When the Immune System Turns the Blood Against Itself

The immune system and the clotting system evolved as allies, and when that alliance goes wrong the consequences can be devastating. A comprehensive review published in The Lancet Regional Health – Europe, led by haematologist Deepa J. Arachchillage of Imperial College London together with Megan V. Preece and Mike Laffan, argues that autoimmune-driven thrombosis has been chronically under-recognised as a driver of premature heart attacks, strokes, venous clots, pregnancy complications and death across Europe. The authors make the case that lupus, rheumatoid arthritis, vasculitis and related disorders should be treated not just as diseases of joints and skin, but as cardiovascular risk conditions in their own right, deserving the same preventive attention as diabetes or hypertension.

The numbers behind the argument are striking. Antiphospholipid syndrome, the archetypal autoimmune clotting disorder, affects roughly 40 to 50 per 100,000 people in western populations, with a four-to-one female predominance, and carries an annual incidence of one to two cases per 100,000. Around 20 to 30 percent of patients with systemic lupus erythematosus carry antiphospholipid antibodies, and about 40 percent of those go on to develop secondary antiphospholipid syndrome. Patients who have both lupus and antiphospholipid antibodies face significantly higher risks of clotting and of recurrence than either condition alone. Rheumatoid arthritis, giant cell arteritis, Takayasu’s arteritis, polyarteritis nodosa and ANCA-associated vasculitis all add to the burden, as do immune-driven syndromes such as heparin-induced thrombocytopenia and the vaccine-induced clotting disorder VITT that emerged during the COVID-19 pandemic.

What makes these conditions clinically treacherous is that, unlike inherited clotting tendencies, they can strike any part of the circulation. In antiphospholipid syndrome, venous thromboembolism accounts for 39 percent of first events, but stroke follows at nearly 20 percent, with transient ischaemic attacks and heart attacks behind it. Clots also form in unusual places: the cerebral venous sinuses, the splanchnic veins, even the retina. In a five-year international cohort, the single most frequent recurrent event was stroke, a sobering signal that standard anticoagulation incompletely protects these patients. Microvascular thrombosis and pregnancy complications complete a picture that disproportionately afflicts younger adults, especially women, precisely the people conventional cardiovascular screening tends to overlook.

At the mechanistic heart of the problem lies immunothrombosis, the ancient host-defence programme that uses clot formation to wall off circulating pathogens. When autoantibodies hijack this machinery, the result is pathological thrombo-inflammation. The best-characterised culprit is the family of antiphospholipid antibodies, particularly those directed against beta-2 glycoprotein I. These antibodies bind phospholipid-binding proteins on endothelial cells, monocytes and platelets, triggering tissue factor expression, thrombin generation and platelet aggregation, and creating a sustained hypercoagulable state that spans arteries, veins and the microcirculation.

Platelets themselves turn out to be immune sentinels, and the review places the platelet Fc gamma receptor IIa at the centre of the story. This receptor, the only Fc receptor on platelets, binds the tail of IgG immune complexes. When pathogenic antibodies cross-link it, a signalling cascade through Src family kinases, Syk and phospholipase C gamma 2 rapidly activates the platelet, spurring granule release, integrin activation and aggregation. Activated platelets shed phosphatidylserine-rich microparticles that serve as catalytic surfaces for thrombin generation and express P-selectin, recruiting neutrophils and monocytes. In antiphospholipid syndrome, heparin-induced thrombocytopenia and VITT alike, Fc gamma receptor IIa signalling is the common final pathway converting adaptive immune mischief into arterial thrombosis, a fact already exploited therapeutically through high-dose intravenous immunoglobulin.

Neutrophils add a second layer of amplification. Activated neutrophils cast out neutrophil extracellular traps, web-like lattices of DNA, histones and granular enzymes that normally ensnare microbes but in autoimmunity provide scaffolds for fibrin deposition, activate platelets and injure the endothelium. In lupus and antiphospholipid syndrome, impaired clearance of these traps sustains vascular inflammation. Meanwhile complement fragments C3a and C5a stoke cytokine release and thrombin generation, while the membrane attack complex punches holes in endothelial cells; experimental work shows complement activation is essential to clotting in antiphospholipid syndrome, making complement inhibition a promising strategy for severe disease.

The endothelium itself is transformed from a guardian into an accomplice. Healthy vessels secrete nitric oxide and prostacyclin and display anticoagulant proteins, but inflammatory cytokines such as tumour necrosis factor-alpha, interleukin-1 and interferon-alpha flip the switch: adhesion molecules appear, von Willebrand factor floods out, natural anticoagulants are downregulated, and plasminogen activator inhibitor-1 throttles fibrinolysis. Oxidative stress strips away nitric oxide bioavailability. In lupus and rheumatoid arthritis this same endothelial dysfunction accelerates atherosclerosis, so patients develop premature arterial disease years or decades ahead of schedule. Traditional risk factors then multiply the damage: smoking boosts autoantibody production, obesity feeds chronic low-grade inflammation, and long-term glucocorticoid therapy worsens blood pressure, lipids and insulin resistance.

Paradoxically, several of these conditions cause clotting despite depleting platelets. In immune thrombocytopenia, antibodies against platelet glycoproteins drive the count down, yet patients still clot more often, through microparticle formation, enhanced thrombin generation and endothelial dysfunction. In autoimmune haemolytic anaemia, antibodies destroy red cells, and the liberated iron, procoagulant microparticles, complement activation and nitric oxide depletion together conspire toward thrombosis. Even antibodies against the natural anticoagulants protein C and protein S have been described, producing catastrophic syndromes such as purpura fulminans and symmetrical peripheral gangrene. The lesson, the authors stress, is that thrombosis in strange contexts or without traditional risk factors should prompt a search for an immune cause.

Diagnosis and risk stratification remain stubbornly difficult because conventional tools are calibrated to ordinary populations. Framingham and SCORE2 scores systematically underestimate vascular risk in inflammatory disease, which is why several rheumatology societies recommend adjustment factors. Laboratory assessment centres on antiphospholipid antibody testing, where persistence on repeat testing after at least twelve weeks confirms clinical significance, and so-called triple positivity marks particularly high recurrence risk. Anticoagulation strategy is similarly nuanced: vitamin K antagonists remain the standard for thrombotic antiphospholipid syndrome because randomised trials showed rivaroxaban and other direct oral anticoagulants carry unacceptably high arterial recurrence rates in triple-positive patients, though carefully selected low-risk patients intolerant of warfarin may still qualify. Hydroxychloroquine, with its platelet-calming and endothelial-protecting effects, statins, aggressive inflammation control and rigorous management of blood pressure, lipids and glucose all form part of the preventive package, alongside minimising cumulative steroid exposure.

The review closes with a policy prescription that amounts to a cultural shift. The authors call for European health systems to designate autoimmune diseases as cardiovascular risk-enhancing conditions, embedding cardiovascular prevention within routine rheumatology and haematology care rather than leaving it to cardiology alone. Multidisciplinary pathways linking primary care, rheumatology, haematology, cardiology and obstetrics, supported by harmonised registries and autoimmune-specific risk prediction tools, would allow earlier detection of high-risk patients through blood pressure, lipid and glucose monitoring, vascular imaging and structured screening of carriers of antiphospholipid antibodies. The economic stakes are substantial: venous thromboembolism costs the United States an estimated seven to ten billion dollars annually, and stroke cost 32 European countries roughly 31 billion euros in 2017, with the autoimmune contribution disproportionately large because patients are young and comorbidities multiply. Emerging therapies, from CD19-directed CAR-T cells to bispecific antibodies that deplete the plasma cells making pathogenic antibodies, hint that in the future the source of the problem, not just its downstream clot, might finally be silenced.

Subject of Research: Mechanisms, epidemiology and prevention of autoimmune-associated thrombosis

Article Title: Autoimmune-associated thrombosis: mechanisms, population burden, and prevention strategies

Article References: Arachchillage, D. J., Preece, M. V., & Laffan, M. (2026). Autoimmune-associated thrombosis: mechanisms, population burden, and prevention strategies. The Lancet Regional Health – Europe, 70, Article 101850. https://doi.org/10.1016/j.lanepe.2026.101850

Image Credits: AI Generated

DOI: 10.1016/j.lanepe.2026.101850

Keywords: autoimmune disease, thrombosis, antiphospholipid syndrome, systemic lupus erythematosus, immunothrombosis, endothelial dysfunction, neutrophil extracellular traps, complement activation, VITT, heparin-induced thrombocytopenia, cardiovascular risk, anticoagulation