Hemostasis Disorders in Patients with De Novo Acute Leukemias

AUTOIMMUNE THROMBOCYTOPENIA ,

OA Polevodova, GM Galstyan, VV Troitskaya, EB Orel, MYu Drokov, EN Parovichnikova

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Gennadii Martinovich Galstyan, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: 8(495)612-48-59; e-mail: gengalst@gmail.com

For citation: Polevodova OA, Galstyan GM, Troitskaya VV, et al. Hemostasis Disorders in Patients with De Novo Acute Leukemias. Clinical oncohematology. 2021;14(2):231–8. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-231-238

ABSTRACT

Aim. To study hemostasis disorders in patients with de novo acute leukemias (AL) prior to chemotherapy.

Materials & Methods. The study enrolled 107 patients with newly diagnosed AL, aged 18–80 years and treated at the National Research Center for Hematology. Acute lymphoblastic leukemia (ALL) was identified in 37 patients, acute myeloid leukemia (AML) was diagnosed in 46 patients, and acute promyelocytic leukemia (APL) was reported in 24 patients. Hemorrhagic and thrombotic complications were analyzed; platelet count, APPT, prothrombin and fibrinogen concentration were determined; thromboelastography (TEG; native tests, functional fibrinogen tests) and rotation thromboelastometry (ROTEM; EXTEM, INTEM, FIBTEM, APTEM) were performed. The data were statistically processed using SAS 9.4 software.

Results. At AL onset hemorrhagic syndrome was detected in 34 (32 %) out of 107 patients. It was manifested by petechia (n = 16), subcutaneous hematomas (n = 12), gingival (n = 10) and nose (n = 6) bleeding, uterine bleeding (n = 2), hematuria (n = 2), gastrointestinal bleeding (n = 1), brain hemorrhage (n = 6), and periorbital hematoma (n = 1). According to TEG and ROTEM hypocoagulation was more common in APL patients. Hyperfibrinolysis could be detected using only ROTEM in 54 % of APL patients, in 8 % of ALL and 4 % of AML patients. Compared to other AL patients those with APL showed different parameters of fibrinogen concentration of < 1.75 g/L (sensitivity 83.3 %, specificity 83.13 %), D-dimer concentration of > 2686 µg/L (sensitivity 72.73 %, specificity 64.79 %), MCFFIBTEM < 12.5 mm (sensitivity 80 %, specificity 80 %), and МАFF < 9.7 mm (sensitivity 86.96 %, specificity 90.12 %).

Conclusion. The parameters that distinguish APL from other categories of AL patients are hypofibrinogenemia, higher D-dimer concentration, ROTEM changes, and hyperfibrinolysis.

Keywords: hemostatic system, acute leukemia, hemorrhagic syndrome, thrombosis, integral tests, thromboelastometry, thromboelastography.

Received: December 2, 2020

Accepted: March 5, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2018. 1008 с.
    [Savchenko VG, ed. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. (Diagnostic algorithms and treatment protocols in hematological diseases.) Moscow: Praktika Publ.; 2018. 1008 p. (In Russ)]
  2. Rea B, Frank D. An uncommon manifestation of acute leukemia. Gastrointest Endosc. 2017;86(1):240–2. doi: 10.1016/j.gie.2016.12.010.
  3. Gallo G, Bigliardi S, Cesinaro A. A case of extramedullary hematopoiesis presenting as hemorrhagic panniculitis and evolving in acute myeloid leukemia. J Cutan Pathol. 2019;46(10):775–7. doi: 10.1111/cup.13498.
  4. Lieberman F, Villgran V, Normolle D, et al. Intracranial Hemorrhage in Patients Newly Diagnosed with Acute Myeloid Leukemia and Hyperleukocytosis. Acta Haematol. 2017;138(2):116–8. doi: 10.1159/000478690.
  5. Галстян Г.М., Кречетова А.В., Троицкая В.В. и др. Высокодозная терапия концентратом антитромбина III больных септическим шоком в состоянии агранулоцитоза. Анестезиология и реаниматология. 2014;59(4):39–45.
    [Galstyan GM, Krechetova AV, Troitskaya VV, et al. High-dose therapy with antithrombin III in agranulocytosis patients with septic shock. Anesteziologiya i reanimatologiya. 2014;59(4):39–45. (In Russ)]
  6. Mitrovic M, Suvajdzic N, Bogdanovic A, et al. International Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular coagulation >6: a new predictor of hemorrhagic early death in acute promyelocytic leukemia. Med Oncol. 2013;30(1):478. doi: 10.1007/s12032-013-0478-y.
  7. Coombs CC, Tavakkoli M, Tallman MS. Acute promyelocytic leukemia: where did we start, where are we now, and the future. Blood Cancer J. 2015;5(4):e304. doi: 10.1038/bcj.2015.25.
  8. Di Bona E, Avvisati G, Castaman G, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000;108(4):689–95. doi: 10.1046/j.1365-2141.2000.01936.x.
  9. Breccia M, Latagliata R, Cannella L, et al. Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation. Haematologica. 2010;95(5):853–4. doi: 10.3324/haematol.2009.017962.
  10. de la Serna J, Montesinos P, Vellenga E, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. 2008;111(7):3395–402. doi: 10.1182/blood-2007-07-100669.
  11. Дементьева И.И., Морозов Ю.А., Чарная М.А. и др. Технологии POINT OF CARE в клинике неотложных состояний. Клиническая лабораторная диагностика. 2013;7:5–10.
    [Dement’eva II, Morozov YuA, Charnaya MA, et al. POINT OF CARE technologies under clinic emergency conditions. Klinicheskaya laboratornaya diagnostika. 2013;7:5–10. (In Russ)]
  12. Lang T, Bauters A, Braun SL, et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinol. 2005;16(4):301–10. doi: 10.1097/01.mbc.0000169225.31173.19.
  13. Rollig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood. 2015;125(21):3246–52. doi: 10.1182/blood-2014-10-551507.
  14. Schochl H, Frietsch T, Pavelka M, et al. Hyperfibrinolysis After Major Trauma: Differential Diagnosis of Lysis Patterns and Prognostic Value of Thrombelastometry. J Trauma Inj Infect Crit Care. 2009;67(1):125–31. doi: 10.1097/TA.0b013e31818b2483.
  15. Баркаган З.С., Момот А.П. Диагностика и контролируемая терапия нарушений гемостаза. М.: Ньюдиамед, 2008. С. 103–13.
    [Barkagan ZS, Momot AP. Diagnostika i kontroliruemaya terapiya narushenii gemostaza. (Diagnosis and monitor therapy of hemostasis disorders.) Moscow: N’yudiamed Publ.; 2008. 103–13. (In Russ)]
  16. Буланов А.Ю., Яцков К.В., Буланова Е.Л. и др. Тромбоэластография: клиническая значимость теста на функциональный фибриноген. Вестник интенсивной терапии. 2017;1:5–11.
    [Bulanov AYu, Yatskov KV, Bulanova EL, et al. Thromboelastography: the clinical significance of the functional fibrinogen test. Vestnik intensivnoi terapii. 2017;1:5–11. (In Russ)]
  17. Chapman MP, Moore EE, Ramos CR, et al. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013;75(6):961–7. doi: 10.1097/TA.0b013e3182aa9c9f.
  18. Gonzalez E, Moore EE, Moore HB. Management of Trauma-Induced Coagulopathy with Thrombelastography. Crit Care Clin. 2017;33(1):119–34. doi: 10.1016/j.ccc.2016.09.002.
  19. Hemker HC, Giesen P, Al Dieri R, et al. Calibrated Automated Thrombin Generation Measurement in Clotting Plasma. Pathophysiol Haemost Thromb. 2003;33(1):4–15. doi: 10.1159/000071636.
  20. McCullough J, Vesole DH, Benjamin RJ, et al. Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: The SPRINT trial. Blood. 2004;104(5):1534–41. doi: 10.1182/blood-2003-12-4443.
  21. Савченко В.Г., Паровичникова Е.Н., Соколов А.Н. и др. Клинические рекомендации по диагностике и лечению острого промиелоцитарного лейкоза у взрослых. Национальное гематологическое общество. 2014. (электронный документ) Доступно по: https://docplayer.ru/50397388-Klinicheskie-rekomendacii-po-diagnostike-i-lecheniyu-ostrogo-promielocitarnogo-leykoza-u-vzroslyh.html. Ссылка активна на 5.02.2021.
    [Savchenko VG, Parovichnikova EN, Sokolov AN, et al. Clinical guidelines on diagnosis and treatment of adult acute promyelocytic leukemia. National Society of Hematology. 201 [Internet] Available from: https://docplayer.ru/50397388-Klinicheskie-rekomendacii-po-diagnostike-i-lecheniyu-ostrogo-promielocitarnogo-leykoza-u-vzroslyh.html. (accessed 02.2021) (In Russ)]
  22. Воробьев А.И., Бронштейн М.И., Баранов А.Е. О промиелоцитарном варианте острого лейкоза. Вестник АМН СССР. 1968;4:36–45.
    [Vorob’ev AI, Bronshtein MI, Baranov AE. On promyelocytic variant of acute leukemia. Vestnik AMN SSSR. 1968;4:36–45. (In Russ)]
  23. Avvisati G, ten Cate JW, Sturk A, et al. Acquired alpha-2-antiplasmin deficiency in acute promyelocytic leukaemia. Br J Haematol. 1988;70(1):43–8. doi: 10.1111/j.1365-2141.1988.tb02432.x.
  24. Wijermans PW, Rebel VI, Ossenkoppele GJ, et al. Combined procoagulant activity and proteolytic activity of acute promyelocytic leukemic cells: reversal of the bleeding disorder by cell differentiation. Blood. 1989;73(3):800–5. doi: 10.1182/blood.V73.3.800.bloodjournal733800.
  25. Wada K, Takahashi H, Hanano M, et al. Plasma urokinase-type plasminogen activator in patients with leukemias. Leuk Lymphoma. 1994;15(5–6):499–502. doi: 10.3109/10428199409049754.
  26. Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. N Engl J Med. 1999;340(13):994–1004. doi: 10.1056/NEJM199904013401303.
  27. Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost. 2018;16(4):652–62. doi: 10.1111/jth.13957.
  28. Negrier C, Ninet J, Bordet J, et al. Use of calibrated automated thrombinography ± thrombomodulin to recognise the prothrombotic phenotype. Thromb Haemost. 2017;96(5):562–7. doi: 10.1160/th06-03-0179.
  29. Abuelkasem E, Lu S, Tanaka K, et al. Comparison between thrombelastography and thromboelastometry in hyperfibrinolysis detection during adult liver transplantation. Br J Anaesth. 2016;116(4):507–12. doi: 10.1093/bja/aew023.
  30. da Luz LT, Nascimento B, Rizoli S. Thrombelastography (TEG®): practical considerations on its clinical use in trauma resuscitation. Scand J Trauma Resusc Emerg Med. 2013;21(1):29. doi: 10.1186/1757-7241-21-29.
  31. Moore HB, Moore EE, Liras IN, et al. Acute Fibrinolysis Shutdown after Injury Occurs Frequently and Increases Mortality: A Multicenter Evaluation of 2,540 Severely Injured Patients. J Am Coll Surg. 2016;222(4):347–55. doi: 10.1016/J.JAMCOLLSURG.2016.01.006.
  32. Lou Y, Suo S, Tong H, et al. Hypofibrinogenemia as a clue in the presumptive diagnosis of acute promyelocytic leukemia. Leuk Res. 2016;50:11–6. doi: 10.1016/j.leukres.2016.09.006.
  33. Zhang X, Hu Y, Bao L, et al. Arsenic trioxide downregulates the expression of annexin II in bone marrow cells from patients with acute myelogenous leukemia. Chin Med J (Engl). 2009;122(17):1969–73. doi: 10.3760/cma.j.issn.0366-6999.2009.17.002.
  34. Stein EM, Tallman MS. Provocative pearls in diagnosing and treating acute promyelocytic leukemia. Oncology (Williston Park). 2012;26(7):636–41.
  35. Yanada M, Matsushita T, Asou N, et al. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. Eur J Haematol. 2007;78(3):213–9. doi: 10.1111/j.1600-0609.2006.00803.x.
  36. Choudhry A, DeLoughery TG. Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol. 2012;87(6):596–603. doi: 10.1002/ajh.23158.
  37. Grisariu S, Spectre G, Kalish Y, et al. Increased risk of central venous catheter–associated thrombosis in acute promyelocytic leukemia: a single-institution experience. 2013;90(5):397–403. doi: 10.1111/ejh.12087.