This lecture by Eric Tse (Department of Medicine, HKU) is a foundational haematology lecture that starts from first principles — how does the body stop bleeding? — and then systematically asks: what goes wrong when it fails? The clinical scenario (bleeding after a tooth extraction) is the classic presenting complaint that forces you to work through platelet disorders vs. coagulation disorders, using a pattern-recognition approach combining clinical features and laboratory tests (PT, APTT, platelet count) to arrive at a specific diagnosis and management plan. ^[1]

1. Describe the three phases of haemostasis (vasoconstriction → platelet plug → fibrin clot)
2. Explain platelet activation (shape change, degranulation, aggregation) including agonists, granule contents, and surface receptors
3. Outline the coagulation cascade — the tissue-factor pathway, amplification loop, and the central role of thrombin
4. Interpret PT and APTT and map abnormal results to specific clinical conditions
5. Differentiate platelet-type bleeding from coagulation-type bleeding by clinical pattern
6. Formulate a diagnostic and management approach for four clinical situations: isolated low platelets, isolated prolonged PT, isolated prolonged APTT, and combined prolonged PT + APTT

This is a perennial HKUMed exam favourite. It has been tested as SAQ stems ("a young man with prolonged bleeding after tooth extraction"), MCQ discriminators (which pattern of bleeding = which disorder?), and interactive tutorial cases. The GC interactive tutorial (Haem Case 2) uses exactly this scenario. ^[2]

"Shape Change → Degranulation → Platelet Aggregation" ^[1]

"Alpha granule: fibrinogen, vWF, factor V, factor XI, HMWK. Dense granule: ADP, ATP, serotonin, calcium." ^[1]

Why this matters:

• Alpha granules contain large adhesive proteins and coagulation cofactors — they bridge primary and secondary haemostasis.
• Dense granules contain small molecules (ADP, calcium, serotonin) that are agonists — they activate MORE platelets, creating a positive feedback loop.

"ADP, Thrombin, Collagen, Adrenaline, Serotonin, Calcium ionophores" ^[1]

"Activation and degranulation → ADP, serotonin, calcium, fibrinogen, Factors V and XI → Aggregation" ^[1]

This positive feedback means that once platelet activation begins, it self-amplifies. A few activated platelets release ADP and thromboxane A2 (TXA2), which activate neighbouring platelets, which release more ADP and TXA2, and so on. This is why antiplatelet drugs (aspirin blocks TXA2; P2Y12 inhibitors block ADP receptor) are so effective — they break this amplification loop.

"Platelet adhesion: GPIa/IIa and GPVI – collagen; GPIb/IX/V – vWF – collagen. Platelet aggregation: GPIIb/IIIa – fibrinogen – GPIIb/IIIa." ^[1]

"(1) Factor VII is the key factor involved. (2) Tissue factor is a principal factor involved in the activation of factor VII. (3) Factor VIIa activates factor X. (4) Factor X converts prothrombin to thrombin. (5) Thrombin activates platelets, factor VIII, factor V, and factor XI. (6) Factor IXa/VIIIa generate large amount of THROMBIN via Xa/Va. (7) Thrombin converts fibrinogen to fibrin. (8) Thrombin is the central molecule involved in blood coagulation." ^[1]

The "old" model divides coagulation into intrinsic, extrinsic, and common pathways. This is still how we interpret lab tests (PT tests extrinsic; APTT tests intrinsic). But in vivo, it works as one integrated system driven by tissue factor exposure:

1. Initiation: Vessel injury exposes tissue factor (TF) on subendothelial cells. TF binds Factor VII → forms TF-VIIa complex.
2. Initial thrombin generation: TF-VIIa activates Factor X → Xa. Xa (with cofactor Va) converts a small amount of prothrombin → thrombin. This small burst of thrombin is not enough to form a stable clot, but it is critical for amplification.
3. Amplification: That small amount of thrombin activates:
   • Factor V → Va (cofactor for Xa)
   • Factor VIII → VIIIa (cofactor for IXa)
   • Factor XI → XIa (generates more IXa)
   • Platelets (exposes phospholipid surface for factor assembly)
4. Propagation (the big burst): Factor IXa + VIIIa (the "tenase complex") generates massive amounts of Factor Xa. Xa + Va (the "prothrombinase complex") then generates a large amount of thrombin.
5. Fibrin formation: Thrombin cleaves fibrinogen → fibrin monomers → spontaneously polymerize → cross-linked by Factor XIIIa (also activated by thrombin) → stable fibrin mesh.

"Thrombin is the central molecule involved in blood coagulation." ^[1]

This is the single most important take-home from the cascade: everything funnels to thrombin. Thrombin activates platelets, activates cofactors V and VIII, activates XI, converts fibrinogen to fibrin, and activates XIII for cross-linking. It is also the target of direct thrombin inhibitors (dabigatran).

"PT (Prothrombin Time): Factor VII + Tissue Factor → extrinsic pathway. APTT (Activated Partial Thromboplastin Time): Factor IX, Factor VIII → intrinsic pathway." ^[1]

Why does PT test extrinsic? The lab adds tissue factor + calcium to citrated plasma → measures time to clot. If Factor VII is deficient, the clot takes longer.

Why does APTT test intrinsic? The lab adds a contact activator (e.g., kaolin) + phospholipid + calcium → activates Factor XII → cascade proceeds through XI → IX → VIII → X → thrombin → fibrin. If VIII or IX is deficient (haemophilia), clot takes longer.

Why is PT prolonged in jaundice/warfarin but APTT is normal (or only mildly prolonged)?

• Vitamin K-dependent factors are II, VII, IX, X (mnemonic: "1972" → factors 10, 9, 7, 2).
• Factor VII has the shortest half-life (~6 hours) of all clotting factors, so it depletes first.
• Since PT depends on VII (extrinsic pathway), PT rises first.
• APTT may eventually prolong if IX, X, or II also drop significantly, but in early/mild deficiency, APTT remains normal.

Why doesn't LMWH prolong APTT?

• UFH inhibits both thrombin (IIa) and Xa → affects intrinsic pathway → prolongs APTT.
• LMWH preferentially inhibits Xa and has less anti-IIa activity → less effect on APTT. LMWH is monitored with anti-Xa levels, not APTT. ^[4]

Why do platelet disorders have normal PT and APTT?

• PT and APTT measure the coagulation cascade in plasma. They do not measure platelet number or function. Platelet problems cause bleeding but do not change clotting times.

"Quantitative: Thrombocytopenia — Decreased production (bone marrow disease); Increased destruction (immune e.g. ITP, drugs; hypersplenism). Qualitative: Platelet function disorder — Drugs (aspirin, NSAIDs); Acquired (renal failure); Inherited (very uncommon, e.g. Bernard-Soulier)." ^[1]

"Acquired: Liver disease (vitamin K deficiency in jaundice; decreased production in liver failure); Drugs (anticoagulants). Inherited: Haemophilias (A, B, and other haemophilias); von Willebrand disease (vWD)." ^[1]

"A. Repeat and confirm (citrate blood if needed). B. Isolated thrombocytopenia or pancytopenia — Pancytopenia: bone marrow failure. C. Isolated thrombocytopenia — Increased destruction: chronic liver disease, ITP, drug-induced. D. Assessment of bleeding risk — CNS bleeding: fundoscopic examination. E. Treatment: platelet transfusion; steroid / IVIg (for ITP)." ^[1]

Step-by-step logic:

1. Repeat and confirm: EDTA (the anticoagulant in purple-top tubes) can cause pseudothrombocytopenia — platelet clumping in vitro that the machine reads as low count. Re-collect in a citrate tube (blue top) to confirm. Always check a blood film for clumps.
2. Isolated vs. pancytopenia: If ALL cell lines are low (anaemia + leucopenia + thrombocytopenia), the problem is likely bone marrow failure (aplastic anaemia, leukaemia infiltration, myelodysplasia) → needs bone marrow biopsy. If only platelets are low, the marrow is likely making enough but they're being destroyed peripherally.
3. Causes of isolated thrombocytopenia:
   • Immune thrombocytopenic purpura (ITP): Autoantibodies against platelet surface glycoproteins → splenic destruction
   • Chronic liver disease / hypersplenism: Portal hypertension → splenomegaly → platelet sequestration
   • Drug-induced: Heparin (HIT), quinine, sulfonamides, etc.
4. Assess bleeding risk: The most dangerous complication of severe thrombocytopenia is intracranial haemorrhage. Perform fundoscopy — retinal haemorrhages suggest risk of CNS bleeding.
5. Treatment:
   • Platelet transfusion: For active severe bleeding or very low counts ( < 10 × 10⁹/L)
   • Steroids (prednisolone): First-line for ITP — suppress immune destruction
   • IVIg: For ITP with severe bleeding or need for rapid platelet rise (e.g., pre-procedure) — blocks Fc receptors on splenic macrophages → reduces phagocytosis of antibody-coated platelets
   • Thrombopoietin receptor agonists (eltrombopag, romiplostim): For refractory ITP — stimulate platelet production from megakaryocytes ^[1]

"1. Repeat and confirm. 2. Assess whether patient is jaundiced (obstructive jaundice). 3. Assess whether patient has liver disease. 4. Drug: warfarin. 5. Why obstructive jaundice? 6. Treatment: parenteral vitamin K. 7. If warfarin overdose: fresh frozen plasma; vitamin K treatment." ^[1]

Why obstructive jaundice causes prolonged PT:

• Vitamin K is a fat-soluble vitamin (along with A, D, E). It requires bile salts for absorption from the gut.
• In obstructive jaundice, bile cannot reach the duodenum → no bile salts → no vitamin K absorption → deficiency of factors II, VII, IX, X.
• Factor VII has the shortest half-life (~6 hours), so PT rises first and most prominently.
• Parenteral (IV/IM) vitamin K bypasses the absorption problem and corrects the PT within 12–24 hours.
• If PT corrects with vitamin K → the liver synthetic function is intact (it's an absorption problem). If it does NOT correct → liver parenchymal disease (hepatocytes are damaged and can't make factors regardless of vitamin K availability). This is a classic clinical discriminator.

Warfarin overdose management:

• FFP (Fresh Frozen Plasma): Contains ALL clotting factors → immediately corrects INR. Used when urgent reversal is needed (active bleeding, need for emergency surgery).
• Vitamin K: Takes 12–24 hours to work but provides sustained correction. Give both for serious bleeding.
• Prothrombin complex concentrate (PCC): More concentrated than FFP, smaller volume, faster — now the preferred agent for life-threatening warfarin-related bleeding in many centres.

"1. Repeat and confirm. 2. Commonest cause of prolonged APTT is heparin contamination (if blood taken from a catheter). 3. Lupus anticoagulant (not associated with bleeding, associated with thrombosis in-vivo). 4. Man: haemophilia A / B (Sex-linked recessive); von Willebrand disease (autosomal dominant). Woman: von Willebrand disease (autosomal dominant). 5. Treatment: Factor concentrates (plasma derived or recombinant); DDAVP for some vWD." ^[1]

Key points:

1. Heparin contamination: The single commonest cause of a prolonged APTT in hospital is artefact — blood drawn from a line that was flushed with heparin. Always check if the sample was drawn correctly.

2. Lupus anticoagulant (LA): This is a classic exam trick.

   • LA is an antiphospholipid antibody → it prolongs APTT in vitro (because the APTT reagent depends on phospholipid).
   • But in vivo, LA is pro-thrombotic (causes DVT, PE, recurrent miscarriages) — the exact OPPOSITE of what "anticoagulant" implies.
   • LA does NOT cause bleeding. ^[1][5]

   How to differentiate LA from factor deficiency using a mixing study ^[5]:

   • Mix patient plasma 50:50 with normal plasma.
   • If APTT corrects → factor deficiency (the normal plasma supplies the missing factor). This is what happens in haemophilia and vWD.
   • If APTT does NOT correct → an inhibitor is present (antibodies in the patient's plasma immediately inactivate the normal plasma's factors). This is lupus anticoagulant.

3. Sex-linked (X-linked) inheritance: Haemophilia A (Factor VIII deficiency) and B (Factor IX deficiency) are X-linked recessive → almost exclusively affects males. Females are carriers (may have mildly reduced factor levels but usually don't bleed significantly).

4. vWD is autosomal dominant → affects both sexes equally. It is the most common inherited bleeding disorder (prevalence ~1%). ^[1][6]

Why vWD prolongs APTT:

• vWF acts as a carrier protein for Factor VIII in plasma, protecting it from degradation.
• When vWF is low/absent → Factor VIII is rapidly cleared → Factor VIII level drops → APTT prolongs.
• This is why vWD can mimic haemophilia A in lab results.

Treatment:

• DDAVP (Desmopressin): Stimulates release of stored vWF and Factor VIII from endothelial Weibel-Palade bodies. Works well in Type 1 vWD (quantitative deficiency) and mild haemophilia A. Does NOT work in severe forms. ^[1][7]
• Factor concentrates: Plasma-derived concentrates containing vWF (for vWD) or recombinant Factor VIII/IX (for haemophilia). ^[1]

"1. Repeat and confirm. 2. Measure fibrinogen concentration. 3. Measure platelet concentration. 4. 'Disseminated intravascular coagulopathy' — ↑PT, ↑APTT, ↓fibrinogen, ↓platelets, Red blood cell fragmentation. 5. DIC with all these components is a very uncommon clinical situation. 6. Treatment of DIC is to replenish the consumed coagulation factors. 7. Reverse the underlying causative factor." ^[1]

Understanding DIC from first principles:

• DIC is a syndrome, not a disease — always triggered by an underlying cause (sepsis, obstetric catastrophe, malignancy especially APL, massive trauma, snake bite).
• Pathophysiology: Massive, uncontrolled activation of coagulation throughout the microvasculature → consumption of platelets and clotting factors → paradoxical bleeding despite ongoing thrombosis.
• Microangiopathic haemolytic anaemia (MAHA): Red blood cells get sheared as they pass through fibrin strands in small vessels → schistocytes (fragmented RBCs) on blood film. ^[1][8]

Lab hallmarks of DIC:

Management:

1. Treat the underlying cause — this is the MOST IMPORTANT step (e.g., antibiotics for sepsis, delivery of the baby in obstetric DIC, ATRA for APL). ^[1]
2. Replenish consumed factors: FFP (clotting factors), cryoprecipitate (fibrinogen, Factor VIII, vWF), platelet transfusion.

Also remember: If both PT and APTT are prolonged, the deficient factor must be in the common pathway (Factor X, V, prothrombin/II, or fibrinogen/I) OR there is multiple factor deficiency (DIC, severe liver disease). ^[5]

• MOA: Stimulates endogenous release of Factor VIII and vWF from endothelial cell Weibel-Palade bodies
• Indication: Mild haemophilia A (before dental extraction), vWD Type 1
• Side effects: Water retention → hyponatraemia (ADH analogue), facial flushing, headache
• Tachyphylaxis: Repeated use within 24-48 hours → depleted stores → diminishing response

• Avoid contact sports, aspirin/NSAIDs, IM injections
• Early recognition of bleeds: tingling sensation, refusal to move affected limb → RICE
• Factor replacement: prophylactic (3×/week for type A, 2×/week for type B) or on-demand
• Complication: inhibitor formation (antibodies against infused factor) — occurs in ~30% of severe haemophilia A patients, usually in first 10-20 exposure days

• For dental scaling: keep the anticoagulant (low bleeding risk)
• For multiple dental extractions: withhold DOAC 48 hours before
• For renal failure patients on DOACs: withhold even longer

1. "A 22-year-old male presents with prolonged bleeding after tooth extraction. His APTT is prolonged but PT is normal. Platelet count is normal. Discuss the differential diagnosis and further investigations."

   • DDx: Haemophilia A (VIII), Haemophilia B (IX), von Willebrand disease, lupus anticoagulant, heparin contamination
   • Ix: Mixing study (corrects → deficiency; doesn't correct → inhibitor), Factor VIII level, Factor IX level, vWF:Ag, vWF:RCo
   • If Factor VIII low + vWF normal → Haemophilia A
   • If Factor VIII low + vWF low → vWD
   • If mixing study not corrected → lupus anticoagulant

2. "A patient with obstructive jaundice has a prolonged PT. Explain the mechanism and outline treatment."

   • Bile salts needed for Vit K absorption → obstructive jaundice prevents bile reaching gut → Vit K deficiency → ↓ factors II, VII, IX, X → PT prolonged (VII shortest half-life)
   • Treatment: Parenteral (IV) vitamin K → bypasses absorption → corrects PT within 12–24 hours
   • If PT doesn't correct → suspect liver parenchymal disease (synthetic failure)

3. "Compare and contrast the clinical features of platelet disorders versus coagulation disorders."

   • Use the table: petechiae/purpura/mucosal = platelet; haemarthrosis/deep muscle = coagulation

4. "A patient has ↑PT, ↑APTT, ↓fibrinogen, ↓platelets, and schistocytes on blood film. What is the diagnosis and management?"

   • DIC. Treat underlying cause (sepsis → antibiotics; obstetric → deliver baby; APL → ATRA). Replace consumed factors: FFP, cryoprecipitate, platelet transfusion.