Hemophilia A and Hemophilia B

Definition, Etiology, ClassificationTop

Hemophilia A and hemophilia B are inherited coagulation disorders. Mutations of the genes of factor VIII or factor IX, located on chromosome X, may result—mostly in men, as in X-linked disorders—in a decrease or absence of synthesis of these factors or in the synthesis of defective factors. Hemophilia A is caused by reduced activity of factor VIII, whereas hemophilia B is caused by reduced activity of factor IX.

A classification of hemophilia based on factor VIII or factor IX activity levels:

1) <1% of normal (<0.01 IU/mL): Severe hemophilia.

2) 1% to 5% of normal (0.01-0.05 IU/mL): Moderate hemophilia.

3) >5% to 40% of normal (>0.05-0.4 IU/mL): Mild hemophilia.

Clinical Features and Natural HistoryTop

Features of bleeding disorder usually appear at the age of 1 to 2 years. In patients with severe hemophilia the dominant features are spontaneous joint hemorrhages; these most frequently affect the knees, elbows, and ankles, and lead to joint destruction, deformation (termed hemophilic arthropathy), and secondary muscle atrophy. Other manifestations include bleeding into muscles (often in the iliopsoas), hematuria, gastrointestinal bleeding, intracranial bleeding (frequently fatal), and bleeding to the posterior pharyngeal wall or lower wall of the oral cavity. A typical feature is delayed and persistent bleeding after surgery or tooth extraction. Spontaneous bleeding is rare in patients with moderate hemophilia and virtually absent in patients with mild hemophilia.

DiagnosisTop

Diagnostic Tests

1. Screening tests: Activated partial thromboplastin time (aPTT) is prolonged in most patients with hemophilia A or B; however, it may be normal in patients with mild hemophilia and factor VIII or IX activity >30%.

2. Studies confirming the diagnosis: Reduced plasma activity of factor VIII or IX, genetic studies.

Diagnostic Criteria

A documented decrease in the plasma activity of factor VIII or factor IX.

Differential Diagnosis

1. Von Willebrand disease.

2. Acquired hemophilia (see Acquired Hemophilia A).

3. Other causes of a prolonged aPTT in a patient with a normal prothrombin time (PT), such as lupus anticoagulant (see Antiphospholipid Syndrome).

TreatmentTop

General Measures

1. Patients with hemophilia should always carry identification indicating their diagnosis, emergency management, and contact details of their physician. Patients can engage in physical activity but should take particular care to avoid injuries and may require pharmacologic prophylaxis (situational prophylaxis). Patients with moderate to severe hemophilia should be followed in a hemophilia treatment center, and their management should be overseen by that center.

2. Do not use antiplatelet agents; in particular, do not use acetylsalicylic acid (ASA). In the treatment of pain (eg, pain caused by hemarthrosis) use acetaminophen (INN paracetamol), selective cyclooxygenase-2 (COX-2) inhibitors, and opioids. Patients with medical conditions requiring antiplatelet treatment are better referred to specialized centers.

3. Avoid intramuscular injections.

4. Prophylactic treatment (see Pharmacotherapy, below) prevents complications of the disease and is recommended in most patients with severe hemophilia where available.

5. Treatment of most cases of bleeding as well as prophylactic treatment may be self-administered at home by a trained patient. In the case of joint bleeding, RICE (rest, ice, compression, elevation) may help contain the pain. The effect on duration of symptoms and arthropathy is unknown.

6. Surgical procedures and treatment of life-threatening hemorrhages should always be conducted in centers that are capable of daily laboratory monitoring of treatment results (measurements of factor VIII or IX activity, titers of factor VIII or IX inhibitors).

Pharmacotherapy

1. Plasma-derived or recombinant factor VIII or factor IX concentrates administered as IV injections:

1) Long-term prophylactic treatment: The goal of the treatment is to maintain the deficient factor plasma level above 1% to 3%. In patients with hemophilia A, use factor VIII concentrates 25 to 40 IU/kg 3 times a week or every other day. In patients with hemophilia B, use factor IX concentrates 25 to 50 IU/kg 2 to 3 times a week. Measurements of plasma factor levels at the end of the treatment interval (trough levels) are recommended to tailor the dose to the individual needs. The frequency of prophylactic administration can be adapted to the schedule of physical activity, particularly in children and adolescents.

2) Prophylactic treatment before planned surgical procedures (including tooth extraction; Table 1): Such procedures should only be managed in expert centers with immediate access to monitoring of coagulation factor levels. In case of emergency surgery, administer factor VIII or IX to raise the level >80% (0.8 IU/mL) trough for the entire duration of the procedure and at least 3 postoperative days.

3) Treatment of bleeding: In patients with hemophilia A, administer a factor VIII concentrate every 8, 12, or 24 hours. In patients with hemophilia B, administer a factor IX concentrate when needed, for instance, every 12, 18, or 24 hours. Dosage: Table 1. Start treatment as soon as possible (optimally within 2 hours); in patients with life-threatening bleeding (head, neck, chest, or gastrointestinal hemorrhage), treatment should be started before completing diagnostics and does not require a factor VIII level prior to its initiation.

IV administration of 1 IU of lyophilized factor VIII concentrate/kg increases plasma factor VIII activity by ~2% of normal (0.02 IU/mL). IV administration of 1 IU of lyophilized factor IX concentrate/kg increases plasma factor IX activity by ~1% of normal (0.01 IU/mL). In patients with a poor clinical response to treatment, suspect factor VIII or factor IX inhibitors.

A variety of long half-life factor VIII and IX variants are available. These products allow extended dosing intervals, increasing convenience of therapy for patients. The extended half-life is achieved through different mechanisms: PEGylation, fusion with the Fc portion of IgG, fusion with albumin. These modifications can significantly alter the increase in the plasma activity after IV administration of factor IX (FIX) products compared with the standard factor IX in the case of albumin fusion and PEGylation. Their availability varies from jurisdiction to jurisdiction and they should be prescribed only on advice from a hemophilia treatment center. Individual patient pharmacokinetic analysis may assist in dosing of both normal half-life and long half-life factor concentrates. Note that routine laboratory testing may be inaccurate in patients treated with these products.

2. Desmopressin is the drug of choice in patients with mild hemophilia A (dosage: see Von Willebrand Disease). Desmopressin causes a 2- to 5-fold increase in plasma factor VIII activity by releasing it from tissue stores. This pool can be exhausted after 3 to 7 days of continuous desmopressin treatment; in such situations, consider the administration of a human-derived factor VIII concentrate. In patients treated with desmopressin (especially children, pregnant women, and the elderly) the drug can induce water retention, hyponatremia, and occasionally seizures. Desmopressin has no effect on plasma factor IX and is not used in hemophilia B.

3. Tranexamic acid is used for clot stabilization in patients with oral bleeding, epistaxis, and urogenital bleeding. Dosage: see Von Willebrand Disease.

4. Emicizumab: Long-term prophylaxis with emicizumab (a monoclonal humanized antibody mimicking the activity of factor VIII) is possible for patients with hemophilia A with or without inhibitors. After a loading dose of 3 mg/kg once a week for 4 weeks, patients can receive 1.5 mg/kg once weekly (this interval can be extended up to a month with dose adjustment). The half-life of emicizumab is ~1 month. It provides a hemostatic protection that is likely comparable with a level of factor VIII of 10% to 15%. The aPTT is artificially shortened even by small amounts of emicizumab and does not reflect the patient’s hemostatic capacity. Breakthrough bleeding episodes are possible. These should be treated with standard doses of factor VIII in patients without inhibitors. In the case of patients with a history of inhibitors, a bypassing agent can be used (such as factor VIIa or alternatively an activated prothrombin complex concentrate [aPCC]), but recombinant factor VIIa is preferred when available. Dosage: see Complications, below. Consultation with a specialist in the use of emicizumab is recommended.

5. Novel treatments: A variety of novel treatments are being explored for the treatment of hemophilia, including implantable microcapsules of genetically modified human-derived cells that secrete a modified factor VIII, small interfering RNA (siRNA) therapies that downregulate anticoagulant proteins in blood (eg, antithrombin), monoclonal antibody targeting anticoagulant proteins (such as tissue factor pathway inhibitors [TFPIs]), and gene therapy, which has shown promise in both hemophilia A and B.

ComplicationsTop

1. Development of inhibitors of factor VIII or factor IX: Neutralizing IgG antibodies against factor VIII (factor VIII inhibitors) develop in about 30% of patients with severe hemophilia A and in 5% to 10% of patients with moderate or mild hemophilia A (in some patients spontaneous clearance of the inhibitor occurs). Antibodies to factor IX develop in <5% of patients with severe hemophilia B and may cause allergic reactions after the administration of factor IX. In prevention and treatment of bleeding in patients with inhibitor titers <5 Bethesda units/mL (BU/mL), administer high doses of factor VIII/IX concentrates while monitoring plasma factor VIII/IX activity. In patients with inhibitor titers >5 BU/mL, use an aPCC 50 to 100 IU/kg every 6 to 12 hours or recombinant factor VIIa 90 to 120 microg/kg every 2 to 3 hours. Do not use aPCC at doses exceeding 100 IU/kg/24 hours in patients using emicizumab for their routine prophylaxis. If specific treatment is not available, a standards prothrombin complex concentrate (PCC) can be used to treat emergency bleeding. Treatment strategies to eliminate inhibitors should only be used in centers with focused skills in this area; referral to such centers should be strongly considered in all patients with inhibitors. In many jurisdictions the availability of emicizumab has greatly simplified care of patients with factor VIII inhibitors; administered once monthly, a subcutaneous injection of this bispecific antibody nullifies the impact of the inhibitor and causes cessation of bleeding. Emicizumab should only be used in consultation with an expert who is familiar with its use.

2. Chronic synovitis, hemophilic arthropathy: Adult patients with severe hemophilia are at risk of arthropathy leading to disability if they have not received effective prophylaxis.

3. Viral infections related to treatment with blood products: Since the late 1980s and the introduction of virally inactivated plasma-derived factor concentrates, the risk of transmission of hepatitis C and B viruses as well as HIV with plasma-derived clotting factor concentrates has been minimal.

TablesTop