Haemophilia A and B

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Haemophilia A and B are deficiencies of factor VIII and IX. The X-linked pattern means affected males are commonest, but women and girls with low levels may bleed and deserve diagnosis and care based on phenotype rather than terminology. Severe disease causes spontaneous haemarthroses and muscle bleeding from infancy; moderate disease may follow minor trauma; mild disease can remain hidden until extraction, surgery or major injury. Bleeding is often delayed because the initial platelet plug forms but lacks durable thrombin-supported fibrin.

Diagnosis combines personal bleeding, pedigree and factor measurement. PT is normal and APTT is often prolonged, but a reagent may miss mild deficiency. A correcting mixing test supports deficiency; lack of correction raises an inhibitor or anticoagulant. Specific factor assays establish type and severity, while VWF testing prevents misclassifying type 2N or severe VWD as haemophilia A. Genetic analysis identifies the familial variant, predicts some inhibitor risk and enables accurate testing of relatives and reproductive counselling.

Acute treatment is anatomical and time critical. A suspected critical-site bleed is treated before imaging, using the factor concentrate and dose recorded by the centre. Minor joint bleeding also benefits from early factor and protected movement, followed by specialist physiotherapy rather than prolonged immobilisation. Target factor level and duration depend on site, severity, surgery and product pharmacokinetics; laboratory recovery confirms whether the planned dose worked. An inhibitor must be considered when response is less than expected.

Prophylaxis prevents bleeding rather than waiting for irreversible joint damage. Standard- or extended-half-life factor is individualised by breakthrough bleeds, troughs, activity and adherence. Emicizumab provides subcutaneous prophylaxis for haemophilia A with or without inhibitors but does not treat acute bleeding and changes interpretation of APTT-based tests. Comprehensive care also covers dentistry, musculoskeletal health, pain, vaccination, hepatitis and HIV history, mental health, schooling or work, transition, pregnancy and safe emergency access.

Key points

Haemophilia A is factor VIII deficiency and haemophilia B is factor IX deficiency; both usually show an isolated prolonged APTT, but mild disease can have a normal screening APTT.
Confirm with one-stage or chromogenic factor assays and repeat or use alternate methods when phenotype and result disagree; measure VWF to distinguish low FVIII caused by VWD.
Severe haemophilia is a baseline factor level below 1 IU/dL, moderate 1–5 IU/dL and mild above 5 to below 40 IU/dL; bleeding history remains essential.
Treat suspected intracranial, neck, gastrointestinal, iliopsoas or major traumatic bleeding immediately with the person's haemophilia-centre factor or bypassing plan before diagnostic imaging.
Factor VIII dosing is guided by the principle that approximately 1 IU/kg raises plasma FVIII by about 2 IU/dL; factor IX recovery is product-specific and must follow the named concentrate protocol.
Prophylaxis is standard for severe disease and recurrent bleeding; recombinant factor, extended-half-life products, emicizumab in haemophilia A and selected gene therapy are specialist choices.
An inadequate factor rise, shortened half-life or breakthrough bleeding should trigger an inhibitor assay; do not keep escalating ordinary factor without checking recovery and contacting the centre.
Avoid aspirin, most NSAIDs, intramuscular injections and unplanned neuraxial procedures; coordinate dental work, surgery, vaccination route, sports, fertility, pregnancy and newborn testing with the haemophilia team.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

F8 or F9 pathogenic variants

Haemophilia A results from factor VIII deficiency and haemophilia B from factor IX deficiency, most often through X-linked inherited variants affecting males.

De novo disease

A substantial minority has no known family history because a new variant arose or affected male relatives were absent or unrecognised.

Female and mosaic expression

Women and girls may have low factor levels from lyonisation, Turner syndrome or biallelic disease and can experience clinically important bleeding despite traditional carrier labels.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Impaired thrombin amplification
Factor VIIIa and IXa form the intrinsic tenase complex; deficiency reduces factor X activation and prevents a stable fibrin clot after initial platelet plugging.
2
Severity follows baseline level
Severe disease below 1 IU/dL causes spontaneous bleeding, moderate disease at 1–5 IU/dL bleeds after modest trauma, and mild disease above 5 IU/dL often appears during surgery.
3
Recurrent joint injury
Blood within a joint drives iron deposition, synovial hypertrophy, inflammation and cartilage damage, producing a cycle of rebleeding, pain and haemophilic arthropathy.
4
Neutralising inhibitors
Alloantibodies can neutralise infused factor, particularly early in severe haemophilia A, making ordinary replacement ineffective and requiring bypassing therapy or immune tolerance.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Haemarthrosis

Tingling, warmth, reduced movement, swelling and pain in ankles, knees or elbows can precede obvious joint enlargement and should be treated early.

Muscle bleeding

Increasing pain, swelling, weakness or nerve symptoms after minor trauma may indicate a deep muscle bleed with compartment or compression risk.

Mild disease

Disproportionate extraction, tonsil, circumcision, childbirth or operative bleeding may be the first clue when spontaneous childhood bleeds were absent.

Female phenotype

Heavy periods, iron deficiency, postpartum haemorrhage and procedure-related bleeding can occur in carriers and women with factor levels in the haemophilia range.

Inhibitor clueRed flag

Bleeding despite appropriately timed concentrate, low measured recovery or a rapidly falling factor level requires urgent inhibitor assessment.

Red flags requiring action

Any significant head injury, new headache, vomiting, confusion, weakness or seizure is an intracranial bleed until urgently treated and imaged, even if examination is initially normal.
Neck, tongue or pharyngeal swelling, voice change, stridor or dysphagia threatens the airway and requires immediate factor cover with anaesthetic and ENT support.
Groin pain, hip flexion, femoral neuropathy, falling haemoglobin or unexplained shock suggests iliopsoas or retroperitoneal bleeding requiring urgent factor treatment and imaging.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: PT, APTT, fibrinogen and FBCFirst stepFirst line
Why
Identify an intrinsic-pathway pattern and alternative causes of bleeding or anaemia.
Interpretation and limitations
PT is usually normal. APTT may be prolonged but can be normal in mild disease; thrombocytopenia or low fibrinogen indicates another or additional disorder.
02
Confirmatory factor VIII and IX assaysConfirmatory
Why
Identify haemophilia type and establish baseline severity.
Interpretation and limitations
Use validated one-stage or chromogenic assays and resolve assay-product discordance. Test VWF antigen and activity when factor VIII is low.
03
Mixing study and inhibitor titre
Why
Separate deficiency from an inhibitor when APTT or clinical response is unexpected.
Interpretation and limitations
Correction supports deficiency, while time-dependent failure to correct suggests factor VIII inhibitor. A Nijmegen-modified Bethesda assay quantifies a confirmed neutralising antibody.
04
Genetic analysis
Why
Define the familial F8 or F9 variant for relatives, reproductive counselling and selected treatment planning.
Interpretation and limitations
Testing begins with an affected person where possible; a negative routine assay may require dosage or inversion analysis and specialist interpretation.
05
Bleed-specific imaging
Why
Define site and complications after immediate haemostatic treatment for critical bleeding.
Interpretation and limitations
Use urgent CT for head or retroperitoneal concern, ultrasound or MRI for selected joints and muscles, and compartment or neurovascular assessment alongside imaging.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Von Willebrand disease

VWF deficiency can lower factor VIII and cause mucosal bleeding; VWF antigen, activity and FVIII-binding studies distinguish type 2N VWD from haemophilia A.

Acquired haemophilia

New soft-tissue bleeding with no personal or family history, isolated prolonged APTT and a factor VIII inhibitor suggests an acquired autoantibody.

Factor XI deficiency

Bleeding is often procedure- and site-dependent rather than predicted by factor level, and inheritance affects all sexes rather than following a classic X-linked pattern.

Platelet or connective-tissue disorder

Mucosal bleeding, easy bruising and immediate surgical oozing with normal factor assays directs evaluation toward primary haemostasis or vascular fragility.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01New suspected haemophiliaConfirm factor deficiencyFirst stepA male or female has deep, delayed or procedure-related bleeding with a compatible pedigree or isolated APTT abnormality.

1Record lifelong bleeding and haemostatic challenges, construct a pedigree and check FBC, PT, APTT and fibrinogen.
2AlternativeMeasure factor VIII, factor IX and VWF antigen and activity, using mixing and alternative assays when results are discordant.
3Refer to a haemophilia centre for confirmation, genetic testing, family screening, emergency card and a preventive treatment plan.

02Critical-site bleedTreat before imagingHead, neck, iliopsoas, gastrointestinal, major trauma or organ-threatening symptoms occur.

1Give the patient's named factor concentrate or bypassing regimen immediately and contact the haemophilia centre; do not await imaging or APTT.
2Use ABCDE, analgesia without platelet inhibition, anatomical source control and urgent site-specific imaging once replacement has started.
3Measure factor recovery, repeat doses to centre-defined targets and duration, and monitor haemoglobin, neurovascular state and rebleeding.

03HaemarthrosisStop bleeding and restore movementA joint develops the patient's typical prodrome, warmth, pain, swelling or restricted range.

1Administer the prescribed home-treatment factor promptly and use relative rest, protected weight bearing, ice with skin protection and appropriate analgesia.
2Reassess within the centre-defined interval; repeat examination or imaging if pain persists, trauma was substantial or fracture, infection or inhibitor is possible.
3Begin guided movement and physiotherapy after haemostasis to prevent stiffness, then review prophylaxis if breakthrough bleeding occurred.

04Poor factor responseTest recovery and inhibitorBleeding continues or measured factor rise or half-life is below the product-specific expectation.

1Confirm product, dose, timing, administration, sampling and current factor activity rather than assuming non-adherence or progression.
2Send an inhibitor screen and Nijmegen Bethesda titre with the haemophilia laboratory and avoid unplanned repeated conventional factor.
3Use bypassing therapy, emicizumab-compatible acute management or high-dose factor only through the specialist inhibitor plan and discuss immune tolerance.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Replaces missing factor VIII for acute bleeding, surgery, on-demand treatment and prophylaxis in haemophilia A without a neutralising inhibitor.

Recombinant factor VIII concentrate

Use the patient's named product and pharmacokinetic plan; for standard factor VIII, required IU is approximately body weight in kg × desired FVIII rise in IU/dL × 0.5, repeated according to measured recovery, half-life, bleed site and healing duration.

Treat critical bleeding before assays, but check recovery afterwards. Products and extended-half-life intervals are not interchangeable; monitor inhibitor development, thrombosis in high target states, hypersensitivity and central-access complications.

Provides factor IX for bleeding, operations and prophylaxis in haemophilia B.

Recombinant factor IX concentrate

Use the exact named product SmPC and individual recovery; calculate units from body weight and desired FIX rise, then repeat by measured level because standard- and extended-half-life concentrates have materially different incremental recovery and intervals.

Avoid a generic one-size conversion between products. Monitor factor levels, inhibitor or anaphylaxis risk, thrombosis at high exposure and renal or hepatic comorbidity that changes procedural risk.

Provides prophylaxis in haemophilia A with or without factor VIII inhibitors by bridging activated factor IX and factor X.

Emicizumab

Give 3 mg/kg subcutaneously once weekly for 4 weeks, then choose 1.5 mg/kg weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks as the centre-defined maintenance schedule.

It does not treat an acute bleed. Avoid high cumulative activated prothrombin-complex concentrate because thrombotic microangiopathy and thrombosis can occur; use emicizumab-aware coagulation assays and a specialist breakthrough-bleed plan.

Releases VWF and factor VIII and can avoid concentrate in selected patients with mild haemophilia A.

Desmopressin for responsive mild haemophilia A

Give 0.3 micrograms/kg intravenously over 20–30 minutes after a documented response trial for a suitable minor bleed or procedure; repeat only under the centre plan.

It has no role in haemophilia B or severe haemophilia A. Restrict excess fluid, monitor sodium when risk warrants and avoid unsafe repeated dosing or use in significant cardiovascular disease.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Haemophilic arthropathy

Repeated haemarthroses cause chronic synovitis, reduced movement, muscle wasting, deformity, chronic pain and eventually joint replacement needs.

Intracranial and deep bleeding

Brain, neck, retroperitoneal, gastrointestinal and compartment bleeding can progress before external signs appear and remain major causes of morbidity.

Factor inhibitors

Neutralising antibodies cause unexpectedly poor recovery or breakthrough bleeding and complicate surgery, prophylaxis and eradication strategies.

Treatment and access burden

Venous-access infection or thrombosis, treatment adherence, historical blood-borne viruses, osteoporosis, chronic pain and psychosocial strain require lifelong multidisciplinary care.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

At comprehensive review, record annualised treated and untreated bleeds, joint examination, activity, pain, adherence, venous access and treatment burden.
Measure inhibitor status at exposure-based and clinical intervals, and whenever recovery, half-life or bleeding response is unexpectedly poor.
For factor prophylaxis, use bleed control and individual pharmacokinetics or troughs rather than applying the same target and interval to every product.
On emicizumab, use specialist assays for factor measurement and emergency management, because routine APTT is shortened and can be falsely reassuring.
Before surgery, pregnancy or delivery, document target levels, product, timing, postoperative duration, thromboprophylaxis, neuraxial criteria and laboratory responsibility.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Treat first in critical bleeding

The harm from delayed haemostasis in head or neck bleeding outweighs the value of obtaining an untreated factor level before replacement.

Mild disease can hide

An APTT within range and an uneventful childhood do not exclude a factor level that becomes inadequate during major surgery.

Women require measured care

X-linked inheritance does not protect every carrier from low factor levels, heavy menstrual bleeding, surgery or postpartum haemorrhage.

Emicizumab changes assays

A normalised APTT during emicizumab is a drug effect and neither quantifies haemostatic protection nor excludes a clinically important bleed.

A joint tingle is meaningful

People with haemophilia often recognise an early haemarthrosis before swelling, allowing prompt treatment that limits synovial injury.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for CT before treating a suspected intracranial bleed.
02
Excluding mild haemophilia because APTT is normal.
03
Assuming women with an F8 or F9 variant cannot bleed.
04
Using a generic dose across different factor IX products.
05
Interpreting APTT normally during emicizumab treatment.
06
Persisting with ordinary factor despite poor recovery from an inhibitor.