Pathophysiology

Factors VIII and IX participate in a complex required for the activation of factor X. Together with phospholipid and calcium, they form the “tenase,” or factor X–activating, complex. Figure 469-1 shows the clotting process as it occurs in the test tube, with factor X being activated by either the complex of factors VIII and IX or the complex of tissue factor and factor VII. In vivo, the complex of factor VIIa and tissue factor activates factor IX to initiate clotting. In the laboratory, prothrombin time (PT) measures the activation of factor X by factor VII and is therefore normal in patients with factor VIII or factor IX deficiency.

After injury, the initial hemostatic event is formation of the platelet plug, together with the generation of the fibrin clot that prevents further hemorrhage. In hemophilia A or B, clot formation is delayed and is not robust. Inadequate thrombin generation leads to failure to form a tightly cross-linked fibrin clot to support the platelet plug. Patients with hemophilia slowly form a soft, friable clot. When untreated bleeding occurs in a closed space, such as a joint, cessation of bleeding may be the result of tamponade. With open wounds, in which tamponade cannot occur, profuse bleeding may result in significant blood loss. The clot that is formed may be friable, and rebleeding occurs during the physiologic lysis of clots or with minimal new trauma.

Clinical Manifestations

Neither factor VIII nor factor IX crosses the placenta; bleeding symptoms may be present from birth or may occur in the fetus. Only 2% of neonates with hemophilia sustain intracranial hemorrhages, and 30% of male infants with hemophilia bleed with circumcision. Thus, in the absence of a positive family history (hemophilia has a high rate of spontaneous mutation), hemophilia may go undiagnosed in the newborn. Obvious symptoms such as easy bruising, intramuscular hematomas, and hemarthroses begin when the child begins to cruise. Bleeding from minor traumatic lacerations of the mouth (a torn frenulum) may persist for hours or days and may cause the parents to seek medical evaluation. Even in patients with severe hemophilia, only 90% have evidence of increased bleeding by 1 yr of age. Although bleeding may occur in any area of the body, the hallmark of hemophilic bleeding is hemarthrosis. Bleeding into the joints may be induced by minor trauma; many hemarthroses are spontaneous. The earliest joint hemorrhages appear most commonly in the ankle. In the older child and adolescent, hemarthroses of the knees and elbows are also common. Whereas the child’s early joint hemorrhages are recognized only after major swelling and fluid accumulation in the joint space, older children are frequently able to recognize bleeding before the physician does. They complain of a warm, tingling sensation in the joint as the first sign of an early joint hemorrhage. Repeated bleeding episodes into the same joint in a patient with severe hemophilia may become a “target” joint. Recurrent bleeding may then become spontaneous because of the underlying pathologic changes in the joint.

Although most muscular hemorrhages are clinically evident owing to localized pain or swelling, bleeding into the iliopsoas muscle requires specific mention. A patient may lose large volumes of blood into the iliopsoas muscle, verging on hypovolemic shock, with only a vague area of referred pain in the groin. The hip is held in a flexed, internally rotated position owing to irritation of the iliopsoas. The diagnosis is made clinically from the inability to extend the hip but must be confirmed with ultrasonography or CT (Fig. 470-1). Life-threatening bleeding in the patient with hemophilia is caused by bleeding into vital structures (central nervous system, upper airway) or by exsanguination (external trauma, gastrointestinal or iliopsoas hemorrhage). Prompt treatment with clotting factor concentrate for these life-threatening hemorrhages is imperative. If head trauma is of sufficient concern to suggest radiologic evaluation, factor replacement should precede radiologic evaluation. Simply put: “Treat first, image second!” Life-threatening hemorrhages require replacement therapy to achieve a level equal to that of normal plasma (100 IU/dL, or 100%).

Figure 470-1 Massive hematoma into the iliopsoas muscle in a patient with hemophilia B. A 38-yr-old man with severe deficiency of factor IX (hemophilia B) was admitted for right lower abdominal pain of progressively increasing severity and tenderness. He had had a common cold with severe cough and loss of appetite for approximately 1 wk. A, Abdominal radiograph shows presence of the psoas sign on the right side and left-shifted colon gas. B, CT scan shows massive hematoma in the right iliopsoas muscle, resulting in anterior translocation of the right kidney. C, Reconstructed 3-dimensional image shows more clearly the kidney translocation and the extended, but intact large vessels. These are useful findings for the diagnostic procedures, because progressive right lower abdominal pain may closely simulate acute appendicitis. The hemorrhage was successfully managed by replacement of factor IX for 1 wk without any recurrence. The patient did not have any inhibitors to factor IX.

(From Miyazaki K, Higashihara M: Massive hemorrhage into the iliopsoas muscle, Intern Med 44:158, 2005.)

Patients with mild hemophilia who have factor VIII or factor IX levels > 5 IU/dL usually do not have spontaneous hemorrhages. These individuals may experience prolonged bleeding after dental work, surgery, or injuries from moderate trauma.

Laboratory Findings and Diagnosis

The laboratory screening test that is affected by a reduced level of factor VIII or factor IX is PTT. In severe hemophilia, the PTT value is usually 2-3 times the upper limit of normal. Results of the other screening tests of the hemostatic mechanism (platelet count, bleeding time, prothrombin time, and thrombin time) are normal. Unless the patient has an inhibitor to factor VIII or IX, the mixing of normal plasma with patient plasma results in correction of PTT value. The specific assay for factors VIII and IX will confirm the diagnosis of hemophilia. If correction does not occur on mixing, an inhibitor may be present. In 25-35% of patients with hemophilia who receive infusions of factor VIII or factor IX, a factor-specific antibody may develop. These antibodies are directed against the active clotting site and are termed inhibitors. In such patients, the quantitative Bethesda assay for inhibitors should be performed to measure the antibody titer.

Differential Diagnosis

In young infants with severe bleeding manifestations, the differential diagnosis includes severe thrombocytopenia; severe platelet function disorders, such as Bernard-Soulier syndrome and Glanzmann Thrombasthenia; type 3 (severe) von Willebrand disease; and vitamin K deficiency. Hemostatic screening tests should differentiate these entities from hemophilia.

Genetics and Classification

Hemophilia occurs in approximately 1 : 5,000 males, with 85% having factor VIII deficiency and 10-15% having factor IX deficiency. Hemophilia shows no apparent racial predilection, appearing in all ethnic groups. The severity of hemophilia is classified on the basis of the patient’s baseline level of factor VIII or factor IX, because factor levels usually correlate with the severity of bleeding symptoms. By definition, 1 IU of each factor is defined as that amount in 1 mL of normal plasma referenced against a standard established by the World Health Organization (WHO); thus, 100 mL of normal plasma has 100 IU/dL (100% activity) of each factor. For ease of discussion, henceforth in this chapter, we use the term % activity to refer to the percentage found in normal plasma (100% activity). Factor concentrates are also referenced against an international WHO standard, so treatment doses are usually referred to in IU. Severe hemophilia is characterized as having <1% activity of the specific clotting factor, and bleeding is often spontaneous. Patients with moderate hemophilia have factor levels of 1-5% and usually require mild trauma to induce bleeding. Individuals with mild hemophilia have levels >5%, may go many years before the condition is diagnosed, and frequently require significant trauma to cause bleeding. The hemostatic level for factor VIII is >30-40%, and for factor IX, it is >25-30%. The lower limit of levels for factors VIII and IX in normal individuals is approximately 50%.

The genes for factors VIII and IX are carried near the terminus of the long arm of the X chromosome and are therefore X-linked traits. The majority of patients with hemophilia have reduced clotting factor protein; 5-10% of those with hemophilia A and 40-50% of those with hemophilia B make a dysfunctional protein. Approximately 45-50% of patients with severe hemophilia A have the same mutation, in which there is an internal inversion within the factor VIII gene that results in production of no protein. This mutation can be detected in the blood of patients or carriers and in the amniotic fluid by molecular techniques. African Americans often have a different FVIII haplotype, and this difference may be the reason that African Americans have higher inhibitor formation (see later). Because of the multiple genetic causes of either factor VIII or factor IX deficiency, most cases of hemophilia are classified according to the amount of factor VIII or factor IX clotting activity. In the newborn, factor VIII values may be artificially elevated because of the acute-phase response elicited by the birth process. This artificial elevation may cause a mildly affected patient to have normal or near-normal levels of factor VIII. Patients with severe hemophilia do not have detectable levels of factor VIII. In contrast, factor IX levels are physiologically low in the newborn. If severe hemophilia is present in the family, an undetectable level of factor IX is diagnostic of severe hemophilia B. In some patients with mild factor IX deficiency, the presence of hemophilia can be confirmed only after several weeks of life.

Through lyonization of the X chromosome, some female carriers of hemophilia A or B have sufficient reduction of factor VIII or factor IX to produce mild bleeding disorders. Levels of these factors should be determined in all known or potential carriers to assess the need for treatment in the event of surgery or clinical bleeding.

Because factor VIII is carried in plasma by von Willebrand factor, the ratio of factor VIII to von Willebrand factor is sometimes used to diagnose carriers of hemophilia. When possible, specific genetic mutations should be identified in the propositus and used to test other family members who are at risk of either having hemophilia or being carriers.

Treatment

Early, appropriate therapy is the hallmark of excellent hemophilia care. When mild to moderate bleeding occurs, values of factor VIII or factor IX must be raised to hemostatic levels, in the 35-50% range. For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity.

Calculation of the dose of recombinant factor VIII (FVIII) or recombinant factor IX (FIX) is as follows:

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