Inherited bleeding disorders are a heterogeneous group of conditions that include disorders of primary and secondary hemostasis. During primary hemostasis, platelets adhere and aggregate at the site of vascular injury to form a platelet plug. Bleeding into the skin (eg, petechiae and/or ecchymosis) and mucous membranes typifies disorders of primary hemostasis such as von Willebrand disease (VWD). Secondary hemostasis leads to stabilization of the platelet plug through activation of the coagulation cascade and production of cross-linked fibrin. Patients affected by a disorder of secondary hemostasis such as hemophilia or 1 of the rare bleeding disorders (RBDs) classically bleed into soft tissues, muscles, and joints. In general, children with a bleeding disorder may present with severe or life-threatening bleeding episodes early in life, or in a more indolent manner, with symptoms that may not seem very unusual (eg, frequent nosebleeds or heavy menstrual bleeding). Recognizing the clinical and laboratory features that suggest the presence of an inherited bleeding disorder is paramount to optimizing treatment and long-term outcomes.
The hemophilias are rare inherited bleeding disorders caused by a deficiency or an absence of coagulation factors, usually factors VIII or IX. Hemophilia A, or classical hemophilia, is caused by mutations in the factor VIII (FVIII) gene (F8); hemophilia B, also known as Christmas disease, is caused by mutations in the factor IX (FIX) gene (F9). The clinical hallmark of the hemophilias is soft tissue and musculoskeletal bleeding that may lead to debilitating arthropathy if untreated. Patients with hemophilia are best managed in a comprehensive care setting by a multidisciplinary team that facilitates accurate diagnosis and ensures proper management and follow-up.
Hemophilia A and B occur with a frequency of 1:5000 and 1:30,000 male births, respectively. As such, the hemophilias are the most common serious inherited coagulation factor deficiencies. Hemophilia occurs in all racial groups. Almost all severely affected individuals are males, as hemophilias A and B are X-linked disorders. However, some heterozygous females may be severely affected through mechanisms such as skewed X-inactivation or chromosomal abnormalities such as Turner syndrome. All female children of a father with hemophilia will be carriers of the disease, but none of his sons will be affected. Furthermore, all male children of a carrier mother have a 50% chance of having the disease, while all female offspring have a 50% chance of being carriers themselves.
Hemophilia A and B are caused by mutations in the genes encoding for FVIII and FIX, respectively, which are located in the long arm of chromosome X. The genetic mutations can cause a quantitative reduction in protein expression or a qualitative decrease in protein activity, or both. Over 2000 different mutations in the F8 gene have been identified to cause hemophilia A, and these are compiled in an international database (Factor VIII Gene (F8) ...