Hemophilia A and B

Risk factors

• X-linked recessive inheritance — sons of carrier mothers (50% affected if male), daughters of affected fathers obligate carriers
• Family history
• Spontaneous mutation (~30% of cases — no family history)
• Severity correlates with residual factor activity, not gene location

Pathophysiology

Factor VIII and IX participate in the intrinsic pathway of coagulation (forming the tenase complex that activates factor X). Deficiency impairs thrombin generation and stable fibrin clot formation. Initial platelet plug forms normally (normal primary hemostasis), but the clot is unstable — leading to delayed or prolonged bleeding, especially in joints and muscles where the intrinsic pathway predominates.

Clinical presentation

Differential diagnosis

• Von Willebrand disease — Mucocutaneous bleeding more than joint bleeding; vWF antigen/activity low; factor VIII may be moderately low (vWF carries VIII)
• Acquired hemophilia (factor VIII inhibitor) — Elderly patient, no family history, autoimmune disease or postpartum, prolonged PTT not corrected with mixing study
• Vitamin K deficiency / warfarin — Prolonged PT and PTT, factors II/VII/IX/X reduced, responds to vitamin K
• Liver disease — Multiple factor deficiencies (V, VII, IX, X), low albumin, thrombocytopenia, abnormal LFTs
• Heparin contamination — Prolonged PTT, normal PT, thrombin time prolonged, history of heparin exposure
• Lupus anticoagulant — Prolonged PTT not corrected by mixing study, paradoxically associated with thrombosis (not bleeding)
• Factor XI deficiency (hemophilia C) — Autosomal recessive, common in Ashkenazi Jews, variable bleeding (often only with hemostatic challenge)

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A["Prolonged PTT<br/>Normal PT and platelets"] --> B[Mixing study]
  B --> C{Corrects?}
  C -->|Yes - factor deficient| D[Measure factor VIII,<br/>factor IX, and vWF]
  D --> E{Pattern}
  E -->|VIII low, IX normal, vWF normal| F[Hemophilia A]
  E -->|IX low, VIII normal| G[Hemophilia B]
  E -->|VIII low + vWF low| H[Von Willebrand disease]
  C -->|No - inhibitor present| I[Inhibitor workup]
  I -->|Bethesda titer| J["Factor VIII inhibitor<br/>(acquired hemophilia)"]
  I -->|dRVVT or LA panel| K["Lupus anticoagulant<br/>(thrombosis, not bleeding)"]
  F --> L[Factor VIII replacement<br/>or emicizumab<br/>± DDAVP if mild]
  G --> M[Factor IX replacement<br/>or gene therapy]

Treatment

Complications

• Hemophilic arthropathy — chronic joint destruction from recurrent hemarthrosis; cartilage damage, fixed deformities, disability
• Intracranial hemorrhage — leading cause of death; high mortality even with treatment
• Compartment syndrome from deep muscle bleeding
• Inhibitor development — alloantibodies against factor VIII (~25-30% severe hemophilia A) or IX (~3-5% hemophilia B); reduces efficacy of factor replacement
• Iliopsoas hemorrhage with femoral neuropathy
• Pseudotumors (chronic encapsulated hematomas) eroding bone
• Historic: HIV and HCV from contaminated plasma factor concentrates (pre-1985); modern recombinant products eliminate this risk

PANCE pearls

• Hemophilia A and B are clinically indistinguishable — both X-linked, both with prolonged PTT and joint/muscle bleeding. Distinction requires individual factor assays.
• vWF carries factor VIII in plasma — severe vWD can lower factor VIII and mimic hemophilia A. Always check vWF in apparent hemophilia A.
• Prolonged PTT in a bleeding patient that corrects on mixing study → factor deficiency. Failure to correct → inhibitor (acquired hemophilia or lupus anticoagulant).
• Emicizumab has transformed care for hemophilia A — subcutaneous q1-4 week dosing, effective in patients with and without inhibitors. (HAVEN trials)
• Desmopressin works only for MILD hemophilia A (factor VIII >5%) — not effective for hemophilia B and not sufficient for severe hemophilia A.
• Avoid aspirin and NSAIDs; use acetaminophen and COX-2 inhibitors with caution.
• Carriers (heterozygous females) can have bleeding tendencies; factor levels are quantitatively variable due to lyonization.
• Always treat suspected intracranial bleeding empirically with factor replacement BEFORE imaging — do not delay for CT.

References

• WFH 2020 — WFH Guidelines for the Management of Hemophilia, 3rd edition (Srivastava et al., Haemophilia 2020)
• HAVEN Trials — Emicizumab Prophylaxis in Hemophilia A with Inhibitors (Oldenburg et al., NEJM 2017)
• NHF MASAC — National Hemophilia Foundation Medical and Scientific Advisory Council Recommendations
• Pipe et al. — Etranacogene dezaparvovec for hemophilia B gene therapy (NEJM 2023)
• ISTH SSC 2021 — A new hemophilia carrier nomenclature to define hemophilia in women and girls: communication from the SSC of the ISTH (van Galen et al., J Thromb Haemost 2021;19:1883-1887)