Hemophilia A

Pathophysiology

FVIII is a plasma glycoprotein consisting of six domains, A1–A2–B–A3–C1–C2 ( Fig. 110.1 ). The encoding gene is found on the long arm of the X chromosome (Xq.28). The mature protein is a heterodimer with a light chain consisting of domains A3–C1–C2 and a heavy chain with the domains A1–A2–B. The majority of FVIII is thought to be synthesized in hepatic endothelial cells, but it may also be produced in endothelial cells in general (e.g., elevated FVIII levels during liver failure). On release into the circulation, it is noncovalently linked to von Willebrand factor (VWF), which prevents enzymatic degradation of nascent FVIII. During coagulation, the tissue factor (TF)–FVIIa complex activates FX and FIX, leading to conversion of prothrombin to thrombin. The initial thrombin cleavage of the FVIII light chain causes FVIII to be released into the circulation and which is then activated to FVIIIa by further thrombin-mediated proteolysis. FVIIIa, along with FIXa, in the presence of calcium, then act as cofactors on a phospholipid surface during activation of factors X, V and, ultimately, thrombin. This is also known as the tenase complex. Patients with hemophilia A are unable to generate adequate thrombin due to lack of FVIII and become dependent on the TF pathway. Circulating tissue factor pathway inhibitor (TFPI) efficiently downregulates the TF–FVIIa pathway as well as FXa, leading to decreased thrombin and bleeding. Thrombin-activated fibrinolysis inhibitor (TAFI) production is also decreased in hemophilia, leading to more rapid dissolution of the fibrin clot. A large number of molecular defects have been described in hemophilia A, including large gene deletions, inversions, single gene rearrangements, deletions, and insertions. A list of mutations leading to hemophilia A can be found at http://hadb.org.uk/ as well as https://www.cdc.gov/ncbddd/hemophilia/champs.html .

Clinical Manifestations

The hallmark of hemophilia-related bleeding is delayed bleeding along with joint and muscle bleeding. As hemophilia A is X-linked, the vast majority of affected patients are male. Females, however, can be affected by extreme X-chromosome lyonization, or with gene abnormalities such as Turner syndrome. Heterozygous female carriers of hemophilia A may exhibit a bleeding tendency, most commonly heavy menstrual bleeding and postsurgical bleeding. There is a high rate of spontaneous mutation within the F8 gene, and approximately 30% of newly diagnosed patients will have no family history of hemophilia.

In general, the severity of bleeding depends on the percentage of residual clotting factor activity. Patients with levels of >5%–40% are classified as having mild hemophilia, patients with levels of 1%–≤5% as moderate and those with less than 1% activity as having severe disease. Approximately 60% of persons with hemophilia have severe disease. They suffer from spontaneous bleeding while those with mild to moderate disease typically bleed only when challenged with trauma or surgery. In the newborn period, the most common findings are bleeding and bruising after venipuncture, heel sticks, immunizations, and circumcision. Intracranial hemorrhage remains the most dreaded complication of hemophilia in the first 2 years of life and occurs in about 7%–10% of infants. Infants born of known carrier mothers should not undergo instrumented birth and should not be circumcised until testing for FVIII rules out hemophilia. Older children and adults may experience excessive bruising, epistaxis, soft tissue hematomas, intracranial bleeding, and hemarthrosis. The single largest preventable cause of morbidity is degenerative joint disease due to recurrent hemarthrosis. Females who carry hemophilia may also have bleeding symptoms such as menorrhagia, oral bleeding, bleeding with childbirth, surgical, and trauma-related bleeding.

Diagnosis

An X-linked inheritance pattern, elevated partial thromboplastin time (PTT), and decreased plasma FVIII levels confirm the diagnosis. The most commonly used PTT reagents may not detect mild deficiency of FVIII. Prenatal diagnosis can be performed in the case of a known family history. Cord blood testing of FVIII levels can also be performed at the time of delivery.

Management