Coagulation Cascade
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Direct answer
A breach in the vessel wall is sealed in three overlapping stages: a primary platelet plug built on von Willebrand factor-mediated adhesion, activation and aggregation; secondary coagulation, in which thrombin converts fibrinogen to fibrin that factor XIII cross-links; and fibrinolysis, where plasmin later dissolves the clot. The extrinsic pathway (tissue factor with factor VII) is screened by prothrombin time, roughly 12-14 seconds, the intrinsic pathway (factors XII, XI, IX, VIII) by aPTT at 30-40 seconds, and both converge on factor X into the common pathway. Reading PT and aPTT together localises any bleeding defect and is the single most-tested skill from this topic.
What you must remember
- PT with INR monitors warfarin and liver synthetic function; aPTT monitors unfractionated heparin — the standard exam pairing.
- Vitamin K dependent factors: II, VII, IX and X, plus proteins C and S; all gamma-carboxylated in the liver, and factor VII has the shortest half-life, so early warfarin prolongs PT first.
- Patterns: both PT and aPTT prolonged in liver disease and DIC; isolated aPTT prolongation in haemophilia A (VIII), haemophilia B (IX) and von Willebrand disease; isolated PT prolongation in early warfarin or factor VII deficiency.
- Bleeding time (Ivy, 2-7 minutes) screens platelet number and function — prolonged in thrombocytopenia, uraemia, aspirin and von Willebrand disease, but normal in haemophilia; clotting time is 5-10 minutes.
- Factor facts for the viva: factor VIII is a cofactor made largely by endothelial cells (so it stays normal even in liver failure); factor III is the only extracellular, tissue factor; factor IV is calcium; factors V and VIII are the most labile.
- Natural anticoagulants: antithrombin III (the heparin cofactor), protein C and S (inactivate factors Va and VIIIa), and tissue factor pathway inhibitor.
- Fibrinolysis: tissue plasminogen activator converts plasminogen to plasmin; D-dimer is a cross-linked fibrin degradation product; tranexamic acid inhibits the system.
Approach to a patient with abnormal bleeding
Classify the defect before naming a disease, using three tests as your sieve. Step one, the bleeding time and platelet count: a prolonged bleeding time with a low platelet count means the plug is failing — idiopathic thrombocytopenic purpura, dengue in the Indian setting, or drugs. Step two, read PT against aPTT. Both prolonged points at the common pathway or its substrate — liver disease, DIC, or warfarin over-anticoagulation; the D-dimer and a peripheral smear for fragments then separate DIC. An isolated prolonged aPTT points to the intrinsic arm, so assay factors VIII and IX and test for von Willebrand factor. Step three, if aPTT prolongs but corrects on a mixing study the factor is merely deficient; if it fails to correct, an inhibitor such as a lupus anticoagulant or acquired factor VIII antibody is present.
Now place the two classic patients inside this sieve. A boy with recurrent haemarthrosis after minor sport has normal bleeding time and platelets, normal PT, prolonged aPTT correcting on mixing — haemophilia A until the factor VIII assay proves it, treated with factor replacement, or desmopressin in the mild form. A girl with lifelong menorrhagia and post-dental-extraction oozing shows a slightly prolonged bleeding time and borderline aPTT — von Willebrand disease, the commonest inherited bleeding disorder, where the platelet adhesion protein itself is missing.
The classic trap
Equating "prolonged bleeding time" with "clotting factor deficiency" ruins many answers: haemophilia has a perfectly normal bleeding time because platelets plug the needle wound fine. The mirror-image trap is drug effects on tests — aspirin prolongs bleeding time by irreversibly acetylating COX-1 and killing thromboxane A2 synthesis in platelets; warfarin prolongs PT-INR; heparin prolongs aPTT through antithrombin III. A subtler favourite: why does factor VIII not fall in liver failure like the other factors? Because endothelial cells, not hepatocytes, make it — and this single fact distinguishes advanced liver disease (factor VIII normal or high) from DIC (factor VIII consumed and low).
Frequently asked questions
Which test monitors warfarin and which monitors heparin?
PT expressed as INR monitors warfarin; aPTT monitors unfractionated heparin, titrated to roughly 1.5-2.5 times control.
Which factors need vitamin K and where are they made?
Factors II, VII, IX and X with proteins C and S, gamma-carboxylated in the liver — hence the clotting defect of obstructive jaundice and of the newborn.
Why is factor VIII spared in liver disease?
It is synthesised mainly by endothelial cells, remaining normal or raised while liver-made factors fall — a discriminating point against DIC.
What is the investigation cascade in suspected haemophilia A?
Prolonged aPTT with normal PT, bleeding time and platelets; correction on mixing study; then a specific factor VIII assay confirming the level.
What is D-dimer and when is it useful?
A fragment released when plasmin degrades cross-linked fibrin; sensitive but poorly specific, so it is best at ruling out DIC and venous thromboembolism, not confirming them.
Why can early warfarin cause skin necrosis?
Protein C has the shortest half-life among vitamin K proteins and drops before factors II, IX and X, briefly creating a hypercoagulable window in deficient patients.