Hemophilia A & B

Essentials of Diagnosis

• Hemophilia A: congenital deficiency of coagulation factor VIII

• Hemophilia B: congenital deficiency of coagulation factor IX

• Recurrent hemarthroses and arthropathy

• Risk of development of inhibitory antibodies to factor VII or factor IX

• Many older patients received blood products contaminated with HIV or hepatitis C virus (HCV)

General Considerations

• Inheritance is X-linked recessive, leading to affected males and carrier (affected) females with variable bleeding tendencies

• Daughters of all affected males are obligate carriers

• There is no race predilection

• Inhibitors to factor VIII will develop in ~20–25% of patients with severe hemophilia A

• Inhibitors to factor IX will develop in < 5% of patients with severe hemophilia B

• Hemophilia is classified according to the level of factor activity in the plasma

  • Mild hemophilia is characterized by > 5% factor activity

  • Moderate hemophilia is characterized by 1–5% factor activity

  • Severe hemophilia is characterized by < 1% factor activity

Demographics

• The frequency of hemophilia A is ~1 per 5000 live male births

• Hemophilia B occurs in ~1 in 25,000 live male births

Symptoms and Signs

• Severe hemophilia presents in infant males or in early childhood with spontaneous bleeding into joints, soft tissues, or other locations

• Spontaneous bleeding is not common in patients with mild hemophilia, but significant bleeding is common during a major hemostatic challenge (eg, surgery, trauma)

• Intermediate clinical symptoms are seen in patients with moderate hemophilia

• Female carriers are can have a wide range of factor VIII activity, and therefore have variable bleeding tendencies

• Joint disease

  • Significant hemophilic arthropathy

    • Usually does not develop in patients who have received long-term prophylaxis with factor concentrate in early childhood

    • Is common in adults who have experienced recurrent hemarthroses

  • Patients tend to have one or two 'target' joints into which they bleed most often

• Development of inhibitor to factor VIII or factor IX is characterized by bleeding episodes that are resistant to treatment with clotting factor VIII or IX concentrate, and by new or atypical bleeding

Differential Diagnosis

• Hemophilia B

• von Willebrand disease

• Disseminated intravascular coagulation

• Heparin administration

• Acquired factor deficiency or inhibitors (eg, paraproteins with anti-VIII or anti-IX activity)

Laboratory Tests

• Factor activity testing is indicated for

  • Male infants with a hemophilic maternal pedigree who are asymptomatic or who experience excessive bleeding

  • All daughters of affected males (100% chance of being affected) and carrier mothers (50% chance of being affected)

  • An otherwise asymptomatic adolescent or adult who experiences unexpected excessive bleeding with trauma or invasive procedures

• An isolated reproducibly low factor VIII or factor IX activity level, in the absence of other conditions

• If the aPTT is prolonged, it typically corrects upon mixing with normal plasma

• Depending on the level of residual factor VIII or factor IX activity and the sensitivity of the thromboplastin used in the aPTT coagulation reaction, the aPTT may or may not be prolonged (although it typically is markedly prolonged in severe hemophilia)

• In the presence of an inhibitor to factor VIII or factor IX, there is accelerated clearance of infused factor and suboptimal or absent rise in measured activity of infused factor, and the aPTT does not correct on mixing

• The Bethesda assay measures the potency of the inhibitor

Medications

• Plasma-derived or recombinant factor VIII or IX products are the mainstay of treatment

• By the age of 4 years, most children with severe hemophilia A or B have begun twice- or thrice-weekly prophylactic infusions of factor VII or IX to prevent the recurrent joint bleeding that otherwise would characterize the disorder and lead to severe musculoskeletal morbidity

• In select cases of less severe hemophilia or in severe cases of hemophilia as an adjunct to prophylaxis, factor products may be given

  • Peri-procedurally

  • Prior to high-risk activities (such as sports)

  • As needed for bleeding episodes (Table 14–8)

• Recombinant factor VIII and factor IX molecules that are bioengineered to have an extended half-life have been approved for clinical use and may allow for extended dosing intervals in patients who are treated prophylactically

• Patients with mild hemophilia A may respond to as-needed intravenous or intranasal treatment with DDAVP

• Antifibrinolytic agents may be useful in cases of mucosal bleeding and are commonly used adjunctively, such as following dental procedures

• Emicizumab

  • FDA approved

  • Novel bi-specific antibody

  • Brings factors IX and X together, effectively replacing the co-factor function of factor VIII in the clotting cascade

  • Is an effective option for patients with and without factor inhibitors

• Celecoxib may be used to treat arthritis symptoms; other NSAIDs and aspirin should be avoided due to the increased risk of bleeding from inhibition of platelet function

• Oral opioid medications are commonly used to control pain

• It may be possible to overcome low-titer factor inhibitors (< 5 Bethesda units, BU) by giving larger doses of factor, whereas treatment of bleeding in the presence of a high-titer inhibitor (> 5 BU) requires infusion of an activated prothrombin complex concentrate or recombinant activated factor VII

• Recombinant porcine factor VIII is also an option but is reserved for selective circumstances given its cost

• Inhibitor tolerance induction, achieved by giving large doses (50–300 units/kg intravenously of factor VIII daily) for 6–18 months, succeeds as eradicating the inhibitor in 70% of patients with hemophilia A and in 30% of patients with hemophilia B

• Hemophilia B patients who receive inhibitor tolerance induction, however, are at risk for development of nephrotic syndrome and anaphylactic reactions, making eradication of their inhibitors less feasible

• Additional immunomodulation may allow for eradication in selected patients who do not respond to inhibitor tolerance induction

• Antiretroviral treatment should be administered to individuals with HIV infection

• Patients with hepatitis C infection should be referred for treatment to eradicate the virus

Surgery

• Total joint replacement is often required

Therapeutic Procedures

• Treat patients with head injuries (with or without neurologic signs) emergently as for major bleeding

Complications

• Arthritis from recurrent joint bleeding

• Hepatitis B and C and HIV infection from recurrent transfusion (incidence decreasing)

Prognosis

• Prognosis markedly improved by availability of factor VIII replacement

• Major limiting factor is disability from recurrent joint bleeding

• Hemophiliacs with hepatitis B or C or HIV have worse prognosis associated with those disorders

• ~15% develop inhibitors to factor VIII and thus cannot be adequately supported with factor VIII

When to Refer

• All patients should be seen regularly in a comprehensive hemophilia treatment center

When to Admit

• Major invasive procedures due to the need for serial infusions of clotting factor concentrate

• Bleeding that is unresponsive to outpatient treatment