Hemophilia - Factor VIII or IX Deficiency

Indications for Testing

Spontaneous or prolonged bleeding suggestive of coagulation disorder
Family history of hemophilia
Acute or recent onset bleeding accompanied by prolonged partial thromboplastin time (PTT)

Initial Laboratory Testing for Coagulation Disorders

CBC with platelet count – normal in hemophilia A, B
Platelet function analysis (bleeding time) – normal in hemophilia A, B
Bleeding disorders panel
- Prothrombin time (PT) – normal in hemophilia A, B
- PTT – prolonged in moderate and severe hemophilia
  - May not be prolonged in mild cases or in female carriers
  - Prolonged PTT that corrects in a mixing study suggests factor deficiency
    - PTT mixing study shows evidence of an inhibitor in hemophilia A or B patients with FVIII or FIX inhibitors
      - Incubated mixing studies are often necessary to identify FVIII inhibitors
      - PTT mixing study will not correct in acquired hemophilia
Thrombin clotting time and plasma concentration of fibrinogen – normal in hemophilia A and B

Laboratory Testing for Hemophilia

FVIII activity level – decreased in hemophilia A
FIX activity level – decreased in hemophilia B
- Not reliable for carrier status detection in females
- Measurement in neonate may need to be repeated when family history of mild disease exists
von Willebrand factor (vWF) level – normal
- Because vWF is a carrier for FVIII, von Willebrand disease (vWD) should be ruled out in patients with decreased FVIII levels
- A rare subtype of vWD (type 2N) has isolated low FVIII activity with normal vWF level and mimics hemophilia A
  - Specialized coagulation or genetic testing can be used to distinguish these disorders
Genetic testing to confirm the causative F8 or F9 mutation in affected individuals
- Patient risk should be calculated by a clinical geneticist using laboratory results and family history
Genetic testing to determine carrier status in at-risk females

Prognosis

Improved prognosis with the advent of FVIII and FIX replacement
Major disability from bleeding – joint disease
Leading cause of death from bleeding – intracranial hemorrhage

Differential Diagnosis

vWD
Rare coagulation factor deficiencies
- FII, FV, FVII, FX, FXI, FXII
- Fibrinogen
- Deficiencies of factor XII, prekallikrein, and high molecular weight kininogen prolong the PTT but do not result in a bleeding tendency
Fibrinolytic disorders
Qualitative platelet function disorders

Hemophilia A and hemophilia B are bleeding disorders caused by genetic mutations in the F8 or F9 genes that result in deficiencies of factor VIII (FVIII) and factor IX (FIX) respectively. These disorders are clinically indistinguishable and present with bleeding symptoms ranging from mild to severe depending on the underlying defect.

Epidemiology

Incidence
- Hemophilia A – 1/4,000-5,000 male births worldwide; rare in females
- Hemophilia B – 1/25,000 male births worldwide; rare in females
- Acquired hemophilia – 1-2/1,000,000 worldwide
  - <1/1,000,000 in children
Age
- Severe disease usually detected in first year of life
- Moderate disease detected before age 5
- Mild disease detected later in life
- Acquired disease – bimodal peaks at 20-40 years and 60-90 years
Types
- Hemophilia A – FVIII deficiency
- Hemophilia B – FIX deficiency
- Acquired hemophilia – autoimmune disorder caused by antibodies to FVIII or rarely FIX

Inheritance

Hemophilia A
- X-linked recessive F8 mutations
  - Penetrance – 100% in males, 10% in females
  - Female offspring of affected males are obligate carriers
    - 10% of female carriers are symptomatic, typically with mild disease
  - In probands with no apparent family history of hemophilia, >80% of mothers are identified as carriers; 10-15% of probands show de novo F8 mutations
  - ~ 1,800 F8 sequence variants reported to date
- Some genotype/phenotype correlations exist for hemophilia A
  - Molecular causes for severe disease
    - Intron 22A inversion – 48%
    - Point mutations – 43%
    - Large gene deletions – 6%
    - Intron 1 inversion – 3%
  - Molecular causes for moderate to mild disease
    - Point mutations or small insertions/deletions – 98%
    - Large gene deletions – <1%
- In probands which appear to have no family history of hemophilia, >80% of mothers are identified as carriers; the remaining 10-15% of probands show de novo F8 mutations
Hemophilia B
- X-linked recessive F9 mutations
  - Penetrance – 100% in males, 10% in females
  - Female offspring of affected males are obligate carriers
    - 10% of female carriers are symptomatic, typically with mild disease
  - ~33-50% of apparently isolated hemophilia B cases result from de novo mutations
  - ~900 F9 sequence variants reported to date

Clinical Presentation

Presentation of hemophilia A is clinically indistinguishable from hemophilia B
Excessive bleeding – occurs spontaneously or from trivial injury
- Common bleeding manifestations – hemarthrosis, hematomas, gastrointestinal bleeding, genitourinary bleeding
Frequency and severity of excessive bleeding based on FVIII or FIX activity
- Mild disease (6-40% factor activity) – bleeding may occur with major trauma or surgery; no spontaneous bleeding
  - Carrier females – 10% have mild disease (<40% factor activity) and are at risk for excessive bleeding
- Moderate disease (1-5% factor activity) – bleeding may occur with minimal trauma or minor surgery; spontaneous bleeding rare
- Severe disease (<1% factor activity) – high risk of severe, spontaneous bleeding
Acquired disease is indistinguishable from inherited disease except that it rarely occurs in children
- Associated conditions
  - Autoimmune – systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren syndrome, Goodpasture syndrome, myasthenia gravis, inflammatory bowel disease
  - Cancer – lymphomas, plasma cell dyscrasia, myelodysplastic syndrome
  - Dermatologic – psoriasis, pemphigus
  - Hepatitis B or C infection (acute)
  - Drugs

Treatment

Refer to a federally funded hemophilia treatment center (HTC) for assessment, education, and genetic consultation
Severely affected individuals – to prevent spontaneous bleeding, prophylactic FVIII or FIX infusions (factor concentrates, recombinant FVIII or IX) to maintain activity at 1-3%
Mild hemophilia A – desmopressin for prophylaxis or treatment
Factor replacement (factor concentrates, recombinant) used for acute bleeding
Carrier females – monitor for delayed bleeding post-partum unless baseline FVIII or IX clotting activity is previously identified as normal
At-risk individuals – until disease is ruled out or diagnosed and appropriately treated, avoid anti-platelet drugs, intramuscular injections, activities with high trauma risk, circumcision
Administer antifibrinolytic agents in applicable situations

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use: