Coagulation Disorders (Haemophilia & von Willebrand)

Meet the patient

A 4-year-old boy is brought in with a swollen, hot, painfully flexed right knee that appeared "for no reason" at nursery. He bruised easily as a toddler and bled for hours after a circumcision. His mother's brother died of a bleed as a child. The APTT is prolonged, the PT and platelet count are normal, and the mixing study corrects.[1]

The second patient is a 19-year-old woman with heavy periods since menarche, frequent nosebleeds, and a mother and sister with the same. Her APTT is borderline and her platelet count is normal.[2]

Two patients, two arms of haemostasis. The boy has failed secondary haemostasis (a missing clotting factor — haemophilia); the woman has failed primary haemostasis (a platelet-plug problem — von Willebrand disease). The site and the timing of the bleeding tell you which arm broke before any test is run.[1][2]

One cascade, two arms, two bleeding patterns

Which protein of the cascade is missing decides where the bleeding happens. Haemophilia is a defect of the fibrin-forming arm, so the clot is weak and delayed and the patient bleeds deep and late — into joints, muscles and the brain, often hours after injury, with rebleeding. VWD is a defect of the platelet-plug arm, so the patient bleeds immediately and superficially — from mucous membranes.[1][2]

Haemophilia is deficiency of factor VIII (haemophilia A, about 80 percent) or factor IX (haemophilia B / Christmas disease, about 20 percent) — both X-linked recessive, so males are affected and females are carriers. A small family of rare factor deficiencies (XI, VII, V, X, XIII, fibrinogen) is mostly autosomal recessive, each with its own signature.[1]

Modern treatment has transformed these conditions. Recombinant factor VIII and IX, the subcutaneous bispecific antibody emicizumab, non-factor rebalancing therapies and AAV-vector gene therapy have turned haemophilia from a crippling, life-shortening disease into a manageable chronic one with near-normal life expectancy where the therapies are funded.[1][4]

The face-off — haemophilia, VWD, acquired

[1]

Severity — the factor level, not the bleeding history

Severity is graded by the endogenous factor activity, and it sets the tempo. This is the single most important prognostic variable in haemophilia.[1]

• Severe — factor level under 1 percent: spontaneous bleeds (joints, muscles, intracranial) from infancy, 2 to 5 a month without prophylaxis.
• Moderate — factor level 1 to 5 percent: bleeding after minor trauma or surgery; occasional spontaneous bleeds.
• Mild — factor level 5 to 40 percent: bleeding only after significant trauma, surgery or dental work; may escape diagnosis until adulthood.[1]

Who gets it

Haemophilia affects about 1 in 5000 male live births (A) and 1 in 30,000 (B). Because it is X-linked, all ethnicities are equally affected and males bleed while females carry. About 30 percent of cases are de novo mutations with no family history — so a negative family history does not exclude haemophilia in a boy with a suggestive bleeding pattern. Symptomatic female carriers occur with skewed X-inactivation, Turner syndrome or homozygosity.[1]

VWD is the commonest inherited bleeding disorder — a symptomatic prevalence of up to 1 in 100 (the much higher screening estimates are mostly asymptomatic low-vWF individuals). Type 1 is about 75 percent, type 2 about 20 to 25 percent, type 3 rare. Blood group O lowers vWF by about 25 percent — the commonest reason for a borderline-low vWF in someone with trivial bleeding.[2]

Acquired coagulopathy risk factors: advanced age, pregnancy and the postpartum period, autoimmune disease (SLE, rheumatoid), lymphoproliferative and solid malignancy, sepsis and trauma (DIC), chronic liver disease, and anticoagulant therapy.[6]

The mechanism — why haemophilia bleeds deep and VWD bleeds mucosal

The cascade is a thrombin-generation engine. The intrinsic tenase complex — factor IXa plus its cofactor VIIIa on the activated platelet surface — activates factor X, which drives the thrombin burst that turns fibrinogen into a cross-linked fibrin clot. Factor VIII and IX are the rate-limiting cofactors of secondary haemostasis. Lose either and the thrombin burst is weak and delayed, the clot is poorly cross-linked (factor XIII not activated) and unusually easy to lyse — hence the deep, rebleeding phenotype.[1]

Von Willebrand factor has two jobs, and VWD is a double hit. First, the high-molecular-weight multimers bridge exposed subendothelial collagen to the platelet glycoprotein GPIb-IX-V receptor under high shear — the initiating step of primary haemostasis. Second, vWF is the plasma carrier and stabiliser of factor VIII, protecting it from clearance and extending its half-life from minutes to about 12 hours. So VWD gives mucocutaneous bleeding from failed adhesion plus a secondary factor VIII deficiency from loss of the carrier.[2]

The subtypes map to distinct lesions: type 1 is a partial quantitative reduction; type 2A loses high-molecular-weight multimers; 2B is a gain-of-function that binds platelets spontaneously and causes thrombocytopenia (worsened by desmopressin); 2M has normal multimers but reduced function; 2N has a defective factor VIII binding site and mimics mild haemophilia A; type 3 is virtual absence of vWF, the severest form.[2]

How they present — deep bleeds versus mucocutaneous

Haemophilia A and B are clinically indistinguishable — they differ only in the deficient factor. Severity sets the tempo.[1]

Haemarthrosis is the hallmark — bleeding into the knees, elbows and ankles (the target joints). The joint is swollen, warm, painful and held flexed; recurrent bleeds drive haemophilic arthropathy (synovial hypertrophy, cartilage destruction, fixed deformity), historically the leading cause of long-term disability. Intramuscular bleeds favour the iliopsoas (groin pain, hip held flexed, femoral nerve compression), the calf and forearm (compartment syndrome), and the gluteal region.[1]

Intracranial haemorrhage is the most feared bleed and the leading cause of death in severe haemophilia, especially in neonates after instrumental delivery and in toddlers after minor head trauma. Any haemophilia patient with a headache, vomiting, altered consciousness, seizure or a head injury is treated empirically with factor to 100 percent before imaging.[1]

VWD causes mucocutaneous bleeding — epistaxis, gum bleeding, easy bruising, prolonged bleeding after dental work, and, characteristically in women, heavy menstrual bleeding and postpartum haemorrhage. Type 3, with virtual absence of vWF, produces a severe haemophilia-like phenotype.[2]

Everyone forgets the atypical presentations that examiners probe: mild haemophilia declaring only after surgery or a dental extraction; a symptomatic female carrier with menorrhagia (skewed X-inactivation); a neonate bleeding after heel-prick, circumcision or intramuscular vitamin K; acquired haemophilia in an elderly patient with no childhood history and dramatic soft-tissue bleeding; type 2N VWD masquerading as mild haemophilia A in a female.[1]

The differential — and the mixing study that sorts it

A prolonged APTT with bleeding is not always haemophilia, and mucocutaneous bleeding is not always VWD. Name the mimic and the discriminator.[1][2]

• Platelet disorders (ITP, Glanzmann, Bernard-Soulier) — petechiae and mucocutaneous bleeding with a normal PT and APTT. Glanzmann is a GPIIb/IIIa defect; Bernard-Soulier a GPIb defect.
• DIC — global consumption; both PT and APTT prolonged, low fibrinogen, raised D-dimer, thrombocytopenia, with a trigger.
• Liver disease — global factor deficiency; PT prolonged first, then APTT, with thrombocytopenia from hypersplenism.
• Vitamin K deficiency — factors II, VII, IX, X low; PT prolonged first (factor VII has the shortest half-life), responding to vitamin K in 6 to 12 hours.
• Acquired haemophilia A — an APTT that does not correct on mixing, a low factor VIII, a positive Bethesda assay, no childhood history.[6]
• Factor XIII deficiency — normal PT and APTT with umbilical stump bleeding and recurrent miscarriage.[1]

[1]

The discriminator line: the mixing study is the single most powerful first step. Corrects — it is a deficiency (haemophilia, VWD). Does not correct — it is an inhibitor (acquired haemophilia, lupus anticoagulant). [1]

The bedside round

The focused examination has three jobs — characterise active bleeding, document chronic damage, and protect the distal neurovascular status of any limb bleed.[1]

Look for the swollen, warm, flexed joint (haemarthrosis); the tender, tense compartment (intramuscular bleed with compartment-syndrome risk); groin pain with a flexed hip and femoral nerve signs (iliopsoas haematoma). Then document the chronic damage — target joints, fixed flexion deformities, muscle wasting, synovial thickening. Examine distal pulses and nerves for every limb bleed; the dangers are compartment syndrome and nerve compression (femoral, median, posterior tibial). Fundoscopy and a neurological exam are mandatory if intracranial bleeding is suspected.[1]

Named bedside phenomena worth knowing: the target joint (three or more bleeds into the same joint in six months — a marker for prophylaxis escalation); iliopsoas haemorrhage (inguinal mass, hip held flexed, femoral nerve palsy — easily mistaken for appendicitis or a psoas abscess); and the airway-threatening parapharyngeal or retropharyngeal haematoma, a true emergency.[1]

The bleeding assessment tool (BAT) endorsed by the ISTH quantifies the lifetime bleeding history. A high score (4 or more in adult males, 6 or more in adult females) favours VWD or a platelet disorder over haemophilia.[2]

Investigations — APTT, mixing, factor assays, the vWF panel, Bethesda

First-line coagulation screen is the entry point and the discriminator:[1][2]

• APTT prolonged in haemophilia (when factor VIII or IX falls below about 30 percent) and variably in VWD; PT, thrombin time and platelet count NORMAL.
• Mixing study — corrects in a factor deficiency (haemophilia, VWD, rare factor deficiencies) and does NOT correct with an inhibitor (acquired haemophilia, lupus anticoagulant).[1]

Specific factor assays confirm and grade severity: factor VIII for haemophilia A, factor IX for B (severe under 1 percent, moderate 1 to 5 percent, mild over 5 percent). Both must be sent before any factor replacement blurs the picture.[1]

The von Willebrand panel — the four tests that define VWD and its subtype: vWF antigen (quantity); vWF activity / ristocetin cofactor (vWF:RCo) or the newer GP1bM assay (function); factor VIII (often low because vWF stabilises it); and vWF multimer analysis to subtype the type 2 variants. Interpret in light of blood group (group O lowers vWF by about 25 percent) and the acute-phase response (vWF rises with inflammation, surgery, pregnancy — a normal result during an acute illness can mask VWD, so repeat when the patient is well).[2]

The inhibitor screen (Bethesda assay) is mandatory in all newly diagnosed haemophilia and whenever bleeding escalates despite adequate factor. A titre of 0.6 Bethesda units (BU) per mL or higher defines a positive inhibitor. Low-responding inhibitors (under 5 BU/mL) may be transient; high-responding inhibitors (5 BU/mL or higher) persist and rise on re-exposure.[1]

[1]

The acute bleed — factor first, investigate after

[1]

An acute bleed in known haemophilia is treated first and investigated after. The cardinal error is to wait for a factor level or a scan before treating.[1]

The dosing rule: one unit of factor VIII per kilogram raises the plasma level by about 2 percent; one unit of factor IX per kilogram raises it by about 1 percent (standard product). Practical targets:[1]

• Joint or muscle bleed — raise factor to 50 to 80 percent: factor VIII 25 to 50 IU/kg (repeat at 12 hours; half-life about 12 hours), or factor IX 40 to 80 IU/kg (longer half-life, less frequent).
• Intracranial haemorrhage, major trauma or major surgery — raise factor to 100 percent immediately and sustain above 50 percent for 7 to 14 days. Suspect ICH on clinical grounds and give factor before the CT scan.
• Life-threatening oropharyngeal or airway bleeding — treat as for ICH (100 percent) and secure the airway early.
• Mild haemophilia A with a minor bleed and a documented desmopressin response — desmopressin 0.3 microgram per kilogram subcutaneously or IV over 30 minutes may suffice (it roughly triples the factor VIII level).[1]

Adjuncts: RICE (rest, ice, compression, elevation) for joint bleeds; analgesia with paracetamol or opioids — avoid intramuscular injections, aspirin and NSAIDs; tranexamic acid 15 mg/kg IV or 1 g orally three times daily for mucosal and dental bleeding — but avoid in haematuria (risk of a clot obstructing the ureter). Take venous samples from a single peripheral stab; do not attempt arterial or central puncture without factor cover.[1]

Haemophilia prophylaxis — emicizumab changes everything

The principle of prophylaxis is to keep the factor trough above 1 to 3 percent so spontaneous bleeds — and the arthropathy they cause — are prevented. Prophylaxis is now the standard of care from early childhood in severe haemophilia.[1]

Emicizumab is a subcutaneous bispecific antibody that simultaneously binds activated factor IX and factor X, functionally replacing factor VIIIa. It is first-line prophylaxis for severe haemophilia A, with or without inhibitors: 3 mg/kg subcutaneously once weekly for the first four weeks, then 1.5 mg/kg once weekly (or 3 mg/kg every two weeks, or 6 mg/kg every four weeks). It cut the annualised bleed rate by roughly 80 percent in the HAVEN trials and freed patients from frequent venous access.[3]

Recombinant factor VIII prophylaxis is 25 to 40 IU/kg IV three times weekly (every other day); extended-half-life products allow twice-weekly dosing. Desmopressin is for mild haemophilia A only — 0.3 microgram per kilogram, effective for minor bleeds or dental work, limited to three consecutive days to avoid hyponatraemia. Haemophilia B prophylaxis uses extended-half-life factor IX 40 to 80 IU/kg once or twice weekly.[1]

Gene therapy — a functional cure for selected adults

Two AAV-vector gene therapies are approved and represent a potential functional cure:[4][5][7]

• Valoctocogene roxaparvovec for haemophilia A — a single IV infusion of an AAV5 vector carrying a B-domain-deleted factor VIII gene. The GENEr8-1 trial showed mean factor VIII of about 40 IU/dL at one year, sustained at two years, with most patients stopping routine prophylaxis; durability declines gradually over several years.[4][5]
• Etranacogene dezaparvovec for haemophilia B — an AAV5 vector delivering a factor IX Padua variant (R338L, with about eightfold higher specific activity). Stable factor IX of about 37 IU/dL at 18 months, allowing prophylaxis to stop. The Padua variant, discovered in a family with thrombosis, is the engine that delivers useful levels at modest vector doses.[7]

Candidate selection is strict: adult men only, no pre-existing neutralising anti-AAV antibodies, no active or chronic liver disease. Transient corticosteroids manage the immune-mediated transaminitis that accompanies vector infusion.[4]

VWD management — subtype-driven

Type 1 (and selected type 2) — desmopressin 0.3 microgram per kilogram subcutaneously or IV over 30 minutes, releasing vWF and factor VIII from endothelial stores. Test the response first with a DDAVP trial (a 2- to 3-fold rise at 1 to 2 hours defines a responder). Caution in type 2B (can worsen thrombocytopenia) and avoid in pregnancy.[2]

Types 2 and 3 — vWF-containing concentrate (Haemate-P / Humate-P, Wilate), delivering both vWF and factor VIII, dosed 20 to 60 IU of ristocetin cofactor activity per kilogram per dose for bleeding or surgery.[2]

Tranexamic acid — 1 g orally three times daily (or a mouthwash for dental work) — is adjunctive across all subtypes; avoid in haematuria. Heavy menstrual bleeding is managed with a combined oral contraceptive pill or a levonorgestrel intrauterine system.[1]

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Inhibitors — the biggest complication

Inhibitors — neutralising IgG antibodies to factor VIII (less often IX) — develop in 20 to 30 percent of children with severe haemophilia A (1 to 5 percent of haemophilia B), risk concentrated in the first 50 exposure days. They render standard factor replacement ineffective and are the single most important determinant of morbidity and mortality after severity.[1][6]

Acute bleeding with an inhibitor is treated with bypassing agents:[1]

• Recombinant activated factor VII (rFVIIa, novoseven) — 90 microgram per kilogram IV every 2 hours until bleeding stops.
• Activated prothrombin complex concentrate (FEIBA) — 50 to 100 units per kilogram IV every 8 to 12 hours (cumulative daily ceiling to limit thrombosis).
• Emicizumab provides effective prophylaxis in patients with inhibitors and is the backbone of long-term care.[1]

Eradication by immune tolerance induction (ITI) — daily or alternate-day factor VIII with immunosuppression — achieves tolerance in roughly two-thirds; rituximab for refractory cases. Acquired haemophilia uses bypassing agents plus immunosuppression (prednisolone 1 mg/kg/day with or without cyclophosphamide, or rituximab).[6]

The rare factors — and why factor XIII fools everyone

• Factor XI deficiency (haemophilia C) — common in Ashkenazi Jews (carrier frequency up to 8 percent); bleeding is disproportionate to the factor level and is provoked at sites of high fibrinolytic activity (mouth, tonsils, urinary tract). First-line is tranexamic acid, then fresh frozen plasma or factor XI concentrate for major bleeding. The APTT is prolonged, PT normal.[1]
• Factor VII deficiency — the commonest of the rare factor deficiencies; PT prolonged, APTT normal. Treat with recombinant activated factor VII 15 to 30 microgram/kg.
• Factor XIII deficiency — PT and APTT are both normal (the clot forms but is not cross-linked and is fragile). Hallmarks: umbilical stump bleeding in neonates, delayed bleeding, recurrent miscarriage, intracranial bleeding. Treat with factor XIII concentrate monthly.[1]
• Fibrinogen disorders — afibrinogenaemia (prolonged PT, APTT and thrombin time) and dysfibrinogenaemia (some variants cause thrombosis). Treat with cryoprecipitate or fibrinogen concentrate.[1]

Acquired coagulopathies

• Acquired haemophilia A — autoantibodies to factor VIII in the elderly, in pregnancy, or with autoimmune disease or malignancy. The APTT does not correct on mixing; the Bethesda assay quantifies the inhibitor. Treat bleeds with bypassing agents and eradicate the antibody with prednisolone 1 mg/kg/day plus cyclophosphamide or rituximab.[6]
• DIC — treat the underlying cause and support with platelets, fresh frozen plasma and cryoprecipitate (platelets over 50, fibrinogen over 1.5 g/L).
• Liver disease — vitamin K 10 mg IV if reversible, fresh frozen plasma and prothrombin complex concentrate for active bleeding.
• Vitamin K deficiency — vitamin K 10 mg IV slowly (PT corrects in 6 to 12 hours; full correction in 24 to 48 hours).[1]

The subtypes that bite

• Severe haemophilia A in a child — start prophylaxis before age 2 (primary prophylaxis) to prevent arthropathy: emicizumab subcutaneously avoids central venous access; those on factor VIII need a port-a-cath. Vaccines (including hepatitis A and B) must be given subcutaneously, never intramuscularly.[1]
• Type 3 VWD behaves like severe haemophilia and needs regular vWF concentrate prophylaxis (50 to 100 IU/kg twice weekly).
• Type 2N VWD is the great mimic of mild haemophilia A — the clue is autosomal inheritance with both sexes affected and a normal vWF antigen but a very low factor VIII.[1]
• Acquired haemophilia in the elderly — dramatic subcutaneous and soft-tissue bleeding with no childhood history, an APTT that does not correct on mixing, and an underlying autoimmune or neoplastic trigger.[6]

When it goes wrong — complications and the traps that cost marks

Disease complications: haemophilic arthropathy (the leading long-term morbidity, prevented by primary prophylaxis); intracranial haemorrhage (the leading cause of death — factor to 100 percent before imaging); compartment syndrome from intramuscular bleeds; airway compromise from parapharyngeal haematomas.[1]

Treatment complications: inhibitor formation in 20 to 30 percent of severe haemophilia A; transfusion-transmitted infection (the historical hepatitis C and HIV catastrophe of plasma-derived factor in the 1970s and 1980s — modern recombinant, viral-inactivated products are safe); thrombosis from repeated bypassing agents or from the dangerous combination of emicizumab plus activated prothrombin complex concentrate (never combine them).[1]

The classic pitfalls: [1]

• Delaying factor replacement to await levels or imaging in a suspected intracranial bleed.
• Intramuscular injections, aspirin or NSAIDs in a haemophilia patient.
• Giving desmopressin in type 2B VWD (worsens thrombocytopenia) or without a prior DDAVP trial.
• Relying on the APTT alone — factor XIII deficiency, mild haemophilia and type 2N VWD can present with a normal APTT.
• Failing to screen for an inhibitor when bleeding escalates on adequate factor.
• Missing acquired haemophilia in an elderly patient with new bleeding — the mixing study is the discriminator.[1]

Prognosis and disposition

With modern prophylaxis — emicizumab, recombinant factor and gene therapy — life expectancy in severe haemophilia is now near-normal in high-income countries, a transformation from the 1970s when most severe haemophilia patients died before 20. The determinants of outcome are severity, the presence and titre of inhibitors, access to comprehensive care, and adherence to prophylaxis.[1]

Disposition from the emergency department depends on the bleed. A joint or muscle bleed gets a single factor dose, RICE, analgesia and next-day review. An ICH, airway bleed, iliopsoas or compartment bleed mandates admission with sustained factor cover above 50 to 100 percent for 7 to 14 days. A new inhibitor or acquired haemophilia needs haematology admission for bypassing therapy, eradication and investigation of the trigger. Every patient benefits from a comprehensive haemophilia treatment centre.[6]

Special populations

• Neonates — suspect haemophilia in a male neonate with prolonged bleeding after heel-prick, circumcision, vacuum extraction or intramuscular vitamin K. Do not withhold vitamin K — give it subcutaneously or IV, never intramuscularly. Avoid instrumental delivery where haemophilia is known in the family.[1]
• Pregnancy and the peripartum — the single most dangerous time for a woman with VWD or a haemophilia carrier. vWF rises two- to threefold through pregnancy, normalising most type 1 disease — but crashes within hours of delivery, so postpartum haemorrhage dominates. Type 3 needs vWF concentrate throughout. Avoid neuraxial anaesthesia unless vWF activity and factor VIII are above 50 IU/dL (catastrophic spinal epidural haematoma). Determine fetal sex antenatally; avoid fetal scalp electrodes and instrumental delivery.[2]
• The elderly — acquired haemophilia with no childhood history, dramatic subcutaneous bleeding, an APTT that does not correct on mixing, and an autoimmune or neoplastic trigger.[6]
• Surgery and dentistry — plan with haematology in advance: pre-treatment factor cover to 80 to 100 percent and tranexamic acid mouthwash for dental work, sustained factor cover for 7 to 14 days for major surgery. A patient on emicizumab still needs additional factor for surgery.[1]

The evidence and regional differences

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Regional deltas. In high-income regions, emicizumab is first-line prophylaxis for severe haemophilia A and gene therapy is being deployed. In India and South Asia, cost is the dominant constraint — plasma-derived factor VIII and IX remain widely used, emicizumab access is expanding but not universal, prophylaxis uptake is lower and arthropathy remains common in adults. The historical HIV and hepatitis C cohort from the 1970s and 1980s persists everywhere.[1]

Controversies the exam may probe: the durability of gene therapy (factor VIII levels decline gradually; re-dosing is blocked by pre-formed anti-AAV antibodies); whether emicizumab monotherapy suffices for surgery (it does not — additional factor is required); and the place of non-factor rebalancing therapies (fitusiran, anti-TFPI agents).[1]

The mantra, and the mnemonic

[1]

The mantra: Factor first and investigate after — for an intracranial bleed, factor to 100 percent before the scan.[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the boy with the swollen knee (answer)

A 4-year-old with a painful flexed knee, easy bruising and a maternal uncle who died of bleeding. APTT prolonged, PT and platelets normal, mixing study corrects. What is the diagnosis, the confirmatory test, and the first treatment step? Model: This is haemophilia (A or B — clinically identical). The mixing study correcting confirms a factor deficiency rather than an inhibitor. Send factor VIII and factor IX assays to confirm and grade severity (severe under 1 percent). Treat the acute bleed by raising factor to 50 to 80 percent — factor VIII 25 to 50 IU/kg if haemophilia A, or factor IX 40 to 80 IU/kg if B — plus RICE and analgesia (no IM injections, no NSAIDs). Long-term, severe disease gets prophylaxis — emicizumab 1.5 mg/kg SC monthly is first-line for haemophilia A.[1]

Stem 2 — the head injury that cannot wait for the scan (answer)

A 3-year-old with severe haemophilia A falls off a bed and vomits. He is drowsy. The registrar wants a CT head before any treatment. What do you do? Model: Do not wait for imaging. Intracranial haemorrhage is the leading cause of death in severe haemophilia, and any headache, vomiting, altered consciousness or head injury is treated empirically with factor to 100 percent before the CT scan. Give factor VIII to raise the level to 100 percent (about 50 IU/kg), then image, then sustain factor above 50 percent for 7 to 14 days. The cardinal error in haemophilia is delaying factor for a level or a scan in a suspected ICH.[1]

Stem 3 — the elderly man with new bruising (answer)

A 78-year-old presents with dramatic spontaneous bruising and a thigh haematoma. He has no childhood or family history of bleeding. APTT prolonged, PT and platelets normal — but the mixing study does NOT correct. What is this, and what is the next test? Model: This is acquired haemophilia A — autoantibodies neutralising factor VIII, typically in the elderly, in pregnancy, or with autoimmune disease or malignancy. The APTT that does not correct on mixing is the key discriminator from inherited haemophilia (which corrects). The next test is the Bethesda assay to quantify the inhibitor titre, and a factor VIII level (which will be low). Treat acute bleeds with bypassing agents (rFVIIa 90 mcg/kg or FEIBA 50 to 100 U/kg), and eradicate the antibody with immunosuppression — prednisolone 1 mg/kg/day plus cyclophosphamide or rituximab. Search for the underlying trigger.[6]

References

1. [1]Berntorp E, Fischer K, Hart DP, et al. Haemophilia Nat Rev Dis Primers, 2021.PMID 34168126
2. [2]Connell NT, Flood VH, Brignardello-Petersen R, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease Blood Adv, 2021.PMID 33570647
3. [3]Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors N Engl J Med, 2018.PMID 30157389
4. [4]Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A N Engl J Med, 2022.PMID 35294811
5. [5]Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A N Engl J Med, 2023.PMID 36812433
6. [6]Kruse-Jarres R, Kempton CL, Baudo F, et al. Acquired hemophilia A: Updated review of evidence and treatment guidance Am J Hematol, 2017.PMID 28470674
7. [7]George LA Factor IX Padua for haemophilia B gene addition: universal adaptation and repeated success Lancet Haematol, 2022.PMID 35772422