Clinical Description
Hemophilia B in the untreated individual is characterized by immediate or delayed bleeding or prolonged oozing after injuries, tooth extractions, or surgery or renewed bleeding after initial bleeding has stopped [Josephson 2013, Peyvandi et al 2016]. Muscle hematomas or intracranial bleeding can occur immediately or up to four to five days after the original injury. Intermittent oozing may last for days or weeks after tooth extraction. Prolonged or delayed bleeding or wound hematoma formation after surgery is common. After circumcision, males with hemophilia B of any severity may have prolonged oozing, or they may heal normally. In severe hemophilia B, spontaneous joint bleeding is the most frequent sign.
The age of diagnosis and frequency of bleeding episodes are generally related to the factor IX clotting activity (see Table 2). In any affected individual, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. To some extent, this greater frequency is a function of both physical activity levels and vulnerability during more rapid growth.
Individuals with severe hemophilia B are usually diagnosed as newborns due to birth- or neonatal-related procedures or during the first year of life [Kulkarni et al 2009]. In untreated toddlers, bleeding from minor mouth injuries and large "goose eggs" from minor head bumps are common; these are the most frequent presenting symptoms of severe hemophilia B. Intracranial bleeding may also result from head injuries. The untreated child almost always has subcutaneous hematomas; some have been referred for evaluation of possible non-accidental trauma.
As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and young adults with severe hemophilia B who are not treated have an average of two to five spontaneous bleeding episodes each month. Joints are the most common sites of spontaneous bleeding; other sites include the muscles, kidneys, gastrointestinal tract, brain, and nose. Without prophylactic treatment, individuals with hemophilia B have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Individuals with moderate hemophilia B seldom have spontaneous bleeding but bleeding episodes may be precipitated by relatively minor trauma. Without pretreatment (as for elective invasive procedures) they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years. The frequency of bleeding episodes requiring treatment with factor IX concentrates varies from once a month to once a year. Signs and symptoms of bleeding are otherwise similar to those found in severe hemophilia B.
Individuals with mild hemophilia B do not have spontaneous bleeding. However, without treatment, abnormal bleeding occurs with surgery, tooth extractions, and major injuries. The frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma.
Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [Plug et al 2006].
Complications of untreated bleeding. The leading cause of death related to bleeding is intracranial hemorrhage. The major cause of disability from bleeding is chronic joint disease [Luck et al 2004]. Currently available treatment with clotting factor concentrates is normalizing life expectancy and reducing chronic joint disease for children and adults with hemophilia B. Prior to the availability of such treatment, the median life expectancy for individuals with severe hemophilia B was 11 years (the current life expectancy for affected individuals in several developing countries). Excluding death from HIV, life expectancy for those severely affected individuals receiving adequate treatment was 63 years in 2000 [Darby et al 2007], having been greatly improved with factor replacement therapy [Tagliaferri et al 2010].
Other. Since the late1960s, the mainstay of treatment of bleeding episodes has been factor IX concentrates that initially were derived solely from donor plasma. By the late 1970s, more purified preparations became available, reducing the risk for thrombogenicity. Viral inactivation methods and donor screening of plasmas were introduced by 1990 and a recombinant factor IX concentrate became available shortly thereafter [Monahan & Di Paola 2010]. A second recombinant factor IX concentrate was FDA licensed in 2013. Two long-acting modified recombinant factor IX concentrates are now FDA approved, extending the factor IX half-life three- to fivefold compared to unmodified products [Powell et al 2013, Santagostino et al 2016] . HIV transmission from concentrates occurred between 1979 and 1985. Approximately half of these individuals died of AIDS prior to the advent of effective HIV therapy.
Hepatitis B transmission from earlier plasma-derived concentrates was eliminated with donor screening and then vaccination introduced in the 1970s. Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of the hepatitis C virus. Viral inactivation methods implemented in concentrate preparation and donor screening assays developed by 1990 have essentially eliminated hepatitis C transmission from plasma-derived concentrates.
Alloimmune inhibitors occur much less frequently than in hemophilia A. Approximately 2% of individuals with severe hemophilia B develop alloimmune inhibitors to factor IX [Puetz et al 2014]. These individuals usually have partial- or whole-gene deletions or certain nonsense variants (see Genotype-Phenotype Correlations and Table A, Locus-Specific Databases). At times, the onset of an alloimmune response has been associated with anaphylaxis to transfused factor IX or development of nephrotic syndrome [DiMichele 2007, Chitlur et al 2009].
Genotype-Phenotype Correlations
Disease severity
Alloimmune inhibitors
Unlike hemophilia A, severe hemophilia B is often caused by a missense variant and several of these are associated with normal cross-reacting material (factor IX antigen) levels (see Table A, Locus-Specific Databases).
Uncommon variants within the carboxylase-binding domain of the propeptide cause increased sensitivity to warfarin anticoagulation in individuals without any baseline bleeding tendency [Oldenburg et al 2001] (see Management).
In hemophilia B Leyden, more than 20 different causative variants in the proximal F9 promoter region have been described [Funnell & Crossley 2014]; the severity of disease decreases after puberty; mild disease disappears and severe disease becomes mild, depending on the specific pathogenic variant.