Paediatrics chapters
Haemophilia A and B
The X-linked deficiencies of factor VIII and factor IX: inheritance and carrier risks, severity by factor level, joint and muscle bleeding, the isolated prolonged APTT, factor replacement doses, desmopressin, inhibitors and how they differ from von Willebrand disease.
- Haemophilia A (factor VIII, about 1 in 5000 boys) and haemophilia B (factor IX, about 1 in 25,000) are X-linked recessive; boys are affected, mothers are carriers, and about a third arise from new mutations.
- Severity follows factor level: severe below 1% (spontaneous bleeds), moderate 1-5%, mild above 5% (bleeds only after trauma or surgery); the hallmark is haemarthrosis, with muscle haematomas, bleeding after circumcision, and intracranial haemorrhage as the main cause of death.
- Only the APTT is prolonged (PT, platelets and bleeding time normal); confirm with factor assays; treat with factor concentrate (factor VIII dose = desired % × kg × 0.5), desmopressin for mild or moderate A, antifibrinolytics for mouth bleeds, early prophylaxis, no aspirin or IM injections.
On this page
Overview
The haemophilias are inherited deficiencies of clotting factors in the intrinsic pathway:
- Haemophilia A (classic haemophilia): factor VIII deficiency, about 1 in 5000 males.
- Haemophilia B (Christmas disease): factor IX deficiency, about 1 in 25,000 males.
Both are X-linked, both cause deep bleeding into joints and muscles, and clinically they cannot be told apart except by factor assay. Factor VIII and IX deficiency are the commonest severe inherited bleeding disorders, whereas von Willebrand disease is the commonest inherited bleeding disorder overall but is usually milder.
Genetics and inheritance
- The genes for factor VIII and IX are on the X chromosome.
- Almost all patients are boys; their mothers are usually carriers.
- A positive family history is common, but about one-third of cases are new mutations.
| Parents | Sons | Daughters |
|---|---|---|
| Carrier mother, normal father | 50% affected, 50% normal | 50% carriers, 50% normal |
| Affected father, normal mother | All normal | All carriers |
An affected father cannot pass haemophilia to his sons (he gives them his Y chromosome), but all his daughters are carriers.
Pathophysiology
Factors VIII and IX form the "tenase" complex that activates factor X on the platelet surface. Without them, thrombin generation is delayed, the fibrin clot is weak, and the platelet plug is not stabilised. The platelet plug forms normally, so small cuts may stop at first but ooze again later.
Clinical features
Severity by factor level
| Severity | Factor level | Bleeding |
|---|---|---|
| Severe | Below 1% | Spontaneous bleeding into joints and muscles; presents in infancy or when the child starts to crawl and walk |
| Moderate | 1-5% | Bleeding after minor or moderate trauma |
| Mild | Above 5% (Akbar: about 6-30%) | Bleeding only with significant trauma or surgery; may go undiagnosed for years |
(Normal factor VIII activity is about 50-150%.)
Typical bleeding
- Newborn: factor VIII does not cross the placenta, so bleeding can follow circumcision or injections.
- Toddler: easy bruising and large bruises as the child crawls and walks.
- Haemarthrosis: the hallmark of severe disease; knee, elbow and ankle become painful, hot, swollen and held flexed. Repeated bleeds destroy the joint, leaving chronic arthropathy with deformity.
- Muscle haematomas: large intramuscular bleeds can cause compartment syndrome with nerve and muscle damage.
- Intracranial haemorrhage: the leading disease-related cause of death.
- Haematuria, gut bleeding, prolonged bleeding after dental extraction or surgery.
Platelet problems bleed "superficially" (petechiae, gums, nose); factor problems bleed "deep" (joints, muscles, late re-bleeding).
Investigations
| Test | Haemophilia A | Haemophilia B | von Willebrand disease |
|---|---|---|---|
| APTT | Prolonged | Prolonged | Prolonged or normal |
| PT | Normal | Normal | Normal |
| Platelet count | Normal | Normal | Normal |
| Bleeding time / PFA | Normal | Normal | Prolonged |
| Factor VIII | Low | Normal | Low or normal |
| Factor IX | Normal | Low | Normal |
| vWF antigen and activity | Normal | Normal | Low |
| Ristocetin cofactor activity | Normal | Normal | Low |
| Inheritance | X-linked | X-linked | Autosomal dominant (usually) |
- In a 1:1 mixing test with normal plasma, the long APTT corrects (showing a factor deficiency).
- Specific factor assays confirm the type and severity.
- Carrier detection: ratio of factor VIII activity to vWF antigen, and molecular genetic tests.
- Prenatal diagnosis by molecular testing is possible.
A boy with bleeding after circumcision, normal platelets, normal PT and prolonged APTT has haemophilia. If PT is also prolonged, think of vitamin K deficiency or liver disease instead.
Management
General care
- Early replacement at the first sign of a bleed; children with severe disease and trained parents give home treatment.
- Prophylaxis (regular factor infusions from early childhood) greatly reduces joint damage and is the modern standard where available.
- Avoid aspirin and NSAIDs that affect platelets; avoid intramuscular injections.
- Hepatitis B vaccine for all, since they are exposed to blood products.
- Prevent trauma sensibly, but encourage normal activity; dental care.
- Cover surgery and dental extractions with factor and antifibrinolytics.
Factor replacement
| Situation | Target factor VIII level |
|---|---|
| Life-threatening bleed (intracranial, airway), major surgery | 80-100% |
| Haemarthrosis, muscle bleed (mild to moderate) | About 40% (factor IX: 30-40%) |
- Factor VIII: 1 unit/kg raises the plasma level by about 2%, so:
- Dose (units) = desired rise (%) × weight (kg) × 0.5
- Half-life about 12 hours, so doses are repeated.
- Factor IX: a larger dose per 1% rise is needed than for factor VIII; the multiplier depends on the product (check the product information and local protocol).
- Recombinant factor concentrates are preferred because they carry no viral risk.
Boy of 20 kg with severe haemophilia A and a knee haemarthrosis
Target level 40%
Dose = 40 × 20 × 0.5 = 400 units of factor VIII
Same boy with a head injury (target 100%): 100 × 20 × 0.5 = 1000 units
If concentrate is not available
- Haemophilia A: cryoprecipitate (contains factor VIII, vWF, fibrinogen and factor XIII) or fresh frozen plasma.
- Haemophilia B: fresh frozen plasma (cryoprecipitate contains no factor IX).
Other drugs
- Desmopressin (DDAVP): a synthetic vasopressin analogue with little pressor effect; releases stored factor VIII and vWF, raising factor VIII three- to four-fold. It is the treatment of choice for mild and moderate haemophilia A when it achieves a high enough level. No effect in haemophilia B and not enough in severe A.
- Tranexamic acid and aminocaproic acid (antifibrinolytics): useful for mouth, nose and dental bleeding.
Desmopressin does not work in haemophilia B, and cryoprecipitate does not contain factor IX.
For mild or moderate haemophilia A, desmopressin is the treatment of choice when it raises factor VIII enough; for haemophilia B use factor IX concentrate.
Inhibitors
- IgG antibodies against the transfused factor, seen in about 15% of severe haemophilia A, less often in B.
- Suspect when bleeding does not respond to the usual dose.
- Treatment: high-dose factor for low-titre inhibitors; bypassing agents such as recombinant factor VIIa for high-titre inhibitors; long-term immune tolerance induction.
Prophylactic factor replacement from early childhood prevents the chronic joint disease of severe haemophilia.
Complications
- Chronic arthropathy (the main long-term disability).
- Compartment syndrome and nerve palsies from muscle bleeds.
- Intracranial haemorrhage.
- Inhibitors.
- From older plasma-derived products: HIV, hepatitis B and C (a major cause of death in older patients treated before recombinant factors).
Genetic counselling and prevention
- Construct a pedigree and test female relatives for carrier status.
- Explain the risks: each son of a carrier has a 50% chance of haemophilia; each daughter has a 50% chance of being a carrier.
- Prenatal diagnosis by molecular testing for carrier mothers who wish it.
- Prognosis is good when the child's physical, emotional, social and educational needs are all looked after.
Von Willebrand disease in brief
- The commonest inherited bleeding disorder (about 1% of people); usually autosomal dominant, so girls are affected too.
- vWF links platelets to damaged vessel wall and carries factor VIII, so deficiency causes platelet-type (mucocutaneous) bleeding: epistaxis, gum bleeding, easy bruising, menorrhagia, bleeding after dental extraction or surgery. Haemarthrosis is unusual except in severe type 3.
- Types: 1 (partial quantitative, about 80%), 2 (qualitative), 3 (near-complete absence, severe).
- Tests: prolonged bleeding time/PFA, low vWF antigen and ristocetin cofactor activity, low or normal factor VIII, APTT normal or prolonged.
- Treatment: desmopressin for type 1; vWF-containing factor VIII concentrate for types 2 and 3 or major bleeding; antifibrinolytics; avoid aspirin.
Expect: a boy with bleeding after circumcision or a swollen knee without trauma; X-linked inheritance and carrier risks (affected father, carrier mother); severity bands (below 1%, 1-5%, above 5%); haemarthrosis as the hallmark and intracranial bleeding as the main cause of death; isolated prolonged APTT with normal PT, bleeding time and platelets; factor VIII dose formula and target levels (40% for joints, 80-100% for life-threatening bleeds); desmopressin only for mild or moderate haemophilia A; cryoprecipitate lacks factor IX; inhibitors; avoiding aspirin and IM injections; and the laboratory differences from von Willebrand disease.
Quick revision
- A = factor VIII (1 in 5000 males); B = factor IX (1 in 25,000). Both X-linked.
- One-third new mutations; carrier mother: half of sons affected.
- Severe below 1%, moderate 1-5%, mild above 5%.
- Haemarthrosis is the hallmark; ICH is the main cause of death.
- APTT prolonged; PT, platelets, bleeding time normal; factor assay confirms.
- Factor VIII dose = % × kg × 0.5; target 40% joint, 80-100% life-threatening.
- DDAVP for mild/moderate A only; tranexamic acid for mouth bleeds.
- Cryo has VIII, vWF, fibrinogen, XIII, not IX.
- Prophylaxis prevents arthropathy; avoid aspirin and IM injections; hepatitis B vaccine.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
Can girls have haemophilia?
Rarely; almost all patients are boys because the genes are on the X chromosome. A girl who bleeds easily is much more likely to have von Willebrand disease.
Why is the bleeding time normal in haemophilia?
Bleeding time tests the platelet plug, which forms normally in haemophilia; the defect is in fibrin clot formation, which shows as a prolonged APTT.
How do you calculate the dose of factor VIII?
Multiply the desired rise in factor level (as a percentage) by the body weight in kilograms and by 0.5, since one unit per kilogram raises the level by about 2%.
When is desmopressin useful?
In mild or moderate haemophilia A and type 1 von Willebrand disease, where it releases stored factor VIII and vWF; it does not help haemophilia B or severe haemophilia A.