5.2 Haemostasis Physiology, Coagulation Testing and Inherited Bleeding Disorders

5.2 Haemostasis Physiology, Coagulation Testing and Inherited Bleeding Disorders

Why Haemostasis Matters

Bleeding and thrombosis are central to perioperative medicine. EDAIC questions test the physiology of clot formation, the meaning of each laboratory test, the effect of hypothermia and acidosis, and the management of inherited disorders. A clear model of coagulation also explains how anticoagulants and their reversal agents work.

Primary Haemostasis: Vessel and Platelets

When the endothelium is breached, subendothelial collagen and von Willebrand factor (vWF) are exposed.

1. Adhesion: Platelet glycoprotein Ib-IX-V binds vWF; glycoprotein VI and Ia/IIa bind collagen directly.
2. Activation: Platelets change shape and release granules: dense granules contain ADP, serotonin and calcium; alpha granules contain fibrinogen, vWF and factor V. Thromboxane A2 is synthesised through cyclo-oxygenase-1.
3. Aggregation: ADP (through P2Y12 receptors), thromboxane A2 and thrombin activate the glycoprotein IIb/IIIa receptor, which binds fibrinogen and links platelets together.

Normal platelet count is about $150-400 \times 10^9/\text{L}$, and the platelet life span is about 7-10 days. The intact endothelium stays non-thrombogenic by releasing prostacyclin and nitric oxide, expressing thrombomodulin, and carrying heparan sulphate on its surface.

Secondary Haemostasis: The Cell-Based Model

The classical cascade (extrinsic, intrinsic and common pathways) explains laboratory tests but not bleeding in vivo. The cell-based model describes three overlapping phases:

1. INITIATION (tissue factor-bearing cell, e.g. fibroblast)
   Tissue factor + factor VIIa --> activates X and IX
   Xa + Va --> small amount of thrombin
2. AMPLIFICATION (platelet surface)
   Thrombin activates platelets, factors V, VIII and XI,
   and releases VIII from von Willebrand factor
3. PROPAGATION (activated platelet surface)
   Tenase (IXa + VIIIa) --> large amounts of Xa
   Prothrombinase (Xa + Va) --> thrombin burst
   Thrombin converts fibrinogen to fibrin; XIIIa cross-links it

Key points:

• Calcium (factor IV) and phospholipid surfaces are needed for the tenase and prothrombinase complexes.
• Factor XII is not needed for haemostasis in vivo: deficiency prolongs the aPTT but does not cause bleeding.
• Vitamin K-dependent factors are II, VII, IX and X, plus proteins C and S. Vitamin K allows gamma-carboxylation of glutamate residues so these proteins can bind calcium.
• Factor XIII cross-links fibrin; deficiency causes bleeding with normal routine tests.

Natural Anticoagulants and Fibrinolysis

Plasmin is inhibited by alpha-2 antiplasmin; plasminogen activator inhibitor-1 opposes tissue plasminogen activator. Tranexamic acid blocks the lysine-binding sites on plasminogen, preventing it from binding to fibrin.

Factor V Leiden makes factor Va resistant to activated protein C and is the commonest inherited thrombophilia in people of European origin (about 3-8% are heterozygous).

Laboratory Tests

• The INR standardises the PT for warfarin monitoring using the reagent's International Sensitivity Index; it is less reliable in liver disease.
• Factor VII has the shortest half-life (about 4-6 hours), so the INR rises first when vitamin K-dependent factors fall.
• Mixing studies: if a prolonged aPTT corrects with normal plasma, a factor deficiency is likely; if not, an inhibitor (for example lupus anticoagulant) is present.
• Standard tests are performed at 37 °C on plasma, so they underestimate the effect of hypothermia and do not assess platelet function or fibrinolysis. Viscoelastic tests (ROTEM, TEG) assess whole-blood clot formation and lysis at the bedside.

Effects of Hypothermia, Acidosis and Hypocalcaemia

• Hypothermia below about 34 °C slows enzyme activity and impairs platelet function.
• Acidosis with pH below about 7.2 reduces the activity of the tenase and prothrombinase complexes.
• Ionised calcium below about 0.9 mmol/L impairs coagulation; massive transfusion lowers it through citrate.

These three factors form the "lethal triad" with coagulopathy in trauma.

Inherited Bleeding Disorders

Desmopressin (DDAVP) releases vWF and factor VIII from endothelial Weibel-Palade bodies. It raises levels two- to fourfold within about 30-60 minutes. Repeated doses cause tachyphylaxis and water retention with hyponatraemia, so fluids should be restricted. It is also used for uraemic platelet dysfunction and mild haemophilia A.

Acquired Disorders

• Disseminated intravascular coagulation (DIC): widespread activation consumes platelets and factors; PT and aPTT are prolonged, fibrinogen is low and D-dimers are high. Treat the cause and replace components when bleeding.
• Liver disease: both procoagulant and anticoagulant factors fall, so the INR overstates the bleeding risk; the haemostatic balance is "rebalanced" but fragile.
• Heparin-induced thrombocytopenia: antibodies against platelet factor 4-heparin complexes cause a fall in platelets 5-10 days after exposure and paradoxical thrombosis.