Convergence model of coagulation

Jun Yong
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, UK
Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, UK
- The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, UK

Cheng-Hock Toh
Contact Details: Department of Clinical Infection, Microbiology and Immunology,Ronald Ross Building, 8 West Derby St, Liverpool, L69 7BE, UK
Email: c.h.toh@liverpool.ac.uk

Increasingly recognized interplay between coagulation and innate immunity (immunothrombosis).
Proposes a convergent model of coagulation, linking inflammation and innate immunity in response to vascular injury.
Damage-associated molecular patterns (DAMPs) play a crucial role in wound healing and clot resolution.
Aims to develop novel diagnostics and therapeutics addressing medical challenges, including COVID-19 and vaccine-induced thrombotic conditions.

coagulation, damage-associated molecular patterns, histones, innate immunity, neutrophil extracellular traps, thrombin

Describes coagulation as inseparable from innate immune and inflammatory responses to injury.
Evolutionary coevolution of hemostatic, immune, and inflammatory responses rooted in a common ancestral response.

Crosstalk examples:
- Induction of monocytic tissue factor (TF) expression by IL-1 and type 1 IFN.
- α-thrombin triggering inflammation through protease-activated receptors (PARs).
- Anti-inflammatory effects of activated protein C (APC).

DAMPs recognized as critical in inflammation and innate immune responses.
Examples include cell-free histones, nucleic acids, HMGB1, and calprotectin.
Modulate coagulation enzyme kinetics and platelet surfaces, enhancing clot formation and potentially inhibiting clot resolution.

Procoagulant mechanisms of DAMPs can be explained within the cell-based model (CBM) framework.
- Initiation phase can be triggered by CFH and HMGB1.
- Amplification of thrombin spark involving platelet-von Willebrand factor axis activation.

NETs contribute significantly to clot formation by enhancing thrombin generation and promoting platelet activation.
Interaction examples include platelet-derived DAMPs activating neutrophils and influencing clot stability.

DAMPs facilitate complex interactions enhancing coagulation and inflammatory responses.

Upon injury, DAMPs induce TF and phosphatidylserine exposure on cell surfaces, enhancing procoagulant activity.
Reciprocally, activated platelets enhance neutrophil recruitment through DAMP release.

Highlights coagulation's role in responses to infections, including COVID-19 and sepsis-associated coagulopathy.
Past research emphasized the importance of anticoagulant proteins during sepsis, exploring therapeutic options.

Recent therapeutic failures suggest a need for deeper understanding of coagulation dynamics during critical illness.
The risks of bleeding and coagulation complications must be balanced with emerging therapeutic strategies.

Recognition of DAMPs in driving thrombotic risks leads to proposals for new therapeutic approaches across specialties.
The integration of innovative therapeutic strategies is needed to address complex coagulation syndromes.

The convergent model integrates current knowledge on coagulation emphasizing its relationship with inflammation and immune response.
Further interdisciplinary research is essential for developing new diagnostics and treatments for coagulation disorders.