To the editor:

Controlled studies in polycythemia vera (PV) have demonstrated the value of aggressive phlebotomy, aspirin, and cytoreductive therapy in preventing thrombotic complications.1-3  In the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) prospective study of 1638 patients diagnosed by using criteria from the Polycythemia Vera Study Group, risk factors for all thromboses were age older than 65 years and prior thrombotic events.4  However, diagnosis criteria for PV have since undergone substantial revision in the World Health Organization system for disease classification, with special emphasis on bone marrow morphology and JAK2 mutational status.5  Accordingly, this study includes 1545 patients with strictly World Health Organization–defined PV who were diagnosed and followed up in 7 centers in Italy, Austria, and the United States that belong to the International Working Group for Myeloproliferative Neoplasms. The study was approved by the institutional review board at each institution. Objectives were to (1) describe the rate of thrombosis, (2) report the sites and frequency of recurrences after a first arterial or venous event, and (3) identify risk factors for arterial vs venous thrombosis.

The characteristics of the cohort recruited at diagnosis (Table 1) reflect the heterogeneity of epidemiologic and clinical features that are found in the routine clinical practice of diagnosing PV. Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) and 114 (7.4%) patients, respectively. The frequencies of arterial and venous thrombosis were lower than those recorded in the ECLAP study4  (27% and 11%, respectively) but comparable to those reported in the recent Cyto-PV study2  (arterial 17%, venous 12%). Major hemorrhage before or at diagnosis was reported in 4.5% of patients in this study vs 8% in ECLAP and 1.7% in Cyto-PV cohorts. The prevalence of hypertension, hyperlipidemia, diabetes, and tobacco use was similar to that reported in the ECLAP and Cyto-PV studies.

Table 1

Patients’ characteristics at diagnosis and during follow-up

Characteristic No. evaluable No. of patients 95% CI 
At diagnosis     
 Age, years 1545    
  Median  61  
  Range  18-95  
 Sex 1545    
  Male  760 49  
  Female  785 51  
 Hemoglobin, g/dL 1545    
  Median  18.4  
  Range  15.1-26.5  
 Hematocrit, % 1545    
  Median  55  
  Range  36-78  
 Leukocyte count, × 109/L 1545    
  Median  10.4  
  Range  3-171.6  
 Platelet count, × 109/L 1545    
  Median  466  
  Range  7-2370  
 JAK2V617F mutation 1268 1239 98  
 Pruritus 1349 485 36  
 Vasomotor symptoms 1412 403 29  
 Palpable spleen 1477 534 36  
 History of tobacco use 1301 206 16  
 History of diabetes 1149 97  
 History of hyperlipidemia 1073 196 18  
 History of hypertension 1388 638 46  
 Leukoerythroblastic smear 1056 63  
 Abnormal karyotype 631 77 12  
 Arterial thrombosis before/at diagnosis 1545 246 16  
   Acute myocardial infarction 1545 65  
  Stroke/transient ischemic attack 1545 138  
  Peripheral arterial thrombosis 1545 29  
  Other/unknown 1545 14  
 Venous thrombosis before/at diagnosis 1545 114  
   Deep vein thrombosis/pulmonary embolism 1545 78  
  Splanchnic thrombosis 1545 30  
  Other/unknown 1545  
 Major hemorrhage before/at diagnosis 572 24  
Follow-up     
 Years of follow-up 1545    
  Median  6.9  
  Range  0-39  
 Treatments     
  Cytoreductive therapy* 1545 1129 73  
  Aspirin therapy 1535 1281 84  
 Total thrombosis 1545 290 19  
  Incidence rate, % patients per year   2.62 2.34-2.94 
 Arterial thrombosis 1545 184 12  
  Incidence rate, % patients per year  1.59 1.38-1.84 
  Acute myocardial infarction 1545 35  
  Stroke/transient ischemic attack 1545 104  
  Peripheral arterial thrombosis 1545 34  
  Other/unknown 1545 11  
 Venous thrombosis 1545 137  
  Incidence rate, % patients per year   1.05 0.88-1.25 
   Deep vein thrombosis/pulmonary embolism 1545 88  
  Splanchnic thrombosis 1545 27  
  Other/unknown 1545 22  
 Fatal cardiovascular events 1545 51 15  
 Myelofibrosis/acute myeloid leukemia transformations 1545 174 11  
  Incidence rate, % patients per year   1.42 1.22-1.65 
 Death 1545 347 23  
  Incidence rate, % patients per year   2.74 2.46-3.04 
Characteristic No. evaluable No. of patients 95% CI 
At diagnosis     
 Age, years 1545    
  Median  61  
  Range  18-95  
 Sex 1545    
  Male  760 49  
  Female  785 51  
 Hemoglobin, g/dL 1545    
  Median  18.4  
  Range  15.1-26.5  
 Hematocrit, % 1545    
  Median  55  
  Range  36-78  
 Leukocyte count, × 109/L 1545    
  Median  10.4  
  Range  3-171.6  
 Platelet count, × 109/L 1545    
  Median  466  
  Range  7-2370  
 JAK2V617F mutation 1268 1239 98  
 Pruritus 1349 485 36  
 Vasomotor symptoms 1412 403 29  
 Palpable spleen 1477 534 36  
 History of tobacco use 1301 206 16  
 History of diabetes 1149 97  
 History of hyperlipidemia 1073 196 18  
 History of hypertension 1388 638 46  
 Leukoerythroblastic smear 1056 63  
 Abnormal karyotype 631 77 12  
 Arterial thrombosis before/at diagnosis 1545 246 16  
   Acute myocardial infarction 1545 65  
  Stroke/transient ischemic attack 1545 138  
  Peripheral arterial thrombosis 1545 29  
  Other/unknown 1545 14  
 Venous thrombosis before/at diagnosis 1545 114  
   Deep vein thrombosis/pulmonary embolism 1545 78  
  Splanchnic thrombosis 1545 30  
  Other/unknown 1545  
 Major hemorrhage before/at diagnosis 572 24  
Follow-up     
 Years of follow-up 1545    
  Median  6.9  
  Range  0-39  
 Treatments     
  Cytoreductive therapy* 1545 1129 73  
  Aspirin therapy 1535 1281 84  
 Total thrombosis 1545 290 19  
  Incidence rate, % patients per year   2.62 2.34-2.94 
 Arterial thrombosis 1545 184 12  
  Incidence rate, % patients per year  1.59 1.38-1.84 
  Acute myocardial infarction 1545 35  
  Stroke/transient ischemic attack 1545 104  
  Peripheral arterial thrombosis 1545 34  
  Other/unknown 1545 11  
 Venous thrombosis 1545 137  
  Incidence rate, % patients per year   1.05 0.88-1.25 
   Deep vein thrombosis/pulmonary embolism 1545 88  
  Splanchnic thrombosis 1545 27  
  Other/unknown 1545 22  
 Fatal cardiovascular events 1545 51 15  
 Myelofibrosis/acute myeloid leukemia transformations 1545 174 11  
  Incidence rate, % patients per year   1.42 1.22-1.65 
 Death 1545 347 23  
  Incidence rate, % patients per year   2.74 2.46-3.04 

CI, confidence interval.

*

Cytoreductive treatments included hydroxyurea, interferon, busulfan, pipobroman, 32P, anagrelide.

Median follow-up was 6.9 years, and treatment included aspirin (84%) and cytoreductive agents (73%), in addition to phlebotomy (Table 1). Postdiagnosis total major thrombosis rate was 2.62% patients per year, lower than that reported in the ECLAP trial (4.4% patients per year) but comparable to the rate in the Cyto-PV study (2.7% patients per year) in which management of cardiovascular risk factors was more intensive than in the ECLAP study.

Arterial or venous thrombosis occurred in 184 (12%; rate: 1.59% patients per year) and 137 (9%; rate: 1.05% patients per year) patients, respectively. In addition, in 75% of the patients, arterial events were associated with subsequent arterial events, and in the remaining 25%, they were associated with venous thrombosis including splanchnic vein events. Conversely, in patients with prior venous events, 61% had venous recurrences and 39% had arterial recurrences. In multivariable analysis, previous arterial event (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.2 to 2.4) and hypertension (HR, 1.6; 95% CI, 1.2 to 2.2) were significantly associated with subsequent arterial events whereas previous venous event (HR, 2.6; 95% CI, 1.5 to 4.4) and age ≥65 years (HR, 1.7; 95% CI, 1.2 to 2.5) were significant predictors of future venous thrombosis.

A potential limitation of our study is its retrospective design; however, the strength is the large sample size, the well-defined patient population, the evaluation at diagnosis, and the long follow-up period. The frequencies of events in our study were similar to those reported in the Cyto-PV2  study and generally lower than those reported in the ECLAP4  study. It is possible that this reflects a change of clinical epidemiology in contemporary PV patients, but note that these different studies are not necessarily comparable, although earlier diagnosis and treatment, improved management of cardiovascular risk factors, and more appropriate use of cytoreductive drugs, aspirin, and phlebotomy might have contributed to the improved outcome in this study. Regardless, such details are important to consider for future clinical trials in PV. Of note, patients with a prior venous thrombosis had a more frequent subsequent recurrence in the venous district but a proportion of them (39%) also experienced arterial events and vice versa. This finding may have practical implications and suggests antiplatelet therapy and anticoagulant therapy (vitamin K antagonists or direct factor X inhibitors) as the favorite choice to prevent arterial and venous thrombosis, respectively, but also suggests studies of antithrombotic drug combinations. In this regard, statins that are specifically targeted to prevent arterial thrombosis and also seem promising for reducing risk of venous thrombosis6  may be candidates to be tested in addition to recommended therapy. The concept of combination therapy is further supported by the fact that currently reported rates of recurrent thrombosis in PV have not improved that much over those reported in much earlier Polycythemia Vera Study Group studies.7 

Authorship

Acknowledgments: This work was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC-Milano) “Special Program Molecular Clinical Oncology 5x1000” to AIRC-Gruppo Italiano Malattie Mieloproliferative (T.B.).

Contribution: T.B. and A.T. designed the research, contributed patients, participated in data analysis and interpretation, and wrote the paper; A.C. performed statistical analysis; T.B., E.R., G.F., H.G., F.R., M.L.R., A.R., B.G., L.P., I.B., I.C., A.P., A.M.V., and A.T. contributed patients; and all authors read and approved the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Tiziano Barbui, Hematology and Research Foundation, Ospedale Papa Giovanni XXIII, Piazza OMS 1, 24127 Bergamo, Italy; e-mail: tbarbui@hpg23.it.

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