Page 3 of 25

PA20.1-2 | Normal Haemostasis — Part 2

Secondary Haemostasis: The Coagulation Cascade

The coagulation cascade converts the loose platelet plug into a stable, cross-linked fibrin clot. It is a series of enzymatic reactions where each activated factor (zymogen → serine protease) activates the next, producing enormous amplification.

Classically divided into three pathways:

Intrinsic pathway (contact activation):
XII → XI → IX; VIII is a cofactor for IXa
All factors in this pathway are measured by aPTT (activated partial thromboplastin time). Prolonged aPTT = defect in XII, XI, IX, or VIII.

Extrinsic pathway (tissue factor pathway):
Tissue factor (TF, aka Factor III) + VII → VIIa
This is the physiologically dominant initiating pathway. Measured by PT/INR (prothrombin time). Prolonged PT = defect in VII, or in the common pathway.

Common pathway:
X + Va (cofactor) → prothrombin (II) → thrombin → fibrinogen (I) → fibrin → cross-linked fibrin (XIII)
Affected by defects in X, V, II, I, or XIII. Prolonged PT + prolonged aPTT = common pathway defect.

IMPORTANT: Factor VII has the shortest half-life (~6 hours). Therefore, warfarin or vitamin K deficiency first prolongs the PT (extrinsic arm), before the aPTT.

Complete Coagulation Cascade: Classical Pathways, Thrombin Function, and Cell-Based Model

Thrombin: The Central Molecule of Haemostasis

Thrombin (activated factor IIa) is the pivotal effector of the coagulation cascade. It is not merely a fibrinogen-cleaver — it is a master amplifier:

1. Cleaves fibrinogen → fibrin monomers → polymerisation → soft clot
2. Activates factor XIII → cross-links fibrin → insoluble, stable clot
3. Activates factors V and VIII (positive feedback amplification of its own generation)
4. Activates platelets (via PAR-1 receptor) — the most potent platelet activator
5. Binds thrombomodulin on intact endothelium → activates Protein C (anticoagulant feedback)

Thrombin is simultaneously pro-coagulant (on damaged surfaces) and anti-coagulant (on intact endothelium). The local vascular context determines which role predominates.

The Cell-Based Model: How Coagulation Actually Works In Vivo

The classical cascade model (intrinsic vs. extrinsic pathways) is a lab construct, not a physiological reality. The modern cell-based model better explains why haemophilia A (factor VIII deficiency) causes severe bleeding even though factor VIII is 'only' in the intrinsic pathway.

The cell-based model has three phases:

1. Initiation — on tissue factor–bearing cells (fibroblasts, monocytes exposed at injury site):
TF + VIIa → small amounts of Xa, IIa (thrombin) — not enough for clot, but enough to prime platelets

2. Amplification — on activated platelets:
Thrombin activates VIII (from vWF–VIII complex), V, and XI on the platelet surface; platelet surface becomes a phospholipid scaffold

3. Propagation — on platelets:
IXa–VIIIa complex (tenase) + Xa–Va complex (prothrombinase) → explosive thrombin burst → fibrin clot

Clinical insight: Without factor VIII (haemophilia A), the tenase complex cannot form on the platelet surface during propagation → insufficient thrombin burst → clot forms but is fragile → deep tissue bleeding. The extrinsic pathway initiates normally (PT is normal), but the intrinsic/amplification arm collapses (aPTT is prolonged).