Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children71410.24287/1726-1708-2023-22-3-156-165CLINICAL OBSERVATIONSКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯAge-dependent changes in platelet function of a patient with SLFN14-related macrothrombocytopeniaВозрастные изменения характера нарушений функции тромбоцитов у пациентки с SLFN14-связанной макротромбоцитопениейhttps://orcid.org/0000-0002-1650-1817RashevskayaE. Yu.РашевскаяЕ. Ю.
Russian Federation

Elena Yu. Rashevskaya - a resident in hematology.

1 Ostrovityanova St., Moscow 117997

Рашевская Елена Юрьевна - врач-ординатор по специальности «гематология».

117997, Москва, ул. Островитянова, 1

Elena.rashevskaya98@mail.ruhttps://orcid.org/0000-0001-6905-2878PolokhovD. M.ПолоховД. М.
Russian Federation

Moscow

Дмитрий Михайлович Полохов

Москва

dmitrii.polokhov@gmail.comhttps://orcid.org/0000-0003-4567-1871FyodorovaD. V.ФедороваД. В.
Russian Federation

Moscow

Дарья Викторовна Федорова

Москва

darya.v.fedorova@gmail.comhttps://orcid.org/0000-0002-5217-3937IgnatovaA. A.ИгнатоваА. А.
Russian Federation

Moscow

Анастасия Александровна Игнатова

Москва

procyonnlotor@gmail.comhttps://orcid.org/0000-0002-8697-7570PonomarenkoE. A.ПономаренкоЕ. А.
Russian Federation

Moscow

Евгения Александровна Пономаренко

Москва

pappe@bk.ruhttps://orcid.org/0000-0002-7634-2053RaykinaE. V.РайкинаЕ. В.
Russian Federation

Moscow

Елена Владиславовна Райкина

Москва

Elena.Raykina@fccho-moscow.ruhttps://orcid.org/0000-0003-0471-2956MersiyanovaI. V.МерсияноваИ. В.
Russian Federation

Moscow

Ирина Викторовна Мерсиянова

Москва

imers@mail.ruhttps://orcid.org/0000-0003-4451-2553PoletayevA. V.ПолетаевА. В.
Russian Federation

Moscow

Александр Владимирович Полетаев

Москва

aleksandr.poletaev@fccho-moscow.ruTrukhinaE. V.ТрухинаЕ. В.
Russian Federation

Moscow

Екатерина Викторовна Трухина

Москва

ekaterina.truchina@fccho-moscow.ruhttps://orcid.org/0000-0002-4503-0735PlyasunovaS. A.ПлясуноваС. А.
Russian Federation

Moscow

Светлана Александровна Плясунова

Москва

Svetlana.Plyasunova@fccho-moscow.ruhttps://orcid.org/0000-0003-4384-6754ZharkovP. А.ЖарковП. А.
Russian Federation

Moscow

Павел Александрович Жарков

Москва

pavel.zharkov@fccho-moscow.ruhttps://orcid.org/0000-0002-8128-7757PanteleevM. A.ПантелеевМ. А.
Russian Federation

Moscow

Михаил Александрович Пантелеев

Москва

mapanteleev@yandex.ruThe N.I. Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian FederationФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава РоссииThe Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава РоссииCenter for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of SciencesФГБУН «Центр теоретических проблем физико-химической фармакологии» РАНThe M.V. Lomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»031020232231561652504202320062023Copyright ©; 2023, «D. Rogachev NMRCPHOI»Copyright ©; 2023, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2023«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/714

Platelet-type bleeding disorder-20 is a rare inherited thrombocytopenia caused by mutations in the SLFN14 gene. We report a case of a female patient with SLFN14 mutation, macrothrombocytopenia, severe hemorrhagic syndrome and a positive family history who was followed up from the age of 17 to 19. The 3-year follow-up showed a tendency towards partial normalization of platelet counts (from 47 to 82 × 109/L) and morphology. Platelet size and granularity as well as the density of glycoprotein (GP) membrane receptors such as GP Ib/V/IX and GP IIb/IIIa decreased. GP IIb/IIIa activation was impaired and there were no positive changes over time. The dense granules indicators were stably elevated. The parameters of a-granules (assessed by P-selectin expression) did not differ from the control group. The proportion of procoagulant phosphatidylserine-positive platelets at rest was increased and the potential to form procoagulant platelets upon activation was reduced. As the patient grew older, her bleeding disorder symptoms abated and she showed a tendency towards normalization of platelet laboratory parameters. All investigations were performed after obtaining informed consent from the patient and her parents in accordance with the Declaration of Helsinki.

Нарушение свертываемости крови тромбоцитарного типа-20 является редкой наследственной тромбоцитопенией, вызываемой мутациями в гене SLFN14. Нами наблюдалась пациентка в возрасте с 17 до 19 лет с мутацией SLFN14, макротромбоцитопенией, тяжелым геморрагическим синдромом и отягощенным семейный анамнезом. В ходе 3-летнего обследования наблюдалась тенденция к частичной нормализации количества (с 47 до 82 × 109/л) и морфологии тромбоцитов. Уменьшались размер, гранулярность, плотность рецепторов гликопротеина (ГП) Ib/V/IX и ГП IIb/IIIa мембраны тромбоцитов. Активация ГП IIb/IIIa была нарушена и положительной динамики не имела. Показатели плотных гранул были стабильно повышены. Показатели a-гранул (по Р-селектину) не отличались от значений контрольной группы. Доля прокоагулянтных фосфатидилсерин-положительных тромбоцитов была повышена в покое, способность образовывать прокоагулянтные тромбоциты при активации была ослаблена. У пациентки по мере взросления наблюдалось облегчение проявлений геморрагического синдрома в сочетании с тенденцией к нормализации лабораторных показателей тромбоцитов. Все исследования проводились после получения письменного информированного согласия пациентки и ее родителей в соответствии с Хельсинкской декларацией.

BDPLT-20SLFN14inherited thrombocytopeniahemorrhagic syndromeflow cytometryBDPLT-20SLFN14наследственная макротромбоцитопениягеморрагический синдромпроточная цитометрияНе указанBury L., Falcinelli E., Gresele P. Learning the Ropes of Platelet Count Regulation: Inherited Thrombocytopenias // Journal of Clinical Medicine. 2021. Vol. 10, № 3.Bury L., Falcinelli E., Gresele P. Learning the Ropes of Platelet Count Regulation: Inherited Thrombocytopenias. J Clin Med 2021; 10 (3): 533.Oved J.H. et al. Population based frequency of naturally occurring loss-of-function variants in genes associated with platelet disorders // Journal of Thrombosis and Haemostasis. 2021. Vol. 19, № 1. P. 248–254.Oved J.H., Lambert M.P., Kowalska M.A., Poncz М., Karczewski K.J. Population based frequency of naturally occurring loss-of-function variants in genes associated with platelet disorders. J Thromb Haemost 2021; 19 (1): 248–54.Fletcher S.J. et al. SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects // J Clin Invest. American Society for Clinical Investigation, 2015. Vol. 125, № 9. P. 3600–3605.Fletcher S.J., Johnson B., Lowe G.C., Bem D., Drake S., Lordkipanidzé M., et al. SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects. J Clin Invest 2015; 125 (9): 3600–5.Marconi C. et al. SLFN14-related thrombocytopenia: identification within a large series of patients with inherited thrombocytopenia // Thromb Haemost. 2016. Vol. 115, № 5. P. 1076–1079.Marconi C., Di Buduo C.A., Barozzi S., Palombo F., Pardini S., Zaninetti C., et al. SLFN14-related thrombocytopenia: identification within a large series of patients with inherited thrombocytopenia. Thromb Haemost 2016; 115 (5): 1076–9.Saes J.L. et al. Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis // Haemophilia. 2019. Vol. 25, № 1. P. 127–135.Saes J.L., Simons A., de Munnik S.A., Nijziel M.R., Blijlevens N.M.A., Jongmans M.C., et al. Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis. Haemophilia 2019; 25 (1): 127–35.Stapley R.J. et al. SLFN14 gene mutations associated with bleeding // null. Taylor & Francis, 2020. Vol. 31, № 3. P. 407–410.Stapley R.J., Pisareva V.P., Pisarev A.V., Morgan N.V. SLFN14 gene mutations associated with bleeding. Platelets 2020; 31 (3): 407–10.Stapley R.J. et al. Heterozygous mutation SLFN14 K208N in mice mediates species-specific differences in platelet and erythroid lineage commitment // Blood Advances. 2021. Vol. 5, № 2. P. 377–390.Stapley R.J., Smith C.W., Haining E.J., Bacon A., Lax S., Pisareva V.P., et al. Heterozygous mutation SLFN14 K208N in mice mediates species-specific differences in platelet and erythroid lineage commitment. Blood Adv 2021; 5 (2): 377–90.Polokhov, D., Fedorova, D., Ignatova, A. et al. Novel SLFN14 mutation associated with macrothrombocytopenia in a patient with severe haemorrhagic syndrome. Orphanet J Rare Dis 18, 74 (2023). https://doi.org/10.1186/s13023-023-02675-9.Polokhov D., Fedorova D., Ignatova A., Ponomarenko E., Rashevskaya E., Martyanov A., et al. Novel SLFN14 mutation associated with macrothrombocytopenia in a patient with severe haemorrhagic syndrome. Orphanet J Rare Dis 2023; 18 (1): 74. DOI: 10.1186/s13023-023-02675-9Mezzano D., Pereira J. Approach to the Patient with Platelet-Related Bleeding // Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics: an Update / ed. Gresele P. et al. Cham: Springer International Publishing, 2017. P. 717–725.Mezzano D., Pereira J. Approach to the Patient with Platelet-Related Bleeding. In: Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics: an Update. Gresele P., et al. (eds.) Cham: Springer International Publishing; 2017. Pр. 717–25.Polokhov D.M. et al. Platelet phenotype in children with ANKRD26-related thrombocytopenia: 2 // Pediatric Hematology/Oncology and Immunopathology. 2021. Vol. 20, № 2. P. 65–73.Полохов Д.М., Федорова Д.В., Пшонкин А.В., Игнатова А.А., Пономаренко Е.А., Алексенко М.Ю. и др. Особенности фенотипа тромбоцитов у детей с ANKRD26-ассоциированной тромбоцитопенией. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2021; 20 (2): 65–73. DOI: 10.24287/1726-1708-2021-20-2-65-73Polokhov D.M. et al. Specifities of the storage pool and morphology of platelets in children with unspecified hemorrhagic syndrome: 1 // Pediatric Hematology/Oncology and Immunopathology. 2021. Vol. 20, № 1. P. 58–65.Полохов Д.М., Пшонкин А.В., Игнатова А.А., Пономаренко Е.А., Федорова Д.В., Алексенко М.Ю. и др. Особенности пула хранения и морфологии тромбоцитов у детей с неуточненным геморрагическим синдромом. Вопросы гематологии/ онкологии и иммунопатологии в педиатрии 2021; 20 (1): 58–65. DOI: 10.24287/1726-1708-2021-20-1-58-65Polokhov D.M. et al. Platelet function and blood coagulation system status in childhood essential thrombocythemia // Platelets. 2020. Vol. 31, № 8. P. 1001–1011.Polokhov D.M., Ershov N.M., Ignatova A.A., Ponomarenko E.А., Gaskova M.V., Zharkov P.A., et al. Platelet function and blood coagulation system status in childhood essential thrombocythemia. Platelets 2020; 31 (8): 1001–11.Bidlingmaier C. et al. Prospective evaluation of a pediatric bleeding questionnaire and the ISTH bleeding assessment tool in children and parents in routine clinical practice // Journal of Thrombosis and Haemostasis. 2012. Vol. 10, № 7. P. 1335–1341.Bidlingmaier C., Grote V., Budde U., Olivieri M., Kurnik K. Prospective evaluation of a pediatric bleeding questionnaire and the ISTH bleeding assessment tool in children and parents in routine clinical practice. J Thromb Haemost 2012; 10 (7): 1335–41.Reference intervals for immature platelet fraction and immature platelet count - Seo - 2015 - International Journal of Laboratory Hematology - Wiley Online Library [Electronic resource]. URL: https://onlinelibrary.wiley.com/doi/10.1111/ijlh.12237 (accessed: 03.07.2022).Reference intervals for immature platelet fraction and immature platelet count – Seo – 2015 – International Journal of Laboratory Hematology – Wiley Online Library [Electronic resource]. URL: https://onlinelibrary.wiley.com/doi/10.1111/ijlh.12237 (accessed 03.07.2022).Aslan J.E. Platelet Shape Change // Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics: an Update / ed. Gresele P. et al. Cham: Springer International Publishing, 2017. P. 321–336.Aslan J.E. Platelet Shape Change. In: Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics: an Update. Gresele P., et al. (eds.). Cham: Springer International Publishing; 2017. Pр. 321–36.Polokhov D.M. Diagnostics of platelet dysfunction in children using the method of flow cytometry: dissertation for the degree of Candidate of Medical Sciences: 3.1.28 / Polokhov Dmitry Mikhailovich. – M., 2023. – 157 p.Полохов Д.М. Диагностика нарушений функции тромбоцитов у детей с использованием метода проточной цитометрии. Дис. … кандидат медицинских наук. М.; 2023. 157 с.Glembotsky A.C. et al. Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets // Journal of Thrombosis and Haemostasis. 2014. Vol. 12, № 5. P. 761–772.GlembotskyA.C.,BluteauD.,Espasandin Y.R., Goette N.P., Marta R.F., Marin Oyarzun C.P., et al. Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets. J Thromb Haemost 2014; 12 (5): 761–72.Melazzini F. et al. Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia // Haematologica. 2016. Vol. 101, № 11. P. 1333–1342.Melazzini F., Palombo F., Balduini A., De Rocco D., Marconi C., Noris P., et al. Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia. Haematologica 2016; 101 (11): 1333–42.Sadler J.E. Biochemistry and genetics of von Willebrand factor // Annu Rev Biochem. 1998. Vol. 67. P. 395–424.Sadler J.E. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 199; 67: 395–424.Calvete J.J. On the structure and function of platelet integrin alpha IIb beta 3, the fibrinogen receptor // Proc Soc Exp Biol Med. 1995. Vol. 208, № 4. P. 346–360.Calvete J.J. 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.Shcherbina A., Rosen F.S., Remold-O’Donnell E. Pathological events in platelets of Wiskott-Aldrich syndrome patients // British Journal of Haematology. 1999. Vol. 106, № 4. P. 875–883.Shcherbina A., Rosen F.S., Remold-O’Donnell E. Pathological events in platelets of Wiskott– Aldrich syndrome patients. Br J Haematol 1999; 106 (4) 875–83.Obydennyi et al. Mechanisms of increased mitochondria-dependent necrosis in Wiskott-Aldrich syndrome platelets // Haematologica. 2020. Vol. 105, № 4 SE-Articles. P. 1095–1106.Obydennyi S.I., Artemenko E.O., Sveshnikova A.N., Ignatova A.A., Varlamova T.V., Gambaryan S., et al. Mechanisms of increased mitochondria-dependent necrosis in Wiskott– Aldrich syndrome platelets. Haematologica 2020; 105 (4): 1095–106.Catani L. et al. Dendritic cells of immune thrombocytopenic purpura (ITP) show increased capacity to present apoptotic platelets to T lymphocytes // Experimental Hematology. 2006. Vol. 34, № 7. P. 879–887.Catani L., Fagioli M.E., Tazzari P.L., Ricci F., Curti A., Rovito M., et al. Dendritic cells of immune thrombocytopenic purpura (ITP) show increased capacity to present apoptotic platelets to T lymphocytes. Exp Hematol 2006; 34 (7): 879–87.Platelet apoptosis in paediatric immune thrombocytopenia is ameliorated by intravenous immunoglobulin - Winkler - 2012 - British Journal of Haematology - Wiley Online Library [Electronic resource]. URL: https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08973.x (accessed: 20.06.2022).Platelet apoptosis in paediatric immune thrombocytopenia is ameliorated by intravenous immunoglobulin – Winkler – 2012 – British Journal of Haematology – Wiley Online Library [Electronic resource]. URL: https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08973.x (accessed 20.06.2022).Shin H.-W., Takatsu H. Phosphatidylserine exposure in living cells // Crit Rev Biochem Mol Biol. 2020. Vol. 55, № 2. P. 166–178.Shin H.-W., Takatsu H. Phosphatidylserine exposure in living cells. Crit Rev Biochem Mol Biol 2020; 55 (2): 166–78.Ma R. et al. Phosphatidylserine-mediated platelet clearance by endothelium decreases platelet aggregates and procoagulant activity in sepsis: 1 // Sci Rep. Nature Publishing Group, 2017. Vol. 7, № 1. P. 4978.Ma R., Xie R., Yu С., Si Y., Wu X., Zhao L., et al. Phosphatidylserine-mediated platelet clearance by endothelium decreases platelet aggregates and procoagulant activity in sepsis. Sci Rep 2017; 7 (1): 4978.Fletcher S.J. et al. SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects // Journal of Clinical Investigation. 2015. Vol. 125, № 9. P. 3600–3605.Thon J.N., Macleod H., Begonja A.J., Zhu J., Lee K.-C., Mogilner A., et al. Microtubule and cortical forces determine platelet size during vascular platelet production. Nat Commun 2012; 3 (1): 852.Thon J.N. et al. Microtubule and cortical forces determine platelet size during vascular platelet production // Nature Communications. 2012. Vol. 3, № 1. P. 852.White J.G., Key N.S., King R.A., Vercellotti G.M. The White platelet syndrome: A new autosomal dominant platelet disorder. Platelets 2004; 15 (3): 173–84.Marconi C. et al. SLFN14-related thrombocytopenia: identification within a large series of patients with inherited thrombocytopenia // Thromb Haemost. 2016. Vol. 115, № 05. P. 1076–1079.Nurden А.Т., Nurden P. The gray platelet syndrome: Clinical spectrum of the disease. Blood Rev 2007; 21 (1): 21–36.White J.G. et al. The White platelet syndrome: A new autosomal dominant platelet disorder - I. Structural abnormalities // Platelets. 2004. Vol. 15, № 3. P. 173–184.Botero J.P., Chen D., He R., Viswanatha D.S., Majerus J.A., Coon L.M., et al. Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: A detailed phenotypic study of a family. Platelets 2016; 27 (7):712–5.Nurden et al. The gray platelet syndrome: Clinical spectrum of the disease // Blood Reviews. 2007. Vol. 21, № 1. P. 21–36.Botero et al. Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: A detailed phenotypic study of a family // Platelets. Taylor & Francis, 2016. Vol. 27, № 7. P. 712–715.Polokhov D.M. et al. Platelet phenotype in children with ANKRD26-related thrombocytopenia // Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2021. Vol. 20, № 2. P. 65–73.