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Hemophilia
Katie L. Westerfield, DO
Bryan Malave, MD
image BASICS
DESCRIPTION
  • Deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) coagulation proteins leading to bleeding tendencies in affected individuals. The majority of cases are due to inherited genetic mutations in factor VIII or factor IX coagulation proteins. However, an estimated 30% of all hemophilia cases result from spontaneous mutations.
  • Hemophilia A and B are clinically indistinguishable, but can be differentiated by assays that detect levels of factors VIII and IX, respectively.
  • Disease severity correlates with the relative levels of coagulation factors present in serum analysis:
    • Severe: frequent spontaneous bleeding (factor activity <1%)
    • Moderate: bleeding with mild to moderate trauma (factor activity 1-5%)
    • Mild: bleeding with major trauma, tooth extraction, or surgery (factor activity 5-40%)
  • Frequency of bleeding is similar when levels of severity are comparable in hemophilia A and B.
  • Synonym(s): Christmas disease (hemophilia B)
EPIDEMIOLOGY
  • Worldwide, an estimated 400,000 people are affected with hemophilia. Estimated frequency of 1 in 10,000 births (1).
  • Hemophilia A represents 80-85% of the total hemophilia population; hemophilia B comprises the remaining 15-20%.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Damage to vascular endothelium leads to exposure of subendothelial tissue factors, which interact with platelets, plasma proteins, and coagulation factors to produce a localized platelet plug contributing to hemostasis. Complexes involving factors VIII and IX participate in the intrinsic coagulation pathway to activate factor X, FXa. Downstream interactions involving FXa culminate in the conversion of prothrombin to thrombin, mediating platelet activation and fibrin deposition necessary for stabilization of the platelet plug.
  • Deficiencies of factor VIII or factor IX result in decreased production of FXa, leading to an unstable platelet plug and impaired hemostasis.
Genetics
  • Exhibits an X-chromosome linked inheritance pattern. Males are almost exclusively affected; females are asymptomatic carriers, unless their factor activity is <40% of normal.
  • Carriers with symptomatically low clotting factor levels are treated similarly to patients with the trait:
    • May bleed at the time of surgery
  • Males within the same family share similar deficiencies and level of severity owing to the same genetic defect.
GENERAL PREVENTION
  • Patients should carry medical ID tags listing their bleeding disorder or factor deficiency, inhibitor status, type of treatment products used, and initial treatment doses for mild, moderate, or severe bleeding.
  • Immediate family members of affected patients should have factor VIII and IX levels checked prior to invasive procedures, childbirth, and if bleeding tendencies occur.
  • Genetic testing should be offered to at-risk female family members to facilitate genetic counseling.
image DIAGNOSIS
  • History and initial presentation
    • 2/3 of presenting hemophilic patients have a positive family history. All male infants born to known carriers should have factor level testing.
    • Prolonged bleeding with circumcision, dental work, surgery, or injury
    • Excessive or easy bruising in early childhood
    • Spontaneous bleeding, especially in joints, muscle, or soft tissue
    • Typical presentation times: mild (36 months), moderate (8 months), severe (1 month)
    • Pregnancy Considerations: Treat all males born to a carrier as if they have hemophilia. Test at birth. Avoid vacuum/forceps deliveries (2)[B].
    • Cord blood can be used for testing (3)[A].
  • Life-threatening bleeds
    • Intracranial hemorrhage: generally resulting from trauma; incidence of 1:10; fatal in 30% of cases
    • Hematomas of bowel wall can cause obstruction or intussusception as well as pain mimicking appendicitis.
    • Neck or throat bleeds: can lead to airway obstruction
  • Serious bleeds
    • Hemarthrosis, most commonly of ankles, elbows, and knees
      • Infants may present with irritability or decreased use of limb.
      • Adults may have prodromal stiffness, acute pain, and swelling of joint.
      • Arthropathy results from repeated bleeding into joints, damaging cartilage, and subchondral bone:
        • Can result in fixed joints, muscle wasting, and significantly impaired mobility
    • Muscular hematomas most commonly occur in quadriceps, iliopsoas, and forearm:
      • May result in compartment syndrome and ischemic nerve damage, such as femoral nerve neuropathy due to undetected retroperitoneal hemorrhage
    • Mucous membrane bleeding, such as in the genitourinary tract, leading to hematuria
    • Pseudotumor syndrome: untreated hemorrhage causing a hematoma, which calcifies (named because it can be mistaken for cancer)
DIFFERENTIAL DIAGNOSIS
  • Von Willebrand disease
  • Vitamin K deficiency, anticoagulant (warfarin, rivaroxaban, argatroban, heparin, enoxaparin) therapy (factor IX is vitamin K-dependent)
  • Other factor deficiencies: afibrinogenemia, dysfibrinogenemia, fibrinolytic defects, platelet disorders
  • Child abuse
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC with platelet count, PT, aPTT, platelet function (preferred) or bleed time, vWF, factor VIII:C assay, factor IX assay. Prolonged aPTT: corrected when mixed with pooled normal plasma in absence of inhibitors
  • PT, platelet count, and platelet function are normal.
  • Diagnosis based on factor VIII:C or IX activity
    • Normal factor levels: 50 to 150 IU/dL
    • Mild: 5 to 40 IU/dL
    • Moderate: 1 to 5 IU/dL
    • Severe: <1 IU/Dl
Follow-Up Tests & Special Considerations
Inhibitors to factor VIII and IX (see “Complications”):
  • Should be periodically measured using the Nijmegen or Bethesda assay, which quantifies the alloantibody titer
  • Screen before invasive procedures and at regular intervals.
Diagnostic Procedures/Other
Prenatal diagnosis: genetic testing of a sample of chorionic villus or fluid obtained at amniocentesis. Not recommended (2)[B]
Test Interpretation
In affected joints: synovial hemosiderosis, articular cartilage degeneration, thickening of periarticular tissues, bony hypertrophy
image TREATMENT
GENERAL MEASURES
  • Avoid aspirin or other NSAIDs.
  • Treat early; symptoms may occur before bleeding is clinically apparent. Acute bleeds should be treated as quickly as possible, preferable within 2 hours (1)[A].
  • For surgical prophylaxis
    • If major surgery is undertaken, factor levels should be maintained at >50% for at least 2 to 3 weeks after the procedure:
      • Fibrin glue products may be beneficial for oozing.
    • Dental extractions: Antifibrinolytics (Amicar, tranexamic acid) may be used.
    • Minor procedures: may use desmopressin (DDAVP)
  • Hepatitis A and B vaccinations are recommended.
  • Encourage physical activity for normal neuromuscular development: Patients should avoid high-impact contact sports; restrict activities in proportion to degree of factor deficiency. Organized sports should be encouraged as opposed to unstructured activities (1)[B].
MEDICATION
First Line
  • Principles of therapy
    • Primary prophylaxis: administration of specific factor replacement therapy in the absence of bleeding to maintain adequate baseline plasma levels sufficient for hemostasis in all categories of severity (1)[A]
      • Lower frequency of acute bleeds and episodes of life-threatening hemorrhage compared to on-demand therapy
      • Standard of care for children with severe hemophilia A to prevent joint bleeds and joint degeneration
      • Dosing, frequency, duration of therapeutic regimens tailored to individual patient needs in clinical practice
    • On-demand therapy: treatment administered in response to occurrence of bleeding
      • Amount and duration of factor replacement depends on location and severity of bleeding:
        • Mild bleeds correct to a factor level of >30% major hemorrhages and large muscle bleeds require correction to levels between 50% and 100%.
        • Life-threatening bleeds require levels between 80% and 100%, sustained with bolus dosing or continuous infusion.
  • P.457

  • Specific agents:
    • Hemophilia A: Replacement with factor VIII concentrates is the treatment of choice:
      • Two sources for the factor available:
        • Purified plasma-derived factor VIII: Donor pool is screened and the plasma-derived factor is treated to inactivate viruses (HIV, hepatitis B, and hepatitis C). Theoretical risks still exist.
        • Recombinant factor VIII
          • Dosing: 1 IU of factor VIII (the amount in 1 mL of plasma)/kg body weight administered will raise the plasma level of the recipient by 2%.
          • Most FVIII products have short half-lives, requiring frequent injections novel recombinant factor VIII, rFVIIIFc, dosed prophylactically 1 to 2 times per week (4)[B].
    • Hemophilia B: Replacement with factor IX concentrates is the treatment of choice:
      • Plasma-derived factor IX and recombinant factor IX (preferred) are commercially available.
        • Dosing: 1 IU/kg body weight administered will raise plasma factor IX levels 1%.
  • Hemophilia patients with inhibitors (neutralizing alloantibodies to factors VIII or IX)
    • Inhibitor formation should be suspected when replacement with the deficient factor fails to correct coagulopathy.
    • Low-titer (<5 BU/mL) patients: Replace with high doses of the deficient factor to overcome the circulating inhibitor concentration.
    • High-titer patients: Treat using products that bypass the factor neutralized by the alloantibody, or emergently with high doses of the specific deficient factor:
      • Two bypassing agents are available; both are efficacious at providing 80% of bleeding episodes:
        • Anti-inhibitor coagulation complex (AICC)
        • Recombinant activated factor VII (rFVIIa)
  • Immune tolerance induction (ITI): protocols to promote immune tolerance through repeated exposure to high-dose factor VIII therapy over 12 to 18 months, with or without immunosuppressive therapy (corticosteroids, cyclophosphamide, rituximab). Success rates are 60-80%.
    • Home therapy allows immediate access to clotting factor, resulting in decreased pain, dysfunction, and long term disability (2)[B].
Second Line
  • Cryoprecipitate and fresh frozen plasma (FFP) can be used in instances where the specific factor concentrate is unavailable for emergent hemostasis.
    • FFP: contains all coagulation factors but generally difficult to attain high levels of factors VIII or IX
      • Starting dose: 15 to 20 mL/kg
    • Cryoprecipitate: derived from precipitates of cooled FFP; contains significant levels of factor VIII (up to 100 IU/bag) but not factor IX:
      • Dosing: 1 mL cryoprecipitate has ˜3 to 5 IU factor VIII.
  • Desmopressin (DDAVP): synthetic vasopressin; stimulates endogenous release of factor VIII (and vWF) from endothelial stores; used in mild to moderate hemophilia
    • IV or SC: 0.3 &mgr;g/kg infused 30 minutes prior to procedure; may repeat if needed
    • Intranasal (150 &mgr;g/spray): adult dose, 1 spray to each nostril (300 &mgr;g total). Alternate dose if <50 kg: 150 &mgr;g once.
    • Adverse effect: hyponatremic seizures, especially in children; restrict fluids and watch sodium levels and urine output.
  • Antifibrinolytic agents: inhibit plasminogen activation, thereby stabilizing the clot
    • Effective in controlling mucosal bleeding, such as bleeding in oral cavity, epistaxis, and menorrhagia; can also be used prophylactically (e.g., prior to tooth extractions)
      • Tranexamic acid (25 mg/kg PO q6-8h or 10 mg/kg IV q6-8h)
      • Aminocaproic acid (Amicar) is less frequently used.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Regular evaluations every 6 to 12 months, including a musculoskeletal evaluation, an inhibitor screen, liver tests, and tests for antibodies to hepatitis viruses and HIV
PATIENT EDUCATION
  • National Hemophilia Foundation: http://www.hemophilia.org/
  • World Federation of Hemophilia: http://www.wfh.org/
PROGNOSIS
  • Survival is normal for those with mild disease; mortality is increased 2- to 6-fold in those with moderate to severe disease.
  • Intracranial hemorrhage is a leading cause of death in hemophilia.
  • Hemophilic arthropathy is the main cause of morbidity in patients with severe hemophilia.
COMPLICATIONS
  • Hemophilic arthropathy: Symptoms include pain, limitation of motion, and contractures.
  • Theoretical transmission of bloodborne infections, such as hepatitis A, B, C, and D and HIV; this risk has been greatly reduced with current testing of blood products.
  • Development of inhibitor autoantibodies
    • More common in hemophilia A (20-30% of patients compared to 5% in hemophilia B) and in patients with severe disease requiring multiple transfusions
    • Risk factors for inhibitor development:
      • Specific genetic defect (family history); null mutations have higher inhibitor incidence.
      • Very low or no circulating factor, therefore requiring multiple transfusions
      • Age of first exogenous factor exposure; previous studies report a higher incidence of developing antibodies in those exposed to exogenous factor at <6 months of age, but new studies show this may be due to severity of disease.
      • Concurrent inflammation/infection when administering factor (e.g., surgical prophylaxis)
      • Duration of factor exposure
    • No increased risk of bleeding, but when bleeding occurs, it is more difficult to achieve hemostasis due to decreased response to factor replacement.
REFERENCES
1. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1-e47.
2. Tsui NB, Kadir RA, Chan KC, et al. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. Blood. 2011;117(13):3684-3691.
3. National Hemophilia Foundation. MASAC guidelines for perinatal management of women with bleeding disorders and carriers of hemophilia A nd B. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Guidelines-for-Perinatal-Management-of-Women-with-Bleeding-Disorders-and-Carriers-of-Hemophilia-A-and-B. Accessed June 4, 2015.
4. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123(3);317-325.
Additional Reading
&NA;
  • Benson G, Auerswald G, Elezović I, et al. Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice. Eur J Haematol. 2012;88(5):371-379.
  • Berntorp E, Shapiro AD. Modern haemophilia care. Lancet. 2012;379(9824):1447-1456.
  • Fischer K. Prophylaxis for adults with haemophilia: one size does not fit all. Blood Transfus. 2012;10(2):169-173.
  • Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis. 2012;7:24.
  • Gater A, Thomson TA, Strandberg-Larsen M. Haemophilia B: impact on patients and economic burden of disease. Thromb Haemost. 2011;106(3):398-404.
  • Kulkarni R, Soucie JM, Lusher J, et al. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from the Centers for Disease Control and Prevention's (CDC) Universal Data Collection (UDC) project. Haemophilia. 2009;15(6):1281-1290.
  • Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011;365(18):1684-1692.
  • Ragni MV, Fogarty PJ, Josephson NC, et al. Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres. Haemophilia. 2012;18(1):63-68.
Codes
&NA;
ICD10
  • D66 Hereditary factor VIII deficiency
  • D67 Hereditary factor IX deficiency
  • Z14.01 Asymptomatic hemophilia A carrier