Haemostasis & Coagulation

Haemostasis is the physiological process that arrests bleeding from an injured vessel while keeping blood fluid within the circulation. It proceeds in tightly regulated phases — vascular, platelet (primary), coagulation (secondary), and fibrinolytic — and its bench-side translation (PT, APTT, BT, platelet count) is one of the most repeatedly tested clusters in NEET PG Physiology and Pathology.

Overview & classification

Haemostasis is conventionally divided into stages that occur in rapid, overlapping succession:

1. Vascular phase — immediate reflex vasoconstriction (neurogenic + endothelin + thromboxane A2 / serotonin from platelets) reduces blood loss.
2. Primary haemostasis — platelet adhesion, activation, and aggregation form a fragile platelet plug. Mediated by von Willebrand factor (vWF), GP Ib, and GP IIb/IIIa.
3. Secondary haemostasis (coagulation) — the coagulation cascade generates thrombin, which converts fibrinogen to fibrin, stabilising the plug.
4. Fibrinolysis — plasmin degrades fibrin to allow vessel recanalisation and wound remodelling once healing is underway.

High-yield: Primary haemostasis = platelet plug (vessel + platelets + vWF). Secondary haemostasis = fibrin clot (coagulation factors + thrombin). A defect in primary haemostasis gives mucocutaneous bleeding + prolonged bleeding time; a defect in secondary haemostasis gives deep tissue / joint bleeds + prolonged PT/APTT.

Primary haemostasis — platelet plug formation

Platelets are anucleate fragments (life span 7–10 days, normal count 1.5–4.5 lakh/µL) of megakaryocytes. The sequence is Adhesion → Activation → Aggregation:

• Adhesion: Endothelial injury exposes subendothelial collagen. vWF (made by endothelium [Weibel–Palade bodies] and megakaryocytes) bridges collagen to the platelet GP Ib (Ib-IX-V complex) receptor. This is the rate-limiting tethering step under high shear (arterial flow).
• Activation: Platelets change shape, release granule contents, and synthesise thromboxane A2 (via COX-1). Key second messengers — ADP (acts on P2Y12 receptor) and TXA2 — amplify recruitment.
• Aggregation: Activated GP IIb/IIIa (integrin αIIbβ3) receptors bind fibrinogen, cross-linking adjacent platelets into a plug.

Platelet granules:

Granule	Key contents
Dense (δ) granules	ADP, ATP, serotonin, calcium
Alpha (α) granules	vWF, fibrinogen, factor V, PDGF, P-selectin, β-thromboglobulin

High-yield: Drug–receptor mapping is a favourite — Aspirin → COX-1 (blocks TXA2); Clopidogrel / prasugrel / ticagrelor → P2Y12 (ADP); Abciximab / eptifibatide / tirofiban → GP IIb/IIIa; Dipyridamole → phosphodiesterase / adenosine uptake.

Mnemonic for dense granule contents — "CADS": Calcium, ADP, ATP, Serotonin.

Secondary haemostasis — the coagulation cascade

The cascade is a series of zymogen-to-protease conversions culminating in thrombin (factor IIa) generating fibrin. Classically split into intrinsic, extrinsic, and common pathways. Almost all factors are made in the liver; vWF and a fraction of factor VIII are the notable exceptions (endothelium).

Extrinsic pathway (PT)

Triggered by tissue factor (TF, factor III) released from damaged tissue. TF + factor VIIa activate factor X. Tissue injury → TF + VIIa → activates X → common pathway.

Intrinsic pathway (APTT)

Triggered by contact with negatively charged surfaces (collagen, glass in vitro). Factor XII → XI → IX; IXa + VIIIa → activates X. Contact factors: XII (Hageman), XI, prekallikrein, HMWK (high-molecular-weight kininogen).

Common pathway

Factor Xa + Va (+ Ca²⁺ + phospholipid = prothrombinase) → converts prothrombin (II) to thrombin (IIa) → fibrinogen (I) to fibrin → factor XIII cross-links fibrin.

High-yield: Factor XIII stabilises the clot by covalent cross-linking. Its deficiency gives a normal PT and APTT but a positive urea clot solubility test — classic exam catch.

Vitamin K and calcium

• Vitamin K–dependent factors: II, VII, IX, X plus anticoagulants protein C and protein S ("1972" → 10, 9, 7, 2, or remember "Cs and ten"). Vitamin K is the cofactor for γ-carboxylation of glutamate residues (via γ-glutamyl carboxylase), enabling calcium-dependent membrane binding.
• Warfarin inhibits vitamin K epoxide reductase (VKORC1).
• Factor IV is calcium; factor VI does not exist (it was reclassified as activated factor V).
• Factor VII has the shortest half-life (~4–6 h) → PT/INR rises first with warfarin and in early liver disease.

Factors and their pathways

Pathway	Factors involved	Screening test
Intrinsic	XII, XI, IX, VIII, (prekallikrein, HMWK)	APTT
Extrinsic	VII, tissue factor (III)	PT
Common	X, V, II (prothrombin), I (fibrinogen), XIII	PT + APTT

Mnemonic — Extrinsic = "PeT" (Prothrombin time = External tissue factor = factor VII); Intrinsic = APTT (more factors, "more letters").

High-yield: Thrombin (IIa) is a master enzyme — it converts fibrinogen→fibrin, activates V, VIII, XI, XIII, activates platelets (via PAR receptors), and, by binding thrombomodulin, activates protein C (an anticoagulant). This dual pro- and anticoagulant role is heavily tested.

Natural anticoagulants & regulation

Coagulation is restrained by several physiological brakes:

Inhibitor	Target / action
Antithrombin III (ATIII)	Inhibits thrombin (IIa), Xa, IXa, XIa, XIIa; activity hugely amplified by heparin
Protein C (activated = APC)	Inactivates factors Va and VIIIa; needs protein S as cofactor; activated by thrombin–thrombomodulin complex
Protein S	Cofactor for protein C (vitamin K–dependent)
Tissue factor pathway inhibitor (TFPI)	Inhibits the TF–VIIa–Xa complex (chief brake on extrinsic pathway)

High-yield: Factor V Leiden is a point mutation making factor V resistant to cleavage by activated protein C → APC resistance → most common inherited thrombophilia in Caucasians. Antithrombin III deficiency classically causes heparin resistance.

Endothelial antithrombotic surface: prostacyclin (PGI2), nitric oxide (vasodilators/anti-aggregants), thrombomodulin, heparan sulphate, and ADPase (CD39).

Fibrinolysis

Once the clot has served its purpose, it is dismantled:

Plasminogen → (tPA / urokinase) → Plasmin → degrades fibrin → fibrin degradation products (FDPs) + D-dimer.

• tPA (tissue plasminogen activator) is released from endothelium and is fibrin-specific — it works best bound to fibrin, localising lysis to the clot.
• D-dimer specifically reflects degradation of cross-linked fibrin (i.e., clot that was stabilised by factor XIII) → marker of active thrombosis (DVT/PE/DIC).
• Inhibitors: PAI-1 (plasminogen activator inhibitor) blocks tPA; α2-antiplasmin and TAFI inhibit plasmin.
• Therapeutic fibrinolytics: alteplase, reteplase, tenecteplase, streptokinase, urokinase. Antifibrinolytics: tranexamic acid / ε-aminocaproic acid (block plasminogen activation).

Laboratory evaluation — the core of MCQs

Test	What it assesses	Normal range	Prolonged in
Bleeding time (BT)	Platelet number & function, vessel	2–7 min (Ivy)	Thrombocytopenia, vWD, platelet function defects, aspirin
Platelet count	Platelet number	1.5–4.5 lakh/µL	ITP, TTP, DIC, marrow failure
PT (INR)	Extrinsic + common (VII, X, V, II, I)	11–16 s; INR ~1	Warfarin, liver disease, factor VII deficiency, early vit K deficiency, DIC
APTT	Intrinsic + common (XII–VIII, X, V, II, I)	25–40 s	Heparin, haemophilia A/B, vWD, lupus anticoagulant
Thrombin time (TT)	Fibrinogen→fibrin conversion	14–16 s	Heparin, dysfibrinogenaemia, high FDPs

High-yield interpretation grid:

• Isolated ↑PT → factor VII / early warfarin / early liver disease.
• Isolated ↑APTT → haemophilia A (VIII), haemophilia B (IX), factor XI/XII, lupus anticoagulant (paradoxically thrombotic in vivo).
• Both ↑PT and ↑APTT → common pathway (X, V, II, I), DIC, severe liver disease, vitamin K deficiency (late), heparin overdose.
• Both normal but bleeding → factor XIII deficiency, vascular/platelet function defect.

Mixing study: Add normal plasma 1:1. Corrects → factor deficiency; fails to correct → inhibitor (e.g., lupus anticoagulant, factor VIII inhibitor).

High-yield: PT (INR) monitors warfarin; APTT monitors unfractionated heparin. LMWH is monitored (when needed) by anti-factor Xa; dabigatran (direct thrombin inhibitor) and rivaroxaban/apixaban (Xa inhibitors) generally need no routine monitoring.

Clinical features — primary vs secondary defects

Feature	Primary (platelet/vWF)	Secondary (coagulation factor)
Site of bleed	Skin, mucosa (epistaxis, gums, menorrhagia)	Deep — joints (haemarthrosis), muscles, retroperitoneum
Petechiae	Present	Absent
Ecchymoses	Small, superficial	Large, deep haematomas
Bleeding after cut	Immediate, prolonged	Delayed (after initial platelet plug)
Screening test	BT, platelet count	PT / APTT

Key bleeding disorders to differentiate (classic NEET PG table)

Disorder	Defect	Platelets	BT	PT	APTT	Special
Haemophilia A	Factor VIII ↓ (X-linked recessive)	N	N	N	↑	Haemarthrosis; commonest severe inherited
Haemophilia B (Christmas)	Factor IX ↓	N	N	N	↑	Clinically identical to A
von Willebrand disease	vWF ↓/defective	N	↑	N	↑ (mild)	Commonest inherited bleeding disorder; ↓ ristocetin aggregation
ITP	Anti-platelet antibodies	↓	↑	N	N	Isolated thrombocytopenia
TTP	ADAMTS13 ↓	↓	↑	N	N	Pentad: MAHA, fever, renal, neuro, thrombocytopenia
DIC	Consumptive	↓	↑	↑	↑	↓ fibrinogen, ↑ D-dimer, schistocytes
Vitamin K deficiency	II, VII, IX, X ↓	N	↑	N→↑	N→↑	Corrects with vit K
Bernard–Soulier	GP Ib defect	↓ (giant)	↑	N	N	No ristocetin response; not corrected by normal plasma
Glanzmann thrombasthenia	GP IIb/IIIa defect	N	↑	N	N	Absent aggregation to ADP/collagen; normal ristocetin

High-yield distinguishers:

• Bernard–Soulier vs Glanzmann: B-S → GP Ib, giant platelets, low count, no ristocetin aggregation. Glanzmann → GP IIb/IIIa, normal count/size, normal ristocetin, absent aggregation to all other agonists.
• vWD ristocetin test: ristocetin-induced platelet aggregation is decreased but corrects when normal plasma/vWF is added (distinguishes from Bernard–Soulier, which does not correct).
• DIC: the only common cause with low platelets + prolonged PT + prolonged APTT + low fibrinogen + high D-dimer simultaneously.

Investigations of choice & confirmatory tests

• vWD: vWF antigen, vWF activity (ristocetin cofactor assay), factor VIII level, multimer analysis.
• Haemophilia: specific factor VIII / IX assay (severity: <1% severe, 1–5% moderate, 5–40% mild).
• TTP: ADAMTS13 activity (<10%); peripheral smear shows schistocytes.
• DIC: ↓ platelets, ↑ PT/APTT, ↓ fibrinogen, ↑ D-dimer/FDPs, schistocytes.
• Factor XIII deficiency: urea (5M) clot solubility test — clot dissolves.
• Platelet function: PFA-100 (replacing classic BT), light transmission aggregometry.

Management / drug of choice

• Haemophilia A: recombinant/plasma factor VIII concentrate; mild disease → desmopressin (DDAVP) (releases endogenous vWF/VIII from endothelium). Emicizumab (factor VIIIa-mimetic bispecific antibody) for prophylaxis/inhibitors.
• Haemophilia B: recombinant factor IX.
• von Willebrand disease: DDAVP for type 1; vWF-containing factor VIII concentrate for type 3/severe. Avoid DDAVP in type 2B (worsens thrombocytopenia).
• ITP: corticosteroids ± IVIG (first line); TPO-receptor agonists (eltrombopag/romiplostim), rituximab, splenectomy later.
• TTP: plasma exchange (emergency, life-saving) + steroids ± caplacizumab/rituximab; platelet transfusion contraindicated (fuels microthrombi).
• DIC: treat the underlying cause; supportive FFP, cryoprecipitate (for fibrinogen), platelets if bleeding.
• Warfarin reversal: vitamin K; for urgent reversal 4-factor PCC (preferred over FFP). Heparin reversal: protamine sulphate.
• Antifibrinolytics: tranexamic acid for mucosal bleeds, menorrhagia, trauma (CRASH-2).

High-yield: Cryoprecipitate is the richest source of fibrinogen, factor VIII, vWF, factor XIII, and fibronectin → used in DIC with low fibrinogen and in dysfibrinogenaemia.

Complications

• Thrombotic: DVT, PE, arterial thrombosis (Factor V Leiden, prothrombin G20210A, ATIII/protein C/S deficiency, antiphospholipid syndrome).
• Warfarin-induced skin necrosis — transient hypercoagulable state from rapid fall of protein C (short half-life) before procoagulant factors decline; worse in protein C deficiency.
• Heparin-induced thrombocytopenia (HIT) — IgG against platelet factor 4–heparin complex → paradoxical thrombosis; stop heparin, use a non-heparin anticoagulant (argatroban, fondaparinux).
• Bleeding from over-anticoagulation; transfusion-related complications.

Key differentials

• Thrombocytopenia (low count): ITP, TTP/HUS, DIC, drug-induced, hypersplenism, marrow failure, HIT.
• Microangiopathic haemolytic anaemia (schistocytes): TTP, HUS, DIC, malignant hypertension, mechanical valve.
• Isolated ↑APTT, no bleeding: lupus anticoagulant, factor XII deficiency.
• Mucocutaneous bleeding, normal counts: vWD, platelet function defect, aspirin/NSAID effect.

Recently asked / exam angle

• "Which factor has the shortest half-life?" → Factor VII.
• "vWF binds platelet to collagen via which receptor?" → GP Ib.
• "Receptor for fibrinogen-mediated platelet aggregation?" → GP IIb/IIIa.
• "Test prolonged in factor XIII deficiency?" → urea clot solubility (PT/APTT normal).
• "Normal PT, prolonged APTT, haemarthrosis, X-linked?" → Haemophilia A.
• "Which anticoagulant is heparin-dependent?" → Antithrombin III.
• "Vitamin K–dependent anticoagulants?" → Protein C and Protein S.
• "Bernard–Soulier vs Glanzmann" receptor and ristocetin discrimination.
• "Best/most specific marker of thrombosis?" → D-dimer (cross-linked fibrin).
• "Monitoring of UFH vs warfarin vs LMWH" → APTT / INR / anti-Xa.
• "TTP management; what is contraindicated?" → plasma exchange; avoid platelet transfusion.
• "Most common inherited thrombophilia?" → Factor V Leiden (APC resistance).

Rapid revision

1. Primary haemostasis = platelet plug (vWF–GP Ib adhesion, GP IIb/IIIa–fibrinogen aggregation); defect → ↑BT, mucocutaneous bleed.
2. Secondary haemostasis = fibrin clot via thrombin; defect → ↑PT/APTT, deep/joint bleed.
3. PT = extrinsic (VII) + common; APTT = intrinsic + common; TT = fibrinogen step.
4. Vitamin K–dependent: II, VII, IX, X + protein C & S; warfarin blocks VKORC1.
5. Factor VII = shortest half-life → INR rises first; factor XIII cross-links fibrin (urea solubility test).
6. Thrombin is central: makes fibrin, activates V/VIII/XI/XIII/platelets, and (via thrombomodulin) activates protein C.
7. Natural anticoagulants: ATIII (heparin-boosted, hits IIa & Xa), protein C/S (degrade Va, VIIIa), TFPI.
8. Factor V Leiden = APC resistance = commonest inherited thrombophilia.
9. vWD = commonest inherited bleeding disorder; ↓ ristocetin aggregation corrects with normal plasma; Bernard–Soulier does not.
10. DIC = ↓platelets + ↑PT + ↑APTT + ↓fibrinogen + ↑D-dimer + schistocytes.
11. Reversal: warfarin → vitamin K / 4-factor PCC; heparin → protamine; fibrinolytic bleeding → tranexamic acid.
12. TTP = ADAMTS13 deficiency → plasma exchange; never transfuse platelets routinely.