Hemophilia B

Pathophysiology

FIX is a single-chain vitamin K–dependent glycoprotein and has a molecular weight of 57,000 Da. Its gene is 33 kb long and is positioned on the long arm (q) of the X chromosome (Xq27.1). FIX is a serine protease believed to be synthesized in the liver and released into the circulation in its inactive form. During coagulation, FIX is activated by both the intrinsic and extrinsic pathways. In the extrinsic pathway, tissue factor (TF), along with FVIIa, activates FIX. In the first step of the intrinsic or contact pathway, FIX is directly activated by FXIa. This step is nonphospholipid dependent. FIXa in turn activates FVIII. FVIIIa along with FIXa and calcium then act as cofactors on a phospholipid surface (typically a platelet) during activation of factors X and V and, ultimately, thrombin. Patients with hemophilia B are unable to generate adequate thrombin and become dependent on the less robust TF pathway. Tissue factor pathway inhibitor (TFPI) quickly downregulates the TF pathway and, as a result, a bleeding diathesis ensues.

A number of mutations have been described in the F9 gene, including small and large deletions and additions, rearrangements, and missense mutations. A list of mutations can be found at http://www.factorix.org and https://www.cdc.gov/ncbddd/hemophilia/champs.html . A unique variant, hemophilia B Leyden, occurs when point mutations in the promoter region disrupt transcription factor binding sites. During puberty, androgen effects on this promoter region lead to rising FIX levels.

Clinical Manifestations

The hallmark of hemophilia-related bleeding is delayed bleeding along with joint and muscle bleeding. In comparison, patients with von Willebrand disease more commonly manifested immediate and mucocutaneous bleeding. As hemophilia B is X-linked, the vast majority of affected patients are male. Females can be affected in cases of extreme X-chromosome lyonization, or with gene abnormalities such as Turner syndrome.

In general, the severity of bleeding depends on the residual circulating FIX activity. Patients with levels of ≥5%–40% are historically 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 patients have severe disease. Commonly, patients with severe disease will suffer from spontaneous bleeding while those with mild to moderate disease typically bleed with trauma or surgery. In the newborn period, the most common findings are bleeding from blood draws, heel sticks, immunizations, and circumcision. Neonates may also have birth-related intracranial hemorrhage. Infants born of known carrier mothers should not undergo instrumented birth and should not be circumcised until testing for FIX rules out hemophilia. Older children and adults may experience excessive bruising, hematomas, intracranial bleeding, joint bleeding, muscle bleeding, and mouth bleeding. The single largest preventable cause of morbidity is degenerative joint disease due to recurrent hemarthrosis. Carrier females may experience bleeding symptoms such as menorrhagia, oral bleeding, surgical, and trauma-related bleeding.

Diagnosis

Hemophilia B presents with an X-linked inheritance pattern and an elevated partial thromboplastin time (PTT), normal prothrombin time (PT) and decreased plasma FIX activity. Commonly used PTT reagents may not be sensitive enough to diagnose mild FIX deficiencies, in which case residual plasma FIX activity would be diagnostic. Prenatal diagnosis can be performed in the case of a known family history. Cord blood testing of FIX levels should be performed at the time of delivery in cases of known carrier mothers. It should be noted, however, that FIX levels in term neonates are reduced to around 50% of normal adult values and normalize at around 6 months of age. Neonates with moderate and severe disease will still have distinctly low FIX levels, but diagnosis of mild hemophilia B in a neonate is complicated by the low normal levels at birth.