Haemophilia

Question 1

Genetic inheritance of haemophilia A & B?

Answer 1

X linked, recessive (primarily affects males with female carriers)

Sporadic mutations are, however, also quite common

Question 2

Factors deficiencies in haemophilia A and B

Answer 2

Haemophilia A: factor VIII deficiency

Haemophilia B: factor IX deficiency

Question 3

Haemophilia C and acquired factor deficiencies?

Answer 3

• Haemophilia C - (inherited) factor XI deficiency. More common in Ashkenazi Jews. Provoked bleeding.
• Acquired factor deficiencies are caused by autoautibodies (often to factor VIII) and are sometimes called acquired haemophilia.

Question 4

What are ‘inhibitors’ in the realm of haemophilia?

Answer 4

An antibody that forms in response to infused factor - more common in individuals with very low baseline factor levels (severe disease).

Question 5

How do we grade haemophilia severity?

Answer 5

Based on the baseline factor activity level - usually corresponds to the degree of bleeding.

• Severe haemophilia: <1% factor activity (<0.01 IU/mL)
• Moderate haemophilia: 1-5% factor activity (>0.01 to <0.05IU/mL)
• Mild haemophilia: factor level >5 and <40% of normal (>0.05 and < 0.40IU/mL)

Question 6

Epidemiology of haemophilia A and B - sex, incidence and percentage with severe disease

Answer 6

Mostly males as X lined (severe disease almost exclusively males)

Haemophilia A more common: 1 in 5000, 2/3 of which have severe disease

Haemophilia B less common: 1/15000-30000, and 1/3 to 1/2 have severe disease

Question 7

What is haemophilia B leyden?

Answer 7

Leyden phenotype: severe bleeding in childhood, that progressively becomes milder after puberty.

Due to mutations in factor IX promote (rather than coding region). Expression is changed (i.e. factor IX increased) by hormonal state after puberty

Question 8

Sites of bleeding in infants with severe haemophilia?

Answer 8

CNS, cephalohaematoma, sites of medical interventions

3-5% of infants with severe haemophilia will develop subgaleal or IC haemorrhage

Question 9

Where do adults with severe haemophilia bleed?

Answer 9

Joints & muscles (80%), CNS (less commonly), oral, GI tract, genitourinary tract

Question 10

What is a ‘target joint’?

Answer 10

Once joint damage and inflammation occurs post bleed, a joint is more susceptible to further bleeding and can becomes a ‘target joint’

Prevention, early diagnosis and prompt treatment of haemarthroses may preserve joints and delay progression

Question 11

Complications of muscular bleeding?

Answer 11

Bleeding may compromise NV structures & cause compartment syndrome…
Especially quads, iliopsoas, arm.

Question 12

Females with haemophilia mutations?

Answer 12

Females are heterozygotes with one abnormal allele - therefore they are expected to have 50% of factor function (generally sufficient to prevent bleeding). If they do bleed, it’s mild, unless they inherit two bad genes, or lose parts of the X chromosome that contain the normal alleles (i.e. possibly in Turner’s syndrome)

Question 13

Diagnostic tests?

Answer 13

PT, APTT and Plt count.
If APTT is prolonged, do mixing studies. If APTT corrects, this indicates factor deficiency (rather than an inhibitor).
Then measure factor levels.

Ensure to exclude vWD (VWF:Ag testing) if factor VIII deficiency is found.

Consider genetic testing in female carriers to identify the familial mutation.

Question 14

APTT in mild haemophilia?

Answer 14

A normal APTT does not exclude mild haemophilia (factor levels >15% can have normal APTT) . If you have a high index of suspicion, do factor levels anyway.

Question 15

What condition must you exclude if testing identifies a reduced factor VIII Level?

Answer 15

VWD! Type 2N and 3 VWD have decreased factor VIII levels, because vWF stabilises circulating factor VIII. Test with VWF:Ag

Question 16

What can interfere with factor testing (4)?

Answer 16

1. Factor VIII is an acute phase reactant. Higher in periods of illness/stress.
2. All newborns have reduced factor IX levels at birth
3. Lupus anticoagulant can interfere with coagulation in vitro
4. Factor inhibitors may cause factor depletion. Test with inhibitor assay. Situations include malignancy, rheumatological disease, postpartum

Question 17

Common genetic mutations in haemophilia A and B

Answer 17

1. Mild haemophilia A: point mutation in F8 gene (90%)
2. Severe haemophilia A: inversion in intron 22 (40-50%)
3. Haemophilia B: variety of F9 mutations

Question 18

Where is the mutation in haemophilia C?

Answer 18

Autosomal (i.e. not X linked). Everyone can be carriers or have disease.

Question 19

Diagnostic criteria for haemophilia A

Answer 19

Factor VIII activity <40% (<0.40 IU/mL) OR
activity >40% but with pathogenic F8 gene variant.
Ensure VWF:Ag normal

Question 20

Diagnostic criteria for haemophilia B

Answer 20

Factor IX level <40% (or >40% but with pathogenic F9 mutation).

Question 21

Differential diagnoses for haemophilia

Answer 21

1. VWD - inherited bleeding disorder that may be associated with prolonged APTT (and may have reduced factor VIII). Autosomal transmission. Disease severity similar in males & females
2. Inherited platelet disorders. Should have normal coags. Autosomal, not X linked
3. Haemophilia C - exhibit provoked rather than spontaneous bleeding. Factor XI deficiency
4. Other factor deficiencies (e.g. factor XII) - not associated with clinical bleeding
5. Acquired factor inhibitors (factors VIII, XIII). Most commonly present in adulthood. Prolonged APTT, mixing studies do NOT correct.

Question 22

Management of serious, life threatening bleeding?

Answer 22

Urgent factor concentrate to target factor levels of 80-100%

Question 23

Management of joint / muscle bleeding?

Answer 23

Factor concentrate infusion within 2 hours, to target factor levels of 50%

Bed rest
Toilet privileges only
Elevate and ice pack
Surgeons involved if worried about compartment syndrome

Question 24

Management of bleeding in a patient with inhibitors?

Answer 24

Challenging.
- For patients with a high titre of inhibitor, use a bypassing product (FEIBA or recombinant factor VIIa)
- For patients with a low titre or low-respodning inhibitor, give factor concentrates or other haemostatic agents

Question 25

Additional therapies during bleeding

Answer 25

• Antifibrinolytics: in areas of increased fibrinolysis (oral/nasal)
• Mild haemophilia A patients may respond to desmopressin (DDAVP)

Question 26

Primary prophylaxis for bleeding in haemophilia?

Answer 26

Recommended for patients at high risk of bleeding.
Start before age of 3 and before the second large joint bleed.

Question 27

Secondary prophylaxis for bleeding in haemophilia?

Answer 27

Recommended for patients after 2 or more large joint bleeds, and before the onset of chronic arthropathy.

Question 28

Prophylaxis for mild-moderate haemophilia with minor or no bleeding?

Answer 28

Individualised.

Tertiary prophylaxis for those with arthropathy to prevent further damage

Question 29

Peri-operative?

Answer 29

Individualised based on surgery and risk.
Can use intermittent factor infusions

Question 30

What is emicizumab?

Answer 30

A bispecific monoclonal antibody that binds to factor IXa and factor X, substituing for the role of factor VIII in haemostasis.

Trials have shown it to be more efficacious and have less A/Es than factor VIII infusion.

Route: subcut initially weekly, then spaced out to every few weeks

Can be used as prophylaxis for patients with haemophilia A both with and without inhibitors (better than factor VIII). Is NOT effective in acute bleeding.

A/E: thrombotic events and thrombotic microangiopathy

Question 31

Prophylactic options for patients with haemophilia A

Answer 31

• Factor VIII concentrate from plasma
• Recombinant human or porcine factor VIII
• Longer lasting recombinant factor VIII
• Emicizumab

Question 32

Prophylactic options for patients with haemophilia B?

Answer 32

• Factor IX concentrate from plasma, recombinant factor IX, longer-lasting recombinant factor IX

Question 33

If giving factor concentrate for haemophilia prophylaxis, how often will patients need it?

Answer 33

Unless it is just being used intermittently around times of higher risk, patients need to receive factor concentrate at least 85% of the year (45 weeks of the year)