Hemophilia The 5 Minute Pediatric Consult


	Hemophilia

Kara M. Kelly

Database
Differential Diagnosis
Data Gathering
Physical Examination
Laboratory Aids
Therapy
Follow-Up
Common Questions and Answers
Bibliography

DATABASE

DEFINITION

Inherited bleeding disorder caused by the absence, severe deficiency or defective functioning of plasma coagulation factor VIII (hemophilia A) or IX (hemophilia B).

PATHOPHYSIOLOGY

Thrombin generation via the intrinsic pathway is delayed in patients with absent or reduced (<25%) factor VIII or factor IX.
Patients do not bleed more rapidly; instead there is delayed formation of a clot.
The friable clot formed has a tendency to rebleed.
In closed spaces (e.g., joint), bleeding stops by tamponade; in open spaces (e.g., iliopsoas muscle, open wounds), large amounts of blood may be lost.
Repeated joint hemorrhages lead to synovial thickening and joint cartilage erosion. Joint space becomes narrowed and eventually fuses.

GENETICS

X-linked recessive disorder
Carrier status and prenatal testing available:
Hemophilia A:
- Gene inversion in the factor VIII gene is present in 45% of severe hepatitis A. Detectable by genetic screening
- In families with unknown mutations, a coagulation assay comparing the level of factor VIII with von Willebrand factor can be used to identify carriers
- Accuracy of screening: 90%
Hemophilia B:
- Majority of factor IX gene defects are due to missense point mutations, which can be identified in nearly all affected individuals and carriers

EPIDEMIOLOGY

Most common severe hereditary coagulation disorder
Distribution
- Hemophilia A: 80% to 85%
- Hemophilia B: 10% to 15%
Incidence:
- Hemophilia A: 1 per 5,000 male births
- Hemophilia B: 1 per 25,000 male births
No geographic or ethnic associations

COMPLICATIONS

Complications of Disease

Hemophilic arthropathy: joint contractures, limited range of motion, and chronic pain
Intracranial bleeding
Compartment syndrome
Airway compromise due to bleeds in the pharynx, tongue, or neck
Life-threatening hemorrhage due to gastrointestinal, post-traumatic or perioperative bleeds

Complications of Therapy

Viral transmission through pooled coagulation factor concentrates (HIV, hepatitis B, C)
Inhibitors: Antibodies against factor VIII or IX, which can inactivate infused factor
Anaphylaxis: Continued factor IX replacement in severe factor IX deficient patients with inhibitors may lead to anaphylaxis
Thromboembolic disease: Use of prothrombin complex concentrates is associated with thromboembolism and myocardial infarctions in children

DIFFERENTIAL DIAGNOSIS

Prolonged Coagulation Time Associated with Increased Bleeding Tendency

von Willebrand disease
“Acquired hemophilia” due to development of an inhibitor to factor VIII or IX
Hereditary factor XI deficiency

Prolonged Coagulation Time But No Increased Bleeding Tendency

Factor XII deficiency
High molecular weight kininogen deficiency
Prekallikrein deficiency
Antiphospholipid antibody (lupus anticoagulant)
Heparin artifact

DATA GATHERING

HISTORY

Question: Familial history?
Significance: Familial history of hemophilia in male offspring of female blood relatives is present in 30% to 40% of cases.

Question: Excessive bleeding in male neonate?
Significance: Excessive bleeding with circumcision or of the umbilical cord may be an initial presentation of hemophilia. 1% to 2% of neonates may present with an intracranial hemorrhage.

Question: Pattern of bleeding?
Significance: Characterized by spontaneous joint and muscle hemorrhages, easy bruising and prolonged and potentially fatal hemorrhage after trauma or surgery.

Question: Age of onset of bleeding?
Significance: Bleeds generally occur with increasing frequency around the time the child begins to walk or starts teething.

Question: Location of hemarthrosis?
Significance: Large weight bearing joints are most often involved: knees, elbows, ankles, shoulders, hips.

Question: Early symptoms of a hemarthrosis?
Significance: Aura of tingling or warmth, followed by increasing pain and decreasing range of motion.

PHYSICAL EXAMINATION

Finding: Joint examination
Significance:

Acute hemathrosis: limitation of motion of the joint, warmth, swelling, tenderness
Chronic joint: crepitus, decreased range of motion, proximal muscle weakness; typically occurs in knees, ankles, elbows
Intramuscular hematomas: often little seen on exam; vague feeling of pain with motion

LABORATORY AIDS

TESTS

Test: Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen or thrombin time and platelet count.
Significance: Screen for bleeding disorder.

Test: Factor VIII, IX levels
Significance:

Less than 1%: severe hemophilia. Most common, characterized by spontaneous hemarthroses; will need frequent factor replacement therapy.
1% to 5%: moderate hemophilia. Spontaneous hemorrhage common; will require occasional factor replacement therapy.
5% to 25%: mild hemophilia. Rare bleeding; requires factor replacement therapy only with significant trauma or surgery.

PITFALLS

Neonates have a physiological reduction in the vitamin K dependent factors, including factor IX, making a determination of the degree of factor IX deficiency difficult in the neonatal period
Delivery-related stress and other neonatal problems may cause a transient elevation of factor VIII levels
Poor venipuncture technique can artifactually elevate or normalize the PTT.

THERAPY

ACUTE BLEEDING EPISODES

Factor Replacement

Factor VIII replacement products
- Recombinant non–plasma-derived factor VIII
- Monoclonal purified plasma-derived factor VIII concentrate; heat or detergent treated for viral inactivation
- Cryoprecipitate (rarely used today)
Factor IX replacement products
- Recombinant non–plasma-derived factor IX
- Monoclonal purified plasma-derived factor IX concentrate; heat or detergent treated for viral inactivation
- Prothrombin complex concentrate: crude plasma fraction, which contains variable amounts of factors II, VII, IX, and X viral inactivated
- Rarely used: fresh frozen plasma
Dose
- Factor VIII dose = % desired rise in factor VIII level × body weight (kg) × 0.5
- Factor IX dose = % desired rise in factor IX level × body weight (kg)
Target Levels:
- 30% twice for most joint bleeds
- 70% repeated over 12 to 48 hours for large muscle bleeds
- 100% maintained over 10 to 14 days for intracranial bleeds, surgery

DDAVP

Synthetic vasopressin analog which stimulates release of endogenous factor VIII and von Willebrand factor
Only suitable for patients with mild or moderate factor VIII deficiency who have shown a response to DDAVP in a therapeutic trial
Tachyphylaxis may occur with repeated dosing

Antifibrinolytic Therapy

Antifibrinolytic agents for oral mucosal bleeding, dental extractions
Epsilon aminocaproic acid 50 to 100 mg/kg/dose PO every 6 hours, or Tranxemic acid 25 mg/kg/dose every 6 to 8 hours

Immobilization

Splints, casts, crutches, and/or bedrest
Prolonged immobilization may reduce recovery of joint range of motion; initiation of physical therapy with factor coverage is recommended, particularly after joint surgery

SPECIAL BLEEDING SITUATIONS

Intracranial Hemorrhage

Significant bleeding can occur despite the absence of external bruising
Factor replacement to 100% should be administered immediately
CT scan of the head is useful but may be negative early in a bleed

Major Surgery

Factor replacement to 100% pre- and post-operatively
Regular dosing of factor for a minimum of 1 week post-operatively, even in mild hemophilia

Compartment Syndrome

Bleeding within the fascial compartments of muscles
Most often occurs in the forearm and calf
Neurovascular compromise can lead to Volkman contracture

Iliopsoas Bleed

Lower abdominal or upper thigh pain may be first symptom
Examination is notable for inability to extend hip with preservation of internal and external rotation (which distinguishes it from hip joint bleed)
Diagnosis confirmed by ultrasound or CT scan
Large volumes of blood can be lost into the retroperitoneal space. Check CBC.

Oral Bleeding/Epistaxis

Constant pressure for 15 to 20 minutes
Epsilon amino caproic acid or tranxemic acid
Topical thrombin directly to the site of bleeding

Dental Care

Significant dental procedures (e.g., tooth extraction) should be performed by a dentist with experience treating hemophiliac patients and preferably, in a hospital setting where hematology consultation is available
Factor replacement is required pre- and post-procedures

Lacerations

Sutures should be avoided when possible
If sutures are required, factor replacement is necessary at time of placement and removal

Hematuria

Increased fluid intake and bedrest as initial treatment
If hematuria persists, factor replacement
Prednisone in HIV negative patients

FOLLOW-UP

Patients should be followed regularly at a comprehensive hemophilia treatment center, in which care is coordinated by a team including the pediatric hematologist, nurse coordinator, social worker, psychologist, physical therapist, dentist, orthopedic surgeon, and financial counselor.

PREVENTION

Prophylaxis

Primary prophylaxis: regular dosing in patients with no complications to prevent chronic joint damage
Secondary prophylaxis: regular dosing in patients with target joints to prevent additional damage and facilitate healing and rehabilitation

Anticipatory Guidance and Prevention

Good dental hygiene
Immunizations: no intramuscular injections; give SC with a small gauge needle
Rapid treatment of hemarthrosis to avoid chronic joint damage
Avoidance of aggressive contact sports, e.g., football, basketball, lacrosse, hockey, rugby; tennis, baseball are okay, but may be prone to small joint bleeds
Home infusion therapy as appropriate
Self-infusion training: usually start at age 11 years

COMMON QUESTIONS AND ANSWERS

Q: Are there any medications contraindicated in a child with hemophilia?
A: Aspirin should not be given as it interferes with platelet function. Non-steroidal inflammatory agents cause a milder effect on platelets, and should also be avoided when possible.

Q: Can immunizations be given to a child with hemophilia?
A: Immunizations should be given SC (instead of IM) with the smallest gauge needle; ice or cold packs should be applied to the area to minimize hematoma formation; if excessive bleeding occurs, the child should receive factor replacement.

ICD-9-CM 286.0

BIBLIOGRAPHY

DiMichele D. Hemophilia 1996. New approach to an old disease. Pediatr Clin N Am 1996;43(3):709–736.

Hoyer LW. Hemophilia A. N Engl J Med 1994;330(1):38–47.

Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am 1993;7:1269–1280.

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