thrombosis

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

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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.

Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

GM Galstyan, OA Polevodova, AV Bazhenov, VV Troitskaya, OA Gavrilina, DG Gitel’zon, AE Vasil’ev, EN Parovichnikova

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

For correspondence: Gennadii Martinovich Galstyan, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(916)488-50-73; e-mail: gengalst@gmail.com

For citation: Galstyan GM, Polevodova OA, Bazhenov AV, et al. Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase. Clinical oncohematology. 2018;11(1):89-99.

DOI: 10.21320/2500-2139-2018-11-1-89-99

ABSTRACT

The article provides a literature review on the use of the L-asparaginase (ASP) in acute lymphoblastic leukemia (ALL) and describes two clinical cases. During the treatment with ASP as part of remission induction therapy thrombotic and hemorrhagic complications in the central nervous system were registered. In both cases these complications were associated with reduced plasma levels of antithrombin III (АТ), hypofibrinogenemia and thrombocytopenia. The risk factors for thrombohemorrhagic complications in ALL patients during ASP treatment are reviewed including combined ASP + anthracycline therapy, oral contraceptives, glucocorticosteroids, thrombophilia and the presence of central venous catheter (CVC). Possible mechanisms of thrombosis as well as the timing of its occurrence and possible localisation are discussed. The article considers different strategies for prevention and treatment of thrombotic and hemorrhagic complications in ALL patients receiving ASP. In all ALL patients receiving ASP plasma levels of fibrinogen and AT should be assessed before treatment initiation, on day 3 after the injection and further every 5 to 7 days within a period of 3 weeks after the injection. Novel oral anticoagulants are not dependent on blood AT levels and may be used for prevention and treatment of thrombotic and hemorrhagic complications associated with ASP intake. Finally, recommendations for the correction of AT levels and hypofibrinogenemia are given.

Keywords: L-asparaginase, thrombosis, thromboelastography, antithrombin III, hypofibrinogenemia, thrombocytopenia, novel oral anticoagulants.

Received: August 16, 2017

Accepted: October 27, 2017

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REFERENCES

  1. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. и др. Национальные клинические рекомендации по диагностике и лечению острых миелоидных лейкозов взрослых. Гематология и трансфузиология. 2014;59(1):1–32. [Savchenko VG, Parovichnikova EN, Afanas’ev BV, et al. National clinical recommendations for the diagnosis and treatment of acute myeloid leukemia in adults. Gematologiya i transfuziologiya. 2014;59(1):1–32. (In Russ)]
  2. Asselin BL. The three asparaginases. In: Kaspers GJL, Pieters R, Veerman AJP, eds. Drug Resistance in Leukemia and Lymphoma III. Advances in Experimental Medicine and Biology, vol. 457. Boston: Springer; 1999. pp. 621–9. doi: 10.1007/978-1-4615-4811-9_69.
  3. Попа А.В. Возможности адекватного выбора различных препаратов аспарагиназы. Онкогематология. 2007;1:52–6. [Popa AV. The abilities of adequate choice of different asparaginase products. Onkogematologiya. 2007;1:52–6. (In Russ)]
  4. Priest JR, Ramsay NK, Steinherz PG, et al. A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. J Pediatr. 1982;100(6):984–9. doi: 10.1016/s0022-3476(82)80535-0.
  5. Caruso V, Iacoviello L, Castelnuovo A Di, et al. Thrombotic complications in childhood acute lymphoblastic leukemia : a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood. 2006;108(7):2216–22. doi: 10.1182/blood-2006-04-015511.
  6. Rozen L, Noubouossie D, Dedeken L, et al. Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase: A cohort study. Pediatr Blood Cancer. 2017;26(2):294–301. doi: 10.1002/pbc.26228.
  7. Caruso V, Iacoviello L, Di Castelnuovo A, et al. Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia: results from a meta-analysis. J Thromb Haemost. 2007;5(3):621–3. doi: 10.1111/j.1538-7836.2007.02383.x.
  8. Ranta S, Heyman MM, Jahnukainen K, et al. Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinol.  2013;24(7):749–56. doi: 10.1097/mbc.0b013e328363b147.
  9. Abbott LS, Deevska M, Fernandez CV, et al. The impact of prophylactic fresh-frozen plasma and cryoprecipitate on the incidence of central nervous system thrombosis and hemorrhage in children with acute lymphoblastic leukemia receiving asparaginase. Blood. 2009;114(25):5146–51. doi: 10.1182/blood-2009-07-231084.
  10. Grace RF, Dahlberg SE, Neuberg D, et al. The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol. 2011;152(4):452–9. doi: 10.1111/j.1365-2141.2010.08524.x.
  11. Merlen C, Bonnefoy A, Wagner E, et al. L-Asparaginase Lowers Plasma Antithrombin and Mannan-Binding-Lectin Levels: Impact on Thrombotic and Infectious Events in Children With Acute Lymphoblastic Leukemia. Pediatr Blood Cancer. 2015;62(8):1381–7. doi: 10.1002/pbc.25515.
  12. Mizrahi T, Leclerc J-M, David M, et al. ABO Group as a Thrombotic Risk Factor in Children With Acute Lymphoblastic Leukemia: A Retrospective Study of 523 Patients. J Pediatr Hematol Oncol. 2015;37(5):e328–32. doi: 10.1097/mph.0000000000000333.
  13. Lauw MN, Van der Holt B, Middeldorp S, et al. Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: Effect of fresh frozen plasma supplementation. Thromb Haemost. 2013;109(4):633–42. doi: 10.1160/th12-11-0845.
  14. Mitchell LG, Andrew M, Hanna K, et al. A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer. 2003;97(2):508–16. doi: 10.1002/cncr.11042.
  15. Sibai H, Seki JT, Wang TQ, et al. Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia. Curr Oncol. 2016;23(4):e355–61. doi: 10.3747/co.23.3077.
  16. Goyal G, Bhatt VR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. Fut Oncol. 2015;11(17):2459–70. doi: 10.2217/fon.15.114.
  17. Couturier M-A, Huguet F, Chevallier P, et al. Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience. Am J Hematol. 2015;90(11):986–91. doi: 10.1002/ajh.24130.
  18. Wani NA, Kosar T, Pala NA, Qureshi UA. Sagittal sinus thrombosis due to L-asparaginase. J Pediatr Neurosci. 2010;5(1):32–5. doi: 10.4103/1817-1745.66683.
  19. Guzman-Uribe P, Vargas-Ruiz AG. Thrombosis in Leukemia: Incidence, Causes, and Practical Management. Curr Oncol Rep. 2015;17(5):444. doi: 10.1007/s11912-015-0444-2.
  20. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with philadelphia chromosome-negative acute lymphoblastic leukemia: The GRAALL-2003 study. J Clin Oncol. 2009;27(6):911–8. doi: 10.1200/jco.2008.18.6916.
  21. Santoro N, Colombini A, Silvestri D, et al. Screening for coagulopathy and identification of children with acute lymphoblastic leukemia at a higher risk of symptomatic venous thrombosis: an AIEOP experience. J Pediatr Hematol Oncol. 2013;35(5):348–55. doi: 10.1097/mph.0b013e31828dc614.
  22. Pui C, Chesney CM, Bergum PW, et al. Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginase-prednisone-vincristine therapy for leukaemia. Br J Haematol. 1986;64(2):283–90. doi: 10.1111/j.1365-2141.1986.tb04121.x.
  23. Mauz-Korholz C, Junker R, Gobel U, Nowak-Gottl U. Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). Thromb Haemost. 2000;83(6):840–3.
  24. Risseeuw-Appel IM, Dekker I, Hop WC, Hahlen K. Minimal effects of E. coli and Erwinia asparaginase on the coagulation system in childhood acute lymphoblastic leukemia: a randomized study. Med Pediatr Oncol. 1994;23(4):335–43. doi: 10.1002/mpo.2950230404.
  25. Domenech C, Thomas X, Chabaud S, et al. L-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: Results of the GRASPALL 2005-01 randomized trial. Br J Haematol. 2011;153(1):58–65. doi: 10.1111/j.1365-2141.2011.08588.x.
  26. Nowak-Gottl U, Ahlke E, Fleischhack G, et al. Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. Blood. 2003;101(7):2529–33. doi: 10.1182/blood-2002-06-1901.
  27. Hernandez-Espinosa D, Minano A, Ordonez A, et al. Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment. J Thromb Haemostasis. 2009;7(7):1128–33. doi: 10.1111/j.1538-7836.2009.03449.x.
  28. Hunault-Berger M, Chevallier P, Delain M, et al. Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of supportive coagulation therapy and clinical outcome: The CAPELAL study. Haematologica. 2008;93(10):1488–94. doi: 10.3324/haematol.12948.
  29. Ueno T, Ohtawa K, Mitsui K, et al. Cell cycle arrest and apoptosis of leukemia cells induced by L-asparaginase. Leukemia. 1997;11(11):1858–61. doi: 10.1038/sj.leu.2400834.
  30. Sugimoto K, Suzuki HI, Fujimura T, et al. A clinically attainable dose of L-asparaginase targets glutamine addiction in lymphoid cell lines. Cancer Sci. 2015;106(11):1534–43. doi: 10.1111/cas.12807.
  31. De Stefano V, Za T, Ciminello A, et al. Haemostatic alterations induced by treatment with asparaginases and clinical consequences. Thromb Haemost. 2015;113(2):247–61. doi: 10.1160/th14-04-0372.
  32. Giordano P, Molinari AC, Del Vecchio GC, et al. Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am J Hematol. 2010;85(5):325–30. doi: 10.1002/ajh.21665.
  33. Nowak-Gottl U, Boos J, Wolff J, et al. Asparaginase decreases clotting factors in vitro: a possible pitfall? Int J Clin Lab Res. 1995;25(3):146–8. doi: 10.1007/bf02592556.
  34. Bushman JE, Palmieri D, Whinna HC, Church FC. Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. Leuk Res. 2000;24(7):559–65. doi: 10.1016/s0145-2126(00)00017-5.
  35. Priest JR, Ramsay NKC, Bennett AJ, et al. The effect of L-asparaginase on antithrombin, plasminogen, and plasma coagulation during therapy for acute lymphoblastic leukemia. J Pediatr. 1982;100(6):990–5. doi: 10.1016/s0022-3476(82)80536-2.
  36. Mazzucconi MG, Gugliotta L, Leone G, et al. Antithrombin III infusion suppresses the hypercoagulable state in adult acute lymphoblastic leukaemia patients treated with a low dose of Escherichia coli L-asparaginase. A GIMEMA study. Blood Coagul Fibrinol. 1994;5(1):23–8. doi: 10.1097/00001721-199402000-00004.
  37. Mitchell L, Andrew M, Hanna K, et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost. 2003;90(2):235–44. doi: 10.1160/th02-11-0283.
  38. Farrell K, Fyfe A, Allan J, et al. An antithrombin replacement strategy during asparaginase therapy for acute lymphoblastic leukemia is associated with a reduction in thrombotic events. Leuk Lymphoma. 2016;57(11):2567–74. doi: 10.3109/10428194.2016.1165815.
  39. Elhasid R, Lanir N, Sharon R, et al. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinol. 2001;12(5):367–70. doi: 10.1097/00001721-200107000-00005.
  40. Meister B, Kropshofer G, Klein-Franke A, et al. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2008;50(2):298–303. doi: 10.1002/pbc.21222.
  41. Plander M, Szendrei T, Bodo I, Ivanyi JL. Successful treatment with rivaroxaban of an extended superficial vein thrombosis in a patient with acquired antithrombin deficiency due to Peg-asparaginase treatment. Ann Hematol. 2015;94(7):1257–8. doi: 10.1007/s00277-015-2368-1.

Genetic Markers of Hereditary Thrombophilia and Risk of Thrombotic Complications in Patients with Polycythemia Vera

MYELOID TUMORS , ,

DI Shikhbabaeva, LB Polushkina, VA Shuvaev, IS Martynkevich, SI Kapustin, TB Zamotina, MS Fominykh, VU Udal’eva, II Zotova, VM Shmeleva, OA Smirnova, SV Voloshin, SS Bessmel’tsev, AV Chechetkin, KM Abdulkadyrov

Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Dzhariyat Ismailovna Shikhbabaeva, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel: +7(931)201-71-28; e-mail: djeri.shih@mail.ru

For citation: Shikhbabaeva DI, Polushkina LB, Shuvaev VA, et al. Genetic Markers of Hereditary Thrombophilia and Risk of Thrombotic Complications in Patients with Polycythemia Vera. Clinical oncohematology. 2017;10(1):85–92 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-85-92

ABSTRACT

Background. Thrombotic complications are one of the main problems of polycythemia vera (PV) treatment. They significantly impair the quality of life of these patients and may lead to the lethal outcome. A thrombotic event often precedes the diagnosis of this hematological disease. The pathogenesis of thrombosis in myeloproliferative neoplasms, PV, in particular, is a complex one. Prescription of antiaggregants in the absence of thrombosis and anticoagulants after a thrombotic event requires special attention and development of corresponding recommendations. The prescription of anticoagulants is impossible without taking into account the risks of hemorrhagic complications, which are also typical for myeloproliferative neoplasms.

Aim. Assessment of the impact of hereditary thrombophilia genetic markers on the risk of thrombotic complications in patients with PV.

Methods. The study examined 116 patients with PV, who were screened for markers of hereditary thrombophilia: factor V (G1691A, FV Leiden), prothrombin, methylenetetrahydrofolate reductase (MTHFR), fibrinogen (FI), plasminogen activator inhibitor (PAI-1), and platelet fibrinogen receptor type IIIA (GPIIIA). The incidence of these markers and their role in thrombosis in such patients was investigated.

Results. The study provided data on the incidence of hereditary thrombophilia markers in patients with PV. Statistically significant differences in the incidence of these markers and homocysteine level were found between patients with thrombosis and without them.

Conclusion. The information about the hereditary thrombophilia markers presence may be useful for the prescription of adequate antiaggregant and anticoagulant therapy for PV patients. Further research in this field is justified and it will probably demonstrate the relevance of hereditary thrombophilia markers as prognostic factors for thrombotic complications risk assessment.

Keywords: polycythemia vera, hereditary thrombophilia, thrombosis.

Received: December 11, 2016

Accepted: December 21, 2016

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REFERENCES

  1. Wolanskyj AP, Schwager SM, McClure RF, et al. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006;81(2):159–66. doi: 10.4065/81.2.159.
  2. Carobbio A, Finazzi G, Guerini V, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors and Jak2 mutation status. Blood. 2007;109(6):2310–3. doi: 10.1182/blood-2006-09-046342.
  3. Гусева С.А., Бессмельцев С.С., Абдулкадыров К.М., Гончаров Я.П. Истинная полицитемия. Киев, СПб.: Логос, 2009. 405 с.
    [Guseva SA, Bessmel’tsev SS, Abdulkadyrov KM, Goncharov YaP. Istinnaya politsitemiya. (Polycythemia vera.) Kiev, Saint Petersburg: Logos Publ.; 2009. 405 p. (In Russ)]
  4. Finazzi G, Rambaldi A, Guerini V, et al. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. Haematologica. 2007;92(1):135–6. doi: 10.3324/haematol.10634.
  5. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2 V617F allele burden. Leukemia. 2007;21(9):1952–9. doi: 10.1038/sj.leu.2404854.
  6. Besses C, Cervantes F, Pereira A, et al. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia. 1999;13(2):150–4. doi: 10.1038/sj.leu.2401270.
  7. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755–61. doi: 10.1016/j.amjmed.2004.06.032.
  8. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22–33. doi: 10.1155/2011/794240.
  9. Hebbel RP, Boogaerts MA, Eaton JW, et al. Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity. N Engl J Med. 1980;302(18):992–5. doi: 10.1056/nejm198005013021803.
  10. Wautier JL, Paton RC, Wautier MP, et al. Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus and its relation to vascular complications. N Engl J Med. 1981;305(5):237–42. doi: 10.1056/nejm198107303050501.
  11. Wautier MP, El Nemer W, Gane P, et al. Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin alpha5 chain and Lu/BCAM. Blood. 2007;110(3):894–901. doi: 10.1182/blood-2006-10-048298.
  12. Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2012;2012(1):571–81.
  13. Goette NP, Lev PR, Heller PG, et al. Monocyte IL-2Ralpha expression is associated with thrombosis and the JAK2V617F mutation in myeloproliferative neoplasms. Cytokine. 2010;51(1):67–72. doi: 10.1016/j.cyto.2010.04.011.
  14. Jensen MK, De NullyBrown P, Lund BV, et al. Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders. Br J Haematol. 2000;110(1):116–24. doi: 10.1046/j.1365-2141.2000.02030.x.
  15. Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, et al. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica. 2006;91(2):169–75.
  16. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. ACC Curr J Rev. 2004;13(4):4–10. doi: 10.1016/j.accreview.2004.03.074.
  17. Abdulkarim K, Ridell B, Johansson P, et al. The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera. Eur J Haematol. 2011;86(2):148–55. doi: 10.1111/j.1600-0609.2010.01548.x.
  18. Barbui T, Thiele J, Passamonti F, et al. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood. 2012;119(10):2239–41. doi: 10.1182/blood-2011-11-393819.
  19. Barbui T, Thiele J, Passamonti F, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29(23):3179–84. doi: 10.1200/jco.2010.34.5298.
  20. Vaidya R, Gangat N, Jimma T, et al. Plasma cytokines in polycythemia vera: phenotypic correlates, prognostic relevance, and comparison with myelofibrosis. Am J Hematol. 2012;87(11):1003–5. doi: 10.1002/ajh.23295.
  21. 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):2224–32. doi: 10.1200/jco.2005.07.062.
  22. Gruppo Italiano Studio Policitemia. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med. 1995;123(9):656–64. doi: 10.7326/0003-4819-123-9-199511010-00003.
  23. Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117(22):5857–9. doi: 10.1182/blood-2011-02-339002.
  24. Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease characteristics and clinical outcomes in polycythemia vera. Leuk Lymphoma. 2013;54(9):1989–95. doi: 10.3109/10428194.2012.759656.
  25. Giona F, Teofili L, Moleti ML, et al. Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biologic features, treatment, and long-term outcome. Blood. 2012;119(10):2219–27. doi: 10.1182/blood-2011-08-371328.
  26. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840–6. doi: 10.1182/blood-2006-12-064287.
  27. Alvarez-Larran A, Cervantes F, Bellosillo B, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia. 2007;21(6):1218–23. doi: 10.1038/sj.leu.2404693.
  28. Wolansky AP, Schwager SM, McClure RF, et al. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006;81(2):159–66. doi: 10.4065/81.2.159.
  29. Сervantes F, Alvarez-Larran A, Arellano-Rodrigo E, et al. Frequency and risk factors for thrombosis in idiopathic myelofibrosis: analysis in a series of 155 patients from a single institution. Leukemia. 2006;20(1):55–60. doi: 10.1038/sj.leu.2404048.
  30. Barbui T, Carobbio A, Cervantes F, et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood. 2010;115(4):778–82. doi: 10.1182/blood-2009-08-238956.
  31. Gangat N, Wolanskyj AP, Tefferi A. Abdominal vein thrombosis in essential thrombocythemia: prevalence, clinical correlates, and prognostic implications. Eur J Haematol. 2006;77(4):327–33. doi: 10.1111/j.1600-0609.2006.00715.x.
  32. De Stefano V, Fiorini A, Rossi E, et al. Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost. 2007;5(4):708–14. doi: 10.1111/j.1538-7836.2007.02424.x.
  33. Landolfi R, Di Gennaro L, Nicolazzi MA, et al. Polycythemia vera: gender-related phenotypic differences. Int Emerg Med. 2011;7(6):509–15. doi: 10.1007/s11739-011-0634-3.
  34. Grandone E, Colaizzo D, Tiscia GL, et al. Venous thrombosis in oral contraceptive users and the presence of the JAK2 V617F mutation. Thromb Haemost. 2008;99(3):640–2. doi: 10.1160/th07-09-0570.
  35. Капустин С.И., Кармацкая И.И., Дрижун Ю.С. и др. Опыт диагностики наследственных факторов риска тромбоза у больных истинной полицитемией. Вестник гематологии. 2011;4:25–6.
    [Kapustin SI, Karmatskaya II, Drizhun YuS, et al. Experience in diagnosing of hereditary thrombosis risk factors in patients with polycythemia vera. Vestnik gematologii. 2011;4:25–6. (In Russ)]
  36. Капустин С.И., Шмелева В.М., Сидорова Ж.Ю. и др. Молекулярные детерминанты наследственной тромбофилии: современное состояние и перспективы генодиагностики (обзор литературы). Вестник гематологии. 2011;VII(4):84–90.
    [Kapustin SI, Shmeleva VM, Sidorova ZhYu, et al. Molecular determinants of hereditary thrombophilia: present state and perspectives of genetic diagnostics (literature review). Vestnik gematologii. 2011;VII(4):84–90. (In Russ)]
  37. Bick R., Kaplan H. Syndromes of thrombosis and hypercoagulability: congenital and acquired thrombophilias. Clin Appl Thromb Hemost. 1998;4(1):25–50. doi: 10.1177/107602969800400106.
  38. O’Shaughnessy D, Markis M, Lillicap D, eds. Practical hemostasis and thrombosis. Oxford: Blackwell Publishing; 2005. рр. 224. doi: 10.1002/9780470988633.
  39. Khan S, Dickerman JD. Hereditary thrombophilia. Thromb J. 2006;4(1):15. doi: 10.1186/1477-9560-4-15.
  40. Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood. 2000;95(5):1517–32.
  41. Honda S, Honda Y, Baer B, et al. The impact of three-dimensional structure on the expression of P1A alloantigens on human integrin beta 3. Blood. 1995;86(1):234–42.
  42. Капустин С.И., Салтыкова Н.Б., Каргин В.Д. и др. Генетические факторы риска тромбоэмболии легочной артерии у больных с тромбозом глубоких вен. Клинико-лабораторный консилиум. 2007;16:56–60.
    [Kapustin SI, Saltykova NB, Kargin VD, et al. Genetic factors of risk of pulmonary embolism in patients with deep vein thrombosis. Kliniko-laboratornyi konsilium. 2007;16:56–60. (In Russ)]
  43. Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost. 2005;94(5):907–15. doi: 10.1160/th05-05-0313.
  44. Tevet M, Ionescub R, Dragan C, et al. Influence of the JAK2 V617F Mutation and Inherited Thrombophilia on the Thrombotic Risk among Patients with Myeloproliferative Disorders. J Clin Med. 2015;10(1):27–32.
  45. Gisslinger H, Mullner M, Pabinger I, et al. Mutation of the prothrombin gene and thrombotic events in patients with polycythemia vera or essential thrombocythemia: a cohort study. Haematologica. 2005;90(3):408–10.
  46. De Stefano V, Za T, Rossi E, et al. Influence of the JAK2 V617F mutation and inherited thrombophilia on the thrombotic risk among patients with essential thrombocythemia. Haematologica. 2009;94(5):733–7. doi: 10.3324/haematol.13869.
  47. Kreher S, Ochsenreither S,Trappe RU, et al. 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 (OGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.). Ann Hematol. 2014;93(12):1953–63. doi: 10.1007/s00277-014-2224-8.
  48. Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost. 2013;11(7):1215–27. doi: 10.1111/jth.12265.
  49. Stefano V, Za T, Rossi E, et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica. 2008;93(3):372–80. doi: 10.3324/haematol.12053.