Диагностика тромбастении Гланцмана с помощью исследования показателей плазменного и тромбоцитарного звеньев гемостаза

Статья в Elpub

Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2015; 14: 17-24

Диагностика тромбастении Гланцмана с помощью исследования показателей плазменного и тромбоцитарного звеньев гемостаза

Кумскова Мария Алексеевна, Дёмина Ирина Андреевна, Подоплелова Надежда Александровна, Баландина Анна Николаевна, Серёгина Елена Александровна, Бондар Елена Владимировна, Полетаев Александр Владимирович, Коняшина Надежда Ивановна, Пантелеев Михаил Александрович

https://doi.org/10.24287/1726-1708-2015-14-4-17-24

Аннотация

Тромбастения Гланцмана (ТГ) - наследственное заболевание из группы тромбоцитопатий, развивающееся вследствие аномалии структурного белка тромбоцитов, приводящей к дефициту или дисфункции мембранного белка интегрина αIIbß3. Клинически заболевание характеризуется геморрагическими проявлениями спонтанного и пост-травматического характера. ТГ имеет характерную картину при исследовании агрегации тромбоцитов - отсутствие агрегации со всеми агонистами при сохранении нормального ответа в присутствии ристоцетина. В статье описан клинический случай ТГ у ребенка 3 лет 10 мес с характерной клинической картиной геморрагического синдрома. Подробно представлены этапы диагностики заболевания и результаты лабораторного исследования системы гемостаза. Кроме оценки агрегационной способности тромбоцитов, проведены исследования их функциональной активности методом проточной цитометрии, что позволило установить у обследуемого ребенка снижение интегрина aIIbß3 как количественное (снижение экспрессии CD61 на 76,4% при исследовании неактивированных тромбоцитов и на 88% при исследовании активированных тромбоцитов), так и качественное (снижение экспрессии PAC1 на 34% при исследовании неактивированных тромбоцитов и на 79,3% при исследовании активированных тромбоцитов) по сравнению со здоровыми донорами.

Список литературы

1. George JN, Caen JP, Nurden AT. Glanzmann’s thrombasthenia: the spectrum of clinical disease. Blood. 1990; 75(7): 1383-95.

2. Nurden AT, Fiore M, Nurden P, Pillois X. Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. Blood. 2011; 118(23): 5996-6005.

3. Nurden AT, Pillois X, Nurden P. Understanding the genetic basis of Glanzmann thrombasthenia: implications for treatment. Expert Rev Hematol. 2012; 5(5): 487-503.

4. Cong NV, Uzan G, Gross MS, Jegou-Foubert C, Frachet P, Boucheix C, et al. Assignment of human platelet GP2B (GPIIb) gene to chromosome 17, region q21.1-q21.3. Hum Genet. 1988; 80(4): 389-92.

5. Coller BS, Shattil SJ. The GPIIb/IIIa (integrin alpha Ilb beta 3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood. 2008; 112(8): 3011-25.

6. Thornton MA, Poncz M, Korotishevsky M, Yakobson E, Usher S, Seligsohn U, et al. The human platelet alpha Ilb gene is not closely linked to its integrin partner beta3. Blood. 1999; 94(6): 2039-47.

7. Shattil SJ. Signaling through platelet integrin alpha Ilb beta 3: inside-out, outsidein, and sideways. Thromb Haemost. 1999; 82(2): 318-25.

8. Воробьев АИ, ред. Руководство по гематологии. 4-е изд. М.: Ньюдиамед, 2007; 530-40.

9. Шабалов НП, ред. Детские болезни. Учебник. 5-е изд. Т. 2. СПб.: Питер, 2007; 335-43.

10. Emambokus NR, Frampton J. The glycoprotein Ilb molecule is expressed on early murine hematopoietic progenitors and regulates their numbers in sites of hematopoiesis. Immunity. 2003; 19(1): 33-45.

11. Arnaout MA, Mahalingam B, Xiong JP. Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol. 2005; 21: 381-410.

12. Perutelli P, Mori PG. Biochemical and molecular basis of Glanzmann’s thrombasthenia. Haematologica. 1992; 77(5): 421-6.

13. Calvete JJ. On the structure and function of platelet integrin alpha IIb beta 3, the fibrinogen receptor. Proc Soc Exp Biol Med. 1995; 208(4): 346-60.

14. Mitchell WB, Li J, French DL, Coller BS. alpha IIb beta 3 biogenesis is controlled by engagement of alpha IIb in the calnexin cycle via the N15-linked glycan. Blood. 2006; 107(7): 2713-9.

15. Wilcox DA, Wautier JL, Pidard D, Newman PJ. A single amino acid substitution flanking the fourth calcium binding domain of alpha IIb prevents maturation of the alpha IIb beta 3 integrin complex. J Biol Chem. 1994; 269(6): 4450-7.

16. Nelson EJ, Li J, Mitchell WB, Chandy M, Srivastava A, Coller BS. Three novel betapropeller mutations causing Glanzmann thrombasthenia result in production of normally stable pro-alphaIIb, but variably impaired progression of pro-alphaIIb beta3 from endoplasmic reticulum to Golgi. J Thromb Haemost. 2005; 3(12): 2773-83.

17. Gonzalez-Manchön C, Arias-Salgado EG, Butta N, Martin G, Rodriguez RB, Elalamy I, et al. A novel homozygous splice junction mutation in GPIIb associated with alternative splicing, nonsense-mediated decay of GPIIb-mRNA, and type II Glanzmann’s thrombasthenia. J Thromb Haemost. 2003; 1(5): 1071-8.

18. Mansour W, Einav Y, Hauschner H, Koren A, Seligsohn U, Rosenberg N. An allb mutation in patients with Glanzmann thrombasthenia located in the N-terminus of blade 1 of the ß-propeller (Asn2Asp) disrupts a calcium binding site in blade 6. J Thromb Haemost. 2011; 9(1): 192-200.

19. Bolton-Maggs PH, Chalmers EA, Collins PW, Harrison P, Kitchen S, Liesner RJ, et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol. 2006; 135(5): 603-33.

20. Israels SJ, Kahr WH, Blanchette VS, Luban NL, Rivard GE, Rand ML. Platelet disorders in children: A diagnostic approach. Pediatr Blood Cancer. 2011; 56(6): 975-83.

21. Toogeh G, Sharifian R, Lak M, Safaee R, Artoni A, Peyvandi F. Presentation and pattern of symptoms in 382 patients with Glanzmann thrombasthenia in Iran. Am J Hematol. 2004; 77(2): 198-9.

22. Israels SJ. Diagnostic evaluation of platelet function disorders in neonates and children: an update. Semin Thromb Hemost. 2009; 35(2): 181-8.

23. Biss TT, Blanchette VS, Clark DS, Wakefield CD, James PD, Rand ML. Use of a quantitative pediatric bleeding questionnaire to assess mucocutaneous bleeding symptoms in children with a platelet function disorder. J Thromb Haemost. 2010; 8(6): 1416-9.

24. Eshghi P, Jenabzadeh A, Habibpanah B. Hemorrhage treatment report of patients suffering from Glanzmann’s thrombasthenia resulting hospitalization from 2006 to 2011 at Mofid Children’s Hospital. Iran J Blood Cancer. 2014; 6(3): 127-31.

25. Farsinejad A, Abolghasemi H, Kazemi A, Aghaiipour M, Hadjati E, Faranoush M, et al. Classification of Iranian patients with Glanzmann’s thrombasthenia using a flow cytometric method. Platelets. 2011; 22(5): 321-7.

26. Farsinejad A, Farajollahi MM, Kazemi A, Saemi N, Faranoush M. Different biochemical expression pattern of platelet surface glycoproteins suggests molecular diversity of Glanzmann’s thrombasthenia in Iran. Blood Coagul Fibrinolysis. 2013; 24(6): 613-8.

27. Poon MC, Demers C, Jobin F, Wu JW. Recombinant factor VIIa is effective for bleeding and surgery in patients with Glanzmann thrombasthenia. Blood. 1999; 94(11): 3951 -3.

28. Nair S, Ghosh K, Kulkarni B, Shetty S, Mohanty D. Glanzmann’s thrombasthenia: updated. Platelets. 2002; 13(7): 387-93.

29. Bennett JS, Vilaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest. 1979; 64(5): 1393-401.

30. Belloc F, Heilmann E, Combrie R, Boisseau MR, Nurden AT. Protein synthesis and storage in human platelets: a defective storage of fibrinogen in platelets in Glanzmann's thrombasthenia. Biochim Biophys Acta. 1987; 925(2): 218-25.

31. Alberio L, Safa O, Clemetson KJ, Esmon CT, Dale GL. Surface expression and functional characterization of alpha-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin. Blood. 2000; 95(5): 1694-702.

32. Dale GL, Friese P, Batar P, Hamilton SF, Reed GL, Jackson KW, et al. Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Nature. 2002; 415(6868): 175-9.

33. Yakimenko AO, Verholomova FY, Kotova YN, Ataullakhanov FI, Panteleev MA. Identification of different proaggregatory abilities of activated platelet subpopulations. Biophys J. 2012; 102(10): 2261-9.

34. Topal A, Kilicaslan A, Erol A, Cankaya B, Otelcioglu Ç. Anaesthetic management with thromboelastography in a patient with Glanzmann thrombasthenia. Turk J Anaesth Reanim. 2014; 42(4): 227-9.

Pediatric Hematology/Oncology and Immunopathology. 2015; 14: 17-24

Diagnosis of Glanzmann’s thrombasthenia by assessment of plasma and platelet hemostatic parameters

Kumskova M. A., Demina I. A., Podoplelova N. A., Balandina A. N., Seregina E. A., Bondar E. V., Poletaev A. V., Konyashina N. I., Panteleev M. A.

https://doi.org/10.24287/1726-1708-2015-14-4-17-24

Abstract

Glanzmann's thrombasthenia (GT) is a hereditary disorder referred to the group of thrombocytopathies. It develops as a result of abnormality in the platelet structural protein, leading to deficiency or dysfunction of membrane protein integrin aIIbß3. Clinically the disease is characterized by spontaneous and posttraumatic bleedings. A typical pattern of platelet aggregation in GT is the absence of aggregation with all agonists and normal response in the presence of ristocetin. A clinical case of GT is described: a boy aged 3 years 10 months with a characteristic clinical manifestation of the hemorrhagic syndrome. Stages in the disease diagnosis and results of laboratory assays of the hemostatic system are described in detail. In addition to evaluation of the platelet aggregation activity, the functional activity of these cells was assessed by flow cytometry, which showed reduction of integrin aIIbß3 - quantitative (76.4% lower expression of CD61 in assessment of non-activated platelets and 88% lower in assessment of activated platelets) and qualitative (34% lower expression of PAC1 in non-activated platelets and 79.3% lower in activated platelets) in comparison with healthy donors.

References