[The Functional Roles and the Potential as Drug Targets of Glycoproteins Regulating Complement and Coagulation
1Department of Clinical Pharmacy, School of Medicine, Fujita Health University.
Insights
Chondroitin sulfate (CS) may treat disseminated intravascular coagulation (DIC) by binding extracellular histones. CS offers a safer alternative to heparin for patients with DIC at high bleeding risk.
Area of Science:
- Immunology and hematology
- Molecular biology
- Pathophysiology
Context:
- Complement (C) and coagulation systems interact, contributing to inflammation and tissue injury.
- Disseminated intravascular coagulation (DIC) involves dysregulated coagulation and systemic inflammation, exacerbated by complement-coagulation crosstalk.
- Extracellular histones act as damage-associated molecular patterns, promoting thrombosis and interacting with complement component 5 (C5).
Purpose:
- To explore the therapeutic potential of chondroitin sulfate (CS) in treating DIC.
- To investigate the role of complement receptor type-1-related gene Y (Crry) in endothelial cell complement activation.
- To identify potential therapeutic targets for acute lung injury related to complement activation.
Summary:
- Extracellular histones drive thrombosis, with C5 mediating lethal histone-induced thrombosis. Heparin and CS bind histones; CS shows promise for DIC treatment due to less impact on coagulation compared to heparin.
- Crry inhibits classical and alternative complement pathways by binding C3b and C4b. Endothelial damage from histones reduces Crry expression, promoting complement activation on endothelial cells.
- Preventing C3 cleavage on endothelial cells may offer a therapeutic strategy for acute lung injury.
Impact:
- Chondroitin sulfate (CS) presents a potential therapeutic agent for disseminated intravascular coagulation (DIC), particularly in patients prone to bleeding.
- Understanding Crry's role in endothelial complement activation could lead to novel treatments for inflammatory conditions.
- Targeting complement component C3 cleavage on endothelial cells may represent a new therapeutic avenue for acute lung injury.
Abstract:
Complement (C) activation occurs via three pathways, namely the classical, lectin, and alternative pathways. Intercommunication occurs between the complement and coagulation systems, which can trigger tissue injury and inflammation. Disseminated intravascular coagulation (DIC) is a life-threatening disease characterized by disordered coagulation and systemic inflammation; here, the intercommunication between the complement and coagulation systems contributes to the development of DIC. Extracellular histones, which are contributors to the damage-associated molecular pattern, induce severe thrombosis. C5 is a key molecule in the intercommunication between the complement and coagulation systems and is associated with the development of lethal histone-induced thrombosis. Heparin and chondroitin sulfate (CS) are negatively charged, allowing them to bind to extracellular histones. As the coagulation system is less affected by CS than heparin, CS shows potential as an effective drug for the treatment of patients with DIC who have a high risk of bleeding. Complement receptor type-1-related gene Y (Crry) inhibits the complement pathway via binding to C3b and C4b. Hence, Crry is a potent inhibitor of the classical and alternative C pathways. The expression of Crry is decreased by the endothelial damage induced by extracellular histones. Crry dysfunction promotes the activation of C on the surface of endothelial cells. The prevention of C3 cleavage on endothelial cells might be a useful therapy targeting acute lung injury.
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