Blood & Lymphoreticular

Hemophilia A and B: management and factor replacement

Clinical Overview and When to Suspect Hemophilia

— Severe (<1%): spontaneous joint/muscle bleeds, usually present by age 1–2 with hemarthrosis when ambulatory; intracranial hemorrhage risk in neonates

— Moderate (1–5%): bleeds with minor trauma

— Mild (5–40%): bleeds only with surgery, dental work, or major trauma — often diagnosed in adulthood after a procedure

— Isolated prolonged aPTT with normal PT, platelet count, and bleeding time in a male with bleeding history

— Hemarthrosis (knees, ankles, elbows — large joints), intramuscular hematomas (iliopsoas → groin pain, hip flexion), excessive post-circumcision or post-dental bleeding

— Delayed bleeding after trauma (initial platelet plug forms, then fails) — classic distinguishing feature from platelet/vWD disorders

— Family history on maternal side (X-linked); ~30% are spontaneous de novo mutations, so absent family history does not rule it out

Board pearl: A male toddler with a large joint effusion after starting to walk, isolated aPTT prolongation, and normal platelets — order factor VIII and IX activity assays, not just a mixing study first. The mixing study tells you it's a factor deficiency vs. inhibitor, but specific factor levels confirm the diagnosis and guide therapy.

Step 3 management: When hemophilia is suspected in a bleeding patient, do not delay factor replacement waiting for labs — treat empirically and draw confirmatory levels simultaneously, especially with suspected head trauma or compartment syndrome.

Hemophilia A = factor VIII deficiency (X-linked recessive, ~1:5,000 male births); Hemophilia B ("Christmas disease") = factor IX deficiency (~1:25,000 male births). Clinically indistinguishable — both cause intrinsic-pathway bleeding.

Severity stratification by baseline factor activity:

Suspect hemophilia when you see:

Acquired hemophilia A in adults: new-onset bleeding + isolated prolonged aPTT in a previously healthy older adult, postpartum patient, or patient with autoimmune disease/malignancy — autoantibody (inhibitor) against factor VIII.

Presentation Patterns and Key History

— Intracranial hemorrhage — headache after even trivial trauma, vomiting, altered mental status → treat first, image after factor given

— Iliopsoas bleed — vague groin/lower abdominal pain, hip held in flexion and external rotation, femoral neuropathy

— Retropharyngeal/neck bleed — airway compromise

— Compartment syndrome in forearm or calf

— Age of first bleed and bleed frequency (defines severity)

— Inhibitor history — has prior factor stopped working? Any allergic reactions to infusions?

— Prior product type (recombinant vs. plasma-derived), prophylaxis vs. on-demand regimen

— HIV/HCV exposure history (older patients exposed pre-1985 to contaminated pooled products)

— Family pedigree — maternal uncles, grandfathers, female carriers (carriers can have factor levels 30–60% and bleed mildly)

Key distinction: Hemophilia causes deep tissue and joint bleeding with delayed onset; vWD and platelet disorders cause mucocutaneous bleeding (epistaxis, menorrhagia, petechiae) with immediate onset. A teenage girl with heavy menses is vWD until proven otherwise; a teenage boy with a swollen knee after sports is hemophilia until proven otherwise.

Board pearl: Always ask about last factor dose timing and product name in any hemophilia patient presenting with bleeding — it changes dosing math immediately.

Neonatal/infant: prolonged bleeding from circumcision, heel sticks, vitamin K injection sites; intracranial hemorrhage (3–4% of newborns with severe disease — consider screening cranial US if known carrier mother); cephalohematoma exceeding expected size.

Toddler: oral mucosal bleeding from frenulum tears, easy bruising disproportionate to activity, first hemarthrosis as ambulation begins.

School-age and adolescent: recurrent hemarthroses (target joint = ≥3 bleeds in same joint in 6 months), intramuscular hematomas, hematuria (often painless, may pass clots causing colic).

Adult: post-surgical or post-traumatic bleeding (mild disease often unmasked here), GI bleeding, chronic hemophilic arthropathy from cumulative joint damage.

Life-threatening bleeds to recognize on history:

Key history points to elicit:

Physical Exam Findings and Hemodynamic Assessment

— Acute hemarthrosis: warm, tense, painful joint held in flexion; patient resists passive motion; aura of tingling/stiffness may precede swelling ("the patient knows before you do")

— Chronic hemophilic arthropathy: flexion contractures, crepitus, muscle atrophy (quadriceps wasting around chronically affected knee), limited ROM, valgus/varus deformity

— Target joints: knees > elbows > ankles in adults; ankles often first in children on prophylaxis

— Iliopsoas: positive psoas sign, hip flexion contracture, femoral nerve palsy (decreased quadriceps strength, absent patellar reflex, anterior thigh sensory loss)

— Forearm/calf: tense compartments, pain with passive stretch, pallor, paresthesia — surgical emergency

— Tachycardia and orthostasis may be the only early signs of a large occult retroperitoneal or thigh bleed — these spaces hold liters

— Hypotension is a late finding in adolescents/young adults — do not be reassured by normal BP

— Estimate blood loss conservatively; serial Hgb every 4–6 h in active bleeding

— GCS, pupils, focal deficits → ICH workup

— Cauda equina or radiculopathy → spinal/retroperitoneal bleed

— Distal pulses, 2-point discrimination → compartment syndrome screen

CCS pearl: On CCS, a hemophilia patient with a swollen thigh after a fall — order factor level, CBC, type and screen, measure thigh circumference, give factor replacement immediately, then obtain CT/MRI of thigh. Do not order compartment pressures before factor — you'll cause bleeding.

Board pearl: A hemophilia patient with back/flank pain and inability to extend the hip = iliopsoas bleed until proven otherwise. Confirm with CT or US, treat to 100% factor activity for 5–7 days.

Joint exam (cornerstone of hemophilia exam):

Muscle hematomas:

Mucocutaneous: typically less prominent than in vWD; petechiae are notably absent (platelets work). Ecchymoses are large, deep, palpable.

Hemodynamic assessment:

Neuro exam mandatory with any head trauma, back pain, or limb hematoma:

Diagnostic Workup — Initial Labs

— PT/INR: normal in hemophilia (extrinsic and common pathway intact)

— aPTT: prolonged (intrinsic pathway — factors VIII, IX, XI, XII)

— Platelet count: normal

— Fibrinogen: normal

— Bleeding time / PFA-100: normal (platelet function preserved)

— Corrects → factor deficiency (hemophilia A, B, or other intrinsic factor deficiency)

— Does NOT correct → inhibitor present (acquired hemophilia, or alloantibody in previously treated hemophiliac); incubate at 37°C for 1–2 h because factor VIII inhibitors are time- and temperature-dependent

— Factor VIII activity → Hemophilia A

— Factor IX activity → Hemophilia B

— Always order both when hemophilia is suspected — phenotypes are identical

— Also order vWF antigen, vWF activity (ristocetin cofactor), and factor VIII together if vWD is on the differential — type 3 vWD or type 2N vWD can mimic hemophilia A

— Head trauma → non-contrast head CT (after factor given)

— Joint → bedside US or plain film (rule out fracture); MRI for chronic arthropathy planning

— Suspected iliopsoas/retroperitoneal → CT abdomen/pelvis

— Hematuria → CT urogram only if persistent; avoid antifibrinolytics in urinary tract bleeding (clot retention → obstruction)

Key distinction: Isolated prolonged aPTT narrows your differential rapidly — hemophilia A/B, factor XI deficiency, factor XII deficiency (no bleeding!), heparin contamination, lupus anticoagulant (paradoxically thrombotic), or acquired inhibitor.

Board pearl: A prolonged aPTT that does not correct on mixing in a previously healthy 70-year-old with new bruising → acquired hemophilia A — send factor VIII activity and Bethesda assay for inhibitor titer.

Screening coagulation panel in a bleeding patient:

Mixing study (1:1 with normal plasma):

Specific factor activity assays (the definitive test):

CBC and type & screen in active bleeding; fibrinogen, D-dimer if DIC is considered.

Imaging is driven by site:

Advanced and Confirmatory Studies

— Low-titer inhibitor: <5 BU — can often overcome with high-dose factor concentrate

— High-titer inhibitor: ≥5 BU — requires bypassing agents (aPCC/FEIBA or recombinant factor VIIa)

— Distinguish low-responding (titer stays <5 BU even after factor exposure) vs. high-responding (anamnestic rise >5 BU) — affects long-term strategy

— F8 gene (Xq28): intron 22 inversion accounts for ~45% of severe hemophilia A

— F9 gene (Xq27): point mutations dominate

— Used for carrier detection in female relatives, prenatal diagnosis, and inhibitor risk prediction (large deletions and nonsense mutations carry higher inhibitor risk)

— Measure factor VIII or IX activity (carriers may have low-normal levels and bleed)

— Genetic confirmation needed because lyonization makes phenotype unreliable

— Pre-conception counseling — recommend hematology + maternal-fetal medicine referral

— Plain films for staging (Pettersson score)

— MRI most sensitive for early synovitis and cartilage loss — guides prophylaxis intensification

— Musculoskeletal ultrasound at point-of-care increasingly used to confirm hemarthrosis vs. soft tissue swelling

Board pearl: Hemophilia B Leyden — point mutation in F9 promoter; factor IX levels are low in childhood but rise after puberty (androgen-responsive element), and bleeding phenotype improves with age. Classic vignette: a boy with severe hemophilia B whose disease "becomes mild" as a teenager.

Step 3 management: Any new hemophilia diagnosis warrants referral to a federally-funded Hemophilia Treatment Center (HTC) — multidisciplinary care (hematology, PT, social work, dental, orthopedics) reduces mortality by ~40% compared to non-HTC care.

Bethesda assay — quantifies inhibitor titer in Bethesda Units (BU):

Genetic testing:

Carrier testing in female relatives:

Joint imaging:

Pharmacokinetic (PK) studies: individualized factor half-life testing guides personalized prophylaxis dosing — particularly useful with extended half-life products and in pediatrics.

Risk Stratification and Management Logic

— Acute bleed → factor replacement now, dose by site and severity

— No active bleed → prophylaxis vs. on-demand based on severity and phenotype

— Severe (<1%): primary prophylaxis starting before age 3 or after first joint bleed — standard of care, prevents arthropathy

— Moderate (1–5%): prophylaxis if bleeding phenotype is severe; otherwise on-demand

— Mild (>5%): on-demand treatment for trauma/surgery; DDAVP trial for hemophilia A

— Minor (early joint bleed, superficial hematoma, simple dental): trough 30–50% × 1–3 days

— Major (deep muscle, large hemarthrosis, GI, major surgery): 50–80% × 5–7 days

— Life/limb-threatening (CNS, neck/airway, retroperitoneal, compartment): 80–100% for 7–14 days, then taper

— Hemophilia A (factor VIII): dose (units) = weight (kg) × desired % rise × 0.5

(Each unit/kg raises factor VIII by ~2%)

— Hemophilia B (factor IX): dose (units) = weight (kg) × desired % rise × 1.0 (recombinant) or × 1.2–1.4 for plasma-derived

(Each unit/kg raises factor IX by ~1% — IX distributes more widely)

— Standard factor VIII: ~8–12 h → q8–12h dosing or continuous infusion

— Standard factor IX: ~18–24 h → q12–24h

— Extended half-life (EHL) products extend intervals 1.5–2× (VIII) or 3–5× (IX)

CCS pearl: For a 70-kg adult with severe hemophilia A and head trauma — target 100% activity: 70 × 100 × 0.5 = 3,500 units factor VIII IV bolus immediately, then redose q8–12h or continuous infusion 2–4 U/kg/h, then CT head.

Board pearl: Treat first, image second in any suspected CNS bleed.

First decision: bleeding now, or prevention?

Severity-based long-term strategy:

Bleed-severity tiering for dosing targets:

Dosing formulas to memorize:

Half-life considerations for redosing:

Pharmacotherapy — Factor Replacement and First-Line Agents

— Avoid plasma-derived in newly diagnosed/previously untreated patients to minimize transfusion-transmitted infection risk (though modern plasma products are virally inactivated)

— Extended half-life (EHL) products use Fc fusion, PEGylation, or albumin fusion

— Bispecific monoclonal antibody mimicking factor VIIIa by bridging factor IXa and X

— Subcutaneous, weekly to monthly dosing

— Effective in patients with or without inhibitors — first-line prophylaxis for severe hemophilia A in many centers

— Does NOT treat acute breakthrough bleeds — still need factor VIII or bypassing agent for those

— Caution: do NOT combine with aPCC (FEIBA) — risk of thrombotic microangiopathy and thrombosis; use rFVIIa instead for breakthrough bleeds

— aPTT becomes uninterpretable on emicizumab — use chromogenic factor VIII assay (bovine-based) for monitoring

— 0.3 mcg/kg IV/SC or 300 mcg intranasal; raises factor VIII 2–5×

— Trial dose to confirm response before relying on it

— Tachyphylaxis after 2–3 doses; hyponatremia risk → fluid restrict, watch Na in children and elderly

— Useless in hemophilia B

— Tranexamic acid or aminocaproic acid for mucosal bleeding (oral, dental, epistaxis, menorrhagia)

— Contraindicated in urinary tract bleeding (clot in ureter → obstruction) and DIC

— rFVIIa (NovoSeven): 90 mcg/kg q2–3h

— aPCC/FEIBA: 50–100 U/kg q8–12h, max 200 U/kg/day

Board pearl: A child on emicizumab prophylaxis develops a joint bleed — treat with rFVIIa, not FEIBA.

Step 3 management: Always pair factor replacement with RICE (rest, ice, compression, elevation), pain control with acetaminophen (avoid NSAIDs/aspirin), and early PT after bleed resolution.

Recombinant factor VIII and IX concentrates — first-line in US:

Emicizumab (Hemlibra) — game-changer for hemophilia A:

DDAVP (desmopressin) — hemophilia A only, mild disease:

Antifibrinolytics — adjuncts:

Bypassing agents for inhibitors:

Procedures, Surgery, and Perioperative Management

— Confirm diagnosis, severity, inhibitor status (Bethesda titer within last 3 months), prior product, allergies

— Coordinate with HTC hematologist; never elective surgery at a non-HTC center without consultation

— Type & cross, baseline factor level, CBC, coags

— Major surgery (joint replacement, intracranial, intra-abdominal): 80–100% preop, maintain >50% for 7–14 days post-op

— Minor surgery (central line, biopsy, simple dental): 50–80% preop, maintain 30% for 1–5 days

— Dental extractions: 30–50% pre-procedure + tranexamic acid mouthwash for 7 days

— Lumbar puncture: correct to ≥50–80% before procedure

— Bolus to target, then continuous infusion (2–4 U/kg/h factor VIII) or scheduled boluses

— Monitor trough levels daily; check inhibitor at 7–10 days post-op (anamnestic response risk)

— Radiosynovectomy for target joint with chronic synovitis refractory to prophylaxis

— Total joint arthroplasty for end-stage hemophilic arthropathy — outcomes excellent at HTCs

— First action: give factor, then assess. Do not wait for imaging in suspected CNS bleed.

— Trauma activation should trigger automatic factor replacement protocol per institutional plan

CCS pearl: Elective knee arthroplasty in severe hemophilia A — order factor VIII to 100% 2 h preop, continuous infusion to maintain >80% × 3 days, then >50% × 14 days, with daily factor levels, and start DVT prophylaxis (mechanical) — pharmacologic anticoagulation is generally avoided.

Pre-procedural planning — single highest-yield Step 3 scenario:

Target factor levels by procedure type:

Dosing strategy:

Vaccinations — give subcutaneously when possible, or IM with smallest needle and pressure × 5 min; consider factor cover for IM injections in severe disease. Hepatitis A and B vaccination is standard.

Joint procedures:

Emergency/trauma:

Gene therapy (newer): etranacogene dezaparvovec (hemophilia B) and valoctocogene roxaparvovec (hemophilia A) — AAV-vector single infusions producing sustained factor expression; monitor LFTs (immune response to vector) and durability.

Special Populations — Elderly and Renal/Hepatic Impairment

— Life expectancy now approaches the general population due to safer factor products and prophylaxis

— Cardiovascular disease is the leading non-bleeding mortality cause — these patients still develop coronary artery disease, atrial fibrillation, and stroke

— Statins, BP control, and lifestyle interventions apply identically to non-hemophilia patients

— ACS/stent: dual antiplatelet therapy is not contraindicated — coordinate with HTC; maintain factor trough ≥20–30% during DAPT; minimize duration of DAPT

— Atrial fibrillation: rate control preferred; if anticoagulation needed (CHA₂DS₂-VASc high), use DOAC with HTC co-management and factor prophylaxis

— Avoid NSAIDs throughout life; prefer acetaminophen and COX-2 selective with caution

— Many older hemophiliacs have HCV (or cured HCV with residual fibrosis) and/or HIV from pre-1985 pooled products

— Cirrhosis worsens bleeding diathesis (decreased synthesis of clotting factors including IX) and complicates factor pharmacokinetics

— Treat HCV with direct-acting antivirals — cure rate >95%

— Hepatocellular carcinoma surveillance with US + AFP q6 months in cirrhotic patients

— Hematuria is common; hydrate, treat with factor; avoid tranexamic acid in urinary tract bleeding

— DDAVP causes hyponatremia — extra caution with CKD

— Renal biopsy requires factor correction to 80–100%

Board pearl: An older man with severe hemophilia A presents with NSTEMI — do not withhold aspirin and clopidogrel out of bleeding fear. Coordinate with HTC, give factor coverage during the periprocedural and DAPT window, and treat the ACS per standard guidelines.

Step 3 management: Annual screening in older hemophiliacs: HCV/HIV viral loads, LFTs, lipid panel, BP, age-appropriate cancer screening, bone density (factor-treated patients have lower BMD).

Aging hemophilia population (a Step 3 favorite — modern cohort effect):

Antiplatelets and anticoagulation in hemophilia:

Chronic hepatic disease:

Renal impairment:

Special Populations — Pregnancy, Pediatrics, Carriers

— ~30% have factor levels <40% and bleed mildly (menorrhagia, postpartum hemorrhage)

— Check factor levels pre-conception and in third trimester (factor VIII rises physiologically in pregnancy; factor IX does not)

— Tranexamic acid and combined OCPs help menorrhagia

— Genetic counseling and prenatal diagnosis (CVS at 10–13 weeks or amniocentesis) for known carriers

— Fetal sex determination (cell-free DNA at 9–10 weeks) — if female, less concern; if male, plan delivery carefully

— Avoid invasive fetal monitoring (scalp electrodes, scalp pH sampling), vacuum extraction, and mid-cavity forceps in male fetuses of carriers — high risk of intracranial hemorrhage

— Cesarean if prolonged or difficult labor anticipated

— Maternal factor level should be >50% at delivery for vaginal birth and for neuraxial anesthesia

— Postpartum: factor VIII drops back to baseline within days → delayed postpartum hemorrhage at 1–4 weeks; counsel and follow

— Cord blood factor VIII/IX levels at birth (factor IX physiologically low until 6 months — confirm with later testing if mild)

— Vitamin K SC (not IM) until hemophilia status known

— Delay circumcision; cranial US if any concern for ICH

— Start before age 3 or after first joint bleed

— Venous access challenges → central venous access device common in young children; weigh infection risk

— Emicizumab SC has revolutionized pediatric care — avoids central lines

— Inhibitor surveillance every 5–10 exposure days during first 50 exposures (highest risk window)

Key distinction: Factor VIII rises during pregnancy (acute phase reactant) — mild hemophilia A carriers may normalize at term. Factor IX does not rise — hemophilia B carriers remain at risk.

Board pearl: A male newborn of a known carrier with a cephalohematoma after vacuum delivery — cranial imaging, cord factor level, and empiric factor replacement if any neurologic concern.

Carrier females:

Pregnancy management of carriers:

Neonates of carrier mothers:

Pediatric primary prophylaxis:

Complications and Adverse Outcomes

— Iron deposition → synovitis → cartilage destruction → fibrosis and ankylosis

— Target joints lose ROM, develop contractures, cause chronic pain and disability

— Prevention = prophylaxis; treatment = PT, radiosynovectomy, arthroplasty

— Occurs in ~25–30% of severe hemophilia A and ~3–5% of severe hemophilia B

— Highest risk in first 50 exposure days, intensive treatment (surgery, major bleed)

— Hemophilia B inhibitors often accompanied by anaphylaxis to factor IX and nephrotic syndrome with immune tolerance induction

— Management: bypassing agents (rFVIIa or FEIBA), immune tolerance induction (ITI) with high-dose daily factor for months to years, or emicizumab (hem A)

— HCV (~80% of pre-1985 recipients), HIV, hepatitis B

— Modern recombinant and viral-inactivated products have eliminated new transmissions

— Intracranial hemorrhage — leading cause of bleeding death

— Compartment syndrome

— Pseudotumor (encapsulated chronic hematoma, typically pelvis/femur) — surgical challenge, may erode bone

— GI bleeding, hematuria with ureteral obstruction

— DDAVP → hyponatremic seizures (especially children)

— aPCC + emicizumab → thrombotic microangiopathy

— Central line infections and thrombosis

— Allergic reactions, especially with plasma-derived products

— Chronic pain, opioid dependence risk, school/work absenteeism, depression

Board pearl: A hemophilia A patient's bleed stops responding to usual factor dose → suspect inhibitor. Send Bethesda assay; switch to bypassing agent for acute management.

Step 3 management: Inhibitor eradication via ITI is standard of care for high-responding inhibitors — daily high-dose factor (typically 100–200 U/kg) for months; success rates ~70%.

Hemophilic arthropathy — the dominant chronic morbidity:

Inhibitor development — most feared treatment complication:

Transfusion-transmitted infections (historical but ongoing implications):

Bleeding complications:

Treatment-related:

Psychosocial:

When to Escalate Care — ICU, Consult, Inpatient Triage

— Any CNS bleed (intracranial, intraspinal) — neuro ICU, neurosurgery consult, factor to 100% with continuous infusion, repeat imaging

— Airway compromise from neck/retropharyngeal hematoma — anesthesia/ENT at bedside, controlled airway

— Hemodynamic instability from any bleeding site

— Compartment syndrome — surgical emergency; factor first, then fasciotomy

— Iliopsoas bleed with femoral neuropathy — admit, factor to 100% × 5–7 days, PT

— Any acute bleed in a hemophilia patient (even minor — guides product choice and dosing)

— Suspected new inhibitor

— Pre-procedural planning

— Pregnancy in a carrier

— Early uncomplicated hemarthrosis without neurovascular compromise — single factor dose at home, RICE, follow-up in 24–48 h

— Stable epistaxis/oral bleed responsive to local measures + factor + antifibrinolytic

— Routine prophylaxis administration

— Reliable patient, established self-infusion, mild bleed → home with phone follow-up at 24 h

— Pediatric patient, first bleed, family inexperienced → observe in ED or admit short stay

— Any concerning anatomic location → admit

— Hospitalist not familiar with factor dosing → mandatory HTC co-management or telephone consultation

— ED hand-off: document last factor product, dose, time, response

CCS pearl: A hemophilia patient with a headache after MVC — sequence: IV access, factor VIII to 100% empirically, CT head, neurosurgery consult if positive, ICU admission, continuous factor infusion, repeat CT at 24 h. Do not order CT before factor.

Board pearl: "Treat first, image second" is the single highest-yield Step 3 reflex for hemophilia + suspected major bleed.

Immediate ICU/admission criteria:

Always consult hematology / HTC:

Outpatient management is appropriate for:

Disposition decision framework:

Transitions of care risks:

Key Differentials — Other Bleeding Disorders (Same Category)

— Mucocutaneous bleeding (epistaxis, gum, menorrhagia, easy bruising) — immediate onset, unlike hemophilia's delayed pattern

— Labs: prolonged aPTT (because vWF carries factor VIII — secondary low VIII), prolonged PFA-100, low vWF antigen and activity

— Type 2N (Normandy) mimics hemophilia A — vWF binds VIII poorly → low VIII, normal vWF antigen; distinguish with VIII:vWF binding assay

— Type 3 — severe deficiency, can present like hemophilia

— Treatment: DDAVP (type 1), vWF concentrates (Humate-P) for type 2/3

— Autosomal recessive, common in Ashkenazi Jews

— Bleeding out of proportion to factor level, often triggered by surgery

— Prolonged aPTT, normal PT

— Treat with FFP (no specific concentrate in US) or rFVIIa

— Prolonged aPTT but NO bleeding — finding aPTT prolongation in an asymptomatic preop patient → screen for these

— Adult, no prior bleeding history, dramatic mucocutaneous and soft tissue bleeding

— Associations: postpartum, autoimmune disease (RA, SLE), malignancy, drug reactions, idiopathic in elderly

— Labs: prolonged aPTT not correcting with mixing, low VIII, positive Bethesda assay

— Treatment: bypassing agents for bleeding + immunosuppression (steroids ± rituximab/cyclophosphamide) to eradicate antibody

Key distinction: Mixing study corrects = factor deficiency; does not correct = inhibitor. This single test orients your differential immediately.

Board pearl: Postpartum woman with new bruising and oozing from IV sites, isolated aPTT prolongation that fails to correct on mixing → acquired hemophilia A; start steroids and rFVIIa.

von Willebrand disease (vWD) — most common inherited bleeding disorder:

Factor XI deficiency ("hemophilia C"):

Factor XII, prekallikrein, HMWK deficiency:

Acquired hemophilia A:

Other rare factor deficiencies (II, V, VII, X, XIII): VII isolated PT prolongation; XIII normal PT/aPTT but delayed wound healing and umbilical stump bleeding.

Key Differentials — Other Categories

— ITP: petechiae, low platelet count, normal coags

— Glanzmann thrombasthenia, Bernard-Soulier: mucocutaneous bleeding, abnormal platelet function tests, normal count (Glanzmann) or large platelets and thrombocytopenia (BSS)

— Distinguished by normal aPTT and mucocutaneous (not deep tissue) pattern

— Sick patient with sepsis, malignancy, trauma, obstetric catastrophe

— Prolonged PT and aPTT, low fibrinogen, elevated D-dimer, thrombocytopenia, schistocytes

— Treat underlying cause; supportive blood products

— Prolonged PT > aPTT initially (factor VII shortest half-life); later both

— Thrombocytopenia from splenic sequestration

— Factor VIII often elevated (extrahepatic synthesis + acute phase) — useful distinguishing feature from DIC

— Factors II, VII, IX, X affected

— Prolonged PT first, then aPTT

— Treat with vitamin K ± FFP or 4-factor PCC

— UFH prolongs aPTT; LMWH and fondaparinux affect anti-Xa

— DOACs: dabigatran prolongs aPTT and thrombin time; apixaban/rivaroxaban affect PT variably and anti-Xa

— Ehlers-Danlos, scurvy → easy bruising, normal coags

— Always on the differential in a pediatric bleeding/bruising presentation; bruises in protected areas, patterned bruises, fractures of varying ages → mandatory reporting, but rule out bleeding disorders concurrently (CBC, PT/aPTT, vWF, factor VIII/IX) — failure to do so is a documented diagnostic error

Board pearl: A toddler with bruising and a swollen knee — order PT, aPTT, CBC, vWF panel, factor VIII and IX before concluding abuse. Both diagnoses can coexist; missing hemophilia is a sentinel event.

Step 3 management: When liver disease and a "hemophilia-like" picture overlap, check factor VIII — high in liver disease, low in hemophilia A.

Platelet disorders:

DIC:

Liver disease coagulopathy:

Vitamin K deficiency / warfarin:

Heparin/DOAC effect:

Connective tissue disorders:

Child abuse:

Long-Term Prophylaxis, Discharge, and Secondary Prevention

— Hemophilia A: factor VIII 25–40 U/kg 3×/week, or EHL 2×/week, or emicizumab SC weekly to monthly

— Hemophilia B: factor IX 40–100 U/kg 2×/week, or EHL every 7–14 days

— Targets trough ≥1–3% (older standard) or higher (≥10–15%, modern aim with EHL/emicizumab) to prevent breakthrough bleeds

— Continue factor at therapeutic dose until full resolution (typically 3–14 days by bleed severity)

— Written action plan with: product name, dose, dosing schedule, signs of recurrence, when to call

— Home infusion teaching for self-administration

— Pain control: acetaminophen, COX-2 inhibitors; avoid aspirin/NSAIDs

— Begin physical therapy as soon as acute bleed stabilizes — prevents contracture

— Hepatitis A and B (complete series)

— Annual influenza, COVID-19, pneumococcal per schedule

— SC route preferred; IM with smallest needle and 5-min pressure

— Encourage low-impact exercise (swimming, cycling) — strong muscles protect joints

— Avoid contact sports in severe disease

— MedicAlert bracelet

— Dental hygiene to minimize need for extractions

— Annual lipids, BP, diabetes screening per USPSTF

— Statin therapy as indicated — hemophilia is not a contraindication

— Smoking cessation, weight management

Board pearl: Modern prophylaxis (particularly emicizumab) has shifted bleeding mortality so dramatically that cardiovascular disease screening and prevention are now central to long-term hemophilia care.

Step 3 management: Every discharge should include HTC follow-up within 2–4 weeks, written infusion plan, and confirmed home factor supply.

Primary prophylaxis — standard for severe hemophilia:

Secondary prophylaxis: after established arthropathy or recurrent bleeds — same regimens, often more intensive

Discharge after acute bleed:

Vaccinations:

Lifestyle counseling:

Cardiovascular prevention (especially in aging hemophiliacs):

Follow-Up, Monitoring, and Rehabilitation

— Comprehensive annual visit: hematology, PT, social work, dental, orthopedics, nursing — labs and joint assessments

— Routine outpatient visits q6 months for severe disease on prophylaxis

— Pediatrics: more frequent in first 50 exposure days (inhibitor surveillance)

— CBC, factor activity trough, inhibitor screen (Bethesda), HCV/HIV serology and viral load if indicated

— LFTs, BMP, lipids (aging cohort)

— Pharmacokinetic study every 1–3 years to individualize prophylaxis

— Hemophilia Joint Health Score (HJHS) annually

— Plain films q3–5 years or for new symptoms; MRI/US for early synovitis

— Track target joints — escalate prophylaxis if breakthrough bleeds occur

— Early mobilization after acute bleeds (within 24–48 h once pain controlled)

— Quadriceps, hamstring, calf strengthening to protect knees and ankles

— Aquatic therapy especially valuable

— Avoid prolonged immobilization → muscle atrophy → re-bleeding cycle

— Multimodal: acetaminophen, COX-2 inhibitors, topical agents

— Avoid opioids if possible; if needed, short courses with clear taper

— Intra-articular steroids occasionally for synovitis

— Joint replacement when conservative measures fail

— Recognize early bleed symptoms (aura, tingling, warmth before swelling)

— Self-infusion technique

— Bleed log/diary — many use mobile apps

— When to call HTC vs. ED

Board pearl: Early infusion at the first symptom (even before objective swelling) shortens bleed duration dramatically — empower patients to treat early.

Step 3 management: A 12-year-old with severe hemophilia A on prophylaxis develops 3 ankle bleeds in 4 months → target joint forming — escalate prophylaxis intensity, add PT, consider MRI to assess synovitis.

HTC visit cadence:

Annual labs:

Joint health monitoring:

Rehabilitation principles:

Pain management for chronic arthropathy:

Patient self-management education:

Ethical, Legal, and Patient Safety Considerations

— Carrier testing of female relatives is ethically complex — respect autonomy, including the right not to know

— Prenatal diagnosis raises pregnancy termination decisions — provide non-directive counseling

— Pediatric carrier testing for asymptomatic girls is generally deferred until the child can participate in decision-making (adolescence) unless clinically necessary

— Gene therapy is a one-time, largely irreversible intervention with long-term unknowns — requires extended consent discussions, ideally over multiple visits, with documented understanding of durability, hepatotoxicity, and that re-dosing is generally not possible due to AAV immunity

— Off-label use of emicizumab in mild disease — discuss limited data

— Suspected abuse requires reporting regardless of underlying bleeding disorder

— Conversely, failure to consider hemophilia in a bruised child has led to wrongful family separations — always send coagulation workup before social work referral when bleeding pattern is atypical

— Pediatric → adult HTC transition at 18–21 is high-risk: bleed rates, ED visits, and prophylaxis adherence often worsen; structured transition programs reduce harm

— Discharge from hospital to home: explicit written plan with factor product name, lot, dose, and 24-h contact number — verbal handoffs alone have caused fatal delays in retreatment

— Switching products (e.g., to gene therapy, to emicizumab) requires careful washout planning and inhibitor surveillance

— Factor concentrates are extremely expensive ($200,000–$500,000/year per patient); insurance/coverage barriers can interrupt prophylaxis

— 340B program and HTC pharmacy services help mitigate access disparities

— Document discussions about cost when therapy changes

— Schools may need 504 plans; counsel honestly about contact-sport risks without paternalism

— Survivors of the 1980s contamination tragedy may need additional psychosocial support and advance care planning

Board pearl: Failure to consider hemophilia in a child with unexplained bruising — and instead immediately reporting suspected abuse — is a tested patient-safety vignette. Send coags first.

Genetic counseling and reproductive autonomy:

Informed consent edge cases:

Mandatory reporting and child abuse evaluation:

Transitions of care risks (Step 3 favorite):

Health systems and access:

Sports and school:

End-of-life and HIV/HCV cohort:

High-Yield Associations and Rapid-Fire Facts

Board pearl: Memorize the dosing formulas and the emicizumab + FEIBA contraindication — these are repeatedly tested.

Inheritance: both X-linked recessive; ~30% spontaneous mutations

Lab signature: isolated prolonged aPTT, normal PT/platelets/fibrinogen

Mixing study: corrects in deficiency, fails to correct in inhibitor (incubate at 37°C for VIII inhibitors)

Factor VIII dose: kg × % rise × 0.5; half-life 8–12 h

Factor IX dose: kg × % rise × 1.0 (recombinant); half-life 18–24 h

Each 1 U/kg raises: VIII by 2%, IX by 1%

DDAVP: hemophilia A mild only; raises VIII 2–5×; watch hyponatremia

Emicizumab + FEIBA = thrombotic microangiopathy — never combine

Tranexamic acid contraindicated in urinary tract bleeding and DIC

Hemophilia B Leyden: factor IX promoter mutation; phenotype improves after puberty

Intron 22 inversion: ~45% of severe hemophilia A

Inhibitor incidence: ~25–30% in severe hem A, ~3–5% in severe hem B

Hem B inhibitors associated with: anaphylaxis and nephrotic syndrome

Target joints: knees > elbows > ankles (adults); ankles often first in kids

Iliopsoas bleed sign: hip flexed/externally rotated, femoral nerve palsy

Treat first, image second for any suspected CNS bleed

Vaccinate SC preferred; avoid IM without coverage

Avoid NSAIDs, aspirin, IM injections without factor cover

Carrier factor VIII rises in pregnancy but factor IX does not

Avoid vacuum extraction and scalp electrodes in male fetuses of carriers

HTC care reduces mortality ~40% vs. non-HTC

Factor VIII is elevated in liver disease (distinguishes from hem A); factor IX is decreased

Acquired hem A: postpartum, autoimmune, malignancy, elderly idiopathic

Gene therapy: AAV-vector, watch LFTs, durability variable, no re-dosing

Bethesda ≥5 BU = high-titer inhibitor → bypassing agent needed

rFVIIa for breakthrough bleed in emicizumab patients (not FEIBA)

Pseudotumor: encapsulated chronic hematoma, often pelvic/femoral

Aging cohort: leading killer is CVD, not bleeding

Board Question Stem Patterns

Board pearl: Step 3 questions reward management sequences — know what to order first, second, and when to escalate.

Stem 1 — Toddler with first hemarthrosis: 14-month-old boy, swollen warm knee after starting to walk, no trauma; aPTT prolonged, PT normal. → Order factor VIII and IX activity. Answer: hemophilia A or B.

Stem 2 — Treat first, image second: 8-year-old with severe hem A struck head during play, now headache. → Give factor VIII to 100%, then CT head. Wrong answers: order CT first, observe, give FFP.

Stem 3 — Iliopsoas bleed: Adolescent with severe hemophilia, vague groin pain, hip flexed, decreased quadriceps strength, absent patellar reflex. → CT abdomen/pelvis + factor to 80–100% × 5–7 days. Recognize femoral neuropathy.

Stem 4 — Inhibitor: Patient with severe hem A whose usual factor dose no longer controls bleeds. → Bethesda assay; switch to rFVIIa or FEIBA.

Stem 5 — Emicizumab + FEIBA: Child on emicizumab gets FEIBA for breakthrough bleed and develops AKI, thrombocytopenia, hemolysis. → Thrombotic microangiopathy; use rFVIIa instead.

Stem 6 — Acquired hemophilia A: Elderly woman, new spontaneous bruising, aPTT prolonged not correcting on mixing, low factor VIII. → Bypassing agent + prednisone ± rituximab.

Stem 7 — Mild hemophilia A pre-procedure: Adult with baseline VIII 15% needs tooth extraction. → DDAVP trial dose + tranexamic acid mouthwash.

Stem 8 — Hemophilia B Leyden: Boy with severe hem B whose phenotype improves at puberty. → Recognize promoter mutation.

Stem 9 — Carrier in pregnancy: Female carrier of hemophilia A, third trimester, factor VIII level 35%. → Recheck at term (rises in pregnancy); maintain ≥50% for delivery; avoid vacuum/scalp electrodes in male fetus.

Stem 10 — Hematuria management: Hemophilia patient with painless hematuria. → Hydrate, factor; do not give tranexamic acid.

Stem 11 — Aging hemophiliac with NSTEMI: 65-year-old with severe hem A, NSTEMI. → Standard ACS therapy + factor coverage; do not withhold antiplatelets.

Stem 12 — Bruised child with normal coags initially: Send full workup including vWF and factors before concluding abuse.

One-Line Recap

In hemophilia A and B, an isolated prolonged aPTT in a male with deep-tissue or joint bleeding mandates immediate factor replacement to a site-specific target — before imaging in any suspected major bleed — with lifelong management built around prophylaxis (factor concentrates or emicizumab for hem A), inhibitor surveillance, multidisciplinary HTC care, and prevention of arthropathy and cardiovascular disease in an aging cohort.

Dosing reflex: VIII dose = kg × %rise × 0.5; IX dose = kg × %rise × 1.0; target 30–50% (minor), 50–80% (major), 80–100% for CNS/airway/compartment.

Treat first, image second for suspected ICH, retropharyngeal, or compartment bleed — never wait for CT to dose factor.

Emicizumab transformed prophylaxis in hem A (subcutaneous, works with inhibitors) — but never combine with FEIBA (thrombotic microangiopathy); use rFVIIa for breakthrough bleeds.

Mixing study fails to correct → inhibitor; send Bethesda assay and treat with bypassing agents while planning immune tolerance induction (or immunosuppression in acquired hemophilia).

Long-term care = HTC-based multidisciplinary management, joint preservation, vaccination, cardiovascular risk reduction (the modern leading cause of death), and structured pediatric-to-adult transition.