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1 November 1995 | Volume 123 Issue 9 | Pages 656-664
Objective: To reassess the natural history of polycythemia vera and to obtain reliable estimates of both incidence of thrombosis and survival for use in defining the sample size for therapeutic clinical trials.
Study Design: Retrospective cohort study of patients with polycythemia who had been followed for 20 years.
Setting: 11 Italian hematology institutions.
Patients: 1213 patients with polycythemia vera, which was diagnosed according to criteria established by the Polycythemia Vera Study Group and commonly used in clinical practice.
Main Outcome Measures: All-cause mortality, venous and arterial thrombosis, and hematologic and nonhematologic neoplastic disease. Myocardial infarction and stroke were classified as major thrombotic events, and venous and peripheral arterial thrombosis were considered minor thrombotic events. The number of patients who died and the number of those who had major thrombotic events (combined end point) were used as a comprehensive measure of the benefit-risk ratio associated with the use of myelosuppressive agents.
Results: 634 fatal and nonfatal arterial and venous thromboses were recorded in 485 patients (41%); 36% of these episodes occurred during follow-up in 230 patients (19%), and 64% occurred either at presentation or before diagnosis. Thrombotic events occurred more frequently in the 2 years preceding diagnosis, suggesting a causal relation between the latent myeloproliferative disorder and the vascular event. The incidence of thrombosis during follow-up was 3.4%/y; older patients or those with a history of thrombosis had a higher risk for thrombosis. Overall mortality was 2.9/100 patients per year; thrombotic events and hematologic or nonhematologic cancers had similar effects on mortality. Patients receiving chemotherapy died three to four times more frequently than those not receiving chemotherapy. The increased risk for cancer in patients receiving myelosuppressive agents was seen approximately 6 years after diagnosis. In addition, the combined end point, computed as the sum of the hardest available events (death, nonfatal myocardial infarction, or stroke), suggests that myelosuppressive agents have an overall unfavorable effect.
Conclusions: Cytoreduction favorably affects the incidence of thrombotic events, but aggressive treatment seems to be associated with increased risk for neoplasm. These results provide a basis for reevaluating the therapeutic strategy in patients with polycythemia vera and for estimating the size of clinical trials aimed at testing new therapeutic approaches.
*For members of the Gruppo Italiano Studio Policitemia, see the Appendix.
We retrospectively reviewed patients with polycythemia vera in an attempt to reevaluate the natural history of the disease and obtain reliable estimates of the incidence of thrombosis and survival. Such data can then be used to define the sample size needed for intervention trials. We especially emphasized thrombotic events, the incidence of which was investigated both in the whole study group and in patient subgroups that had a presumably different risk for thrombosis or life expectancy.
To collect data from clinical records, we sent the clinicians a standard, one-time questionnaire. We regularly contacted the clinicians by mail or telephone during the data collection phase. Information was collected on date of birth; date of diagnosis of polycythemia vera; thrombotic events before, at, or after diagnosis; type of thrombotic events (myocardial infarction, transient ischemic attack, stroke, venous thromboembolic events, or acute peripheral arterial occlusion); phlebotomy in the last year of follow-up; pharmacologic treatments in the past and at the last follow-up visit (such as radiophosphorus agents, alkylating and nonalkylating myelosuppressive agents, antiplatelet agents, and anticoagulant agents); onset of neoplastic disease or myelofibrosis; and cause of death. Because only a few patients were prescribed radiophosphorus agents, we analyzed them with patients receiving alkylating myelosuppressive agents. We categorized patients into four mutually exclusive groups according to the type of treatment received during follow-up: no chemotherapy (n = 373); alkylating myelosuppressive agents (n = 613); nonalkylating myelosuppressive agents (n = 125); and both types of myelosuppressive agents (n = 102). To increase the feasibility of the study, we collected no information on the degree of disease control and nonfatal hemorrhagic events. Only fatal bleeding could be evaluated. We did not consider the so-called "microvascular" thrombotic phenomena, including erythromelalgia, the Raynaud phenomenon, and specific visual or hearing symptoms, because the thrombotic nature of such phenomena is uncertain and because correct assessment is difficult and largely subjective. We requested that clinicians classify the diagnosis of thrombotic events as anamnestic, clinical, or instrumental. Overall, 58% of the thrombotic events appearing before diagnosis of polycythemia vera were considered anamnestically diagnosed, 13% were considered clinically diagnosed, and 29% were considered instrumentally diagnosed. Forty-eight percent of thromboses seen at diagnosis were instrumentally diagnosed. Only 6.7% of thrombotic events were reported as being anamnestically diagnosed during the follow-up.
Outcome Measures
The primary outcomes were all-cause mortality, venous and arterial thrombosis, and hematologic and nonhematologic neoplastic disease.
Because the study was retrospective, we did some analyses using end points less prone to bias. We therefore classified myocardial infarction and stroke as major thrombotic events and considered venous and peripheral arterial thrombosis to be minor thrombotic events.
To make a comprehensive estimate of the benefit-risk ratio associated with the use of alkylating and nonalkylating myelosuppressive agents, we used a combined end point: the number of patients who died plus the number of those who had nonfatal myocardial infarction or stroke.
We censored all living patients on the date of the last follow-up. Because the date of death was not available for 16 patients, we calculated the duration of survival by adding the time between diagnosis and the last visit to half the time between the date of collection of information and the date of the last visit.
Statistical Analysis
We computed age- and sex-standardized mortality ratios by comparing the category-specific mortality rates of patients who had polycythemia vera with the corresponding rates of the Italian population in 1988. We used chi-square tests to ascertain differences in proportions. Kaplan-Meier cumulative incidence plots and two-sided nominal P values derived from the unweighted log-rank statistics are given. When comparing the patients in the four treatment subgroups, we limited the analysis to 15 years of follow-up because of the limited number of events. We used the Mantel-Haenszel procedure to calculate relative risks for disease and their 95% CIs. All analyses were done using the SAS statistical package (SAS Institute, Inc., Cary, North Carolina).
Age and Sex Distribution
Figure 1 shows the frequency of the diagnosis of polycythemia vera according to age and sex and the ratio of men to women. Approximately 7% of patients were younger than 40 years of age, 40% were 40 to 59 years of age, 33% were 60 to 70 years of age, and 20% were older than 70 years of age. At diagnosis, the age distribution of the 671 men and 542 women (ratio of men to women, 1.2:1) differed. Although the overall ratio of men to women (1.2) was similar to that reported in other studies, we found that this mean value was the result of a 1:1 ratio in patients younger than 40 years, with higher ratios for patients between 40 and 75 years of age and lower ratios for older patients. The median age at diagnosis was slightly lower in men (60 years) than in women (62 years). ARTICLE
Polycythemia Vera: The Natural History of 1213 Patients Followed for 20 Years
Polycythemia vera is a rare hematologic disorder characterized by clonal proliferation of bone marrow progenitors. This proliferation increases the production of leukocytes, erythrocytes, and platelets and causes clinical symptoms largely related to the expansion of erythrocyte mass. Early studies in untreated patients with polycythemia found a high incidence of thrombotic events and a life expectancy of about 18 months after diagnosis. Cytoreductive treatment of blood hyperviscosity by phlebotomy or chemotherapy has been shown to dramatically reduce the number of thrombotic events and substantially improve survival. However, thrombosis remains a major cause of illness and death, and long-term use of cytostatic agents has been associated with an increased development of secondary cancers [1-3]. The identification of safer cytostatic agents and the improvement of antithrombotic strategies are therefore important areas of research. Current knowledge of the natural history of polycythemia vera is inadequate for designing clinical trials of new treatment strategies. In fact, available data on the prevalence of major complications of polycythemia vera largely derive from clinical studies of limited sample size or those that were designed to test obsolete treatments.
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Methods
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Discussion
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References
Our study was conducted in 11 Italian hematology institutions that retrospectively collected data from 1213 patients with polycythemia vera. The participating centers diagnosed polycythemia vera and followed the patients from 1953 to 1992; in more than 90% of the patients, the disorder was diagnosed after 1975. The diagnostic criteria for polycythemia vera were established by the Polycythemia Vera Study Group and were commonly used in clinical practice [1].
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Methods
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Patient Characteristics at Diagnosis
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History of Thrombosis and Thrombosis as the Presenting Symptom
One hundred seventy-one patients (14%) had 184 thrombotic events before diagnosis of polycythemia vera, and 233 (20%) had a thrombotic event as the presenting symptom of disease. Arterial and venous thrombosis constituted about two thirds and one third, respectively, of thromboses either before or when polycythemia vera was diagnosed. Ischemic stroke and transient ischemic attacks accounted for 70% of arterial thromboses at diagnosis and were as prevalent as myocardial infarction (30%) before diagnosis of polycythemia vera.
We also studied previous thromboses in relation to their temporal association with diagnosis. As shown in Figure 2, most previous thromboses (46%) were seen during the 2 years before diagnosis. Considering the years preceding the diagnosis of polycythemia vera, the rate of events was highest in the 12 months before the diagnosis (4%). Events that occurred 10 years or more before the diagnosis of polycythemia vera are probably not related to the disease. Moreover, we determined 75% of events by adding the number of events leading to diagnosis and the number of events in the preceding 2 years; the remaining 25% of events occurred over a range of more than 30 years before diagnosis.
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Follow-up
The mean (±SD) duration of follow up was 6.1 ± 4.9 years (median, 5.3 years; range, 0 to 32.9 years).
Analysis of Thrombosis-Free Survival
Two hundred fifty-four thrombotic events (200 nonfatal, 54 fatal) were recorded in 230 patients (19%). After diagnosis of polycythemia vera, myocardial infarction and transient ischemic attacks were the most frequent nonfatal arterial complications Table 1, and myocardial infarction accounted for half of all fatal thrombotic events. The thrombosis-free survival of the various age groups is shown in Figure 3. The overall rate of thrombotic events was 3.4/100 patients per year. The rate of thrombotic events increased with age: For patients younger than 40 years, the rate was 1.8/100 patients per year; for those aged 40 to 59 years, 2.8/100 patients per year; for those aged 60 to 69 years, 4.0/100 patients per year; for those older than 70 years, 5.1/100 patients per year (P < 0.001).
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History of thrombosis was predictive of a second thrombotic episode. Figure 4 shows the thrombosis-free survival in patients with a history of thrombosis and in those without such a history (24.6% compared with 17.3%; P = 0.001). Compared with patients who had never had thrombosis and those with a history of major thrombosis, patients with a history of minor thrombosis had the highest risk for developing thrombotic events during follow-up. The frequency of thrombotic events during follow-up was as follows: 17.3% for patients without a history of thrombosis; 26.5% for patients with a history of minor thrombotic events; and 22% for patients with a history of major thrombotic events (P = 0.0001 for minor events compared with no events and P = 0.02 for major events compared with no events).
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The apparent increase in thrombotic events in patients receiving myelosuppressive agents (increase of 13% in patients receiving no chemotherapy and of 20.8% in those receiving chemotherapy) was not unexpected because the group of patients receiving chemotherapy probably included most patients with the highest risk for thrombosis.
Survival Analysis
The cumulative median duration of survival was more than 15 years; the overall mortality rate was 2.94 deaths/100 persons per year. The median duration of survival differed among the age groups, ranging from 8 years in patients older than 70 years to more than 15 years in younger patients. Sixty-nine percent of patients aged 40 to 60 years at diagnosis and more than 90% of those younger than 40 years survived more than 15 years of follow-up. The age- and sex-standardized mortality rate indicated that the observed mortality rate for patients with polycythemia is 1.7 times greater than that of the age- and sex-specific mortality rate of the general Italian population in 1988. Men had higher mortality rates than women in each age group: 11.2 compared with 5.1/1000 persons per year for patients younger than 40 years; 24.5 compared with 16.2/1000 persons per year for patients aged 40 to 59 years; 41.8 compared with 32.0/1000 persons per year for patients aged 60 to 69 years; and 61.3 compared with 53.7/1000 persons per year for patients aged 70 years and older.
Two hundred twenty-five patients (18.5%) died during the study; the cause of death was reported in 192 cases (85%). Table 2 shows the specific causes of death. The most frequent fatal complications were thrombosis (57 cases [30%]) and cancer (15% of patients with acute leukemia and 15% with other cancers). The prevalence of death from vascular causes was similar among the four age groups, whereas deaths from cancer occurred less frequently in older patients (43% of patients aged 41 to 60 years; 39% for those aged 61 to 70 years; and 14% for those older than 70 years; P = 0.40).
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Cancer
Four times as many patients who had previously received radiophosphorus alkylating or nonalkylating myelosuppressive agents died of cancer compared with patients who received phlebotomy or other pharmacologic treatments (6.7% compared with 1.6%; P = 0.06). Patients who received alkylating myelosuppressive agents during the course of the disease had a higher frequency of malignant events Figure 5 than patients not receiving chemotherapy. As reported by the Polycythemia Vera Study Group [1, 2], the increased risk for cancer in patients treated with myelosuppressive agents became evident approximately 6 years after diagnosis.
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Combined End Point
To comprehensively evaluate the benefit-risk ratio associated with myelosuppressive therapy during the course of the disease, we computed a cumulative end point by combining total mortality with the number of nonfatal major thrombotic events (Figure 6). The overall risk for these events seemed higher in patients receiving more aggressive myelosuppressive therapy than in patients receiving other treatments (P = 1.0).
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Discussion
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The current treatment strategy for patients with polycythemia vera is primarily derived from clinical studies of the Polycythemia Vera Study Group [1, 3], which showed an increased risk for neoplasms in patients given alkylating agents, increased risk for thrombosis and myelofibrosis in patients who received phlebotomy, and an unacceptable risk for bleeding associated with high-dose aspirin [1, 3, 6]. However, the Polycythemia Vera Study Group guidelines are now being debated because of uncertainty about the very-long-term risk for neoplasms associated with nonalkylating agents. Debate has also arisen because of preliminary findings indicating that aspirin, if used at the proper dosage, may be well tolerated [7-9] and selectively effective in relieving some of the typical ischemic manifestations experienced by patients with myeloproliferative disorders [9-13]. Moreover, antiplatelet agents have a well-established role in preventing vascular events in high-risk patients [14, 15]. In a single, small clinical trial of patients with polycythemia vera, high-dose aspirin (900 mg/d) was associated with an excessive risk for gastrointestinal bleeding [6]. As shown by recent clinical trials in patients with vascular disease, however, lower aspirin doses (that is, 30 to 75 mg/d) are at least as effective as higher doses and are also better tolerated [14-18]. However, the efficacy and safety of low-dose aspirin in preventing thrombosis in patients with polycythemia vera has not been tested, and the information currently available is of little use in calculating the sample size for such a trial.
Incidence of Thrombotic Events
The incidence of thrombosis in patients with polycythemia vera ranged from 4 to 11.4 events/100 patients per year, as reported by the few prospective studies testing largely obsolete therapeutic strategies [2, 19] and a retrospective series with a limited number of cases [20-23]. In addition, the rate of thrombosis strongly depended on age and previous thrombotic events [1, 24-26]. We showed a relatively low incidence of major thrombotic events (that is, 3.4/100 patients per year during follow-up); this finding may indicate that aggressive treatment of polycythemia vera in high-risk patients is associated with a reduced risk for thrombosis. This hypothesis is supported by the finding that major thromboses recurred far less frequently than expected, both on the basis of data from previous studies and comparisons between the major thrombosis-free survival curve in patients with previous major thrombotic events and the curve in patients with a history of minor thromboses. A tentative explanation of this finding is that high-risk patients are more likely to have been prescribed a more aggressive treatment, with a consequently reduced risk for thrombosis.
Thrombotic events observed during follow-up provided interesting information, particularly when analyzed in patients grouped according to age or presence or type of previous thrombotic events. The relation between age and risk for thrombosis is potentially clinically useful. In fact, the recommended strategy for treating polycythemia vera is based on the balance between the risk for neoplasms and the risk for thrombosis in the individual patient. However, previous studies have not provided age-adjusted estimates for risk for thrombosis, except for an approximate comparison of the risk in patients older or younger than 60 years. Our results suggest that the risk for thrombosis increases with age, from 1.8 events/100 patients per year in patients younger than 40 years to 5.1 events/100 patients per year in those older than 70 years. Age and previous thrombosis have also been reported to be independent risk factors for thrombosis in patients with essential thrombocythemia [27].
Long-Term Benefit and Risk Ratio of Chemotherapy
Another finding from our study concerns the life expectancy of patients with polycythemia vera. The median duration of survival reported by the Polycythemia Vera Study Group ranged from 9 to 13.5 years [1, 3]. However, other retrospective studies have reported a much longer life expectancy [24, 28]. For example, Rozman and colleagues [28] suggested that the expected survival in patients with polycythemia does not differ from the survival in a control sample. In contrast with this study, our results suggest a 70% excess mortality compared with mortality data from the Italian population. The excess mortality is not dramatic and highlights the benefits achievable with current interventions. However, the greater than threefold increase in cancer-related mortality in patients receiving radiophosphorus or alkylating myelosuppressive agents is of concern. Moreover, the use of a combined end point, computed as the sum of the hardest available events (nonfatal myocardial infarction or stroke and total mortality), might suggest that chemotherapy is given to patients with more aggressive disease or that myelosuppressive agents have an overall negative effect. The latter hypothesis is in agreement with the results of the Polycythemia Vera Study Group investigation published in 1981 [2]. Overall, patients treated with phlebotomy survived longer than aggressively treated patients: Median survival was 11.8 years for patients receiving radiophosphorous, 8.9 years for patients receiving chlorambucil, and 13.9 years for patients receiving phlebotomy. On the basis of these results, the best therapeutic approach in subgroups of patients with polycythemia vera is still unknown.
Thrombotic Events as the First Manifestation of Disease
In our study, the incidence of thrombotic events increased during the 2 to 3 years before diagnosis. This finding strongly suggests a causal relation between the progressive expansion of the clonal disorder and the increased risk for thrombosis. Researchers have suggested that the preclinical phase of the disease may be associated with a prothrombotic state because patients with apparently idiopathic venous thrombosis in the portal district subsequently developed a myeloproliferative disorder [29-36]. The growth of erythropoietin-independent erythroid colonies in some adults with idiopathic portal vein thrombosis suggests that a latent myeloproliferative disease may underlie a prothrombotic state [29-37]. This growth is usually seen in myeloproliferative diseases and has been proposed as an additional diagnostic criterion for the diagnosis of polycythemia vera [38]. Our study suggests that thrombosis occurring shortly before the overt development of polycythemia vera encompasses the whole spectrum of major arterial thromboses, such as myocardial infarction and cerebrovascular occlusions, as well as peripheral arterial and venous thrombosis. Myocardial infarction is currently considered less indicative of an underlying congenital or acquired disease than is splanchnic vein thrombosis, and this may explain the lack of reports relating arterial thromboses to a latent myeloproliferative disorder [31-37]. The incidence of thrombotic events in our study was highest at presentation and in the 2 years preceding diagnosis. However, because we did not evaluate erythroid colonies, a latent form of polycythemia vera can only be argued on the basis of the temporal relation between these events and diagnosis.
The excess number of ischemic strokes seen at diagnosis compared with the lower incidence of this event during the preclinical phase of the disease is also interesting. If real, this phenomenon might reflect the high sensitivity of cerebral flow to blood hyperviscosity [20, 39-42]. Earlier recognition and treatment of the disease might help prevent this phenomenon.
Conclusion
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On the basis of our findings, we conservatively estimate that the control group of a clinical trial testing the efficacy of low-dose aspirin in patients with polycythemia without clear indications or contraindications to aspirin would have an 8.4% event rate after 3 years of follow-up, or 14% after 5 years. If the expected reduction of thrombotic events in the aspirin group is set at 30% (
equals 0.05; ß equals 0.2), then 1646 patients per arm would be needed for the trial with 3 years of follow-up; 940 patients per arm would be needed for the trial with 5 years of follow-up. The many patients with polycythemia vera needed for a clinical trial in this setting, the rarity of the disease, and the possible negative effects of current myelosuppressive drugs all call for international collaboration for assessing safer and more effective treatment.
Appendix
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Writing Committee
Ospedali Riuniti, Bergamo, Italy: T. Barbui and G. Finazzi; Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy: G. de Gaetano, R. Marchioli, and G. Tognoni; Universita Gabriele D'Annunzio, Chieti, Italy: C. Patrono; Universita Cattolica del Sacro Cuore, Roma, Italy: R. Landolfi.
Principal Investigators
Ospedale Nuovo di Torrette, Ancona, Italy: P. Leoni, and S. Rupoli; Ospedali Riuniti, Bergamo, Italy: T. Barbui, S. Cortelazzo, G. Finazzi, and O. Vestri; Universita di Bologna, Italy: S. Tura, C. Finelli, and F. Nocentini; Universita Gabriele D'Annunzio, Chieti, Italy: C. Patrono; Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy: R. Marchioli, G. Tognoni, G. de Gaetano, G. Angeli, A. Di Pasquale, V. Kramer, R. Marfisi, M. Olivieri, L. Sciulli, and R. Spoltore; Policlinico Careggi, Firenze, Italy: P. Rossi Ferrini, A. Grossi, and G. Longo; Ospedale Niguarda, Milano, Italy: F. De Cataldo, L. Gargantini, and F. Baudo; Ospedale S. Gerardo, Monza, Italy: E.M. Pogliani and I.R. Miccolis; Universita Cattolica del Sacro Cuore, Roma, Italy: B. Bizzi, R. Landolfi, B. Rocca, and R. Tartaglione; Universita La Sapienza, Roma, Italy: F. Mandelli, E. Montefusco, and A. Spadea; Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy: M. Carotenuto, M. Nobile, and R. Morelli; Ospedale Molinette, Torino, Italy: L. Resegotti and M.A. Ciocca Vasino; Ospedale S. Bartolo, Vicenza, Italy: F. Rodeghiero and M. Ruggeri.
Advisory Board
Universita di Bologna, Italy: S. Tura; Universita La Sapienza, Roma, Italy: F. Mandelli; Policlinico Careggi, Firenze, Italy: P. Rossi-Ferrini.
Data Management and Statistical Analysis
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy: G. Angeli, A. Di Pasquale, V. Kramer, R.M. Marfisi, M. Olivieri, L. Sciulli, and R. Spoltore.
References
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1. Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI, Wasserman LR. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol. 1986; 23:132-43.
2. Berk PD, Goldberg JD, Silverstein MN, Weinfeld A, Donovan PB, Ellis JT, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med. 1981; 304:441-7.
3. Najean Y, Dresch C, Rain JD. The very-long-term course of polycythaemia: a complement to the previously published data of the Polycythaemia Vera Study Group. Br J Haematol. 1994; 86:233-5.
4. Hoffman R, Silverstein MN. Polycythemia vera. In: Hoffman R. Hematology: Basic Principles and Practice. New York: Churchill Livingstone; 1991:834-54.
5. McCarthy DM. Annotation. Fibrosis of the bone marrow: contents and causes. Br J Haematol. 1985; 59:1-7.
6. Tartaglia AP, Goldberg JD, Berk PD, Wasserman LR. Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera. Semin Hematol. 1986; 23:172-6.
7. Egli F, Wieczorek A, Niemoller M, Rhyner K. Polycythaemia vera: klinik und verlauf bei 86 patienten. [Polycythemia vera: clinical aspects and course in 86 patients.] Schweiz Med Wochenschr. 1988; 118:1969-75.
8. Frohli P, Graf C, Rhyner K. Die Prophylaxe vaskularer komplikationen bei polycythaemia vera und primarer thrombozythamie mit niedrig dosierter acetylsalicylsaure. [Prevention of vascular complications in polycythemia vera and primary thrombocythemia treated with low doses of acetylsalicyclic acid.] Schweiz Med Wochenschr. 1983; 113:1622-7.
9. Michiels JJ, Abels J, Steketee J, van Vliet HH, Vuzevski VD. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med. 1985; 102:466-71.
10. Michiels JJ, Zijlstra F. Prostaglandin cyclooxygenase products but not thromboxane A2 are involved in the pathogenesis of erythromelalgia in thrombocythaemia. Mediators of Inflammation. 1993; 2:385-9.
11. Michiels JJ, Koudstaal PJ, Mulder AH, van Vliet HH. Transient neurologic and ocular manifestations in primary thrombocythemia. Neurology. 1993; 43:1107-10.
12. Michiels JJ, ten Kate FJ. Erythromelalgia in thrombocythemia of various myeloproliferative disorders. Am J Hematol. 1992; 39:131-6.
13. Landolfi R, Ciabattoni G, Patrignani P, Castellana MA, Pogliani E, Bizzi B, et al. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo. Blood. 1992; 80:1965-71.
14. "Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. 1994; 308:81-106.".
15. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994; 330:1287-94.
16. "A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. N Engl J Med. 1991; 325:1261-6.".
17. "Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet. The RISC Group. 1990; 336:827-30.".
18. "Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. The SALT Collaborative Group. Lancet. 1991; 338:1345-9.".
19. "Treatment of polycythaemia vera by radiophosphorus or busulphan: a randomized trial. Leukemia and Hematosarcoma Cooperative Group, European Organization for Research on Treatment of Cancer (E.O.R.T.C.). Br J Cancer. 1981; 44:75-80.
20. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet. 1978; 2:1219-22.
21. Randi ML, Stocco F, Rossi C, Tison T, Girolami A. Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases). J Med. 1991; 22:213-23.
22. Wehmeier A, Daum I, Jamin H, Schneider W. Incidence and clinical risk factors for bleeding and thrombotic complications in myeloproliferative disorders. A retrospective analysis of 260 patients. Ann Hematol. 1991; 63:101-6.
23. Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol. 1990; 8:556-62.
24. Najean Y, Mugnier P, Dresch C, Rain JD. Polycythaemia vera in young people: an analysis of 58 cases diagnosed before 40 years. Br J Haematol. 1987; 67:285-91.
25. Zankovich R, Thiele J, Fiessler WD, Fischer R, Diehl V. Prognostic parameters in polycythaemia vera rubra. Correlations of clinical and histomorphological features in 60 patients. Med Klin. 1987; 82:889-4, 927.
26. Najean Y, Dresch C, Poirier O. Accidents vasculaires dans la polyglobulie. [Vascular complications of polycythemia]. Ann Med Interne (Paris). 1983; 134:390-4.
27. Barbui T, Cortelazzo S, Viero P, Bassan R, Dini E, Semeraro N. Thrombohaemorrhagic complications in 101 cases of myeloproliferative disorders: relationship to platelet number and function. Eur J Cancer Clin Oncol. 1983; 19:1593-9.
28. Rozman C, Giralt M, Feliu E, Rubio D, Cortes MT. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Cancer. 1991; 67:2658-63.
29. Reid CD, Chanarin I, Lewis J. Formes frustes in myeloproliferative disorders. Identification by the growth of an endogenous erythroid clone in vitro in patients with arterial vascular disease. Lancet. 1982; 1:14-5.
30. Barosi G, Buratti A, Costa A, Liberato LN, Balduini C, Cazzola M, et al. An atypical myeloproliferative disorder with high thrombotic risk and slow disease progression. Cancer. 1991; 68:2310-8.
31. Valla D, Casadevall N, Huisse MG, Tulliez M, Grange JD, Muller O, et al. Etiology of portal vein thrombosis in adults. A prospective evaluation of primary myeloproliferative disorders. Gastroenterology. 1988; 94:1063-9.
32. Drenou B, Le Prise PY, Poilane B, Bernard Griffiths I, Ghandour C, Fauchet R. Polycythaemia and portal vein thrombosis. Nouv Rev Fr Hematol. 1992; 34:399-403.
33. Cardin F, Graffeo M, McCormick PA, McIntyre N, Burroughs A. Adult idiopathic extrahepatic venous thrombosis. Importance of putative latent myeloproliferative disorders and comparison with cases with known etiology. Dig Dis Sci. 1992; 37:335-9.
34. Pagliuca A, Mufti GJ, Janossa-Tahernia M, Eridani S, Westwood NB, Thumpston J, et al. In vitro colony culture and chromosomal studies in hepatic portal vein thrombosis—possible evidence of an occult myeloproliferative state. Q J Med. 1990; 76:981-9.
35. Tossou H, Iglicki F, Casadevall N, Delamarre J, Dupas JL, Capron JP. Superior mesenteric vein thrombosis as a manifestation of a latent myeloproliferative disorder [Letter]. J Clin Gastroenterol. 1991; 13:597-8.
36. Valla D, Casadevall N, Lacombe C, Varet B, Goldwasser E, Franco D, et al. Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med. 1985; 103:329-34.
37. Teofili L, De Stefano V, Leone G, Micalizzi P, Iovino MS, Alfano G, et al. Hematological causes of venous thrombosis in young people: high incidence of myeloproliferative disorder as underlying disease in patients with splanchnic venous thrombosis. Thromb Haemost. 1992; 67:297-301.
38. Westwood N, Dudley JM, Sawyer B, Messinezy M, Pearson TC. Primary polycythaemia: diagnosis by non-conventional positive criteria. Eur J Haematol. 1993; 51:228-32.
39. Pearce JM, Chandrasekera CP, Ladusans EJ. Lacunar infarcts in polycythaemia with raised packed cell volumes. Br Med J (Clin Res Ed). 1983; 287:935-6.
40. Thomas DJ, Marshall J, Russell RW, Wetherley-Mein G, du Boulay GH, Pearson TC, et al. Effect of haematocrit on cerebral blood-flow in man. Lancet. 1977; 2:941-3.
41. Thomas DJ, du Boulay GH, Marshall J, Pearson TC, Ross Russell RW, Symon L, et al. Cerebral blood-flow in polycythaemia. Lancet. 1977; 2:161-3.
42. Pearson TC, Humprey PRD, Thomas DJ, Wetherly-Mein G. Hematocrit, blood viscosity, cerebral blood flow and vascular occlusion In: Lowe GD, Barbenel JC, Forbes CD, eds. Clinical Aspects of Blood Viscosity and Cell Deformability. Berlin: Springer-Verlag; 1981.
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