Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a “high risk” or “low risk”. Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies.

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are chronic myeloproliferative neoplasms (MPN) characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell. Their natural history is marked by thrombohemorrhagic complications and a propensity to transform into myelofibrosis and acute leukemia. The understanding of the MPN pathophysiology dramatically improved following the description of recurrent molecular abnormalities, mainly represented by the V617F mutation in JAK2 exon 14, which involves >95% of PV and ∼60% to 70% of ET and PMF patients.1,2 

The aim of this paper is to update the incidence and risk factors, the mechanisms of thrombogenesis, and the management recommendations of vascular complications in MPN.

In the largest epidemiologic study in PV, the European Collaboration on Low-dose Aspirin (ECLAP), cardiovascular mortality accounted for 41% of all deaths (1.5 deaths per 100 persons per year), mainly due to coronary heart disease (15% of all deaths), congestive heart failure (8%), nonhemorrhagic stroke (8%), and pulmonary embolism (8%). The cumulative rate of nonfatal thrombosis was 3.8 events per 100 persons per year, without a difference between arterial and venous thrombosis.3  In prospective studies in ET, the rate of fatal and nonfatal thrombotic events ranged from 2% to 4% patient-years4,5  and the incidence of arterial events was 2 to 3 times higher than that of venous events.4-6  These rates were observed both in patients with World Health Organization (WHO)-defined ET5,6  and in those defined by the Polycythemia Vera Study Group (PVSG) criteria, which also included cases of early/prefibrotic PMF.4,7  A serious complication typically associated with MPN is splanchnic vein thrombosis. In a large study of 1062 patients with Budd-Chiari syndrome and 855 patients with portal vein thrombosis, the prevalence of MPN was 40.9% and 31.5%, respectively.8  In addition to large vessel thrombosis, ET and PV patients may suffer from microcirculatory symptoms including vascular headaches, dizziness, visual disturbances, distal paresthesia, acrocyanosis, and erythromelalgia.9  In PMF, the prevalence of major thrombosis was assessed in 707 patients followed in 4 European institutions. By excluding thrombosis after splenectomy, the overall cumulative rate of cardiovascular death and nonfatal thrombotic complications was 2.23 events per 100 persons per year. No significant difference between nonfatal venous and arterial thrombosis was registered (0.76% and 0.86% patients per year, respectively). The relatively low thrombotic rate in PMF could depend on other competing events, such as acute leukemia development or other noncardiovascular major complications, including early death.10 

The pathogenesis of thrombosis in MPN patients is complex. Clinical factors (age, previous history of thrombotic events, obesity, hypertension, and hyperlipemia) as well as the increase in blood cell counts (ie, leukocytosis, erythrocytosis, and thrombocytosis) contribute to the increased risk of thrombosis to a different extent in these patients. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative but also qualitative changes that characterize the switch of these cells from a resting to a procoagulant phenotype (Figure 1). Prothrombotic features include the expression by blood cells of procoagulant and proteolytic properties, the secretion of inflammatory cytokines, and the expression of adhesion molecules. In addition to these mechanisms, prothrombotic changes occur in the normal vascular endothelium in response to the insults of inflammatory cytokines, hyperviscosity, and leukocyte-derived proteases (ie, elastase, cathepsin-G, and myeloperoxidase). Specifically, the upregulation of endothelial adhesion receptors favors the attachment of platelets, erythrocytes, and leukocytes to the vascular wall, with subsequent localization of clotting reactions and fibrin deposition. Therefore, a procoagulant background exists in MPN patients, who present with a hypercoagulable state, a subclinical condition demonstrated by the alterations of plasma thrombotic markers. Among these, the increased levels of circulating procoagulant microparticles (MPs) and the occurrence of an acquired activated protein C (APC) resistance are the most prominent features of hypercoagulability in these subjects.

Figure 1

Pathogenesis of thrombophilia in MPN. The pathogenesis of the acquired thrombophilic state in ET and PV is multifaceted. Mechanisms involved in the pathogenesis of the acquired thrombophilic state associated with these diseases include abnormalities of MPN-clone–derived blood cells (ie, erythrocytes, platelets, and leukocytes), which display prothrombotic features, and abnormalities of normal vascular cells, which become procoagulant in response to inflammatory stimuli. Once activated, neutrophils can also affect the hemostatic system through different pathways. In particular, the release of proteolytic enzymes and of reactive oxygen species can activate or damage platelets and endothelial cells and impair some coagulation proteins. Activated platelets express P-selectin and tissue factor (TF) and release MPs. The increased expression of CD11b on the neutrophil surface allows the adhesion of neutrophils to endothelial cells and platelets and the assembly of coagulation proteases on the neutrophil surface. In addition, abnormalities in red blood cells (RBC), including biochemical changes in the cell membrane and content, may independently impair blood flow also through the formation of RBC aggregates. Furthermore, RBC aggregation facilitates the platelet and leukocyte interaction with the vessel wall.

Figure 1

Pathogenesis of thrombophilia in MPN. The pathogenesis of the acquired thrombophilic state in ET and PV is multifaceted. Mechanisms involved in the pathogenesis of the acquired thrombophilic state associated with these diseases include abnormalities of MPN-clone–derived blood cells (ie, erythrocytes, platelets, and leukocytes), which display prothrombotic features, and abnormalities of normal vascular cells, which become procoagulant in response to inflammatory stimuli. Once activated, neutrophils can also affect the hemostatic system through different pathways. In particular, the release of proteolytic enzymes and of reactive oxygen species can activate or damage platelets and endothelial cells and impair some coagulation proteins. Activated platelets express P-selectin and tissue factor (TF) and release MPs. The increased expression of CD11b on the neutrophil surface allows the adhesion of neutrophils to endothelial cells and platelets and the assembly of coagulation proteases on the neutrophil surface. In addition, abnormalities in red blood cells (RBC), including biochemical changes in the cell membrane and content, may independently impair blood flow also through the formation of RBC aggregates. Furthermore, RBC aggregation facilitates the platelet and leukocyte interaction with the vessel wall.

Close modal

Principal hemostatic abnormalities of MPN blood and vascular cells

Platelets

In the past, reduced levels of membrane adhesion molecules, acquired storage pool disease, and defective platelet metabolism were reported.11  However, more recent studies show that platelets from MPN patients circulate in an activated status, as assessed by the detection of increased expression of surface P-selectin and tissue factor12-14  and by the increased fraction of platelets phagocytosed by circulating neutrophils and monocytes.15  An enhanced in vivo platelet activation is further suggested by the finding of increased levels of platelet activation products both in the plasma (ie, β-thromboglobulin and platelet factor 4) and urine (ie, thromboxane A2 metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2).16  The early findings of some platelet function defects in ET are possibly due to the platelet overtiredness and to the dilution technique of platelet-rich plasma needed for some aggregation assays.17  Activated platelets provide a catalytic surface for the generation of thrombin, which further amplifies their own activation. Accordingly, in ET and PV patients, the thrombin generation induced by platelets was recently found to be increased and associated with platelet activation, particularly in carriers of the JAK2V617F mutation.18  Furthermore, immature platelets, the newly formed platelets (reticulated platelets) that show a higher hemostatic activity,19  are more elevated and more reactive than their mature counterparts both in PV and ET patients20  and positively correlate with the presence of the JAK2V617F mutation.20 

Red blood cells

The prothrombotic mechanisms of an elevated hematocrit (HCT) have been clearly demonstrated in PV.21  An elevated HCT level can increase the thrombotic risk by multiple pathways (Figure 2). Under the low shear rates, as in the venous bed, a major thrombotic role is played by hyperviscosity, while at high shear rates, the raise of red cell mass displaces platelets toward the vessel wall, thus facilitating shear-induced platelet activation and enhancing platelet–platelet interactions. In addition, in ET and PV, biochemical changes have been reported in the cell membrane and intracellular content of red blood cells leading to the formation of red blood cell aggregates and impaired blood flow.22  Recently, in PV patients, an abnormal adhesion of red blood cells to the subendothelial protein laminin, due to the phosphorylation of Lu/BCAM by a JAK2V617F pathway, has been shown.23 

Figure 2

The prothrombotic effect of an elevated HCT in ET and PV patients. Elevated HCT can increase the thrombotic risk by multiple mechanisms: (1) it determines an increase in blood viscosity; (2) at high shear rates, the raise of red cell mass displaces platelets toward the vessel wall, thus facilitating shear-induced platelet activation and enhancing platelet–platelet interactions; (3) under the low shear rates, as in the venous bed, hyperviscosity can increase the thrombotic risk by causing a major disturbance to the blood flow; and (4) biochemical changes in cell membrane and intracellular content of red blood cells.

Figure 2

The prothrombotic effect of an elevated HCT in ET and PV patients. Elevated HCT can increase the thrombotic risk by multiple mechanisms: (1) it determines an increase in blood viscosity; (2) at high shear rates, the raise of red cell mass displaces platelets toward the vessel wall, thus facilitating shear-induced platelet activation and enhancing platelet–platelet interactions; (3) under the low shear rates, as in the venous bed, hyperviscosity can increase the thrombotic risk by causing a major disturbance to the blood flow; and (4) biochemical changes in cell membrane and intracellular content of red blood cells.

Close modal

Leukocytes

Neutrophils, the most abundant proportion of leukocytes, have a central role in the inflammatory response and in the activation of the blood coagulation system.24  In particular, the release of proteolytic enzymes (ie, elastase and cathepsin G) and reactive oxygen species and the increased expression of CD11b on their surface can activate or damage platelets and endothelial cells and impair some coagulation proteins.25  In patients with ET and PV, the occurrence of neutrophil activation is demonstrated by the detection of specific phenotypic changes (increment in membrane-associated CD11b) and increased plasma concentration of granule-derived proteases (ie, elastase and myeloperoxidase).12,26  The adhesion of platelets to leukocytes and the formation of platelet–leukocyte aggregates mediate the crosstalk among platelets, neutrophils, and monocytes.27  Data suggest that aspirin may inhibit the interaction between neutrophils and platelets.12 

Endothelial cells

Several factors may perturb the physiological state of endothelium in MPN patients and turn it into a proadhesive and procoagulant surface. In particular, reactive oxygen species and intracellular proteases released by activated neutrophils can induce detachment or lysis of endothelial cells affecting functions involved in thromboregulation.27  High levels of circulating endothelial cells (resting, activated, apoptotic, and circulating precursor endothelial cells) are measured in MPN.28-30  In addition, high circulating levels of endothelial activation markers, such as thrombomodulin, selectins, and von Willebrand factor, are released and favor the formation of cellular aggregates.14,31,32  Finally, the decrease in endogenous nitric oxide production, a physiologic negative-feedback mechanism for thrombus propagation, vascular hemodynamics, and interactions of leukocytes and platelets with endothelial cells, further contributes to the procoagulant scenario.32 

Plasma prothrombotic features

The increased count and/or activation status of blood and vascular cells is likely the basis of the hypercoagulable state of MPN patients, characterized by high concentrations of plasma markers of blood clotting (ie, thrombin-antithrombin complex, prothrombin fragment 1 + 2, and d-dimer) and vascular endothelium activation (ie, thrombomodulin and von Willebrand factor/factor VIII).27  In some instances, these plasma abnormalities correlate well with features of blood cell activation.26  More recently, the findings of incremented circulating MPs, shed by blood cells, and the presence of an acquired resistance to APC, have provided 2 important tools to detect the prothrombotic state in MPN patients, although the role of these and other prothrombotic markers in predicting thrombosis in MPN patients is still undefined.

MPs are membrane fragments released upon activation by all blood cell types (particularly platelets) and endothelial cells and are considered one of the major player in thrombus formation in vivo. They are found elevated in thrombotic diseases and malignancies,33  including patients with MPN.34  In particular, MPs from patients with ET show a high thrombin generation potential. Finally, circulating MPs determine the occurrence of an acquired “thrombomodulin-resistant” phenotype in PV and ET patients.35  The inherited as well as the acquired APC resistance is associated with an increased risk of thrombosis in many conditions (ie, pregnancy, oral contraceptive use, hormone replacement therapy, and cancer) and in MPN can be determined by decreased levels of protein C and protein S.36  By using the thrombin generation assay, an APC resistance phenotype has been demonstrated in ET and PV patients, particularly in JAK2V617F mutation carriers.37  Acquired APC resistance was more frequently found in ET patients with a history of thrombosis.38  A decrease in the free PS level seems to be the major determinant of APC resistance and can be due to the PS cleavage by a protease from platelets.39  Protein S cleavage was indeed significantly increased in patients with ET and an elevated platelet count and returned to normal values in ET subjects receiving hydroxyurea (HU) treatment and with a normal platelet count.40  The results of several studies13,14,41,42  support the evidence that all hemostatic alterations are worse in JAK2V617F mutation carriers than in the wild-type MPN population. However, the role of these biomarkers in identifying MPN patients at higher risk of thrombosis remains to be established. Prospective studies to evaluate this role are warranted to incorporate these markers in the decision-making risk-assessment scores.

Age and previous thrombosis

Increasing age and a history of thrombosis have consistently proven to be independent predictors of future events in PV, ET, and PMF. In the ECLAP study, the incidence of cardiovascular complications was higher in PV patients >65 years (5.0% patient-years; P < .006) or with a history of thrombosis (4.93% patient-years; P = .0017) than in younger subjects with no history of thrombosis (2.5% patient-years).3  In 891 ET patients diagnosed according to the WHO criteria, age >60 years and previous thrombosis were respectively associated with a 1.5 and 1.93 hazard ratio (HR) to develop major thrombosis during a median follow-up of 6.2 years.6 

Blood cell counts

A predominant increase of red cell count characterizes the PV hematologic phenotype, and the consequent blood hyperviscosity is a major cause of vascular disturbances that severely impact on morbidity and mortality.43  At variance, no study has demonstrated a significant correlation between platelet number or function and thrombosis in PV and ET. In the ECLAP study, neither the currently proposed therapeutic target of 400 × 109/L nor any of the other platelet-count thresholds evaluated predicted a higher risk of thrombosis.44  In the prospective Primary Thrombocythemia-1 (PT-1) trial, longitudinal blood counts in ET patients treated with aspirin showed a significant association of thrombosis with leucocytosis but not with platelet count. Instead, the risk of major hemorrhage significantly increased (HR = 3.7) during the time periods in which platelet counts were above the normal range (>450 × 109/L) as opposed to those in which platelets were within normal limits. The hemorrhagic risk was approximately 10-fold increased when platelets were >1250 × 109/L.45  These findings suggest that current treatment should not primarily aim at lowering the platelet count for thrombosis prevention. However, platelet-lowering drugs should be considered at platelet counts >1500 × 109/L to reduce the risk of bleeding.46 

Leukocytosis was found to be an independent risk factor for arterial thrombosis in MPN.47  PV patients with a white blood cell (WBC) count >15 × 109/L, compared with those with a WBC count <15 × 109/L, had a significant 70% increase of myocardial infarction.48  Three large-cohort studies in ET reported that an increased baseline leukocyte count was an independent risk factor for both thrombosis and inferior survival.49-51  An elevated WBC count developing during follow-up was also correlated with major thrombosis (P < .05) and major hemorrhage (P < .01).45,52  Based on these data, an expert consensus conference indicated that one aim of cytoreduction in ET and PV should be to keep the WBC count within the normal range,46  although this assumption remains to be confirmed in randomized clinical trials. Interestingly, as in PV, the prognostic role of WBC count in ET was mostly observed on the occurrence of arterial thrombosis.6  These findings link WBC and their activation and inflammation in the pathogenesis of thrombosis. This relation was recently demonstrated in PV and ET by the constitutive elevation of the inflammatory biomarkers C-reactive protein and pentraxin-3 and their correlation with JAK2V617F allele burden.53 

Other risk factors

Conventional risk factors for atherosclerosis, including hypertension, hyperlipidemia, diabetes, and smoking, have been assessed in multivariable analysis in MPN with variable results.54,55  Some authors suggested that the presence of these conditions can upgrade the low-risk patients with ET to an intermediate-risk or an high-risk category.4,55  In the recently developed “IPSET-thrombosis” score (see below),55  cardiovascular risk factors were among the variables significantly and independently associated with an increased rate of total thrombosis in ET patients.

The influence of the JAK2V617F mutational status and allele burden on the thrombotic risk has been evaluated in several studies. In 173 patients with PV, those harboring greater than 75% JAK2 V617F allele were at higher relative risk (RR) to develop major cardiovascular events during follow-up than were those with <25% mutant allele (RR = 7.1; P = .003).56  In ET, a systematic literature review showed that JAK2 V617F patients have a 2-fold risk of developing thrombosis (odds ratio [OR] = 1.92; 95% confidence interval [CI], 1.45–2.53) both of venous and arterial vessels (OR = 2.49 and 1.77 respectively), but a significant heterogeneity between studies should be pointed out.57  In PMF, the highest incidence of fatal and nonfatal thrombosis was observed when the mutation was present along with leukocytosis (3.9% patient-years; HR = 3.13; 95% CI, 1.26–7.81).10  A high frequency of JAK2V617F was reported in splanchnic vein thrombosis,8  and, interestingly, patients who were JAK2V617F negative were found to harbor JAK2 46/1 haplotype.58  These findings and the identification of JAK2V617F mutation in the liver and spleen endothelial cells of patients with Budd-Chiari syndrome59,60  may suggest a perturbance of endothelium mediated by the mutation with a consequent and possibly local prothrombotic state contributing to the pathogenesis of thrombosis. As to the presence of an MPL mutation, higher rates of arterial thrombosis were found in an Italian study61  but not in the PT-1 trial cohort.62 

Instead, in this latter trial, an increased bone marrow reticulin fibrosis was an independent predictor of subsequent thrombotic and hemorrhagic complications.7  This finding was confirmed by other studies showing an increased risk of both bleeding63  and thrombosis64  in patients with early myelofibrosis vs those with ET defined according to the WHO classification.

The frequency of genetic thrombophilic factors, such as factor V Leiden or prothrombin mutations, was higher in MPN with venous thrombosis, suggesting that these tests should be performed in younger patients with a familial or personal history of thrombosis.65-67  On the contrary, in regard to the role of antiphospholipid antibodies68,69  and hyperhomocysteinemia,70,71  data so far produced are too limited to recommend their evaluation in the work-up of patients with MPN.

By incorporating this body of knowledge into a simple, clinically oriented scheme (Table 1), the classification of patients with either PV or ET into a “high-risk” or “low-risk” category according to their age and history of thrombosis is currently recommended.46  More recently, an International Prognostic Score of thrombosis has been developed in WHO-diagnosed ET (IPSET-thrombosis).55  Risk scores were assigned based on multivariable-analysis–derived HRs to age >60 years (HR = 1.5, 1 point), thrombosis history (HR = 1.9, 2 points), cardiovascular risk factors (HR = 1.6, 1 point), and JAK2V617F (HR = 2.0, 2 points). Subsequently, a 3-tiered prognostic model (low-risk, <2 points; intermediate risk, 2 points; and high-risk, >2 points) was devised, allowing a clear identification of the thrombotic risk: 1.03% patient-years vs 2.35% patient-years vs 3.56% patient-years in the 3 groups, respectively. This validated IPSET-thrombosis model may provide objective estimates of the probability of thrombotic events in patients with newly diagnosed ET that can be useful for future prospective clinical studies.

Table 1

Risk stratification in PV and ET based on thrombotic risk

Risk categoryAge >60 y or history of thrombosis
Low No 
High Yes 
Risk categoryAge >60 y or history of thrombosis
Low No 
High Yes 

Extreme thrombocytosis (platelet count >1500 × 109/L) is a risk factor for bleeding, not for thrombosis. Both increasing leukocyte count and JAK2 V617F mutation or allele burden have been identified as novel risk factors for thrombosis, but confirmation is required.

Table 2

Flow chart of the recommended treatment for patients with PV

Flow chart of the recommended treatment for patients with PV
Flow chart of the recommended treatment for patients with PV
Table 3

Flow chart of the recommended treatment for patients with ET

Flow chart of the recommended treatment for patients with ET
Flow chart of the recommended treatment for patients with ET

Based on such risk stratification, the potential dangers of cytoreductive therapy with the intent of preventing thrombotic complications may be justified only in high-risk patients.46 

Interventions on lifestyle

The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in MPN, as in the general population, should be considered a cornerstone of vascular prevention.

Phlebotomy

Phlebotomy (Table 2) is the recommended main tool to control HCT in PV patients. The optimal target of HCT levels for reducing vascular events was a matter of debate.44,72  In a recent large-scale, multicenter, randomized clinical trial (Cyto-PV), 365 JAK2V617F PV patients were assigned to receive either more intensive therapy to maintain an HCT target of <45% or a less intensive treatment with an HCT target of 45% to 50%. After a median follow-up of 31 months, the primary end point of cardiovascular death and major thrombosis was recorded in 5 of 182 patients in the low-HCT group (2.7%) and in 18 of 183 patients in the high-HCT group (9.8%) (HR in the high-HCT group = 3.91; P = .007). This study demonstrates that high HCT is associated with a 4 times higher rate of thrombotic events and supports the importance of the strict control of HCT levels to prevent thrombosis in PV.43 

Low-dose aspirin

The efficacy and safety of low-dose aspirin (100 mg daily) in PV has been assessed in the ECLAP double-blind, placebo-controlled, randomized clinical trial.73  In this study, 532 PV patients were randomized to receive 100 mg aspirin or placebo. After a follow-up of about 3 years, data analysis showed a significant reduction of a primary combined end point, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and major venous thromboembolism (RR = 0.4; 95% CI, 0.18-0.91; P = .0277).

In ET (Table 3), the efficacy of aspirin has not been tested in randomized clinical trials. Low-dose aspirin (100 mg daily) controls microvascular symptoms, such as erythromelalgia and transient neurologic and ocular disturbances. A retrospective study74  has suggested that antiplatelet therapy reduces the incidence of venous thrombosis in JAK2-positive patients and the rate of arterial thrombosis in patients with associated cardiovascular risk factors. In regard to bleeding, the annual incidence of major hemorrhages attributed to aspirin in PV and ET ranges between 0.3% and 0.8%, and this rate is higher in ET patients presenting with prefibrotic myelofibrosis (1.39% patient-years), suggesting that major bleeding might be relatively specific to this entity as opposed to WHO-defined ET (0.79% patient-years).63  Interestingly, a recent study has shown that the effect of once-daily low-dose aspirin in ET is shorter-lasting through faster renewal of platelet cyclooxygenase-1 and suggests that impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose.75  This new concept deserves to be validated in prospective studies, but prescribing low-dose aspirin twice daily to prevent severe arterial thrombotic recurrence in MPN is now suggested.76 

Hydroxyurea

HU is an antimetabolite that prevents DNA synthesis and was introduced in the therapy of PV and ET to reduce thrombosis by the PVSG investigators, who assumed this drug was not leukemogenic.77  In the unique randomized trial comparing HU with another cytoreductive drug in PV, the cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) at 10, 15, and 20 years was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm, respectively (P = .004).78  Other studies from registry data and prospective analysis failed to attribute a clear leukemogenic risk to HU.79-81  Overall, the bulk of evidence does not attribute a definite leukemogenic risk of HU, but it should be emphasized that this risk may appear after a long-term exposure to this drug. It is wise to adopt a cautionary principle and to consider carefully the use of this agent in young subjects and in those previously treated with other myelosuppressive agents or carrying cytogenetic abnormalities.

The antithrombotic efficacy of this drug in ET was demonstrated in a seminal randomized clinical trial54  showing that HU reduced the rate of thrombotic events mainly represented by cerebral transient ischemic attacks. Interestingly, HU antithrombotic effect may recognize additional mechanisms of action besides pan myelosuppression, including qualitative changes in leukocytes, decreased expression of endothelial adhesion molecules, and enhanced nitric oxide generation.82 

IFN-α

Interferon α (IFN-α) was considered for the treatment of patients with MPN because this agent suppresses the proliferation of hematopoietic progenitors, has a direct inhibiting effect on bone marrow fibroblast progenitor cells, and antagonizes the action of platelet-derived growth factor, transforming growth factor-β, and other cytokines that may be involved in the development of myelofibrosis.83  Two phase 2 studies have shown that pegylated IFN-α 2a therapy led to a high rate of hematologic response and reduced the malignant clone as quantitated by the percentage of the mutated allele JAK2V617F.84,85  In contrast, more limited effects on JAK2 mutational status have been reported after therapy with pegylated IFN-α 2b in a small group of patients with PV and ET.86  The tolerability of pegylated IFN-α 2a at 90 μg weekly was excellent. However, whether this drug is more efficacious than HU in reducing the rate of vascular events remains to be demonstrated in the clinical trials that currently are underway.

Anagrelide

Anagrelide, an imidazoquinazolin compound, has a potent platelet-reducing activity devoid of leukemogenic potential and appears to be an alternative to HU for reducing platelet counts in younger ET patients at high risk of thrombosis and resistant to or intolerant of HU.46  Anagrelide and HU have been compared head to head in 2 randomized clinical trials. The first (PT-1) included 809 ET patients diagnosed according to PVSG criteria and treated with aspirin (100 mg/d).4  Compared with HU, patients in the anagrelide arm showed an increased rate of arterial thrombosis (OR = 2.16; P = .03), major bleeding (OR = 2.61; P = .008), and myelofibrotic transformation (OR = 2.92; P = .01) but a decreased incidence of venous thrombosis (OR = 0.27; P = .006). In the ANAHYDRET (Anagrelide vs Hydroxyurea Efficacy and Tolerability Study in Patients with Essential Thrombocythaemia) noninferiority randomized clinical trial, 259 previously untreated, high-risk WHO-diagnosed ET patients were randomized to HU and anagrelide.5  During the total observation time of 730 patient-years, there was no significant difference between the anagrelide and HU groups regarding incidences of major arterial (7 vs 8) and venous (2 vs 6) thrombosis and severe bleeding events (5 vs 2). Disease transformation into myelofibrosis or secondary leukemia was not reported. According to the ELN, anagrelide is currently recommended as a second-line therapy in high-risk ET patients resistant to or intolerant of HU.46 

In the largest study that specifically analyzed the incidence of recurrent thrombosis after the first episode,87  thrombosis recurred in 166 of 494 (34%) PV and ET patients, corresponding to 7.6% patient-years. Sex, diagnosis (PV or ET), and presence of vascular risk factors did not predict recurrence, whereas age >60 years did (multivariable HR = 1.67; 95% CI, 1.19-2.32). In this retrospective analysis, the use of a cytoreductive drug together with an antiplatelet agent reduced the risk of recurrence in comparison with both cytoreduction alone (univariate HR = 0.56; 95% CI, 0.24-0.85) and antiplatelet agents alone (univariate HR = 0.67; 95% CI, 0.41-0.99). After the first venous thromboembolic event, long-term oral anticoagulation was associated with a 63% reduction in the risk of recurrence without a significant increase of the incidence of major bleeding (0.9% patient-years) as compared with patients without antithrombotic treatment (1.2% patient-years).

Current recommendations for the management of MPN should take into consideration the advent of new-generation drugs with JAK2 inhibitory activity. These agents have been found to be effective for the treatment of disease-related splenomegaly or symptoms in adult patients with myelofibrosis. However, no data are available so far on the efficacy of preventing thrombotic complications, which remains the primary goal of therapy in PV and ET.

This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (Milano, “Special Program Molecular Clinical Oncology 5x1000” to the AIRC287 Gruppo Italiano Malattie Mieloproliferative, project #1005) (T.B. and G.F.) and by grants from the Italian Association for Cancer Research (AIRC grants IG10558 and “5 per mille” 12237) (A.F.).

Contribution: All authors contributed equally to the manuscript, and each author read and approved the final draft.

Conflict-of-interest disclosure: Dr Barbui reports receiving consulting fees from Shire, Novartis, and Italfarmaco. The remaining authors declare no competing financial interests.

Correspondence: Tiziano Barbui, Research Foundation, Ospedale Papa Giovanni XXIII, P.zza OMS, 1, 24127 Bergamo (Bg) Italy; e-mail: [email protected].

1
Tefferi
 
A
Vainchenker
 
W
Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies.
J Clin Oncol
2011
, vol. 
29
 
5
(pg. 
573
-
582
)
2
Cross
 
NC
Genetic and epigenetic complexity in myeloproliferative neoplasms.
Hematology (Am Soc Hematol Educ Program)
2011
, vol. 
2011
 (pg. 
208
-
214
)
3
Marchioli
 
R
Finazzi
 
G
Landolfi
 
R
et al. 
Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.
J Clin Oncol
2005
, vol. 
23
 
10
(pg. 
2224
-
2232
)
4
Harrison
 
CN
Campbell
 
PJ
Buck
 
G
et al. 
United Kingdom Medical Research Council Primary Thrombocythemia 1 Study
Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.
N Engl J Med
2005
, vol. 
353
 
1
(pg. 
33
-
45
)
5
Gisslinger
 
H
Gotic
 
M
Holowiecki
 
J
et al. 
ANAHYDRET Study Group
Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial.
Blood
2013
, vol. 
121
 
10
(pg. 
1720
-
1728
)
6
Carobbio
 
A
Thiele
 
J
Passamonti
 
F
et al. 
Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients.
Blood
2011
, vol. 
117
 
22
(pg. 
5857
-
5859
)
7
Campbell
 
PJ
Bareford
 
D
Erber
 
WN
et al. 
Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy.
J Clin Oncol
2009
, vol. 
27
 
18
(pg. 
2991
-
2999
)
8
Smalberg
 
JH
Arends
 
LR
Valla
 
DC
Kiladjian
 
JJ
Janssen
 
HL
Leebeek
 
FW
Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.
Blood
2012
, vol. 
120
 
25
(pg. 
4921
-
4928
)
9
Elliott
 
MA
Tefferi
 
A
Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia.
Br J Haematol
2005
, vol. 
128
 
3
(pg. 
275
-
290
)
10
Barbui
 
T
Carobbio
 
A
Cervantes
 
F
et al. 
Thrombosis in primary myelofibrosis: incidence and risk factors.
Blood
2010
, vol. 
115
 
4
(pg. 
778
-
782
)
11
Landolfi
 
R
Rocca
 
B
Patrono
 
C
Bleeding and thrombosis in myeloproliferative disorders: mechanisms and treatment.
Crit Rev Oncol Hematol
1995
, vol. 
20
 
3
(pg. 
203
-
222
)
12
Falanga
 
A
Marchetti
 
M
Vignoli
 
A
Balducci
 
D
Barbui
 
T
Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera.
Exp Hematol
2005
, vol. 
33
 
5
(pg. 
523
-
530
)
13
Arellano-Rodrigo
 
E
Alvarez-Larrán
 
A
Reverter
 
JC
Villamor
 
N
Colomer
 
D
Cervantes
 
F
Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status.
Haematologica
2006
, vol. 
91
 
2
(pg. 
169
-
175
)
14
Falanga
 
A
Marchetti
 
M
Vignoli
 
A
Balducci
 
D
Russo
 
L
Guerini
 
V
Barbui
 
T
V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules.
Exp Hematol
2007
, vol. 
35
 
5
(pg. 
702
-
711
)
15
Maugeri
 
N
Malato
 
S
Femia
 
EA
et al. 
Clearance of circulating activated platelets in polycythemia vera and essential thrombocythemia.
Blood
2011
, vol. 
118
 
12
(pg. 
3359
-
3366
)
16
Jensen
 
MK
de Nully Brown
 
P
Lund
 
BV
Nielsen
 
OJ
Hasselbalch
 
HC
Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders.
Br J Haematol
2000
, vol. 
110
 
1
(pg. 
116
-
124
)
17
Grignani
 
C
Noris
 
P
Tinelli
 
C
Barosi
 
G
Balduini
 
CL
In vitro platelet aggregation defects in patients with myeloproliferative disorders and high platelet counts: are they laboratory artefacts?
Platelets
2009
, vol. 
20
 
2
(pg. 
131
-
134
)
18
Panova-Noeva
 
M
Marchetti
 
M
Spronk
 
HM
et al. 
Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera.
Am J Hematol
2011
, vol. 
86
 
4
(pg. 
337
-
342
)
19
Harrison
 
P
Robinson
 
MS
Mackie
 
IJ
Machin
 
SJ
Reticulated platelets.
Platelets
1997
, vol. 
8
 
6
(pg. 
379
-
383
)
20
Panova-Noeva
 
M
Marchetti
 
M
Buoro
 
S
et al. 
JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients.
Blood
2011
, vol. 
118
 
9
(pg. 
2599
-
2601
)
21
Adams
 
BD
Baker
 
R
Lopez
 
JA
Spencer
 
S
Myeloproliferative disorders and the hyperviscosity syndrome.
Hematol Oncol Clin North Am
2010
, vol. 
24
 
3
(pg. 
585
-
602
)
22
Turitto
 
VT
Weiss
 
HJ
Red blood cells: their dual role in thrombus formation.
Science
1980
, vol. 
207
 
4430
(pg. 
541
-
543
)
23
De Grandis
 
M
Cambot
 
M
Wautier
 
MP
et al. 
JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway.
Blood
2013
, vol. 
121
 
4
(pg. 
658
-
665
)
24
Falanga
 
A
Marchetti
 
M
Barbui
 
T
Smith
 
CW
Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils.
Semin Hematol
2005
, vol. 
42
 
4
(pg. 
239
-
247
)
25
Afshar-Kharghan
 
V
Thiagarajan
 
P
Leukocyte adhesion and thrombosis.
Curr Opin Hematol
2006
, vol. 
13
 
1
(pg. 
34
-
39
)
26
Falanga
 
A
Marchetti
 
M
Evangelista
 
V
et al. 
Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera.
Blood
2000
, vol. 
96
 
13
(pg. 
4261
-
4266
)
27
Marchetti
 
M
Falanga
 
A
Leukocytosis, JAK2V617F mutation, and hemostasis in myeloproliferative disorders.
Pathophysiol Haemost Thromb
2008
, vol. 
36
 
3-4
(pg. 
148
-
159
)
28
Treliński
 
J
Wierzbowska
 
A
Krawczyńska
 
A
et al. 
Plasma levels of angiogenic factors and circulating endothelial cells in essential thrombocythemia: correlation with cytoreductive therapy and JAK2-V617F mutational status.
Leuk Lymphoma
2010
, vol. 
51
 
9
(pg. 
1727
-
1733
)
29
Belotti
 
A
Elli
 
E
Speranza
 
T
Lanzi
 
E
Pioltelli
 
P
Pogliani
 
E
Circulating endothelial cells and endothelial activation in essential thrombocythemia: results from CD146+ immunomagnetic enrichment—flow cytometry and soluble E-selectin detection.
Am J Hematol
2012
, vol. 
87
 
3
(pg. 
319
-
320
)
30
Alonci
 
A
Allegra
 
A
Bellomo
 
G
Penna
 
G
D’Angelo
 
A
Quartarone
 
E
Musolino
 
C
Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases.
Hematol Oncol
2008
, vol. 
26
 
4
(pg. 
235
-
239
)
31
Friedenberg
 
WR
Roberts
 
RC
David
 
DE
Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative disorders.
Am J Hematol
1992
, vol. 
40
 
4
(pg. 
283
-
289
)
32
Cella
 
G
Marchetti
 
M
Vianello
 
F
et al. 
Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms.
Thromb Haemost
2010
, vol. 
104
 
1
(pg. 
151
-
156
)
33
Zwicker
 
JI
Liebman
 
HA
Neuberg
 
D
Lacroix
 
R
Bauer
 
KA
Furie
 
BC
Furie
 
B
Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy.
Clin Cancer Res
2009
, vol. 
15
 
22
(pg. 
6830
-
6840
)
34
Trappenburg
 
MC
van Schilfgaarde
 
M
Marchetti
 
M
et al. 
Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia.
Haematologica
2009
, vol. 
94
 
7
(pg. 
911
-
918
)
35
Duchemin
 
J
Ugo
 
V
Ianotto
 
JC
Lecucq
 
L
Mercier
 
B
Abgrall
 
JF
Increased circulating procoagulant activity and thrombin generation in patients with myeloproliferative neoplasms.
Thromb Res
2010
, vol. 
126
 
3
(pg. 
238
-
242
)
36
Bucalossi
 
A
Marotta
 
G
Bigazzi
 
C
Galieni
 
P
Dispensa
 
E
Reduction of antithrombin III, protein C, and protein S levels and activated protein C resistance in polycythemia vera and essential thrombocythemia patients with thrombosis.
Am J Hematol
1996
, vol. 
52
 
1
(pg. 
14
-
20
)
37
Marchetti
 
M
Castoldi
 
E
Spronk
 
HM
et al. 
Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera.
Blood
2008
, vol. 
112
 
10
(pg. 
4061
-
4068
)
38
Arellano-Rodrigo
 
E
Alvarez-Larrán
 
A
Reverter
 
JC
Colomer
 
D
Villamor
 
N
Bellosillo
 
B
Cervantes
 
F
Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: relationship with thrombosis occurrence and JAK2 V617F allele burden.
Am J Hematol
2009
, vol. 
84
 
2
(pg. 
102
-
108
)
39
Brinkman
 
HJ
Mertens
 
K
van Mourik
 
JA
Proteolytic cleavage of protein S during the hemostatic response.
J Thromb Haemost
2005
, vol. 
3
 
12
(pg. 
2712
-
2720
)
40
Dienava-Verdoold
 
I
Marchetti
 
MR
te Boome
 
LC
et al. 
Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies.
Thromb Haemost
2012
, vol. 
107
 
3
(pg. 
468
-
476
)
41
Robertson
 
B
Urquhart
 
C
Ford
 
I
Townend
 
J
Watson
 
HG
Vickers
 
MA
Greaves
 
M
Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies.
J Thromb Haemost
2007
, vol. 
5
 
8
(pg. 
1679
-
1685
)
42
Alvarez-Larrán
 
A
Arellano-Rodrigo
 
E
Reverter
 
JC
Domingo
 
A
Villamor
 
N
Colomer
 
D
Cervantes
 
F
Increased platelet, leukocyte, and coagulation activation in primary myelofibrosis.
Ann Hematol
2008
, vol. 
87
 
4
(pg. 
269
-
276
)
43
Marchioli
 
R
Finazzi
 
G
Specchia
 
G
et al. 
CYTO-PV Collaborative Group
Cardiovascular events and intensity of treatment in polycythemia vera.
N Engl J Med
2013
, vol. 
368
 
1
(pg. 
22
-
33
)
44
Di Nisio
 
M
Barbui
 
T
Di Gennaro
 
L
et al. 
European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Investigators
The haematocrit and platelet target in polycythemia vera.
Br J Haematol
2007
, vol. 
136
 
2
(pg. 
249
-
259
)
45
Campbell
 
PJ
MacLean
 
C
Beer
 
PA
et al. 
Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort.
Blood
2012
, vol. 
120
 
7
(pg. 
1409
-
1411
)
46
Barbui
 
T
Barosi
 
G
Birgegard
 
G
et al. 
European LeukemiaNet
Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.
J Clin Oncol
2011
, vol. 
29
 
6
(pg. 
761
-
770
)
47
Barbui
 
T
Carobbio
 
A
Rambaldi
 
A
Finazzi
 
G
Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor?
Blood
2009
, vol. 
114
 
4
(pg. 
759
-
763
)
48
Landolfi
 
R
Di Gennaro
 
L
Barbui
 
T
et al. 
European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP)
Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera.
Blood
2007
, vol. 
109
 
6
(pg. 
2446
-
2452
)
49
Wolanskyj
 
AP
Schwager
 
SM
McClure
 
RF
Larson
 
DR
Tefferi
 
A
Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors.
Mayo Clin Proc
2006
, vol. 
81
 
2
(pg. 
159
-
166
)
50
Carobbio
 
A
Finazzi
 
G
Guerini
 
V
et al. 
Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status.
Blood
2007
, vol. 
109
 
6
(pg. 
2310
-
2313
)
51
Palandri
 
F
Polverelli
 
N
Catani
 
L
Ottaviani
 
E
Baccarani
 
M
Vianelli
 
N
Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study.
Ann Hematol
2011
, vol. 
90
 
8
(pg. 
933
-
938
)
52
Passamonti
 
F
Rumi
 
E
Pascutto
 
C
Cazzola
 
M
Lazzarino
 
M
Increase in leukocyte count over time predicts thrombosis in patients with low-risk essential thrombocythemia.
J Thromb Haemost
2009
, vol. 
7
 
9
(pg. 
1587
-
1589
)
53
Barbui
 
T
Carobbio
 
A
Finazzi
 
G
et al. 
AGIMM and IIC Investigators
Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3.
Haematologica
2011
, vol. 
96
 
2
(pg. 
315
-
318
)
54
Cortelazzo
 
S
Finazzi
 
G
Ruggeri
 
M
Vestri
 
O
Galli
 
M
Rodeghiero
 
F
Barbui
 
T
Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.
N Engl J Med
1995
, vol. 
332
 
17
(pg. 
1132
-
1136
)
55
Barbui
 
T
Finazzi
 
G
Carobbio
 
A
et al. 
Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis).
Blood
2012
, vol. 
120
 
26
(pg. 
5128
-
5133, quiz 5252
)
56
Vannucchi
 
AM
Antonioli
 
E
Guglielmelli
 
P
et al. 
MPD Research Consortium
Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden.
Leukemia
2007
, vol. 
21
 
9
(pg. 
1952
-
1959
)
57
Lussana
 
F
Caberlon
 
S
Pagani
 
C
Kamphuisen
 
PW
Büller
 
HR
Cattaneo
 
M
Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review.
Thromb Res
2009
, vol. 
124
 
4
(pg. 
409
-
417
)
58
Smalberg
 
JH
Koehler
 
E
Darwish Murad
 
S
et al. 
European Network for Vascular Disorders of the Liver (EN-Vie)
The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis.
Blood
2011
, vol. 
117
 
15
(pg. 
3968
-
3973
)
59
Rosti
 
V
Villani
 
L
Riboni
 
R
et al. 
Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) investigators
Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation.
Blood
2013
, vol. 
121
 
2
(pg. 
360
-
368
)
60
Sozer
 
S
Fiel
 
MI
Schiano
 
T
Xu
 
M
Mascarenhas
 
J
Hoffman
 
R
The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome.
Blood
2009
, vol. 
113
 
21
(pg. 
5246
-
5249
)
61
Vannucchi
 
AM
Antonioli
 
E
Guglielmelli
 
P
et al. 
Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia.
Blood
2008
, vol. 
112
 
3
(pg. 
844
-
847
)
62
Beer
 
PA
Campbell
 
PJ
Scott
 
LM
et al. 
MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort.
Blood
2008
, vol. 
112
 
1
(pg. 
141
-
149
)
63
Finazzi
 
G
Carobbio
 
A
Thiele
 
J
et al. 
Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria.
Leukemia
2012
, vol. 
26
 
4
(pg. 
716
-
719
)
64
Barbui
 
T
Thiele
 
J
Carobbio
 
A
et al. 
Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis.
Blood
2012
, vol. 
120
 
3
(pg. 
569
-
571
)
65
Ruggeri
 
M
Gisslinger
 
H
Tosetto
 
A
et al. 
Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia.
Am J Hematol
2002
, vol. 
71
 
1
(pg. 
1
-
6
)
66
Gisslinger
 
H
Müllner
 
M
Pabinger
 
I
et al. 
Mutation of the prothrombin gene and thrombotic events in patients with polycythemia vera or essential thrombocythemia: a cohort study.
Haematologica
2005
, vol. 
90
 
3
(pg. 
408
-
410
)
67
De Stefano
 
V
Za
 
T
Rossi
 
E
et al. 
Influence of the JAK2 V617F mutation and inherited thrombophilia on the thrombotic risk among patients with essential thrombocythemia.
Haematologica
2009
, vol. 
94
 
5
(pg. 
733
-
737
)
68
Jensen
 
MK
de Nully Brown
 
P
Thorsen
 
S
Hasselbalch
 
HC
Frequent occurrence of anticardiolipin antibodies, Factor V Leiden mutation, and perturbed endothelial function in chronic myeloproliferative disorders.
Am J Hematol
2002
, vol. 
69
 
3
(pg. 
185
-
191
)
69
Harrison
 
CN
Donohoe
 
S
Carr
 
P
Dave
 
M
Mackie
 
I
Machin
 
SJ
Patients with essential thrombocythaemia have an increased prevalence of antiphospholipid antibodies which may be associated with thrombosis.
Thromb Haemost
2002
, vol. 
87
 
5
(pg. 
802
-
807
)
70
Faurschou
 
M
Nielsen
 
OJ
Jensen
 
MK
Hasselbalch
 
HC
High prevalence of hyperhomocysteinemia due to marginal deficiency of cobalamin or folate in chronic myeloproliferative disorders.
Am J Hematol
2000
, vol. 
65
 
2
(pg. 
136
-
140
)
71
Gisslinger
 
H
Rodeghiero
 
F
Ruggeri
 
M
et al. 
Homocysteine levels in polycythaemia vera and essential thrombocythaemia.
Br J Haematol
1999
, vol. 
105
 
2
(pg. 
551
-
555
)
72
Berk
 
PD
Wasserman
 
LR
Fruchtman
 
SM
Goldberg
 
JD
 
Treatment of polycythemia vera: a summary of clinical trials conducted by the Polycythemia Vera Study Group. In: Wasserman LR, Berk PD, Berlin NI, eds. Polycythemia Vera and the Myeloproliferative Disorders. Philadelphia, PA: W.B. Saunders Company; 1995: 166-194
73
Landolfi
 
R
Marchioli
 
R
Kutti
 
J
Gisslinger
 
H
Tognoni
 
G
Patrono
 
C
Barbui
 
T
European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators
Efficacy and safety of low-dose aspirin in polycythemia vera.
N Engl J Med
2004
, vol. 
350
 
2
(pg. 
114
-
124
)
74
Alvarez-Larrán
 
A
Cervantes
 
F
Pereira
 
A
et al. 
Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia.
Blood
2010
, vol. 
116
 
8
(pg. 
1205
-
1210, quiz 1387
)
75
Pascale
 
S
Petrucci
 
G
Dragani
 
A
et al. 
Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target.
Blood
2012
, vol. 
119
 
15
(pg. 
3595
-
3603
)
76
Tefferi
 
A
Barbui
 
T
Personalized management of essential thrombocythemia-application of recent evidence to clinical practice [published online ahead of print April 5, 2013].
Leukemia
77
Fruchtman
 
SM
Mack
 
K
Kaplan
 
ME
Peterson
 
P
Berk
 
PD
Wasserman
 
LR
From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera.
Semin Hematol
1997
, vol. 
34
 
1
(pg. 
17
-
23
)
78
Kiladjian
 
JJ
Chevret
 
S
Dosquet
 
C
Chomienne
 
C
Rain
 
JD
Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980.
J Clin Oncol
2011
, vol. 
29
 
29
(pg. 
3907
-
3913
)
79
Finazzi
 
G
Ruggeri
 
M
Rodeghiero
 
F
Barbui
 
T
Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial.
Br J Haematol
2000
, vol. 
110
 
3
(pg. 
577
-
583
)
80
Björkholm
 
M
Derolf
 
AR
Hultcrantz
 
M
et al. 
Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms.
J Clin Oncol
2011
, vol. 
29
 
17
(pg. 
2410
-
2415
)
81
Finazzi
 
G
Caruso
 
V
Marchioli
 
R
et al. 
ECLAP Investigators
Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study.
Blood
2005
, vol. 
105
 
7
(pg. 
2664
-
2670
)
82
Maugeri
 
N
Giordano
 
G
Petrilli
 
MP
et al. 
Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug?
J Thromb Haemost
2006
, vol. 
4
 
12
(pg. 
2593
-
2598
)
83
Silver
 
RT
Kiladjian
 
JJ
Hasselbalch
 
HC
Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis.
Expert Rev Hematol
2013
, vol. 
6
 
1
(pg. 
49
-
58
)
84
Kiladjian
 
JJ
Cassinat
 
B
Chevret
 
S
et al. 
Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera.
Blood
2008
, vol. 
112
 
8
(pg. 
3065
-
3072
)
85
Quintás-Cardama
 
A
Kantarjian
 
H
Manshouri
 
T
et al. 
Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.
J Clin Oncol
2009
, vol. 
27
 
32
(pg. 
5418
-
5424
)
86
Samuelsson
 
J
Mutschler
 
M
Birgegård
 
G
Gram-Hansen
 
P
Björkholm
 
M
Pahl
 
HL
Limited effects on JAK2 mutational status after pegylated interferon alpha-2b therapy in polycythemia vera and essential thrombocythemia.
Haematologica
2006
, vol. 
91
 
9
(pg. 
1281
-
1282
)
87
De Stefano
 
V
Za
 
T
Rossi
 
E
et al. 
GIMEMA CMD-Working Party
Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments.
Haematologica
2008
, vol. 
93
 
3
(pg. 
372
-
380
)
Sign in via your Institution