Type I interferons – primarily the extensively studied IFN-α and IFN-β – are signaling molecules of the innate immune system. Most human and mouse cells are capable of producing IFNs in response to infection. The primary function of IFNs is to initiate antiviral defense and limit pathogen spread.
Interferon production begins when immune cells recognize molecules characteristic of viruses, bacteria, and damaged tissues. Innate immune receptors, including TLRs and RIG-I, as well as the sensor cGAS, detect viral RNA, DNA, and cytosolic DNA and trigger signaling cascades that induce type I IFN synthesis.
Type I IFN responses are activated not only during viral infections but also during bacterial infections. One of the best-characterized mechanisms involves recognition of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, by TLR4, activatштп signaling pathways that stimulate the production of IFN-α and IFN-β.
Type I IFNs act both on the producing cell and on neighboring cells through the IFNAR receptor. Upon binding to IFNAR, interferons activate the JAK–STAT signaling pathway and increase the expression of hundreds of interferon-stimulated genes (ISGs). As a result, the body initiates protective programs against infection and maintains homeostasis.
However, excessive or prolonged activation of IFN-I signaling can be detrimental. Dysregulation of the IFN-I pathway may contribute to pathological blood coagulation during both viral and bacterial infections. Furthermore, activation of the coagulation system can itself further enhance type I interferon production.
Scientists from the School of Biochemistry and Immunology at the Trinity Biomedical Sciences Institute (Ireland) summarized current knowledge of type I interferon effects on blood coagulation and proposed the IFN-I signaling pathway as a therapeutic target for the treatment of coagulopathy.
Type I Interferons Regulate Blood Coagulation
Under normal conditions, blood coagulation prevents blood loss following vascular injury. During sepsis, however, this process can become uncontrolled and lead to thrombosis. Excessive type I interferon activation plays an important role in this process.
In models of sepsis induced by LPS or polymicrobial infection, mice with impaired IFN-I signaling – either lacking the adaptor protein TRIF, which transmits signals from TLR3 and TLR4, or lacking IFNAR – exhibited reduced thrombin generation and decreased fibrin deposition in the liver and lungs. These mice were protected from coagulopathy and showed improved survival during sepsis.
The cytokine IL-6 promotes coagulation by increasing fibrinogen synthesis in the liver. Administration of anti-IFNAR antibodies or genetic deletion of IFNAR reduces levels of the proinflammatory cytokine IL-6, decreases endothelial damage, and suppresses the expression of factors that inhibit fibrinolysis. These findings suggest that IFN-I suppresses thrombus-clearance mechanisms, thereby promoting a prothrombotic state.
Type I Interferons, the Noncanonical Inflammasome, and Coagulation
Type I IFNs promote coagulopathy through several interconnected mechanisms. One mechanism involves activation of caspase-11 in mice and caspases-4 and -5 in humans, which are required for formation of the noncanonical inflammasome – an intracellular protein complex that drives inflammation and can initiate pyroptosis, an inflammatory form of cell death.
During Gram-negative bacterial infections, IFN-I facilitates caspase-11 activation. Recognition of bacterial LPS by macrophages activates caspase-11, which in turn activates gasdermin D, leading to pore formation in the cell membrane and pyroptosis. As a result, tissue factor (TF) and other proinflammatory mediators are released, promoting thrombosis. Deletion of caspase-11 or gasdermin D, or administration of anti-TF antibodies, significantly reduced blood coagulation and mortality in septic mice.
Expression of caspase-11 and gasdermin D is regulated by the transcription factor IRF2. Targeting IRF2 or the noncanonical inflammasome may therefore represent a novel strategy for suppressing IFN-I-driven thrombosis.
Another key IFN-associated factor in coagulation is HMGB1. This protein amplifies IFN-I signaling, promotes caspase-11 activation, increases tissue factor expression, and sustains inflammation. In addition, HMGB1 contributes to the formation of neutrophil extracellular traps (NETs) and has been linked to venous thrombosis.
The interferon-stimulated protein IFITM3 is required for IFN-I-induced thrombosis. In response to IFN-α, IFITM3 enhanced fibrinogen uptake by megakaryocytes and increased platelet aggregation in mice. Elevated IFITM3 expression has also been observed in patients with nonviral sepsis.
cGAS–STING and Blood Coagulation
The cGAS–STING signaling pathway plays an important role in inflammation and coagulation disorders during infection. Activation of this pathway induces production of type I IFNs and other proinflammatory cytokines.
During SARS-CoV-2 infection, activation of cGAS–STING in endothelial cells enhances expression of coagulation-related genes and increases IL-6 levels. Treatment with a STING inhibitor reverses these effects, indicating a role for STING in COVID-19-associated coagulopathy.
At the same time, STING activation may enhance antiviral defense. In experimental studies, a STING agonist effectively suppressed SARS-CoV-2 replication and reduced mortality in infected mice. Its effects on preventing weight loss and reducing mortality were greater than those achieved by interferon administration after infection. These findings highlight the potential of targeting STING in the treatment of COVID-19-associated inflammation and coagulopathy.
STING may also promote coagulation independently of IFN-I. In experimental sepsis models, STING activation increased TF release by monocytes and macrophages through gasdermin D-mediated pyroptosis. This effect occurred independently of IFN-I, as disseminated intravascular coagulation markers were unaffected by IFN-I status. These observations suggest that therapeutic STING inhibition may represent a promising strategy for treating inflammation-associated coagulopathy regardless of IFN-I involvement.
Type I Interferons, COVID-19, and Blood Coagulation
Rapid activation of IFN-I is essential for protection against SARS-CoV-2. However, dysregulated IFN-I signaling is associated with elevated coagulation markers and more severe COVID-19.
Patients with COVID-19 exhibit signs of marked coagulopathy, including elevated D-dimer levels, fibrin deposition, and endothelial activation. SARS-CoV-2 infection also shifts monocytes toward a more prothrombotic phenotype and enhances tissue factor release, promoting excessive thrombin generation and thrombosis.
Studies in mice demonstrated that COVID-19-associated coagulopathy is linked to the IFN-I–caspase-11–tissue factor axis. Furthermore, thrombin directly cleaves the SARS-CoV-2 spike protein, enhancing viral entry into airway epithelial cells. The anticoagulant heparin can suppress caspase-11-mediated pyroptosis and reduce mortality in some patients during the early stages of COVID-19, before severe disease develops. However, therapeutic heparin administration in critically ill patients has not shown benefits over standard pharmacological thromboprophylaxis.
Long COVID has also been associated with persistent fibrin microclots. Because elevated type I interferon activity can persist for months after infection, it may contribute to microthrombus formation and long-term symptoms.
Type I Interferonopathies and Blood Coagulation
In type I interferonopathies, chronic IFN-I hyperactivation is associated with an increased risk of vascular complications and thrombosis. The most prominent example is systemic lupus erythematosus (SLE), in which patients exhibit an increased incidence of atherothrombotic cardiovascular disease.
Patients with SLE exhibit increased tissue factor expression, enhanced platelet activation, and evidence of vascular injury, all of which are associated with persistent IFN-I signaling. In lupus-prone mice, deletion of IFNAR improved endothelial function and reduced the severity of atherosclerosis.
The cGAS–STING pathway plays a central role in SLE pathogenesis. Patients with SLE exhibit elevated cytosolic DNA levels and increased cGAS expression, leading to excessive type I interferon production.
Additional evidence linking dysregulated IFN-I signaling and coagulopathy comes from disorders caused by mutations in the JAK–STAT signaling pathway. Such mutations are associated with increased risks of thrombosis and mortality, further underscoring the role of IFN-I in regulating coagulation.
Pharmacological Targeting of Type I Interferons for the Treatment of Coagulopathy
Studies conducted during the COVID-19 pandemic demonstrated that suppression of excessive IFN-I signaling can reduce both inflammation and coagulopathy. In clinical trials, JAK inhibitors that block IFN-I signaling improved COVID-19 outcomes: tofacitinib reduced the risk of death and respiratory failure, while baricitinib combined with corticosteroids reduced D-dimer and C-reactive protein levels in hospitalized patients. The greatest benefits were observed when treatment was initiated before severe COVID-19 developed.
JAK inhibition simultaneously suppresses IL-6 signaling, further limiting inflammation and coagulation. In addition, JAK inhibition may reduce thromboinflammation associated with COVID-19.
The Influence of Blood Coagulation on Type I Interferons
Coagulation factors not only maintain hemostasis but can also directly influence innate immunity. In particular, thrombin can stimulate the production of proinflammatory cytokines and type I interferons through protease-activated receptors (PARs).
This mechanism may enhance host defense during infection; however, excessive activation can sustain a pathological cycle of inflammation and thrombosis. Accumulation of thrombin is associated with an increased risk of microvascular and macrovascular thrombosis and the development of tissue ischemia.
Stimulation of Type I Interferon Production Through PAR Receptors
Thrombin can activate inflammatory signaling through PAR receptors, potentially contributing to thromboinflammation. PARs interact with TLRs on innate immune cells and may therefore enhance type I interferon production.
Experiments in mice demonstrated that PAR1 enhances IFN-I-dependent antiviral responses. PAR1-deficient mice exhibited reduced expression of IFN-β and antiviral genes, while blockade of tissue factor or thrombin worsened viral myocarditis. These findings indicate a protective role for physiological coagulation during viral infection.
Unlike PAR1, PAR2 may suppress IFN-I signaling and reduce secretion of proinflammatory cytokines. The effects of PAR2 depend on the specific TLR being activated. Thus, interactions between individual PARs and TLRs can have opposing effects on innate immune signaling, particularly regarding IFN-I responses.
Thrombin directly stimulates production of proinflammatory cytokines, including IL-6, IL-1β, IL-1α, and TNF. IL-1α is important for rapid thrombopoiesis and wound healing. Thrombin-activated IL-1α is elevated in the plasma of patients with acute respiratory distress syndrome (ARDS) and may therefore serve as a biomarker of thromboinflammatory conditions.
In addition, the TF–FVIIa–FXa complex can activate signaling pathways that lead to type I interferon production.
Conclusion
Dysregulated type I interferon signaling is an important contributor to pathological blood coagulation in infectious and autoimmune diseases, including systemic lupus erythematosus and STING-associated vasculopathy with onset in infancy (SAVI).
Type I interferons can promote thrombosis through multiple coagulation-related mechanisms, while coagulation factors, in turn, can stimulate the production of interferons and proinflammatory cytokines.
These findings support the view that type I interferons are key regulators of thromboinflammation and represent a promising therapeutic target for the prevention and treatment of coagulopathy in infectious and inflammatory diseases, including sepsis.
Reference
An Emerging Role for Type I Interferons as Critical Regulators of Blood Coagulation
