Download PDF
Thromb Haemost 2024; 124(04): 286-296
DOI: 10.1055/s-0043-1776713
Review Article

COVID-19 and Long-COVID Thrombosis: From Clinical and Basic Science to Therapeutics

Francesco Violi 
1   Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
2   Mediterranea Cardiocentro, Via Orazio, Naples, Italy
,
Job Harenberg
3   Medical Faculty Mannheim, Ruprecht–karls University Heidelberg, Heidelberg, Germany
,
Pasquale Pignatelli
1   Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
2   Mediterranea Cardiocentro, Via Orazio, Naples, Italy
,
Vittoria Cammisotto
1   Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
› Author Affiliations
› Further Information
    Permissions and Reprints


Abstract

Coronavirus infectious disease-19 (COVID-19) is a pandemic characterized by serious lung disease and thrombotic events in the venous and circulation trees, which represent a harmful clinical sign of poor outcome. Thrombotic events are more frequent in patients with severe disease requiring intensive care units and are associated with platelet and clotting activation. However, after resolution of acute infection, patients may still have clinical sequelae, the so-called long-COVID-19, including thrombotic events again in the venous and arterial circulation. The mechanisms accounting for thrombosis in acute and long COVID-19 have not been fully clarified; interactions of COVID-19 with angiotensin converting enzyme 2 or toll-like receptor family or infection-induced cytokine storm have been suggested to be implicated in endothelial cells, leucocytes, and platelets to elicit clotting activation in acute as well in chronic phase of the disease. In acute COVID-19, prophylactic or full doses of anticoagulants exert beneficial effects even if the dosage choice is still under investigation; however, a residual risk still remains suggesting a need for a more appropriate therapeutic approach. In long COVID-19 preliminary data provided useful information in terms of antiplatelet treatment but definition of candidates for thrombotic prophylaxis is still undefined.

Keywords

COVID-19 - long-COVID - SARS-CoV-2 infection - thrombosis - cardiovascular diseases - platelets - leucocytes


Publication History

Received: 01 June 2023

Accepted: 09 October 2023

Article published online:
15 November 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 2020; 324 (08) 782-793
    CrossrefPubMedGoogle Scholar
  • 2 Piazza G, Campia U, Hurwitz S. et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol 2020; 76 (18) 2060-2072
    CrossrefPubMedGoogle Scholar
  • 3 Zhang L, Yan X, Fan Q. et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost 2020; 18 (06) 1324-1329
    CrossrefPubMedGoogle Scholar
  • 4 Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 2022; 22 (04) e102-e107
    CrossrefPubMedGoogle Scholar
  • 5 Violi F, Cangemi R, Falcone M. et al; SIXTUS (Thrombosis-Related Extrapulmonary Outcomes in Pneumonia) Study Group. Cardiovascular complications and short-term mortality risk in community-acquired pneumonia. Clin Infect Dis 2017; 64 (11) 1486-1493
    CrossrefPubMedGoogle Scholar
  • 6 Cangemi R, Calvieri C, Falcone M. et al; SIXTUS Study Group. Relation of cardiac complications in the early phase of community-acquired pneumonia to long-term mortality and cardiovascular events. Am J Cardiol 2015; 116 (04) 647-651
    CrossrefPubMedGoogle Scholar
  • 7 Corrales-Medina VF, Alvarez KN, Weissfeld LA. et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA 2015; 313 (03) 264-274
    CrossrefPubMedGoogle Scholar
  • 8 Cangemi R, Calvieri C, Falcone M. et al. Comparison of thrombotic events and mortality in patients with community-acquired pneumonia and COVID-19: a multicenter observational study. Thromb Haemost 2022; 122 (02) 257-266
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Lund LC, Hallas J, Nielsen H. et al. Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study. Lancet Infect Dis 2021; 21 (10) 1373-1382
    CrossrefPubMedGoogle Scholar
  • 10 Yeo I, Baek S, Kim J. et al. Assessment of thirty-day readmission rate, timing, causes and predictors after hospitalization with COVID-19. J Intern Med 2021; 290 (01) 157-165
    CrossrefPubMedGoogle Scholar
  • 11 Katsoularis I, Fonseca-Rodríguez O, Farrington P. et al. Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. BMJ 2022; 377: e069590
    CrossrefPubMedGoogle Scholar
  • 12 Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med 2022; 28 (03) 583-590
    CrossrefPubMedGoogle Scholar
  • 13 Knight R, Walker V, Ip S. et al; CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study. Association of COVID-19 with major arterial and venous thrombotic diseases: a population-wide cohort study of 48 million adults in England and Wales. Circulation 2022; 146 (12) 892-906
    CrossrefPubMedGoogle Scholar
  • 14 Wan EYF, Mathur S, Zhang R. et al. Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality: a prospective cohort in UK Biobank. Cardiovasc Res 2023; 119 (08) 1718-1727
    CrossrefPubMedGoogle Scholar
  • 15 Violi F, Pignatelli P, Vestri AR. et al; ADA GROUP. The ADA (Age-D-Dimer-Albumin) score to predict thrombosis in SARS-CoV-2. Thromb Haemost 2022; 122 (09) 1567-1572
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA. et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost 2020; 18 (06) 1517-1519
    CrossrefPubMedGoogle Scholar
  • 17 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
    CrossrefPubMedGoogle Scholar
  • 18 Bradley BT, Maioli H, Johnston R. et al. Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Lancet 2020; 396 (10247): 320-332
    CrossrefPubMedGoogle Scholar
  • 19 Evans PC, Rainger GE, Mason JC. et al. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res 2020; 116 (14) 2177-2184
    CrossrefPubMedGoogle Scholar
  • 20 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
    CrossrefPubMedGoogle Scholar
  • 21 Canzano P, Brambilla M, Porro B. et al. Platelet and endothelial activation as potential mechanisms behind the thrombotic complications of COVID-19 patients. JACC Basic Transl Sci 2021; 6 (03) 202-218
    CrossrefPubMedGoogle Scholar
  • 22 Zhang S, Liu Y, Wang X. et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13 (01) 120
    CrossrefPubMedGoogle Scholar
  • 23 McCracken IR, Saginc G, He L. et al. Lack of evidence of angiotensin-converting enzyme 2 expression and replicative infection by SARS-CoV-2 in human endothelial cells. Circulation 2021; 143 (08) 865-868
    CrossrefPubMedGoogle Scholar
  • 24 Cardot-Leccia N, Hubiche T, Dellamonica J, Burel-Vandenbos F, Passeron T. Pericyte alteration sheds light on micro-vasculopathy in COVID-19 infection. Intensive Care Med 2020; 46 (09) 1777-1778
    CrossrefPubMedGoogle Scholar
  • 25 Green DJ, Jones H, Thijssen D, Cable NT, Atkinson G. Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter?. Hypertension 2011; 57 (03) 363-369
    CrossrefPubMedGoogle Scholar
  • 26 Oikonomou E, Souvaliotis N, Lampsas S. et al. Endothelial dysfunction in acute and long standing COVID-19: a prospective cohort study. Vascul Pharmacol 2022; 144: 106975
    CrossrefPubMedGoogle Scholar
  • 27 Brambilla M, Canzano P, Becchetti A. et al. Alterations in platelets during SARS-CoV-2 infection. Platelets 2022; 33 (02) 192-199
    CrossrefPubMedGoogle Scholar
  • 28 Koupenova M, Freedman JE. Platelets and COVID-19: inflammation, hyperactivation and additional questions. Circ Res 2020; 127 (11) 1419-1421
    CrossrefPubMedGoogle Scholar
  • 29 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
  • 30 Choudhury A, Mukherjee S. In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J Med Virol 2020; 92 (10) 2105-2113
    CrossrefPubMedGoogle Scholar
  • 31 Violi F, Carnevale R, Loffredo L, Pignatelli P, Gallin JI. NADPH Oxidase-2 and Atherothrombosis: insight from chronic granulomatous disease. Arterioscler Thromb Vasc Biol 2017; 37 (02) 218-225
    CrossrefPubMedGoogle Scholar
  • 32 Koupenova M, Corkrey HA, Vitseva O. et al. The role of platelets in mediating a response to human influenza infection. Nat Commun 2019; 10 (01) 1780
    CrossrefPubMedGoogle Scholar
  • 33 Oliva A, Cammisotto V, Cangemi R. et al. Low-grade endotoxemia and thrombosis in COVID-19. Clin Transl Gastroenterol 2021; 12 (06) e00348
    CrossrefPubMedGoogle Scholar
  • 34 Carnevale R, Cammisotto V, Bartimoccia S. et al. Toll-like receptor 4-dependent platelet-related thrombosis in SARS-CoV-2 infection. Circ Res 2023; 132 (03) 290-305
    CrossrefPubMedGoogle Scholar
  • 35 Nadir Y, Brenner B, Fux L, Shafat I, Attias J, Vlodavsky I. Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII. Haematologica 2010; 95 (11) 1927-1934
    CrossrefPubMedGoogle Scholar
  • 36 Folco EJ, Mawson TL, Vromman A. et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G. Arterioscler Thromb Vasc Biol 2018; 38 (08) 1901-1912
    CrossrefPubMedGoogle Scholar
  • 37 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
    CrossrefPubMedGoogle Scholar
  • 38 Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010; 207 (09) 1853-1862
    CrossrefPubMedGoogle Scholar
  • 39 Skendros P, Mitsios A, Chrysanthopoulou A. et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest 2020; 130 (11) 6151-6157
    CrossrefPubMedGoogle Scholar
  • 40 Holter JC, Pischke SE, de Boer E. et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci U S A 2020; 117 (40) 25018-25025
    CrossrefPubMedGoogle Scholar
  • 41 Defendi F, Leroy C, Epaulard O. et al. Complement alternative and mannose-binding lectin pathway activation is associated with COVID-19 mortality. Front Immunol 2021; 12: 742446
    CrossrefPubMedGoogle Scholar
  • 42 Ma L, Sahu SK, Cano M. et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol 2021; 6 (59) eabh2259
    CrossrefPubMedGoogle Scholar
  • 43 Carvelli J, Demaria O, Vély F. et al; Explore COVID-19 IPH group, Explore COVID-19 Marseille Immunopole group. Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis. Nature 2020; 588 (7836) 146-150
    CrossrefPubMedGoogle Scholar
  • 44 Cugno M, Meroni PL, Gualtierotti R. et al. Complement activation in patients with COVID-19: a novel therapeutic target. J Allergy Clin Immunol 2020; 146 (01) 215-217
    CrossrefPubMedGoogle Scholar
  • 45 de Nooijer AH, Grondman I, Janssen NAF. et al; RCI-COVID-19 study group. Complement activation in the disease course of coronavirus disease 2019 and its effects on clinical outcomes. J Infect Dis 2021; 223 (02) 214-224
    CrossrefPubMedGoogle Scholar
  • 46 Magro C, Mulvey JJ, 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
    CrossrefPubMedGoogle Scholar
  • 47 Swank Z, Senussi Y, Manickas-Hill Z. et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin Infect Dis 2023; 76 (03) e487-e490
    CrossrefPubMedGoogle Scholar
  • 48 Phetsouphanh C, Darley DR, Wilson DB. et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol 2022; 23 (02) 210-216
    CrossrefPubMedGoogle Scholar
  • 49 Galán M, Vigón L, Fuertes D. et al. Persistent overactive cytotoxic immune response in a spanish cohort of individuals with long-COVID: identification of diagnostic biomarkers. Front Immunol 2022; 13: 848886
    CrossrefPubMedGoogle Scholar
  • 50 Pretorius E, Venter C, Laubscher GJ. et al. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with long COVID/post-acute sequelae of COVID-19 (PASC). Cardiovasc Diabetol 2022; 21 (01) 148
    CrossrefPubMedGoogle Scholar
  • 51 Dryden M, Mudara C, Vika C. et al. Post-COVID-19 condition 3 months after hospitalisation with SARS-CoV-2 in South Africa: a prospective cohort study. Lancet Glob Health 2022; 10 (09) e1247-e1256
    CrossrefPubMedGoogle Scholar
  • 52 Van Cleemput J, van Snippenberg W, Lambrechts L. et al. Organ-specific genome diversity of replication-competent SARS-CoV-2. Nat Commun 2021; 12 (01) 6612
    CrossrefPubMedGoogle Scholar
  • 53 Gaebler C, Wang Z, Lorenzi JCC. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 2021; 591 (7851) 639-644
    CrossrefPubMedGoogle Scholar
  • 54 Gyöngyösi M, Alcaide P, Asselbergs FW. et al. Long COVID and the cardiovascular system-elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases. Cardiovasc Res 2023; 119 (02) 336-356
    CrossrefPubMedGoogle Scholar
  • 55 Lopez-Leon S, Wegman-Ostrosky T, Perelman C. et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep 2021; 11 (01) 16144
    CrossrefPubMedGoogle Scholar
  • 56 Ceban F, Ling S, Lui LMW. et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: a systematic review and meta-analysis. Brain Behav Immun 2022; 101: 93-135
    CrossrefPubMedGoogle Scholar
  • 57 Grobler C, Maphumulo SC, Grobbelaar LM. et al. Covid-19: the rollercoaster of Fibrin(Ogen), D-dimer, von Willebrand factor, P-selectin and their interactions with endothelial cells, platelets and erythrocytes. Int J Mol Sci 2020; 21 (14) 5168
    CrossrefPubMedGoogle Scholar
  • 58 Pasini E, Corsetti G, Romano C. et al. Serum metabolic profile in patients with long-Covid (PASC) syndrome: clinical implications. Front Med (Lausanne) 2021; 8: 714426
    CrossrefPubMedGoogle Scholar
  • 59 Wong SW, Fan BE, Huang W, Chia YW. ST-segment elevation myocardial infarction in post-COVID-19 patients: a case series. Ann Acad Med Singap 2021; 50 (05) 425-430
    CrossrefPubMedGoogle Scholar
  • 60 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
  • 61 Fan BE, Wong SW, Sum CLL. et al; COVID-19 Clotting and Bleeding Investigators. Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: assessing the long-term outcomes in COVID-19 patients. Am J Hematol 2022; 97 (07) 915-923
    CrossrefPubMedGoogle Scholar
  • 62 Fogarty H, Townsend L, Morrin H. et al; Irish COVID-19 Vasculopathy Study (iCVS) investigators. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost 2021; 19 (10) 2546-2553
    CrossrefPubMedGoogle Scholar
  • 63 Kruger A, Vlok M, Turner S. et al. Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system. Cardiovasc Diabetol 2022; 21 (01) 190
    CrossrefPubMedGoogle Scholar
  • 64 Mejia-Renteria H, Travieso A, Sagir A. et al. In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19. Int J Cardiol 2021; 345: 153-155
    CrossrefPubMedGoogle Scholar
  • 65 Szeghy RE, Province VM, Stute NL. et al. Carotid stiffness, intima-media thickness and aortic augmentation index among adults with SARS-CoV-2. Exp Physiol 2022; 107 (07) 694-707
    CrossrefPubMedGoogle Scholar
  • 66 Prasad M, Leon M, Lerman LO, Lerman A. Viral endothelial dysfunction: a unifying mechanism for COVID-19. Mayo Clin Proc 2021; 96 (12) 3099-3108
    CrossrefPubMedGoogle Scholar
  • 67 Willems LH, Jacobs LMC, Groh LA. et al. Vascular function, systemic inflammation, and coagulation activation 18 months after COVID-19 infection: an observational cohort study. J Clin Med 2023; 12 (04) 1413
    CrossrefPubMedGoogle Scholar
  • 68 Zhu Y, Chen X, Liu X. NETosis and neutrophil extracellular traps in COVID-19: immunothrombosis and beyond. Front Immunol 2022; 13: 838011
    CrossrefPubMedGoogle Scholar
  • 69 Krinsky N, Sizikov S, Nissim S. et al. NETosis induction reflects COVID-19 severity and long COVID: insights from a 2-center patient cohort study in Israel. J Thromb Haemost 2023; 21 (09) 2569-2584
    CrossrefPubMedGoogle Scholar
  • 70 Harenberg J, Violi F. Waves of SARS-CoV-2 infection and blood coagulation-a link and beyond. Thromb Haemost 2021; 121 (01) 4-6
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Drouet L, Harenberg J, Torri G. The multiple faces of heparin: opportunities in COVID-19 infection and beyond. Thromb Haemost 2020; 120 (10) 1347-1350
    Article in Thieme ConnectPubMedGoogle Scholar
  • 72 Spyropoulos AC, Levy JH, Ageno W. et al; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
    CrossrefPubMedGoogle Scholar
  • 73 Cuker A, Tseng EK, Nieuwlaat R. et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv 2021; 5 (03) 872-888
    CrossrefPubMedGoogle Scholar
  • 74 Loffredo L, Di Castelnuovo A, Chiariello GA, Pignatelli P, Violi F. Full versus prophylactic-intermediate doses of anticoagulants in COVID-19: a meta-analysis. Haematologica 2022; 107 (08) 1933-1939
    CrossrefPubMedGoogle Scholar
  • 75 Bianconi V, Violi F, Fallarino F, Pignatelli P, Sahebkar A, Pirro M. Is acetylsalicylic acid a safe and potentially useful choice for adult patients with COVID-19?. Drugs 2020; 80 (14) 1383-1396
    CrossrefPubMedGoogle Scholar
  • 76 Schulman S, Harenberg J. Anticoagulant treatment of COVID-19 as early as possible-sulodexide and perspectives. Thromb Haemost 2021; 121 (07) 849-853
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 Bolek T, Samoš M, Jurica J. et al. COVID-19 and the response to antiplatelet therapy. J Clin Med 2023; 12 (05) 2038
    CrossrefPubMedGoogle Scholar
  • 78 Carnevale R, Sciarretta S, Valenti V. et al. Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction. Eur Heart J 2020; 41 (33) 3156-3165
    CrossrefPubMedGoogle Scholar
  • 79 Evering TH, Chew KW, Giganti MJ. et al; ACTIV-2/A5401 Study Team. Safety and efficacy of combination SARS-CoV-2 neutralizing monoclonal antibodies amubarvimab plus romlusevimab in nonhospitalized patients with COVID-19. Ann Intern Med 2023; 176 (05) 658-666
    CrossrefPubMedGoogle Scholar
  • 80 Basili S, Carnevale R, Nocella C. et al; PRO-LIVER Collaborators. Serum albumin is inversely associated with portal vein thrombosis in cirrhosis. Hepatol Commun 2019; 3 (04) 504-512
    CrossrefPubMedGoogle Scholar
  • 81 Violi F, Cangemi R, Romiti GF. et al. Is albumin predictor of mortality in COVID-19?. Antioxid Redox Signal 2021; 35 (02) 139-142
    CrossrefPubMedGoogle Scholar
  • 82 Violi F, Ceccarelli G, Cangemi R. et al. Hypoalbuminemia, coagulopathy, and vascular disease in COVID-19. Circ Res 2020; 127 (03) 400-401
    CrossrefPubMedGoogle Scholar
  • 83 Chi G, Violi F, Pignatelli P. et al. External validation of the ADA score for predicting thrombosis among acutely ill hospitalized medical patients from the APEX trial. J Thromb Thrombolysis 2023; 55 (02) 211-221
    CrossrefPubMedGoogle Scholar
  • 84 Violi F, Ceccarelli G, Loffredo L. et al. Albumin supplementation dampens hypercoagulability in COVID-19: a preliminary report. Thromb Haemost 2021; 121 (01) 102-105
    Article in Thieme ConnectPubMedGoogle Scholar
  • 85 Laurence J, Mulvey JJ, Seshadri M. et al. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin Immunol 2020; 219: 108555
    CrossrefPubMedGoogle Scholar
  • 86 Giudice V, Pagliano P, Vatrella A. et al. Combination of ruxolitinib and eculizumab for treatment of severe SARS-CoV-2-related acute respiratory distress syndrome: a controlled study. Front Pharmacol 2020; 11: 857
    CrossrefPubMedGoogle Scholar
  • 87 Diurno F, Numis FG, Porta G. et al. Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci 2020; 24 (07) 4040-4047
    PubMedGoogle Scholar
  • 88 Zelek WM, Cole J, Ponsford MJ. et al. Complement inhibition with the C5 blocker LFG316 in severe COVID-19. Am J Respir Crit Care Med 2020; 202 (09) 1304-1308
    CrossrefPubMedGoogle Scholar
  • 89 Vlaar APJ, de Bruin S, Busch M. et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol 2020; 2 (12) e764-e773
    CrossrefPubMedGoogle Scholar
  • 90 Mastellos DC, Pires da Silva BGP, Fonseca BAL. et al. Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy. Clin Immunol 2020; 220: 108598
    CrossrefPubMedGoogle Scholar
  • 91 Mastaglio S, Ruggeri A, Risitano AM. et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin Immunol 2020; 215: 108450
    CrossrefPubMedGoogle Scholar
  • 92 Talasaz AH, Sadeghipour P, Mehdizadeh K. et al. Knowledge gaps for prophylactic use of antithrombotic agents in patients with COVID-19: insights into new SARS-CoV-2 variants, vaccination status, and emerging oral antivirals. Thromb Haemost 2023; 123 (02) 186-191
    Article in Thieme ConnectPubMedGoogle Scholar
  • 93 Bradbury CA, Lawler PR, Stanworth SJ. et al; REMAP-CAP Writing Committee for the REMAP-CAP Investigators. Effect of antiplatelet therapy on survival and organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA 2022; 327 (13) 1247-1259
    CrossrefPubMedGoogle Scholar
  • 94 Lawler PR, Goligher EC, Berger JS. et al; ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med 2021; 385 (09) 790-802
    CrossrefPubMedGoogle Scholar