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PA20.1-2 | Coagulation Factor Disorders — Haemophilia & vWD — Part 3

Acquired Coagulation Factor Deficiencies

⚑ AI image — pending faculty review (auto-QA score 7/10; best of 3 attempts)

Acquired deficiencies are far more common in clinical practice than inherited haemophilias.

Liver disease:
The liver synthesises all coagulation factors except factor VIII and von Willebrand factor. In cirrhosis or acute liver failure:
• Factors II, V, VII, IX, X, XI, XII, fibrinogen are all reduced
• Factor VIII is preserved (or elevated)
• Both PT and aPTT are prolonged
• Thrombocytopenia co-exists (splenic sequestration + reduced thrombopoietin)
• Vitamin K–dependent factors (II, VII, IX, X) fall first and furthest

Vitamin K deficiency:
Vitamin K is essential for gamma-carboxylation of factors II, VII, IX, and X (and anticoagulant proteins C and S). Deficiency causes:
• Early: isolated prolonged PT (factor VII falls first)
• Late: both PT and aPTT prolonged
• Causes: dietary deficiency, fat malabsorption (cholestasis, coeliac), prolonged antibiotic use (destroys gut bacteria that synthesise menaquinone), neonatal haemorrhagic disease
• Treatment: parenteral (IV/IM) vitamin K₁ (phytomenadione); corrects PT within 6–24 h

Anticoagulants (therapeutic and accidental):
• Warfarin (vitamin K antagonist) → both PT and aPTT prolonged
• Heparin → aPTT prolonged (PT may also be prolonged at high doses); not corrected by vitamin K
• Direct oral anticoagulants (DOACs) — dabigatran (thrombin inhibitor), rivaroxaban/apixaban (Xa inhibitors) — may not be detected on standard PT/aPTT; require specific assays

CLINICAL PEARL

The liver vs. vitamin K trap: Both liver disease and vitamin K deficiency reduce factors II, VII, IX, and X. The key differentiating laboratory test is factor V level: factor V requires no vitamin K for synthesis (it is not gamma-carboxylated). In liver disease, factor V is LOW (hepatocytes cannot produce it). In vitamin K deficiency, factor V is NORMAL. This single test distinguishes the two in a critically ill jaundiced patient.

Haemarthrosis and Haemophilic Arthropathy

Three-panel diagram showing progression from acute haemarthrosis to chronic synovitis and end-stage haemophilic arthropathy, with target joints and prophylaxis highlighted. — **Panel A:** Acute haemarthrosis showing blood in synovial space, distended joint capsule, intact articular cartilage, normal subchondral bone, and normal synovium.. **Panel B:** Chronic synovitis showing haemosiderin deposits, thickened proliferative synovium, activated macrophages, early pannus formation, and early cartilage damage.. **Panel C:** End-stage haemophilic arthropathy showing cartilage loss, narrowed joint space, subchondral bone erosion, extensive pannus, joint deformity, and ankylosis.. **Bottom flow strip:** Pathogenesis sequence: repeated bleeding, haemosiderin deposition, chronic inflammatory synovitis and pannus, protease-mediated cartilage destruction, bone erosion and ankylosis.. **Prevention inset:** Primary prophylactic factor replacement starting at age 1-2 years before first joint bleed prevents arthropathy.. **Target joint inset:** Human outline highlighting knees, elbows, and ankles as common target joints in severe haemophilia..

Haemarthrosis is the most characteristic complication of severe haemophilia and the leading cause of disability in affected patients.

Pathogenesis of joint damage:
1. Repeated bleeding → blood accumulates in the synovial space
2. Synovitis: Iron (haemosiderin) deposits in the synovium → chronic inflammatory synovitis; synovial proliferation (pannus)
3. Cartilage destruction: Proteases released by activated macrophages and synovial cells degrade articular cartilage
4. Subchondral bone erosion → loss of joint space → ankylosis
5. End-stage: fixed, deformed joint — haemophilic arthropathy

Target joints in haemophilia: knees, elbows, ankles (weight-bearing + highly mobile joints subjected to repeated minor trauma).

Three-panel diagram showing progressive stages of haemophilic arthropathy from acute bleeding to chronic joint destruction. — **Panel A:** Acute haemarthrosis with blood in joint space, normal cartilage and bone structure. **Panel B:** Chronic synovitis with hemosiderin deposits, synovial thickening, and early pannus formation. **Panel C:** End-stage arthropathy with cartilage loss, bone erosion, and extensive pannus formation.

Prophylactic factor replacement (primary prophylaxis starting before the first joint bleed, at age 1–2 years) is the current standard of care for severe haemophilia — it prevents arthropathy entirely if started early. This is a major advance over on-demand treatment, which waits until bleeds occur.

SELF-CHECK

In a patient with severe liver cirrhosis and a coagulopathy, which of the following coagulation factor levels would most likely be NORMAL or even ELEVATED?

A. Factor II (prothrombin)

B. Factor V

C. Factor VII

D. Factor VIII

Reveal Answer

Answer: D. Factor VIII

Factor VIII is the only major procoagulant factor NOT synthesised by hepatocytes — it is produced primarily by vascular endothelial cells (Weibel-Palade bodies) and can act as an acute-phase reactant, remaining normal or elevated in liver disease. All other listed factors (II, V, VII) are hepatically synthesised and fall in liver failure. This is also the key to distinguishing liver disease (low factor V) from vitamin K deficiency (normal factor V).

SELF-CHECK

A patient's mixing study shows that the prolonged aPTT corrects immediately on 1:1 mixing with normal plasma but fails to correct after 2 hours of incubation at 37°C. What is the most likely explanation?

A. Time-dependent (warm-reacting) factor VIII inhibitor

B. Lupus anticoagulant

C. Factor XII deficiency

D. Severe factor IX deficiency

Reveal Answer

Answer: A. Time-dependent (warm-reacting) factor VIII inhibitor

Immediate correction followed by prolongation after warm incubation is the hallmark of a time-dependent (warm-reacting) inhibitor, most classically the acquired IgG factor VIII inhibitor seen in acquired haemophilia A. Lupus anticoagulant does not correct even on immediate mixing. Factor deficiencies (XII, IX) correct immediately and remain corrected after incubation.

Laboratory Summary — Distinguishing Factor Disorders at a Glance

A four-panel laboratory comparison infographic distinguishes haemophilia A, haemophilia B, and von Willebrand disease using PT, aPTT, platelet count, BT/PFA, and confirmatory assays. — **Panel A:** Comparison matrix showing Haemophilia A, Haemophilia B, vWD Type 1, vWD Type 3, PT, aPTT, platelet count, BT/PFA, Factor VIII assay, Factor IX assay, ristocetin cofactor, and vWF antigen.. **Panel B:** Coagulation screening pathways showing extrinsic pathway, intrinsic pathway, common pathway, PT, aPTT, Factor VIII, Factor IX, Factor X, thrombin, and fibrin.. **Panel C:** Platelet adhesion mechanism showing damaged endothelium, exposed collagen, von Willebrand factor bridge, platelet GPIb receptor, platelet adhesion, and prolonged BT/PFA in vWD.. **Panel D:** Diagnostic flowchart distinguishing isolated prolonged aPTT with normal BT/PFA from increased BT/PFA with or without prolonged aPTT..

Disorder	PT	aPTT	Platelets	BT/PFA	Key specific test
Haemophilia A	N	↑	N	N	Factor VIII assay ↓
Haemophilia B	N	↑	N	N	Factor IX assay ↓
vWD Type 1	N	N / ↑	N	↑	Ristocetin cofactor ↓; vWF antigen ↓
vWD Type 3	N	↑	N	↑	vWF antigen markedly ↓; Factor VIII also ↓
Liver disease	↑	↑	↓	Variable	Factor V ↓; Factor VIII N/↑
Vitamin K def. (early)	↑	N	N	N	Factor VII ↓; Factor V N
Vitamin K def. (late)	↑	↑	N	N	Factors II, VII, IX, X ↓
Haemophilia A + inhibitor	N	↑ (no correction)	N	N	Mixing study: no correction

N = Normal; ↑ = prolonged/elevated; ↓ = reduced

This table is the key discriminator for long-case presentations and USMLE-style single-best-answer questions. Commit the PT/aPTT column to memory — then the specific test column follows logically from pathway anatomy.