Obstetrics, Gynecology and Reproduction

Advanced search

Thrombotic storm, hemostasis disorders and thromboinflammation in COVID-19

Full Text:


The rate of thrombosis and disseminated intravascular coagulation (DIC) has been increasing in COVID-19 patients. Key features related to such condition include minimal or no risk of bleeding, moderate thrombocytopenia, high plasma fibrinogen as well as complement components level in the areas of thrombotic microangiopathy. The clinical picture is not typical for classic DIC. This review systematizes the pathogenetic mechanisms of hypercoagulation in sepsis and its extreme forms in patients with COVID-19. The latter consist of the thrombosis-related immune mechanisms, the complement activation, the macrophage activation syndrome, the formation of antiphospholipid antibodies, the hyperferritinemia, and the dysregulation of the renin-angiotensin system. Taking into consideration the pathogenetic mechanisms, the biomarkers had been identified related to the prognosis of the disease development. Patients with pre-existing cardiovascular disease and other risk factors, including obesity, diabetes, hypertension, and aging pose the peak risk of dying from COVID-19. We also summarize new data on platelet and endothelial dysfunction, immunothrombosis, and, as a result, thrombotic storm as essential components of COVID-19 severe features.

About the Authors

A. D. Makatsariya
Sechenov University
Russian Federation

Alexander D. Makatsariya – MD, Dr Sci Med, Academician of RAS, Professor, Head of the Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

Scopus Author ID: 57222220144

Researcher ID: M-5660-2016


E. V. Slukhanchuk
Sechenov University; Petrovsky National Research Centre of Surgery
Russian Federation

Ekaterina V. Slukhanchuk – MD, PhD, Associate Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health; Obstetrician-Gynecologist, Department of Abdominal Surgery and Oncology 2

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991;

2 Abrikosovskiy Lane, Moscow 119991

V. O. Bitsadze
Sechenov University
Russian Federation

Victoria O. Bitsadze – MD, Dr Sci Med, Professor of RAS, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

Scopus Author ID: 6506003478

Researcher ID: F-8409-2017


J. Kh. Khizroeva
Sechenov University
Russian Federation

Jamilya Kh. Khizroeva – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

Scopus Author ID: 57194547147

Researcher ID: F-8384-2017


M. V. Tretyakova
«Medical Center» LLC
Russian Federation

Maria V. Tretyakova – MD, PhD, Obstetrician-Gynecologist, Department of Gynecology

15/1 Timura Frunze Str., Moscow 119021

A. S. Shkoda
Vorokhobov City Clinical Hospital № 67, Moscow Healthcare Department
Russian Federation

Andrey S. Shkoda – MD, Dr Sci Med, Professor, Chief Physician

2/44 Salyama Adilya Str., Moscow 123423

S. V. Akinshina
«Medical Centre for Women» LLC
Russian Federation

Svetlana V. Akinshina – MD, PhD, Obstetrician-Gynecologist, Hematologist

62 Str. Zemlyanoi Val, Moscow 109004

N. A. Makatsariya
Sechenov University
Russian Federation

Nataliya A. Makatsariya – MD, PhD, Associate Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

Researcher ID: F-8406-2017


V. I. Tsibizova
Almazov National Medical Research Centre, Health Ministry of Russian Federation
Russian Federation

Valentina I. Tsibizova – MD, PhD, Obstetrician-Gynecologist, Research Laboratory of Operative Gynecology, Institute of Perinatology and Pediatrics; Physician, Department of Functional and Ultrasound Diagnostics

2 Akkuratova Str., Saint Petersburg 197341

J.-C. Gris
Sechenov University; University of Montpellier

Jean-Christophe Gris – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health, Sechenov University

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991;

163 Rue Auguste Broussonnet, Montpellier 34090

Researcher ID: AAA-2923-2019


I. Elalamy
Sechenov University; Medicine Sorbonne University; Hospital Tenon

Ismail Elalamy – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health, Sechenov University; Professor, Medicine Sorbonne University, Paris, France; Director of Hematology, Department of Thrombosis Center, Hospital Tenon

163 Rue Auguste Broussonnet, Montpellier 34090;

12 Rue de l’École de Médecine, 75006 Paris;

4 Rue de la Chine, 75020 Paris

Scopus Author ID: 7003652413

Researcher ID: AAC-9695-2019


С. Ay
University of Vienna

Cihan Ay – MD, PhD, Professor, Department of Medicine I, Clinical Division of Haematology and  Haemostaseology

Scopus Author ID: 55356863800.

1 Universitätsring, Vienna 1010, Austria

E. Grandone
Sechenov University; Research Center «Casa Sollievo della Sofferenza»

Elvira Grandone – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health, Sechenov University; Head of the Department of Thrombosis and Hemostasis, Research Center «Casa Sollievo della Sofferenza», San Giovanni Rotondo

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991;

1 Viale Cappuccini, San Giovanni Rotondo 71013

Scopus Author ID: 7006391091

Researcher ID: M-1127-2019



1. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844–7.

2. 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(4):268–77.

3. Vulliamy P., Jacob S., Davenport R.A. Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19. Br J Haematol. 2020;189:1053–4.

4. Xu X., Chang X., Pan H. et al. Pathological changes of the spleen in ten patients with coronavirus disease 2019 (COVID-19) by postmortem needle autopsy. Zhonghua Bing Li Xue Za Zhi. 2020;49(6):576–82. [Article in Chinese].

5. Klok F., Kruip M., van der Meer N. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 2020;191:148–50.

6. Middeldorp S., Coppens M., van Haaps T.F. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1995–2002.

7. Lodigiani C., Iapichino G., Carenzo L. et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9–14.

8. Poissy J., Goutay J., Caplan M. et al. Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence. Circulation. 2020;142(2):184–6.

9. Ackermann M., Verleden S.E., Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–8.

10. Li Y., Li H., Zhu S. et al. Prognostic value of right ventricular longitudinal strain in patients with COVID-19. JACC Cardiovasc Imaging. 2020;13(11):2287–99.

11. Polat V., Bostancı G.I. Sudden death due to acute pulmonary embolism in a young woman with COVID-19. J Thromb Thrombolysis. 2020;50(1):239–41.

12. Inciardi R.M., Lupi L., Zaccone G. et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):819–24.

13. Oxley T.J., Mocco J., Majidi S. et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020;382(20):e60.

14. Zhou B., She J., Wang Y., Ma X. Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report. J Thromb Thrombolysis. 2020;50(1):229–32.

15. Griffin D.O., Jensen A., Khan M. et al. Arterial thromboembolic complications in COVID-19 in low-risk patients despite prophylaxis. Br J Haematol. 2020;190(1):e11–e13.

16. Helms J., Tacquard C., Severac F. et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089–98.

17. Hughes C., Nichols T., Pike M. et al. Cerebral venous sinus thrombosis as a presentation of COVID-19. Eur J Case Rep Intern Med. 2020;7(5):001691.

18. Zhang Y., Cao W., Xiao M. et al. Clinical and coagulation characteristics in 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28;41(0):E006. [Article in Chinese]. [Online ahead of print].

19. Fernandez-Nieto D., Jimenez-Cauhe J., Suarez-Valle A. et al. Characterization of acute acral skin lesions in nonhospitalized patients: A case series of 132 patients during the COVID-19 outbreak. J Am Acad Dermatol. 2020; 83(1):e61–e63.

20. Cordoro K.M., Reynolds S.D., Wattier R., McCalmont T.H. Clustered cases of acral perniosis: clinical features, histopathology, and relationship to COVID-19. Pediatr Dermatol. 2020;37(3):419–23.

21. Müller M.C., Meijers J.C., Vroom M.B., Juffermans N.P. Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review. Crit Care. 2014;18:1–11. 18(1):R30.

22. Wada H. Disseminated intravascular coagulation. Clin Chim Acta. 2004;344(1–2):13–21.

23. Iba T., Levy J.H., Raj A., Warkentin T.E. Advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Clin Med. 2019;8(5):728.

24. Merrill J.T., Erkan D., Winakur J., James J.A. Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications. Nat Rev Rheumatol. 2020;16(10):581–9.

25. Zhou F., Yu T., Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.

26. Cipolloni L., Sessa F., Bertozzi G. et al. Preliminary post-mortem COVID-19 evidence of endothelial injury and factor VIII hyperexpression. Diagnostics (Basel). 2020;10(8):575.

27. Lippi G., Plebani M., Henry B.M. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta. 2020;506:145–8.

28. Thiery-Antier N., Binquet C., Vinault S. et al. Is thrombocytopenia an early prognostic marker in septic shock? Crit Care Med. 2016;44(4):764–72.

29. Pavoni V., Gianesello L., Pazzi M. et al. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia. J Thromb Thrombolysis. 2020;50(2):281–6.

30. Fish R.J., Neerman-Arbez M. Fibrinogen gene regulation. Thromb Haemost. 2012;108(3):419–26.

31. Chousterman B.G., Swirski F.K., Weber G.F. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017;39(5):517–28.

32. Mehta P., McAuley D.F., Brown M. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4.

33. England J.T., Abdulla A., Biggs C.M. et al. Weathering the COVID-19 storm: lessons from hematologic cytokine syndromes. Blood Rev. 2021;45:100707.

34. Karakike E., Giamarellos-Bourboulis E.J. Macrophage activation-like syndrome: a distinct entityleading to early death in sepsis. Front Immunol. 2019;10:55.

35. Crayne C.B., Albeituni S., Nichols K.E., Cron R.Q. The immunology of macrophage activation syndrome. Front Immunol. 2019;10:119.

36. Chen G., Wu D., Guo W. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Investigat. 2020;130(5):2620–9.

37. Henry B.M., De Oliveira M.H.S., Benoit S. et al. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clini Chem Lab Med. 2020;58(7):1021–8.

38. Giamarellos-Bourboulis E.J., Netea M.G., Rovina N. et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27(6):992–1000.e3.

39. Ranucci M., Ballotta A., Di Dedda U. et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost. 2020;18(7):1747–51.

40. Bowles L., Platton S., Yartey N. et al. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med. 2020;383(3):288–90.

41. Giannis D., Ziogas I.A., Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020;127:104362.

42. Ng L.F., Hibberd M.L., Ooi E.-E. et al. A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection. BMC Infect Dis. 2004;4:34.

43. Poon T.C., Pang R.T., Chan K.A. et al. Proteomic analysis reveals platelet factor 4 and beta-thromboglobulin as prognostic markers in severe acute respiratory syndrome. Electrophoresis. 2012;33(12):1894–900.

44. Subramaniam S., Scharrer I. Procoagulant activity during viral infections. Front Biosci (Landmark Ed). 2018;23:1060–81.

45. Lupu F., Keshari R.S., Lambris J.D., Coggeshall K.M. Crosstalk between the coagulation and complement systems in sepsis. Thromb Res. 2014;133 Suppl 1(01):S28–S31.

46. Qiu P., Cui X., Sun J. et al. Anti-tumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis. Crit Care Med. 2013;41(10):2419–29.

47. Risitano A.M., Mastellos D.C., Huber-Lang M. et al. Complement as a target in COVID-19? Nat Rev Immunol. 2020;20(6):343–4.

48. Gao T., Hu M., Zhang X. et al. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation. medRxiv. June18, 2020.

49. Magro C., Mulvey J.J., Berlin D. et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1–13.

50. Campbell C.M., Kahwash R. Will complement inhibition be the new target in treating COVID-19–related systemic thrombosis? Circulation. 2020;141(22):1739–41.

51. Leslie M. Beyond clotting: the powers of platelets. Science. 2010;328(5978):562–4.

52. Ouseph M.M., Huang Y., Banerjee M. et al. Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis. Blood. 2015;126(10):1224–33.

53. Mason K.D., Carpinelli M.R., Fletcher J.I. et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128(6):1173–86.

54. Lindemann S., Tolley N.D., Dixon D.A. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis. J Cell Biol. 2001;154(3):485–90.

55. Koupenova M., Freedman J.E. Platelets and immunity: going viral. Arterioscler Thromb Vasc Biol. 2020;40(7):1605–7.

56. Maquet J., Lafaurie M., Sommet A. et al. Thrombocytopenia is independently associated with poor outcome in patients hospitalized for COVID-19. Br J Haematol. 2020;190(5):e276–e279.

57. Fitch-Tewfik J., Flaumenhaft R. Platelet granule exocytosis: a comparison with chromaffin cells. Front Endocrinol (Lausanne). 2013;4:77.

58. Sut C., Tariket S., Aubron C. et al. The non-hemostatic aspects of transfused platelets. Front Med (Lausanne). 2018;5:42.

59. Hottz E.D., Lopes J.F., Freitas C. et al. Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood. 2013;122(20):3405–14.

60. Middleton E.A., He X.Y., Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood. 2020;136(10):1169–79.

61. Zarbock A., Polanowska-Grabowska R.K., Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev. 2007;21(2):99–111.

62. Melchinger H., Jain K., Tyagi T., Hwa J. Role of platelet mitochondria: life in a nucleus-free zone. Front Cardiovasc Med. 2019;6:153.

63. Tang W.H., Stitham J., Jin Y. et al. Aldose reductase – mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation. 2014;129(15):1598–609.

64. Zulfiqar A.-A., Lorenzo-Villalba N., Hassler P., Andrès E. Immune thrombocytopenic purpura in a patient with Covid-19. N Engl J Med. 2020;382(18):e43.

65. Zhang Y., Xiao M., Zhang S. et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020;382(17):e38.

66. Manne B.K., Denorme F., Middleton E.A. et al. Platelet gene expression and function in patients with COVID-19. Blood. 2020;136(11):1317–29.

67. Hoffmann M., Kleine-Weber H., Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Сell. 2020;181(2):271–280.e8.

68. Gomez-Casado C., Villaseñor A., Rodriguez-Nogales A. et al. Understanding platelets in infectious and allergic lung diseases. Int J Mol Sci. 2019;20(7):1730.

69. Perdomo J., Leung H.H., Ahmadi Z. et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019;10(1):1322.

70. Monsalvo A.C., Batalle J.P., Lopez M.F. et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med. 2011;17(2):195–9.

71. Boilard E., Paré G., Rousseau M. et al. Influenza virus H1N1 activates platelets through FcγRIIA signaling and thrombin generation. Blood. 2014;123(18):2854–63.

72. Flaujac C., Boukour S., Cramer-Bordé E. Platelets and viruses: an ambivalent relationship. Cell Mol Life Sci. 2010;67(4):545–56.

73. Lefrançais .E, Looney M.R. Platelet biogenesis in the lung circulation. Physiology (Bethesda). 2019;34(6):392–401.

74. Teuwen L.-A., Geldhof V., Pasut A., Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020;20(7):389–91.

75. O'Sullivan J.M., Mc Gonagle D., Ward S.E. et al. Endothelial cells orchestrate COVID-19 coagulopathy. Lancet Haematol. 2020;7(8):e553–e555.

76. Goshua G., Pine A.B., Meizlish M.L. et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. The Lancet Haematol. 2020;7(8):e575–e582.

77. Meizlish M.L., Pine A.B., Goshua G. et al. Circulating markers of angiogenesis and endotheliopathy in COVID-19. medRxiv. 2020;2020.06.29.20140376. Preprint.

78. Wiersinga W.J., Rhodes A., Cheng A.C. et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782–93.

79. Ungvari Z., Tarantini S., Kiss T. et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol. 2018;15(9):555–65.

80. Widlansky M..E, Gokce N., Keaney J.F., Vita J.A. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42(7):1149–60.

81. Csiszar A., Ungvari Z., Koller A. et al. Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging. Physiol Genomics. 2004;17(1):21–30.

82. Ley K., Laudanna C., Cybulsky M.I., Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7(9):678–89.

83. Fuchs T.A., Abed U., Goosmann C. et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41.

84. Kenny E.F., Herzig A., Krüger R. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. Elife. 2017;6:e24437.

85. Ivan F.X., Rajapakse J.C., Welsch R.E. et al. Differential pulmonary transcriptomic profiles in murine lungs infected with low and highly virulent influenza H3N2 viruses reveal dysregulation of TREM1 signaling, cytokines, and chemokines. Funct Integr Genomics. 2012;12(1):105–17.

86. Ashar H.K., Mueller N.C., Rudd J.M. et al. The role of extracellular histones in influenza virus pathogenesis. Am J Pathol. 2018;188(1):135–48.

87. Kobasa D., Jones S.M., Shinya K. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007;445(7125):319–23.

88. Gould T., Lysov Z., Liaw P. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost. 2015;13(Suppl 1):S82–91.

89. Jimenez-Alcazar M., Napirei M., Panda R. et al. Impaired DN ase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J Thromb Haemost. 2015;13(3):732–42.

90. Martinod K., Wagner D.D. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768–76.

91. Naudin C., Burillo E., Blankenberg S. et al. Factor XII contact activation. Semin Thromb Hemost. 2017;43(8):814–26.

92. Vu T.T., Leslie B.A., Stafford A.R. et al. Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway. Thromb Haemost. 2016;115(1):89–98.

93. Noubouossie D.F., Whelihan M.F., Yu Y.-B. et al. In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood. 2017;129(8):1021–9.

94. Saffarzadeh M., Juenemann C., Queisser M.A. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PloS One. 2012;7(2):e32366.

95. Semeraro F., Ammollo C.T., Morrissey J.H. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118(7):1952–61.

96. Carestia A., Rivadeneyra L., Romaniuk M.A. et al. Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost. 2013;110(5):1035–45.

97. Barranco-Medina S., Pozzi N., Vogt A.D., Di Cera E. Histone H4 promotes prothrombin autoactivation. J Biol Chem. 2013;288(50):35749–57.

98. Varjú I., Longstaff C., Szabó L. et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost. 2015;113(6):1289–98.

99. Ammollo C.T., Semeraro F., Xu J. et al. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost. 2011;9(9):1795–803.

100. Healy L.D., Puy C., Fernández J.A. et al. Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem. 2017;292(21):8616–29.

101. Komissarov A.A., Florova G., Idell S. Effects of extracellular DNA on plasminogen activation and fibrinolysis. J Biol Chem. 2011;286(49):41949–62.

102. Longstaff C., Varjú I., Sótonyi P. et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013;288(10):6946–56.

103. Löf A., Müller J.P., Brehm M.A. A biophysical view on von Willebrand factor activation. J Cell Physiol. 2018;233(2):799–810.

104. Zhang C., Kelkar A., Neelamegham S. von Willebrand factor self-association is regulated by the shear-dependent unfolding of the A2 domain. Blood Advances. 2019;3(7):957–68.

105. South K., Lane D.A. ADAMTS-13 and von Willebrand factor: a dynamic duo. J Thromb Haemost. 2018;16(1):6–18.

106. Colafrancesco S., Alessandri C., Conti F., Priori R. COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Autoimmun Rev. 2020;19(7):102573.

107. Kuhn J., Li W., Choe H., Farzan M. Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus. Cell Mol Life Sci. 2004;61(21):2738–43.

108. Li M.-Y., Li L., Zhang Y., Wang X.-S. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty. 2020;9(1):45.

109. Hamming I., Timens W., Bulthuis M. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–7.

110. Patel V.B., Zhong J.-C., Grant M.B., Oudit G.Y. Role of the ACE2/angiotensin 1–7 axis of the renin–angiotensin system in heart failure. Circ Res. 2016;118(8):1313–26.

111. Liu Y., Yang Y., Zhang C. et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364–74.

112. Nadar S., Lip G.Y. The prothrombotic state in hypertension and the effects of antihypertensive treatment. Curr Pharm Des. 2003;9(21):1715–32.

113. Brown N.J., Vaughan D.E. Prothrombotic effects of angiotensin. Adv Intern Med. 2000;45:419–29.

114. Giacomelli E., Dorigo W., Fargion A. et al. Acute thrombosis of an aortic prosthetic graft in a patient with severe COVID-19–related pneumonia. Ann Vasc Surg. 2020;66:8–10.

115. Sun T., Ghosh A.K., Eren M. et al. PAI-1 contributes to homocysteine-induced cellular senescence. Cell Signal. 2019;64:109394.

116. Wright F.L., Vogler T.O., Moore E.E. et al. Fibrinolysis shutdown correlation with thromboembolic events in severe COVID-19 infection. J Am Coll Surg. 2020;231(2):193–203.e1.

117. Bouwman J., Diepersloot R., Visseren F. Intracellular infections enhance interleukin-6 and plasminogen activator inhibitor 1 production by cocultivated human adipocytes and THP-1 monocytes. Clin Vaccine Immunol. 2009;16(8):1222–7.

118. Zhao X., Nicholls J.M., Chen Y.-G. Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-β signaling. J Biol Chem. 2008;283(6):3272–80.

119. Lundgren C.H., Brown S.L., Nordt T.K. et al. Elaboration of type-1 plasminogen activator inhibitor from adipocytes: a potential pathogenetic link between obesity and cardiovascular disease. Circulation. 1996;93(1):106–10.

120. Garcia D., Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;378(21):2010–21.

121. Bowles L., Platton S., Yartey N. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med. 10. 2020;383(3):288–90.

122. Harzallah I., Debliquis A., Drénou B. Lupus anticoagulant is frequent in patients with Covid-19. J Thromb Haemost. 2020;18(8):2064–5.

123. Proulle V., Furie R.A., Merrill-Skoloff G. et al. Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS. Blood. 2014;124(4):611–22.

124. Giannakopoulos B., Krilis S.A. The pathogenesis of the antiphospholipid syndrome. N Engl J Med. 2013;368(11):1033–44.

125. Sacharidou A., Chambliss K.L., Ulrich V. et al. Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium. Blood. 2018;131(19):2097–110.

126. Chaturvedi S., Braunstein E.M., Yuan X. et al. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood. 2020;135(4):239–51.

127. Uthman I.W., Gharavi A.E. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum. 2002;31(4):256–63.

128. Lakos G. Interference in antiphospholipid antibody assays. Semin Thromb Hemost. 2012;38(4):353–9.

For citation:

Makatsariya A.D., Slukhanchuk E.V., Bitsadze V.O., Khizroeva J.K., Tretyakova M.V., Shkoda A.S., Akinshina S.V., Makatsariya N.A., Tsibizova V.I., Gris J., Elalamy I., Ay С., Grandone E. Thrombotic storm, hemostasis disorders and thromboinflammation in COVID-19. Obstetrics, Gynecology and Reproduction. 2021;15(5):499-514.

Views: 1333

ISSN 2313-7347 (Print)
ISSN 2500-3194 (Online)