Существует значимая корреляция между гиперактивацией тромбоцитов и их потреблением при COVID-19. Пилотное исследование на пациентах из больницы ЦКБ РАН (г. Троицк)


Введение
Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia
Q. Li, X. Guan, P. Wu, X. Wang, L. Zhou, Y. Tong, R. Ren, K. Leung, E. Lau, J. Wong, X. Xing, N. Xiang, Y. Wu, C. Li, Q. Chen, D. Li, T. Liu, J. Zhao, M. Liu, W. Tu, C. Chen, L. Jin, R. Yang, Q. Wang, S. Zhou, R. Wang, H. Liu, Y. Luo, Y. Liu, G. Shao, H. Li, Z. Tao, Y. Yang, Z. Deng, B. Liu, Z. Ma, Y. Zhang, G. Shi, T. Lam, J. Wu, G. Gao, B. Cowling, B. Yang, G. Leung, Z. Feng
New England Journal of Medicine. 2020, 382, 1199-1207
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
C. Huang, Y. Wang, X. Li, L. Ren, J. Zhao, Y. Hu, L. Zhang, G. Fan, J. Xu, X. Gu, Z. Cheng, T. Yu, J. Xia, Y. Wei, W. Wu, X. Xie, W. Yin, H. Li, M. Liu, Y. Xiao, H. Gao, L. Guo, J. Xie, G. Wang, R. Jiang, Z. Gao, Q. Jin, J. Wang, B. Cao
The Lancet. 2020, 395, 497-506
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Thrombocytopenia and its association with mortality in patients with COVID‐19
X. Yang, Q. Yang, Y. Wang, Y. Wu, J. Xu, Y. Yu, Y. Shang
Journal of Thrombosis and Haemostasis. 2020, 18, 1469-1472
Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis
G. Lippi, M. Plebani, B. Henry
Clinica Chimica Acta. 2020, 506, 145-148
Platelets in COVID-19: “innocent by-standers” or active participants?
O. An, A. Martyanov, M. Stepanyan, A. Boldova, S. Rumyantsev, M. Panteleev, F. Ataullakhanov, A. Rumyantsev, A. Sveshnikova
Pediatric Hematology/Oncology and Immunopathology. None, 20, 184-191
The pathogenesis and treatment of the `Cytokine Storm' in COVID-19
Q. Ye, B. Wang, J. Mao
Journal of Infection. 2020, 80, 607-613
Hematological findings and complications of COVID ‐19
E. Terpos, I. Ntanasis‐Stathopoulos, I. Elalamy, E. Kastritis, T. Sergentanis, M. Politou, T. Psaltopoulou, G. Gerotziafas, M. Dimopoulos
American Journal of Hematology. 2020, 95, 834-847
Hypercoagulability of COVID‐19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis
M. Panigada, N. Bottino, P. Tagliabue, G. Grasselli, C. Novembrino, V. Chantarangkul, A. Pesenti, F. Peyvandi, A. Tripodi
Journal of Thrombosis and Haemostasis. 2020, 18, 1738-1742
Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy
N. Tang, H. Bai, X. Chen, J. Gong, D. Li, Z. Sun
Journal of Thrombosis and Haemostasis. 2020, 18, 1094-1099
Incidence of thrombotic complications in critically ill ICU patients with COVID-19
F. Klok, M. Kruip, N. van der Meer, M. Arbous, D. Gommers, K. Kant, F. Kaptein, J. van Paassen, M. Stals, M. Huisman, H. Endeman
Thrombosis Research. 2020, 191, 145-147
The trinity of COVID-19: immunity, inflammation and intervention
M. Tay, C. Poh, L. Rénia, P. MacAry, L. Ng
Nature Reviews Immunology. 2020, 20, 363-374
Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19
R. Alon, M. Sportiello, S. Kozlovski, A. Kumar, E. Reilly, A. Zarbock, N. Garbi, D. Topham
Nature Reviews Immunology. 2021, 21, 49-64
Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19
R. Alon, M. Sportiello, S. Kozlovski, A. Kumar, E. Reilly, A. Zarbock, N. Garbi, D. Topham
Nature Reviews Immunology. 2021, 21, 49-64
Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19
A. Bonaventura, A. Vecchié, L. Dagna, K. Martinod, D. Dixon, B. Van Tassell, F. Dentali, F. Montecucco, S. Massberg, M. Levi, A. Abbate
Nature Reviews Immunology. 2021, 21, 319-329
Tissue factor as a link between inflammation and coagulation
M. Witkowski, U. Landmesser, U. Rauch
Trends in Cardiovascular Medicine. 2016, 26, 297-303
von Willebrand Factor and Platelet Glycoprotein Ib: A Thromboinflammatory Axis in Stroke
F. Denorme, K. Vanhoorelbeke, S. De Meyer
Frontiers in Immunology. None, 10, 2884
The trinity of COVID-19: immunity, inflammation and intervention
M. Tay, C. Poh, L. Rénia, P. MacAry, L. Ng
Nature Reviews Immunology. 2020, 20, 363-374
Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety
J. Hirsh, T. Warkentin, S. Shaughnessy, S. Anand, J. Halperin, R. Raschke, C. Granger, E. Ohman, J. Dalen
Chest. 2001, 119, 64S-94S
Hematological findings and complications of COVID ‐19
E. Terpos, I. Ntanasis‐Stathopoulos, I. Elalamy, E. Kastritis, T. Sergentanis, M. Politou, T. Psaltopoulou, G. Gerotziafas, M. Dimopoulos
American Journal of Hematology. 2020, 95, 834-847
COVID-19 and its implications for thrombosis and anticoagulation
J. Connors, J. Levy
Blood. 2020, 135, 2033-2040
Higher heparin dosages reduce thromboembolic complications in patients with COVID-19 pneumonia
C. Carallo, F. Pugliese, E. Vettorato, C. Tripolino, L. Delle Donne, G. Guarrera, W. Spagnolli, S. Cozzio
Journal of Investigative Medicine. 2021, 69, 884-887
Risk of Clinically Relevant Venous Thromboembolism in Critically Ill Patients With COVID-19: A Systematic Review and Meta-Analysis
J. Gratz, M. Wiegele, M. Maleczek, H. Herkner, H. Schöchl, E. Chwala, P. Knöbl, E. Schaden
Frontiers in Medicine. 2021, 8, None
Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19 ?
V. Bianconi, F. Violi, F. Fallarino, P. Pignatelli, A. Sahebkar, M. Pirro
Drugs. 2020, 80, 1383-1396
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Coagulation factors bound to procoagulant platelets concentrate in cap structures to promote clotting
N. Podoplelova, A. Sveshnikova, Y. Kotova, A. Eckly, N. Receveur, D. Nechipurenko, S. Obydennyi, I. Kireev, C. Gachet, F. Ataullakhanov, P. Mangin, M. Panteleev
Blood. 2016, 128, 1745-1755
Flow cytometry for pediatric platelets
A. Ignatova, E. Ponomarenko, D. Polokhov, E. Suntsova, P. Zharkov, D. Fedorova, E. Balashova, A. Rudneva, V. Ptushkin, E. Nikitin, A. Shcherbina, A. Maschan, G. Novichkova, M. Panteleev
Platelets. 2019, 30, 428-437
New Fundamentals in Hemostasis
H. Versteeg, J. Heemskerk, M. Levi, P. Reitsma
Physiological Reviews. 2013, 93, 327-358
Clot Contraction Drives the Translocation of Procoagulant Platelets to Thrombus Surface
D. Nechipurenko, N. Receveur, A. Yakimenko, T. Shepelyuk, A. Yakusheva, R. Kerimov, S. Obydennyy, A. Eckly, C. Léon, C. Gachet, E. Grishchuk, F. Ataullakhanov, P. Mangin, M. Panteleev
Arteriosclerosis, Thrombosis, and Vascular Biology. 2019, 39, 37-47
Platelet Apoptosis and Apoptotic Platelet Clearance by Macrophages in Secondary Dengue Virus Infections
M. Alonzo, T. Lacuesta, E. Dimaano, T. Kurosu, L. Suarez, C. Mapua, Y. Akeda, R. Matias, D. Kuter, S. Nagata, F. Natividad, K. Oishi
The Journal of Infectious Diseases. 2012, 205, 1321-1329
Flow cytometry for pediatric platelets
A. Ignatova, E. Ponomarenko, D. Polokhov, E. Suntsova, P. Zharkov, D. Fedorova, E. Balashova, A. Rudneva, V. Ptushkin, E. Nikitin, A. Shcherbina, A. Maschan, G. Novichkova, M. Panteleev
Platelets. 2019, 30, 428-437
The Impact of COVID-19 Disease on Platelets and Coagulation
G. Wool, J. Miller
Pathobiology. 2021, 88, 15-27
New Fundamentals in Hemostasis
H. Versteeg, J. Heemskerk, M. Levi, P. Reitsma
Physiological Reviews. 2013, 93, 327-358
Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19
Y. Zaid, F. Puhm, I. Allaeys, A. Naya, M. Oudghiri, L. Khalki, Y. Limami, N. Zaid, K. Sadki, R. Ben El Haj, W. Mahir, L. Belayachi, B. Belefquih, A. Benouda, A. Cheikh, M. Langlois, Y. Cherrah, L. Flamand, F. Guessous, E. Boilard
Circulation Research. 2020, 127, 1404-1418
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Hematological findings and complications of COVID ‐19
E. Terpos, I. Ntanasis‐Stathopoulos, I. Elalamy, E. Kastritis, T. Sergentanis, M. Politou, T. Psaltopoulou, G. Gerotziafas, M. Dimopoulos
American Journal of Hematology. 2020, 95, 834-847
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Platelets in COVID-19: “innocent by-standers” or active participants?
O. An, A. Martyanov, M. Stepanyan, A. Boldova, S. Rumyantsev, M. Panteleev, F. Ataullakhanov, A. Rumyantsev, A. Sveshnikova
Pediatric Hematology/Oncology and Immunopathology. None, 20, 184-191
Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19
Y. Zaid, F. Puhm, I. Allaeys, A. Naya, M. Oudghiri, L. Khalki, Y. Limami, N. Zaid, K. Sadki, R. Ben El Haj, W. Mahir, L. Belayachi, B. Belefquih, A. Benouda, A. Cheikh, M. Langlois, Y. Cherrah, L. Flamand, F. Guessous, E. Boilard
Circulation Research. 2020, 127, 1404-1418
The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways
J. Burkhart, M. Vaudel, S. Gambaryan, S. Radau, U. Walter, L. Martens, J. Geiger, A. Sickmann, R. Zahedi
Blood. 2012, 120, e73-e82
Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19
Y. Zaid, F. Puhm, I. Allaeys, A. Naya, M. Oudghiri, L. Khalki, Y. Limami, N. Zaid, K. Sadki, R. Ben El Haj, W. Mahir, L. Belayachi, B. Belefquih, A. Benouda, A. Cheikh, M. Langlois, Y. Cherrah, L. Flamand, F. Guessous, E. Boilard
Circulation Research. 2020, 127, 1404-1418
SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19
S. Zhang, Y. Liu, X. Wang, L. Yang, H. Li, Y. Wang, M. Liu, X. Zhao, Y. Xie, Y. Yang, S. Zhang, Z. Fan, J. Dong, Z. Yuan, Z. Ding, Y. Zhang, L. Hu
Journal of Hematology & Oncology. 2020, 13, None
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
The Impact of COVID-19 Disease on Platelets and Coagulation
G. Wool, J. Miller
Pathobiology. 2021, 88, 15-27
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia
F. Taus, G. Salvagno, S. Canè, C. Fava, F. Mazzaferri, E. Carrara, V. Petrova, R. Barouni, F. Dima, A. Dalbeni, S. Romano, G. Poli, M. Benati, S. De Nitto, G. Mansueto, M. Iezzi, E. Tacconelli, G. Lippi, V. Bronte, P. Minuz
Arteriosclerosis, Thrombosis, and Vascular Biology. 2020, 40, 2975-2989
Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia
F. Taus, G. Salvagno, S. Canè, C. Fava, F. Mazzaferri, E. Carrara, V. Petrova, R. Barouni, F. Dima, A. Dalbeni, S. Romano, G. Poli, M. Benati, S. De Nitto, G. Mansueto, M. Iezzi, E. Tacconelli, G. Lippi, V. Bronte, P. Minuz
Arteriosclerosis, Thrombosis, and Vascular Biology. 2020, 40, 2975-2989
Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19
Y. Zaid, F. Puhm, I. Allaeys, A. Naya, M. Oudghiri, L. Khalki, Y. Limami, N. Zaid, K. Sadki, R. Ben El Haj, W. Mahir, L. Belayachi, B. Belefquih, A. Benouda, A. Cheikh, M. Langlois, Y. Cherrah, L. Flamand, F. Guessous, E. Boilard
Circulation Research. 2020, 127, 1404-1418
Подводя итог, тромбоциты пациентов с COVID-19 являются дефектными и причина этого не ясна до конца. В настоящей работе, основываясь на экспериментальных наблюдениях за некрозом и размером тромбоцитов, а также на компьютерном моделировании, мы предполагаем, что наблюдаемые изменения тромбоцитов пациентов с COVID-19 могут быть объяснены их повышенной активацией в кровотоке.
Материалы и методы
Пациенты
32 пациента с диагнозом Коронавирусная инфекция, находившиеся на лечении в ФГБУ «Больница Российской академии наук» (г. Троицк), а также 5 здоровых доноров в возрасте от 21 до 45 лет, которые не болели и не принимали никаких лекарств в течение последнего месяца, участвовали в исследовании. Состояние всех пациентов было охарактеризовано врачами как «легкая степень тяжести» и не требовало искусственной вентиляции легких. Все процедуры соответствуют этическим стандартам Национального комитета по этике исследований и Хельсинкской декларации 1964 года с последующими поправками. Информированное добровольное согласие было получено от каждого из участников, включенных в исследование. В дальнейшем все пациенты были выписаны из больницы в течение 2 недель в связи с улучшением их состояния. Образцы крови пяти пациентов анализировали дважды в разные дни. Исследование одобрено решением Независимого этического комитета Национального исследовательского центра имени Дмитрия Рогачева № 3/2020 от 19 мая 2020 года.
Материалы
Фибриноген-Alexa647, AnnexinV-Alexa647, лактадгерин-FITC (Sony Biotechnology, Сан-Хосе, США), HEPES, бычий сывороточный альбумин, D (+) глюкоза (Sigma, США); NaCl; Na2HPO4; KCl; NaHCO3; MgCl2; CaCl2 (Агат-Мед, Москва, Россия).
Проточная цитометрия
Кровь пациентов забиралась в пробирки объемом 3 мл, содержащие цитрат натрия (3,8%). Собранная кровь хранилась при комнатной температуре в течение 30 минут, за которые наблюдалось оседание эритроцитов в нижних слоях пробирки крови. Затем образцы отбирались из верхних 10 процентов объема пробирки и разбавлялись в буфере Тирода (134 мМ NaCl; 0,34 мМ Na2HPO4; 2,9 мМ KCl; 12 мМ NaHCO3; 20 мМ HEPES; 5 мМ глюкозы; 1 мМ MgCl2; 2 мМ. CaCl2; BSA 2% по весу; pH 7,3) до концентрации тромбоцитов 1 × 103 на 1 мл. После этого к каждому образцу добавляли AnnexinV-Alexa647 (2% по объёму) и Lactadherin-FITC (2% по объёму). Затем полученные образцы были инкубированы в течение 10 минут, согласно
Flow cytometry for pediatric platelets
A. Ignatova, E. Ponomarenko, D. Polokhov, E. Suntsova, P. Zharkov, D. Fedorova, E. Balashova, A. Rudneva, V. Ptushkin, E. Nikitin, A. Shcherbina, A. Maschan, G. Novichkova, M. Panteleev
Platelets. 2019, 30, 428-437
Компьютерная модель
Cellular automata as models of complexity
S. Wolfram
Nature. 1984, 311, 419-424
The biogenesis of platelets from megakaryocyte proplatelets
S. Patel
Journal of Clinical Investigation. 2005, 115, 3348-3354
где P - количество тромбоцитов, продуцируемых мегакариоцитами, n - случайное значение из \( N(\mu=1 ; \sigma=0.1) \), TPO - параметр, отражающий концентрацию тромбопоэтина в соответствии с уравнением (2): \begin{equation} TPO=1-\frac{1}{1+\left(\frac{N_{T P O}}{P l t}\right)^{h}}\tag{2}\end{equation}
где \( N_{TPO} \) приблизительное количество тромбоцитов, ниже которого начинается выработка ТПО в печени, а Plt - количество тромбоцитов в данный момент времени, параметры \( N_{TPO}=120000 \) и h = 6 были подобраны для описания экспериментальных данных о взаимосвязи между количеством тромбоцитов и концентрацией [TPO] в крови из работы Makar et al.
Thrombopoietin levels in patients with disorders of platelet production: Diagnostic potential and utility in predicting response to TPO Receptor agonists
R. Makar, O. Zhukov, M. Sahud, D. Kuter
American Journal of Hematology. 2013, 88, 1041-1044
Platelet clearance by the hepatic Ashwell-Morrell receptor: mechanisms and biological significance
K. Hoffmeister, H. Falet
Thrombosis Research. 2016, 141, S68-S72
где nnat отражает естественное удаление тромбоцитов и представляет собой случайное значение из N(0.625‧age; 0.0125‧age), а nthr отражает удаление тромбоцитов из-за их участия в образовании тромба и является случайным значением из N(0.625‧K; 0.0125‧K), где K - индекс потребления, который можно варьировать для имитации тяжести тромбоза. Известно, что размер тромбоцитов связан с возрастом тромбоцитов и содержанием РНК
Platelet reticulated forms, size indexes, and functional activity. Interactions in healthy volunteers
V. V. Bodrova, O. N. Shustova, S. G. Khaspekova, and A. V. Mazurov
Platelets. 2021, None, 1-6
Ultrastructural, transcriptional, and functional differences between human reticulated and non‐reticulated platelets
L. Hille, M. Lenz, A. Vlachos, B. Grüning, L. Hein, F. Neumann, T. Nührenberg, D. Trenk
Journal of Thrombosis and Haemostasis. 2020, 18, 2034-2046
Investigation of the efficacy and safety of eltrombopag to correct thrombocytopenia in moderate to severe dengue patients - a phase II randomized controlled clinical trial
S. Chakraborty, S. Alam, M. Sayem, M. Sanyal, T. Das, P. Saha, M. Sayem, B. Byapari, C. Tabassum, A. Kabir, M. Amin, A. Nabi
EClinicalMedicine. 2020, 29-30, 100624
где s0 отражает исходный размер тромбоцитов и представляет собой значение из N(12; 1) в [fL], параметры Max = 11 [fL] и Min = 6 [fL] отражают распределение по размеру тромбоцитов, обнаруженное у здоровых доноров
Mean Platelet Volume and Immature Platelet Fraction in Autoimmune Disorders
D. Schmoeller, M. Picarelli, T. Paz Munhoz, C. Poli de Figueiredo, H. Staub
Frontiers in Medicine. 2017, 4, None
Investigation of the efficacy and safety of eltrombopag to correct thrombocytopenia in moderate to severe dengue patients - a phase II randomized controlled clinical trial
S. Chakraborty, S. Alam, M. Sayem, M. Sanyal, T. Das, P. Saha, M. Sayem, B. Byapari, C. Tabassum, A. Kabir, M. Amin, A. Nabi
EClinicalMedicine. 2020, 29-30, 100624
Platelet reticulated forms, size indexes, and functional activity. Interactions in healthy volunteers
V. V. Bodrova, O. N. Shustova, S. G. Khaspekova, and A. V. Mazurov
Platelets. 2021, None, 1-6
Ultrastructural, transcriptional, and functional differences between human reticulated and non‐reticulated platelets
L. Hille, M. Lenz, A. Vlachos, B. Grüning, L. Hein, F. Neumann, T. Nührenberg, D. Trenk
Journal of Thrombosis and Haemostasis. 2020, 18, 2034-2046
Investigation of the efficacy and safety of eltrombopag to correct thrombocytopenia in moderate to severe dengue patients - a phase II randomized controlled clinical trial
S. Chakraborty, S. Alam, M. Sayem, M. Sanyal, T. Das, P. Saha, M. Sayem, B. Byapari, C. Tabassum, A. Kabir, M. Amin, A. Nabi
EClinicalMedicine. 2020, 29-30, 100624
Клинические данные
Результаты общего анализа крови, биохимического анализа, теста на свертываемость крови, компьютерной томографии, данные ежедневных обследований, возраст и диагнозы пациентов любезно предоставлены больницей с согласия пациентов.
Обработка данных
Данные проточной цитометрии были обработаны с использованием программного обеспечения FlowJoTM. Статистический анализ проводился посредством GraphPad Prizm.
Результаты и Обсуждение
У пациентов с COVID-19 увеличен размер тромбоцитов, а также увеличена доля фосфатидилсерин положительных тромбоцитов
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia
F. Taus, G. Salvagno, S. Canè, C. Fava, F. Mazzaferri, E. Carrara, V. Petrova, R. Barouni, F. Dima, A. Dalbeni, S. Romano, G. Poli, M. Benati, S. De Nitto, G. Mansueto, M. Iezzi, E. Tacconelli, G. Lippi, V. Bronte, P. Minuz
Arteriosclerosis, Thrombosis, and Vascular Biology. 2020, 40, 2975-2989
Characteristics of platelet count and size and diagnostic accuracy of mean platelet volume in patients with venous thromboembolism. A systematic review and meta-analysis
S. Kovács, Z. Csiki, K. Zsóri, Z. Bereczky, A. Shemirani
Platelets. 2019, 30, 139-147
Anatomical and Pathological Observation and Analysis of SARS and COVID-19: Microthrombosis Is the Main Cause of Death
W. Chen, J. Pan
Biological Procedures Online. 2021, 23, None
Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2
S. Yin, M. Huang, D. Li, N. Tang
Journal of Thrombosis and Thrombolysis. 2021, 51, 1107-1110
The value of the platelet count and platelet indices in differentiation of COVID‐19 and influenza pneumonia
N. Ozcelik, S. Ozyurt, B. Yilmaz Kara, A. Gumus, U. Sahin
Journal of Medical Virology. 2021, 93, 2221-2226
Severe thrombocytopenia as a complication of acute Epstein-Barr virus infection
R. Likic, D. Kuzmanic
Wiener Klinische Wochenschrift. 2004, 116, 47-50
Measurement of phosphatidylserine exposure during storage of platelet concentrates using the novel probe lactadherin: a comparison study with annexin V
A. Albanyan, M. Murphy, J. Rasmussen, C. Heegaard, P. Harrison
Transfusion. 2009, 49, 99-107
Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia
F. Taus, G. Salvagno, S. Canè, C. Fava, F. Mazzaferri, E. Carrara, V. Petrova, R. Barouni, F. Dima, A. Dalbeni, S. Romano, G. Poli, M. Benati, S. De Nitto, G. Mansueto, M. Iezzi, E. Tacconelli, G. Lippi, V. Bronte, P. Minuz
Arteriosclerosis, Thrombosis, and Vascular Biology. 2020, 40, 2975-2989
Известно, что PS+ тромбоциты образуются в ответ на сильную стимуляцию, например, комбинацией коллагена и тромбина
Procoagulant Platelets: Mechanisms of Generation and Action
N. Podoplelova, D. Nechipurenko, A. Ignatova, A. Sveshnikova, M. Panteleev
Hämostaseologie. 2021, 41, 146-153
Collagen But Not Fibrinogen Surfaces Induce Bleb Formation, Exposure of Phosphatidylserine, and Procoagulant Activity of Adherent Platelets: Evidence for Regulation by Protein Tyrosine Kinase-Dependent Ca2+ Responses
J. Heemskerk, W. Vuist, M. Feijge, C. Reutelingsperger, T. Lindhout
Blood. 1997, 90, 2615-2625
Coated-Platelets Improve Prediction of Stroke and Transient Ischemic Attack in Asymptomatic Internal Carotid Artery Stenosis
A. Kirkpatrick, A. Tafur, A. Vincent, G. Dale, C. Prodan
Stroke. 2014, 45, 2995-3001
The trinity of COVID-19: immunity, inflammation and intervention
M. Tay, C. Poh, L. Rénia, P. MacAry, L. Ng
Nature Reviews Immunology. 2020, 20, 363-374
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329

Корреляция параметров тромбоцитов с клинической картиной
The pathogenesis and treatment of the `Cytokine Storm' in COVID-19
Q. Ye, B. Wang, J. Mao
Journal of Infection. 2020, 80, 607-613
Доля PS + тромбоцитов коррелировала (r = 0,69, p <0,01) с повреждением легких (по данным компьютерной томографии, выполненной не позднее, чем через 2 дня от даты исследования тромбоцитов, таблица 1). Эти результаты хорошо согласуются с гипотезой о влиянии воспалительного процесса, происходящего в легких, на систему свертывания, поскольку увеличение площади пораженных альвеол приводит к активации соседних эндотелиальных тканей
Inflammation, endothelium, and coagulation in sepsis
M. Schouten, W. Wiersinga, M. Levi, T. van der Poll
Journal of Leukocyte Biology. 2008, 83, 536-545
The lung microvascular endothelium as a therapeutic target in severe influenza
S. Armstrong, S. Mubareka, W. Lee
Antiviral Research. 2013, 99, 113-118
The Impact of COVID-19 Disease on Platelets and Coagulation
G. Wool, J. Miller
Pathobiology. 2021, 88, 15-27
Thrombocytopenia and its association with mortality in patients with COVID‐19
X. Yang, Q. Yang, Y. Wang, Y. Wu, J. Xu, Y. Yu, Y. Shang
Journal of Thrombosis and Haemostasis. 2020, 18, 1469-1472

Корреляция параметров тромбоцитов и применяемой терапии
ISTH interim guidance on recognition and management of coagulopathy in COVID‐19
J. Thachil, N. Tang, S. Gando, A. Falanga, M. Cattaneo, M. Levi, C. Clark, T. Iba
Journal of Thrombosis and Haemostasis. 2020, 18, 1023-1026
Temporal Aspects of Heparin-Induced Thrombocytopenia
T. Warkentin, J. Kelton
New England Journal of Medicine. 2001, 344, 1286-1292
Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin
T. Warkentin, M. Levine, J. Hirsh, P. Horsewood, R. Roberts, M. Gent, J. Kelton
New England Journal of Medicine. 1995, 332, 1330-1336
Use of antiplatelet drugs and the risk of mortality in patients with COVID-19: a meta‐analysis
C. S. Kow and S. S. Hasan
Journal of Thrombosis and Thrombolysis. 2021, None, None
Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset
J. Chan, Y. Yao, M. Yeung, W. Deng, L. Bao, L. Jia, F. Li, C. Xiao, H. Gao, P. Yu, J. Cai, H. Chu, J. Zhou, H. Chen, C. Qin, K. Yuen
Journal of Infectious Diseases. 2015, 212, 1904-1913
Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial
I. Hung, K. Lung, E. Tso, R. Liu, T. Chung, M. Chu, Y. Ng, J. Lo, J. Chan, A. Tam, H. Shum, V. Chan, A. Wu, K. Sin, W. Leung, W. Law, D. Lung, S. Sin, P. Yeung, C. Yip, R. Zhang, A. Fung, E. Yan, K. Leung, J. Ip, A. Chu, W. Chan, A. Ng, R. Lee, K. Fung, A. Yeung, T. Wu, J. Chan, W. Yan, W. Chan, J. Chan, A. Lie, O. Tsang, V. Cheng, T. Que, C. Lau, K. Chan, K. To, K. Yuen
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При сравнении групп пациентов на наличие хронических заболеваний статистически значимые различия (p = 0,027) выявлены только для группы пациентов с хроническими заболеваниями легких. Процент событий PS + при наличии заболевания был ниже, чем при отсутствии (среднее значение ± стандартное отклонение: 0,81 ± 0,37% для отсутствия, 0,41 ± 0,17% для присутствия, рис. 2B), что может быть связано с наличием компенсаторный механизм в системе свертывания крови этих пациентов. Когорта пациентов, включенных в это исследование, весьма неоднородна с точки зрения возраста и состояния здоровья. Однако отсутствие значимых различий между разными группами пациентов (рис. 2B, рис. S1) и отсутствие наблюдаемого измененного фенотипа тромбоцитов при хронических заболеваниях
Small procoagulant platelets in diabetes type 2
M. Edvardsson, M. Oweling, P. Järemo
Thrombosis Research. 2020, 195, 1-7
Coagulation testing and management in liver disease patients
M. Stotts, J. Davis, N. Shah
Current Opinion in Gastroenterology. 2020, 36, 169-176
Platelet and coagulation disorders in newly diagnosed patients with pulmonary arterial hypertension
E. Vrigkou, I. Tsangaris, S. Bonovas, P. Kopterides, E. Kyriakou, D. Konstantonis, A. Pappas, A. Anthi, A. Gialeraki, S. Orfanos, A. Armaganidis, A. Tsantes
Platelets. 2019, 30, 646-651
Levels of procoagulant microvesicles are elevated after traumatic injury and platelet microvesicles are negatively correlated with mortality
N. Curry, A. Raja, J. Beavis, S. Stanworth, P. Harrison
Journal of Extracellular Vesicles. 2014, 3, 25625

Компьютерная модель предсказывает, что в основе тромбоцитопатии COVID-19 лежит усиленное потребление тромбоцитов
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
The Impact of COVID-19 Disease on Platelets and Coagulation
G. Wool, J. Miller
Pathobiology. 2021, 88, 15-27
Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19
Y. Zaid, F. Puhm, I. Allaeys, A. Naya, M. Oudghiri, L. Khalki, Y. Limami, N. Zaid, K. Sadki, R. Ben El Haj, W. Mahir, L. Belayachi, B. Belefquih, A. Benouda, A. Cheikh, M. Langlois, Y. Cherrah, L. Flamand, F. Guessous, E. Boilard
Circulation Research. 2020, 127, 1404-1418
Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia
F. Taus, G. Salvagno, S. Canè, C. Fava, F. Mazzaferri, E. Carrara, V. Petrova, R. Barouni, F. Dima, A. Dalbeni, S. Romano, G. Poli, M. Benati, S. De Nitto, G. Mansueto, M. Iezzi, E. Tacconelli, G. Lippi, V. Bronte, P. Minuz
Arteriosclerosis, Thrombosis, and Vascular Biology. 2020, 40, 2975-2989
Примечательно, что доля PS+ тромбоцитов слабо коррелировала со средними значениями FS-A (таблица 1). Этот вывод подтверждает гипотезу о том, что при COVID-19 тромбоциты потребляются из-за тромбоза, что приводит к увеличению фракции PS + тромбоцитов, снижению среднего возраста тромбоцитов и, следовательно, увеличению их размера. Слабость корреляции может быть вызвана повышенным клиренсом PS+ тромбоцитов печенью и селезенкой
Platelet clearance by the hepatic Ashwell-Morrell receptor: mechanisms and biological significance
K. Hoffmeister, H. Falet
Thrombosis Research. 2016, 141, S68-S72

Заключение
Clot Contraction Drives the Translocation of Procoagulant Platelets to Thrombus Surface
D. Nechipurenko, N. Receveur, A. Yakimenko, T. Shepelyuk, A. Yakusheva, R. Kerimov, S. Obydennyy, A. Eckly, C. Léon, C. Gachet, E. Grishchuk, F. Ataullakhanov, P. Mangin, M. Panteleev
Arteriosclerosis, Thrombosis, and Vascular Biology. 2019, 39, 37-47
Characteristics of platelet count and size and diagnostic accuracy of mean platelet volume in patients with venous thromboembolism. A systematic review and meta-analysis
S. Kovács, Z. Csiki, K. Zsóri, Z. Bereczky, A. Shemirani
Platelets. 2019, 30, 139-147
The trinity of COVID-19: immunity, inflammation and intervention
M. Tay, C. Poh, L. Rénia, P. MacAry, L. Ng
Nature Reviews Immunology. 2020, 20, 363-374
Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19
R. Alon, M. Sportiello, S. Kozlovski, A. Kumar, E. Reilly, A. Zarbock, N. Garbi, D. Topham
Nature Reviews Immunology. 2021, 21, 49-64
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19
Y. Zaid, F. Puhm, I. Allaeys, A. Naya, M. Oudghiri, L. Khalki, Y. Limami, N. Zaid, K. Sadki, R. Ben El Haj, W. Mahir, L. Belayachi, B. Belefquih, A. Benouda, A. Cheikh, M. Langlois, Y. Cherrah, L. Flamand, F. Guessous, E. Boilard
Circulation Research. 2020, 127, 1404-1418
Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia
F. Taus, G. Salvagno, S. Canè, C. Fava, F. Mazzaferri, E. Carrara, V. Petrova, R. Barouni, F. Dima, A. Dalbeni, S. Romano, G. Poli, M. Benati, S. De Nitto, G. Mansueto, M. Iezzi, E. Tacconelli, G. Lippi, V. Bronte, P. Minuz
Arteriosclerosis, Thrombosis, and Vascular Biology. 2020, 40, 2975-2989
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
Thrombocytopenia and its association with mortality in patients with COVID‐19
X. Yang, Q. Yang, Y. Wang, Y. Wu, J. Xu, Y. Yu, Y. Shang
Journal of Thrombosis and Haemostasis. 2020, 18, 1469-1472
Platelet gene expression and function in patients with COVID-19
B. Manne, F. Denorme, E. Middleton, I. Portier, J. Rowley, C. Stubben, A. Petrey, N. Tolley, L. Guo, M. Cody, A. Weyrich, C. Yost, M. Rondina, R. Campbell
Blood. 2020, 136, 1317-1329
The Impact of COVID-19 Disease on Platelets and Coagulation
G. Wool, J. Miller
Pathobiology. 2021, 88, 15-27
Таким образом, можно предположить, что терапевтическая коррекция протромбогенного состояния эндотелия сосудов легких может улучшить качество тромбоцитов. Тем не менее, необходимо дальнейшее изучение тромбоцитов и их роли в развитии COVID-19, поскольку тромбоциты потенциально можно использовать для мониторинга системы гемостаза у пациентов с COVID-19.
Вклад авторов
Финансирование
Работа была поддержана Стипендией Президента СП-2675.2019.4; грантом эндаунмент фонда “Наука - детям” и Школой Цифровой Медицины Московского Государственного Университета им. М.В. Ломоносова.
Библиографические ссылки статьи:
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