Coagulation cascade

Because initiation is deliberately self-limiting. Tissue factor-factor VIIa generates only trace factor Xa before tissue factor pathway inhibitor shuts it down. Everything after that depends on amplification: thrombin activates factors XI, VIII and V, and the intrinsic tenase (IXa-VIIIa) on the platelet surface then produces the bulk of factor Xa. Without factor VIII or factor IX that amplification never happens, so a clot forms and then fails — which is why haemophiliacs characteristically re-bleed hours after an injury rather than bleeding immediately.

Do a 50:50 mix with normal plasma. If it corrects, it is a factor deficiency of the intrinsic limb — factor VIII (haemophilia A or von Willebrand disease), IX (haemophilia B), XI, XII, prekallikrein or HMWK — and a factor assay names it. If it does not correct, it is an inhibitor: a lupus anticoagulant (immediate, associated with thrombosis) or a factor VIII antibody (time and temperature dependent, associated with bleeding). Also exclude heparin contamination, which prolongs the thrombin time as well and is excluded by a normal reptilase time.

A common pathway problem or a multi-factor process. If the thrombin time is normal, the defect is above fibrinogen: factor X, factor V or prothrombin. If the thrombin time is also prolonged, suspect a fibrinogen problem or a thrombin inhibitor: DIC, hypofibrinogenaemia, dysfibrinogenaemia, heparin or dabigatran. Multi-factor causes — DIC, liver failure, vitamin K deficiency, warfarin and massive transfusion — are far commoner than an isolated congenital deficiency.

Measure factor VIII. It is made by liver sinusoidal endothelium rather than hepatocytes, so it is normal or raised in liver disease and consumed (low) in DIC. Supporting features of DIC are a falling fibrinogen on serial testing, a markedly raised D-dimer, schistocytes on the film and an identifiable trigger. Thrombotic thrombocytopenic purpura is the third mimic — it gives thrombocytopenia and schistocytes but with a normal PT, APTT and fibrinogen.

Warfarin blocks VKORC1 and therefore new carboxylation, but has no effect on factors already in the circulation. The INR moves within a day because factor VII has a half-life of only 4-6 hours, yet true antithrombotic effect awaits the decay of prothrombin at 60-72 hours. Protein C has a half-life of about 8 hours, so the natural anticoagulant disappears before prothrombin does — hence the need for heparin cover at initiation, and the risk of warfarin-induced skin necrosis in undiagnosed protein C deficiency.

That fibrin was cross-linked by factor XIIIa and then lysed by plasmin — a clot was made and broken down. Degrading fibrinogen alone does not generate a D-dimer. Its value is its negative predictive value: a normal D-dimer with a low or moderate Wells score excludes DVT or PE without imaging. It is not a rule-in test, since pregnancy, age, sepsis, malignancy, surgery and trauma all raise it; the age-adjusted cut-off (age times 10 microgram/L over 50 years) recovers some specificity.

Three groups. Factor XIII deficiency acts after the clot has formed, so PT, APTT and thrombin time are all normal and the urea clot solubility test is required. Von Willebrand disease may have a normal APTT whenever factor VIII is preserved, so it needs vWF antigen and activity assays. And all the platelet disorders — thrombocytopenia aside, conditions such as Glanzmann thrombasthenia, Bernard-Soulier syndrome, aspirin effect and Scott syndrome — are disorders of primary haemostasis that the screen does not test at all.