A strong correlation exists between platelet consumption and platelet hyperactivation in COVID-19 patients. Pilot study of the patient cohort from CCH RAS Hospital (Troitsk).
Introduction
SARS-CoV-2 is the cause of the pandemic that broke out worldwide in 2020
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The key driving enzyme of blood plasma coagulation, thrombin, could induce platelet hyperactivation and procoagulant response
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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
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New Fundamentals in Hemostasis
H. Versteeg, J. Heemskerk, M. Levi, P. Reitsma
Physiological Reviews. 2013, 93, 327-358
The mechanisms of SARS-CoV-2 influence on platelet functioning and the role of the platelet hemostasis in the pathology of COVID-19, in general, are currently actively studied. Younes et al. have shown that viral RNA was present in patients' platelets in 22% of cases, both severe and non-severe
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
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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
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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
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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
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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
To summarize the above platelets of the COVID-19 patients are defective due to reasons that are poorly understood. Here, based on the experimental observations of platelet necrosis and size, as well as computational modeling, we suggest that the observed changes in platelets may be explained by their increased activation in circulation in COVID-19 patients.
Materials and Methods
Patients
32 patients, diagnosed with coronavirus infection, who were treated at the Federal State Budgetary Healthcare Institution Hospital of the Russian Academy of Sciences (Troitsk), as well as five healthy donors, aged from 21 to 45 years, who have not been ill and have not taken any medications within the last month, were enrolled in the study. All patients' condition was described as "mild severity" by physicians and did not require mechanical ventillation. All procedures comply with the ethical standards of the National Research Ethics Committee and the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. Informed voluntary consent was obtained from each of the participants included in the study. All patients were subsequently discharged from the hospital within 2 weeks due to improvement in their condition. Blood samples of five patients were analyzed twice on different days. The study was approved by the decision of the Independent Ethics Committee of the Dmitry Rogachev National Research Center No. 3/2020 dated May 19, 2020.
Materials
Annexin-Alexa647, lactadherin-FITC (Sony Biotechnology, San-Jose, USA), HEPES, bovine serum albumin (BSA), D(+)glucose (Sigma, USA); NaCl; Na2HPO4; KCl; NaHCO3; MgCl2; CaCl2 (Agat-Med, Moscow, Russia).
Flow Cytometry
Blood was collected in 3 mL tubes containing sodium citrate (3,8%) and was kept at room temperature for 30 minutes. During that time, red blood cells sedimented into the lower layers of the blood sample. Blood was then collected from the top 10 percent of the tube’s volume, was diluted in Tyrode’s buffer (134 мМ NaCl; 0.34 мМ Na2HPO4; 2.9 мМ KCl; 12 мМ NaHCO3; 20 мМ HEPES; 5 мМ glucose; 1 мМ MgCl2; 2 мМ CaCl2; BSA 2% by weight; pH 7.3) to platelet concentration of 1×103 per 1 mL. After that, AnnexinV-Alexa647 (2% v/v) and Lactadherin-FITC (2% v/v) were added to each sample, and cells were incubated for 10 minutes, as previously described
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
Computational model
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S. Wolfram
Nature. 1984, 311, 419-424
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S. Patel
Journal of Clinical Investigation. 2005, 115, 3348-3354
where P is the number of platelets produced by the megakaryocyte, n is the random value from \( N(\mu=1 ; \sigma=0.1) \), TPO is the parameter reflecting thrombopoietin concentration according to equation (2): \begin{equation} TPO=1-\frac{1}{1+\left(\frac{N_{T P O}}{P l t}\right)^{h}}\tag{2}\end{equation}
where \( N_{TPO} \) is the approximate number of platelets below which TPO production in the liver is initiated, and Plt is the number of platelets at the given time point, the parameters \( N_{TPO}=120000 \) and h = 6 were adjusted to describe experimental data on the relationship between platelet counts and [TPO] concentration in blood from 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
where nnat reflects the natural platelet removal and is a random value from N(0.625‧age; 0.0125‧age), and nthr reflects the platelets removal due to their participation in thrombus formation and is a random value from N(0.625‧K; 0.0125‧K), where K is the consumption index, which can be varied to simulate severity of thrombosis. Platelet size is known to be related to the platelet's age and RNA content
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
where s0 reflects the initial platelet size and is a value from N(12; 1) in [fL], parameters Max = 11 [fL] and Min = 6 [fL] reflect the platelet size distribution found in healthy donors
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
Clinical data
The results of complete blood count, biochemical analysis, blood clotting test, CT scans, data of daily objective examinations, age, and diagnoses of patients were kindly provided by the hospital with the patients' consent.
Data processing
Raw flow cytometry data were processed using FlowJoTM Software. Statistical analysis was performed utilizing GraphPad Prizm.
Results and Discussion
Platelets size and phosphatidylserine exposure are increased in patients with COVID-19
The patients with mild Covid-19 disease examined in this study did not suffer from thrombocytopenia, as the platelets numbers in all patients were between 139x103 and 519x103 platelets per μl. To examine the size and activation status of the platelets we performed flow cytometry analyisis of cells in patients’ blood stained with lactadherin and Annexin V (Fig. 1). Analysis of the platelet’s forward scattering (FS-A) revealed a significant increase in patients FS-A compared to healthy donors (mean value ± SD: 213±25‧103 a.u. for patients, 185±20‧103 a.u. for healthy donors, p=0.027, Fig. 1C). These findings are in line with previously published data
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
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The percentage of PS+ platelets in patients was more than two times higher than that in healthy donors (mean value ± SD: 0.74±0.37% for patients, 0.29±0.07% for healthy donors; p<0.0001, Fig. 1D-F). The average percentage of PS+ events was higher for lactadherin than for annexin V (p=0.0372, Fig. 1E, F), which is consistent with the literature data on the higher effectivity of lactadherin for PS+ cells detection
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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
The PS+ platelets are known to form in response to strong stimulation, for example, dual collagen and thrombin
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According to previously published recommendations, other therapeutic agents are prescribed for the patients in the hospital, including the antiretroviral drug lopinavir
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When comparing groups of patients for the presence of chronic diseases, statistically significant differences (p=0.027) were found only for the group of patients with chronic lung diseases. The percentage of PS+ events in the presence of the disease was lower than in the absence (mean value ± SD: 0.81±0.37% for absence, 0.41±0.17% for presence, Fig. 2B), which may be due to the presence of a compensatory mechanism in these patients' coagulation system. The patient cohort included in this study is highly heterogenic in terms of age and health status. However, the lack of significant differences between different patients' groups (Fig. 2B, Fig. S1) and the absence of the observed altered platelet phenotype in chronic diseases
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The computational model predicts that the enhanced platelet consumption underlies thrombocytopathy in COVID-19 patients
Platelet phenotype of COVID-19 patients appeared to be distinctive: while no significant thrombocytopenia was detected in our study as well as in the literature
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
In the model, in the absence of additional platelet consumption, the average platelet counts are between 155x103 platelets/μl and 177x103 platelets/μl (Fig. 3B). The number of platelets and platelet size were stochastically fluctuating (Fig. S2 A and B correspondingly). Introduction of additional consumption, which did not significantly alter platelet counts (∆Plt < 25 000/μl), results in a significant increase in the platelet size (Fig. 3B,C; S2A,B). Increased consumption also resulted in the platelets becoming younger (Fig. S2C,D). Enhancement of the platelet consumption above 2 resulted in mild thrombocytopenia and platelets becoming younger (Fig. 3B). Severe thrombocytopenia appeared at platelet consumption above K = 5, which corresponded to more than half of the produced platelets being consumed (Fig. 3B, S2). Additional sensitivity analysis revealed that model outcome was most sensitive to the TPO synthesis, platelet consumption, and platelet clearance parameters. These reactions are highlighted in red (Fig. 3A).
It is noteworthy that in patients the PS+ platelet fraction weakly correlated with the mean FS-A values (Table 1). This finding supports the hypothesis that in COVID-19, platelets are consumed due to thrombosis which leads to the increase in PS+ platelet fraction, younger overall age of platelets and therefore larger size. The weakness of the correlation could be caused by the enhanced PS+ platelet consumption by the liver and spleen [36]. However, it should also be kept in mind that the cells were resting during the experiment, and no comparison of the degree of activation for patients and healthy donors was carried out.
Conclusions
Here we observed a significant increase in the fraction of PS+ platelets in COVID-19 patients (Fig. 1). This phenomenon does not correlate either with therapeutic interventions carried out in the hospital or with chronic diseases in the patients (Fig. 2). Therefore, we assume that the observed increase in platelet size and phosphatidylserine exposure is mainly caused by COVID-19 and associated pneumonia. Previously it has been reported that such changes could be caused by active thrombosis [26], [41]. The proposed computational model demonstrates that moderate consumption, which does not result in pronounced thrombocytopenia, could result in a 1.3-fold increase in mean platelet volume observed for the COVID-19 patients (Fig. 1).
Based on our experimental results and theoretical findings, we propose the following scheme of the COVID-19 impact on human platelets:
· SARS-CoV-2 induces lung damage. This results in the blood vascular endothelium activation and tissue factor (TF) exposure to the blood flow
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
· TF induces thrombus formation and platelet consumption;
· Fraction of PS+ platelets is increased (Fig. 1) as a result of strong platelet activation, and platelets production is enhanced by the megakaryocytes (Fig. 3)
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
· A mild reduction of the platelet count occurs
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
Therefore, it can be assumed that a therapeutic correction of the pro-thrombogenic state of the lung vascular endothelium could improve the platelet's quality. Still, further study of platelets and their role in the development of COVID-19 is necessary, as platelets can be used to monitor the hemostasis system in COVID-19 patients.
Authors contributions
Funding
The work was supported by the Russian Presidential Scholarship SP-2675.2019.4; a grant from the endowment foundation “Science for Children” and Lomonosov Moscow State University Digital Medicine School.
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