key: cord-0990046-o9v3m71s
authors: Devreese, Katrien M.J.; Linskens, Eleni A.; Benoit, Dominique; Peperstraete, Harlinde
title: Antiphospholipid antibodies in patients with COVID‐19: a relevant observation?
date: 2020-07-03
journal: J Thromb Haemost
DOI: 10.1111/jth.14994
sha: fe3ca94d4ce8423a3536ab12fb0c1467e3b82e34
doc_id: 990046
cord_uid: o9v3m71s

BACKGROUND: High incidence of thrombosis in COVID‐19 patients indicates a hypercoagulable state. Hence, exploring the involvement of antiphospholipid antibodies (aPL) in these patients is of interest. OBJECTIVES: To illustrate the incidence of criteria (lupus anticoagulant (LAC), anticardiolipin (aCL) IgG/IgM, antibeta2‐glycoprotein I antibodies (aβ2GPI) IgG/IgM) and non‐criteria (anti‐prothrombin/phosphatidyl serine (aPS/PT), aCL and aβ2GPI IgA) aPL in a consecutive cohort of critically ill SARS‐CoV‐2 patients, their association with thrombosis, antibody profile and titers of aPL. PATIENTS/METHODS: Thirty one consecutive confirmed COVID‐19 patients admitted to the Intensive Care Unit were included. aPL were measured at one time point, with part of the aPL positive patients retested after one month. RESULTS: Sixteen patients were single LAC positive, two triple positive, one double positive, one single aCL and three aCL IgG and LAC positive. Seven out of 9 thrombotic patients had at least one aPL. 16 out of 22 patients without thrombosis were aPL positive, amongst them two triple positives. Nine out of ten retested LAC positive patients were negative on a second occasion, as well as the double positive patient. Seven patients were aPS/PT positive associated to LAC. Three patients were aCL and aβ2GPI IgA positive. CONCLUSION: Our observations support the frequent single LAC positivity during (acute phase) observed in COVID‐19 infection, however not clearly related to thrombotic complications. Triple aPL positivity and high aCL/aβ2GPI titers are rare. Repeat testing suggests aPL to be mostly transient. Further studies and international registration of aPL should improve understanding the role of aPL in thrombotic COVID‐19 patients.

Since the description of the first patients with coronavirus disease 2019 (COVID-19) associated pneumonia there is a growing understanding of the derangement of hemostasis in these patients (1) (2) (3) . Although the clinical evolution in coronavirus 2 (SARS-CoV-2) infected patients with severe acute respiratory syndrome is mostly favorable, patients may develop acute respiratory insufficiency requiring admittance in the intensive care unit (ICU) (4) . Also, many patients develop a hypercoagulable state influencing the unfavorable clinical outcome (3, 5) . Several hemostasis laboratory parameters are disturbed pointing to a coagulopathy (2) (3) (4) (5) (6) . Recently reports have been published on antiphospholipid antibodies (aPL) in SARS-CoV-2 patients (5, (7) (8) (9) . Investigators started to measure aPL in these patients because of the hypercoagulable state.

Indeed, antiphospholipid syndrome (APS) is an important required cause of thrombotic complications, and is defined by the presence of aPL (10). In the current classification criteria for APS lupus anticoagulant (LAC), anticardiolipin (aCL) and antibeta2-glycoprotein I antibodies (aβ2GPI) IgG or IgM are included as laboratory criteria, if persistently present (10,11). APS is a challenging diagnosis as the incidence of thrombosis is high and often determined by underlying factors not related to aPL resulting in over-diagnosis (12, 13) . To prevent misdiagnosis the diagnostic workup for a patient with thrombosis requires besides adequate testing also a good collaboration between the clinician and the laboratory (14) .

The information on aPL in SARS-CoV-2 patients that is available so far is interesting, but often incomplete.

Inherent to the recent development of the pandemic COVID-19 situation, in these patients only one point of measurement is obtained without confirmation after at least three months, as defined in the laboratory criteria of APS (10). aPL can arise transiently in patients with critical illness and various infections (15). The presence of these antibodies may rarely lead to thrombotic events that are difficult to differentiate from other causes of multifocal thrombosis in critically ill patients. To further investigate the role of aPL in SARS-CoV-2 patients, it is important to report all criteria aPL, including LAC, aCL and aβ2GPI antibodies, the latter with their isotype and titer. This information is often lacking in the published reports. Measuring LAC, aCL and aβ2GPI allows to make antibody profiles that help in identifying patients at risk (10).

Current criteria recommend increased levels of IgG and IgM aCL and aβ2GPI to confirm APS (10). The role of IgM aPL has been discussed based on a less strong association with thrombosis compared to IgG (16) (17) (18) . In a recent study we illustrated that IgM was not an independent risk factor for thrombosis, but addition of IgM aCL and aβ2GPI to LAC and aCL IgG and aβ2GPI IgG increased the odd ratio for thrombosis, suggesting that testing for IgM might be useful to improve thrombotic risk stratification (18) .

This article is protected by copyright. All rights reserved Previously, it was demonstrated that the presence of aCL and aβ2GPI of the same isotype reinforces the clinical probability of APS (19). In the first report on aPL in patients with COVID-19, three patients were described with IgA (and IgG) aCL and aβ2GPI, without LAC positivity (7) . IgA aCL and aβ2GPI are not included in the current classification criteria (10, 11, 20) . In most cases with thrombosis, IgA aPL are usually found in association with IgG and/or IgM (21).

The association with other aPL, such as anti-prothrombin/phosphatidyl serine (aPS/PT) merit also attention. Recent literature described their association with thrombosis (22, 23) . In the published series of COVID-19 patients aPS/PT is not included.

In this report, we illustrate the presence of criteria and non-criteria aPL, including LAC, aCL (IgG, IgM, IgA), aβ2GPI (IgG, IgM, IgA), aPS/PT (IgG and IgM), in a cohort of critically ill patients with SARS-CoV-2 and discuss the relevance.

Three-step LAC testing was carried out in a dRVVT-and aPTT-based test system according to ISTH guidelines (24) . All tests were carried out on a STA-R Evolution ® analyzer (Stago, Asnières, France) using Stago STA-Staclot ® dRVV Screen, STA-Staclot ® DRVV Confirm, PTT-LA ® and Staclot ® LA reagents. When dRVVT confirm results exceeded the local cutoff values, screen mix/confirm mix ratios were applied in the confirmation step (25) . Conclusion based on screening, mixing and confirmatory step were formulated for each test system, together with a final conclusion of positivity or negativity for LAC. This is important to check the C-reactive protein (CRP) levels to avoid false positive conclusions if only the aPTT system is positive, since the aPTT-based test system is prone to interferences by CRP (26, 27) . Applying the three step procedure, unfractionated heparin (UFH) do not result in false positive LAC, while enoxaparin cause false positive aPTT-based LAC at supra-therapeutic anti-Xa activity levels that exceed the heparin neutralizing capabilities of the reagents (28, 29) . In each sample we checked the anti-Xa level to avoid false conclusions.

aCL and aβ2GPI IgG, IgM and IgA were measured by ACL AcuStar® (Werfen/Instrumentation Laboratories, Bedford, USA). A cut-off value of 20 U/ml was applied (30-32) as previously described or transferred from the manufacturer for IgA (33). aPS/PT IgG and IgM was measured by QUANTA Lite

This article is protected by copyright. All rights reserved ELISA® (Inova Diagnostics, San Diego, USA) with a cut-off value of 30 U/ml transferred from the manufacturer (33). Solid phase assays were performed according to the ISTH guidelines (33).

Thirty one consecutive patients with confirmed COVID-19 admitted into the Ghent University Hospital ICU between March 11 th and April 9 th 2020 were included. The study was approved by the local ethical committee. Patient characteristics are listed in Table 1 .

All patients received prophylactic or therapeutic dose low molecular weight heparin (LMWH) (enoxaparin) or unfractionated heparin (UFH) (See Table 1 ). It is local practice to choose UFH under a calculated creatinine clearance of 30mL/min. By this, when patients had deteriorating or improving kidney function during their stay at ICU, it was possible that the treating physician switched from LMWH to UFH therapy or vice versa. UFH is also chosen during Extracorporeal Membrane oxygenation (ECMO) therapy, since dose changes are more frequent and thus the desired heparinization effect can be adjusted more quickly. Measurement of anti-Xa levels (chromogenic assays STA ® -Liquid anti-Xa, Stago) were performed routinely to ensure prophylactic/therapeutic levels of both LMWH and UFH heparin, taking the coagulopathy and interaction with acute phase proteins into account (34) . Dose adjustments where done based on peak anti-Xa concentration from the 3th dose of enoxaparin, in case of LMWH-therapy. UFH therapy was titrated on steady state levels of UFH every 6 hours. In highly inflammatory patients and in every ECMO patient, antithrombin levels were measured at the beginning of the LMWH or UFH heparin, but also if there were clinical concerns doubting appropriate levels. Patients were routinely tested for D-

Thrombotic complications were confirmed by duplex ultrasound in case of deep venous thrombosis (DVT) or central venous catheter (CVC) thrombosis, the one patient with stroke underwent computed tomography angiography. Circuit devices were assessed routinely by visual inspection for the presence of clots.

Median age in the patient population was 63 (range 38-82) years, with a male/female ratio of 28/3. The median stay at the ICU was 25 (range 5-60) days. 26 patients received mechanical ventilation, five ECMO, and five renal dialysis. Anticoagulant therapy, medical history and comorbidity, as well as thrombotic complications are shown in Table 1 .

This article is protected by copyright. All rights reserved In all patients (n=31) LAC, aCL and aβ2GPI IgG, IgM and IgA, aPS/PT IgG and IgM were measured.

Results are shown in Table 2 and Table 3 .

Eight out of 31 patients were negative for all criteria aPL (LAC, aCL and aβ2GPI IgG and IgM), 23 patients had at least one aPL positive. 21 out of 31 patients were LAC positive. One (patient 15) out of 21 positive LAC patients was positive only in the aPTT system, but we are confident that this is not a false positive result since CRP was elevated up to 57 mg/L and routine aPTT (PTT-A, Stago) was more prolonged then expected according to the CRP level (27, 34, 35) , and aCL IgG was positive. One LAC negative patient was single positive for aCL IgG (patient 12) and one LAC negative patient was double positive for aCL IgG Repeat testing of positive aPL results one month after the first occasion could be performed in part (11/31) of the patient population. Samples after one month were not available from all patients.

LAC was repeated in ten out of 21 patients that were LAC positive during the first period of testing. Nine out of ten patients were LAC negative on the second occasion. One (patient 19) out of the two triple positive patients was included in the repeat testing series, and showed persistent LAC positivity after one month. However, the aCL IgG originally positive around the cut-off value was negative by repeat testing.

In this patient aβ2GPI IgG persisted positive by repeat testing, albeit with a lower titer. Repeat testing of borderline positive aCL IgG and low positive aβ2GPI IgG (patient 20) was negative on the second testing. 

This article is protected by copyright. All rights reserved aCL IgA and aβ2GPI IgA was combined positive in three patients (patient 17, 19, 24) , all associated with LAC. One patient had DVT.

All patients had elevated D-Dimers (Table 2 ).

The incidence of both arterial and venous thromboembolism is high in COVID-19 patients, and laboratory markers may help in raising suspicion of underlying thrombotic problems (36) (37) (38) (39) . Changes in coagulation parameters detecting the procoagulant state in COVID-19 patients associated with poor clinical outcome were reported (3) (4) (5) (6) . Simple, and for most institutions available laboratory markers as platelet count, Ddimers, prothrombin time and fibrinogen seemed relevant for laboratory monitoring for COVID-19 related coagulopathy in addition to clinical assessment (39, 40) . The hemostatic changes observed in COVID-19 are previously also been shown in association with other coronaviruses (41) and some viruses are known to activate the coagulation system (42) .

Clinical experience learns that the hypercoagulable state in critically ill COVID-19 patients comprise diverse types of thromboembolic complications that need adequate anticoagulant therapy (5, 39, (43) (44) (45) .

Triggered by the hypercoagulable state of these patients and the high incidence of thrombosis, involvement of aPL has been suggested and reports have been published on measurement of aPL in COVID-19 patients (5,7-9,45).

Zhang et al described three patients with multiple cerebral infarctions and presence of aCL IgA and aβ2GPI IgG and IgA positivity, measured on one occasion, without details on the titers provided. No LAC was detected in these patients (7) . The three patients fulfilled the clinical criteria for APS (11) , but had also other comorbidities associated with thrombosis (7).

Harzallah et al tested 56 COVID-19 patients for aPL, and found 45% LAC positive, and 10% either aCL or aβ2GPI IgG or IgM positive, of which three were associated with LAC. Titers of aCL or aβ2GPI were not reported, no details were provided on whether LAC was positive in the aPTT and/or dRVVT test system and associated thrombosis was not mentioned (9). 

coagulation disorder was suspected based on prolonged aPTT (5) . LAC testing did not include a confirmatory step for the aPTT system, and LAC was considered positive based on the dRVVT test system results only. They observed 88% positives for LAC (5) . aCL and aβ2GPI were not tested, but one patient seemed to have aCL IgM (48 MLP) positive before the COVID-19 infection. The number of LAC positive patients with confirmed thrombosis is not reported. In the overall population 64 out of 150 patients (43%) had thrombosis (5) .

In two out of the four published studies, COVID-19 patients were not tested for aCL and aβ2GPI (5, 8) . If not all criteria aPL are measured, no antibody profiles can be made, that proved to be useful since combining the aPL may improve risk assessment (10, 11, [46] [47] [48] . Combined positivity for LAC, aCL and aβ2GPI antibodies (i.e. triple positivity) has been shown to be associated with a high risk of both a first thrombotic event and recurrence (49) (50) (51) . Double positive (LAC negative) patients are at lower risk than triple positive patients, and single positive patients are less likely to develop APS related clinical symptoms (10,47). Isolated positivity for LAC is often observed in absence of clinical symptoms, in elderly patients, on a first occasion not confirmed after 12 weeks (47, 52, 53) . Though, an isolated LAC is an independent risk factor for myocardial infarction and ischemic stroke (54, 55) .

The aPL antibody profiles demonstrated in COVID-19 patients have a low risk profile for thrombosis.

Studies that included aCL and aβ2GPI showed mainly single LAC positive patients (9) . In the study of Zhang et al (7), considering the criteria aPL (10), the three patients that are described show single positivity for aβ2GPI IgG. In our study population 23% (7/31) of patients had aCL and/or aβ2GPI, slightly higher compared with the study of Harzallah (9) . In previously reported cohorts (7, 9) aCL or aβ2GPI titers were not reported and cannot be valued against the high titers that are required according to the guidelines (11, 33) . In our cohort, the titers of aCL IgG ranged from 22.4 to 36.2 U/ml, although our cut-off value corresponds to the 99 th percentile (33) experience learns that these titers are "low" positive for the solid phase test system we used (30, 31) . Moreover, values around the cut-off value (three out of the five positive samples) should be interpreted with care (33). Only triple positive patients demonstrated higher titers (patient 9 and 19). All patients with high titers aCL or aβ2GPI did not have thrombotic complications so far.

As far as interpretable and based on available results in previous studies (5, (7) (8) (9) , in none of the patients triple positivity was demonstrated. In our patient cohort, only two patients were triple positive of whom none showed thrombotic complications. While the incidence of aPL in our cohort was high with 74% of patients positive for at least one criterion aPL, the majority of patients showed a low risk profile: 16 single

This article is protected by copyright. All rights reserved LAC positives, one sample with single aCL, one sample with double positivity, three samples with LAC and aCL positivity.

In previous studies (5,7-9) the association of aPL and thrombosis is strongly highlighted, but it is unclear whether all these patients were prophylactically anticoagulated. In our cohort of ICU patients, who tested all positive for D-dimers, we observed no strong association of aPL and thrombotic complications. Among the described thrombotic complications in COVID-19 patients ( clotting of CVC, clotting of dialysis filters, stroke, DVT, and ischemic limbs), we mainly observed CVC and circuit device clotting, one out of the nine patients with thrombotic complications showed stroke, and another patient showed DVT (43, 56) . There was no relationship between D-dimers and aPL, thrombosis or outcome. In patients with thrombosis 67% showed positivity for aPL, in the patients without thrombosis 72% tested positive for at least one aPL. During ECMO treatment, all five patients received UFH. Importantly, in our cohort the majority of patients were treated with heparins to prevent thrombotic complications. This supports that patients should be anticoagulated since coagulopathy is one of the key features which is associated with poor outcomes (36, 39) .

Regarding the isotype, in our study one triple positive patient (patient 9) was positive for aPL IgM.

In the patient population described by Harzallah et al maximally 10% were IgM positive, all aCL/aβ2GPI positive patients were associated with LAC. In our study population we observed two patients with aCL/aβ2GPI not associated to LAC, all IgG positive. This is in line with what we illustrated in a recent multicenter study, that isolated positivity of IgM was rare in thrombotic APS and that it was not an independent risk factor for thrombosis (18) .

Despite aCL and aβ2GPI IgA are not included in the current classification criteria (10), we tested for IgA.

Zhang et al found all three patients (with cerebral infarctions) positive for both aCL and aβ2GPI IgA without LAC positivity (7) . We observed three patients positive for both aCL and aβ2GPI IgA (high titers), associated with LAC, of whom one patient had DVT. In two out of the three patients aCL/aβ2GPI IgG and IgM were negative, what is relatively high (2/31, 6%) compared to APS setting where isolated IgA positivity is rare in patients with clinical manifestations of APS (32) . In most cases with major APS manifestations (i.e. thrombosis), IgA aPL are usually found in association with IgG and/or IgM (21). The number of patients positive for IgA aPL (n=3) compared to IgG (n=8) and IgM (n=2), is comparable low.

In this COVID-19 cohort the role of IgA is unclear, without added value on top of the current classification criteria, equally as previously illustrated in APS (10, 21, 31).

This article is protected by copyright. All rights reserved Amongst non-criteria aPL, aPS/PT is a group of aPL that merit attention, based on recent literature describing their association with thrombosis (22, 23) . aPS/PT antibodies are strongly associated with LAC and frequently present in APS patients (52,57). In our COVID-19 cohort, we observed aPS/PT IgM positivity in 25% (4/16; patient 13, 14, 24, 27) of the single LAC positives, of whom one patient suffered from DVT. Three patients were positive for aPS/PT IgG (patient 6, 19, 30) , two with single LAC positivity, of whom one had CVC thrombosis, and two (one with triple positivity) had no thromboembolic complications. The association of LAC and aPS/PT seems lower than expected based on results in APS patients. Today, aPL against only two plasma proteins, β2GPI and prothrombin, are found frequently enough in APS patients to attribute them a pathophysiological role. In the absence of aβ2GPI, LAC positivity signifies a β2GPI-independent LAC whose association with thrombosis is uncertain (47) . The single LAC positivity frequently observed in COVID-19 patients might be explained by LAC activity through other co-factors. We can speculate that in these single LAC positive patients (hence aβ2GPI negativity, and also aPS/PT negative), aPL binding through other co-factors, such as complement C4 or factor H, may be responsible for the LAC positivity. The more, the role of complement activation and cytokine storm has been described in COVID-19 and play a role in the microvascular injury and organ dysfunction (10, 45, 58) . All aPL analyses were performed during the acute phase, what is discouraged in the guidelines because of possible interferences with the test result (24) . Single LAC positivity is a common finding in all COVID-19 related studies measuring aPL. Isolated LAC may also be the consequence of the complicated methodology of phospholipid-dependent coagulation tests that are prone to interferences (24, 26, 35) . In some of the published reports there is concern on the methodology since most of these critically ill patients have raised levels of CRP, that may results in false positive LAC (35) In some publications we can

This article is protected by copyright. All rights reserved rule out this reason for false positivity (5, 8) , but in others we cannot (9) . One of the major drawbacks of LAC testing is also the interference of anticoagulant therapy (29). COVID-19 patients are treated with heparins (39), but interference of heparins is probably not a real issue here, since reagents dedicated for LAC testing contain heparin neutralizers, and LAC analysis is reliable if antiXa levels of heparins are within the therapeutic range (29). Although we also tested during the acute phase, in our observational study we are confident not having false positive LAC since we checked for CRP and antiXa levels, and nevertheless, observed 52% (16/31) single LAC positive patients.

A major drawback of all COVID-19 related studies on aPL is the lack of confirmed positivity of aPL after three months (10). Positive results of LAC, aCL or aβ2GPI need to be confirmed on a second occasion, after 12 weeks to confirm persistent positivity (10). We had the occasion to retest some patients at a second time point, at one month distance from the first testing period. All but one patient retested for LAC became negative, for aCL IgG all retested positive patients were negative. It is noteworthy that the retested triple positive patient turned into negative for one aPL (aCL IgG) after one month. Transient antibodies have been described in infectious diseases or drugs and are thought not being of clinical significance, therefore re-testing was originally meant to avoid over-diagnosis of APS patients that were not persistently positive (10, 11) . Some studies demonstrated that aPL, with properties similar to those found in patients with APS, can be induced by immunization with β2GPI-like PL-binding viral and bacterial products. However, it is not certain that these aPL antibodies are pathogenic and the clinical significance remains unknown. These infection induced aPL are transient in some patients and in some individuals they persist, and can be associated with thrombosis (15,60). Infectious agents are triggers for the formation of aPL and molecular mimicry between structures of bacteria or viruses and β2GPI-derived amino acid sequences are thought to contribute to the formation of autoantibodies (61) . But only with the appropriate genetic background or following secondary triggers do these antibodies become pathogenic.

Triggers probably push the haemostatic balance in favor of thrombosis and might include environmental factors such as infection (62).

Limitations of our study are the small patient population, and the limited number of patients that were retested on a second occasion on distance from the first testing.

In summary, the observations in our study support the finding of frequent single LAC positivity in the acute phase of the COVID-19 infection, but not clearly related to thrombotic complications. Albeit our study population is small, triple positive patients are rare, and titers of aCL and aβ2GPI are high only in the minority of patients. LAC positivity do not correspond with aPS/PT as we observe in APS. Repeat testing in a limited number of patients suggests that most of the aPL are transient.

This article is protected by copyright. All rights reserved 

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Accepted Article This article is protected by copyright. All rights reserved 62

Antiphospholipid syndrome

Inflammation and coagulation

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