Vascular Thrombosis in COVID-19: A Potential Association with Antiphospholipid Antibodies
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Abstract
Background
Vascular thrombosis is common in patients with coronavirus disease 2019 (COVID-19). Etiologies underlying this complication are unclear.
Purpose
To determine the prevalence of antiphospholipid (aPL), including lupus anticoagulant, anti-cardiolipin and anti-β2-glycoprotein-1 antibodies, and its possible association with thrombotic manifestations of COVID-19.
Data Sources
We searched MEDLINE indexed journals on September 24, 2020 using the tool LitCovid and the pre-print server medRxIV.
Study Selection
Original investigations (cross-sectional studies, cohort studies, case series, and research letters) on COVID-19 and thrombosis were included.
Data Extraction
Data were independently extracted, and compiled into spreadsheets based on the PRISMA principles.
Data Synthesis
Hospitalized patients with COVID-19 showed a higher prevalence of lupus anticoagulant compared to non-COVID-19 patients. Temporally, lupus anticoagulant was generally positive early in the course of illness, whereas anti-cardiolipin and anti-β2-glycoprotein-1 antibodies appeared to emerge later in the disease. Some patients who were aPL-negative at an early time-point after disease onset became aPL-positive at a later time-point. Lupus anticoagulant was independently associated with thrombosis in 60 COVID-19 patients in New York had who had 32 thrombotic events (8 arterial and 24 venous). In 88 patients in Wuhan, who had more than 20 each of arterial and venous thrombotic events, medium/high positivity for multiple aPL was significantly associated with arterial thrombosis. However, the association of aPL with thrombosis was not evident in reports that had an overall lower number of or predominantly venous thrombotic events. Analysis of pooled patients revealed that aPL were significantly more frequent in COVID-19 patients with stroke than stroke patients in the general population. Furthermore, injection of IgG aPL fractions from COVID-19 patients into mice accelerated venous thrombosis.
Limitation
Limited data and paucity of prospective studies.
Conclusion
The aPL are prevalent in patients with COVID-19 and their presence is associated with thrombosis. Importantly, these antibodies may be a key mechanism of thrombosis in COVID-19. Follow-up studies are required to understand the relationship between aPL and the spectrum of vascular thrombosis during and after infection with SARS-CoV-2.
Primary Funding Source
None.
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SciScore for 10.1101/2020.11.02.20224642: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources We used the following search terms: “COVID-19”, “Coronavirus”, “ncov”, “2019-ncov” and “Antiphospholipid antibodies”, “Antiphospholipid antibody syndrome”, “Lupus anticoagulant” and “Stroke”, “Venous thromboembolism”, “Deep vein thrombosis” (DVT), “Myocardial infarction” and “Acute limb ischemia”. “COVID-19”, “Coronavirus”, “ncov”, “2019-ncov” and “Antiphospholipid antibodies”,suggested: NoneSoftware and Algorithms Sentences Resources Data Sources and Searches: We searched MEDLINE indexed … SciScore for 10.1101/2020.11.02.20224642: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources We used the following search terms: “COVID-19”, “Coronavirus”, “ncov”, “2019-ncov” and “Antiphospholipid antibodies”, “Antiphospholipid antibody syndrome”, “Lupus anticoagulant” and “Stroke”, “Venous thromboembolism”, “Deep vein thrombosis” (DVT), “Myocardial infarction” and “Acute limb ischemia”. “COVID-19”, “Coronavirus”, “ncov”, “2019-ncov” and “Antiphospholipid antibodies”,suggested: NoneSoftware and Algorithms Sentences Resources Data Sources and Searches: We searched MEDLINE indexed journals using the tool LitCovid (8) on September 24, 2020. MEDLINEsuggested: (MEDLINE, RRID:SCR_002185)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our analysis has several limitations. First, the Sapporo classification criteria for APS requires the aPL to be measured twice over a period of 12 weeks to establish that the levels are not transient (33). In this regard, most studies have tested aPL in hospitalized patients with SARS-CoV-2 infection within days of the onset of symptoms. Therefore, follow up studies are required to truly understand whether the patient developed APS or simply had a transient elevation of aPL. Second, the guidelines from the International Society on Thrombosis and Hemostasis state that anticoagulation must be discontinued for 12 hours before the testing for LA or the testing must be done before anticoagulation is started (34). Since critically ill patients are often anticoagulated, it is important to interpret a positive LA result with caution in this setting. Elevated levels of the acute phase reactant C-reactive protein, as commonly seen in patients hospitalized with COVID-19, have also been shown to interfere with reagents commonly used to test LA (35). Antibody assays for aCL and aβ2GP1 antibodies also suffer from a lack of standardization and the presence of inter-laboratory variation, which can influence the interpretation of tests with borderline results (36). Third, many patients with COVID-19 in most reports analyzed had comorbidities including diabetes and hypertension, which could contribute to a pro-thrombotic milieu. Other complications, including heparin-induced thrombocytopenia, ...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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