key: cord-0793646-6vhjp97b
authors: El Hasbani, Georges; Taher, Ali T; Jawad, Ali; Uthman, Imad
title: COVID-19, Antiphospholipid Antibodies, and Catastrophic Antiphospholipid Syndrome: A Possible Association?
date: 2020-12-03
journal: Clin Med Insights Arthritis Musculoskelet Disord
DOI: 10.1177/1179544120978667
sha: 83b56978532d2a7cf0caae1f1717270afdde58f0
doc_id: 793646
cord_uid: 6vhjp97b

Since the 2019 novel coronavirus (COVID-19) was first detected in December 2019, research on the complications and fatality of this virus has hastened. Initially, case reports drew an association between COVID-19 and abnormal coagulation parameters. Subsequently, cross-sectional studies found a high prevalence of thrombosis among ICU and non-ICU COVID-19 patients. For that reason, certain studies tried to explain the pathogenic mechanisms of thrombosis, one of which was the emergence of anti-phospholipid antibodies (aPL). Although aPL have been found positive in very few patients, their association with thrombotic events stays debatable. Given the thrombotic manifestations of COVID-19 and the potential role of aPL, the catastrophic form of APS (CAPS) might be a major fatal phenomenon. However, to date, there has been no clear association of CAPS to COVID-19. Moreover, since infections, including viral respiratory similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are considered main etiologies for CAPS, it could be possible that SARS-CoV-2 can induce CAPS although no evidence is currently found. High quality studies are needed to develop a clear idea on the pathogenic role of aPL in the progression of thrombosis in COVID-19 patients, and how such patients could be fit into a thromboprophylaxis plan.

184 ICU patients on thrombophylactic regimens, 75 underwent thrombotic events, the majority of which were pulmonary embolism (PE) events (65/75) . 13 These patients were at a significantly higher risk of all-cause death, in spite of therapeutic anticoagulation. 13 Similar observations have been reported in ICU patients in France and Italy. 14, 15 Interestingly, Tang et al suggested that thrombosis was associated with a poorer prognosis. 3 Autopsies performed on 12 COVID-19 patients showed that PE was the direct cause of death in 4 patients. 16 Furthermore, histologic analysis of pulmonary vessels of 7 COVID-19 patients showed widespread thrombosis with microangiopathy. 17 The high prevalence of PE among COVID-19 patients has been explained by the inflammatory nature of the disease rather than by an embolic mechanism of DVT in critically ill patients. 18 The placentas of COVID-19 pregnant patients seem to be susceptible to thrombosis as well, which might predispose to recurrent miscarriages, a hallmark of antiphospholipid syndrome. For instance, Mulvey et al studied the placental pathology of 5-full term births to COVID-19 patients. All 5 placentas exhibited thrombosis with no complement deposition. 19 Similarly, Shanes et al assessed 16 placentas from patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 20 Compared to controls, COVID-19 placentas show increased prevalence of placental injury patterns reflecting abnormalities in oxygenation which may reflect a systemic inflammatory or hypercoagulable state. 20 

Although emerging evidence hints on the association of COVID-19 with thrombosis in ICU and non-ICU patients, the real incidence is still unknown. The primary aim of this review is to shed light on the thrombotic role of antiphospholipid antibodies in the setting of COVID-19, possibly leading to catastrophic antiphospholipid syndrome. As a second aim, we try to discuss the thrombophylactic plans that COVID-19 positive patients with presence of antiphospholipid antibodies can undergo.

COVID-19 infection may predispose to thrombophilia in several ways. Endothelial dysfunction, characterized by increased levels of von Willebrand factor (vWF), systemic inflammation, by activation of Toll-like receptors, and a procoagulatory state, by tissue factor pathway activation, are among the suggested pathogenic mechanisms. 21 Given that in a subgroup of patients with severe COVID-19 infection, high plasma levels of proinflammatory cytokines were found, a state of pro-coagulation is possible. 22 For example, elevated levels of factor VIII, fibrinogen, vWF, and D-dimer were found among COVID-19 patients with acute ischemic stroke. 23 In addition, complement activation may contribute to hemostatic activation leading to pathological features such as microvascular injury and coagulopathy. 24 Angiotensin-converting enzyme (ACE)-2 acts as a viral receptor on the surface of several pulmonary and extra-pulmonary cell types including endothelial cells, which allows viral binding and entry. 25 As such, SARS-CoV-2 can infect endothelial cells contributing to systemic vasculitis, thromboembolism, and disseminated intravascular coagulation (DIC). 26 Because Neutrophil Extracellular Traps (NETs) have the potential to propagate inflammation and microvascular thrombosis, Zuo et al assessed the sera of COVID-19 patients versus controls for NETs proteins. Cellfree DNA, myeloperoxidase (MPO)-DNA, and citrullinated histone H3 (Cit-H3) were elevated in patients which might contribute to cytokine release and respiratory failure. 27 Furthermore, because severe hypoxia develops in some COVID-19 patients, hypoxia-inducible transcription factors might alter genes that regulate thrombus formation in these patients. 27 Of note, immune-mediated damage by antiphospholipid antibodies (aPL) might be of a contributing role.

In 2003, Chow and Chiu cross-sectional study found incidentally a weak positivity of lupus anticoagulant (LAC) in pediatric patients who were admitted for severe acute respiratory syndrome coronavirus (SARS-CoV). 28 For severe acute SARS-CoV-2 infection, an initial case series found elevated anticardiolipin (aCL) IgA antibodies and anti-β2-glycoprotein I (anti-β2-GPI) IgA and IgG antibodies among 3 patients with multiple cerebral infarctions. 29 This case series was criticized for reporting only IgA antibodies for aCL, as only high titer IgM and IgG isotypes, which are the isotypes included in antiphospholipid syndrome (APS) laboratory criteria, can be evaluated for thrombotic sequelae, 30 although Ali et al later found that severe COVID-19 illness is significantly associated with serum total IgA as well as anti-β2-GPI IgA and aCL IgA. 31 In addition, 2 of the 3 patients in the case series reported had a history of thrombotic events, and all of them had preexisting cardiovascular disease which further increased the thrombotic risk.

Subsequently, multiple case reports, case series, cohort studies, and cross-sectional studies assessed aPL in COVID-19 patients and some of these studies tried to associate thrombotic manifestations to aPL status. The assessment of LAC in these studies were challenged by the use of low molecular weight heparin (LWMH) and unfractioned heparin that can lead to false positive results. 32, 33 Moreover, LAC has a significant association with inflammatory conditions which might explain its intermittent nature 34 and high prevalence among thrombotic COVID-19 patients. Thus, the results are difficult to interpret. In addition, a majority of these studies assessed aPL at one time point and did not perform a repeat test at least 12 weeks apart. In one study, 35 a repeat testing was done after 4 weeks for some aPL positive patients. Interestingly, a major proportion of patients who tested positive for LAC, IgG aCL, and aβ2GP1 on the first occasion turned out negative on the second subsequent test, with around half of LAC negative patients undergoing thrombotic complications, which suggests that thrombosis in COVID-19 patients are secondary to other coagulative processes. However, a significant difference in the prevalence of aPL between critically ill and non-critically ill patients was noted, 36 which justifies the need of studies that can assess the difference of the association between aPL and thrombosis among ICU patients compared to non-ICU patients. A summary of the studies that discussed aPL in the setting of COVID-19 is listed in Table 1 . All antiphospholipid assays were performed by ELISA. In addition, the LAC assays were performed according to the International Society on Thrombosis and Haemostasis (ISTH) guidelines. 37 To date, the real prevalence of aPL among COVID-19 patients is still unknown.

Antiphospholipid syndrome (APS), characterized by recurrent thrombotic episodes and/or obstetric complications with persistently elevated titers of aPL confirmed at least 12 weeks apart, 55 is recognized as one of the most common causes of acquired thrombophilia. 56 Several clinical complications can arise as a result of APS manifestations, one of which is catastrophic APS (CAPS) (Asherson's syndrome), which is lifethreatening. The earliest description of CAPS was in 1984 57 before Ronald Asherson formally defined CAPS in 1992. 58 El Hasbani et al 3 Patients with CAPS share certain clinical and laboratory criteria including: involvement of 3 or more organs, systems, and/or tissues, acuity of manifestations, small-vessel occlusion in at least 1 organ, and presence of elevated titers of aPL. 59 When all 4 criteria are present, a "definite CAPS" diagnosis is confirmed. 60 If a patient meets 3 of the 4 criteria, "possible CAPS" is diagnosed. 60 CAPS is frequently associated with thrombocytopenia and hemolytic anemia. 61 LAC, which best predicts thrombotic events in APS patients, 62 is highly prevalent among CAPS patients. 61 The IgG isotype of aCL antibodies is more frequent than the IgM isotype. 61 To date, few data exist on the association of COVID-19 thrombosis and CAPS. Since Robba et al hinted on multiple organ dysfunction including lungs, brain, heart, and kidneys with hematological complications, 63 Suri and Bening suggested that COVID-19 thrombosis could be a form of presentation of CAPS. 64 On the other hand, the single center study performed by Previtali et al studied the sera of 35 deceased patients for the presence of IgA, IgG, and IgM aCL and anti-β2GP1 antibodies, as well as IgG and IgM anti phosphatidylserine/prothrombin (PS/PT) antibodies. 42 Only 3 patients had slightly positive aCL and another 3 patients were positive for PS/PT antibodies. 42 Although the patients in this cohort fulfilled the main clinical diagnostic criteria of CAPS, almost all patients were negative for aPL. Even the aPL positive patients were not considered CAPS positive because aPL levels in CAPS are very high. 65 In addition, the major difference between CAPS and COVID-19 associated thrombosis is the normal fibrinogen levels in CAPS which comes in contrast to COVID-19 thrombosis 66 (Figure 1 ).

The pathogenesis of CAPS is not well understood due to the limitation of current studies. However, it is well known that a precipitating factor usually plays an inciting role. Infections El Hasbani et al 5 are the risk factors in around half of the patients, followed by surgical procedures (17%), malignancies (16%), anticoagulation withdrawal or low international normalized ratio (INR) (8%), obstetric complications (8%), drugs (5%), and systemic lupus erythematosus (SLE) flares (3%). 61 With regards to infections, the most commonly involved system is respiratory (33%) followed by urinary tract (19%), followed by the dermatologic (13%) and the gastrointestinal (8%). 67 It seems that by molecular mimicry, some of the infectious agents might induce nonpathogenic aPL and pathogenic anti-β2-GPI. 68 In addition, vascular endothelial injury might induce the event of thrombosis. 69 Since complement activation, which is a phenomenon that has been linked to COVID-19, is contributory to APS pathogenesis, at least in murine models, the association between thrombosis in APS and COVID-19 could be valid but necessitates further functional studies. 70, 71 Infectious agents. Escherichia coli has been reported to be the most frequently causative microorganism for CAPS. 67 However, viruses, fungi, and protozoa can also induce catastrophic events. Questioning whether SARS-CoV-2 can induce CAPS, the association of other viral infections with CAPS can give an idea. A few respiratory viral infections have been outlined to cause CAPS. For instance, Durkin et al reported the first case of CAPS presumably induced by the influenza A virus subtype H1N1 virus. 72 A second report of CAPS triggered by swine flu (H1N1) viral infection with adult respiratory distress syndrome (ARDS) has been published in 2019. 73 Similarly, Kallur et al reported a catastrophic hypercoagulable state case induced by influenza B infection. 74 In addition, 7 cases of CMV associated with CAPS that have been reported 67, [75] [76] [77] [78] although CMV infection itself is a known thrombotic agent. 69 Epstein Barr Virus (EBV) has been reported as a cause of CAPS. 77, 79 Despite all these reports, there are still no clear reports of CAPS associated with COVID-19.

The huge burden of thrombotic events, in the presence or absence of aPL, on COVID-19 patients sheds light on the thrombophylactic regimen that such patients must undergo. The American Society of Hematology recommends an escalated dose (One-half ) thrombophylaxis for ICU patients compared to the standard dose for ward patients. 80 The options of anticoagulation include low molecular weight heparin (LMWH), unfractionated heparin (UFH), and fondaparinux. 80 Direct oral anticoagulants (DOACs) can also be considered, although the implications on using the intermediate doses are not clear. 80 The ISTH recommendations relied on expert opinion to determine the thrombophylactic regimens for admitted COVID-19 patients. 81 Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders accordingly ( Figure 2 ). The thromboprophylactic regimens should be modified according to body weight. 81 The exact thrombophylactic recommendation for aPL positive COVID-19 patients is still unclear. Whether triple or double positive patients should receive the same thrombophylactic regimen as single positive patients is also unclear. Increasing the LMWH dose or introducing aspirin with a direct oral anticoagulant (DOACs) are among the suggestions, taking into consideration the risk of bleeding. There is an urgent need for high quality data, especially from randomized controlled trials, to determine the safest and most effective thrombophylactic regimen for aPL positive COVID-19 patients with or without thrombotic complications.

COVID-19 seems to induce a hypercoagulable state, particularly in severe cases despite thrombophylactic regimens. Although aPL have been present in few patients in single-center studies, the majority of these patients had positive LAC which is associated with infectious and inflammatory conditions. On the contrary, aCL and anti-β2-GPI antibodies were found positive in very few patients with venous thrombotic complications. Since Abbreviations: ICU, intensive care unit; CI, contraindications; NCI, no contraindications; UfH, unfractioned heparin; DOACs, direct oral anticoagulation; LMwH, low molecular weight heparin. *Advanced age, stay in the ICU, cancer, a prior history of VTE, thrombophilia, severe immobility, an elevated D-dimer (>2 times ULN), and an IMPROVE VTE score of 4 or more.

infectious etiologies, including viral respiratory agents similar to SARS-CoV-2, are the main risk factors for the development of CAPS, the role of SARS-CoV-2 in inducing vascular events seems reasonable, but needs further studies. To date, there are no studies that link COVID-19 to CAPS. Therefore, screening COVID-19 patients for aPL, to assess the possibility of developing fatal thrombotic complications such as CAPS, is currently not supported by evidence. Although standard management with LMWH has been recommended, COVID-19 patients with or without presence of aPL are still suffering thrombotic complications. Thus, different thrombophylactic regimens could be useful taking into consideration the bleeding risk. High quality studies, such as randomized clinical trials, are needed to guide anticoagulation in aPL positive COVID-19 patients who undergo thrombotic events.

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Georges El Hasbani reviewed the literature and wrote the first draft of this manuscript. Ali T Taher critically revised the manuscript and conceptualised the figures. Ali Jawad critically revised the manuscript. Imad Uthman proposed the manuscript and critically revised it.

Georges El Hasbani https://orcid.org/0000-0003-2571-1450 Imad Uthman https://orcid.org/0000-0001-8285-6483