The classical pre-metastatic niche paradigm, developed over the past two decades, holds that primary tumors actively prepare distant sites for colonization by releasing soluble factors and extracellular vesicles that travel through the bloodstream and reprogram future metastatic destinations. Bone marrow–derived cells are recruited, blood vessels become leaky and adhesive, immune defenses are suppressed, and the extracellular matrix is degraded and reorganized. What this paradigm does not explain, the review’s authors note, is whether catastrophic systemic inflammation by itself, without any tumor present, can generate similar tissue states. Their answer, assembled from a synthesis of immunological, vascular, and matrix biology, is that it plausibly can, through what they term an Immuno–Vascular–Matrix Triad.

The first arm of the triad is immunological. Sepsis unleashes a storm of damage-associated molecular patterns, including high-mobility group box 1, mitochondrial DNA, and adenosine triphosphate, which flood the circulation as injured cells rupture. These alarmins engage Toll-like receptors, most notably TLR4, on immune and stromal cells, igniting signaling cascades that sustain inflammation well beyond the initial insult. In the acute phase, neutrophils respond with explosive production of neutrophil extracellular traps, web-like lattices of DNA and antimicrobial proteins that normally help contain pathogens. When this NETosis becomes dysregulated, it feeds immunothrombosis, promoting platelet activation and diffuse microthrombosis that choke off capillary beds and create focal pockets of hypoxia throughout the body’s tissues.

Hypoxia is not a passive consequence in this framework but an active remodeling signal. Oxygen-starved regions stabilize hypoxia-inducible factor-1α, a transcription factor that reprograms cellular metabolism and drives angiogenic and pro-adhesive gene expression, echoing the low-oxygen conditions that characterize developing metastatic niches. Meanwhile, the immune system enters a prolonged state of dysfunction that the authors describe as immunodisruption. Lymphopenia, the depletion of circulating lymphocytes, can persist long after a patient has technically recovered. Surviving T cells become exhausted through checkpoint pathways such as PD-1 and CTLA-4, the same molecular brakes that tumors exploit to escape immune attack. Regulatory T cells expand, dampening inflammatory responses but also blunting anti-tumor surveillance, and monocytes lose expression of human leukocyte antigen-DR, impairing their ability to present antigens and coordinate adaptive immunity.

The second arm of the triad concerns the vasculature. Sepsis inflicts direct injury on the endothelium, the single-cell lining of blood vessels that normally acts as a selective barrier and a gatekeeper for immune cell traffic. Glycocalyx degradation, endothelial activation, and increased vascular permeability allow plasma proteins and cells to leak into surrounding tissue. In the pre-metastatic niche literature, vascular leakiness and endothelial hyperadhesiveness are hallmark features that facilitate the extravasation of circulating tumor cells. The review argues that post-sepsis endothelium displays a functionally analogous phenotype: vessels that are more permeable, more adhesive to circulating myeloid cells, and less selective about what crosses them. Persistent recruitment of myeloid cells into tissues, a process sustained by altered chemokine signaling, mirrors the way tumors co-opt bone marrow–derived cells to prepare metastatic sites.

The third arm involves the extracellular matrix, the fibrous scaffold that gives tissues their architecture and mechanical properties. During sepsis, mesenchymal stromal cells and inflammatory extracellular vesicles drive the release of matrix metalloproteinases, enzymes that cleave collagen, laminin, and fibronectin. The result is a matrix that is mechanically unstable, abnormally permeable, and richly pro-adhesive, presenting cryptic binding sites and altered stiffness cues to any cell that encounters it. In established cancer biology, matrix remodeling of this kind lowers the barriers to tumor cell invasion and supports the survival of newly arrived malignant cells. The review proposes that a post-sepsis matrix, transiently or perhaps chronically remodeled, could create comparable conditions of systemic permissiveness, lowering tissue resistance to aberrant cellular persistence of many kinds.

What makes the framework scientifically interesting is its convergence logic. None of the individual components is novel; immunothrombosis, endothelial activation, lymphopenia, and matrix degradation are each well documented in sepsis research. The review’s contribution is to assemble them into a coordinated model and to point out that their combined output, endothelial hyperadhesiveness, reduced immune selectivity, persistent myeloid recruitment, and increased tissue susceptibility, is precisely the functional signature that tumor biologists use to define a pre-metastatic niche. In this reading, sepsis does not cause cancer directly, and the authors are careful to frame the triad as a host-conditioned state of biological plausibility rather than an oncogenic event. The claim is about vulnerability and permissiveness, not causation, and it is explicitly presented as a generator of testable hypotheses rather than a settled conclusion.

That framing matters, because the epidemiological question of whether sepsis survivors face elevated cancer risk remains open and contested in the broader literature. What the review offers is a mechanistic roadmap for investigating that question rigorously. If post-sepsis patients carry measurable, persistent signatures of niche-like priming, elevated circulating markers of endothelial activation, sustained shifts in lymphocyte subsets, altered matrix turnover products, then longitudinal cohort studies could track whether these signatures predict subsequent malignancy diagnoses. Such biomarkers would also serve a second purpose: stratifying the growing population of sepsis survivors, whose numbers have grown as intensive care keeps more patients alive, by their biological risk profile rather than by clinical appearance alone.

The clinical implications extend to post-sepsis recovery monitoring more broadly. Post-sepsis syndrome, encompassing cognitive decline, physical disability, and renewed susceptibility to infection, is increasingly recognized as a major public health burden, yet follow-up care for survivors remains fragmentary in most health systems. If the Immuno–Vascular–Matrix Triad proves measurable in routine clinical practice, it could anchor a new category of surveillance: not merely checking whether organs have recovered their function, but assessing whether tissues have returned to a state of immunological and structural integrity. Interventions that restore immune competence, protect the endothelium, or modulate matrix remodeling could then be evaluated for their ability to reverse primed tissue states before they translate into disease.

The authors are candid about the limits of their synthesis. It is a review, built on mechanistic reasoning across literatures that rarely speak to one another, and it does not present direct experimental evidence that sepsis-primed tissues accept circulating tumor cells more readily. Animal models that induce sepsis and then challenge animals with tumor cell lines would be an obvious next step, as would careful analysis of cancer incidence in large sepsis registries with adequate follow-up and control for confounders such as smoking, comorbidities, and post-sepsis surveillance bias, since survivors undergo more medical attention and thus more diagnosis. Even so, the conceptual payoff is considerable: it reframes sepsis not only as an acute crisis to survive but as a systemic remodeling event whose biological echoes may persist, and it hands researchers a concrete, three-part framework for testing whether the body’s fiercest inflammatory storm can quietly prepare the ground for its next great challenge.

Subject of Research: Post-sepsis tissue remodeling as a mimic of the pre-metastatic niche through immune, vascular, and extracellular matrix alterations

Article Title: Sepsis as a pre-metastatic niche mimic: post-sepsis microenvironmental priming through an Immuno–Vascular–Matrix Triad

Article References: Izquierdo-Condoy, J. S., Saavedra-Torres, J. S., Nati-Castillo, H. A., Gil, J. C., García-Aguilera, M. F., Alexander-León, H. A., Lara Puello, I. M., Vargas Saltos, M., & Ortiz-Prado, E. (2026). Sepsis as a pre-metastatic niche mimic: post-sepsis microenvironmental priming through an Immuno–Vascular–Matrix Triad. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08951-z

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08951-z

Keywords: sepsis, pre-metastatic niche, metastasis, immunothrombosis, immunodisruption, extracellular matrix remodeling, endothelial dysfunction, HMGB1, neutrophil extracellular traps, HIF-1α, matrix metalloproteinases, cancer microenvironment

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

The study, led by María Payá, Gemma Serrano-Heras, and Tomás Segura of the General University Hospital of Albacete and collaborators across Spain, compared cerebral thrombi from six pre-Omicron COVID-19 stroke patients with those from six matched non-infected controls treated at the same institutions. All patients had experienced acute ischemic stroke due to large vessel occlusion and underwent endovascular thrombectomy, during which the retrieved clot material was carefully preserved for research. Although the cohort was small, the breadth of analytical techniques applied to each thrombus was unusual: whole-slide digital imaging quantified immune cells, platelets, and red blood cells; transmission electron microscopy revealed clot architecture at nanometer resolution; liquid chromatography–tandem mass spectrometry with SWATH acquisition profiled more than 1,200 proteins; and total reflection X-ray fluorescence measured fifteen chemical elements.

Clinically, the contrast between the two groups was sobering. Twenty-four hours after treatment, COVID-19 patients had significantly worse neurological scores than controls, and at ninety days their functional outcomes, measured by the modified Rankin Scale, were markedly poorer. Cryptogenic stroke, in which no clear cause is identified, was the most common subtype in both groups. Routine blood counts showed no overt anemia or thrombocytopenia, but COVID-19 patients tended toward higher monocyte counts, elevated hemolysis indices, increased ferritin, and lactate dehydrogenase levels above the normal range, subtle laboratory signals hinting at red blood cell injury and iron release that had gone largely unrecognized at stroke presentation.

Under the microscope, the COVID-19 clots looked fundamentally different. Immunostaining for citrullinated histone H3 and myeloperoxidase showed similar burdens of neutrophil extracellular traps and neutrophils in both groups, but COVID-19 thrombi contained a trend toward more macrophages displaying a diffuse, scattered CD68 staining pattern suggestive of a hyperactivated state. Platelet content, quantified by CD61 staining, was reduced by roughly a third in the infected clots. Histology revealed an extracellular fibrillar matrix that was irregular and less densely packed, and electron microscopy confirmed a disordered ultrastructure: instead of the well-organized peripheral fibrin meshwork enclosing packed cellular regions seen in control clots, COVID-19 thrombi showed fibrillar material strewn chaotically through the section, along with numerous membrane protrusions resembling the filopodia of highly activated platelets.

The most striking discovery emerged from elemental and proteomic analysis. The COVID-19 clots had a distinctive dark-red, brownish coloration that persisted even in protein extracts, a visual clue typically pointing to heme pigments. Total reflection X-ray fluorescence confirmed markedly elevated iron concentrations: more than 80 percent of the COVID-19 thrombi exceeded nine sulfur-normalized units of iron, compared with fewer than 30 percent of controls, while all other measured elements were unchanged. Crucially, the excess iron could not be explained by a simple excess of red blood cells, because glycophorin A immunostaining showed comparable erythrocyte content in both groups.

Proteomics then revealed where that iron was coming from. Of 720 proteins shared between the two groups, 48 were significantly differentially expressed, and among the 28 upregulated in COVID-19 clots were the alpha, beta, gamma, and delta hemoglobin subunits, haptoglobin, biliverdin reductase B, and carbonic anhydrase 1, a signature of free hemoglobin and heme degradation. Because erythrocyte structural proteins such as spectrin, ankyrin-1, and band 3 were not differentially expressed, the hemoglobin within the COVID-19 thrombi appears to have been largely liberated from its cellular packaging, circulating in a cell-free form before being swept into the growing clot. The researchers also found proteins found exclusively in COVID-19 clots: classical complement components including C1QB, C1QC, and C1S, acute-phase reactants such as C-reactive protein and serum amyloid proteins, ubiquitin–proteasome components, and immunoglobulin chains, together painting a picture of intense immune-inflammatory activation and oxidative stress inside the infected thrombi.

How does free hemoglobin promote clotting? The authors draw on a substantial literature showing that cell-free and oxidized hemoglobin are potent procoagulant molecules. Free hemoglobin scavenges nitric oxide, promoting vasoconstriction, and it directly activates platelets by binding glycoprotein Ib alpha, while enhancing von Willebrand factor–mediated platelet adhesion and inhibiting ADAMTS13, the enzyme that normally regulates von Willebrand factor. Heme, its breakdown product, activates endothelial cells through TLR4, stimulates tissue factor expression, and triggers complement deposition on endothelial surfaces. Iron overload further damages endothelial mitochondria through reactive oxygen species. In this framework, the reduced platelet content seen in COVID-19 clots likely reflects platelet consumption and hyperactivation during widespread microthrombus formation rather than a quiet coagulation system, with the surviving platelets showing the morphological stress of filopodia formation observed by electron microscopy.

The source of the free hemoglobin remains an open question. The authors propose that SARS-CoV-2 infection may drive subclinical or compensated hemolysis through cytokine-mediated erythroid injury, complement attack on red blood cells, or direct viral effects on erythrocyte membrane integrity, mechanisms that previous proteomic and lipidomic studies have independently suggested. They caution that their observational design cannot prove causation, that the pre-Omicron viral strains studied may differ from current variants, and that the small sample size and selection of only fully analyzable thrombi impose limitations. Notably, the proteomic signature tracked infection status rather than stroke etiology, suggesting that the hemoglobin-iron enrichment is a distinctive feature of COVID-19 clots independent of the underlying embolic source.

Still, the implications are considerable. Retrieved thrombi are thought to preserve at least part of the molecular milieu present at the moment of clot formation, and the convergence of hemolysis markers, complement activation, antioxidant responses, and platelet depletion in these clots offers a coherent mechanistic account of COVID-19 immunothrombosis that goes beyond the traditional triad of endothelial injury, immune activation, and coagulopathy. If cell-free hemoglobin and iron indeed help drive the prothrombotic state, they become candidate therapeutic targets: haptoglobin infusion, heme-scavenging strategies, or iron-chelating approaches could, in principle, blunt thrombotic risk during severe viral infection. The authors call for larger multicenter studies to directly quantify circulating cell-free hemoglobin and iron-handling biomarkers in COVID-19 patients and to test whether targeting these pathways can reduce ischemic complications, including stroke, and improve the response of these unusually stubborn clots to thrombolysis and mechanical removal.

Subject of Research: Cell-free hemoglobin and iron accumulation in cerebral thrombi as drivers of the SARS-CoV-2-induced prothrombotic state in COVID-19 stroke patients

Article Title: High levels of cell-free hemoglobin and iron in cerebral thrombi of pre-Omicron COVID-19 stroke patients: novel drivers of SARS-CoV-2–induced prothrombotic state

Article References: Payá, M., Alcahut-Rodríguez, C., Barbella-Aponte, R. A., Hernández-Fernández, F., Molina-Nuevo, J. D., Barroso-García, G., Castro-Robles, B., López-López, S., Arias-Salazar, L., Ayo-Martín, Ó., García-García, J., Yélamos-Sanz, B., García-Flores, N., Arandilla, A. G., Moreno-Luna, R., Aliena-Valero, A., Vielba-Gómez, I., Tembl, J. I., Salom, J. B., … Segura, T. (2026). High levels of cell-free hemoglobin and iron in cerebral thrombi of pre-Omicron COVID-19 stroke patients: novel drivers of SARS-CoV-2–induced prothrombotic state. Acta Neuropathologica, 152(1), Article 26. https://doi.org/10.1007/s00401-026-03074-7

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03074-7

Keywords: COVID-19, stroke, cell-free hemoglobin, iron, cerebral thrombi, hypercoagulability, immunothrombosis, proteomics, complement activation, platelets, hemolysis, SARS-CoV-2