Hemophilia

Background

• TREAT FIRST, Diagnose second. Assume bleeding until proven otherwise.
• Two types (clinically indistinguishable):
  • Hemophilia A: Factor VIII deficiency
  • Hemophilia B (Christmas disease): Factor IX deficiency
• Substantial proportion (~1/3) of both types arise from spontaneous mutations
• Most common X-linked disorder(overwhelmingly a disease of men)
• ICH is most common cause of hemorrhagic death
• Do not give NSAIDs or IM injections
• Avoid invasive procedures (e.g. central lines, LP)

Prehospital Care

• Rapid transport to definitive care
• Apply pressure and achieve hemostasis in active bleeding patients
• Bring Factor therapy with patient and encourage use during transport
• Determine history of trauma or prior complications with hemophilia
• For hemarthrosis; elevate, ice, and protect joint (crutches for knee/ankle)

Clinical Features

Patient does not need objective exam finding to treat. Subjective complaints are a harbinger of serious issues.

Hemarthroses

• Location
  • Peds: Ankle 80% of the time
  • Adults: Knees, then elbows, then ankles
• Leads to joint destruction and chronic arthropathy if not adequately treated
• Patients can reliably report when bleeding is occurring
• Most common bleeding complaint

Hematomas

• Bleeding into soft tissues or muscle
  • Neck (airway compromise)
  • Limbs (compartment syndromes)
  • Eye (retro-orbital hematoma)
  • Spine (epidural hematoma)
  • Retroperitoneum (iliopsoas bleeds and massive blood loss)
• Most common initial complaint

Mucocutaneous bleeding

• Spontaneous bleeding uncommon from oropharynx, GI tract, epistaxis, or hemoptysis

CNS

• Intracranial bleeding is most common cause of hemorrhagic death
• Subdural hematomas occur spontaneously or with minimal trauma

Hematuria

• Common, usually not serious, source is rarely found

Differential Diagnosis

Coagulopathy

Platelet Related

• Too few
  • Thrombocytopenia
• Nonfunctional
  • Aspirin
  • Von Willebrand disease

Factor Related

• Acquired (Drug Related)
  • Warfarin (Coumadin)
  • Unfractionated heparin
  • Low molecular weight heparin (i.e. enoxaparin (Lovenox), dalteparin)
  • Factor Xa Inhibitors (e.g. rivaroxaban, apixaban, fondaparinux, edoxaban)
  • Direct thrombin inhibitors (e.g. dabigatran, argatroban, bivalirudin)
• Illness induced
  • Vitamin K deficiency
  • Disseminated Intravascular Coagulation (DIC)
  • Liver disease induced coagulopathy
  • Uremic bleeding syndrome
• Genetic
  • Hemophilia
  • Factor VIII inhibitor
  • Lupus anticoagulant

Evaluation

Work-Up

• Coags
  • Only helpful in making the diagnosis; once established unlikely to yield new information
  • PT - normal
  • PTT - abnormal (unless mild hemophilia)
  • PTT s/p factor - should correct to normal
• Factor VIII assay

Consider

• Head CT
  • If headache, altered mental status, blunt head injury
  • MRI is preferred to CT if available (better visualization of posterior fossa)
• CT A/P
  • Back, thigh, groin, or abdominal pain
• If LP required
  • replete factor before attempting

Evaluation

• Pain in soft tissue is bleeding until proven otherwise
• Paresthesias in legs - consider retroperitoneal bleed
• Flexion contracture at the hip- iliopsoas bleed
• Easy bruising or bleeding out of proportion to the history of trauma
• Recurrent bleeding into joints and muscles
  • Arthrocentesis not indicated
• Prolonged PTT; normal PT

Factor VIII assay

Consider before treatment (for heme to follow)

• Normal: 50-150%
• Mild: >5% (usually an insult causes bleeding)
• Moderate: 1-5% (usually an insult causes bleeding)
• Severe: <1% (spontaneous bleeding not uncommon, multiple bleeding episodes/month)

Treatment

• Always inquire whether patient has known inhibitors - may be refractory to conventional treatment
  • If so, obtain hematology consult before treatment
  • If no known inhibitors, and patient not improving after replacement, order mixing study
    • PTT will not correct if inhibitors present

Indications for Factor Replacement

• Suspected bleeding into muscles or joints
• Trauma to head or neck
• Any new or concerning headache (spontaneous or traumatic)
• Trauma with potential for internal bleeding
• Prior to any planned invasive procedure or surgery
• Gastrointestinal bleeding
• Acute fractures, dislocations and sprains

Factor Replacement

• Major bleeding (GI, CNS, large muscle, trauma) requires factor replacement level 80-100%
• Moderate bleeding (soft tissue, small muscle, joint) requires 30-50%
• Diagnosis unknown
  • Give FFP (contains VIII and IX)
  • Each bag raises factor levels by 3-5%
• Severe mechanism of injury (head, neck trauma), even without evidence of bleeding
  • Hemophilia is factor deficiency, not platelet deficiency/malfunction so initial hemostasis may be achieved but clot stabilization will not persist
  • Delayed bleeding is a serious risk, so factor replacement must occur immediately

Hemophilia A

• Dose of Factor VIII = weight (kg) x % increased desired x 0.5
  • After initial correction give half this dose q8-12hr
  • 1 IU/kg will increase the plasma concentration by 2%
  • For severe bleeding, desired factor level is 80-100%.
  • For less severe bleeding, the desired factor level is 30-50%
• Desmopressin
  • May be sufficient in patients with mild bleeding
  • 0.3mcg/kg IV over 15-30min

Hemophilia B

• Dose of Factor IX = weight (kg) x % increase desired
  • After initial correction give half this dose 24 hr later
  • 1 IU/kg will increase the plasma concentration by 1%
  • For severe bleeding, desired factor level is 80-100%.
  • For less severe bleeding, the desired factor level is 30-50%

Use the percentage as integer, not percentage (e.g. for 25% multiply by "25" not "0.25")

Desired Level Repletion

Site of Bleed	Hemostatic Level	Hemophilia A	Hemophilia B
Joint	80% acutely, then 40% every other day until resolved	40 units/kg initially and then 20 units/kg every other day until healed	80 units/kg initially and then 40 units/kg every other day or third day as needed
Muscles	40-50%	20-40 units/kg per day until healed	40-60 units/kg then 20-30 every other day as needed
Oral	100%	50 units/kg	100 units/kg
Nose	Initially 80-100%, then 30% until healing	40-50 units/kg, then 30-40 units per day	80-100 units/kg then 35-40 units every day
Gastrointestinal	Initially 100%, then 50% until healing	50 units/kg, then 30-40 units/ kg per day	100 units/kg then 30-40 units every day
Genitourinary	Initially 100%, then 30% until healing	50 units/kg then 30-40 units/ kg/day	100 units/kg then 30-40 units every day
Central Nervous System	Initially 100%, then 50-100% for 14 days	50 units/kg then 25 units/kg every 12 hours	100 units/kg then 50 units/kg every day
Surgery/trauma	Initially 100%, then 80-100% until wound healing begins, then 30% until suture removed	50 units/kg then 40-50 units every 12 hours adjusted according to healing	100 units/kg then 50 units every day adjusted according to healing

• For isolated oral mucosal bleeding consider antifibrinolytic agents (e.g. - TXA)

Inhibitors to Factors

• Antibody inhibitors to factor therapy more common in Factor concentrates and rare in recombinant factor therapy
• Treatment should be in consultation with hematologist
• In major bleeding, rVII has been suggested as potential salvage therapy for patients with inhibitors to recombinant factor

Treatment Options

• Activated Prothrombin Complex Concentrate Dosing: 75 units/kg
• FEIBA (Immuno)
• Recombinant Activate VII Dosing: 90ug/kg every 2-3 hours
• Several studies suggest treatment with higher dosing of Recombinant Activate VII initially
  • 270 mcg/kg dosing
  • Separate further dosing by at least 6 hours

Disposition

Admit

• Patients requiring multiple factor replacement doses
• Bleeding in head, neck, pharynx, retropharynx, or retroperitoneum
• Potential for compartment syndrome

Discharge

• If close follow-up and mild hemarthrosis
• If no bleeding and prophylaxis given
• Coordinate follow-up with patient's hematologist or primary care provider

See Also

• Coagulopathy (Main)
• Von Willebrand Disease (vWD)