Haemostasis and coagulation
Haemostasis and coagulation: platelets, clotting cascade, PT, APTT and bleeding disorders
How vessels, platelets and clotting factors stop bleeding, and how PT, APTT and bleeding time localise a defect, for FCPS Part 1. Covers aspirin, warfarin, vitamin K, von Willebrand disease, haemophilia, DIC and D-dimer.
One of the most tested topics in past papers
Vascular spasm and the endothelium
- Injury triggers reflex constriction, helped by thromboxane A₂ and serotonin from platelets and endothelin from endothelium.
- Healthy endothelium resists clotting with prostacyclin (PGI₂) and nitric oxide (inhibit platelets), thrombomodulin (lets thrombin activate protein C), heparan sulphate (assists antithrombin) and tissue plasminogen activator.
- Weibel–Palade bodies in endothelial cells store von Willebrand factor and P-selectin; desmopressin and adrenaline release them. Platelet α granules also contain vWF.
Platelet plug (primary haemostasis)
Platelets come from megakaryocytes under thrombopoietin (from the liver). Count 150–400 ×10⁹/L, lifespan 7–10 days; about a third are pooled in the spleen, so the count rises after splenectomy.
- Adhesion: exposed collagen binds vWF, which binds platelet glycoprotein Ib.
- Activation: shape change and granule release: dense granules (ADP, calcium, serotonin) and α granules (vWF, fibrinogen, factor V, PDGF). Platelets make thromboxane A₂ through COX-1.
- Aggregation: ADP and thromboxane activate glycoprotein IIb/IIIa, which binds fibrinogen to bridge platelets.
| Drug | Target | Note |
|---|---|---|
| Aspirin | Irreversibly acetylates COX-1 | Platelets have no nucleus to make new enzyme, so one dose lasts their lifetime, 7–10 days |
| Clopidogrel, prasugrel, ticagrelor | P2Y12 ADP receptor | Stop 5–7 days before surgery |
| Abciximab, tirofiban, eptifibatide | GPIIb/IIIa | |
| Dipyridamole | Phosphodiesterase, adenosine uptake |
Disorders of platelets and vWF
| Disorder | Defect | Clues |
|---|---|---|
| Von Willebrand disease | Low or abnormal vWF; usually autosomal dominant | Commonest inherited bleeding disorder; gum bleeding, menorrhagia; bleeding time and APTT prolonged (vWF carries factor VIII), PT normal; affects both sexes |
| Bernard–Soulier | GPIb absent | Giant platelets, mildly low count, mucosal bleeding, no ristocetin aggregation |
| Glanzmann thrombasthenia | GPIIb/IIIa absent | Normal count and size, no aggregation |
| ITP | Antiplatelet antibodies | Isolated low count; children after viral illness; adults chronic |
| HIT | Antibodies to heparin–PF4 | Count falls 5–10 days after heparin (for example after cardiac surgery); paradoxical thrombosis |
| HUS, TTP | Microvascular platelet thrombi | Low platelets, schistocytes, renal failure; HUS follows bloody diarrhoea (*E. coli* O157) |
- ITP in pregnancy not responding to full-dose steroids is treated with IV immunoglobulin.
- Pancytopenia with macrocytosis (MCV 110, low platelets and white cells) and numbness suggests B12 deficiency.
Coagulation (secondary haemostasis)
- Initiation: tissue factor from damaged tissue binds factor VIIa and activates small amounts of X and IX, producing a little thrombin.
- Amplification: thrombin activates platelets and factors V, VIII and XI.
- Propagation: the tenase complex (IXa with VIIIa) and prothrombinase complex (Xa with Va), assembled on the platelet phospholipid surface, make a burst of thrombin.
- Fibrin formation: thrombin cleaves fibrinopeptides A and B from fibrinogen, leaving fibrin monomers that polymerise; factor XIIIa cross-links them.
- Calcium (factor IV) and phospholipid are needed at several steps; citrate and EDTA anticoagulate blood tubes by binding calcium.
| Test | Measures | Key factors | Prolonged by |
|---|---|---|---|
| PT/INR | Extrinsic and common | VII, X, V, II, fibrinogen | Warfarin, vitamin K deficiency, liver disease |
| APTT | Intrinsic and common | XII, XI, IX, VIII, X, V, II | Unfractionated heparin, haemophilia A and B, vWD, lupus anticoagulant |
| Thrombin time | Fibrinogen to fibrin | Fibrinogen | Heparin, low fibrinogen, dabigatran |
| Bleeding time, platelet count | Platelets and vWF | — | Thrombocytopenia, platelet dysfunction, vWD, aspirin |
- Reading a profile: normal PT, long APTT, normal bleeding time points to haemophilia; long APTT and long bleeding time with normal PT points to vWD; long PT alone points to factor VII, warfarin or early liver disease.
- Liver disease: the major defect is reduced synthesis of clotting factors (PT rises first), plus thrombocytopenia from hypersplenism.
Vitamin K and warfarin
- Vitamin K is the cofactor for γ-carboxylation of glutamate on factors II, VII, IX and X and proteins C and S, allowing them to bind calcium.
- Warfarin blocks vitamin K epoxide reductase. Factor VII falls first (shortest half-life, about 6 hours), so the PT rises first. Protein C also falls early, so warfarin is briefly prothrombotic and is started under heparin cover.
- Newborns have low vitamin K: poor placental transfer, a sterile gut and little in breast milk. Without prophylactic vitamin K at birth they risk haemorrhagic disease of the newborn.
Natural anticoagulants and thrombophilia
- Antithrombin inactivates thrombin and Xa; heparin greatly accelerates it. Low-molecular-weight heparin acts mainly on Xa (monitor with anti-Xa levels).
- Activated protein C with protein S inactivates Va and VIIIa. Factor V Leiden resists this; it is the commonest inherited thrombophilia. Antiphospholipid syndrome is the commonest acquired thrombophilia (lupus anticoagulant prolongs APTT in vitro yet causes clots).
- Tissue factor pathway inhibitor limits initiation.
Fibrinolysis and D-dimer
- Plasminogen is converted to plasmin by tPA and urokinase; plasmin digests fibrin into degradation products including D-dimer (from cross-linked fibrin).
- D-dimer is sensitive but not specific. With a low clinical probability, a negative D-dimer safely excludes DVT or PE; a positive result needs imaging.
- Tranexamic acid blocks plasminogen activation (trauma, menorrhagia). Alteplase and streptokinase are thrombolytics.
Haemophilia
| Type | Factor | Inheritance | Tests |
|---|---|---|---|
| A | VIII | X-linked recessive | APTT long; PT, bleeding time, platelets normal |
| B (Christmas) | IX | X-linked recessive | Same pattern |
- Boys with haemarthrosis, muscle haematomas, bleeding after circumcision or dental extraction; a brother or maternal uncle affected. Screen with APTT, confirm with factor assays. Treat with factor concentrate; desmopressin helps mild haemophilia A.
DIC and blood components
- DIC (sepsis, abruption, amniotic fluid embolism, trauma, malignancy) consumes factors and platelets: PT and APTT long, platelets and fibrinogen low, D-dimer high, schistocytes.
| Need | Component | Why |
|---|---|---|
| Low fibrinogen (below 1.5 g/L) | Cryoprecipitate | Richest source of fibrinogen, factor VIII, vWF, XIII |
| Multiple factor deficiency | Fresh frozen plasma | All factors |
| Thrombocytopenic bleeding | Platelets | Stored at 20–24 °C with agitation: cold makes them change shape and be cleared rapidly, so function is lost |
| Warfarin reversal | Prothrombin complex concentrate and IV vitamin K |
Remember Adhesion is vWF on GPIb; aggregation is fibrinogen on GPIIb/IIIa.
Exam trap Haemophilia prolongs the APTT but leaves the PT and bleeding time normal.
How FCPS asks about this
- What thrombin releases from fibrinogen: fibrinopeptides A and B.
- Why one aspirin lasts 7–10 days: irreversible COX-1 acetylation in anucleate platelets.
- Vitamin K-dependent factors: II, VII, IX, X, proteins C and S; newborns given vitamin K for low stores and intake.
- Normal PT, long APTT and bleeding time, both sexes: von Willebrand disease.
- Boy bleeding after circumcision with long APTT: haemophilia A or B.
- Fibrinogen 0.8 g/L in DIC: give cryoprecipitate.
- Negative D-dimer with low clinical probability: DVT safely excluded.
Test yourself on this topic
5 of the 31 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A man with Gram-negative septicaemia oozes from cannula sites. Platelets are low, PT and APTT are prolonged, fibrinogen is low and D-dimer is very high. What is the underlying process?
Answer: DIC
In DIC, tissue factor exposure (sepsis, obstetric emergencies such as placental abruption and amniotic fluid embolism, trauma, burns, malignancy—especially acute promyelocytic leukaemia, snake bites) triggers systemic thrombin generation. Microthrombi cause organ ischaemia while consumption of platelets and factors plus fibrinolysis cause bleeding. Findings: low platelets, prolonged PT and APTT, low fibrinogen, raised D-dimer or FDPs, and schistocytes. Treatment targets the cause, with platelets, fresh frozen plasma and cryoprecipitate for active bleeding. TTP shows thrombocytopenia and haemolysis but normal coagulation tests.
DIC
- Triggers: sepsis, obstetric, trauma, APML, snake bite
- Platelets↓, PT/APTT↑, fibrinogen↓, D-dimer↑
- Clots + bleeding together
- Treat cause; FFP, platelets, cryoprecipitate
Remember Everything consumed, D-dimer sky high.
Why the other options are wrong
- Isolated vitamin K deficiency Platelets and fibrinogen would be normal.
- Haemophilia A Platelets and fibrinogen normal.
- Immune thrombocytopenia Coagulation tests normal.
- TTP with normal clotting Coagulation tests usually normal in TTP.
A bleeding patient with DIC has fibrinogen of 0.8 g/L. Which blood component is the richest source of fibrinogen?
Answer: Cryoprecipitate
Cryoprecipitate is made by thawing FFP slowly at 4 °C; the precipitate is rich in fibrinogen, factor VIII, von Willebrand factor, factor XIII and fibronectin. It is used to replace fibrinogen (e.g. below 1.5 g/L in major haemorrhage, DIC, obstetric bleeding). FFP contains all coagulation factors at plasma concentrations. Prothrombin complex concentrate contains factors II, VII, IX and X (warfarin reversal). Platelets are given for thrombocytopenia or platelet dysfunction.
Blood components
- Cryoprecipitate: fibrinogen, VIII, vWF, XIII
- FFP: all factors
- PCC: II, VII, IX, X (warfarin reversal)
- Platelets: low count or dysfunction
Remember Cryo for fibrinogen.
Why the other options are wrong
- Platelet concentrate Platelets, little fibrinogen.
- Packed red cells No clotting factors.
- Albumin 20% No clotting factors.
- Prothrombin complex concentrate Vitamin K-dependent factors only.
Weibel–Palade bodies in endothelial cells store which substances?
Answer: vWF and P-selectin
Weibel–Palade bodies are rod-shaped granules in endothelial cells containing von Willebrand factor and P-selectin. When the endothelium is activated (by thrombin, histamine or desmopressin), they release vWF for platelet adhesion and P-selectin for leucocyte rolling. Desmopressin is used in mild von Willebrand disease and haemophilia A for this reason.
Weibel–Palade bodies
- Endothelial granules
- vWF: platelet adhesion
- P-selectin: leucocyte rolling
- Released by desmopressin
Remember Desmopressin empties Weibel–Palade bodies.
Exam trap Platelet alpha granules also contain vWF.
Why the other options are wrong
- Thromboxane A₂ and ADP Platelet products.
- Factor VII and tissue factor Not stored here.
- Heparin and histamine Mast cell granules.
- Plasminogen and antithrombin Plasma proteins made by the liver.
Which clotting factors require vitamin K for their activation?
Answer: II, VII, IX, X, C and S
Vitamin K is a cofactor for γ-glutamyl carboxylase, which adds carboxyl groups to glutamate residues on factors II, VII, IX and X and the natural anticoagulants proteins C and S, allowing them to bind calcium and phospholipid. Warfarin inhibits vitamin K epoxide reductase (VKORC1), preventing recycling of vitamin K. Factor VII has the shortest half-life, so PT/INR rises first. Proteins C and S also fall early, causing a transient prothrombotic state (warfarin skin necrosis), so heparin cover is used initially.
Vitamin K factors
- II, VII, IX, X + protein C, S
- γ-carboxylation of glutamate
- Warfarin blocks VKORC1
- VII falls first → PT/INR ↑
Remember 1972: ten, nine, seven, two.
Why the other options are wrong
- Factors V and VIII Not vitamin K dependent.
- Factors XI and XII Not vitamin K dependent.
- Fibrinogen and XIII Not vitamin K dependent.
- vWF and factor VIII Not vitamin K dependent.
In pre-eclampsia, changes in the placenta and platelets favour vasoconstriction, platelet aggregation and placental thrombosis. Which imbalance of prostanoids is characteristic?
Answer: Thromboxane A2 high, prostacyclin low
In normal pregnancy prostacyclin production by endothelium and trophoblast rises, helping to keep vessels dilated and platelets quiet. In pre-eclampsia the damaged endothelium makes less prostacyclin, while activated platelets and the placenta make more thromboxane A2, which constricts vessels and promotes aggregation. This shift is the basis for using low-dose aspirin, which suppresses platelet thromboxane. Leukotrienes and lipoxins are not the central pathway.
Prostanoid balance
- Normal pregnancy: prostacyclin up
- Pre-eclampsia: thromboxane A2 up
- Prostacyclin down
- Basis of low-dose aspirin
Remember Pre-eclampsia tips the balance to thromboxane.
Exam trap Do not confuse the normal pregnancy rise in prostacyclin with the pre-eclampsia picture.
Why the other options are wrong
- Prostacyclin high, thromboxane A2 low That is the normal pregnancy pattern, opposite to pre-eclampsia.
- Prostaglandin E2 high, PGF2α low These are not the key pair in pre-eclampsia.
- Leukotriene B4 high, lipoxin A4 low Leukotrienes and lipoxins are not the central change.
- Prostacyclin high, PGE2 low Prostacyclin falls in pre-eclampsia.
Where this sits in the CPSP syllabus
- Paper 1: Blood and immunity, Haemostasis and coagulation
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