Hemophilia

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Background

  • TREAT FIRST, Diagnose second. Assume bleeding until proven otherwise.
  • Two types (clinically indistinguishable):
    • Hemophilia A: Factor VIII deficiency
    • Hemophilia B: Factor IX deficiency
  • Substantial proportion (~1/3) of both types arise from spontaneous mutations
  • Most common X-linked disorder[1](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

Factor Related

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, significant blunt head injury
    • MRI is preferred to CT if available (better visualization of posterior fossa)
  • CT A/P
    • Back, thigh, groin, or abdominal pain
  • LP
    • 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[2]

  • Always inquire whether patient has known inhibitors - may be refractory to conventional treatment
    • If so, obtain hematology consult before treatment
    • If no know 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[3]

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

Inhibitors to Factors

  • Antibody inhibitors to factor therapy more common in Factor concentrates and rare in recombinant factor therapy[4]
  • 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[5]

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[6]
    • 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

References

  1. Medscape: Hemophilia A
  2. Bitting RL, Bent S, Li Y, Kohlwes J. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis. Oct 2009;20(7):517-23
  3. DiMichele D. Hemophilia 1996. New approach to an old disease. Pediatr Clin North Am. 1996 Jun;43(3): 709-36.
  4. Franchini M. et al. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia: A 2013 Update. Semin Thromb Hemost. 2013 Oct;39(7):752-66
  5. O'Connell N, Mc Mahon C, Smith J, Khair K, Hann I, Liesner R, et al. Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors. Br J Haematol. Mar 2002;116(3):632-5
  6. Shwartz K, Rubinstein M. Hemophilia And Von Willebrand Disease in Children: Emergency Department Evaluation and Management. Pediatric Emergency Medicine Practice. Sept. 2015; (cited 2015 Sept 7th). Available from: https://www.ebmedicine.net/topics.php?paction=showTopic&topic_id=465&inittopicdload=1