Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (398 page)

Hemophilia A (factor VIII [F VIII] deficiency) and hemophilia B (factor IX [F IX] deficiency) are congenital bleeding disorders, both inherited as X chromosome– linked recessive conditions, hence limited almost exclusively to males. Hemophilia A prevalence is 1:10,000 live male births, and hemophilia B is 1:30,000. Factor XI deficiency was classified in the past as hemophilia C; it will be presented separately. Acquired hemophilia is a severe bleeding diathesis, resulting from the development of autoantibodies against factor VIII or rarely IX, in a patient with no previous bleeding history. Hemophilia affects both males and females.

   Who Should Be Suspected?

A male with a bleeding family history in other males on the maternal side (one third of cases have a negative family history due to new mutations) and with a personal history of spontaneous major bleeding episodes (mostly in joints, skeletal muscles, gastrointestinal tract, and occasionally in the central nervous system or in other organs). Recurring joint bleeding may result in chronic disability or even fatalities if not treated promptly. In infants bleeding at circumcision, on tooth eruption, or when first standing (in knee joints) should raise the suspicion of hemophilia. The severity of bleeding is similar for the same levels of factor deficiency in hemophilia A and B. The development of alloantibodies (either against F VIII or IX) is suspected in hemophiliacs multiply infused with the respective factor, who become refractory to replacement therapy. They develop in 15–30% of hemophilia A and 3–5% of hemophilia B patients. The majority develop before age 20. Acquired hemophilia should be suspected in bleeding postpartum females, patients with lymphoproliferative neoplasms, or in the elderly without other predisposing factors except age.

   Laboratory Findings

   Screening tests: Platelet counts, PT, and PTT are recommended as the initial workup of patients presenting with a bleeding diathesis. Of those, the platelet count and PT are normal in hemophiliacs, whereas the PTT is variably prolonged.

   Definitive tests: Factor VIII and IX levels are established by quantitation of factor VIII or IX, respectively. Severe hemophiliacs have factor VIII or IX levels below 1%, moderate hemophiliac have factor levels between 1% and 5%, and the mild cases >5%. Patients in the latter group do not bleed spontaneously but may have severe bleeding on traumatic events, sometimes surprisingly, since they have no previous bleeding history. Mild hemophilia A individuals may develop inhibitors without having been ever infused with factor VIII preparations.

   Obligate female carriers are mothers to more than one hemophiliac son or daughters of a hemophiliac. Carriers usually have coagulant factor VIII levels around 50%, but there is a wide scatter in these levels, and when skewed to low levels, may result in clinical bleeding (a “female hemophiliac”). A more definitive diagnosis in suspected carriers or as prenatal diagnosis may be obtained through genetic analysis using DNA-based techniques. The most common abnormality found in carriers of severe hemophilia A is intron 22 inversion in the factor VIII gene. The genetic diagnosis is easier in factor IX carriers because of a large deletion in the factor IX gene.

   The diagnosis of inhibitors to factor VIII or IX is established by specific assays, and inhibitor titers are reported in Bethesda units.

   Limitations

   Type III and severe 2 N von Willebrand disease have the same clinical presentation as hemophilia, and both may have very low F VIII values. Detailed laboratory assays are necessary to distinguish these two conditions from hemophilia. Moreover, they are also present in females.

Suggested Readings

Verbruggen B, Meijer P, Novakova I, et al. Diagnosis of factor VIII deficiency Haemophilia. 2008;14(Suppl 3):76–82. Whelan SFJ, Hofbauer CJ, Horling FM, et al. Distinct characteristics of antibody response against

factor VIII in healthy individuals and in different cohorts of hemophilia A patients.
Blood.
2013;121:1039–1048.

VON WILLEBRAND DISEASE (VWD)

   Definition

Willebrand Factor (vWF) resulting in excessive mucocutaneous bleeding. In severe cases, coagulation-type defect is present. It is the most common inherited bleeding diathesis, seen in up to 1% of the Caucasian population. vWF is synthesized in endothelial cells and megakaryocytes and released as large multimers. It is acted on by a metalloprotease, ADAMTS 13, to form variably sized multimers. It mediates platelet adhesion through a platelet receptor, GP1b. It also functions as a carrier for factor VIII. Inheritance of vWD is autosomal recessive in most cases.

   Who Should Be Suspected?