Download PDF
Semin Thromb Hemost 2024; 50(02): 213-223
DOI: 10.1055/s-0043-57010
Review Article

The Pitfalls of Global Hemostasis Assays in Myeloproliferative Neoplasms and Future Challenges

Andrew Tiu
1   Division of Hematology-Oncology, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia
,
Thita Chiasakul
2   Division of Hematology, Department of Medicine, Center of Excellence in Translation Hematology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
,
Craig M. Kessler
1   Division of Hematology-Oncology, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Venous and arterial thromboembolism are major complications of myeloproliferative neoplasms (MPNs), comprising polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Global hemostasis assays, including thrombin generation assay (TGA), rotational thromboelastometry (ROTEM), and thromboelastography (TEG), have been proposed as biomarkers to assess the hypercoagulability and thrombotic risk stratification in MPNs. We performed a systematic literature review on the parameters of TGA, ROTEM, and TEG and their association with thrombotic events and treatment strategies in MPNs. Thirty-two studies (all cross-sectional) were included, which collectively enrolled 1,062 controls and 1,608 MPN patients. Among the 13 studies that reported arterial or venous thrombosis, the overall thrombosis rate was 13.8% with 6 splanchnic thromboses reported. Out of the 27 TGA studies, there was substantial heterogeneity in plasma preparation and trigger reagents employed in laboratory assays. There was a trend toward increased peak height among all MPN cohorts versus controls and higher endogenous thrombin potential (ETP) between ET patients versus controls. There was an overall trend toward lower ETP between PV and PMF patients versus. controls. There were no substantial differences in ETP between JAK2-positive versus JAK2-negative MPNs, prior history versus negative history of thrombotic events, and among different treatment strategies. Of the three ROTEM studies, there was a trend toward higher maximum clot firmness and shorter clot formation times for all MPNs versus controls. The three TEG studies had mixed results. We conclude that the ability of parameters from global hemostasis assays to predict for hypercoagulability events in MPN patients is inconsistent and inconclusive. Further prospective longitudinal studies are needed to validate these biomarker tools so that thrombotic potential could be utilized as a primary endpoint of such studies.

Keywords

global hemostatic assays - myeloproliferative neoplasms - thrombin generation assay - rotational thromboelastometry - thromboelastography

Authors' Contributions

A.T., T.C., and C.M.K. conceived the idea, did the systematic literature review, analyzed the data, and wrote the manuscript.




Publication History

Article published online:
17 April 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Spivak JL. Myeloproliferative neoplasms. N Engl J Med 2017; 376 (22) 2168-2181
    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 Hultcrantz M, Björkholm M, Dickman PW. et al. Risk for arterial and venous thrombosis in patients with myeloproliferative neoplasms: a population-based cohort study. Ann Intern Med 2018; 168 (05) 317-325
    CrossrefPubMedGoogle Scholar
  • 4 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
  • 5 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
  • 6 Tefferi A, Guglielmelli P, Lasho TL. et al. MIPSS70+ version 2.0: mutation and karyotype-enhanced international prognostic scoring system for primary myelofibrosis. J Clin Oncol 2018; 36 (17) 1769-1770
    CrossrefPubMedGoogle Scholar
  • 7 Ronner L, Venugopal S, Moshier E, Mascarenhas J. Improving the investigative approach to polycythaemia vera: a critical assessment of current evidence and vision for the future. Lancet Haematol 2021; 8 (08) e605-e612
    CrossrefPubMedGoogle Scholar
  • 8 Tripodi A, Chantarangkul V, Gianniello F. et al. Global coagulation in myeloproliferative neoplasms. Ann Hematol 2013; 92 (12) 1633-1639
    CrossrefPubMedGoogle Scholar
  • 9 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
  • 10 Ma LL, Wang YY, Yang ZH, Huang D, Weng H, Zeng XT. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better?. Mil Med Res 2020; 7 (01) 1-11
    PubMedGoogle Scholar
  • 11 Efremova E, Korsakova N, Matvienko O. et al. The natural anticoagulants in patients with Philadelphia-negative myeloproliferative neoplasms. HemaSphere 2019; 3 (Suppl. 01) 1000-1001
    CrossrefPubMedGoogle Scholar
  • 12 Matvienko O, Silina N, Korsakova N. et al. Microparticle-associated thrombin generation in patients with philadelphia-negative myeloproliferative neoplasms. Res Pract Thromb Haemost 2020; 4 (Suppl. 01) 173-174
    PubMedGoogle Scholar
  • 13 Korsakova N, Golovina O, Matvienko O. et al. Increased coagulation potential in patients with polycythemia vera and essential thrombocythemia with thrombotic history. Res Pract Thromb Haemost 2020; 4 (Suppl. 01) 1051-1052
    PubMedGoogle Scholar
  • 14 Duchemin J, Ugo V, Ianotto JC, Lecucq L, Mercier B, Abgrall JF. Increased circulating procoagulant activity and thrombin generation in patients with myeloproliferative neoplasms. Thromb Res 2010; 126 (03) 238-242
    CrossrefPubMedGoogle Scholar
  • 15 Ng C, Nandurkar H, Ho P. Evaluation of thromboelastography (TEG) in patients with myeloproliferative neoplasm (MPN): platelet count > 600 associated with prothrombotic parameters. J Thromb Haemost 2016; 14 (Suppl. 01) 79
    PubMedGoogle Scholar
  • 16 Palova M, Slavik L, Hlusi A. et al. Thrombin generation testing in patients with myelofibrosis. Clin Lab 2018; 64 (09) 1373-1383
    PubMedGoogle Scholar
  • 17 Trappenburg MC, van Schilfgaarde M, Marchetti M. et al. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica 2009; 94 (07) 911-918
    CrossrefPubMedGoogle Scholar
  • 18 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
  • 19 Marchetti M, Castoldi E, Spronk HMH. et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 2008; 112 (10) 4061-4068
    CrossrefPubMedGoogle Scholar
  • 20 Rusak T, Ciborowski M, Uchimiak-Owieczko A, Piszcz J, Radziwon P, Tomasiak M. Evaluation of hemostatic balance in blood from patients with polycythemia vera by means of thromboelastography: the effect of isovolemic erythrocytapheresis. Platelets 2012; 23 (06) 455-462
    CrossrefPubMedGoogle Scholar
  • 21 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
  • 22 Berens C, Ruhl H, Muller J. et al. Platelet-dependent thrombin generation induced by ADP or activated factor X does not contribute to increased in vivo thrombin formation in myeloproliferative neoplasms. Blood 2018; 132 (Suppl. 01) DOI: 10.1182/blood-2018-99-118487.
    CrossrefPubMedGoogle Scholar
  • 23 Perrin J, Ranta D, Empereur F, Vigneron C, Feugier P, Lecompte T. Polymorphonuclear neutrophils from JAK2(V617F) positive MPD patients do not support hypercoagulability: a study with calibrated automated thrombography (CAT). Blood Cells Mol Dis 2011; 46 (03) 235-238
    CrossrefPubMedGoogle Scholar
  • 24 Papakonstantinou E, Yfantis E, Theofani A. et al. Endogenous thrombin potential (ETP) in myeloproliferative disorders (MPD). Haematologica 2010; 95 (Suppl. 02) 600
    PubMedGoogle Scholar
  • 25 Stein BL, McMahon B, Weiss I, Kwaan HC. Tissue-factor bearing microparticles and thrombotic risk in the myeloproliferative neoplasms. Blood 2012; 120 (21) 1145
    CrossrefPubMedGoogle Scholar
  • 26 Marchetti M, Tartari CJ, Russo L. et al. Phospholipid-dependent procoagulant activity is highly expressed by circulating microparticles in patients with essential thrombocythemia. Am J Hematol 2014; 89 (01) 68-73
    CrossrefPubMedGoogle Scholar
  • 27 Van Aalderen MC, Trappenburg MC, Van Schilfgaarde M. et al. Increased numbers of microparticles and microparticle specific thrombin generation in patients with myeloproliferative disease. Clin Exp Rheumatol 2010; 28 (2 Suppl 58): 86
    PubMedGoogle Scholar
  • 28 Vignoli A, Marchetti M, Russo L. et al. Monocyte (MNC) hemostatic profile in essential thrombocythemia (ET) or polycythemia vera (PV) patients is influenced by JAK2V617F mutational load. J Thromb Haemost 2009; 7 (S2): 49
    PubMedGoogle Scholar
  • 29 Panova-Noeva M, Marchetti M, Russo L. et al. ADP-induced platelet aggregation and thrombin generation are increased in essential thrombocythemia and polycythemia vera. Thromb Res 2013; 132 (01) 88-93
    CrossrefPubMedGoogle Scholar
  • 30 Matvienko O, Silina N, Korsakova N. et al. Efficiency of anticoagulant protein c system in patients with primary myelofibrosis. Res Pract Thromb Haemost 2019; 3 (Suppl. 01) 97
    PubMedGoogle Scholar
  • 31 Efremova E, Matvienko O, Fominykh M. et al. The coagulation system functioning in patients with myelofibrosis. HemaSphere 2018; 2 (Suppl. 02) 703-704
    PubMedGoogle Scholar
  • 32 Baccouche H, Ben Jemaa M, Chakroun A. et al. The evaluation of the relevance of thrombin generation and procoagulant activity in thrombotic risk assessment in BCR-ABL-negative myeloproliferative neoplasm patients. Int J Lab Hematol 2017; 39 (05) 502-507
    CrossrefPubMedGoogle Scholar
  • 33 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
  • 34 Faille D, Lamrani L, Loyau S. et al. Interferon alpha therapy increases pro-thrombotic biomarkers in patients with myeloproliferative neoplasms. Cancers (Basel) 2020; 12 (04) 992
    CrossrefPubMedGoogle Scholar
  • 35 Caron C, Wemeau M, Cambier N. et al. Hydroxyurea reduces thrombin generation (TG). J Thromb Haemost 2011; 9 (Suppl. 02) 433
    PubMedGoogle Scholar
  • 36 Matvienko O, Silina N, Korsakova N. et al. Influence of specific therapy on microparticle-associated thrombin generation in patients with primary myelofibrosis. Res Pract Thromb Haemost 2020; 4 (Suppl. 01) 175-176
    PubMedGoogle Scholar
  • 37 Silina N, Korsakova N, Golovina O. et al. Effect of therapy on thrombin generation in patients with polycythemia vera. Res Pract Thromb Haemost 2021; 5 (Suppl. 02) 830
    PubMedGoogle Scholar
  • 38 Giaccherini C, Marchetti M, Verzeroli C. et al. Rotational thrombo elastometry (ROTEM) detects the hypercoagulable profile of patients with essential thrombocythemia (ET) and polycythemia vera (PV) and is influenced by mutational status. Blood Transfus 2016; 14 (Suppl. 05) s792
    PubMedGoogle Scholar
  • 39 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
  • 40 de Laat-Kremers RMW, Ninivaggi M, Devreese KMJ, de Laat B. Towards standardization of thrombin generation assays: inventory of thrombin generation methods based on results of an International Society of Thrombosis and Haemostasis Scientific Standardization Committee survey. J Thromb Haemost 2020; 18 (08) 1893-1899
    CrossrefPubMedGoogle Scholar
  • 41 Ninivaggi M, de Laat-Kremers R, Tripodi A. et al. Recommendations for the measurement of thrombin generation: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2021; 19 (05) 1372-1378
    CrossrefPubMedGoogle Scholar
  • 42 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
  • 43 Moliterno AR, Ginzburg YZ, Hoffman R. Clinical insights into the origins of thrombosis in myeloproliferative neoplasms. Blood 2021; 137 (09) 1145-1153
    CrossrefPubMedGoogle Scholar
  • 44 Silina N, Matvienko O, Korsakova N. et al. The coagulation system state in patients with Philadelphia-negative myeloproliferative neoplasms. Res Pract Thromb Haemost 2018; 2 (Suppl. 01) 266
    PubMedGoogle Scholar
  • 45 Nytofte N, Pedersen O, Hasselbalch H. Determinants of clot strength in polycythemia vera and primary myelofibrosis using rotational thromboelastometry. Res Pract Thromb Haemost 2017; 1 (Suppl. 01) 573-574
    PubMedGoogle Scholar