Haemostasis and Coagulation

Haemostasis and Coagulation

Blood Module — 2026. Lecturer: Dr. Adesola Oyelese, Department of Pathology and Molecular Medicine, University of Otago.

Overview

Haemostasis is the physiological process that rapidly stops bleeding after blood vessel injury, while maintaining blood in a fluid state within intact vessels. It involves three overlapping phases: vascular response, primary haemostasis (platelet plug), and secondary haemostasis (coagulation cascade), followed by fibrinolysis.

Primary Haemostasis — The Platelet Plug

1. Vascular Spasm

Immediately after vessel injury, reflex vasoconstriction reduces local blood flow, buying time for platelet and coagulation responses.

2. Platelet Adhesion

Sub-endothelial collagen is exposed. von Willebrand factor (vWF), synthesised in endothelial cells and megakaryocytes, is stored in Weibel-Palade bodies and platelet alpha-granules. vWF binds collagen and acts as a bridge to platelet glycoprotein GPIb-IX-V. Platelet GPVI also binds directly to collagen. At high shear rates (arterioles), vWF-GPIb interaction is essential for adhesion.

3. Platelet Activation

Adhered platelets undergo activation — a dramatic shape change from discoid to spiny spheres — and release granule contents:

• Dense granules: ADP, serotonin (vasoconstriction)
• Alpha-granules: vWF, fibrinogen, factor V, P-selectin, platelet-derived growth factor (PDGF)
• Thromboxane A₂ (TXA₂): synthesised by activated platelets from arachidonic acid via COX-1; amplifies platelet activation and causes vasoconstriction

ADP binds P2Y₁ and P2Y₁₂ receptors; thrombin (generated by coagulation) binds PAR-1 and PAR-4 receptors — these are the most potent platelet agonists.

4. Platelet Aggregation

GPIIb/IIIa (integrin αIIbβ₃) on activated platelets changes conformation, binding fibrinogen (and vWF), cross-linking adjacent platelets to form the primary platelet plug. Aspirin irreversibly inhibits COX-1, blocking TXA₂; clopidogrel blocks P2Y₁₂ — both used clinically as antiplatelet agents.

Endothelial antithrombotic properties (prevent clotting in intact vessels):

• Prostacyclin (PGI₂): vasodilator, inhibits platelet activation
• Nitric oxide (NO): vasodilator, antiplatelet
• CD39 (ectonucleotidase): degrades ADP → AMP
• Tissue factor pathway inhibitor (TFPI): blocks TF/VIIa complex
• Thrombomodulin: binds thrombin → activates protein C → anticoagulant

Secondary Haemostasis — The Coagulation Cascade

The cascade is a sequential series of zymogen (inactive protease) activations that amplify the signal. Coagulation factors are designated by Roman numerals; activated forms carry a lower-case 'a'.

Coagulation factor sources:

| Factor | Name | Source | Vitamin K dependent? |

|--------|------|--------|---------------------|

| I | Fibrinogen | Liver | No |

| II | Prothrombin | Liver | Yes |

| V | Proaccelerin (cofactor) | Liver, platelets | No |

| VII | Proconvertin | Liver | Yes |

| VIII | Antihaemophilic A | Liver endothelium | No |

| IX | Antihaemophilic B | Liver | Yes |

| X | Stuart-Power | Liver | Yes |

| XI | Antihaemophilic C | Liver | No |

| XII | Hageman factor | Liver | No |

| XIII | Fibrin stabilising | Liver, platelets | No |

| vWF | von Willebrand | Endothelium, megakaryocytes | No |

Extrinsic (Tissue Factor) Pathway — initiates coagulation:

1. Tissue factor (TF) is expressed by sub-endothelial cells after vessel damage
2. TF binds plasma factor VIIa → TF/VIIa complex (extrinsic tenase)
3. TF/VIIa complex + phospholipid + Ca²⁺ → activates factor X → Xa
4. Also activates factor IX → IXa (important for amplification)

Measured by: Prothrombin Time (PT), reference interval 9–13 s; reported as INR (reference interval 0.8–1.2)

Intrinsic (Contact Activation) Pathway — amplifies coagulation:

1. Contact activation: Factor XII activated by exposed collagen or artificial surfaces (kaolin/silica in lab tests)
2. XII → XIIa → activates XI → XIa
3. XIa activates IX → IXa
4. IXa + cofactor VIIIa + phospholipid + Ca²⁺ → intrinsic tenase complex → activates X → Xa

Measured by: Activated Partial Thromboplastin Time (APTT), reference interval 22–34 s

Common Pathway:

1. Xa + cofactor Va + phospholipid + Ca²⁺ → prothrombinase complex
2. Prothrombinase converts prothrombin (II) → thrombin (IIa)
3. Thrombin cleaves fibrinopeptides A and B from fibrinogen → fibrin monomers
4. Fibrin polymerises spontaneously; factor XIIIa (activated by thrombin) cross-links fibrin → stable clot
5. Thrombin also activates factors V, VIII, XI, XIII → positive feedback amplification

Vitamin K (fat-soluble) is required for gamma-carboxylation of glutamate residues on factors II, VII, IX, X and the anticoagulants protein C and protein S. Carboxylation allows these factors to bind Ca²⁺ and assemble on phospholipid surfaces. Warfarin inhibits vitamin K epoxide reductase (VKOR), blocking regeneration of active vitamin K → reduces functional levels of II, VII, IX, X, protein C and S.

Coagulation inhibitors:

• Antithrombin III (ATIII): serine protease inhibitor; inactivates thrombin, Xa, IXa; heparin dramatically accelerates ATIII activity (1000-fold) → therapeutic anticoagulation
• Protein C/S system: thrombomodulin-thrombin activates protein C; protein C + protein S → inactivate Va and VIIIa
• TFPI: inhibits TF/VIIa/Xa complex

Fibrinolysis

• Plasminogen (inactive) circulates in blood; binds to fibrin clot
• Tissue plasminogen activator (tPA) and urokinase (uPA) secreted by endothelium → convert plasminogen → plasmin
• Plasmin degrades fibrin → D-dimers (measured in diagnostic lab to detect recent clot formation/DIC)
• PAI-1 (plasminogen activator inhibitor-1) and TAFI inhibit fibrinolysis
• Tranexamic acid inhibits plasmin activation → used clinically for heavy menstrual bleeding, surgery, trauma

Disseminated Intravascular Coagulation (DIC)

Widespread pathological activation of coagulation throughout the vasculature, consuming clotting factors and platelets (consumptive coagulopathy), resulting in simultaneous thrombosis AND bleeding.

Causes: gram-negative septicaemia (endotoxin activates monocytes → TF expression), meningococcal septicaemia (very high endotoxin), obstetric emergencies (amniotic fluid embolism, placental abruption), malignancy, major trauma, transfusion reactions.

Pathogenesis: TF or procoagulant material enters circulation → widespread thrombin generation → fibrin microthrombi in small vessels (ischaemia) → consumption of platelets, fibrinogen, and other factors → bleeding from multiple sites.

Laboratory findings:

| Test | DIC finding |

|------|-------------|

| PT/INR | Prolonged (factor consumption) |

| APTT | Prolonged |

| Fibrinogen | Low (consumed; normal 1.8–4.0 g/L) |

| D-dimers | Markedly elevated |

| Platelet count | Falling/low |

| Blood film | Schistocytes (microangiopathic haemolysis) |

Treatment: treat the underlying cause; supportive — fresh frozen plasma (replaces all clotting factors), cryoprecipitate (fibrinogen, FVIII, vWF), platelet transfusions; in some settings low-dose heparin (to halt consumption) — controversial.

Von Willebrand Disease

The most common inherited bleeding disorder (~1 in 500–1000). vWF gene on chromosome 12; protein is a multimeric glycoprotein that bridges collagen to platelet GPIb and stabilises factor VIII (half-life increases from ~2.4 h when free to ~12 h when bound to vWF). ADAMTS13 metalloprotease cleaves large vWF multimers.

Types:

| Type | Inheritance | Defect | APTT | vWF:Ag | vWF:Activity |

|------|-------------|--------|------|---------|--------------|

| 1 | AD | Partial quantitative deficiency | Normal/mild ↑ | Low | Low |

| 2A | AD | Loss of large multimers | Mild ↑ | Low–normal | Very low |

| 2B | AD | Increased GPIb affinity, platelet consumption | Mild ↑ | Low | Very low |

| 2N | AR | Reduced FVIII binding | Elevated | Normal | Normal |

| 3 | AR | Complete absence of vWF | Elevated | Absent | Absent |

Clinical features: mucosal bleeding (epistaxis, menorrhagia, gum bleeds), easy bruising, prolonged bleeding after cuts/dental/surgery. Unlike haemophilia, joint bleeds (haemarthroses) are NOT typical.

Treatment: desmopressin (DDAVP) stimulates endothelial release of vWF and FVIII (2–5× increase, lasts 2–8 h); vWF/FVIII concentrate (Biostate); tranexamic acid for menstrual/mucosal bleeding.

Haemophilia

X-linked recessive inherited coagulation disorders affecting males:

• Haemophilia A: deficiency of FVIII (most common, ~1 in 5000 males)
• Haemophilia B: deficiency of FIX (1 in 30,000 males)

Severity correlates with factor level: severe ≤1% (spontaneous bleeding), moderate 2–5% (minor trauma), mild 5–50% (major trauma/surgery). Classic features: haemarthroses (joint bleeds → haemophilic arthropathy), muscle bleeds. PT normal (extrinsic pathway intact); APTT prolonged.

Treatment: recombinant FVIII or FIX infusions; emicizumab (bispecific antibody bridging FIXa and FX) now available for haemophilia A.