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

CLINICAL SCENARIO

A 9-year-old boy is brought to casualty with a massively swollen, painful right knee after a minor fall in the playground. His mother mentions that a similar episode happened six months ago in the left knee, and that he had prolonged bleeding after a milk-tooth extraction. His younger maternal uncle had a similar problem in childhood. The platelet count and bleeding time are normal. Why is this child's problem so different from a child with thrombocytopenia — and what does the swollen joint tell you about where haemostasis has failed?

WHY THIS MATTERS

Coagulation factor disorders are high-yield for both clinical examinations and long-case presentations. You will be expected to interpret a coagulation screen (PT/aPTT), formulate a differential, and recommend first-line investigations. In clinical postings, you will encounter acquired factor deficiencies — from liver disease and malnutrition — more often than inherited haemophilias, but the haemophilias teach the physiology most sharply. Understanding the mixing study today will serve you in haematology, surgery, and obstetrics rotations.

RECALL

Before proceeding, recall from SDL1:

The coagulation cascade has an extrinsic pathway (tissue factor → factor VII → X), an intrinsic pathway (XII → XI → IX → VIII → X), and a common pathway (X → V → prothrombin → thrombin → fibrinogen → fibrin).
PT (prothrombin time) tests the extrinsic + common pathways; aPTT (activated partial thromboplastin time) tests the intrinsic + common pathways.
Primary haemostasis (platelet plug) is tested by bleeding time / PFA-100; secondary haemostasis (fibrin) is tested by PT and aPTT.
vWF bridges platelets to subendothelial collagen — this was introduced in SDL1 and becomes critical here.

The Pattern of Secondary Haemostasis Failure

Four-panel diagram comparing primary and secondary haemostasis failure, showing failed fibrin stabilisation, delayed rebleeding, deep tissue bleeding, and haemarthrosis. — **Panel A:** Vascular injury, platelet plug, failed fibrin mesh stabilisation, coagulation factors, red blood cells. **Panel B:** Primary failure with petechiae and mucosal bleeding versus secondary failure with deep muscle and joint bleeding. **Panel C:** Immediate prolonged ooze, initial haemostasis, delayed rebleeding hours later, delayed post-surgical haemorrhage at 6-12 h. **Panel D:** Haemarthrosis with joint space blood, synovitis, articular cartilage destruction, repeated bleeding episodes.

When the fibrin-forming step of haemostasis fails, the initial platelet plug forms but cannot be consolidated into a stable clot. This produces a characteristic deep-tissue bleeding pattern that is completely different from the mucocutaneous bleeding of platelet disorders:

Feature	Primary failure (platelets/vWF)	Secondary failure (coagulation factors)
Site	Skin, mucous membranes	Deep: joints, muscles, retroperitoneum
Petechiae	Present	Absent
Haemarthrosis	Rare	Hallmark
After cuts	Immediate, prolonged	Stops initially, rebleeds hours later
After surgery	Immediate ooze	Delayed haemorrhage (6–12 h)

Haemarthrosis (bleeding into a joint space) is pathognomonic of secondary haemostasis failure. Repeated episodes → synovitis → cartilage destruction → haemophilic arthropathy, a crippling end-stage complication.

Muscle haematomas, retroperitoneal bleeds, and intracranial haemorrhage are the other life-threatening manifestations. The delay between injury and significant bleeding reflects the time needed for the platelet plug to be overwhelmed in the absence of fibrin reinforcement.

Haemophilia A — Factor VIII Deficiency

A four-panel educational diagram explaining haemophilia A genetics, Factor VIII function in the intrinsic pathway, severity classification, and laboratory-clinical features. — **Panel A:** X-linked recessive inheritance, carrier female, affected male, F8 gene mutation, Xq28 locus, intron 22 inversion in severe cases. **Panel B:** Intrinsic tenase complex, Factor IXa, Factor VIIIa cofactor, platelet phospholipid surface, calcium ions, Factor X activation, reduced thrombin generation, unstable fibrin clot. **Panel C:** Severity classification by residual Factor VIII level: severe <1%, moderate 1-5%, mild 5-40%, with corresponding bleeding manifestations. **Panel D:** Laboratory features and clinical relevance: prolonged aPTT, normal PT, normal platelet count, haemarthrosis of knee joint.

Haemophilia A is the commonest inherited coagulation factor disorder, accounting for ~80% of all haemophilias.

Genetics: X-linked recessive. The F8 gene on Xq28 is mutated. Females are carriers (usually asymptomatic); males are affected. ~30% arise from new mutations — a family history may be absent.

IMPORTAN: The most common F8 mutation is an inversion of intron 22, found in ~45% of severe cases.

Pathogenesis: Factor VIII is the non-enzymatic cofactor for factor IXa in the tenase complex of the intrinsic pathway. Without adequate VIII, the intrinsic pathway cannot efficiently activate factor X → thrombin generation is severely impaired → unstable clot.

Severity classification (by residual factor VIII level):

Severity	Factor VIII level	Clinical manifestation
Severe	< 1%	Spontaneous haemarthroses, life-threatening bleeds
Moderate	1–5%	Bleeds with minor trauma
Mild	5–40%	Bleeds only with major trauma/surgery

Laboratory features:
• aPTT — prolonged (intrinsic pathway defective)
• PT — normal (extrinsic pathway intact)
• Platelet count — normal
• Bleeding time / PFA-100 — normal
• Specific factor VIII assay — reduced

IMPORTAN: Isolated prolonged aPTT with normal PT in a male with haemarthroses = Haemophilia A until proven otherwise.

Inhibitors: ~30% of severe haemophilia A patients develop IgG alloantibodies (inhibitors) against infused factor VIII concentrate. This is detected by the mixing study (covered below) and makes treatment far more difficult.

X-linked recessive inheritance pedigree for Haemophilia A alongside clinical comparison of Haemophilia A versus Haemophilia B. — **Panel A:** X-linked recessive pedigree showing carrier mother (X^H X^h), affected son (X^h Y), carrier daughters (X^H X^h), normal son (X^H Y) with inheritance patterns. **Panel B:** Clinical comparison table contrasting Haemophilia A (Factor VIII deficiency) versus Haemophilia B (Factor IX deficiency) including genetics, frequency, presentation, and treatment.

Treatment principle: On-demand or prophylactic recombinant factor VIII concentrate. Desmopressin (DDAVP) releases endogenous vWF-bound factor VIII and is useful in mild disease.

Haemophilia B — Christmas Disease

Three-panel medical infographic explaining Haemophilia B as Factor IX deficiency, its X-linked inheritance, and the diagnostic need for specific Factor VIII and IX assays. — **Panel A:** Intrinsic coagulation pathway with Factor XII, Factor XI, Factor IX, Factor VIII cofactor, Factor X, and highlighted 'Factor IX deficiency or dysfunction'.. **Panel B:** X-linked recessive pedigree showing carrier mother, unaffected father, affected male child, carrier female child, and F9 gene location at Xq27.. **Panel C:** Clinical and laboratory features: recurrent haemarthrosis, prolonged aPTT, normal PT, normal platelet count, normal bleeding time, and specific Factor VIII and Factor IX assays..

Haemophilia B (Christmas disease) is caused by deficiency or dysfunction of factor IX (the Christmas factor), accounting for ~15–20% of all haemophilias.

Key facts:
• Also X-linked recessive (F9 gene, Xq27)
• Clinically indistinguishable from Haemophilia A: same deep-tissue bleeding pattern, same severity classification, same aPTT prolongation with normal PT
• Diagnosis requires specific factor IX assay to differentiate from Haemophilia A
• Treatment: recombinant factor IX concentrate
• Historically important: Christmas disease was named after Stephen Christmas, the first patient studied in 1952 — separating it from Haemophilia A and proving that haemophilia was not a single disease

Examination trap: When presented with an isolated prolonged aPTT, you must assay both factor VIII and factor IX to distinguish the two haemophilias. The mixing study (below) tells you only whether a factor is deficient — not which one.

SELF-CHECK

A 14-year-old male presents with recurrent haemarthroses. His aPTT is prolonged and PT is normal. His platelet count and bleeding time are normal. Which single investigation would best differentiate Haemophilia A from Haemophilia B?

A. Ristocetin cofactor assay

B. Bone marrow examination

C. Mixing study with normal plasma

D. Specific factor VIII and factor IX assays

Reveal Answer

Answer: D. Specific factor VIII and factor IX assays

Both haemophilias share identical clinical and basic coagulation profiles (isolated prolonged aPTT). The mixing study distinguishes factor deficiency from inhibitor, but does not identify which factor is absent. Only specific factor assays for VIII and IX will discriminate between the two conditions. Ristocetin cofactor assay is used for von Willebrand disease diagnosis.