Introduction
The cell-based model of coagulation offers a physiologically accurate and clinically relevant framework for understanding hemostasis. First proposed by Hoffman and Monroe (2001), this model emphasizes the importance of cell surfaces—especially tissue factor (TF)-bearing cells and activated platelets—as platforms for the regulation of coagulation. Unlike the classic “intrinsic/extrinsic” cascade model, the cell-based model explains how clotting is localized to the site of vascular injury and why some coagulation factor deficiencies have unexpected clinical phenotypes.
Limitations of the Classic Cascade Model
The traditional model divides coagulation into intrinsic, extrinsic, and common pathways, reflecting how coagulation factors interact in test tubes. While helpful for interpreting plasma-based assays like PT and aPTT, it does not reflect the cell-dependent and surface-anchored nature of coagulation that occurs in vivo.
For example: in the older ‘cascade model’, in the intrinsic pathway, the process appears to be led by factor XII. In the ‘cascade,’ factor XIa appears essential, but congenital factor XI deficiency rarely causes severe bleeding. Conversely, deficiencies in platelet function or tissue factor exposure—underemphasized in the cascade model—can be profoundly hemostatic. The cell-based model helps correct this disconnect.
Three Phases of the Cell-Based Model
1. Initiation (On TF-bearing cells)
Hemostasis begins when vascular injury exposes tissue factor (TF) on subendothelial cells (e.g., fibroblasts). Circulating factor VIIa rapidly binds to TF, forming the TF–VIIa complex, which activates factor X to Xa, as well as factor IX to IXa.
Factor Xa on the TF-bearing cell surface associates with factor Va to form an ‘extrinsic tenase’ or prothrombinase complex, generating small amounts of thrombin (factor IIa). This initial thrombin is weak and insufficient for clot formation but is critical for activating platelets and cofactors V and VIII, setting the stage for amplification.
Regulation and Localization: When factor Xa or TF–VIIa complexes move away from the injury site, they are quickly inactivated by tissue factor pathway inhibitor (TFPI) and antithrombin. This mechanism ensures that coagulation remains limited to the site of injury.
2. Amplification (On activated platelets)
Thrombin generated during initiation activates:
- Platelets, causing shape change, granule release, and formation of a phospholipid surface suitable for factor activation and platelet adherence.
- Factor V → Va, factor VIII → VIIIa, and factor XI → XIa (on platelet surfaces).
This phase prepares the platelet surface for the explosive generation of thrombin that follows. Importantly, factor XI is activated by thrombin, not by factor XIIa as previously thought. FXI deficiency causes only mild bleeding; it is not the only source of factor IX activation which, as part of the intrinsic tenase complex, is a significant contributor to the process of clot generation.
3. Propagation (On activated platelets)
With the support of cofactors and activated platelets, intrinsic tenase (IXa-VIIIa) and extrinsic tenase or prothrombinase (Xa-Va) complexes assemble on the platelet surface. These dramatically accelerate the production of Factor Xa and Thrombin.
This thrombin burst rapidly converts fibrinogen to fibrin to form the clot. It also activates factor XIII to support fibrin cross-linking which stabilizes the clot.
Importantly, these complexes form only on activated platelet surfaces, helping to explain how the coagulation system is generated and amplified locally, and limited from occurring systemically.
Clinical Relevance of the Cell-Based Model in Patient Blood Management
- It explains why clotting is localized: this is due to procoagulant activity being tied to cellular membranes and being neutralized or inactivated in the plasma (when away from cell surfaces).
- It aligns with viscoelastic assays (e.g., TEG, ROTEM), which assess platelet–fibrin interactions and the dynamics of thrombin.
- It offers a rationale for factor deficiencies:
- Factor XI deficiency: mild bleeding because thrombin can propagate clotting without reliance on FXI.
- Factor VIII or IX deficiency (Hemophilia A/B): severe bleeding, due to impaired propagation.
- Platelet dysfunction: profound bleeding risk due to loss of key amplification/propagation surfaces.
Key References
- Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemost. 2001;85(6):958–965.
- Monroe DM, Hoffman M. The clotting system—a major player in wound healing. Haemophilia. 2012;18 Suppl 5:11–16.
- Weitz JI, Fredenburgh JC. Factors XI and XII as targets for new anticoagulants. Front Med. 2017;4:19.
- Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost. 1999;82(2):165–174.
