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REVIEW Venous thromboembolism in patients with essential thrombocythemia and polycythemia vera H Reikvam1 and RV Tiu2 1 Department of Hematology, Institute of Medicine University of Bergen and Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway and 2Department of Translational Hematology and Oncology Research and Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs), which generally follow a benign and indolent clinical course. However, venous thromboses are common and constitute the main cause of morbidity and mortality. The discovery of the JAK2V617F mutation and other biomarkers has advanced our understanding of these diseases. There is a strong association between the presence of the JAK2V617F mutation and the development of thrombosis in ET. If venous thrombosis presents with unusual manifestations, the diagnosis of a MPN, such as PV or ET, should be part of the differentials. Treatment of venous thrombosis in MPN follows the same principle as in other patients with venous thrombosis, but careful attention to primary and secondary prophylaxis in addition to heparin-induced thrombocytopenia should be given. Cytoreductive therapy is indicated in high-risk subgroups of PV and ET patients, and alternative therapeutic agents have different effects on risk of venous thrombosis. New therapeutic approaches are emerging, and JAK2 inhibitors, histone deacetylase inhibitors and next-generation anticoagulants are in various stages of clinical development for the treatment of MPN, but their exact role in thrombosis prevention and treatment remains unclear. Leukemia (2012) 26, 563–571; doi:10.1038/leu.2011.314; published online 11 November 2011 Keywords: myeloproliferative neoplasms; polycythemia vera; essential thrombocythemia; thrombosis; novel therapeutics

Introduction The myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic diseases characterized by excessive production of cells belonging to the myeloid lineage in the bone marrow. They are related to, and may evolve into, myelodysplastic syndromes and acute myeloid leukemia, although MPNs as a whole have a much better prognosis than these conditions. Chronic myeloid leukemia is cytogenetically characterized by the defining translocation t(9;22) BCR-ABL, which the other MPNs by definition lack.1 This can divide MPN into Philadelphia chromosome-positive and -negative MPN (Table 1). Among the Philadelphia chromosome-negative MPN, polycythemia vera (PV) and essential thrombocythemia (ET) constitute the most common phenotypes, with an incidence of 0.7 – 2.6 per 100 000 individuals in Europe and North America for PV,2 and 0.6 – 2.5 per 100 000 per year for ET.3 Thrombotic Correspondence: Dr RV Tiu, Department of Translational Hematology and Oncology Research and Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. E-mail: [email protected] Received 27 September 2011; accepted 3 October 2011; published online 11 November 2011

and hemorrhagic complications are common in PV and ET, contributing to the main reasons for both morbidity and mortality among these patients.4 The thrombotic diathesis can affect both the arterial and/or venous circulation and contributes to 45% of death in this population.5 This review will focus mainly on the aspects of venous thrombosis in PV and ET, with a minor emphasis on other MPN subtypes. The discovery of the JAK2V617F mutation in various MPN has allowed us to better understand the pathophysiology of these diseases. Since the initial discovery of JAK2V617F, several other genetic mutations have been discovered and their contribution to disease pathogenesis, including thrombotic risk, has been closely investigated. We will further explore the pathophysiology, risk stratification and management, including both prevention and treatment of venous thrombosis. Finally, future aspects of emerging therapeutic alternatives will be discussed.

Molecular genetics A detailed description of the etiology and an update of molecular genetics in PV and ET are beyond the scope of this review, and readers are referred to other excellent reviews.6 – 9 In short, the JAK2V617F mutation has now been established as an important marker for diagnosis of both PV and ET, as noted by the latest World Health Organization classification.1,4,9 – 11 The mutation is a valine – to-phenylalanine substitution at amino-acid position 617, leading to a gain of function with constitutive tyrosine phosphorylation activity, and downstream signaling through the JAK– STAT, PI3K/AKT and ERK1/2 – MAPK pathways.12 Studies of purified hematopoietic progenitors have demonstrated that the expanded stem cell compartment in PV is preferentially shifted toward erythroid differentiation.13 Subsequently, the mutation was also found to be frequent in ET.14 The JAK2V617F mutation is found in over 90% of PV patients, and B55% of ET patients.4,9 There are other mutations that have been discovered in PV and ET. It is noteworthy that several mutations in exon 12 of JAK2 have been described in the remaining PV patients.15,16 Mutations of the ten – eleven translocation-2 (TET2) gene were recently described in various hematological neoplasms.17 These mutations are extremely heterogeneous and not exclusive to MPN,17 but seem to be important in some cases of ET and PV.18 Finally, a subset of ET patients have mutations in the myeloproliferative leukemia virus (MPL) gene (MPLW515L/K),19,20 and in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes.21 Further mutations and their relevance will probably be identified with the introduction of single-nucleotide polymorphism arrays and other high throughput genomic sequencing technologies, which have

Venous thromboembolism in ET and PV H Reikvam and RV Tiu

564 Table 1

Classification of MPNs

Table 3 Major contributors to increase risk of thrombosis in PV and ET patients

Philadelphia chromosome-positive MPN

Philadelphia chromosome-negative MPN

General factors

Features

Key references

Chronic myeloid leukemia

Polycythemia vera Essential thrombocythemia Primary myelofibrosis

Major risk stratification criteria Other criteria

Advanced age Prior history of thrombosis Hypercholesterolemia Smoking Diabetes Hereditary thrombophilia JAK2 allele burden JAK2 mutation (ET) Leukocytosis

5,36,39,41,42 5,36,37,39 39 40,41 41 43,44 45 – 47 48,49 29,41,50

Abbreviation: MPN, myeloproliferative neoplasm. MPNs can be classified according to the presence or absence of the cytogenetic abnormality t(9;22) (Philadelphia chromosome) into Philadelphia chromosome-positive and -negative MPN, respectively.

Table 2

The frequency of selected mutations in PV and ET

Mutation JAKV617F JAK2exon12 MPL TET2 IDH1/2

PV (%)

ET (%)

95 3 F 16 1

55 F 3 5 2

Key references Tefferi9 Pardanani et al.19 Vannucchi et al.20 Tefferi et al.18 Tefferi et al.21

Abbreviations: ET, essential thrombocythemia; IDH1/2, isocitrate dehydrogenase 1 and 2; MPL, myeloproliferative leukemia virus; PV, polycythemia vera; TET2, ten – eleven translocation-2.

emerged as an important tool in the identification of molecular genetic defects.22 The most clinically relevant mutations occurring in PV and ET are summarized in Table 2.

Pathophysiology Rudolf Virchow23 described the three main factors that can influence the pathogenesis of thrombosis: abnormalities of the vessel wall, blood components and the dynamics of flow. Historically, arterial and venous thromboses are considered as separate pathophysiological entities, with arterial thrombi comprising predominantly platelets (white clot) and venous thrombi of fibrin and red blood cells (red clot). However, it is now known that there are more similarities between these two thrombotic processes than previously believed.24 First, platelets and fibrin are found in both arterial and venous thrombi. There is evidence for both platelet activation and accumulation in the pathogenesis of venous thrombosis. Furthermore, the association between arterial and venous thrombosis is also supported by patient observations. Arterial and venous thrombosis share common risk factors, for example, age, smoking or hypercholesterolemia.24 In addition, patients with venous thrombosis have more frequent adverse cardiovascular events.25 These observations do not provide all the evidence to suggest that arterial and venous thromboses have a common origin, but may explain the overlapping pathological features between the two conditions. These overlapping features are also strikingly common in PV and ET. These patients are at risk for both venous and arterial thrombosis, and the pathophysiological processes behind these events are probably shared. However, it is also important to look for differences between arterial and venous thrombosis in PV and ET. The mechanisms behind the increased thrombotic tendency in PV and ET are complex and not completely understood. Pathophysiological mechanisms probably involve all cellular blood components, plasma, interaction with endothelial cells and hemodynamic changes. In MPN, platelets have the feature of spontaneous aggregation,26 and in addition have demonLeukemia

Novel diseaseassociated risk factors

Abbreviations: ET, essential thrombocythemia; PV, polycythemia vera. The table describes established risk stratification criteria, other general criteria and novel disease-associated risk factors.

strated abnormal expression of glycoprotein.27 Leukocytes also contribute to platelet activation in MPN,28,29 and erythrocytes showed an increased tendency to adhere to the endothelium.30 Interestingly, leukocyte counts seem to be a stronger predictor for thrombosis than platelet counts and hemoglobin/hematocrit levels.29 The hemodynamic changes include increased viscosity,31 with displacement of circulating platelets toward the endothelium. Increased levels of microparticles with procoagulant activity are found in MPN patients.32 Increased cytokine expression in MPN, leading to a general inflammatory response, probably also contributes to the thrombotic tendency.33 An increased number of prothrombotic circulating endothelial cells are seen among these patients,34 and interestingly the JAK2V617F mutation is found in these endothelial cells.35

Risk stratification

General risk factors The thrombotic diathesis is characterized by microcirculatory disturbances and an increased risk for both arterial and venous thromboses. The main aim of treatment in PV and ET is to prevent thrombotic complications that increase morbidity and mortality. Therefore, risk classification systems aimed at identifying high-risk patients who will benefit from more intensive therapeutic approaches have been developed. The general risk factors that are well established are age older than 60 years and previous history of thrombosis,4,6,36,37 and are currently used to divide patients into low- and high-risk categories.6 However, additional risk factors have also been established, and alternative risk stratification systems have been proposed.38 Among the other described general risk factors are hypercholesterolemia,39 smoking40,41 and diabetes mellitus41 (Table 3). As seen in Table 3, the thrombotic risk seems to be more related to patient characteristics (age, previous thrombosis and cardiovascular risk factors) than to the disease itself. Given that arterial thrombosis and venous thrombosis share several common risk factors,24 general intervention will probably reduce the risk for both. Therefore, primary prevention strategies such as those employed in cardiovascular diseases, for example, avoidance of smoking, maintenance of good physical activity and weight reduction, should also be carefully advised to PV and ET patients. Hypertension and dyslipidemia should be treated using standard guidelines, if necessary. Interestingly, statins have recently also been demonstrated to reduce the risk of venous thrombosis.51

Venous thromboembolism in ET and PV H Reikvam and RV Tiu

Disease-associated risk factors In contrast to the general risk factors for thromboembolism, some seem to be related to the biology of the disease itself, for example, disease-associated risk factors, and should be considered in risk stratification and treatment optimization. Of special interest is the presence of the JAK2V617F mutation. First, there seems to be biological differences between patients heterozygous or homozygous for the JAK2V617F mutation, resulting in different laboratory and clinical findings.48,52 However, no significant differences in the incidence of thromboembolic events were identified between these two groups in PV patients.48,52 In contrast, an increase in cardiovascular events was observed in homozygous JAK2V617F ET patients as compared with heterozygous and wild-type ET patients,48 in concordance with an observed risk of recurrent thrombosis in homozygous JAK2V617F patients.49 Second, the JAK2V617F allele burden is also believed to be important for the risk stratification of PV and ET patients.53 Patients with PV and ET and a high allele burden seem to have a higher risk for thrombotic episodes.45 – 47 Taken together, these observations indicate that the JAK2V617F mutation status (homozygous or heterozygous) has a defined role in the development of thrombosis in ET, whereas patients who harbor a higher JAK2V617F allele burden may represent a subgroup of PV patients with particularly higher risk of thromboembolic events.53 Interestingly, hemoglobin levels and platelet counts, as long as they are not extremely high, are not considered as risk factors for thrombotic events, in contrast to high white blood cell count, defined as WBC 415  109/l.41,50 The thrombotic risk seen with elevated white blood cells may be related to JAK2V617F allele burden,54 and should be evaluated and carefully incorporated in the risk stratification for deciding whether a patient should be started on cytoreductive treatment. Extreme thrombocytosis is associated with increased hemorrhagic risk,55 but does not seem to be a risk factor for thrombotic events. Moreover, recent evidence suggests that outside of age and prior thrombotic events, even at extreme levels high platelet counts may not be all predictive for thrombotic events.56

565 MPN among patients with spontaneous DVT and PE has been raised. This has been addressed by several studies.60 – 68 The rates of occurrence in the different studies are in general low, ranging from 0 to 3.0%.60 – 68 Given the low prevalence of MPN in this patient group, a general screening for JAK2V617F to detect an occult MPN is not recommended among patients with idiopathic DVT and PE. However, clinicians should keep these diagnoses in mind if general laboratory tests, such as blood parameters, and clinical manifestations, such as presence of splenomegaly or extramedullary hematopoiesis, indicate a MPN.

Unusual manifestations An interesting feature in MPN, in particular PV and ET, is the occurrence of venous thrombosis in unusual locations. Of special interest are thromboses in the splanchnic veins,69 cerebral sinus venous thrombosis,70,71 thrombosis of vena cava72 and even intraventricular thrombosis.73 Thromboses in the splanchnic veins are associated with high rates of morbidity and mortality and can sometimes involve the intrahepatic veins, causing Budd – Chiari syndrome.69 The prevalence of JAK2V617F in these cases is generally high,66,68,69,74 – 82 in contrast to venous thrombosis present in typical or common regions. Table 4 summarizes studies regarding the prevalence of JAK2V617F in the setting of thrombosis in the splanchnic veins, including patients with and without overt MPN. This emphasizes the importance of paying close attention in diagnosing splanchnic vein thromboses in patients with PV or ET with symptoms and signs suggestive of involvement of these blood vessels, especially as the clinical features may be subtle and not overt at the onset. In addition, it highlights the importance of considering a diagnosis of MPN if thrombosis manifests at an unusual location.69,83 In contrast to patients with spontaneous DVT and PE, these patients should be screened for JAK2V617F,64,66 especially as gastrointestinal bleeding and hypersplenism can mask general signs of PV and ET, such as increased hemoglobin and/or platelet count.

Management

Occurrence of venous thrombosis in PV and ET

Treatment of acute venous thrombosis in PV and ET

The cumulative rate of thrombosis ranges from 2.5 to 5.0% per patient-year in PV, and slightly lower in ET, 1.9 to 3.0% per patient-year.5,57 The prevalence of thrombosis at the time of diagnosis ranges between 34 and 39% for PV, and 10 and 29% for ET.58 Occurrence of thrombosis at follow-up ranges from B8 to 19% for PV patients, and 8 to 31% for ET patients.58 In general, arterial thrombotic episodes were more frequent than venous events.58 Venous thromboses seem to be more common in PV than ET.58 Interestingly, JAK2V617F-positive ET patients seem to have significantly more venous thrombosis than JAK2V617F-negative ET patients, indicating that JAK2V617Fpositive ET patients have a clinical phenotype related to PV.59

Table 4 Reported frequencies of JAK2V617F mutation in patients with thromboses involving the splanchnic veins.

Usual manifestations The most common manifestations of venous thrombosis in PV and ET are the same as in the general population, thrombosis of deep veins (DVT) in the lower limbs and pulmonary embolism (PE). Diagnostic management of these conditions in the setting of MPN follows the same principles as for the general population. After the discovery of the JAK2V617F mutation, the question regarding the occurrence of JAK2V617F and a latent or occult

Treatment of DVT of extremities or PE in PV and ET patients should be treated the same as any bona fide DVT or PE from other causes. Low-molecular heparin is given unless contraindicated, simultaneously with a vitamin K antagonist (warfarin),

Study Boissinot et al.74 Colaizzo et al.75 De Stefano et al.76 Kiladjian et al.69 McMahon et al.77 Patel et al.78 Primignani et al.79 Regina et al.66 Shetty et al.68 Smalberg et al.80 Tondeur et al.81 Xavier et al.82

Number of patients included

Prevalence of JAK2V617F mutation (%)

45 99 94 241 28 41 93 44 215 40 43 108

31 17 34 39 25 24 37 18 7 41 9 22

These include patients both with and without overt myeloproliferative neoplasm. Leukemia

Venous thromboembolism in ET and PV H Reikvam and RV Tiu

566 aiming for an international normalized ratio in the range of 2.0 to 3.0. In the general population, secondary prevention of venous thrombosis relies on short- or long-term anticoagulation, whereas secondary prevention of arterial events is largely based on antiplatelet treatment, for example, aspirin eventually in combination with other agents such as clopidogrel. However, it is unclear whether this recommendation is also applicable for PV and ET. The use of vitamin K antagonists seems to generate good protection against recurrence of venous thrombosis in PV and ET patients.84 A combination of aspirin and a vitamin K antagonist could be an approach in certain special circumstances, but is complicated by an increased risk of bleeding.84 Whether the site of first thrombosis should be the primary determinant in choosing further antithrombotic therapy is unclear and would need to be further clarified in large wellcontrolled studies.38 Recent guidelines therefore recommend oral anticoagulation in venous thrombosis for 3 – 6 months in PV and ET patients.4 An important exception is the diagnosis of splanchnic vein thrombosis, where life-long oral anticoagulation is recommended.4 Recent recommendations state that lowmolecular-weight heparin is superior to vitamin K antagonists in patients with malignant diseases and venous thromboembolism.85 Given the neoplastic nature of ET and PV, such an approach could also be attempted in these patients. This may be appealing given the fact that patients will not need the recurrent chronic monitoring that is needed for warfarin and, more importantly, the lesser potential for drug interactions associated with the use of low-molecular-weight heparin. However, there are several considerations that should be kept in mind. First, the incidence of cachexia that can complicate warfarin dosing is not common in PV and ET patients, making it less difficult to control the target level of international normalized ratio. Second, PV and ET patients are not only at increased risk for thrombotic events, but also from hemorrhage. Vitamin K can be given to reverse the effects of vitamin K antagonists, whereas no specific antidotes are available for low-molecular-weight heparin, although protamine sulfate has been used, making warfarin more attractive as a treatment option. Finally, the development of heparin-induced thrombocytopenia (HIT) should be considered. Although the incidence of HIT probably is higher in patients treated with unfractionated heparin than lowmolecular-weight heparin,86 the condition should not be ignored in patients treated with low – molecular-weight heparin.86 Although good data are lacking, the incidence is probably higher in PV and ET patients than in the general population,87,88 and the condition is harder to diagnose and probably underestimated in PV and ET patients.71,87,88 The high platelet count in ET and PV patients demonstrate that physicians should be more attentive to platelet count variations rather than the typical thrombocytopenia threshold. Therefore, treatment with low-molecular-heparin should be carried out carefully in these patients, keeping a potential diagnosis of HIT in mind.

Prophylaxis for venous thrombosis in ET and VT

saturated at low doses, the lack of a dose – response relationship in association with its antithrombotic effects and the doserelated side effects, especially gastrointestinal, supported the use of lower doses of aspirin for clinical use.90,91 This resulted in a large randomized controlled trial using 100 mg of aspirin a day in the intervention group. Treatment with aspirin significantly reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, major venous thrombosis or death from cardiovascular causes.92 The study documented that the effect of aspirin in the reduction of venous thrombosis (RR 0.49) is similar to that observed for arterial events, although it did not reach statistical significance for the more limited number of patients.92 No significant increase in the risk of major bleeding was observed.92 On the basis of these results, 75 – 100 mg aspirin is now recommended for use in all PV patients who have no contraindications to this therapy. Interestingly, no study has documented a significant reduction of venous thrombosis in PV patients. In the case of ET, the data on the effects of aspirin in the reduction of venous thrombosis are even more limited. The rationale for its use was mainly extrapolated from PV studies.93 Alvarez-Larran et al.94 recently demonstrated an effect of aspirin on incidence of venous thrombosis in JAK2V617F-positive patients and arterial thrombosis in patients with associated risk factors. For low-risk ET patients who do not carry the JAK2 V617F mutation and have no associated cardiovascular risk factors, aspirin did not decrease the incidence of thrombotic events.94 Given these considerations, recent guidelines therefore recommend aspirin for all PV patients,4 and aspirin for ET patients who have microvascular disturbances.4 Patients who are refractory or intolerant to aspirin can try other platelet inhibitors, such as clopidogrel or ticlopidine;95 however, data are limited.

Phlebotomy The rationale for phlebotomy in PV patients lies in the fact that the increased viscosity is believed to be a major contributor to the thrombotic tendency in these patients. The largest randomized clinical trial was carried out 30 years ago.96 Patients treated in the phlebotomy arm had a better median overall survival compared with the other treatment arms, chlorambucil and radioactive phosphorus.96 However, this was mainly attributed to the lesser incidence of acute myeloid leukemia and other malignancies in the phlebotomy arm, albeit an excess of thrombosis was observed in phlebotomized patients during the first 3 years of treatment.96 The data supporting the role of phlebotomy in reducing the incidence of venous thrombosis are limited, and this is further supported by the lack of correlation between hematocrit levels and thrombotic episodes. A randomized clinical trial that seeks to compare the efficacy and safety of two levels of hematocrit (o45 vs o50%) in PV patients97 is ongoing. Despite these limited data, the recent guidelines state that all patients with PV should be managed with low-dose aspirin and phlebotomy, with a HCT target below 45%.4 ET patients should not be offered phlebotomy.4

Several approaches should be undertaken to avoid thrombotic complications in PV and ET patients.

Cytoreductive therapy Aspirin Early clinical trials failed to show a benefit of aspirin treatment in patients with PV, and the intervention group actually had an increase in gastrointestinal bleeding.89 However, as further research showed that the antiplatelet effects of aspirin are Leukemia

Hydroxyurea (HU) is an antimetabolite that prevents DNA synthesis and has emerged as the treatment of choice in highrisk patients with ET because of its efficacy and relatively good safety profile. The efficacy of HU in preventing thrombosis in high-risk ET patients was demonstrated in a seminal randomized clinical trial.98 A total of 114 patients with ET were randomized

Venous thromboembolism in ET and PV H Reikvam and RV Tiu

567 to receive no treatment or HU, dosed to a target of platelet count o600  109/l. A total of 14 patients in the control group had thrombotic events, compared with only two in the HU group, revealing a significant difference in thrombosis-free survival between the HU group and the control group.98 Initial concerns regarding a potential leukemic transformation effect of HU has not been supported by larger epidemiological studies.42,99 Interferon (IFN) has a wide range of biological properties, including immunomodulatory, proapoptotic and antiangiogenic activities. It suppresses the proliferation of hematopoietic progenitors, making the drug attractive in the treatment of hematological malignancies. IFN-a induces about 80% of hematologic responses in PV and ET and also reduces the incidence of thrombotic events.100,101 The main problem with IFN-a therapy is the incidence of side effects. Fever and flu-like symptoms are experienced by most patients and usually require treatment with acetaminophen. More severe symptoms, such as weakness, myalgia and depressed mood, often lead to discontinuation of the treatment. The use of lower doses of IFN and the use of pegylated forms of IFN-a have improved the toxicity profile and have led to better compliance.102,103 Anagrelide works by inhibiting the maturation of megakaryocytes to platelets. The exact mechanism of action is unclear, although there is evidence to suggest that it is an inhibitor of phosphodiesterase.104 Anagrelide has a potent platelet-reducing activity devoid of leukemogenic potential.104 However, in a head-to-head study between HU and anagrelide plus low-dose aspirin in both arms, anagrelide was inferior to HU in terms of response, for example, incidence of arterial thrombosis, bleeding and decreased myelofibrotic transformation. Interestingly, the anagrelide group had a significantly decreased incidence of venous thrombosis compared with the HU group.57 On the basis of these data, HU is recommended as the drug of choice for most PV and ET patients requiring cytoreductive therapy.4 However, given the limited evidence on the effect of HU on venous thrombosis, it is possible that subgroups of patients that are vulnerable to venous thrombosis, for example, patients with a history of venous thrombosis, should be treated differently. Given that anagrelide may have beneficial effects compared with HU in the prevention of venous thrombosis, this could be a treatment option for certain subgroups of patients. However, it is important to remember that the evidence here is limited and accordingly not stated in treatment guidelines, and this needs further evaluation in larger well-designed clinical trials.

Future perspective: novel therapeutics

JAK2 inhibitors Targeted therapy of specific oncoproteins has been successfully demonstrated in chronic myeloid leukemia with the use of tyrosine kinase inhibitors and all-trans retinoic acid in acute promyelocytic leukemia, and remains an ideal approach for the management of specific hematological diseases.105,106 JAK2 mutations have remarkably improved our understanding of the pathogenesis of PV and ET, and orally bioavailable smallmolecule inhibitors of JAK2 have been developed,107 initiating the era of targeted therapies for Philadelphia chromosomenegative MPN patients. The majority of data in the use of JAK2 inhibitors have been focused on the management of MF patients.108 JAK2 inhibitor therapy in MF patients induces a marked improvement in constitutional symptoms and reduction in spleen size, which translates into improvements in quality of life.108 JAK2 inhibitors have also been studied in PV and ET, and preliminary data have been presented.109 – 111 The data are

limited, but suggest that these drugs represent a safe alternative for patients who fail therapy with HU.109 White blood cell counts were reported to decrease and, given that leukocytosis is an independent risk factor for thrombosis, potential benefits could be expected.109 However, preliminary data suggested that JAK2 inhibitor therapy may not prevent thrombosis in high-risk patients with PV and ET,110 and may actually increase the risk of venous thrombosis.110 This should be carefully followed, as novel therapeutics for other conditions, for example, thalidomide- and lenalidomide-based regimen in treatment of multiple myeloma, significantly increase the risk of venous thrombosis.112

Epigenetic targeting Epigenetics refers to stable alterations in gene expression, with no underlying modifications in the genetic sequence.113 DNA methylation and histone modifications lead to permanent changes in the expression of genes that regulate the neoplastic phenotype. Targeting epigenetic modifiers has been referred to as epigenetic therapy.113 The potential of this approach in hematopoietic malignancies validates the importance of epigenetics, and special histone deacetylase inhibitors (HDACIs) seem promising in MPN. The HDACI ITF2357 (also called givinostat) inhibits proliferation of cells bearing the JAK2V617F mutation through specific downregulation of the mutated protein and inhibition of its downstream signaling.114 The first clinical data regarding HDACIs in PV and ET evaluated ITF2357 in JAK2V617F-positive MPN patients. Among 13 PV and ET patients, the responses included one complete, six partial and four no responses (2 patients went off-study).115 The intervention was in general well tolerated, and there was a reduction of the JAK2V617F allele burden.115 As the JAK2V617F allele burden is linked to risk for thrombosis,45 it is possible that this drug also can reduce thrombosis frequency, although further and larger studies are warranted.

New anticoagulants Of interest in the setting of thrombosis and PV and ET are the development of emerging new oral anticoagulants. Among the most interesting are the specific factor Xa inhibitors, apixaban and rivaroxaban,116,117 and dabigatran which inhibits factor IIa/ thrombin.118 These new agents do not require anticoagulation monitoring, which is the mainstay for vitamin K antagonist therapy, and obviate the risk of HIT, which is the main risk with heparin-based treatment. In addition, these new agents have limited food – and drug – drug interactions due to their minimal metabolism through the CYP450 system. Of special interest in the setting of PV and ET is the fact that the bleeding complications seem to be lower compared with vitamin-K antagonist.118

Special situations

Pregnancy The prevalence of PV and ET in women of childbearing age is low, making it difficult to carry out clinical trials. Given that pregnancy itself is a hypercoagulable state with increased risk of thromboembolism,119 this risk is probably further increased in women with PV and ET. In addition, there is increased risk of fetal loss observed throughout all trimesters, prematurity and poor fetal outcome in women with PV.120 The same is also true for ET patients, where the occurrence of JAK2V617F mutation is probably associated with adverse outcomes.121 Leukemia

Venous thromboembolism in ET and PV H Reikvam and RV Tiu

568 Venous thrombosis may occur, particularly in the postpartum period, and the risk is higher in patients with a history of prior vascular events. Keeping HCT to o45% in PV patients, lowdose aspirin and prophylactic dose, low-molecular-weight heparin, after delivery until 6 weeks postpartum are now recommended for all patients.4 Patient with special high-risk pregnancy should probably be treated even more intensively.4

Surgery including splenectomy The thrombotic risk associated with surgical interventions is well known. This is particularly true for neurosurgical cases,122 and certain orthopedic surgeries, such as knee and hip replacements.123 The presence of an underlying MPN complicates this further. In a retrospective study conducted by the GIMEMA Chronic MPD Working Party, the frequency of thrombotic and hemorrhagic events after surgical procedures were verified in 255 patients with PV and ET who had at least one surgery.124 With a total of 311 surgical interventions, 12 arterial and 12 venous thrombotic events were noted. The investigators mentioned that the use of heparin and even antiplatelet agents did not influence adverse outcomes, with only a possible trend for prevention of venous thromboembolism in patients who received heparin.124 The optimal approach for surgical thrombosis prophylaxis in PV and ET patients remains subjective.124 Splenectomy is now carried out less frequently in PV and ET, because of improvement in treatment options. The relative perioperative mortality of splenectomy is B10%.125 Additional post-splenectomy complications include infections, a potential increased risk for malignancy and thrombosis.126 Current indications for splenectomy include symptomatic portal hypertension or drug-refractory marked splenomegaly associated with pain or severe cachexia. Cytoreduction, to keep platelet count below 400  109/l, and anticoagulants are recommended prophylactically before splenectomy. Surgery should preferably be carried out only by an experienced surgical team.

constitute the major causes of morbidity and mortality, together with disease evolution to MF or transformation to myelodysplastic syndrome/acute myeloid leukemia. The discovery of the JAK2V617F mutation has greatly facilitated the approach to diagnosis and biological understanding of these diseases, although the thrombotic features of the diseases are still not completely understood. Established risk factors for thrombotic events are represented by old age and previous thrombosis, although other risk factors should also be taken into consideration, including JAK2V617F allele burden. Thrombotic accidents often manifest at diagnosis or in the preclinical phase of the disease; however, an overt PV or ET is unlikely in venous thrombosis with usual manifestations, for example, DVT or PE. In contrast, when venous thromboses manifest at an unusual site, the diagnosis should always be kept in mind. The JAK2V617F mutation occurs in 7 – 41 % of patient with thromboses in splanchnic veins. The main treatment options in the prevention of thrombosis, for example, aspirin as antiplatelet drug and HU for cytoreduction, have proven overall benefits, such as reduced morbidity and mortality in PV and ET patients. Further studies are warranted to investigate effects on venous thrombosis, and whether a subset of patients, such as, patients with venous thrombosis instead of arterial thrombosis, should be treated differently and more intensively. Acute DVT or PE in the setting of PV and ET should be treated similarly as venous thrombosis from other causes, but a possible increase of risk and difficulties in diagnosing HIT should be kept in mind when using heparins. Emerging targeted therapy, for example, JAK2 inhibitors and HDACIs, are currently being tested in clinical trials, and should be carefully evaluated for their effects on venous thrombosis. New anticoagulants are also entering clinical practice, but their potential role among MPN patients have to be further evaluated.

Conflict of interest The authors declare no conflict of interest.

Hereditary thrombophilia Our knowledge about hereditary thrombophilia has increased in the last two decades and this has led to widespread testing in patients with venous thromboembolism for hereditary thrombophilia. The most common of the mutations leading to increase risk of venous thromboembolism is the mutation in factor V (FV), the so-called Leiden mutation. Ruggeri et al.43 investigated whether the presence of FV Leiden could be a risk factor for thrombosis in PV and ET patients. FV Leiden was found in 4.6%, approximately the same as in the general population.127 FV Leiden mutation was associated with venous thromboembolism before and at diagnosis and with recurrence of venous thromboembolism.43 This effect was not found for arterial thrombosis. The issue of hereditary thrombophilia is not limited to FV Leiden. The prothrombin 20210 G4A mutation44 as well as the rarer forms of thrombophilias, such as antithrombin III, protein C and protein S hereditary deficiencies, should be also considered. Screening for hereditary thrombophilia may be considered to identify high-risk PV and ET patients, and should at least be considered in patients with relapse of venous thromboembolism, which may require more intensive treatment.

Summary/Conclusion PV and ET are chronic MPN characterized by a benign and indolent clinical course. Arterial and venous thromboses Leukemia

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