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Semin Thromb Hemost 2023; 49(02): 173-181
DOI: 10.1055/s-0042-1753483
Review Article

Thrombosis Risk Assessment in Myeloproliferative Neoplasm—Is There a Role for Viscoelastic Testing?

Hui Yin Lim
1   Department of Hematology, Northern Pathology Victoria, Northern Hospital, Epping VIC, Australia
2   Australian Centre for Blood Diseases, Monash University, Melbourne VIC, Australia
3   Department of Medicine, Northern Health, University of Melbourne, Heidelberg, VIC, Australia
,
Prahlad Ho 
1   Department of Hematology, Northern Pathology Victoria, Northern Hospital, Epping VIC, Australia
2   Australian Centre for Blood Diseases, Monash University, Melbourne VIC, Australia
3   Department of Medicine, Northern Health, University of Melbourne, Heidelberg, VIC, Australia
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Abstract

Philadelphia chromosome-negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. They are associated with increased thrombotic events, and the primary goal of therapy, in particular those with polycythemia vera and essential thrombocythemia, is the prevention of thrombotic complications typically with antiplatelet therapy and/or cytoreduction. While several patient-, disease-, and genomic-related factors have been identified to influence thrombotic risks, there are no routine laboratory investigations to date that are sufficiently accurate to assess the underlying procoagulant state and predict the thrombotic risks. Conventional coagulation testing only measures time to clot formation and cannot reliably predict bleeding and thrombotic risks. Global coagulation assays such as thromboelastography, thrombin, and fibrin generation may provide a more thorough assessment of hemostatic function. Thromboelastography and thromboelastometry are viscoelastic tests which measure the mechanical properties of the hemostatic process, including the global dynamics of clot formation, stabilization, and dissolution. While viscoelastic testing is gaining traction in the investigations of coagulopathies and goal-directed blood product replacement in trauma and massive transfusion settings, the role of these assays in thrombosis is less well defined. Here, we provide a review of the current evidence of the role of viscoelastic testing in myeloproliferative neoplasm, particularly in the thrombotic risk assessment.

Keywords

viscoelastic test - thromboelastography - thromboelastometry - thrombosis - myeloproliferative neoplasm


Publication History

Article published online:
02 September 2022

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  • References

  • 1 Arber DA, Orazi A, Hasserjian R. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20) 2391-2405
    CrossrefPubMedGoogle Scholar
  • 2 Rungjirajittranon T, Owattanapanich W, Ungprasert P, Siritanaratkul N, Ruchutrakool T. A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms. BMC Cancer 2019; 19 (01) 184
    CrossrefPubMedGoogle Scholar
  • 3 Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005; 128 (03) 275-290
    CrossrefPubMedGoogle Scholar
  • 4 Hamulyák EN, Daams JG, Leebeek FWG. et al. A systematic review of antithrombotic treatment of venous thromboembolism in patients with myeloproliferative neoplasms. Blood Adv 2021; 5 (01) 113-121
    CrossrefPubMedGoogle Scholar
  • 5 Marchioli R, Finazzi G, Landolfi R. et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005; 23 (10) 2224-2232
    CrossrefPubMedGoogle Scholar
  • 6 Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Büller HR, Cattaneo M. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res 2009; 124 (04) 409-417
    CrossrefPubMedGoogle Scholar
  • 7 Landolfi R, Cipriani MC, Novarese L. Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: pathogenetic mechanisms and prevention. Best Pract Res Clin Haematol 2006; 19 (03) 617-633
    CrossrefPubMedGoogle Scholar
  • 8 Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood 2017; 129 (06) 680-692
    CrossrefPubMedGoogle Scholar
  • 9 Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood 2013; 122 (13) 2176-2184
    CrossrefPubMedGoogle Scholar
  • 10 Kelliher S, Falanga A. Thrombosis in myeloproliferative neoplasms: a clinical and pathophysiological perspective. Thromb Update 2021; 5: 100081
    CrossrefPubMedGoogle Scholar
  • 11 Borowczyk M, Wojtaszewska M, Lewandowski K. et al. The JAK2V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms. Thromb Res 2015; 135 (02) 272-280
    CrossrefPubMedGoogle Scholar
  • 12 Zhang Y, Zhou Y, Wang Y. et al. Thrombosis among 1537 patients with JAK2V617F -mutated myeloproliferative neoplasms: risk factors and development of a predictive model. Cancer Med 2020; 9 (06) 2096-2105
    CrossrefPubMedGoogle Scholar
  • 13 Guglielmelli P, Loscocco GG, Mannarelli C. et al. JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis. Blood Cancer J 2021; 11 (12) 199
    CrossrefPubMedGoogle Scholar
  • 14 Pietra D, Rumi E, Ferretti VV. et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia 2016; 30 (02) 431-438
    CrossrefPubMedGoogle Scholar
  • 15 Rotunno G, Mannarelli C, Guglielmelli P. et al; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014; 123 (10) 1552-1555
    CrossrefPubMedGoogle Scholar
  • 16 Squizzato A, Romualdi E, Passamonti F, Middeldorp S. Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 2013; 4 (04) CD006503
    PubMedGoogle Scholar
  • 17 Chu DK, Hillis CM, Leong DP, Anand SS, Siegal DM. Benefits and risks of antithrombotic therapy in essential thrombocythemia: a systematic review. Ann Intern Med 2017; 167 (03) 170-180
    CrossrefPubMedGoogle Scholar
  • 18 Dielis AW, Castoldi E, Spronk HM. et al. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost 2008; 6 (01) 125-131
    CrossrefPubMedGoogle Scholar
  • 19 Barbui T, Carobbio A, De Stefano V. Thrombosis in myeloproliferative neoplasms during cytoreductive and antithrombotic drug treatment. Res Pract Thromb Haemost 2022; 6 (01) e12657
    CrossrefPubMedGoogle Scholar
  • 20 Lim HY, Nandurkar H, Ho P. Direct oral anticoagulants and the paradigm shift in the management of venous thromboembolism. Semin Thromb Hemost 2018; 44: 261-266
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 García Rodríguez LA, Martín-Pérez M, Hennekens CH, Rothwell PM, Lanas A. Bleeding risk with long-term low-dose aspirin: a systematic review of observational studies. PLoS One 2016; 11 (08) e0160046
    CrossrefPubMedGoogle Scholar
  • 22 Sankar K, Stein BL. Do all patients with polycythemia vera or essential thrombocythemia need cytoreduction?. J Natl Compr Canc Netw 2018; 16 (12) 1539-1545
    CrossrefPubMedGoogle Scholar
  • 23 De Stefano V, Rossi E, Carobbio A. et al. Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases. Blood Cancer J 2018; 8 (11) 112
    CrossrefPubMedGoogle Scholar
  • 24 Barbui T, Finazzi G, Carobbio A. et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 2012; 120 (26) 5128-5133 , quiz 5252
    CrossrefPubMedGoogle Scholar
  • 25 Guglielmelli P, Carobbio A, Rumi E. et al. Validation of the IPSET score for thrombosis in patients with prefibrotic myelofibrosis. Blood Cancer J 2020; 10 (02) 21
    CrossrefPubMedGoogle Scholar
  • 26 Bose P, Verstovsek S. Updates in the management of polycythemia vera and essential thrombocythemia. Ther Adv Hematol 2019; 10: 2040620719870052
    CrossrefPubMedGoogle Scholar
  • 27 Sankar K, Stein BL, Rampal RK. Thrombosis in the Philadelphia chromosome-negative myeloproliferative neoplasms. Cancer Treat Res 2019; 179: 159-178
    CrossrefPubMedGoogle Scholar
  • 28 Grinfeld J, Nangalia J, Baxter EJ. et al. Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med 2018; 379 (15) 1416-1430
    CrossrefPubMedGoogle Scholar
  • 29 Lim HY, O'Malley C, Donnan G, Nandurkar H, Ho P. A review of global coagulation assays—is there a role in thrombosis risk prediction?. Thromb Res 2019; 179: 45-55
    CrossrefPubMedGoogle Scholar
  • 30 Lim HY, Donnan G, Nandurkar H, Ho P. Global coagulation assays in hypercoagulable states. J Thromb Thrombolysis 2022; 54 (01) 132-144
    CrossrefPubMedGoogle Scholar
  • 31 Lancé MD. A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. Thromb J 2015; 13: 1-6
    CrossrefPubMedGoogle Scholar
  • 32 Bowbrick VA, Mikhailidis DP, Stansby G. The use of citrated whole blood in thromboelastography. Anesth Analg 2000; 90 (05) 1086-1088
    CrossrefPubMedGoogle Scholar
  • 33 McCrath DJ, Cerboni E, Frumento RJ, Hirsh AL, Bennett-Guerrero E. Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction. Anesth Analg 2005; 100 (06) 1576-1583
    CrossrefPubMedGoogle Scholar
  • 34 Carll T, Wool GD. Basic principles of viscoelastic testing. Transfusion 2020; 60 (Suppl. 06) S1-S9
    PubMedGoogle Scholar
  • 35 Wikkelsø A, Wetterslev J, Møller AM, Afshari A. Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. Cochrane Database Syst Rev 2016; 8 (08) CD007871
    PubMedGoogle Scholar
  • 36 Sarode K, Hussain SS, Tyroch A, Mukherjee D. A review of the current role of blood clotting analyzers in clinical practice. Cardiovasc Hematol Disord Drug Targets 2017; 17 (03) 167-179
    CrossrefPubMedGoogle Scholar
  • 37 Hincker A, Feit J, Sladen RN, Wagener G. Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. Crit Care 2014; 18 (05) 549
    CrossrefPubMedGoogle Scholar
  • 38 Walsh M, Kwaan H, McCauley R. et al. Viscoelastic testing in oncology patients (including for the diagnosis of fibrinolysis): review of existing evidence, technology comparison, and clinical utility. Transfusion 2020; 60 (Suppl. 06) S86-S100
    PubMedGoogle Scholar
  • 39 Walsh M, Moore EE, Moore H. et al. Use of viscoelastography in malignancy-associated coagulopathy and thrombosis: a review. Semin Thromb Hemost 2019; 45 (04) 354-372
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Yao X, Dong Q, Song Y, Wang Y, Deng Y, Li Y. Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. Cerebrovasc Dis 2014; 38 (03) 182-190
    CrossrefPubMedGoogle Scholar
  • 41 Rafiq S, Johansson PI, Ostrowski SR, Stissing T, Steinbrüchel DA. Hypercoagulability in patients undergoing coronary artery bypass grafting: prevalence, patient characteristics and postoperative outcome. Eur J Cardiothorac Surg 2012; 41 (03) 550-555
    CrossrefPubMedGoogle Scholar
  • 42 Ferrante EA, Blasier KR, Givens TB, Lloyd CA, Fischer TJ, Viola F. A novel device for the evaluation of hemostatic function in critical care settings. Anesth Analg 2016; 123 (06) 1372-1379
    CrossrefPubMedGoogle Scholar
  • 43 Tripodi A, Chantarangkul V, Gianniello F. et al. Global coagulation in myeloproliferative neoplasms. Ann Hematol 2013; 92 (12) 1633-1639
    CrossrefPubMedGoogle Scholar
  • 44 Lim HY, Ng C, Rigano J. et al. An evaluation of global coagulation assays in myeloproliferative neoplasm. Blood Coagul Fibrinolysis 2018; 29 (03) 300-306
    CrossrefPubMedGoogle Scholar
  • 45 Treliński J, Okońska M, Robak M, Chojnowski K. Assessment of rotation thromboelastometry parameters in patients with essential thrombocythemia at diagnosis and after hydroxyurea therapy. Blood Coagul Fibrinolysis 2016; 27 (02) 205-209
    CrossrefPubMedGoogle Scholar
  • 46 Şahin DG, Akay OM, Uskudar Teke H, Andıc N, Gunduz E. Use of rotational thromboelastometry for a global screening of coagulation profile in patients of myeloproliferative neoplasms. Platelets 2021; 32 (02) 280-283
    CrossrefPubMedGoogle Scholar
  • 47 Gadomska G, Rość D, Stankowska K, Boinska J, Ruszkowska-Ciastek B, Wieczór R. Selected parameters of hemostasis in patients with myeloproliferative neoplasms. Blood Coagul Fibrinolysis 2014; 25 (05) 464-470
    CrossrefPubMedGoogle Scholar
  • 48 Rość D, Kremplewska-Nalezyta E, Gadomska G, Zastawna E, Michalski A, Drewniak W. Plasminogen activators (t-PA and u-PA) and plasminogen activators inhibitors (PAI-1 and PAI-2) in some myeloproliferative syndromes. Med Sci Monit 2000; 6 (04) 684-691
    PubMedGoogle Scholar
  • 49 Moore HB, Paniccia A, Lawson PJ. et al. Utility of viscoelastic assays beyond coagulation: can preoperative thrombelastography indices predict tumor histology, nodal disease, and resectability in patients undergoing pancreatectomy?. J Am Coll Surg 2018; 227 (01) 55-62
    CrossrefPubMedGoogle Scholar
  • 50 Giannakopoulou N, Diamantopoulos P, Politou M. et al. Correlation of hemostatic parameters with poly (ADP-ribose) olymerase-1 (PARP-1) polymorphisms, mutations, laboratory, and clinical characteristics in 114 patients with Philadelphia-negative myeloproliferative neoplasms. J Hematol Blood Disord 2021; 7: 103
    PubMedGoogle Scholar
  • 51 Hattori N, Fukuchi K, Nakashima H. et al. Megakaryopoiesis and platelet function in polycythemia vera and essential thrombocythemia patients with JAK2V617F mutation. Int J Hematol 2008; 88 (02) 181-188
    CrossrefPubMedGoogle Scholar
  • 52 Nagler M, Ten Cate H. Thromboelastometry changes in myeloproliferative neoplasms-surrogate for a procoagulant haemostatic imbalance or a consequence of technical reasons?: Comment on A. Tripodi et al. Ann Hematol (2013) 92:1633-1639. Ann Hematol 2014; 93 (10) 1781-1782
    CrossrefPubMedGoogle Scholar
  • 53 Lim HY, Choy KW, Wang J, Nandurkar H, Ho P. Global coagulation assays—proposed reference intervals for healthy controls. Int J Lab Hematol 2022; 44 (03) e103-e106
    PubMedGoogle Scholar
  • 54 Nagler M, Kathriner S, Bachmann LM, Wuillemin WA. Impact of changes in haematocrit level and platelet count on thromboelastometry parameters. Thromb Res 2013; 131 (03) 249-253
    CrossrefPubMedGoogle Scholar
  • 55 Panova-Noeva M, Marchetti M, Spronk HM. et al. Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera. Am J Hematol 2011; 86 (04) 337-342
    CrossrefPubMedGoogle Scholar
  • 56 Mignon I, Grand F, Boyer F, Hunault-Berger M, Hamel JF, Macchi L. Thrombin generation and procoagulant phospholipids in patients with essential thrombocythemia and reactive thrombocytosis. Am J Hematol 2013; 88 (12) 1007-1011
    CrossrefPubMedGoogle Scholar
  • 57 Farina M, Russo D, Hoffman R. The possible role of mutated endothelial cells in myeloproliferative neoplasms. Haematologica 2021; 106 (11) 2813-2823
    CrossrefPubMedGoogle Scholar
  • 58 Giordano G, Napolitano M, Cellurale M. et al. Circulating endothelial cell levels correlate with treatment outcomes of splanchnic vein thrombosis in patients with chronic myeloproliferative neoplasms. J Pers Med 2022; 12 (03) 364
    CrossrefPubMedGoogle Scholar
  • 59 Chung I, Lip GY. Virchow's triad revisited: blood constituents. Pathophysiol Haemost Thromb 2003; 33 (5-6): 449-454
    CrossrefPubMedGoogle Scholar
  • 60 Giaccherini C, Verzeroli C, Marchetti M. et al. PO-26 - Whole blood rotational thromboelastometry (ROTEM) to detect hypercoagulability in patients with myeloproliferative neoplasms (MPN). (abstract) Thromb Res 2016; 140 (Suppl. 01) S185-S186
    CrossrefPubMedGoogle Scholar
  • 61 Nytofte N, Pedersen O, Hasselbalch H. Determinants of clot strength in polycythemia vera and primary myelofibrosis using rotational thromboelastometry. (abstract) Res Pract Thromb Haemost 2017; 1: 573-574
    PubMedGoogle Scholar
  • 62 Cini M, Portelli C, Vella K. et al. Thromboelastographic changes in patients with BCR-ABL negative myeloproliferative disorders. Res Pract Thromb Haemost 2018; 2: 266-267
    PubMedGoogle Scholar
  • 63 Liszewski W, Safah H, Leissinger C. Investigating hemostasis in patients with newly diagnosed hematologic malignancies using a thromboelastography protocol. (abstract) J Investig Med 2013; 61: 465
    PubMedGoogle Scholar
  • 64 Petkova N, Hristoskova R, Danchev D, Nikolov I, Raynov J. Essential thrombocythemia complicated with portal vein thrombosis and liver cirrhosis—a case report. (abstract) Res Pract Thromb Haemost 2020; 4: 1129-1130
    PubMedGoogle Scholar