Ann Hematol (2014) 93:1953–1963 DOI 10.1007/s00277-014-2224-8
REVIEW ARTICLE
Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (ÖGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.) Stephan Kreher & Sebastian Ochsenreither & Ralf U. Trappe & Ingrid Pabinger & Frauke Bergmann & Petro E. Petrides & Steffen Koschmieder & Axel Matzdorff & Andreas Tiede & Martin Griesshammer & Hanno Riess
Received: 29 June 2014 / Accepted: 25 September 2014 / Published online: 14 October 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) like polycythemia vera and essential thrombocythemia are at increased risk of arterial and venous thrombosis. Strategies of prevention may consist of platelet aggregation inhibitors and/or cytoreductive agents depending on the underlying disease and the individual risk. Clinical evidence for management of acute venous thromboembolic events in MPN patients is limited. Modality and duration of therapeutic anticoagulation after venous thrombosis has to be evaluated critically with special regard to the increased risk for spontaneous bleeding events associated with the underlying diseases. Both for therapy of the acute event
and for secondary prophylaxis, low-molecular-weight heparins should preferentially be used. A prolongation of the therapeutic anticoagulation beyond the usual 3 to 6 months can only be recommended in high-risk settings and after careful evaluation of potential risks and benefits for the individual patient. New direct oral anticoagulants (NOAC) should not preferentially be used due to lack of clinical experience in patients with MPN and potential drug interactions (e.g. with JAK inhibitors). Consequent treatment of the underlying myeloproliferative disease and periodical evaluation of the response to therapy is crucial for optimal secondary prophylaxis of thromboembolic events in those patients.
S. Kreher (*) : S. Ochsenreither : H. Riess Department of Hematology and Oncology, Charite Berlin, Berlin, Hindenburgdamm 30, 12200 Berlin, Germany e-mail:
[email protected]
S. Koschmieder Department of Hematology, Oncology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany
R. U. Trappe Department of Hematology and Oncology, DIAKO, Ev. Diakonie-Krankenhaus GmbH, Bremen, Germany I. Pabinger Clinical Department for Hematology and Hemostaseology, Vienna General Hospital–University Clinic, Vienna, Austria F. Bergmann MVZ Wagnerstibbe Für Laboratoriumsmedizin Und Pathologie GmbH, Hannover, Germany P. E. Petrides Hematology Oncology Center, Munich Isartor, Munich, Germany
A. Matzdorff Department of Hematology and Oncology, Caritas Klinikum Saarbrücken, Saarbrücken, Germany A. Tiede Department for Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany M. Griesshammer Department of Hematology, Oncology and Palliative Care, Mühlenkreiskliniken Johannes Wesling Klinikum Minden, Minden, Germany
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Keywords Venous thromboembolism . Myeloproliferative neoplasm . Essential thrombocythemia . Polycythemia vera
Background Myeloproliferative neoplasms (MPN) are clonal diseases originating from the hematopoietic stem cell, which are characterised by increased proliferative activity in one or more myeloid lineages. The actual WHO classification discriminates not only between Philadelphia chromosome (Ph)-positive chronic myeloid leukemia and Ph-negative MPN, but also further subdivided the latter group in several entities including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, and mastocytosis [1]. According to the effective WHO criteria of 2008, a representative bone marrow biopsy and the molecular proof of monoclonality is mandatory for diagnosis of Phnegative MPN. That being said, the majority of available clinical trials based the diagnosis on the formerly established PVSG criteria [2], which misclassified particularly early PV and PMF as ET. Hence, most available data on ET refer to mixed populations consisting of patients with ET, PMF and early PV (so-called PVSG-ET). Among the Ph-negative MPN, PV and ET are the most common ones, with annual incidences of 0.7 to 2.6 and 0.5 to 2.5 per 100,000 population, respectively [3, 4], with actual data from the USA indicating even higher numbers [5]. PMF in fibrotic stage is less frequent with an annual incidence of 0.5 to 1.5 per 100,000 [5, 6]. The identification of an increasing numbers of recurrent molecular alterations like the V617F mutation of Janus kinase 2 (JAK2), the MPL W515L/K mutation and mutations of calreticulin (CALR) contributed to a better understanding of the pathogenic mechanism shared by the different entities [7–16]. The clinical course of PV, ET and PMF (subsequently addressed to as Ph-negative MPN) is characterised by significantly increased risk for thromboembolic and hemorrhagic complications. Arterial and venous thromboembolisms (TE) contribute substantially to morbidity and mortality in this patient group causing approximately 45 % of all diseaseassociated fatal events [8, 17–20]. The safe and effective prophylaxis of TE events remains the main obstacle in the management of Ph-negative MPN patients. Despite existing guideline recommendations for primary and secondary prophylaxis of vascular events based on few prospective randomised clinical trials [8, 21, 22], useful evidence for management of acute venous thromboembolic events (VTE) remains insufficient. How and how long anticoagulation therapy after VTE event should be conducted in Ph-negative MPN patients is not an easy question to be answered, especially taking in account the increased bleeding
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risk, which may yet be aggravated by an acquired von Willebrand syndrome (vWS). The present study gives an overview over incidence, risk factors and therapeutic management of VTE, and it is supposed to provide help for individual therapeutic decision making in patients with Ph-negative MPN.
Incidence and pathophysiology of venous thromboembolism The cumulative incidence of all thromboembolic events amounts to 2.5 to 5.0 % per patient year in PV and to 1.9 to 3.0 % per patient year in ET patients [17, 23–26]. In patients with PMF, cardiovascular events are observed in 1.75 % of patients per year, a rate which is similar to the incidence in ET patients [27]. At first diagnosis, the prevalence of clinically relevant thrombosis has been reported by different epidemiological studies to be 11 to 39 % (PV) and 8 to 29 % (ET). In 8 to 19 % of the PV patients and in 8 to 31 % of the patients with ET, TE complications occur during the course of the disease [20, 22, 26, 28]. These rates are opposed by an overall incidence of at least 5.5 % serious bleeding events in this patient population [20, 29]. Only 30 % of all vascular events in Ph-negative MPN patients are VTE, which are less common than arterial TE. VTE preferentially present as deep vein thrombosis of the leg (DTL), lung artery embolism (LE) and thrombophlebitis [17, 19, 20, 29]. The prevalence of VTE at first diagnosis and the incidence during course of disease are given in Table 1. In patients with PV, VTE tend to occur more often than in patients with ET or PMF [28] and are associated with a significantly poorer overall survival [30]. One characteristic of Ph-negative MPN is the occurrence of venous thrombosis in uncommon locations. Typical sites of thrombosis in these patients are the splanchnic veins (SVT), including extra- and intrahepatic veins presenting with the clinical symptoms of Budd-Chiari syndrome (BCS), the portal vein and mesenteric veins. Furthermore, MPN patients suffer, above-average, frequently from cerebral sinus thrombosis [31, 32]. The prevalence of abdominal thrombosis amounts to 5.5 to 10 % in patients with PV and to 9.2 to 13 % in patients suffering from ET and PMF [33]. Abdominal venous thrombosis is often an
Table 1 Prevalence and incidence of MPN-associated VTE [26]
Prevalence at time of diagnosis Incidence after diagnosis (per year)
PV
ET
PMF
4–11 % 2%
2–8 % 0.6 %
3–7 % 0.6 %
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early event during course of disease. Oftentimes, the diagnosis of abdominal thrombosis yet antecedes the diagnosis of a Ph-negative MPN, and its incidence is frequently associated with the JAK2 V617F mutation [15, 31, 34–37]. Altogether, about 40 % of all abdominal thrombotic events are caused by latent or manifest MPN (Table 2) [38–40]. Therefore, it is strongly recommended to test all patients with thrombotic events in uncommon locations for MPN including the specific search for a myeloid clone with JAK2 point mutation [41]. Thrombophilia in MPN is caused by a complex interplay of a multitude of pathogenic mechanisms. Besides of universal factors, which affect the risk of thrombotic events in general (age, thrombotic event in patient history, exogenous factors like immobilisation), MPN-associated mechanisms, which include pathophysiologic alterations on cellular, plasmatic and hemodynamic levels, can play pivotal roles in pathogenesis of thrombosis (Table 3) [18, 19, 42]. Thrombocytes, leukocytes and erythrocytes originating from the affected hematopoietic stem cell are characterised by an activated phenotype and exhibit procoagulatory and/or proaggregatory features: Thrombocytes tend to spontaneous aggregation due to up-regulation of surface receptors like P-selectin, thrombospondin and activated fibrinogen receptor gpIIb/IIIa [43], activated leukocytes secrete procoagulatory and proaggregatory molecules and contribute to platelet activation by formation of thrombogenic leukocyte–thrombocyteaggregates [44–48], and finally, erythrocytes in MPN exhibit an increased adherence to vascular endothelium [49]. Thrombogenic plasmatic and hemodynamic alterations in MPN include increased viscosity, which appears proportional to hematocrit [50], an elevated number of circulating endothelial cells with thrombogenic potential [51] as well as thrombogenic microparticles [52], elevated resistance against activated protein C [48, 53] and a generalised inflammatory activation of the vascular endothelium mediated by upregulated secretion of cytokines and inflammation mediators by the neoplastic cells [54–57].
Incidence and pathophysiology of acquired vWS in Ph-negative MPN Like TE events, the genesis of bleeding complications in PV and ET has to be considered multifactorial. Nevertheless, in the majority of patients with PV or ET, signs of an acquired vWS are apparent in laboratory testing. Primarily depending on the absolute platelet number, an increasing proteolysis of von Willebrand factor (vWF) by ADAMTS13, resulting in the selective loss of big vWF multimers, can be observed. Especially with platelets exceeding 1000 x 109/l, a clinically relevant tendency to spontaneous bleeding events has to be expected [58, 59]. Additional causes of elevated bleeding risk are an acquired storage pool defect, the increased activation level in platelets common in Ph-negative MPN and a reduced surface density of certain platelet receptors [59–61].
Clinical risk factors and therapeutic strategies for the prevention of VTE The prevention of TE events is an important goal in management of Ph-negative MPN, and the choice of therapeutic measures should primarily be oriented on the presence of clinical risk factors (Table 3). In several prospective and retrospective studies, advanced age and history of thrombosis have been identified as main risk factors for thrombotic events in MPN patients [17, 27, 62–67]. While the extent of erythrocytosis appears to have direct impact on the rate of cardiovascular death and major thrombosis [62, 68], such a correlation between platelet count and respective risk for TE has not been proven contrary to popular opinion. Furthermore, several studies have identified general cardiovascular risk factors like arterial hypertension, nicotine abuse, hypercholesterolemia and diabetes mellitus [64], together with positive JAK2 mutational status in ET patients [69, 70], the allelic frequency of JAK2 V617F mutation [71–73] and leukocytosis [65, 66, 74] as additional risk factors for TE in MPN. ET Table 3 Cause and risk factors for MPN-associated VTE
Table 2 Mean prevalence of MPN in patients diagnosed with BCS and portal vein occlusion [40] BCS (n=440)
MPN PV ET PMF Unclassifiable MPN Solitary JAK2 V617F positive
40.9 % 52.9 % 24.6 % 6.7 % 17.0 % 6.5 %
Portal vein occlusion (n=615) 31.5 % 27.5 % 26.2 % 12.8 % 17.7 % 24.0 %
MPN-related
Patient-related
JAK2 mutational allelic burden Erythrocytosis and hyperviscosity Leukocytosis/leukocyte activation Thrombocytosis/thrombocyte activation Inflammatory mediators Circulating microparticles Activation of endothelial cells etc.
Age (>60 years) Sex History of VTE VTE in family history Hereditary thrombophilia Reduced mobility Trauma, surgery etc.
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patients with mutations of CALR have a lower risk of thrombosis than JAK2 and MPL mutated patients [75, 76]. However, for the main part, all these factors are predictors of arterial TE. Concerning venous thrombosis, the available studies produce mostly no or minimal, not significant associations with the mentioned risk factors. In a multivariate analysis of 891 patients with ET regarding age >60 years, history of thrombosis, sex, cardiovascular risk factors, leukocytosis >11 x 109/l, hemoglobin 1,000 x 109/l and JAK2 V617F mutational status, only male gender was associated with a significant higher risk for venous thrombotic events (HR 1.99; 95 % CI 1.03–3.83) [77]. On the other hand, Campbell et al. showed in a total population of 806 patients a significantly higher risk for thromboembolic events in patients with JAK2 V617F-mutated ET compared with JAK2 V617F-wild type ET [15]. For patients with PV, the ECLAP trial with 1,638 enrolled patients identified age >65 years (HR 2.03; 95 % CI 1.05–3.9), clinical history of venous thrombosis (HR 4.19; 95 % CI 2.01–8.72) and preexistent intermittent claudication (HR 2.81; 95 % CI 1.14–6.83) as statistically significant risk factors. An antedated arterial thrombosis, on the other hand, had no impact on the risk of VTE (HR 1.09; 95 % 0.57–2.05) [66]. In patients with ET and PV, the presence of a hereditary thrombophilic disorder like, e.g. the heterozygous factor-V Leiden mutation (FVL) R506Q is accompanied by increased risk for venous thrombosis; the prevalence of FVL mutations, however, is not higher in patients with ET and PV compared with a normal population [78]. Taken together, to date, only age and history of thrombosis are assured factors, which can be used to predict the specific risk of venous thrombosis in MPN patients. The actual guideline recommendations for management of PV and ET state, aside from stringent reduction of cardiovascular risk factors like arterial hypertension, diabetes mellitus, hyperlipoproteinemia and smoking, a risk-adapted prevention strategy taking into account age (>60 years), history of thrombosis and previous bleeding events [8, 21]. Based on these factors, patients are discriminated in a low-risk group (age 60 years and/or history of bleeding/thrombosis and/or platelets >1,500 x 109/l in patients with ET). Additional factors like JAK2-mutational status, leukocytosis >15 x 10 9 /l, and the presence of elevated inflammatory markers are evaluated for risk stratification in alternative approaches [79, 80]. In accordance with effective guidelines, all patients with PV should be managed with phlebotomy to maintain the hematocrit at less than 45 % and, in the absence of contraindication, should be treated with low-dose ASS (75 to 100 mg per day) to prevent thromboembolic events (Table 4). Cytoreductive treatment is additionally recommended in high-risk constellation, poor tolerability of phlebotomy, progressing splenomegaly, progressing thrombocytosis or
Ann Hematol (2014) 93:1953–1963 Table 4 Prophylaxis of MPN-associated VTE
ASS Phlebotomy (Hkt60 years) compared with cytoreduction alone (29.2 vs. 8.6 TE/1,000 patient-years, P = 0.02). However, this number has to be put in context with a significant increase in bleeding complications (14.4 vs. 1.4 events/ 1,000 patient-years, P = 0.006) [85]. General
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recommendations for prophylactic application of ASS in patients with ET with aim of reduction of vascular TE cannot be drawn from this data. In case an antiplatelet treatment has been started because of high cardiovascular risk profile or manifest microangiopathic affliction, one recommended strategy for daily routine may be the functional characterisation of vWF (e.g. Ristocetin Cofactor, vWF activity, vWF collagen binding activity, etc.) in patients with more than 1,000 x 109/l thrombocytes in order to assess the extent of secondary vWS. ASS should not be administered to patients with vWF activityL/K mutation in essential thrombocythemia. Blood 112(3):844–847. doi:10.1182/ blood-2008-01-135897 15. Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, Duffy A, Boyd EM, Bench AJ, Scott MA, Vassiliou GS, Milligan DW, Smith SR, Erber WN, Bareford D, Wilkins BS, Reilly JT, Harrison CN, Green AR (2005) Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 366(9501):1945–1953. doi:10.1016/S0140-6736(05)67785-9 16. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369(25):2391–2405. doi:10.1056/NEJMoa1312542 17. Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, Marilus R, Villegas A, Tognoni G, Barbui T (2005) Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 23(10):2224– 2232. doi:10.1200/JCO.2005.07.062 18. Landolfi R, Di Gennaro L, Falanga A (2008) Thrombosis in myeloproliferative disorders: pathogenetic facts and speculation. Leukemia 22(11):2020–2028. doi:10.1038/leu.2008.253 19. Reikvam H, Tiu RV (2012) Venous thromboembolism in patients with essential thrombocythemia and polycythemia vera. Leukemia 26(4):563–571. doi:10.1038/leu.2011.314 20. Papadakis E, Hoffman R, Brenner B (2010) Thrombohemorrhagic complications of myeloproliferative disorders. Blood Rev 24(6): 227–232. doi:10.1016/j.blre.2010.08.002 21. McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D, Polkey MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B (2005) Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 130(2):174–195. doi:10.1111/j.1365-2141.2005.05535.x
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