Semin Thromb Hemost 2022; 48(01): 072-092
DOI: 10.1055/s-0041-1728832
Review Article

COVID-19 and Antiphospholipid Antibodies: Time for a Reality Check?

1   Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
2   School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia
,
3   Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
,
4   Section of Clinical Biochemistry, University of Verona, Verona, Italy
› Author Affiliations

Abstract

Antiphospholipid antibodies (aPL) comprise a panel of autoantibodies that reflect a potential prothrombotic risk in several autoimmune conditions, most notably antiphospholipid (antibody) syndrome (APS). aPL can be divided into those that form part of the laboratory criteria for APS, namely, lupus anticoagulant (LA), as well as anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I antibodies (aβ2GPI) of the immunoglobulin G and M classes, and those that form a group considered as “noncriteria antibodies.” The noncriteria antibodies include, for example, antiphosphatidylserine antibodies (aPS), antiprothrombin antibodies (aPT), and antiphosphatidylserine/prothrombin complex antibodies (aPS/PT). COVID-19 (coronavirus disease 2019) represents a prothrombotic disorder, and there have been several reports of various aPL being present in COVID-19 patients. There have also been similarities drawn between some of the pathophysiological features of COVID-19 and APS, in particular, the most severe form, catastrophic APS (CAPS). In this review, we critically appraise the literature on aPL and COVID-19. This is a companion piece to a separate review focused on LA. In the current review, we primarily concentrate on the so-called solid phase identifiable aPL, such as aCL and aβ2GPI, but also reflect on noncriteria aPL. We conclude that aPL positivity may be a feature of COVID-19, at least in some patients, but in general, identified “solid-phase” aPL are of low titer and not able to be well-linked to the thrombotic aspects of COVID-19. Also, most publications did not assess for aPL persistence, and where persistence was checked, the findings appeared to represent transient aPL. Importantly, high-titer aPL or multiple aPL positivity (including double, triple) were in the minority of COVID-19 presentations, and thus discount any widespread presence of APS, including the most severe form CAPS, in COVID-19 patients.



Publication History

Article published online:
15 June 2021

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  • References

  • 1 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
  • 2 Devreese KMJ, Ortel TL, Pengo V, de Laat B. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
  • 3 Tkachenko O, Lapin S, Mazing A. et al. Profiling of non-criteria antiphospholipid antibodies in patients with SLE: differentiation of thrombotic SLE patients and risk of recurrence of thrombosis. Lupus 2020; 29 (05) 490-498
  • 4 Liu T, Gu J, Wan L. et al. “Non-criteria” antiphospholipid antibodies add value to antiphospholipid syndrome diagnoses in a large Chinese cohort. Arthritis Res Ther 2020; 22 (01) 33
  • 5 Žigon P, Podovšovnik A, Ambrožič A. et al. Added value of non-criteria antiphospholipid antibodies for antiphospholipid syndrome: lessons learned from year-long routine measurements. Clin Rheumatol 2019; 38 (02) 371-378
  • 6 Zohoury N, Bertolaccini ML, Rodriguez-Garcia JL. et al. Closing the serological gap in the antiphospholipid syndrome: the value of “non-criteria” antiphospholipid antibodies. J Rheumatol 2017; 44 (11) 1597-1602
  • 7 Favaloro EJ, Wong RC. Antiphospholipid antibody testing for the antiphospholipid syndrome: a comprehensive practical review including a synopsis of challenges and recent guidelines. Pathology 2014; 46 (06) 481-495
  • 8 Lakos G, Favaloro EJ, Harris EN. et al. International consensus guidelines on anticardiolipin and anti-β2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2012; 64 (01) 1-10
  • 9 Pierangeli SS, de Groot PG, Dlott J. et al. ‘Criteria’ aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. Lupus 2011; 20 (02) 182-190
  • 10 Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101 (05) 1827-1832
  • 11 Favaloro EJ, Henry BM, Lippi G. Is lupus anticoagulant a significant feature of COVID-19? A critical appraisal of the literature. Semin Thromb Hemost 2021; DOI: 10.1055/s-0041-1729856.
  • 12 COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. . Accessed March 16, 2021 at: https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6
  • 13 Lippi G, Sanchis-Gomar F, Favaloro EJ, Lavie CJ, Henry BM. Coronavirus disease 2019-associated coagulopathy. Mayo Clin Proc 2021; 96 (01) 203-217
  • 14 Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost 2020; 46 (07) 763-771
  • 15 Jenner WJ, Kanji R, Mirsadraee S. et al. Thrombotic complications in 2928 patients with COVID-19 treated in intensive care: a systematic review. J Thromb Thrombolysis 2021; 51 (03) 595-607
  • 16 Uaprasert N, Moonla C, Sosothikul D, Rojnuckarin P, Chiasakul T. Systemic coagulopathy in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Clin Appl Thromb Hemost 2021;27:1076029620987629
  • 17 Carsana L, Sonzogni A, Nasr A. et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020; 20 (10) 1135-1140
  • 18 Wichmann D, Sperhake JP, 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
  • 19 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
  • 20 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
  • 21 Favaloro EJ, Lippi G. Recommendations for minimal laboratory testing panels in patients with COVID-19: potential for prognostic monitoring. Semin Thromb Hemost 2020; 46 (03) 379-382
  • 22 Christensen B, Favaloro EJ, Lippi G, Van Cott EM. Hematology laboratory abnormalities in patients with coronavirus disease 2019 (COVID-19). Semin Thromb Hemost 2020; 46 (07) 845-849
  • 23 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
  • 24 Thachil J, Srivastava A. SARS-2 Coronavirus-Associated Hemostatic Lung Abnormality In COVID-19: is it pulmonary thrombosis or pulmonary embolism?. Semin Thromb Hemost 2020; 46 (07) 777-780
  • 25 Schulman S. Coronavirus disease 2019, prothrombotic factors, and venous thromboembolism. Semin Thromb Hemost 2020; 46 (07) 772-776
  • 26 Kwaan HC. Coronavirus disease 2019: the role of the fibrinolytic system from transmission to organ injury and sequelae. Semin Thromb Hemost 2020; 46 (07) 841-844
  • 27 Larsen JB, Pasalic L, Hvas AM. Platelets in coronavirus disease 2019. Semin Thromb Hemost 2020; 46 (07) 823-825
  • 28 Favaloro EJ, Henry BM, Lippi G. Increased VWF and decreased ADAMTS13 in COVID-19: creating a milieu for (micro)thrombosis?. Semin Thromb Hemost 2021; In press  
  • 29 Mendoza-Pinto C, Escárcega RO, García-Carrasco M, Bailey DJO, Gálvez-Romero JL, Cervera R. Viral infections and their relationship with catastrophic antiphospholipid syndrome: a possible pathogenic mechanism of severe COVID-19 thrombotic complications. J Intern Med 2020; 288 (06) 737-739
  • 30 El Hasbani G, Taher AT, Jawad A, Uthman I. COVID-19, antiphospholipid antibodies, and catastrophic antiphospholipid syndrome: a possible association?. Clin Med Insights Arthritis Musculoskelet Disord 2020;13:1179544120978667
  • 31 Previtali G, Seghezzi M, Moioli V. et al. The pathogenesis of thromboembolic disease in covid-19 patients: could be a catastrophic antiphospholipid syndrome?. Thromb Res 2020; 194: 192-194
  • 32 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
  • 33 Metjian A, Lim W. ASH evidence-based guidelines: should asymptomatic patients with antiphospholipid antibodies receive primary prophylaxis to prevent thrombosis?. Hematology (Am Soc Hematol Educ Program) 2009; 247-249
  • 34 Mustonen P, Lehtonen KV, Javela K, Puurunen M. Persistent antiphospholipid antibody (aPL) in asymptomatic carriers as a risk factor for future thrombotic events: a nationwide prospective study. Lupus 2014; 23 (14) 1468-1476
  • 35 Pengo V, Ruffatti A, Legnani C. et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011; 118 (17) 4714-4718
  • 36 Yelnik CM, Urbanski G, Drumez E. et al. Persistent triple antiphospholipid antibody positivity as a strong risk factor of first thrombosis, in a long-term follow-up study of patients without history of thrombosis or obstetrical morbidity. Lupus 2017; 26 (02) 163-169
  • 37 Devreese KMJ, de Groot PG, de Laat B. et al. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: update of the guidelines for lupus anticoagulant detection and interpretation. J Thromb Haemost 2020; 18 (11) 2828-2839
  • 38 Keeling D, Mackie I, Moore GW, Greer IA, Greaves M. British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012; 157 (01) 47-58
  • 39 Ledford-Kraemer M, Moore GW, Bottenus R. et al. Clinical and Laboratory Standards Institute (CLSI). Laboratory Testing for the Lupus Anticoagulant; Approved Guideline. CLSI document H60-A. Wayne, PA: CLSI; 2014
  • 40 Yasri S, Wiwanitkit V. COVID-19, antiphospholipid syndrome and thrombosis. Clin Appl Thromb Hemost 2020;26:1076029620931927
  • 41 Lerma LA, Chaudhary A, Bryan A, Morishima C, Wener MH, Fink SL. Prevalence of autoantibody responses in acute coronavirus disease 2019 (COVID-19). J Transl Autoimmun 2020; 3: 100073
  • 42 Galeano-Valle F, Oblitas CM, Ferreiro-Mazón MM. et al. Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism. Thromb Res 2020; 192: 113-115
  • 43 Gatto M, Perricone C, Tonello M. et al. Frequency and clinical correlates of antiphospholipid antibodies arising in patients with SARS-CoV-2 infection: findings from a multicentre study on 122 cases. Clin Exp Rheumatol 2020; 38 (04) 754-759
  • 44 Siguret V, Voicu S, Neuwirth M. et al. Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients?. Thromb Res 2020; 195: 74-76
  • 45 Fan S, Xiao M, Han F. et al. Neurological manifestations in critically ill patients with COVID-19: a retrospective study. Front Neurol 2020; 11: 806
  • 46 Pineton de Chambrun M, Frere C, Miyara M. et al. High frequency of antiphospholipid antibodies in critically ill COVID-19 patients: a link with hypercoagulability?. J Intern Med 2021; 289 (03) 422-424
  • 47 Popovic B, Varlot J, Metzdorf PA, Jeulin H, Goehringer F, Camenzind E. Changes in characteristics and management among patients with ST-elevation myocardial infarction due to COVID-19 infection. Catheter Cardiovasc Interv 2021; 97 (03) E319-E326
  • 48 Rothstein A, Oldridge O, Schwennesen H, Do D, Cucchiara BL. Acute cerebrovascular events in hospitalized COVID-19 patients. Stroke 2020; 51 (09) e219-e222
  • 49 Devreese KMJ, Linskens EA, Benoit D, Peperstraete H. Antiphospholipid antibodies in patients with COVID-19: a relevant observation?. J Thromb Haemost 2020; 18 (09) 2191-2201
  • 50 Reyes Gil M, Barouqa M, Szymanski J, Gonzalez-Lugo JD, Rahman S, Billett HH. Assessment of lupus anticoagulant positivity in patients with coronavirus disease 2019 (COVID-19). JAMA Netw Open 2020; 3 (08) e2017539
  • 51 Amezcua-Guerra LM, Rojas-Velasco G, Brianza-Padilla M. et al. Presence of antiphospholipid antibodies in COVID-19: case series study. Ann Rheum Dis. 2020:annrheumdis-2020-218100
  • 52 de Ocáriz XGL, Quismondo NC, Guerrero EV, Rodríguez MR, Díaz RA, López JM. Thrombosis and antiphospholipid antibodies in patients with SARS-COV-2 infection (COVID-19). Int J Lab Hematol 2020; 42 (06) e280-e282
  • 53 Cuenca Saez MA, Gomez-Biezna SL. Immunoglobulin A antiphospholipid antibodies in patients with chilblain-like lesions during the COVID-19 pandemic. Actas Dermosifiliogr 2021; 112 (03) 290-292
  • 54 Tvito A, Ben-Chetrit E, Zimmerman FS, Asher E, Helviz Y. Lupus anticoagulant in patients with COVID-19. Int J Lab Hematol 2021; 43 (01) e17-e18
  • 55 Bertin D, Brodovitch A, Beziane A. et al. Anticardiolipin IgG autoantibody level is an independent risk factor for COVID-19 severity. Arthritis Rheumatol 2020; 72 (11) 1953-1955
  • 56 Ferrari E, Sartre B, Squara F. et al. High prevalence of acquired thrombophilia without prognosis value in patients with coronavirus disease 2019. J Am Heart Assoc 2020; 9 (21) e017773
  • 57 Pascolini S, Vannini A, Deleonardi G. et al. COVID-19 and immunological dysregulation: can autoantibodies be useful?. Clin Transl Sci 2021; 14 (02) 502-508
  • 58 Hasan Ali O, Bomze D, Risch L. et al. Severe COVID-19 is associated with elevated serum IgA and antiphospholipid IgA-antibodies. Clin Infect Dis 2020; (ePub ahead of print) DOI: 10.1093/cid/ciaa1496.
  • 59 Zhang Y, Cao W, Jiang W. et al. Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients. J Thromb Thrombolysis 2020; 50 (03) 580-586
  • 60 Tan YK, Goh C, Leow AST. et al. COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature. J Thromb Thrombolysis 2020; 50 (03) 587-595
  • 61 Lee KW, Yusof Khan AHK, Ching SM. et al. Stroke and novel coronavirus infection in humans: a systematic review and meta-analysis. Front Neurol 2020; 11: 579070
  • 62 Tu TM, Goh C, Tan YK. et al. Cerebral venous thrombosis in patients with COVID-19 infection: a case series and systematic review. J Stroke Cerebrovasc Dis 2020; 29 (12) 105379
  • 63 Xiao M, Zhang Y, Zhang S. et al. Antiphospholipid antibodies in critically ill patients with COVID-19. Arthritis Rheumatol 2020; 72 (12) 1998-2004
  • 64 Borghi MO, Beltagy A, Garrafa E. et al. Anti-phospholipid antibodies in COVID-19 are different from those detectable in the anti-phospholipid syndrome. Front Immunol 2020; 11: 584241
  • 65 Woodruff MC, Ramonell RP, Lee FE, Sanz I. Broadly-targeted autoreactivity is common in severe SARS-CoV-2 infection. [preprint]. 2020 DOI: 10.1101/2020.10.21.20216192
  • 66 Fan BE, Ng J, Chan SSW. et al. COVID-19 associated coagulopathy in critically ill patients: a hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis. J Thromb Thrombolysis 2021; 51 (03) 663-674
  • 67 Zuo Y, Estes SK, Ali RA. et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci Transl Med 2020; 12 (570) eabd3876
  • 68 Gazzaruso C, Mariani G, Ravetto C, Malinverni L, Tondelli E, Cerrone M, Sala V, Bevilacqua L, Altavilla T, Coppola A, Gallotti P. Lupus anticoagulant and mortality in patients hospitalized for COVID-19. J Thromb Thrombolysis 2021; 52: 85-91
  • 69 Le Joncour A, Frere C, Martin-Toutain I. et al. Antiphospholipid antibodies and thrombotic events in COVID-19 patients hospitalized in medicine ward. Autoimmun Rev 2021; 20 (02) 102729
  • 70 Novelli L, Motta F, De Santis M, Ansari AA, Gershwin ME, Selmi C. The JANUS of chronic inflammatory and autoimmune diseases onset during COVID-19 - a systematic review of the literature. J Autoimmun 2021; 117: 102592
  • 71 Frapard T, Hue S, Rial C, de Prost N, Mekontso Dessap A. Antiphospholipid autoantibodies and thrombosis in patients with COVID-19: comment on the article by Bertin et al. Arthritis Rheumatol 2021; 73 (05) 897-899
  • 72 Cristiano A, Fortunati V, Cherubini F, Bernardini S, Nuccetelli M. Anti-phospholipids antibodies and immune complexes in COVID-19 patients: a putative role in disease course for anti-annexin-V antibodies. Clin Rheumatol 2021; (epub ahead of print) DOI: 10.1007/s10067-021-05580-3.
  • 73 Shi H, Zuo Y, Gandhi AA. et al. Endothelial cell-activating antibodies in COVID-19. [preprint]. 2021 DOI: 10.1101/2021.01.18.21250041
  • 74 Hamadé A, Woehl B, Harzallah I, Talbot M, Tousch J, Jambert L. Antiphospholipid antibodies in patients with coronavirus disease 2019 infection hospitalized in conventional unit. Blood Coagul Fibrinolysis 2021; 32 (02) 73-79
  • 75 Karahan S, Erol K, Yuksel RC, Artan C, Celik I. Antiphospholipid antibodies in COVID-19-associated pneumonia patients in intensive care unit. Mod Rheumatol 2021; (ePub ahead of print) DOI: 10.1080/14397595.2021.1892257.
  • 76 Beyrouti R, Adams ME, Benjamin L. et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry 2020; 91 (08) 889-891
  • 77 Abdel-Wahab N, Talathi S, Lopez-Olivo MA, Suarez-Almazor ME. Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis. Lupus 2018; 27 (04) 572-583
  • 78 Abdel-Wahab N, Lopez-Olivo MA, Pinto-Patarroyo GP, Suarez-Almazor ME. Systematic review of case reports of antiphospholipid syndrome following infection. Lupus 2016; 25 (14) 1520-1531
  • 79 Cavalli E, Bramanti A, Ciurleo R. et al. Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: diagnostic and therapeutic perspectives (Review). Int J Mol Med 2020; 46 (03) 903-912
  • 80 Million M, Bardin N, Bessis S. et al. Thrombosis and antiphospholipid antibody syndrome during acute Q fever: a cross-sectional study. Medicine (Baltimore) 2017; 96 (29) e7578
  • 81 Mendoza-Pinto C, García-Carrasco M, Cervera R. Role of infectious diseases in the antiphospholipid syndrome (including its catastrophic variant). Curr Rheumatol Rep 2018; 20 (10) 62