Haematology & coagulation cascade physiology

Why this matters to the anaesthetist

Primary science wants primary vs secondary haemostasis, the intrinsic/extrinsic/common pathways (even if cell-based models are more modern), which test covers which path, and natural anticoagulants/fibrinolysis. Final applies the same map to bleeding, VTE, neuraxial timing, and massive transfusion. Do not recite a biochemistry textbook — recite a teachable cascade with clinical hooks.[1]

One-liner: Injury → platelet adhesion/activation/aggregation (primary) → tissue factor starts thrombin burst → fibrin mesh (secondary) → antithrombin/protein C/S limit spread → plasmin dissolves clot when the job is done. [1]

Primary haemostasis — the platelet plug

1. Endothelial breach exposes collagen and vWF.
2. Adhesion: GPIb–vWF–collagen bridge (Bernard–Soulier if GPIb deficient).
3. Activation: shape change, release of ADP, TXA2, serotonin; GPIIb/IIIa activation.
4. Aggregation: fibrinogen bridges GPIIb/IIIa between platelets (Glanzmann if GPIIb/IIIa deficient).
5. Platelet phospholipid surface becomes the platform for coagulation complexes (link to secondary haemostasis). [1]

Drugs on primary haemostasis: aspirin (irreversible COX-1 → ↓TXA2), P2Y12 inhibitors (clopidogrel etc.), GPIIb/IIIa inhibitors, and quantitative thrombocytopenia. [1]

vWF roles: platelet adhesion and carrier for factor VIII (von Willebrand disease: mucocutaneous bleeding ± low VIII). [1]

Secondary haemostasis — classical cascade (exam map)

Extrinsic (tissue factor) pathway

Tissue factor (III) + VIIa → activates X (and IX). PT/INR screens this path (VII short half-life — first to fall with warfarin/vitamin K deficiency). [1]

Intrinsic (contact) pathway

XII → XI → IX (+ VIII as cofactor) → X. APTT screens this path (and heparin, lupus anticoagulant, VIII/IX/XI deficiency). XII deficiency prolongs APTT without clinical bleeding — classic trap. [1]

Common pathway

X (+ V) → prothrombin (II) → thrombin → fibrinogen (I) → fibrin monomers → polymer; XIII cross-links fibrin (stabilises clot; XIII not well seen on PT/APTT). [1]

Thrombin’s many jobs (viva gold): cleaves fibrinogen; activates V, VIII, XI, XIII; potent platelet activator; when bound to thrombomodulin, activates protein C (negative feedback). [1]

Cell-based model (one paragraph for modern viva)

Initiation on TF-bearing cells → amplification on platelet surfaces → propagation with thrombin burst. Explains why isolated factor tables miss the living process, but you still need the classical map for tests and drug targets. [1]

Natural anticoagulants

Fibrinolysis

Plasminogen → plasmin (tPA, uPA). Plasmin degrades fibrin → D-dimers/FDP. TAFI, PAI-1, α2-antiplasmin restrain fibrinolysis. Hyperfibrinolysis (trauma, liver disease, thrombolysis) → bleeding; antifibrinolytics (tranexamic acid) block plasminogen activation/binding — major anaesthetic drug. [1]

Laboratory tests — what they do and do not tell you

Anticoagulant and antiplatelet physiology targets

• Warfarin: inhibits vitamin K epoxide reductase → ↓II, VII, IX, X, protein C/S.
• Heparin: AT-dependent anti-IIa/Xa; APTT (UFH) or anti-Xa.
• LMWH/fondaparinux: preferential anti-Xa.
• DOACs: direct Xa or IIa inhibitors.
• Aspirin/P2Y12: primary haemostasis.
• Thrombolytics: drive plasmin generation. [1]

Neuraxial timing tables are applied pharmacology on top of this physiology — know half-lives/offset conceptually and follow ASRA/national guidance in clinical leaves. [1]

Anaesthetic relevance board

• Surgical haemostasis needs platelets + factors + fibrinogen + controlled fibrinolysis.
• Massive transfusion: dilute factors/platelets/fibrinogen; citrate; TXA early in trauma protocols.
• Liver failure: synthetic failure (factors, AT, proteins C/S, fibrinogen) + variable fibrinolysis + portal thrombocytopenia/splenomegaly.
• DIC: consumption + fibrinolysis — prolonged times, low platelets/fibrinogen, high D-dimer.
• Obstetric: hypercoagulable baseline; fibrinogen critical in PPH.
• CPB: heparin + AT, then protamine; platelet dysfunction from circuit. [1]

Numbers board

• Normal platelet count ~150–400 × 10⁹/L; many procedures tolerate lower with context.
• Fibrinogen critical often discussed around <1.5–2.0 g/L in bleeding (context-specific).
• Factor VII half-life short (~4–6 h) — INR rises first on warfarin.
• Factor II half-life long (~60 h) — full warfarin effect delayed. [1]

[1] [1] [1]

Viva draw / SAQ scripts

Draw Y-shaped cascade with APTT and PT limbs labelled and heparin/warfarin marks. [1]

Explain why warfarin needs overlap with heparin when treating acute VTE (protein C short half-life → early hypercoagulable window). [1]

Cell-based vs cascade: initiation/amplification/propagation in three sentences. [1]

TXA mechanism and trauma timing principle. [1]

Extended viva dialogue

Examiner: Walk me from vessel injury to a stable clot. [1]

Candidate: Platelets adhere via vWF and collagen receptors, activate and aggregate to form a primary plug. Tissue factor generates small thrombin, which amplifies on platelet surfaces to a thrombin burst converting fibrinogen to fibrin; factor XIII cross-links fibrin. Antithrombin and protein C systems limit spread; later tPA-driven plasmin remodels the clot. [1]

Examiner: Which tests for heparin and warfarin? [1]

Candidate: Unfractionated heparin mainly prolongs APTT (or use anti-Xa); warfarin prolongs PT/INR because factor VII falls quickly. Neither test assesses platelet function. [1]

Clinical synthesis: If you own primary plug, thrombin burst, inhibitors, fibrinolysis, and what each test sees, you can reason any coagulopathy stem. [1]

Cell-based model — three stages for modern viva

1. Initiation: TF-bearing cells + VIIa generate small Xa/thrombin.
2. Amplification: thrombin activates platelets, V, VIII, XI on platelet surfaces.
3. Propagation: tenase and prothrombinase complexes on activated platelets create thrombin burst → fibrin. [1]

This explains why haemophilia (VIII/IX) bleeds despite intact “extrinsic” initiation — amplification/propagation on platelets fails. [1]

Vitamin K cycle

Reduced vitamin K is cofactor for γ-carboxylation of factors II, VII, IX, X and proteins C/S. Warfarin inhibits epoxide reductase → depleted reduced vitamin K. Vitamin K and PCC/FFP reverse depending on urgency. [1]

Worked SAQ

SAQ: Describe primary haemostasis and name two drug targets (7 marks)

Endothelial injury exposes collagen and vWF. Platelets adhere via GPIb–vWF, activate, release ADP and TXA2, and aggregate via GPIIb/IIIa–fibrinogen bridges, forming a primary plug and providing phospholipid surface for coagulation. Aspirin inhibits platelet COX-1 reducing TXA2; P2Y12 inhibitors block ADP amplification; GPIIb/IIIa inhibitors block aggregation. [1]

Primary exam expansion — dense examiner pack

Haemostasis phases (modern cell-based model + classic cascade)

1. Endothelial injury / vasoconstriction. 2. Primary haemostasis: platelet adhesion (GPIb–vWF), activation, aggregation (GPIIb/IIIa–fibrinogen). 3. Secondary haemostasis: thrombin burst generation of fibrin. 4. Stabilisation FXIIIa cross-links fibrin. 5. Regulation/fibrinolysis: protein C/S, antithrombin, TFPI; plasminogen → plasmin. [1]

Classic intrinsic (XII, XI, IX, VIII) vs extrinsic (VII + tissue factor) converge at X → Xa + V → prothrombinase → thrombin (II) → fibrinogen to fibrin. Cell-based model emphasises tissue factor–bearing cells and platelet surfaces — better explains why XII deficiency does not bleed much in vivo. [1]

Platelet physiology

Lifespan ~7–10 days; count 150–400 × 10^9/L teaching. Dense granules ADP/serotonin; alpha granules vWF/fibrinogen/factor V. Drugs: aspirin irreversible COX-1 (TXA2↓); clopidogrel P2Y12; GPIIb/IIIa inhibitors; desmopressin releases vWF (useful in mild haemophilia A/vWD selected cases). [1]

Lab tests mapping

Vitamin K dependent factors

II, VII, IX, X + proteins C/S. Warfarin inhibits vitamin K epoxide reductase → falls first in shortest half-life (VII, protein C) — transient hypercoagulable risk → heparin bridge contexts. Reversal: vitamin K, PCC (preferred emergency), FFP if PCC unavailable. [1]

Heparin and antithrombin

UFH potentiates antithrombin against IIa and Xa; LMWH anti-Xa > IIa; fondaparinux pure anti-Xa. HIT type II: antibodies to PF4–heparin → thrombosis paradox — stop heparin, use alternative anticoagulant. Protamine reverses UFH (partly LMWH); risk anaphylactoid/pulmonary hypertension especially prior sensitisation/NPH insulin history teaching. [1]

Hypercoagulable states and periop VTE physiology

Virchow: stasis, endothelial injury, hypercoagulability. Surgery adds all three. Prophylaxis mechanical + pharmacological balance bleeding risk. Neuraxial timing with anticoagulants — sister safety topic. [1]

DIC physiology

Widespread TF drive → consumption of platelets/factors → thrombosis microvasculature + bleeding. Causes: sepsis, trauma, amniotic fluid embolism, malignancy, mismatched transfusion. Labs: ↓platelets, ↑PT/APTT, ↓fibrinogen, ↑D-dimer/FDPs. Treat cause; support components; heparin rare selected thrombotic phenotypes. [1]

Massive haemorrhage physiology

Lethal triad: hypothermia, acidosis, coagulopathy. Damage-control resuscitation: limit crystalloid, balanced ratios, early fibrinogen, calcium (citrate bind), tranexamic acid antifibrinolysis (time-critical trauma/obstetric evidence base). Viscoelastic-guided algorithms increasingly standard. [1]

SAQ: describe coagulation pathways and point of action of heparin and warfarin (10 marks)

Cascade/cell-based outline (4). Heparin–antithrombin (2). Warfarin–vitamin K factors (2). Monitoring PT vs APTT/ACT (2). [1]

Viva

Q: Why does warfarin raise INR? A: Depletes factor VII (and others) — PT sensitive to extrinsic path. Q: Why can HIT cause thrombosis? A: Antibody-mediated platelet activation. Q: Which factor deficiency prolongs APTT but little bleeding? A: Factor XII (contact pathway) teaching contrast with VIII/IX. [1]

High-yield viva battery and numbers lock-in

Factor half-life teaching (why INR rises first on warfarin)

Factor VII shortest among vitamin K factors → PT/INR prolongs early. Full anticoagulant effect needs II, IX, X decline. Protein C also short → early transient hypercoagulability possible. [1]

Trauma coagulopathy pillars

Tissue injury TF exposure; shock/hypoperfusion-activated protein C pathway acute traumatic coagulopathy; dilution from crystalloid; hypothermia; acidosis; hypocalcaemia from citrate; hyperfibrinolysis in some phenotypes — TXA logic early. [1]

Viscoelastic trace interpretation skeleton

Prolonged R/CT → clotting factor problem/heparin; low α angle/k → fibrinogen problem; low MA/MCF → platelets (±fibrinogen); high LY30/LI30 → fibrinolysis. Algorithms guide plasma, cryoprecipitate/fibrinogen concentrate, platelets, TXA. [1]

Full viva dialogue (additional)

Examiner: Where does heparin act and how do we reverse it? [1]

Candidate: Unfractionated heparin potentiates antithrombin, accelerating inactivation of thrombin and factor Xa. We monitor with APTT or ACT depending on dose context. Protamine forms an inactive complex with heparin; dose roughly matches circulating heparin, and excess protamine can itself anticoagulate mildly and cause pulmonary hypertension or anaphylactoid reactions. [1]

Examiner: Why is the intrinsic/extrinsic cascade incomplete as a story? [1]

Candidate: It explains PT and APTT well but not biology: factor XII deficiency markedly prolongs APTT without severe bleeding, and in vivo initiation is largely tissue-factor driven on cell surfaces with amplification on platelets — the cell-based model. [1]

Exam traps

• Equating INR with full bleeding risk in cirrhosis.
• Giving platelets for all high INR.
• Forgetting calcium in massive transfusion.
• Using cryoprecipitate thinking without fibrinogen level/ROTEM. [1]

References

1. [1]Capecchi M, et al. Involvement of the contact pathway in COVID-19 coagulopathy Intern Emerg Med, 2025.PMID 41206422
2. [2]Stoj KM. Factor V Deficiency 2026.PMID 35593819
3. [3]Zhu Y, et al. Epithelial SERPINB2 Overexpression Contributes to Impaired Fibrinolysis in Chronic Rhinosinusitis With Nasal Polyps via tPA Downregulation Front Biosci (Landmark Ed), 2026.PMID 42216541
4. [4]Iba T, et al. Redefining Fibrinolytic Insufficiency in Sepsis-Associated DIC Semin Thromb Hemost, 2026.PMID 41956121
5. [5]Takenaka R, et al. Prolonged low-dose tPA ameliorates coagulopathy and organ injury in an LPS-induced rat DIC model Int J Hematol, 2026.PMID 41801558
6. [6]Furman K, et al. A review of the perioperative management of direct oral anticoagulants for pediatric anesthesiologists Paediatr Anaesth, 2024.PMID 39244715