Carrageenan-induced immunothrombotic models in rodents (Review).

Carrageenan (CGN)-induced immunothrombotic models are used in rodent thrombosis research. They enable both mechanistic dissection of inflammation-coagulation crosstalk and high-throughput screening of antithrombotic agents. The present narrative review summarizes current knowledge on modeling approaches, thrombotic mechanisms, quality determinants and translational relevance of the CGN model. CGN is a sulfated linear galactan that can be administered by intraperitoneal injection, tail vein injection or subcutaneous injection. Amongst these, intraperitoneal injection of κ-CGN (20-100 mg/kg in mice) is the most widely used due to its simplicity and superior reproducibility. Tail vein injection of CGN (1 mg/kg in rats) combined with ligation results in rapid model formation and is suitable for studying the intrinsic pathway of coagulation, whereas subcutaneous injection is mainly used for exploring mechanisms of local inflammatory thrombosis. By contrast, CGN combined with lipopolysaccharides can be used to establish a disseminated intravascular coagulation model, replicating consumptive coagulopathy and multi-organ microthrombosis. The thrombotic mechanisms of CGN involve Toll-like receptor 4/NF-κB pathway-mediated inflammatory cytokine release, upregulation of tissue factor and endothelial injury caused by the release of neutrophil extracellular traps following intraperitoneal CGN administration, direct activation of coagulation factor XII (which initiates the intrinsic coagulation pathway following tail vein administration) and direct activation of the platelet C-type lectin-like receptor 2 pathway. Model quality is influenced by multiple factors, including the subtype and molecular weight of CGN, animal strain (Kunming mice have the highest sensitivity), sex, age, administration parameters and observation time window (24-72 h). This model simulates the pathological process of sterile inflammation-driven thrombosis and shares similar mechanisms with clinical conditions, such as antiphospholipid syndrome and severe Coronavirus disease-19 coagulopathy. However, limitations exist in terms of anatomical site, hemodynamics, chronic etiology and species differences, which restrict its direct extrapolation to clinical settings. The adoption of a multi-model validation strategy and screening of target patient populations based on inflammatory markers are recommended to improve clinical translation.