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PA20.1 | Normal Haemostasis — SDL Guide (Part 3)

Fibrinolysis: Dissolving the Clot

A three-panel medical diagram shows plasminogen activation to plasmin, fibrin clot breakdown into FDPs and D-dimer, clinical D-dimer use, and inhibition by PAI-1 and alpha-2-antiplasmin. — **Panel A:** Complete fibrinolytic pathway showing plasminogen to plasmin conversion by tPA/uPA, plasmin-mediated fibrin cleavage, FDPs, and D-dimer formation.. **Panel B:** Clinical relevance showing D-dimer testing for suspected DVT/PE, with emphasis on high sensitivity and low specificity.. **Panel C:** Regulation of fibrinolysis showing PAI-1 inhibition of tPA/uPA and alpha-2-antiplasmin inhibition of free plasmin..

Once wound healing is underway, the fibrin clot must be dissolved. The fibrinolytic system prevents excessive clotting and restores vessel patency.

Key pathway:
Plasminogen (inactive) → plasmin (active serine protease)

Activators:
• tPA (tissue plasminogen activator) — released by endothelial cells; the therapeutic principle behind alteplase in acute MI/stroke
• uPA (urokinase-type plasminogen activator)

Plasmin cleaves fibrin → fibrin degradation products (FDPs) and D-dimer (a cross-link-specific FDP)

D-dimer is clinically important: its elevation confirms active fibrinolysis (clot formation AND dissolution). It is used as a sensitive screening test for DVT/PE — but it is non-specific (elevated in many inflammatory states).

Inhibitors of fibrinolysis:
• PAI-1 (plasminogen activator inhibitor-1): inhibits tPA/uPA
• α₂-antiplasmin: directly inhibits free plasmin

Flowchart diagram showing the fibrinolytic pathway with plasminogen activation, fibrin cleavage, and regulatory inhibitors PAI-1 and α2-antiplasmin. — **Panel A:** Complete fibrinolytic pathway showing plasminogen→plasmin conversion via tPA/uPA, fibrin cleavage to FDPs and D-dimer, with PAI-1 and α2-antiplasmin inhibition.

Natural Anticoagulant Mechanisms

⚑ AI image — pending faculty review (auto-QA score 6/10; best of 3 attempts)

A four-panel diagram shows how antithrombin, the Protein C/S pathway, and TFPI inhibit coagulation and prevent thrombosis in intact vessels. — **Panel A:** Intact endothelium, low-level thrombin generation, factor Xa, small fibrin signal, Antithrombin shield, Protein C/S shield, TFPI shield, prevented thrombus expansion. **Panel B:** Antithrombin III, heparin, thrombin IIa, Xa, IXa, XIa, XIIa, neutralised serine proteases, antithrombin deficiency thrombophilia note. **Panel C:** Thrombin, thrombomodulin, Protein C, activated Protein C, Protein S cofactor, Factor Va, Factor VIIIa, prothrombinase complex, tenase complex, Factor V Leiden resistance inset. **Panel D:** Tissue factor, Factor VIIa, Factor Xa, TFPI, inhibited TF-VIIa-Xa complex, small initial thrombin burst, extrinsic pathway shutdown, warfarin initiation clinical pearl.

Coagulation is continuously activated at low levels. The natural anticoagulant system prevents runaway thrombosis in intact vessels. Three major mechanisms:

1. Antithrombin (AT-III)
A serine protease inhibitor (serpin) that neutralises thrombin, Xa, IXa, XIa, XIIa. Its activity is dramatically potentiated by heparin — the therapeutic basis of unfractionated and low-molecular-weight heparin. Antithrombin deficiency → thrombophilia.

2. Protein C / Protein S pathway
• Thrombin binds thrombomodulin on intact endothelium → activates Protein C
• Activated Protein C (aPC) + Protein S (cofactor) → degrades Va and VIIIa → shuts down the prothrombinase and tenase complexes
• Factor V Leiden (Arg506Gln mutation) renders Va resistant to aPC → most common inherited thrombophilia (5% of Europeans)
• Protein C and S are vitamin K–dependent: warfarin depletes them before depleting pro-coagulant factors, paradoxically causing a brief hypercoagulable state at warfarin initiation

3. Tissue Factor Pathway Inhibitor (TFPI)
Produced by endothelial cells; directly inhibits the TF–VIIa–Xa complex, shutting down extrinsic pathway initiation after the first small burst of thrombin is generated. This is why the extrinsic pathway alone cannot sustain a clot — the cell-based amplification/propagation phases (intrinsic arm) are essential.

CLINICAL PEARL

Warfarin paradox at initiation: Protein C has the shortest half-life among vitamin K–dependent proteins (~8 hours). When warfarin is started, Protein C is depleted before the pro-coagulant factors II, IX, and X. This transiently tips the balance toward thrombosis — the mechanism of warfarin-induced skin necrosis, which occurs in protein C–deficient patients given warfarin without heparin bridging. This is why heparin overlap for 4–5 days is mandatory when starting warfarin therapy.

Vitamin K–Dependent Clotting Factors

A four-panel infographic explains how vitamin K enables γ-carboxylation of clotting factors, lists vitamin K–dependent procoagulant and anticoagulant proteins, shows warfarin blocking VKOR, and summarizes deficiency-related clinical effects. — **Panel A:** Vitamin K cofactor, γ-glutamyl carboxylase, glutamate residues, Gla residues, Ca²⁺ binding, phospholipid membrane assembly, active clotting factor. **Panel B:** Pro-coagulant factors II, VII, IX, X; mnemonic 1972; anticoagulant proteins Protein C and Protein S. **Panel C:** Vitamin K epoxide, VKOR, reduced Vitamin K, warfarin blockade, depletion of II, VII, IX, X, Protein C, Protein S. **Panel D:** Vitamin K deficiency causes, prolonged PT and aPTT, neonatal haemorrhagic disease, prophylactic IM vitamin K at birth, VKORC1 and CYP2C9 polymorphisms.

Vitamin K (fat-soluble) is a cofactor for the enzyme that adds γ-carboxyglutamate (Gla) residues to clotting factors. These Gla residues allow the factors to bind calcium and assemble on phospholipid membranes — essential for their activity.

Vitamin K–dependent pro-coagulant factors: II (prothrombin), VII, IX, X — mnemonic: '1972' (I=1, reversed; 9, 7, 2)

Vitamin K–dependent anticoagulant proteins: Protein C, Protein S

Clinical implications:
• Warfarin blocks vitamin K epoxide reductase (VKOR), depleting all six proteins above
• Vitamin K deficiency (malabsorption, prolonged antibiotics, newborn — physiological) → depletes all six → prolonged PT and aPTT
• Neonatal haemorrhagic disease (vitamin K deficiency of the newborn) — prevented by prophylactic IM vitamin K at birth, now standard of care
• VKORC1 and CYP2C9 polymorphisms explain the enormous inter-individual variation in warfarin dosing