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Hemophilia
OVERVIEW: Hemophilia A and hemophilia B are clinically indistinguishable, inherited bleeding disorders due to a deficiency of coagulant factor VIII (hemophilia A) or factor IX (hemophilia B)
• Disease severity is determined by percent of coagulant factor present
• Severe; < 2%
• Moderate; 2-5%
• Mild; > 6%. Patients with greater than 25% factor activity rarely bleed, however bleeding after major surgery can occur in patients or carriers with factor VIII levels in the range of 25-35%.
System(s) affected: Hemic/Lymphatic/Immunologic
Genetics: Both hemophilia A and hemophilia B are X-linked, recessive
Incidence/Prevalence in USA:
• Hemophilia A - 10 in 100,000 males
• Hemophilia B - 2 in 100,000 males
Predominant age:
• Both are congenital conditions
• Severe disease generally noted at birth or in first year
• Mild disease may not be diagnosed until young adulthood
Predominant sex: Females are generally asymptomatic carriers unless their factor level is < 40%. Rare exceptions occur from consanguinity within families, concomitant Turner's syndrome, or extremely disproportionate lyonization resulting in the preponderance of cells in the carrier female containing the X chromosome with the hemophilic gene.
SIGNS AND SYMPTOMS: • Bleeding into soft tissues, muscles, and weight-bearing joints
• Bleeding occurs hours to days after injury, can involve any organ, and can continue for hours to days
• Compartment syndromes and ischemic nerve damage from large hematomas
• Repeated bleeding into a joint causes osteoarthritis, articular fibrosis, and joint ankylosis
• Hematuria
• CNS bleeding, usually post-traumatic
CAUSES: Congenital
RISK FACTORS: Positive family history. Can predict risk to offspring using simple Mendelian genetics for an X-linked recessive disorder.
DIAGNOSIS DIFFERENTIAL DIAGNOSIS: • Von Willebrand's disease
• Vitamin K deficiency (factor IX is vitamin K dependent)
• Other factor deficiencies, afibrinogenemia, dysfibrinogenemia, fibrinolytic defects, platelet disorders
LABORATORY: • Activated partial thromboplastin time (PTT) is prolonged while platelet count, and prothrombin time are normal
• Bleeding time is prolonged in 15-20% of patients with hemophilia A
• PTT is corrected when mixed with normal plasma
• Hemophilia A - diagnostic test is low factor VIII.
• Hemophilia B - diagnostic test is low factor IX
Drugs that may alter lab results: Recent aspirin use will increase bleeding time, leading to confusion with Von Willebrand's disease
Disorders that may alter lab results: N/A
PATHOLOGICAL FINDINGS: • Synovial hemosiderosis
• Articular cartilage degeneration
• Thickening of periarticular tissues
• Bony hypertrophy
SPECIAL TESTS: Hemophilia A - carrier detection compares the ratio of factor VIII to von Willebrand's factor protein and is predictive in up to 95% of cases. Molecular diagnosis is preferred for carrier testing.
IMAGING: N/A
DIAGNOSTIC PROCEDURES: N/A
TREATMENT APPROPRIATE HEALTH CARE: • Outpatient
• Home infusion therapy
• Inpatient for infusions following significant bleeding episodes
GENERAL MEASURES: • Avoid aspirin or aspirin-containing drugs
• Treat early. Symptoms often precede obvious bleeding.
• An uncomplicated, soft tissue bleeding or an early hemarthrosis requires a single infusion to 20-30% activity
• More extensive hemarthrosis or retroperitoneal bleeding requires bid infusions for 72 or more hours to 25-50% activity
• Life-threatening bleeding into the CNS requires maintaining levels greater than 50% activity for 2 weeks
• Major surgery requires greater than 50% activity preoperatively, continued for 1-2 weeks postoperatively
• Orthopedic care and physical therapy to prevent contractures and maintain joint mobility
• Vaccinate against hepatitis B at time of diagnosis
• Maintain good dental care
• Annual evaluation in a comprehensive hemophilia center
• Consideration for three times weekly prophylaxis in severe factor VIII deficiency
SURGICAL MEASURES: • Surgical or radionucleotide synovectomy, in selected patients
• Joint replacement, in selected patients
ACTIVITY: • Attempt to lead as normal a life as possible
• Restrict activities in proportion to the degree of factor deficiency, but maintaining a trim physical condition is important
DIET: No special diet
PATIENT EDUCATION: • Teach patient and family about signs and symptoms to watch for
• Genetic counseling
• Home care with self administered replacement therapy is often used
• Printed patient information available from: National Hemophilia Foundation, 110 Green Street, Room 406, New York, NY, 10012, (212)219-8180
MEDICATIONS DRUG(S) OF CHOICE: • Hemophilia A: Recombinant or monoclonal factor VIII is treatment of choice for hemophilia A patients who are HIV negative and who have had minimal prior concentrate exposure. Less optimal are plasma products enriched in factor VIII [cryoprecipitate, factor VIII concentrate]
• 1 unit of factor VIII (the amount in 1 mL of plasma) per kg of body weight will raise the plasma level of the recipient by 2%
• Number units = [(desired percent activity - current percent activity) times (body weight in kilograms)] divided by 2
• For example: 70 kg patient with 5% activity needs to be taken to 25% activity. Units needed: [(25% - 5%) x (70 kg)] / 2 = [(25 - 5) x (70)] / 2 = 700 units of factor VIII needed
• Half-life of factor VIII is 8-12 hours, therefore need to infuse at least bid to maintain a chosen factor VIII level, and tid when tight control of the level is needed
• Hemophilia B: Recombinant factor IX became available in mid 1997 and is treatment of choice for hemophilia B patients who are HIV negative and who have had minimal prior concentrate exposure. Monoclonal antibody purified factor IX is an effective and apparently safe plasma derived product
• For mild patients: Desmopressin (DDAVP); 0.3 mcg/kg diluted in 10-20 mL of saline IV over 20 minutes. An intranasal preparation is also available.
• Factor IX concentrate for moderate to severe hemorrhage and patients to undergo surgery. One unit/kg will raise levels 1%
• Number units = [(desired percent activity - current percent activity) times (body weight in kilograms)] divided by 1
• For example: 70 kg patient with 5% activity needs to be taken to 25% activity. Units needed: [(25% - 5%) x (70 kg)] / 2 = [(25 - 5) x (70)] / 1 = 1400 units of factor IX needed
Contraindications: None
Precautions: Hemophilia B - some factor IX concentrates contain trace amounts of activated vitamin K-dependent factors and therefore are thrombogenic and carry a risk for thromboembolism
Significant possible interactions: N/A
ALTERNATIVE DRUGS: • Aminocaproic acid (epsilon-aminocaproic acid, EACA) can be used for minor dental work following a single factor VIII infusion. Aminocaproic acid greatly enhances the risk of thromboembolism and should be used with caution with factor IX concentrates.
• Patients with inhibitors to factor VIII may require intensive plasmapheresis, large doses of concentrate, infusion of prothrombin complex concentrates (bypassing products), or porcine factor VIII
FOLLOW UP PATIENT MONITORING: Regular evaluations every 6 to 12 months include a musculoskeletal evaluation, an inhibitor screen, liver tests, and tests for antibodies to hepatitis viruses and human immunodeficiency virus (HIV)
PREVENTION/AVOIDANCE: Genetic counseling
POSSIBLE COMPLICATIONS: • Factor VIII and IX preparations and transfusions may result in viral hepatitis, chronic liver disease, and acquired immunodeficiency syndrome (AIDS). However, recent advances in factor VIII concentrate preparation should prevent future HIV infection and
hepatitis B and C.
• Hemophilia A - 10-20% of patients develop inhibitors to factor VIII, typically those with severe disease receiving multiple transfusions. Type I (high responders) inhibitors to factor VIII rapidly neutralize factor VIII and prevent effective transfusion therapy. Type II (low responders) inhibitors are low-titer and may respond to higher than normal doses of factor VIII.
EXPECTED COURSE AND PROGNOSIS: • Repeated hemarthroses result in eventual deformity and crippling
• Survival is normal for those with mild disease, and mortality is increased 2 to 6 fold in those with moderate to severe disease, primarily due to complications of infection
• Median life expectancy with this condition peaked in late 1970's at 68 years, and is now declining due to the AIDS epidemic
• Up to 70% are HIV seropositive, especially those with severe disease, and 4% with severe disease develop AIDS. Younger patients whose treatment began since the mid-late 80's are largely HIV negative and are not expected to be exposed by modern replacement products. The proportion of HIV positive hemophiliacs is therefore declining.
MISCELLANEOUS ASSOCIATED CONDITIONS: None
AGE-RELATED FACTORS:
Pediatric: Mean age of onset of symptoms is 1.5 years for severe disease (often noted in first year), 3 years for moderate disease, and 5 years or later for mild disease
Geriatric: N/A
Others: N/A
PREGNANCY: • The vast majority of females are asymptomatic carriers, although an occasional carrier will bleed at time of surgery. They require no specific treatment during pregnancy or delivery.
• Prenatal diagnosis previously required sampling fetal blood for coagulant activity. Newer prenatal detection schemes detect an identifiable restriction fragment length polymorphism or a gene deletion or rearrangement in a sample of chorionic villus or from fluid obtained at amniocentesis.
SYNONYMS: • Hemophilia A
• Factor VIII deficiency
• Classic hemophilia
• Hemophilia B
• Factor IX deficiency
• Christmas disease
ICD-9-CM: 286.0 Hemophilia A
286.1 Hemophilia B
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