Chapter 79: Hemophilia A and B

• Hemophilia A and hemophilia B are caused by inherited deficiencies of factor VIII and factor IX, respectively.

• Both result from decreased production of the deficient factor, production of a factor with decreased functional activity, or a combination of these two abnormalities.

• The activated form of factor IX, factor IXa, is a serine protease that functions to activate factor X.

• Activated factor VIII, factor VIIIa, serves as a cofactor, forming a complex with factor IXa on the platelet surface and dramatically accelerating the rate of factor X activation by factor IXa.

• In patients with hemophilia, clot formation is delayed because thrombin generation is markedly decreased. The clot that does form is hemostatically ineffective, leading to excessive bleeding.

• Because deficiency of either factor VIII or factor IX causes an inability to activate factor X, the clinical characteristics and approach to treatment of hemophilia A and hemophilia B are similar.

• Both hemophilia A and B are X-linked recessive disorders, affecting only males, with rare exceptions (Fig. 79–1). Approximately 30 percent of mutations arise de novo.

• Hemophilia is found worldwide in all ethnic groups. Hemophilia A is estimated to occur in 1 of 10,000 male births and hemophilia B in 1 of 25,000 to 30,000 male births.

Clinical Features

• Table 79–1 shows a clinical classification of hemophilia A based on factor VIII levels.

• Hemostasis is generally normal with levels in excess of 30 percent.

• The factor VIII level remains constant throughout the patient's life, and is similar in other affected members of the kindred, but varies between kindreds.

• Hemarthrosis accounts for 75 percent of bleeding episodes in patients with severe hemophilia A.

• The most frequent sites are the knees, followed by the elbows, ankles, shoulders, wrists, and hips.

• The acute form is characterized by initial mild pain without physical findings, followed by more intense pain, swelling and warmth of the joint, and decreased range of motion.

• The patient may have mild fever. Significant or sustained fever suggests infection in the joint.

• When bleeding stops, the blood resorbs and symptoms subside over several days.

• Repeated bleeding into the joint results in synovial hypertrophy and inflammation, with limitation of motion and a tendency for more frequent bleeding in that joint (target joint).

• Eventually, repeated hemorrhage into the joints causes destruction of the articular cartilage, synovial hyperplasia, and joint deformity with muscle atrophy and soft tissue contractures (Fig. 79–2).

• Hematomas may develop after bleeding into muscles or subcutaneous tissues (Fig. 79–3).

• Intramuscular hematomas occur most often in thigh, buttocks, calf muscles, and forearm.

• Hematomas may stabilize and slowly resorb without treatment, but in individuals with moderate or severe hemophilia, they often enlarge progressively and dissect in all directions. This can cause compression of adjacent organs, nerves, or blood vessels, sometimes leading to permanent sequelae. Hematomas may obstruct the airway.

• Pseudotumors are large, organized, encapsulated hematomas that may slowly expand and compress surrounding structures.

• CNS hemorrhage, the most common cause of bleeding mortality, occurs spontaneously or after trauma. The onset of symptoms is usually prompt but may be delayed by several days.

• Virtually all patients with severe hemophilia have episodes of hematuria, which may cause renal colic because of clots in the ureters, but is seldom life-threatening.

• Postsurgical bleeding, often delayed by hours to several days, is associated with poor wound healing.

• Extraction of permanent teeth in patients with hemophilia may be followed by prolonged bleeding. Life-threatening pharyngeal or sublingual hematomas may follow extractions or regional block anesthesia.

• Inhibitory antibodies to factor VIII may develop in patients receiving replacement therapy (discussed below).

Laboratory Findings

• Hemophilia A causes prolongation of the activated partial thromboplastin time (aPTT) which is corrected by the addition of an equal volume of normal plasma. The prothrombin time is normal.

• A specific assay for factor VIII activity is required for definitive diagnosis.

• Immunologic assays coupled with clotting assays permit detection of dysfunctional factor VIII molecules.

Carrier Detection and Prenatal Diagnosis

• The average factor VIII level of carrier females is 50 percent, but occasional carriers have levels less than 30 percent and may have excessive bleeding with trauma or surgery.

• The family history is important for carrier detection (see Fig. 79–1).

• Molecular genetics techniques are available to identify carriers.

• Prenatal diagnosis can be made from fetal cells obtained by amniocentesis or by chorionic villus biopsy.

Differential Diagnosis

• Hemophilia A must be distinguished from hemophilia B and from other congenital disorders of coagulation that prolong the aPTT, such as factor XI and XII deficiencies.

• Hemophilia A must be distinguished from von Willebrand disease (especially the Normandy variant), an acquired inhibitor of factor VIII, and combined congenital deficiency of factor VIII and factor V.

Treatment

General

• Avoid aspirin, other antiplatelet agents, and intramuscular injections.

• Treat bleeding episodes promptly.

• Consider prophylaxis in severely affected patients.

• Home treatment should be available to all patients.

• Plan surgical procedures carefully.

• Hemophilia should preferably be treated in a designated Hemophilia Treatment Center.

Desmopressin (DDAVP)

• Deamino-8-D-Arginine Vasopressin (DDAVP) is often useful in the treatment of mild to moderate hemophilia A and symptomatic carrier females. Administration of 0.3 μg/kg intravenously can increase factor VIII levels of most of these patients two- to three-fold.

• The peak effect is in 30 to 60 minutes.

• Adverse reactions include flushing, rarely hyponatremia (mostly in children, can be prevented by water restriction), and angina in patients with coronary disease.

• Tachyphylaxis occurs with repeated doses.

• An intranasal preparation is also available.

Replacement with Factor Concentrates

• Bleeding episodes in patients with hemophilia A can be managed by replacing factor VIII (see Table 79–2).

• Commercial concentrates prepared from human plasma have been treated to inactivate viruses, including HIV and hepatitis B and C viruses. Hepatitis A and parvovirus are not inactivated by the treatment, and infection with these viruses has been transmitted.

• Recombinant factor VIII concentrates appear to be both safe and effective. These may be formulated with human plasma albumin, and are more expensive.

• The various available concentrates appear to differ little in safety, efficacy, or convenience.

Factor VIII Dosage

• The dose of factor VIII can be determined by multiplying the patient's weight in kilograms by half the needed percent correction of the factor level (see Table 79–3). For example, for a 70-kg patient with a less than 1 percent factor VIII level who needs a 100 percent correction, the dose would be 70 (kg) × 100 percent/2 = 3500 U. The full contents of mixed factor vials should be infused.

• The half-life of factor VIII is 8 to 12 hours. Factor levels may be maintained between 50 and 100 percent by giving half the loading dose every 8 to 12 hours.

• Reconstituted factor VIII concentrates may be administered by continuous intravenous infusion. After an initial loading dose to raise factor VIII to the desired level, 150 to 200 U per hour are administered.

Antifibrinolytic Agents

• Antifibrinolytic agents are useful adjunctive therapy for mucosal bleeding, and particularly so for dental extractions, but are contraindicated if the patient has hematuria.

• ε-Aminocaproic acid (EACA) can be given orally in a loading dose of 4 to 5 g followed by 1 g/h, or 4 g every 4 to 6 hours for 2 to 8 days, depending on the severity of the bleeding episodes.

• Tranexamic acid is given at an oral dose of 0.5 to 1 g four times daily but is not available for oral use in the United States.

• Fibrin glue, a mixture of fibrinogen and factor XIII applied locally to a bleeding site and then clotted with thrombin, may be useful adjunctive therapy for bleeding from circumcision, dental, or orthopedic procedures, including removal of large pseudotumors.

Treatment of Specific Types of Bleeding Episodes

• Superficial cuts and abrasions are managed with local pressure (Table 79–2).

• Epistaxis may require replacement of factor VIII to levels of 50 percent of normal.

• Hematuria is often mild and needs no replacement therapy but may persist and require replacement to levels greater than 50 percent, with replacement continuing until the bleeding stops. Patients should be advised to drink a lot of fluids, to avoid obstructing clots in the urinary tract.

• Prior to endoscopy, factor VIII should be replaced to at least the 50 percent level. A single infusion may suffice, but if the procedure is complicated by bleeding, replacement must be continued until the bleeding stops.

• For expanding soft-tissue hematomas, replacement therapy should be started immediately and continued until the hematoma begins to resolve.

• Hemarthroses should be treated promptly to minimize degenerative changes, deformity, and muscle wasting. For chronic bleeding into a "target" joint, replacement to 100 percent for 6 to 8 weeks may be indicated.

• Retropharyngeal and retroperitoneal hematomas and any central nervous system bleeding require replacement of factor VIII to normal (100%), or nearly normal, levels for 7 to 10 days.

• Major surgical procedures require factor VIII replacement to normal levels before operation and maintenance of normal levels for 7 to 10 days, or until healing is well underway.

• The patient's factor VIII levels should be measured during surgery and once or twice daily postoperatively and the dose of factor VIII adjusted accordingly.

• Home therapy has facilitated prompt treatment of hematomas and hemarthroses and markedly improved the morbidity and mortality of the disease.

• Severely afflicted patients who receive prophylactic therapy with 50 units of factor VIII/kg body weight three times a week have markedly decreased frequency of arthropathy and other long-term complications of hemophilia.

• Transplantation of a normal liver can result in cure of hemophilia, but this has been done rarely.

• Gene therapy for hemophilia is being extensively investigated.

Course and Prognosis

• Unless treated properly, patients develop complications of recurrent bleeding, as noted under "Clinical Features," above.

• The introduction of replacement therapy with factor VIII concentrates in the 1960s led to a significant reduction in the morbidity and mortality from bleeding in hemophilia, but introduced serious complications such as infection with HIV, liver disease from hepatitis B and C, and the development of anti-factor VIII antibodies.

• Since 1985, factor VIII concentrates have been treated to destroy HIV and hepatitis viruses, with virtual elimination of infection with these agents. However, HIV infection and chronic liver disease from hepatitis B and C are still prevalent in older patients with hemophilia.

Factor VIII Inhibitors in Patients with Hemophilia A

• Factor VIII inhibitors are antibodies, most often IgG, usually IgG4 subclass, that interfere with the interaction of factor VIII with its cofactors and activators.

• Factor VIII inhibitors react slowly, and inactivation of factor VIII requires incubation with the inhibitor for 1 to 2 hours at 37°C.

• Laboratory diagnosis of a factor VIII inhibitor requires that an appropriate dilution of the patient's plasma when mixed with normal plasma will neutralize only factor VIII and no other factor that influences the aPTT (factors IX, X, XI, XII, prekallikrien, or high-molecular-weight kininogen).

• Patients with factor VIII inhibitors are classified as "high" responders if their baseline inhibitor levels are above 10 Bethesda units (BU) or if their inhibitor level rises above 10 BU after receiving factor VIII replacement. "Low" responders have factor VIII inhibitor levels below 10 BU even after receiving factor VIII replacement.

• High-responder patients with major bleeding and initial inhibitors below 10 BU can be treated with high doses of human or porcine factor VIII concentrates in efforts to neutralize the inhibitor and still provide enough factor VIII for hemostasis.

• High-responder patients with initial inhibitor levels greater than 10 BU usually will not respond to any doses of human factor VIII, nor to porcine factor VIII if the inhibitor is cross-reactive.

• High-responders should be treated with recombinant factor VIIa or another factor VIII inhibitor-bypassing agent for minor bleeding episodes or for major bleeding if the inhibitor level is high or if factor VIII replacement is ineffective (Table 79–4).

• Low-responders can be treated with recombinant factor VIIa or another factor VIII inhibitor-bypassing agent for major or minor bleeding. In addition, they can be treated with high dose human or porcine factor VIII for major bleeding (Table 79–4).

• Recombinant factor VIIa is the preferred factor VIII inhibitor-bypassing agent. Factor VIIa is believed to activate factor X on the surfaces of activated platelets, and factor Xa can then interact with factor Va, and convert prothrombin to thrombin. The effects of factor VIIa may be localized because activated platelets are found principally at sites of injury. Prothrombin complex preparations are probably of benefit also because of similar effects of activated coagulation factors in these products.

• In some patients, administration of daily doses of factor VIII can reduce the inhibitor titer to undetectable levels, and such immune tolerance regimens offer a promising approach to eradication of factor VIII inhibitors. Bleeding episodes that occur during induction of tolerance can be treated with inhibitor-bypassing agents.

• Details of treatment of patients with inhibitors are presented in Chap. 124 of Williams Hematology, 8th ed.

Spontaneous Factor VIII Inhibitors

• Autoantibodies against factor VIII may appear in patients without hemophilia. This occurs idiopathically in older adults, in pregnant and postpartum women, and in patients with immunologic disorders (e.g., systemic lupus erythematosus and rheumatoid arthritis).

• Clinical manifestations include spontaneous ecchymoses and intramuscular hemorrhages, which often cause compartment syndromes. Hemarthrosis is rare.

• Patients with acquired inhibitors are low responders.

• Transfusion therapy to achieve hemostasis is identical to the treatment of hemophiliacs with inhibitors.

• In contrast to hemophiliacs, most patients with spontaneous inhibitors respond to treatment to eradicate the inhibitor.

• Prednisone 1 mg/kg and oral cyclophosphamide 1 to 2 mg/kg daily have been used separately or in combination with high response rates.

• Intravenous immune globulin 1 g/kg daily for 2 days has also been shown to decrease inhibitor titers in some of these patients. Anecdotal successes after treatment with rituximab have been reported.

Clinical Features

• Table 79–1 shows a clinical classification of hemophilia B based on factor IX levels.

• Bleeding episodes are clinically identical to those in hemophilia A.

• Factor IX inhibitors develop infrequently.

Laboratory Features

• In most cases, the aPTT is prolonged.

• Specific assay of factor IX levels is necessary for diagnosis.

Carrier Detection and Prenatal Diagnosis

• As with hemophilia A, molecular genetic techniques are available for carrier detection and prenatal diagnosis.

Differential Diagnosis

• Hemophilia B must be distinguished from hemophilia A, inherited or acquired deficiencies of other vitamin K–dependent coagulation factors, liver disease, or warfarin overdosage.

Therapy

• General treatment should be the same as for hemophilia A (see above).

• Replacement with factor IX concentrates (Table 79–5):

  — All currently available factor IX concentrates are treated to inactivate viruses.

  — Intermediate purity products ("prothrombin complex concentrates") contain prothrombin; factors VII, IX, and X; and proteins C and S. They may also contain small amounts of activated factors VII, IX, and X, which predispose to thrombosis, especially if large doses are given or the patient has liver disease.

  — Highly purified factor IX concentrates contain only traces of other prothrombin complex factors, and recombinant factor IX contains none. These are the currently preferred preparations for clinical use.

  — Intravascular recovery of factor IX from concentrates is about 50 percent, and is even less with the recombinant product.

  — Initial dosage can be calculated assuming 1 unit of highly purified factor IX per kg body weight will increase the plasma level of factor IX by 1 percent or 0.01 U/mL. Thus, to replace factor IX to 100 percent requires 100 U/kg body weight as a bolus. The half-life of factor IX is 18 to 24 hours. Continued dosage should be one-half of the initial dosage given every 12 to 18 hours. Larger doses are required with recombinant factor IX.

  — Factor IX may also be given by continuous infusion.

  — Factor IX levels should be monitored during therapy and doses adjusted appropriately.

• Prophylactic therapy may also be given for hemophilia B. The recommended dose is 25 to 40 U/kg twice weekly.

• Gene therapy for hemophilia B is being actively investigated.

Course and Prognosis

• Patients with hemophilia B are vulnerable to the same complications of recurrent bleeding that occur with hemophilia A.

• HIV infection and chronic liver disease are common in patients treated before viral inactivation of factor IX concentrates was introduced.

Factor IX Inhibitors

• Factor IX inhibitors at levels less than 10 BU can sometimes be overcome with large doses of purified factor IX concentrates.

• If the factor IX inhibitor level is greater than 10 BU, inhibitor-bypassing products (recombinant factor VIIa or prothrombin complex concentrates) should be used.

• Attempts to induce immune tolerance by administering daily infusions of factor IX concentrates have led to significant adverse reactions, including anaphylaxis and the nephrotic syndrome. Factor VIIa concentrates should be used for treatment of any patient who has developed anaphylaxis.