Download PDF
Hamostaseologie 2022; 42(S 01): S14-S23
DOI: 10.1055/a-1797-0564
Original Article

Platelets and Sera from Donors of Convalescent Plasma after Mild COVID-19 Show No Procoagulant Phenotype

Günalp Uzun
1   Centre for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
,
Anurag Singh
2   Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tübingen, University Hospital of Tübingen, Tübingen, Germany
,
Wissam Abou-Khalel
1   Centre for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
,
Lisann Pelzl
2   Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tübingen, University Hospital of Tübingen, Tübingen, Germany
,
Karoline Weich
1   Centre for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
,
Stefanie Nowak-Harnau
1   Centre for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
,
Karina Althaus
1   Centre for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
2   Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tübingen, University Hospital of Tübingen, Tübingen, Germany
,
Peter Bugert
3   Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Hessen, Mannheim, Germany
,
Harald Klüter
3   Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Hessen, Mannheim, Germany
,
Tamam Bakchoul
1   Centre for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
2   Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tübingen, University Hospital of Tübingen, Tübingen, Germany
› Author Affiliations Funding This work was supported by grants from the German Research Foundation and from the Herzstiftung to T.B. (BA5158/4 and TSG Study), by special funds from the state of Baden-Württemberg for coagulation research and blood donation service of German Red Cross to T.B.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Coronavirus disease-2019 (COVID-19) is associated with increased thromboembolic complications. Long-term alteration in the coagulation system after acute COVID-19 infection is still a subject of research. Furthermore, the effect of sera from convalescent subjects on platelets is not known. In this study, we investigated platelet phenotype, coagulation, and fibrinolysis in COVID-19 convalescent plasma (CCP) donors and analyzed convalescent sera-induced effects on platelets. We investigated CCP donors who had a history of mild COVID-19 infection and donors who did not have COVID-19 were used as controls. We analyzed phosphatidylserine (PS) externalization, CD62p expression, and glycoprotein VI (GPVI) shedding both in platelet-rich plasma (PRP) and after incubation of washed healthy platelets with donors' sera using flow cytometry. Coagulation and fibrinolysis systems were assessed with thromboelastometry. Forty-seven CCP donors (22 males, 25 females; mean age (±SD): 41.4 ± 13.7 years) with a history of mild COVID-19 infection were included. Median duration after acute COVID-19 infection was 97 days (range, 34–401). We did not find an increased PS externalization, CD62p expression, or GPVI shedding in platelets from CCP donors. Sera from CCP donors did not induce PS externalization or GPVI shedding in healthy platelets. Sera-induced CD62p expression was slightly, albeit statistically significantly, lower in CCP donors than in plasma donors without a history of COVID-19. One patient showed increased maximum clot firmness and prolonged lysis time in thromboelastometry. Our findings suggest that procoagulant platelet phenotype is not present after mild COVID-19. Furthermore, CCP sera do not affect the activation status of platelets.

Keywords

procoagulant platelets - platelet activation - convalescent plasma - COVID-19

Author Contributions

G.U., A.S., L.P., K.A., P.B., H.K., and T.B. designed the study. G.U. and S.N-H. collected and analyzed the clinical data. G.U., A.S., W.A-K., L.P., K.W., and K.A. performed the experiments. G.U., A.S., P.B., H.K., and T.B. analyzed the data, interpreted the results, and wrote the manuscript. All authors read and approved the manuscript.




Publication History

Received: 12 October 2021

Accepted: 12 March 2022

Article published online:
26 October 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Levi M, Thachil J. Coronavirus disease 2019 coagulopathy: disseminated intravascular coagulation and thrombotic microangiopathy-either, neither, or both. Semin Thromb Hemost 2020; 46 (07) 781-784
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Bussani R, Schneider E, Zentilin L. et al. Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine 2020; 61: 103104
    CrossrefPubMedGoogle Scholar
  • 3 Wichmann D, Sperhake J-P, Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020; 173 (04) 268-277
    Google Scholar
  • 4 Nadkarni GN, Lala A, Bagiella E. et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (16) 1815-1826
    CrossrefPubMedGoogle Scholar
  • 5 Thachil J, Cushman M, Srivastava A. A proposal for staging COVID-19 coagulopathy. Res Pract Thromb Haemost 2020; 4 (05) 731-736
    CrossrefPubMedGoogle Scholar
  • 6 Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020; 24 (01) 360
    CrossrefPubMedGoogle Scholar
  • 7 Zaid Y, Puhm F, Allaeys I. et al. Platelets can associate with SARS-CoV-2 RNA and are hyperactivated in COVID-19. Circ Res 2020; 127 (17) 1404-1418
    CrossrefPubMedGoogle Scholar
  • 8 Hottz ED, Azevedo-Quintanilha IG, Palhinha L. et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136 (11) 1330-1341
    CrossrefPubMedGoogle Scholar
  • 9 Zlamal J, Althaus K, Jaffal H. et al. Upregulation of cAMP prevents antibody-mediated thrombus formation in COVID-19. Blood Adv 2022; 6 (01) 248-258
    CrossrefPubMedGoogle Scholar
  • 10 Althaus K, Marini I, Zlamal J. et al. Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood 2021; 137 (08) 1061-1071
    CrossrefPubMedGoogle Scholar
  • 11 Khattab MH, Prodan CI, Vincent AS. et al. Increased procoagulant platelet levels are predictive of death in COVID-19. Geroscience 2021; 43 (04) 2055-2065
    CrossrefPubMedGoogle Scholar
  • 12 Balachandar V, Mahalaxmi I, Subramaniam M. et al. Follow-up studies in COVID-19 recovered patients - Is it mandatory?. Sci Total Environ 2020; 729: 139021
    CrossrefPubMedGoogle Scholar
  • 13 von Meijenfeldt FA, Havervall S, Adelmeijer J. et al. Sustained prothrombotic changes in COVID-19 patients 4 months after hospital discharge. Blood Adv 2021; 5 (03) 756-759
    CrossrefPubMedGoogle Scholar
  • 14 Townsend L, Fogarty H, Dyer A. et al. Prolonged elevation of D-dimer levels in convalescent COVID-19 patients is independent of the acute phase response. J Thromb Haemost 2021; 19 (04) 1064-1070
    CrossrefPubMedGoogle Scholar
  • 15 Hulshof A-M, Braeken DCW, Ghossein-Doha C. et al. Hemostasis and fibrinolysis in COVID-19 survivors 6 months after intensive care unit discharge. Res Pract Thromb Haemost 2021; 5 (06) e12579
    CrossrefPubMedGoogle Scholar
  • 16 Joyner MJ, Wright RS, Fairweather D. et al. Early safety indicators of COVID-19 convalescent plasma in 5000 patients. J Clin Invest 2020; 130 (09) 4791-4797
    CrossrefPubMedGoogle Scholar
  • 17 Körper S, Weiss M, Zickler D. et al; CAPSID Clinical Trial Group. Results of the CAPSID randomized trial for high-dose convalescent plasma in patients with severe COVID-19. J Clin Invest 2021; 131 (20) e152264
    CrossrefPubMedGoogle Scholar
  • 18 O'Donnell MR, Grinsztejn B, Cummings MJ. et al. A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19. J Clin Invest 2021; 131 (13) 150646
    CrossrefPubMedGoogle Scholar
  • 19 Heemskerk JWM, Mattheij NJA, Cosemans JMEM. Platelet-based coagulation: different populations, different functions. J Thromb Haemost 2013; 11 (01) 2-16
    CrossrefPubMedGoogle Scholar
  • 20 Tohidi-Esfahani I, Lee CSM, Liang HPH, Chen VMY. Procoagulant platelets: Laboratory detection and clinical significance. Int J Lab Hematol 2020; 42 (Suppl. 01) 59-67
    CrossrefPubMedGoogle Scholar
  • 21 Denorme F, Manne BK, Portier I. et al. COVID-19 patients exhibit reduced procoagulant platelet responses. J Thromb Haemost 2020; 18 (11) 3067-3073
    CrossrefPubMedGoogle Scholar
  • 22 Pelzl L, Singh A, Funk J. et al. Antibody-mediated procoagulant platelet formation in COVID-19 is AKT dependent. J Thromb Haemost 2022; 20 (02) 387-398
    CrossrefPubMedGoogle Scholar
  • 23 Manne BK, Denorme F, Middleton EA. et al. Platelet gene expression and function in patients with COVID-19. Blood 2020; 136 (11) 1317-1329
    CrossrefPubMedGoogle Scholar
  • 24 Weiss LJ, Manukjan G, Pflug A. et al. Acquired platelet GPVI receptor dysfunction in critically ill patients with sepsis. Blood 2021; 137 (22) 3105-3115
    CrossrefPubMedGoogle Scholar
  • 25 Bongiovanni D, Klug M, Lazareva O. et al. SARS-CoV-2 infection is associated with a pro-thrombotic platelet phenotype. Cell Death Dis 2021; 12 (01) 50
    CrossrefPubMedGoogle Scholar
  • 26 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 (05) 1694-1702
    CrossrefPubMedGoogle Scholar
  • 27 Reddy EC, Rand ML. Procoagulant phosphatidylserine-exposing platelets in vitro and in vivo . Front Cardiovasc Med 2020; 7: 15
    CrossrefPubMedGoogle Scholar
  • 28 Harper MT, Londoño JEC, Quick K. et al. Transient receptor potential channels function as a coincidence signal detector mediating phosphatidylserine exposure. Sci Signal 2013; 6 (281) ra50
    CrossrefPubMedGoogle Scholar
  • 29 Ayoubkhani D, Khunti K, Nafilyan V. et al. Post-COVID syndrome in individuals admitted to hospital with COVID-19: retrospective cohort study. BMJ 2021; 372 (693) n693
    CrossrefPubMedGoogle Scholar
  • 30 Rashidi F, Barco S, Kamangar F. et al. Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: Prospective results from a multi-center study. Thromb Res 2021; 198: 135-138
    CrossrefPubMedGoogle Scholar
  • 31 Salisbury R, Iotchkova V, Jaafar S. et al. Incidence of symptomatic, image-confirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up. Blood Adv 2020; 4 (24) 6230-6239
    CrossrefPubMedGoogle Scholar
  • 32 Bourguignon A, Beaulieu C, Belkaid W, Desilets A, Blais N. Incidence of thrombotic outcomes for patients hospitalized and discharged after COVID-19 infection. Thromb Res 2020; 196: 491-493
    CrossrefPubMedGoogle Scholar
  • 33 Patell R, Bogue T, Koshy A. et al. Postdischarge thrombosis and hemorrhage in patients with COVID-19. Blood 2020; 136 (11) 1342-1346
    CrossrefPubMedGoogle Scholar
  • 34 Roberts LN, Whyte MB, Georgiou L. et al. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood 2020; 136 (11) 1347-1350
    CrossrefPubMedGoogle Scholar
  • 35 Engelen MM, Vanassche T, Balthazar T. et al. Incidence of venous thromboembolism in patients discharged after COVID-19 hospitalisation. Res Pract Thromb Haemost 2020;4(Suppl 1 https://abstracts.isth.org/abstract/incidence-of-venous-thromboembolism-in-patients-discharged-after-covid-19-hospitalisation/
    Google Scholar
  • 36 Hulshof A-M, Brüggemann RAG, Mulder MMG. et al. Serial EXTEM, FIBTEM, and tPA rotational thromboelastometry observations in the Maastricht intensive care COVID Cohort - persistence of hypercoagulability and hypofibrinolysis despite anticoagulation. Front Cardiovasc Med 2021; 8: 654174
    CrossrefPubMedGoogle Scholar
  • 37 Hammer S, Häberle H, Schlensak C. et al. Severe SARS-CoV-2 infection inhibits fibrinolysis leading to changes in viscoelastic properties of blood clot: a descriptive study of fibrinolysis in COVID-19. Thromb Haemost 2021; 121 (11) 1417-1426
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Wygrecka M, Birnhuber A, Seeliger B. et al. Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19. Blood Adv 2022; 6 (03) 1074-1087
    CrossrefPubMedGoogle Scholar
  • 39 Magomedov A, Zickler D, Karaivanov S. et al. Viscoelastic testing reveals normalization of the coagulation profile 12 weeks after severe COVID-19. Sci Rep 2021; 11 (01) 13325
    CrossrefPubMedGoogle Scholar
  • 40 Yürekli BPS, Ozcebe OI, Kirazli S, Gürlek A. Global assessment of the coagulation status in type 2 diabetes mellitus using rotation thromboelastography. Blood Coagul Fibrinolysis 2006; 17 (07) 545-549
    CrossrefPubMedGoogle Scholar