Antiphospholipid antibodies and thrombosis in severe COVID-19 pneumonia: A difficult relationship

Dear Editor,

We read with great interest the recent paper written by Galeano-Valle et al. [1] and published in your journal. In this prospective observational study, the authors evaluated the presence of antiphospholipid (aPL) antibodies (anticardiolipin and anti-β2 glycoprotein I) in patients with COVID-19 pneumonia and venous thromboembolism (VTE). They chose not to assess lupus anticoagulant (LAC) due to false positivity in patients treated with heparin. This study found that the prevalence of aPL antibodies among COVID-19 patients with VTE was low, suggesting that aPL antibodies might not be involved in the pathogenesis of VTE in COVID-19 patients. These conclusions allow us to make some observations.

In a recent study, Harzallah et al. [2] reported the presence of LAC in 45% of critically ill COVID-19 patients. In line with these results, Bowles et al. [3] found an elevated positivity of LAC assays (91%) in patients with severe respiratory syndrome coronavirus 2 (SARS-CoV-2) associated with a prolonged activated partial-thromboplastin time (aPTT).

APL antibodies are a conditio sine qua non for diagnosis of antiphospholipid syndrome (APS). The latest update from the Subcommittee for the Standardization (SCC) of the International Society of Thrombosis and Haemostasis (ISTH) for LAC and aPL antibodies recommends performing all three tests (LAC, anticardiolipin and anti-β2 glycoprotein I) to diagnose APS. A LAC result should always be considered in the context of a full laboratory aPL profile. Moreover, positive laboratory tests should be confirmed 12 weeks after the initial testing [4].

A different clinical significance can be attributed to positivity in individual tests. For example, isolated positive tests for the diagnosis of LAC do not appear to be associated with a significant increase in thromboembolic risk and, equally, the isolated positivity for anticardiolipin or anti-ß2 glycoprotein I antibodies. It is widely proven that positivity in more than one test is associated with a higher thromboembolic risk, while triple positivity is associated with the highest risk of thromboembolic complications [5].

We agree with Galeano-Valle [1] that false positive LAC may occur in patients treated with anticoagulant drugs and therefore the LAC test should be interpreted with caution if performed in these patients. However, anticoagulant prophylaxis should not be a reason to not evaluate the LAC, especially in patients with prolonged aPTT.

The presence of LAC can be indicated by two assays: dilute Russell's viper-venom time (dRVVT) and lupus anticoagulant-sensitive activated partial-thromboplastin time. A heparin-neutralizing agent (i.e. heparinase) can be contained in dRVV reagents, quenching heparin up to 0.8 IU mL⁻¹ [6]. Moreover, the guidelines recommend that the LAC testing should be performed 12 h after the last dose of heparin [6].

Of course, the methodology for detecting aPL antibodies is complicated and suffers from many pitfalls [7]. A drawback, reported in the use of coagulation assays in LAC testing, is their sensitivity to elevated C-reactive protein (CRP) levels. Data on LAC should be interpreted with care when CRP-sensitive reagents are used, and tests are conducted in patients with elevated CRP-values. In daily practice, laboratory staff interpreting LAC testing should be aware of this interference overall in COVID-19 patients in which the CRP-values could be high [8].

The relationship between aPL antibodies and thrombosis in COVID-19 patients appears complicated. We agree with Galeano-Valle et al. [1] when they claim that the presence of aPL antibodies during COVID-19 infection may, on rare occasions, lead to thrombosis because of their poor specificity. On the other hand, their findings cannot establish that aPL antibodies might not be involved in the pathogenesis of VTE in patients with COVID-19 pneumonia because they are not elevated; their assays are not complete.

Recently, new tests exploring the presence of subgroups of antibodies directed to β2-glycoprotein I (anti Domain 1 and Domain 4/5 antibodies), could be useful as an additional test in presence of incomplete APL antibody profiles for better antithrombotic treatment [9]. Moreover, antibodies to phosphatidylserine/prothrombin (aPS/PT) have been evaluated with favorable results in APS diagnosis [4,9].

In conclusion, COVID-19 pneumonia appears to induce an inflammatory and hypercoagulable state with elevated interleukin-6, C-reactive protein, fibrinogen, and D-dimer levels that could explain the high incidence of VTE. Abnormalities in coagulation screening measures, including a possible prolonged aPTT, in absence of bleeding signs and in presence of VTE, should suggest to clinicians the possible presence of aPL antibodies; it could prevent the anticoagulant suspension in high risk COVID-19 patients. Further studies are necessary to establish the exact mechanism underlying the pathogenesis of thrombosis that still appears unclear.

Disclosure

None to declare.