Case 76 – summary

This case focussed on a newly diagnosed patient with haemophilia A. The patient was three days old and presented non-specifically unwell and feeding poorly. The differential here is wide from sepsis to hypoglycaemia to congenital heart defects and metabolic disorders. The cause wasn’t obvious from initial clinical assessment but because there was bleeding around the umbilical stump a clotting screen was performed which revealed a prolonged APTT. References ranges are difficult to establish in neonates and vitamin K-dependant factors (II, VII, IX, X) along with XI are frequently low at birth. However the APTT is longer than one may expect. The full blood count was normal.

A 50:50 mix is where normal plasma is added to the patient’s and the APTT is repeated. If the APTT corrects then it is more likely to be a factor deficiency and if it doesn’t correct it is more likely to be an inhibitor e.g. lupus anticoagulant. For investigation into a prolonged APTT see here.

Further investigations revealed a VIII <1%. This is in keeping with severe haemophilia A. You may also wish to document a von Willebrand screen and a 2 stage VIII result.

Imaging revealed a small intracranial bleed. USS imaging is first line in suspected bleeding in a neonate if available. In larger hospitals; especially those with a haemophilia centre, it may be easy to get factor levels quickly but here we were in a district general hospital where it was going to be difficult to get further investigations in a timely manner. In this it would be appropriate to infuse fresh frozen plasma (virally inactivated) pending definitive investigation. It would be important to have enough sample to perform extended clotting factors prior to plasma infusion.

 

Haemophilia A

This is an X-linked genetic condition occurring in 1 in 5000 male births. 40% in neonatal period with bleeding. Common presentations include:

  • Stump bleed
  • Dental work/bleeding when teething
  • Easy bruising
  • Early surgery e.g. circumcision
  • Neonatal e.g. bleed, cephalomalacia
  • Epistaxis rare under two years old unless NAI or local cause
  • Adulthood if mild

 

30% have no family history but possibility of mother being carrier in a spontaneous case is 85%:

  • There is gonadal mosaicism in 13% (i.e. where mutation is in mother’s gonads but not in somatic cells and therefore her genotype is normal).
  • If no family history consider type 2N vWD as this is recessive (not in our case as the VIII is too low)
  • Most mutations occur in spermatogenesis therefore mutation occurs in maternal grandfather’s sperm leading to maternal carrier who passes onto son

Classification:

  • ≤1 – severe = 50%
  • 2-5 – moderate = 30%
  • >5 – mild = 20%

Genetic testing

Genetic testing is important:

  • Confirms diagnosis
  • Predicts inhibitor formation
  • Allows testing of other family members for same mutation (e.g. carriers)

Our patient’s family tree is shownHaemophilia family tree

We know haemophilia A is X linked and therefore passed on from mother to son:

  • Carrier females have a 50:50 chance of passing the mutation onto their son or daughter; therefore there is a 50:50 chance of a son being affected and a daughter being a carrier
  • Men with haemophilia will pass on their abnormal X chomosome to their daughters therefore all of their daughters will be carriers but sons will not be affected.

In the family tree above the mother (3) was a carrier as was her sister (4). It was presumed her mother was also a carrier and therefore the mutation was likely in spermatogenesis from her grandfather (the patient’s great-grandfather). The mother’s sister is currently pregnant and therefore it would be important to find out what sex the baby was as if male could be affected by severe haemophilia A. This would influence management of the woman in labour.

Haemophilia family tree 2

General management of patients with haemophilia

  • Enroll in haemophilia comprehensive care centres
  • MDT should include haematologist, nurses, physiotherapist, occupational therapist, social worker, health psychologist, biomedical scientists, orthopaedics, denists
    • Every 3-4 month if <5
    • Every 6 month if >5
  • 24 hour emergency treatment
  • Full records
  • Genetic counselling, family planning and carrier detection
  • Antenatal management and diagnosis
  • Link with infectious diseases
  • Medical card
  • School visits
  • Hepatitis vaccinations – if not using recombinant products
  • National database
  • Self-care e.g. tranexamic acid at home, education etc.
  • Co-ordinated surgery/pregnancy
  • Monitoring of treatment given
  • Avoiding NSAID/aspirin etc.

Treatment of severe haemophilia

Milder haemophilia may be treated with tranexamic acid and DDAVP but severe haemophilia must be treated with intravenous recombinant VIII replacement. The average half life is 12-14 hours and this may be less in children. For bleeding episodes treatment may be needed twice a day. In our case the patient had a intracerebal bleed and therefore VIII levels of at least 100% are needed. There needs to be regular monitoring of VIII levels to ensure adequate VIII replacement is given. Serial imaging can also guide treatment length.

 

Inhibitors

IgG4 alloantibody to foreign factor (not self, although may cross-react). 30% of patients with severe haemophilia A acquire inhibitors (25% if intron 22 mutation). Inhibitors make treatment of haemophilia difficult due to increased risk of bleeding. Risk factors include:

  • Higher risk if null mutation/large deletion/mutation inducing a stop codon (lower risk if small deletion or missense)
  • Ethnicity – increased risk if Hispanic/African
  • Family history of inhibitor – increased risk
  • Age
    • Increased risk if <5 and >60
    • Mild haemophilia A – risk increases with age
  • Age at first exposure – no effect
  • Reduced risk if HIV positive
  • Highest during early exposure days (10-15); up to 150 exposure days (especially first 50)
  • Intensity
    • Increased risk with ≥5 exposure days as first treatment especially if co-inflammatory stimulus e.g. surgery; therefore monitor closely
    • Prophylaxis – early may reduce risk

Monitoring for inhibitor formation is important to find them early as this makes eradication more straightforward. There is guidance on diagnosis, monitoring and management of inhibitors in haemophilia.

Females and low VIII

May get low VIII in females due to:

  • If develop haemophilia A mutation and have androgen insensitivity e. 46XY but insensitive to testosterone so phenotypically female
  • If develop haemophilia A mutation and have Turner’s syndrome 46XO
  • Mother being a carrier of haemophilia A and father being affected
  • vWD
  • Random process of X chromosome inactivation/Lyonisation
    • Occurs at 64-128 cell stage
    • Only one VIII gene functioning per cell
    • Carriers of haemophilia A have on average 50% of the mean normal factor VIII
    • As random may get more skewing towards inactivation of normal X – 7% have a 90:10% skew so can get significantly low VIII levels

Low VIII levels in a females with a family history of haemophilia implies carriership but a normal VIII does not exclude therefore need genetics on both.

Our patient’s mother had a low VIII and was found to carry the same mutation as her son. This may contribute to bleeding. VIII naturally rises in pregnancy and this may be why she has never suffered from bleeding during pregnancy.

According to our family tree patients 6 and 7 could be carriers. They should be offered/counselled for genetic testing when old enough (generally after 16 years of age and prior to pregnancy). However it is useful to do a VIII level prior to this as this may influence bleeding prior to procedures.

 

Our patient

He went on to have a full recovery. Serial monitoring for inhibitor was negative despite genetics showing a high risk mutation (intron 22). Given the lack of trauma associated with the bleed he was commenced on prophylaxis every 48 hours via a port. His mother was found to be a carrier. This case highlighted the importance of appropriate investigation when there is bleeding and vague symptoms/signs in unwell neonates and prompt treatment with factor replacement (FFP or recombinant VIII depending local availability prior to transfer to regional centre).

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