Venous Thromboembolism in Patients with Essential Thrombocythemia and Polycythemia Vera

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Venous thromboembolism in patients with essential thrombocythemia and polycythemia vera

H Reikvam1 and RV Tiu2

1Department 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 and hemorrhagic complications are common in PV and ET, myeloproliferative neoplasms (MPNs), which generally follow a contributing to the main reasons for both morbidity and benign and indolent clinical course. However, venous throm- mortality among these patients.4 The thrombotic diathesis can boses are common and constitute the main cause of morbidity affect both the arterial and/or venous circulation and contributes and mortality. The discovery of the JAK2V617F mutation and 5 other biomarkers has advanced our understanding of these to 45% of death in this population. diseases. There is a strong association between the presence This review will focus mainly on the aspects of venous of the JAK2V617F mutation and the development of thrombosis thrombosis in PV and ET, with a minor emphasis on other MPN in ET. If venous thrombosis presents with unusual manifesta- subtypes. The discovery of the JAK2V617F mutation in various tions, the diagnosis of a MPN, such as PV or ET, should be part MPN has allowed us to better understand the pathophysiology of the differentials. Treatment of venous thrombosis in MPN follows the same principle as in other patients with venous of these diseases. Since the initial discovery of JAK2V617F, thrombosis, but careful attention to primary and secondary several other genetic mutations have been discovered and their prophylaxis in addition to heparin-induced thrombocytopenia contribution to disease pathogenesis, including thrombotic should be given. Cytoreductive therapy is indicated in high-risk risk, has been closely investigated. We will further explore the subgroups of PV and ET patients, and alternative therapeutic pathophysiology, risk stratification and management, including agents have different effects on risk of venous thrombosis. New both prevention and treatment of venous thrombosis. Finally, therapeutic approaches are emerging, and JAK2 inhibitors, histone deacetylase inhibitors and next-generation anticoagu- future aspects of emerging therapeutic alternatives will be lants are in various stages of clinical development for the discussed. 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 Molecular genetics Keywords: myeloproliferative neoplasms; polycythemia vera; essential thrombocythemia; thrombosis; novel therapeutics 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 Introduction important marker for diagnosis of both PV and ET, as noted by the latest World Health Organization classification.1,4,9 – 11 The myeloproliferative neoplasms (MPN) are a heterogeneous The mutation is a valine–to-phenylalanine substitution at group of hematologic diseases characterized by excessive amino-acid position 617, leading to a gain of function with production of cells belonging to the myeloid lineage in the constitutive tyrosine phosphorylation activity, and downstream bone marrow. They are related to, and may evolve into, signaling through the JAK–STAT, PI3K/AKT and ERK1/2–MAPK myelodysplastic syndromes and acute myeloid leukemia, pathways.12 Studies of purified hematopoietic progenitors have although MPNs as a whole have a much better prognosis than demonstrated that the expanded stem cell compartment in PV is these conditions. Chronic myeloid leukemia is cytogenetically preferentially shifted toward erythroid differentiation.13 Subse- characterized by the defining translocation t(9;22) BCR-ABL, 14 1 quently, the mutation was also found to be frequent in ET. The which the other MPNs by definition lack. This can divide JAK2V617F mutation is found in over 90% of PV patients, and MPN into Philadelphia chromosome-positive and -negative B55% of ET patients.4,9 There are other mutations that have MPN (Table 1). been discovered in PV and ET. It is noteworthy that several Among the Philadelphia chromosome-negative MPN, mutations in exon 12 of JAK2 have been described in the polycythemia vera (PV) and essential thrombocythemia (ET) remaining PV patients.15,16 Mutations of the ten–eleven constitute the most common phenotypes, with an incidence of translocation-2 (TET2) gene were recently described in various 0.7–2.6 per 100 000 individuals in Europe and North America 17 2 3 hematological neoplasms. These mutations are extremely for PV, and 0.6–2.5 per 100 000 per year for ET. Thrombotic 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 Correspondence: Dr RV Tiu, Department of Translational Hematology patients have mutations in the myeloproliferative leukemia virus and Oncology Research and Department of Hematologic Oncology (MPL) gene (MPLW515L/K),19,20 and in the isocitrate dehydro- and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, genase 1 and 2 (IDH1/IDH2) genes.21 Further mutations and Cleveland, OH, USA. E-mail: [email protected] their relevance will probably be identified with the intro- Received 27 September 2011; accepted 3 October 2011; published duction of single-nucleotide polymorphism arrays and other online 11 November 2011 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 Philadelphia chromosome-positive MPN chromosome-negative MPN General factors Features Key references

Chronic myeloid leukemia Polycythemia vera Major risk stratification Advanced age 5,36,39,41,42 Essential thrombocythemia criteria Prior history of thrombosis 5,36,37,39 Primary myelofibrosis Other criteria Hypercholesterolemia 39 Smoking 40,41 Abbreviation: MPN, myeloproliferative neoplasm. Diabetes 41 MPNs can be classified according to the presence or absence of Hereditary thrombophilia 43,44 the cytogenetic abnormality t(9;22) (Philadelphia chromosome) into Novel disease- JAK2 allele burden 45–47 Philadelphia chromosome-positive and -negative MPN, respectively. associated JAK2 mutation (ET) 48,49 risk factors Leukocytosis 29,41,50

Table 2 The frequency of selected mutations in PV and ET Abbreviations: ET, essential thrombocythemia; PV, polycythemia vera. The table describes established risk stratiﬁcation criteria, other general criteria and novel disease-associated risk factors. Mutation PV (%) ET (%) Key references

JAKV617F 95 55 Tefferi9 27 19 strated abnormal expression of glycoprotein. Leukocytes also JAK2exon12 3 F Pardanani et al. 28,29 F 20 contribute to platelet activation in MPN, and erythrocytes MPL 3 Vannucchi et al. 30 TET2 16 5 Tefferi et al.18 showed an increased tendency to adhere to the endothelium. IDH1/2 1 2 Tefferi et al.21 Interestingly, leukocyte counts seem to be a stronger predictor for thrombosis than platelet counts and hemoglobin/hematocrit Abbreviations: ET, essential thrombocythemia; IDH1/2, isocitrate levels.29 dehydrogenase 1 and 2; MPL, myeloproliferative leukemia virus; 31 PV, polycythemia vera; TET2, ten–eleven translocation-2. The hemodynamic changes include increased viscosity, with displacement of circulating platelets toward the endothe- emerged as an important tool in the identification of molecular lium. Increased levels of microparticles with procoagulant genetic defects.22 The most clinically relevant mutations activity are found in MPN patients.32 Increased cytokine occurring in PV and ET are summarized in Table 2. expression in MPN, leading to a general inflammatory response, probably also contributes to the thrombotic tendency.33 An increased number of prothrombotic circulating endothelial Pathophysiology cells are seen among these patients,34 and interestingly the JAK2V617F mutation is found in these endothelial cells.35 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 Risk stratification separate pathophysiological entities, with arterial thrombi comprising predominantly platelets (white clot) and venous General risk factors thrombi of fibrin and red blood cells (red clot). However, it is The thrombotic diathesis is characterized by microcirculatory now known that there are more similarities between these two disturbances and an increased risk for both arterial and thrombotic processes than previously believed.24 First, platelets venous thromboses. The main aim of treatment in PV and ET and fibrin are found in both arterial and venous thrombi. There is to prevent thrombotic complications that increase morbidity is evidence for both platelet activation and accumulation in the and mortality. Therefore, risk classification systems aimed at pathogenesis of venous thrombosis. Furthermore, the associa- identifying high-risk patients who will benefit from more tion between arterial and venous thrombosis is also supported intensive therapeutic approaches have been developed. The by patient observations. Arterial and venous thrombosis share general risk factors that are well established are age older than common risk factors, for example, age, smoking or hypercho- 60 years and previous history of thrombosis,4,6,36,37 and are lesterolemia.24 In addition, patients with venous thrombosis currently used to divide patients into low- and high-risk have more frequent adverse cardiovascular events.25 These categories.6 However, additional risk factors have also been observations do not provide all the evidence to suggest that established, and alternative risk stratification systems have been arterial and venous thromboses have a common origin, but may proposed.38 Among the other described general risk factors are explain the overlapping pathological features between the two hypercholesterolemia,39 smoking40,41 and diabetes mellitus41 conditions. (Table 3). As seen in Table 3, the thrombotic risk seems to be These overlapping features are also strikingly common in PV more related to patient characteristics (age, previous thrombosis and ET. These patients are at risk for both venous and arterial and cardiovascular risk factors) than to the disease itself. Given thrombosis, and the pathophysiological processes behind these that arterial thrombosis and venous thrombosis share several events are probably shared. However, it is also important to common risk factors,24 general intervention will probably look for differences between arterial and venous thrombosis in reduce the risk for both. Therefore, primary prevention strategies PV and ET. such as those employed in cardiovascular diseases, for example, The mechanisms behind the increased thrombotic tendency avoidance of smoking, maintenance of good physical activity in PV and ET are complex and not completely understood. and weight reduction, should also be carefully advised to PV Pathophysiological mechanisms probably involve all cellular and ET patients. Hypertension and dyslipidemia should be blood components, plasma, interaction with endothelial cells treated using standard guidelines, if necessary. Interestingly, and hemodynamic changes. In MPN, platelets have the feature statins have recently also been demonstrated to reduce the risk of spontaneous aggregation,26 and in addition have demon- of venous thrombosis.51

Leukemia Venous thromboembolism in ET and PV H Reikvam and RV Tiu 565 Disease-associated risk factors MPN among patients with spontaneous DVT and PE has been In contrast to the general risk factors for thromboembolism, raised. This has been addressed by several studies.60 – 68 The some seem to be related to the biology of the disease itself, rates of occurrence in the different studies are in general low, for example, disease-associated risk factors, and should be ranging from 0 to 3.0%.60 – 68 Given the low prevalence of MPN considered in risk stratification and treatment optimization. in this patient group, a general screening for JAK2V617F to Of special interest is the presence of the JAK2V617F mutation. detect an occult MPN is not recommended among patients with First, there seems to be biological differences between patients idiopathic DVT and PE. However, clinicians should keep these heterozygous or homozygous for the JAK2V617F mutation, diagnoses in mind if general laboratory tests, such as blood resulting in different laboratory and clinical findings.48,52 parameters, and clinical manifestations, such as presence of However, no significant differences in the incidence of splenomegaly or extramedullary hematopoiesis, indicate a MPN. 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 Unusual manifestations patients as compared with heterozygous and wild-type ET An interesting feature in MPN, in particular PV and ET, is patients,48 in concordance with an observed risk of recurrent the occurrence of venous thrombosis in unusual locations. 69 thrombosis in homozygous JAK2V617F patients.49 Second, the Of special interest are thromboses in the splanchnic veins, 70,71 JAK2V617F allele burden is also believed to be important cerebral sinus venous thrombosis, thrombosis of vena 72 73 for the risk stratification of PV and ET patients.53 Patients with cava and even intraventricular thrombosis. Thromboses in PV and ET and a high allele burden seem to have a higher risk the splanchnic veins are associated with high rates of morbidity for thrombotic episodes.45 – 47 Taken together, these observa- and mortality and can sometimes involve the intrahepatic 69 tions indicate that the JAK2V617F mutation status (homozygous veins, causing Budd–Chiari syndrome. The prevalence 66,68,69,74 – 82 or heterozygous) has a defined role in the development of JAK2V617F in these cases is generally high, in of thrombosis in ET, whereas patients who harbor a higher contrast to venous thrombosis present in typical or common JAK2V617F allele burden may represent a subgroup of PV regions. Table 4 summarizes studies regarding the prevalence of patients with particularly higher risk of thromboembolic JAK2V617F in the setting of thrombosis in the splanchnic veins, events.53 including patients with and without overt MPN. This empha- Interestingly, hemoglobin levels and platelet counts, as long sizes the importance of paying close attention in diagnosing as they are not extremely high, are not considered as risk factors splanchnic vein thromboses in patients with PV or ET with for thrombotic events, in contrast to high white blood cell count, symptoms and signs suggestive of involvement of these blood defined as WBC 415 Â 109/l.41,50 The thrombotic risk seen with vessels, especially as the clinical features may be subtle and not elevated white blood cells may be related to JAK2V617F allele overt at the onset. In addition, it highlights the importance burden,54 and should be evaluated and carefully incorporated in of considering a diagnosis of MPN if thrombosis manifests at an 69,83 the risk stratification for deciding whether a patient should be unusual location. In contrast to patients with spontaneous started on cytoreductive treatment. Extreme thrombocytosis is DVT and PE, these patients should be screened for 64,66 associated with increased hemorrhagic risk,55 but does not seem JAK2V617F, especially as gastrointestinal bleeding and to be a risk factor for thrombotic events. Moreover, recent hypersplenism can mask general signs of PV and ET, such as evidence suggests that outside of age and prior thrombotic increased hemoglobin and/or platelet count. events, even at extreme levels high platelet counts may not be all predictive for thrombotic events.56 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 Treatment of DVT of extremities or PE in PV and ET patients patient-year in PV, and slightly lower in ET, 1.9 to 3.0% per should be treated the same as any bona ﬁde DVT or PE from patient-year.5,57 The prevalence of thrombosis at the time of other causes. Low-molecular heparin is given unless contra- diagnosis ranges between 34 and 39% for PV, and 10 and 29% indicated, simultaneously with a vitamin K antagonist (warfarin), 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 Table 4 Reported frequencies of JAK2V617F mutation in patients general, arterial thrombotic episodes were more frequent than with thromboses involving the splanchnic veins. venous events.58 Venous thromboses seem to be more common in PV than ET.58 Interestingly, JAK2V617F-positive ET patients Study Number of Prevalence of seem to have signiﬁcantly more venous thrombosis than patients included JAK2V617F mutation (%) JAK2V617F-negative ET patients, indicating that JAK2V617F- Boissinot et al.74 45 31 59 positive ET patients have a clinical phenotype related to PV. Colaizzo et al.75 99 17 De Stefano et al.76 94 34 Kiladjian et al.69 241 39 McMahon et al.77 28 25 Usual manifestations 78 The most common manifestations of venous thrombosis in PV Patel et al. 41 24 Primignani et al.79 93 37 and ET are the same as in the general population, thrombosis of Regina et al.66 44 18 deep veins (DVT) in the lower limbs and pulmonary embolism Shetty et al.68 215 7 (PE). Diagnostic management of these conditions in the setting Smalberg et al.80 40 41 of MPN follows the same principles as for the general Tondeur et al.81 43 9 82 population. Xavier et al. 108 22 After the discovery of the JAK2V617F mutation, the question These include patients both with and without overt myeloproliferative regarding the occurrence of JAK2V617F and a latent or occult neoplasm.

Leukemia Venous thromboembolism in ET and PV H Reikvam and RV Tiu 566 aiming for an international normalized ratio in the range of saturated at low doses, the lack of a dose–response relationship 2.0 to 3.0. in association with its antithrombotic effects and the dose- In the general population, secondary prevention of venous related side effects, especially gastrointestinal, supported the use thrombosis relies on short- or long-term anticoagulation, of lower doses of aspirin for clinical use.90,91 This resulted in a whereas secondary prevention of arterial events is largely based large randomized controlled trial using 100 mg of aspirin a day on antiplatelet treatment, for example, aspirin eventually in in the intervention group. Treatment with aspirin significantly combination with other agents such as clopidogrel. However, it reduced the risk of the combined end point of nonfatal is unclear whether this recommendation is also applicable for myocardial infarction, nonfatal stroke, major venous thrombosis PV and ET. The use of vitamin K antagonists seems to generate or death from cardiovascular causes.92 The study documented good protection against recurrence of venous thrombosis in that the effect of aspirin in the reduction of venous thrombosis PV and ET patients.84 A combination of aspirin and a vitamin K (RR 0.49) is similar to that observed for arterial events, although antagonist could be an approach in certain special circum- it did not reach statistical significance for the more limited stances, but is complicated by an increased risk of bleeding.84 number of patients.92 No significant increase in the risk of Whether the site of first thrombosis should be the primary major bleeding was observed.92 On the basis of these results, determinant in choosing further antithrombotic therapy is 75–100 mg aspirin is now recommended for use in all PV unclear and would need to be further clarified in large well- patients who have no contraindications to this therapy. controlled studies.38 Recent guidelines therefore recommend Interestingly, no study has documented a significant reduction oral anticoagulation in venous thrombosis for 3–6 months in PV of venous thrombosis in PV patients. In the case of ET, the data and ET patients.4 An important exception is the diagnosis of on the effects of aspirin in the reduction of venous thrombosis splanchnic vein thrombosis, where life-long oral anticoagulation are even more limited. The rationale for its use was mainly is recommended.4 Recent recommendations state that low- extrapolated from PV studies.93 Alvarez-Larran et al.94 recently molecular-weight heparin is superior to vitamin K antagonists in demonstrated an effect of aspirin on incidence of venous patients with malignant diseases and venous thromboembo- thrombosis in JAK2V617F-positive patients and arterial throm- lism.85 Given the neoplastic nature of ET and PV, such an bosis in patients with associated risk factors. For low-risk ET approach could also be attempted in these patients. This may be patients who do not carry the JAK2 V617F mutation and have no appealing given the fact that patients will not need the recurrent associated cardiovascular risk factors, aspirin did not decrease chronic monitoring that is needed for warfarin and, more the incidence of thrombotic events.94 Given these considera- importantly, the lesser potential for drug interactions associated tions, recent guidelines therefore recommend aspirin for all PV with the use of low-molecular-weight heparin. However, there patients,4 and aspirin for ET patients who have microvascular are several considerations that should be kept in mind. First, the disturbances.4 Patients who are refractory or intolerant to aspirin incidence of cachexia that can complicate warfarin dosing is not can try other platelet inhibitors, such as clopidogrel or common in PV and ET patients, making it less difficult to control ticlopidine;95 however, data are limited. 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 Phlebotomy reverse the effects of vitamin K antagonists, whereas no specific The rationale for phlebotomy in PV patients lies in the fact that antidotes are available for low-molecular-weight heparin, the increased viscosity is believed to be a major contributor to although protamine sulfate has been used, making warfarin the thrombotic tendency in these patients. The largest rando- more attractive as a treatment option. Finally, the development mized clinical trial was carried out 30 years ago.96 Patients of heparin-induced thrombocytopenia (HIT) should be treated in the phlebotomy arm had a better median overall considered. Although the incidence of HIT probably is higher survival compared with the other treatment arms, chlorambucil in patients treated with unfractionated heparin than low- and radioactive phosphorus.96 However, this was mainly molecular-weight heparin,86 the condition should not be attributed to the lesser incidence of acute myeloid leukemia ignored in patients treated with low–molecular-weight hepar- and other malignancies in the phlebotomy arm, albeit an excess in.86 Although good data are lacking, the incidence is probably of thrombosis was observed in phlebotomized patients during higher in PV and ET patients than in the general population,87,88 the first 3 years of treatment.96 and the condition is harder to diagnose and probably under- The data supporting the role of phlebotomy in reducing the estimated in PV and ET patients.71,87,88 The high platelet count incidence of venous thrombosis are limited, and this is further in ET and PV patients demonstrate that physicians should be supported by the lack of correlation between hematocrit levels more attentive to platelet count variations rather than the and thrombotic episodes. A randomized clinical trial that seeks typical thrombocytopenia threshold. Therefore, treatment with to compare the efficacy and safety of two levels of hematocrit low-molecular-heparin should be carried out carefully in these (o45 vs o50%) in PV patients97 is ongoing. Despite these patients, keeping a potential diagnosis of HIT in mind. 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 Prophylaxis for venous thrombosis in ET and VT phlebotomy.4 Several approaches should be undertaken to avoid thrombotic complications in PV and ET patients. Cytoreductive therapy Hydroxyurea (HU) is an antimetabolite that prevents DNA Aspirin synthesis and has emerged as the treatment of choice in high- Early clinical trials failed to show a benefit of aspirin treatment risk patients with ET because of its efficacy and relatively good in patients with PV, and the intervention group actually had an safety profile. The efficacy of HU in preventing thrombosis in increase in gastrointestinal bleeding.89 However, as further high-risk ET patients was demonstrated in a seminal randomized research showed that the antiplatelet effects of aspirin are clinical trial.98 A total of 114 patients with ET were randomized

Leukemia 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 limited, but suggest that these drugs represent a safe alternative o600 Â 109/l. A total of 14 patients in the control group had for patients who fail therapy with HU.109 White blood cell thrombotic events, compared with only two in the HU group, counts were reported to decrease and, given that leukocytosis is revealing a significant difference in thrombosis-free survival an independent risk factor for thrombosis, potential benefits between the HU group and the control group.98 Initial concerns could be expected.109 However, preliminary data suggested that regarding a potential leukemic transformation effect of HU has JAK2 inhibitor therapy may not prevent thrombosis in high-risk not been supported by larger epidemiological studies.42,99 patients with PV and ET,110 and may actually increase the risk Interferon (IFN) has a wide range of biological properties, of venous thrombosis.110 This should be carefully followed, including immunomodulatory, proapoptotic and antiangiogenic as novel therapeutics for other conditions, for example, activities. It suppresses the proliferation of hematopoietic thalidomide- and lenalidomide-based regimen in treatment of progenitors, making the drug attractive in the treatment of multiple myeloma, significantly increase the risk of venous hematological malignancies. IFN-a induces about 80% of thrombosis.112 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 Epigenetic targeting symptoms are experienced by most patients and usually require Epigenetics refers to stable alterations in gene expression, with 113 treatment with acetaminophen. More severe symptoms, such no underlying modifications in the genetic sequence. DNA as weakness, myalgia and depressed mood, often lead to methylation and histone modifications lead to permanent discontinuation of the treatment. The use of lower doses of IFN changes in the expression of genes that regulate the neoplastic and the use of pegylated forms of IFN-a have improved the phenotype. Targeting epigenetic modifiers has been referred 113 toxicity profile and have led to better compliance.102,103 to as epigenetic therapy. The potential of this approach Anagrelide works by inhibiting the maturation of megakar- in hematopoietic malignancies validates the importance of yocytes to platelets. The exact mechanism of action is unclear, epigenetics, and special histone deacetylase inhibitors (HDACIs) although there is evidence to suggest that it is an inhibitor of seem promising in MPN. The HDACI ITF2357 (also called phosphodiesterase.104 Anagrelide has a potent platelet-reducing givinostat) inhibits proliferation of cells bearing the JAK2V617F activity devoid of leukemogenic potential.104 However, in a mutation through specific downregulation of the mutated 114 head-to-head study between HU and anagrelide plus low-dose protein and inhibition of its downstream signaling. The first aspirin in both arms, anagrelide was inferior to HU in terms of clinical data regarding HDACIs in PV and ET evaluated ITF2357 response, for example, incidence of arterial thrombosis, bleed- in JAK2V617F-positive MPN patients. Among 13 PV and ET ing and decreased myelofibrotic transformation. Interestingly, patients, the responses included one complete, six partial and 115 the anagrelide group had a significantly decreased incidence of four no responses (2 patients went off-study). The intervention venous thrombosis compared with the HU group.57 On the basis was in general well tolerated, and there was a reduction of the 115 of these data, HU is recommended as the drug of choice for JAK2V617F allele burden. As the JAK2V617F allele burden is 45 most PV and ET patients requiring cytoreductive therapy.4 linked to risk for thrombosis, it is possible that this drug also However, given the limited evidence on the effect of HU on can reduce thrombosis frequency, although further and larger venous thrombosis, it is possible that subgroups of patients that studies are warranted. are vulnerable to venous thrombosis, for example, patients with a history of venous thrombosis, should be treated differently. New anticoagulants Given that anagrelide may have beneficial effects compared Of interest in the setting of thrombosis and PV and ET are the with HU in the prevention of venous thrombosis, this could be a development of emerging new oral anticoagulants. Among the treatment option for certain subgroups of patients. However, it is most interesting are the specific factor Xa inhibitors, apixaban important to remember that the evidence here is limited and and rivaroxaban,116,117 and dabigatran which inhibits factor IIa/ accordingly not stated in treatment guidelines, and this needs thrombin.118 These new agents do not require anticoagulation further evaluation in larger well-designed clinical trials. 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 Future perspective: novel therapeutics limited food– and drug–drug interactions due to their minimal JAK2 inhibitors metabolism through the CYP450 system. Of special interest in the setting of PV and ET is the fact that the bleeding Targeted therapy of specific oncoproteins has been successfully complications seem to be lower compared with vitamin-K demonstrated in chronic myeloid leukemia with the use of antagonist.118 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 Special situations mutations have remarkably improved our understanding of the pathogenesis of PV and ET, and orally bioavailable small- Pregnancy molecule inhibitors of JAK2 have been developed,107 initiating The prevalence of PV and ET in women of childbearing age is the era of targeted therapies for Philadelphia chromosome- low, making it difficult to carry out clinical trials. Given that negative MPN patients. The majority of data in the use of JAK2 pregnancy itself is a hypercoagulable state with increased risk of inhibitors have been focused on the management of MF thromboembolism,119 this risk is probably further increased in patients.108 JAK2 inhibitor therapy in MF patients induces a women with PV and ET. In addition, there is increased risk marked improvement in constitutional symptoms and reduction of fetal loss observed throughout all trimesters, prematurity in spleen size, which translates into improvements in quality of and poor fetal outcome in women with PV.120 The same is also life.108 JAK2 inhibitors have also been studied in PV and ET, true for ET patients, where the occurrence of JAK2V617F and preliminary data have been presented.109 – 111 The data are 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 constitute the major causes of morbidity and mortality, together period, and the risk is higher in patients with a history of prior with disease evolution to MF or transformation to myelodys- vascular events. Keeping HCT to o45% in PV patients, low- plastic syndrome/acute myeloid leukemia. The discovery of the dose aspirin and prophylactic dose, low-molecular-weight JAK2V617F mutation has greatly facilitated the approach to heparin, after delivery until 6 weeks postpartum are now diagnosis and biological understanding of these diseases, recommended for all patients.4 Patient with special high-risk although the thrombotic features of the diseases are still not pregnancy should probably be treated even more intensively.4 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 considera- Surgery including splenectomy tion, including JAK2V617F allele burden. Thrombotic accidents The thrombotic risk associated with surgical interventions is well often manifest at diagnosis or in the preclinical phase of the known. This is particularly true for neurosurgical cases,122 and disease; however, an overt PV or ET is unlikely in venous certain orthopedic surgeries, such as knee and hip replace- thrombosis with usual manifestations, for example, DVT or PE. ments.123 The presence of an underlying MPN complicates this In contrast, when venous thromboses manifest at an unusual further. In a retrospective study conducted by the GIMEMA site, the diagnosis should always be kept in mind. The Chronic MPD Working Party, the frequency of thrombotic and JAK2V617F mutation occurs in 7–41 % of patient with hemorrhagic events after surgical procedures were verified in thromboses in splanchnic veins. 255 patients with PV and ET who had at least one surgery.124 The main treatment options in the prevention of thrombosis, With a total of 311 surgical interventions, 12 arterial and 12 for example, aspirin as antiplatelet drug and HU for cytoreduc- venous thrombotic events were noted. The investigators men- tion, have proven overall benefits, such as reduced morbidity tioned that the use of heparin and even antiplatelet agents did and mortality in PV and ET patients. Further studies are not influence adverse outcomes, with only a possible trend warranted to investigate effects on venous thrombosis, and for prevention of venous thromboembolism in patients who whether a subset of patients, such as, patients with venous received heparin.124 The optimal approach for surgical throm- thrombosis instead of arterial thrombosis, should be treated bosis prophylaxis in PV and ET patients remains subjective.124 differently and more intensively. Acute DVT or PE in the setting Splenectomy is now carried out less frequently in PV and ET, of PV and ET should be treated similarly as venous thrombosis because of improvement in treatment options. The relative from other causes, but a possible increase of risk and difficulties perioperative mortality of splenectomy is B10%.125 Additional in diagnosing HIT should be kept in mind when using heparins. post-splenectomy complications include infections, a potential Emerging targeted therapy, for example, JAK2 inhibitors and increased risk for malignancy and thrombosis.126 Current HDACIs, are currently being tested in clinical trials, and should indications for splenectomy include symptomatic portal hyper- be carefully evaluated for their effects on venous thrombosis. tension or drug-refractory marked splenomegaly associated with New anticoagulants are also entering clinical practice, but their pain or severe cachexia. Cytoreduction, to keep platelet count potential role among MPN patients have to be further evaluated. below 400 Â 109/l, and anticoagulants are recommended prophylactically before splenectomy. Surgery should preferably be carried out only by an experienced surgical team. 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 thrombo- References philia. The most common of the mutations leading to increase risk of venous thromboembolism is the mutation in factor V (FV), 1 WHO. World Health Organization Classification of Tumors of 43 Haematopoietic and Lymphoid Tissues, 4th edn, International the so-called Leiden mutation. Ruggeri et al. investigated Agency for Cancer: Lyon, 2008. whether the presence of FV Leiden could be a risk factor for 2 Johansson P. Epidemiology of the myeloproliferative disorders thrombosis in PV and ET patients. FV Leiden was found in 4.6%, polycythemia vera and essential thrombocythemia. Semin approximately the same as in the general population.127 FV Thromb Hemost 2006; 32: 171–173. Leiden mutation was associated with venous thromboembolism 3 Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC. before and at diagnosis and with recurrence of venous Incidence, clinical features and outcome of essential thrombo- 43 cythaemia in a well defined geographical area. Eur J Haematol thromboembolism. This effect was not found for arterial 2000; 65: 132–139. thrombosis. The issue of hereditary thrombophilia is not limited 4 Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, to FV Leiden. The prothrombin 20210 G4A mutation44 as well Griesshammer M et al. Philadelphia-negative classical myelo- as the rarer forms of thrombophilias, such as antithrombin III, proliferative neoplasms: critical concepts and management protein C and protein S hereditary deficiencies, should be recommendations from European LeukemiaNet. J Clin Oncol also considered. Screening for hereditary thrombophilia 2011; 29: 761–770. 5 Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono may be considered to identify high-risk PV and ET patients, and C et al. Vascular and neoplastic risk in a large cohort of patients should at least be considered in patients with relapse of venous with polycythemia vera. J Clin Oncol 2005; 23: 2224–2232. thromboembolism, which may require more intensive treatment. 6 Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 2011; 29: 573–582. Summary/Conclusion 7 Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol 2010; 91: 165–173. PV and ET are chronic MPN characterized by a benign and 8 Levine RL. Mechanisms of mutations in myeloproliferative indolent clinical course. Arterial and venous thromboses neoplasms. Best Pract Res Clin Haematol 2009; 22: 489–494.

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