ArticleJCI insight2018
Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers.
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Who cites it
121 citing papers in PubMed, 177 citations in OpenAlex.
- C1-inhibitor treatment in patients with severe complement-mediated autoimmune hemolytic anemia.Blood advances · 2023Trial
- 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 · 2026Article
- Antibody-Dependent and Antibody-Independent Hemolysis in Sickle Cell Disease.Antibodies (Basel, Switzerland) · 2026Review
- In Vitro Hemolytic Performance of the Novel Realheart Total Artificial Heart Versus SynCardia Total Artificial Heart With Human Blood.Artificial organs · 2026Article
- Effect of C5a Receptor Antagonist on the Osteogenic Differentiation of Dental Pulp Stem Cells.Clinical and experimental dental research · 2026Article
- Sickle cell disease-associated pulmonary hypertension: an integrated framework linking pathologies, mechanisms, and clinical phenotypes.EBioMedicine · 2026Review
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- Proteomic Analysis of Golden Sputum Reveals Pulmonary Complement Activation During Acute Chest Syndrome in Children With Sickle Cell Disease.American journal of hematology · 2026Article
- Comprehensive analysis of complement activation in a hydroxyurea-treated patient cohort with sickle cell disease.Blood advances · 2026Article
- Complement in acute kidney injury: a convergent pathogenic pathway in multifactorial renal damage.Frontiers in immunology · 2026Review
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- Article
- Emerging pathways in thromboinflammation of sickle cell disease: novel findings in disease pathogenesis.Research and practice in thrombosis and haemostasis · 2025Review
- HCAR2 is a novel receptor for heme.Blood advances · 2025Article
- Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target.Science translational medicine · 2025Article
- Nitrated fatty acids protect against acute kidney injury in sickle cell disease.Blood advances · 2025Article
- Transcriptomic atlas reveals organ-specific disease tolerance in sickle cell mice.Blood advances · 2025Article
- Transsulfuration pathway activation attenuates oxidative stress and ferroptosis in sickle primary erythroblasts and transgenic mice.Communications biology · 2025Article
- CD47 regulates antigen modulation and red blood cell clearance following an incompatible transfusion.Frontiers in immunology · 2025Article
61 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
26 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In hemolytic diseases, such as sickle cell disease (SCD), intravascular hemolysis results in the release of hemoglobin, heme, and heme-loaded membrane microvesicles in the bloodstream. Intravascular hemolysis is thus associated with inflammation and organ injury. Complement system can be activated by heme in vitro. We investigated the mechanisms by which hemolysis and red blood cell (RBC) degradation products trigger complement activation in vivo. In kidney biopsies of SCD nephropathy patients and a mouse model with SCD, we detected tissue deposits of complement C3 and C5b-9. Moreover, drug-induced intravascular hemolysis or injection of heme or hemoglobin in mice triggered C3 deposition, primarily in kidneys. Renal injury markers (Kim-1, NGAL) were attenuated in C3-/- hemolytic mice. RBC degradation products, such as heme-loaded microvesicles and heme, induced alternative and terminal complement pathway activation in sera and on endothelial surfaces, in contrast to hemoglobin. Heme triggered rapid P selectin, C3aR, and C5aR expression and downregulated CD46 on endothelial cells. Importantly, complement deposition was attenuated in vivo and in vitro by heme scavenger hemopexin. In conclusion, we demonstrate that intravascular hemolysis triggers complement activation in vivo, encouraging further studies on its role in SCD nephropathy. Conversely, heme inhibition using hemopexin may provide a novel therapeutic opportunity to limit complement activation in hemolytic diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.