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

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

The cartoon is a sequence, not three unrelated shapes: a resting discoid platelet becomes spiculated, releases granule contents, and then joins an aggregate. GPIIb/IIIa is already present on the platelet surface; activation changes it into a high-affinity conformation that can bind fibrinogen.

"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]

Reading the receptor/signalling diagram

The bottom of the figure is the damaged vessel wall; the top is the growing platelet plug:

1. Tethering/adhesion: collagen-bound vWF captures platelet GPIb-IX-V, while GPVI and integrin α2β1 (GPIa/IIa) engage collagen more directly.
2. Signal convergence: ADP (P2Y receptors), thrombin (PAR receptors), thromboxane A₂, serotonin, adrenaline, collagen, and PAF use different receptors but converge on intracellular signalling, especially increased cytosolic Ca²⁺.
3. Inside-out activation: signalling switches GPIIb/IIIa into its ligand-binding state.
4. Aggregation: fibrinogen bridges activated GPIIb/IIIa on adjacent platelets. The bridge is therefore platelet–GPIIb/IIIa–fibrinogen–GPIIb/IIIa–platelet, not platelet binding directly to platelet.

This explains why blocking one amplification arm (aspirin or a P2Y12 inhibitor) weakens recruitment, whereas a GPIIb/IIIa inhibitor blocks the final common aggregation step.

"(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.

How to read the slide's cascade figure: The tissue-factor–VIIa complex is the initiation arm; IXa–VIIIa is the platelet-surface tenase complex that generates Xa; Xa–Va is the prothrombinase complex that generates the thrombin burst. Both enzyme–cofactor complexes assemble on an activated phospholipid surface and require Ca²⁺. Thrombin then feeds back to activate platelets and cofactors V, VIII, and XI, before XIIIa cross-links soluble fibrin into an insoluble mesh. Strictly, it is Xa with Va, not inactive factor X alone, that converts prothrombin to thrombin.

"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. When drug-level assessment is specifically indicated, an anti-Xa assay—not APTT—is used. ^[4]

Anti-Xa monitoring is not routine for every LMWH course; it is reserved for selected situations according to local protocol. PT/APTT are also poor universal screens for direct oral anticoagulant effect: a normal result does not reliably exclude a clinically important level of every DOAC. ^[10]

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: Pancytopenia broadens the differential to marrow failure/infiltration, drugs or toxins, infection, nutritional deficiency, hypersplenism, and other systemic disease. It does not automatically mean marrow failure or mandate immediate marrow biopsy. Conversely, isolated thrombocytopenia is compatible with ITP but can also reflect drugs, infection, liver disease/hypersplenism, microangiopathy, or laboratory artefact; review the film and clinical context before assigning mechanism.
3. Causes of isolated thrombocytopenia:
   • Immune thrombocytopenic purpura (ITP): Autoantibodies against platelet surface glycoproteins → splenic destruction
   • Chronic liver disease / hypersplenism: Portal hypertension causes splenic sequestration and liver disease may reduce thrombopoietin; this is not simply immune “destruction”
   • Drug-induced: Heparin (HIT), quinine, sulfonamides, etc.
4. Assess bleeding risk: Look for active mucosal or gastrointestinal bleeding, neurological symptoms, haemodynamic compromise, recent procedures/trauma, anticoagulant or antiplatelet exposure, and the platelet trend. Fundoscopy may identify retinal bleeding when clinically indicated, but it is not a validated surrogate or screening test for intracranial haemorrhage; neurological red flags require urgent neuroimaging.
5. Treatment:
   • Platelet transfusion: Thresholds depend on cause, bleeding, and procedure. A count < 10 × 10⁹/L is a prophylactic threshold only in selected non-bleeding populations, not a universal rule. ^[9]
   • ITP: Treat the patient and bleeding risk, not the count alone. Corticosteroids or IVIg are common initial therapies when treatment is needed; in critical bleeding, platelet transfusion is an adjunct because transfused platelets may be rapidly destroyed. TPO-receptor agonists are established second-line options in persistent/chronic disease rather than being defined simply as “refractory.” ^[16]

"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.
• Vitamin K can be given orally or by slow IV administration depending on urgency and cause; avoid intramuscular injection in a coagulopathic patient because of haematoma risk.
• A response supports vitamin K deficiency, but it is not a clean binary test of “obstruction versus liver failure”: cholestasis, poor intake/antibiotics, warfarin exposure, and impaired hepatic synthesis can coexist.

Warfarin overdose management:

• First define major/life-threatening bleeding and control the bleeding source; a high INR without bleeding is managed differently.
• For major warfarin-related bleeding, give four-factor PCC plus IV vitamin K for rapid and sustained reversal. FFP is an alternative when 4F-PCC is unavailable, but is slower and requires a much larger volume. ^[10]
• Reassess anticoagulation indication and restart timing once haemostasis is secured; reversal is not the end of management.

"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: A common inpatient artefact is blood drawn from a line that was flushed with heparin. Repeat a correctly collected peripheral sample when contamination is plausible; do not assume it is universally the commonest cause in every setting.

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).
   • In vivo, persistent LA may be associated with thrombosis or pregnancy morbidity, but the antibody alone does not diagnose antiphospholipid syndrome.
   • LA by itself usually does not explain bleeding; rare exceptions include lupus-anticoagulant hypoprothrombinaemia or a coexisting haemostatic defect. ^[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 → a factor deficiency is likely (the normal plasma supplies the missing factor).
   • If APTT does not correct → consider an inhibitor or anticoagulant effect, including LA, a specific factor inhibitor, heparin, or a DOAC. Some factor VIII inhibitors are time-dependent, so an initially corrected mixture may prolong after incubation. A mixing study classifies the pattern; it does not identify LA by itself.

3. X-linked inheritance: Haemophilia A and B are X-linked, but “male = affected, female = asymptomatic carrier” is too rigid. Heterozygous women can have reduced factor levels and clinically important bleeding; rarely, women have haemophilia through skewed X-inactivation or other genetic mechanisms. Measure factor levels and assess bleeding phenotype rather than assuming sex excludes disease. ^[14]

4. vWD affects both sexes, but inheritance depends on subtype: type 1 and most type 2 are autosomal dominant; types 2N and 3 are autosomal recessive. ^[12]

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. Confirm response when feasible. It is ineffective in type 3 vWD and generally contraindicated in type 2B because it can worsen thrombocytopenia; it should not be sole therapy for major surgery. Restrict free water and monitor for hyponatraemia. ^[11]
• Factor concentrates: Plasma-derived concentrates containing vWF (for vWD) or recombinant Factor VIII/IX (for haemophilia). ^[1]
• Antifibrinolytic therapy: Tranexamic acid is particularly useful for oral/mucosal bleeding and minor dental procedures, often combined with DDAVP or vWF concentrate according to subtype, baseline levels, and procedure. ^[11]

"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. Support haemostasis when clinically indicated: FFP, fibrinogen replacement/cryoprecipitate, and platelets are generally reserved for active bleeding or a high-risk procedure, guided by serial clinical and laboratory assessment—not given simply to normalise abnormal numbers. ^[15]

DIC is dynamic. Combine the clinical trigger and organ/bleeding findings with serial platelet count, PT, fibrin-related markers (such as D-dimer), and fibrinogen; an ISTH-style score can support overt DIC, but no single result diagnoses it.

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: Selected mild haemophilia A and DDAVP-responsive vWD; establish response and check contraindications rather than prescribing by label alone
• Side effects: Water retention → hyponatraemia (ADH analogue), facial flushing, headache
• Tachyphylaxis: Repeated use within 24-48 hours → depleted stores → diminishing response

• Avoid aspirin and most NSAIDs unless specifically advised. Plan sports, exercise, and intramuscular injections with the haemophilia team according to bleeding phenotype, prophylaxis, and the activity/procedure rather than applying a blanket prohibition.
• Suspected joint or muscle bleeding needs prompt haemostatic treatment and haemophilia-centre advice; supportive measures do not replace factor/non-factor therapy.
• Modern prophylaxis is individualised by phenotype, product half-life, pharmacokinetics, joint status, activity, access, and patient preference; fixed “three-times/two-times weekly” schedules are not universal, and non-factor prophylaxis is available for haemophilia A. ^[14]
• Inhibitors reduce treatment response and require specialist testing/management; risk is greatest early in exposure but is not confined to a fixed number of days. ^[14]

• For a procedure with low bleeding-complication risk, current SDCEP guidance advises treatment without interrupting the DOAC, using local haemostatic measures.
• For a higher-risk dental procedure, the usual approach is to miss the morning apixaban/dabigatran dose or delay the morning rivaroxaban/edoxaban dose—not an automatic 48-hour interruption. ^[13]
• Timing must be individualised for renal function, dose schedule, indication/thrombotic risk, procedure, and local guidance; liaise with the prescriber/haematology team rather than inventing a longer interruption.