Antiphospholipid Syndrome and Endothelial Injury: Unraveling the Links with Complement Hyperactivation and Thrombotic Microangiopathy in Severe COVID-19

By SWA

Related to the article: "SARS-CoV-2 enhances complement-mediated endothelial injury via suppression of membrane complement regulatory proteins"
https://www.tandfonline.com/doi/full/10.1080/22221751.2025.2467781#abstract

Introduction

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs) that promote thrombosis by triggering endothelial dysfunction, platelet activation, and complement activation. A key feature of APS is thrombotic microangiopathy (TMA), a condition marked by widespread microvascular injury and thrombosis. Similarly, severe COVID-19 has been associated with complement hyperactivation, endothelial damage, and TMA-like manifestations, raising questions about the shared mechanisms between APS and severe SARS-CoV-2 infection.

Recent studies suggest that SARS-CoV-2 proteins can directly impair endothelial cells (ECs), enhance complement-mediated injury, and promote microvascular thrombosis. This article explores the relationship between APS, endothelial dysfunction, and COVID-19–induced complement activation, shedding light on how SARS-CoV-2 may exacerbate APS-like thrombosis or trigger APS in susceptible individuals.

Endothelial Dysfunction as the Core of APS and Severe COVID-19

The endothelium plays a critical role in maintaining vascular homeostasis by regulating coagulation, fibrinolysis, and immune responses. In APS, aPLs target endothelial cells, leading to:

  • Increased expression of tissue factor (TF), the primary initiator of coagulation.
  • Upregulation of adhesion molecules (ICAM-1, VCAM-1) that promote leukocyte recruitment and inflammation.
  • Dysregulation of complement regulatory proteins (CRPs), making ECs more susceptible to complement-mediated damage.

Similarly, in severe COVID-19, endothelial injury is a major contributor to microvascular thrombosis and organ failure. A recent study identified that multiple SARS-CoV-2 proteins (M, NSP16, ORF9b) suppress complement regulatory proteins (CD55, CD59), making ECs more vulnerable to complement attack. This mirrors the complement activation seen in APS, suggesting a shared pathogenic mechanism.

Complement Activation: A Key Driver of Thrombotic Microangiopathy

Complement activation is a well-established mechanism in APS-related thrombosis. aPLs directly activate the complement system, leading to:

  • Deposition of C3b and C5b-9 (membrane attack complex, MAC) on ECs, resulting in endothelial injury.
  • Recruitment of neutrophils and monocytes, which release pro-inflammatory cytokines and reactive oxygen species (ROS), worsening endothelial dysfunction.
  • Increased thrombin generation, promoting a hypercoagulable state.

In severe COVID-19, excessive complement activation contributes to TMA and microvascular thrombosis. The study found that SARS-CoV-2 proteins enhance the deposition of ficolin-1 (FCN1), a key component of the lectin pathway, further amplifying complement-mediated endothelial damage. This is significant because the same pathways are activated in APS, suggesting that COVID-19 may induce an APS-like hypercoagulable state.

Interferon Deficiency and APS-Like Thrombosis in COVID-19

Interferons (IFNs), particularly IFN-γ and type I IFNs (IFN-α, IFN-β), play a protective role in modulating complement activation and endothelial function. In APS, dysregulation of IFN signaling has been reported, leading to unchecked complement activation and inflammation.

The study highlighted that IFN-γ upregulates CRPs (CD55, CD59), providing protection against complement-mediated endothelial injury. However, SARS-CoV-2 proteins suppress IFN responses, which may explain why:

  • IFN deficiency in severe COVID-19 exacerbates endothelial damage and thrombosis.
  • Patients with APS, who may already have altered IFN responses, are at increased risk of severe COVID-19 complications.
  • COVID-19 could potentially trigger APS in predisposed individuals, as seen in cases of de novo APS following infection.

SARS-CoV-2 as a Trigger for APS and Catastrophic APS (CAPS)

The hypercoagulable state in severe COVID-19 resembles APS-related thrombosis, leading researchers to investigate whether SARS-CoV-2 can induce APS or catastrophic APS (CAPS) in certain patients. Several cases of de novo APS following COVID-19 have been reported, with patients developing persistent aPLs and life-threatening thrombosis.

Potential mechanisms include:

  • Direct endothelial injury by SARS-CoV-2, mimicking APS-related endothelial dysfunction.
  • Increased production of aPLs post-infection, possibly due to immune dysregulation.
  • Exacerbation of pre-existing APS, leading to CAPS, a severe multi-organ thrombotic event with high mortality.

These findings suggest that COVID-19 may not only worsen APS but also act as a "second hit" in genetically or immunologically predisposed individuals, leading to new-onset APS.

Therapeutic Implications: Targeting Complement and Endothelial Injury

Given the overlap between APS, complement activation, and COVID-19–induced endothelial injury, targeting complement and immune regulation may be a promising therapeutic approach. Potential strategies include:

  1. Complement Inhibitors:

    • Eculizumab and ravulizumab (C5 inhibitors) to prevent MAC formation and endothelial damage.
    • Narsoplimab (MASP-2 inhibitor) to block the lectin pathway, reducing FCN1-mediated endothelial injury.

  2. Interferon Modulation:

    • IFN-γ therapy may restore CRP expression and protect ECs.
    • JAK inhibitors (e.g., baricitinib) to modulate excessive inflammatory responses.

  3. Anticoagulation and Immunomodulation:

    • Heparin or direct oral anticoagulants (DOACs) to prevent thrombosis.
    • Hydroxychloroquine (used in APS) to reduce aPL-induced complement activation.

These strategies may help mitigate endothelial injury, reduce TMA risk, and improve outcomes in severe COVID-19, APS, and APS-like thrombosis.

Conclusion

Antiphospholipid syndrome and severe COVID-19 share common mechanisms of endothelial dysfunction, complement hyperactivation, and thrombotic microangiopathy. The discovery that SARS-CoV-2 proteins impair complement regulatory proteins (CRPs) and enhance complement deposition provides new insights into COVID-19–induced vascular injury. Furthermore, the role of IFN-γ in protecting endothelial cells from complement attack highlights the potential for immunomodulatory therapies.

As research advances, understanding these mechanisms will be crucial in developing targeted treatments for APS, severe COVID-19, and related thrombotic disorders. Future studies should investigate whether COVID-19 triggers APS in susceptible individuals, paving the way for early detection and intervention in high-risk patients.

Key Takeaways

✅ APS and severe COVID-19 share common mechanisms of complement activation and endothelial injury.
✅ SARS-CoV-2 proteins impair complement regulation, making endothelial cells more susceptible to attack.
✅ Thrombotic microangiopathy in severe COVID-19 mirrors APS-related vascular complications.
✅ COVID-19 may act as a trigger for APS or catastrophic APS in predisposed individuals.
✅ Targeting complement and interferon signaling could be promising therapeutic strategies.

Understanding these connections will improve the management of thrombotic complications in both APS and COVID-19, ultimately leading to better patient outcomes.

Reference: 
Ubiquitin-proteasome system: a potential participant and therapeutic target in antiphospholipid syndrome:
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1523799/full

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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