicate in high-risk patients and the drug of choice is hydroxyurea because its leukemogenicity is low, if any. New therapeutic options, theoretically devoid of leukemic risk, such as alpha-interferon, anagrelide and imatinib should be reserved to selected patients and require further clinical experience.     

Platelet density in essential thrombocythemia and polycythemia vera

This study aims to compare platelet density in myeloproliferative disorders (essential thrombocythemia (ET) and polycythemia vera (PV)) with platelet density of healthy subjects. Platelet density peaks were determined using a specially designed apparatus for scanning light transmission variations along test tubes containing density-separated platelets. Eighteen patients with myeloproliferative disorders (nine ET and nine PV) were compared with a control group consisting of 12 healthy volunteers. Compared with healthy volunteers, patients with myeloproliferative disorders had significantly lower platelet peak density ( P< 0.001). It is concluded that determination of peak platelet density may be a useful tool for excluding ET and PV. A high platelet density peak makes a clonal disorder less likely and a low density peak would confirm the suspicion.     

Platelet density in essential thrombocythemia and polycythemia vera

This study aims to compare platelet density in myeloproliferative disorders (essential thrombocythemia (ET) and polycythemia vera (PV)) with platelet density of healthy subjects. Platelet density peaks were determined using a specially designed apparatus for scanning light transmission variations along test tubes containing density-separated platelets. Eighteen patients with myeloproliferative disorders (nine ET and nine PV) were compared with a control group consisting of 12 healthy volunteers. Compared with healthy volunteers, patients with myeloproliferative disorders had significantly lower platelet peak density ( P< 0.001). It is concluded that determination of peak platelet density may be a useful tool for excluding ET and PV. A high platelet density peak makes a clonal disorder less likely and a low density peak would confirm the suspicion.     

Splenectomy after portal thrombosis in patients with polycythemia vera and essential thrombocythemia

BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) and essential thrombocythemia (ET) are two rare acquired myeloproliferative disorders (MPD) with frequent thrombotic and hemorrhagic complications. The occurrence of thrombosis in unusual sites, e.g. splanchnic vasculature, is a severe complication of these diseases. We describe a single-institution experience in patients with ET and PV, diagnosed in agreement with the Polycthemia Vera Study Group criteria, with portal vein thrombosis who did or did not undergo splenectomy. DESIGN AND METHODS: The medical records and the follow-up outcome of 16 MPD patients with portal thrombosis who underwent splenectomy (group A1) and 16 who did not (group A2) were evaluated. Their median follow-up was, respectively, 13.45 and 10.49 years. The overall survival of these patients was compared with that of a population of 32 patients with MPD and no portal thrombosis (group B) matched for sex, age, diagnosis and duration of follow-up. RESULTS: In group A1, 2 patients developed deep vein thrombosis, 1 patient had a surgical hemorrhage and 2 patients died early, one from acute infection, the other from bone marrow aplasia. Among the survivors, one male had a deep vein thrombosis and 1 developed a new portal thrombosis. Four patients died during the follow-up (median 9.48 years, range 3.17-25.1; 1 stroke, 2 gastrointestinal bleedings, 1 leukemic conversion). No difference was observed in the incidence of thrombotic or hemorrhagic complications or in the rate of deaths when group A1 was compared to the other groups. The use of antiplatelets drugs was statistically increased in group A1 after splenectomy, because portal vein thrombosis induced per se an increased use of therapeutic agents. No statistical difference was observed in overall survival between the different groups. INTERPRETATION AND CONCLUSIONS: 1) Bleeding and thrombosis are the leading causes of morbidity and mortality in ET and PV patients with portal vein thrombosis both with or without splenectomy. 2) Portal vein thrombosis, and sometimes splenectomy, requires increased use of drugs which may enhance the risk of leukemic transformation. In spite of this, the patients who survive the first post-splenectomy period may have a long and safe life.     

Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera

Thrombohemorrhagic complications are a major cause of morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia vera (PV). The pathogenesis of these complications is not completely clarified. Several studies have described abnormalities of red blood cells and platelets in these patients. However, no studies are available on changes in the polymorphonuclear leukocytes (PMNs), which can play an important role in the activation of the hemostatic system. In patients with ET (n = 37) and PV (n = 34), a series of PMN activation parameters (PMN membrane CD11b and leukocyte alkaline phosphatase [LAP] antigen expression, cellular elastase content, plasma elastase, and myeloperoxidase levels) was evaluated simultaneously with the levels of plasma markers of endothelial damage (thrombomodulin and von Willebrand factor antigen) and hypercoagulation (thrombin-antithrombin complex, prothrombin fragment 1 + 2, and D-dimer). The results show the occurrence of PMN activation in both groups of patients compared with a control group of healthy subjects. An increase in CD11b and LAP expression by PMN membrane was observed, together with a significant increase in cellular elastase content, plasma elastase, and myeloperoxidase levels. In addition, patients had high plasma levels of endothelial and hypercoagulation markers compared with controls. For the first time, these data show that in ET and PV, 2 hematologic conditions that place patients at increased risk for thrombosis, an in vivo leukocyte activation occurs and is associated with laboratory signs of endothelium and coagulation system activation. (Blood. 2000;96:4261-4266)