PLASMA THROMBOPLASTIN COMPONENT DEFICIENCY HEMOPHILIA B(M), INCLUDED
F9 DEFICIENCY
HEMOPHILIA B LEYDEN, INCLUDED
CHRISTMAS DISEASE
HEMB
factor ix deficiency
Hemophilia B due to factor IX deficiency is phenotypically indistinguishable from hemophilia A (306700), which results from deficiency of coagulation factor VIII (F8; 300841). The classic laboratory findings in hemophilia B include a prolonged activated partial thromboplastin time ... Hemophilia B due to factor IX deficiency is phenotypically indistinguishable from hemophilia A (306700), which results from deficiency of coagulation factor VIII (F8; 300841). The classic laboratory findings in hemophilia B include a prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT) (Lefkowitz et al., 1993). Early studies made a distinction between cross-reactive-material (CRM)-negative and CRM-positive hemophilia B mutants. This classification referred to detection of the F9 antigen in plasma, even in the presence of decreased F9 activity. Detection of the antigen indicated the presence of a dysfunctional F9 protein. Roberts et al. (1968) found that about 90% of patients with hemophilia B were CRM-negative, whereas about 10% were CRM-positive. However, Bertina and Veltkamp (1978) found that a rather large proportion of the hemophilia B patients could be characterized as hemophilia B CRM+. They identified 14 cases of hemophilia B CRM+ from 11 families among a group of 33 patients. After immunologic and activity comparisons, they found at least 7 different factor IX variants. Bertina and Veltkamp (1978) noted the high heterogeneity within this group. In an editorial on variants of vitamin K-dependent coagulation factors, Bertina et al. (1979) stated that 9 defective variants of factor II, 5 variants of factor X, and many variants (about 180 pedigrees) of factor IX had been identified. At least one variant of factor VII (Padua) was also known.
In a patient with severe F9 deficiency who developed an inhibitor, Peake et al. (1984) detected a deletion in the F9 gene using 4 genomic gene probes. Similar studies of 8 female relatives using this method identified 2 ... In a patient with severe F9 deficiency who developed an inhibitor, Peake et al. (1984) detected a deletion in the F9 gene using 4 genomic gene probes. Similar studies of 8 female relatives using this method identified 2 as carriers. Used a genomic probe containing a TaqI polymorphism in the F9 gene, Giannelli et al. (1984) successfully identified carriers of Christmas disease in 3 affected families. In eukaryotic DNA, a high proportion of CpG dinucleotides are methylated at the cytosine residue to give 5-methylcytosine. The restriction enzyme HhaI will not cleave at methylated CpG sites, but PCR can overcome this limitation. Winship et al. (1989) used PCR to detect a polymorphic HhaI site located 8 kb 3-prime to the F9 gene and estimated that almost half of female subjects can be expected to be heterozygous at this site. Detection of this marker using PCR was predicted to increase the proportion of persons in whom the carrier state of hemophilia B could be diagnosed, compared to using the restriction enzyme alone, which could be influenced by methylation status. Koeberl et al. (1990) compared RFLP-based carrier detection of an X-linked disease with a direct method involving genomic amplification with transcript sequencing (GAWTS). They pointed out that the RFLP approach 'suffers from multiple levels of uncertainty.' They found that 22 at-risk females were diagnosed by direct testing, whereas only 11 females could be diagnosed by standard RFLP analysis. Giannelli et al. (1992) used hemophilia B as a model of a genetic disease with marked mutational heterogeneity to lay out an overall strategy for genetic counseling. They started with the construction of a national database which could be used for diagnosis and genetic counseling on the basis of DNA abnormality. In the U.K. there were just over 1,000 patients with hemophilia B and these were probably derived from 500 to 600 families. They characterized the mutation in a group of unrelated patients and in only 1 of 170 patients examined from the Swedish and British series did they fail to find a mutation in the essential regions of the gene. Thus the screening procedures used were capable of detecting all types of mutations. By phenotype/genotype correlations the authors generated information of prognostic value concerning each of those mutations. - Prenatal Diagnosis In 5 kindreds studied in detail, Poon et al. (1987) were able to determine the carrier status of hemophilia B in all 11 females at risk; prenatal diagnosis could be offered to the offspring of each of the 6 carriers identified. Green et al. (1991) suggested a strategy for facilitating carrier and prenatal diagnosis by identification of all hemophilia B mutations in a given population so that only the relevant parts of the molecule need be focused on when performing amplification mismatch detection (AMD) as developed by Montandon et al. (1989).
Aggeler et al. (1952) described a 16-year-old white male with a hemophilia-like disorder in which there appeared to be a deficiency of a coagulation factor, which the authors called 'plasma thromboplastin component' (PTC). They cited reports indicating that ... Aggeler et al. (1952) described a 16-year-old white male with a hemophilia-like disorder in which there appeared to be a deficiency of a coagulation factor, which the authors called 'plasma thromboplastin component' (PTC). They cited reports indicating that blood from some patients with hemophilia was capable of correcting the coagulation defect in other cases of hemophilia in vitro. The authors concluded that these patients had a combined defect of PTC deficiency and 'true' hemophilia (hemophilia A). It was not clear at that time if the disorder was hereditary. Biggs et al. (1952) in the December 27 (Christmas) issue of the British Medical Journal reported a 5-year-old boy, with a surname of 'Christmas' who had this disorder, as well as other patients, some of whom came from families showing a typical X-linked pattern of inheritance, Biggs et al. (1952) defended the familial eponym in the following way: 'The naming of clinical disorders after patients was introduced by Sir Jonathan Hutchinson and is now familiar from serological research; it has the advantage that no hypothetical implication is attached to such a name.' Giangrande (2003) provided historical information concerning the patient Stephen Christmas (1947-1993), whose mutation in the F9 gene (300746.0109) was reported by Taylor et al. (1992) and his physicians. - Hemophilia B(M) A subset of hemophilia B patients have a prolonged prothrombin time when exposed to bovine (or ox) brain tissue, which serves as a source of thromboplastin, or tissue factor (F3; 134390); these CRM+ patients are classified as having hemophilia B(M) (Lefkowitz et al., 1993). Several workers (e.g., Nour-Eldin and Wilkinson, 1959) observed the combination of factor IX deficiency with factor VII (F7; 613878) deficiency. However, inheritance was always X-linked, even though F7 is on chromosome 13. Verstraete et al. (1962) reported 4 families in which all affected males had both Christmas disease and factor VII deficiency. The authors suggested that factor VII deficiency was a consistent secondary phenomenon; thus no separate mutation for the combined defect would be necessary. Hougie and Twomey (1967) defined a variant of hemophilia B that differed from the usual form by the presence of a prolonged PT. They presented evidence these patients had a structurally abnormal and inactive form of factor IX that acted as an inhibitor of the normal reaction between factor VII and bovine brain. They called the variant hemophilia B(M), after the initial of the family surname. Denson et al. (1968) identified 3 blood samples of hemophilia B(M) among samples derived from 27 patients with Christmas disease. In a series of coagulation assays, Denson et al. (1968) demonstrated that the prolongation of the PT involved inhibition of the reaction between ox brain tissue factor, factor VII, and factor X. Noting that this distinct abnormality had only been observed in patients with factor IX deficiency, the authors postulated that the 'inhibitor' may be an abnormal protein similar to or identical with factor IX. Subsequent studies showed that this inhibitor was an abnormal form of factor IX that was functionally inactive but was antigenically indistinguishable from normal factor IX. Lefkowitz et al. (1993) noted that the bovine brain tissue in studies of hemophilia B(M) is the source of thromboplastin, or tissue factor (F3; 134390); PT times determined with thromboplastin from rabbit brain or human brain are not reported to be prolonged. However, in various studies of factor IX Hilo (300746.0031), Lefkowitz et al. (1993) found that either normal F9 or Hilo F9 prolonged the PT regardless of the tissue factor source, but the prolongation required high concentrations of factor IX when rabbit or human brain was used. With bovine thromboplastin, factor IX Hilo was significantly better than normal factor IX at prolonging the PT. In addition, the prolongation times depended on the amounts of factors IX and X used in the assays. - Hemophilia B Leyden Veltkamp et al. (1970) described a variant of hemophilia B, termed hemophilia B Leyden, in a Dutch family. The disorder was characterized by the disappearance of the bleeding diathesis as the patient aged. In affected individuals, plasma factor IX levels were less than 1% of normal before puberty, but after puberty factor IX activity and antigen levels rose steadily in a 1:1 ratio to a maximum of 50 to 60%. Briet et al. (1982) described a similar variant of hemophilia B that took a severe form early in life but remitted after puberty, with an increase in factor IX levels from below 1% of normal to about 50% of normal by age 80 years. Three pedigrees with 27 affected males with this disorder could be traced to a small village in the east of the Netherlands. In affected members of 2 Dutch pedigrees with hemophilia B Leyden, Reitsma et al. (1988) found that patients with hemophilia B Leyden had a mutation in the promoter region of the F9 gene (300746.0001). The findings suggested that a point mutation could lead to a switch from constitutive to steroid hormone-dependent gene expression. The families were probably related. Mandalaki et al. (1986) reported a 5-generation Greek family with hemophilia B. The factor IX levels in the 3 patients from the last generation were extremely low, while those of patients in the older generations were much higher. In 1 patient, the rise of factor IX levels appeared between ages 13 and 14 years. In addition, older patients in the family had much milder symptoms compared to the younger patients. The phenotype was similar to hemophilia B Leyden as described by Veltkamp et al. (1970). - Manifesting Females Lascari et al. (1969) described a daughter of a male with hemophilia B who had an XX karyotype, factor IX level of 5%, and hemarthrosis. The factor IX level in the mother was 100%. The girl was thought to be a manifesting heterozygote with unfortunate lyonization. Spinelli et al. (1976) observed deletion of the short arm of 1 of the X chromosomes in a female with hemophilia B. Family investigations were negative. Hashimi et al. (1978) reported a girl with Christmas disease. Her father was affected, and her parents were related as first cousins, suggesting possible homozygosity for the defect. They referred to a similar instance of plausible homozygosity. Wadelius et al. (1993) reported a female with hemophilia B with factor IX activity of about 1%. Her father had severe hemophilia B. No chromosomal abnormality could be detected, and DNA analysis gave no indication of deletions or mutations of TaqI cleavage sites in the F9 gene. Analysis of the methylation pattern of locus DXS255 indicated that the expression of hemophilia B in this girl was caused by nonrandom X inactivation. Vianna-Morgante et al. (1986) observed de novo t(X;1)(q27;q23) in a girl with hemophilia B who had no affected relatives. In a full description of the case, Krepischi-Santos et al. (2001) stated that the translocated X was preferentially active and that methylation analysis of the DXS255 locus confirmed the skewed X inactivation with the paternal allele being the active one. Molecular analysis showed deletion of at least part of the F9 gene. Nisen et al. (1986) described hemophilia B in a girl with the karyotype 46,X,del(X)q27. They showed that the X chromosome with the deletion was inactivated in all cells. The mother's identical twin sister had a son with severe hemophilia B. The proband was also lacking the paternal factor VIII gene, indicating that the deletion had occurred in the paternal X chromosome and had included the factor VIII locus. However, both the maternal and the paternal factor IX loci were present. The interpretation applied by Nisen et al. (1986) was that inactivation of the deleted, paternally derived X chromosome in all cells had provided the opportunity for expression of the hemophilia B gene which the proband had inherited from her mother. By sequencing the complete factor IX gene in 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis, Costa et al. (2000) found a common 5-prime splice site mutation in intron 3 (300746.0107) and an additional missense mutation (I344T; 300746.0108) in 1 sister. The presence of dysfunctional antigen in the latter strongly suggested that these mutations were in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was a somatic mosaic for the shared splice site mutation. The somatic mosaicism in the mother for the splice site mutation was demonstrated by studies of buccal and uroepithelial cells. The missense mutation was presumed to have resulted from a de novo mutation in the father's gametes. The compound heterozygous proband was a 14-year-old girl with moderate hemophilia B, manifest by hematomas, hemarthrosis, and epistaxis. A sister suffered only from rare hematomas. In a population-based survey in the Netherlands, Plug et al. (2006) found that female carriers of hemophilia A and B bled more frequently than noncarrier women, especially after medical procedures, such as tooth extraction or tonsillectomy. Reduced clotting factor levels correlated with a mild hemophilia phenotype. Variation in clotting levels was attributed to lyonization.
Using genomic DNA probes, Chen et al. (1985) identified a partial intragenic deletion in the F9 gene in 7 affected members of a family with severe hemophilia B.
In affected members of a family with severe ... Using genomic DNA probes, Chen et al. (1985) identified a partial intragenic deletion in the F9 gene in 7 affected members of a family with severe hemophilia B. In affected members of a family with severe factor IX deficiency and no detectable factor IX protein, Taylor et al. (1988) identified a complete deletion of the F9 gene that extended at least 80 kb 3-prime of the gene. The proband did not have antibodies to factor IX, despite total deletion of the gene. Matthews et al. (1988) discussed the family originally reported by Peake et al. (1984) as having an X-chromosome deletion of minimum size 114 kb that included the entire F9 gene. By isolation of further 3-prime flanking probes, they located the 3-prime breakpoint of the deletion to a position 145 kb 3-prime to the start of the F9 gene. Abnormal junction fragments detected at the breakpoint were used in the detection of carriers. In a patient with severe hemophilia B, Siguret et al. (1988) found loss of the Taq1 restriction site at the 5-prime end of exon 8 of the F9 gene. Using oligonucleotide probes and PCR-amplified DNA for sequencing of the affected region, the authors identified a C-to-T change in the catalytic domain of the protein, resulting in premature truncation. The change resulted from a CpG mutation. By use of PCR followed by sequencing, Bottema et al. (1989) identified mutations in the F9 gene (see, e.g., 300746.0051) in all 14 hemophilia B patients studied. Analysis for heterozygosity in at-risk female relatives was then done, either by sequencing the appropriate region or by detection of an altered restriction site. Green et al. (1991) provided a list of point mutations that cause hemophilia B. Sommer et al. (1992) estimated that missense mutations cause only 59% of moderate and severe hemophilia B and that these mutations are almost always (95%) of independent origin (i.e., de novo mutations). In contrast, missense mutations were found in virtually all (97%) families with mild disease and only a minority of these (41%) were of independent origin. Giannelli et al. (1993) reported on the findings in a database of 806 patients with hemophilia B in whom the defect in factor IX had been identified at the molecular level. A total of 379 independent mutations were described. The list included 234 different amino acid substitutions. There were 13 promoter mutations, 18 mutations in donor splice sites, 15 mutations in acceptor splice sites, and 4 mutations creating cryptic splice sites. In analyses of DNA from 290 families with hemophilia B (203 independent mutations), Ketterling et al. (1994) found 12 deletions more than 20 bp long. Eleven of these were more than 2 kb long and one was 1.1 kb. Giannelli et al. (1996) described the sixth edition of their hemophilia B database of point mutations and short (less than 30 bp) additions and deletions. The 1,380 patient entries were ordered by the nucleotide number of their mutation. References to published mutations were given and the laboratories generating the data were indicated. Giannelli et al. (1997) described the seventh edition of their database; 1,535 patient entries were ordered by the nucleotide number of their mutation. When known, details were given on factor IX activity, factor IX antigen in the circulation, presence of inhibitor, and origin of mutation. Ljung et al. (2001) surveyed a series comprising all 77 known families with hemophilia B in Sweden. The disorder was severe in 38, moderate in 10, and mild in 29. A total of 51 different mutations were found. Ten of the mutations, all C-to-T or G-to-A transitions, recurred in 1 to 6 additional families. Using haplotype analysis of 7 polymorphisms in the F9 gene, Ljung et al. (2001) found that the 77 families carried 65 unique, independent mutations. Of the 48 families with severe or moderate hemophilia, 23 (48%) had a sporadic case compared with 31 families of 78 (40%) in the whole series. Five of those 23 sporadic cases carried de novo mutations; 11 of 23 of the mothers were proven carriers; and in the remaining 7 families, it was not possible to determine carriership. Rogaev et al. (2009) identified a splice site mutation in the F9 gene (300746.0113) as the causative mutation for the 'Royal disease,' the form of hemophilia transmitted from Queen Victoria to European royal families and transmitted to her granddaughter, Russian Empress Alexandra and her son, Crown Prince Alexei. - Mutation Rate In an analysis of 1,485 families with hemophilia A or hemophilia B, Barrai et al. (1985) estimated the proportion of sporadic cases to be 0.166 and 0.078, respectively. The age of maternal grandfathers at birth of the mother of hemophilia B cases was higher than that of appropriate controls. In the population of families with hemophilia B at the Malmo Haemophilia Centre, Montandon et al. (1992) estimated that the overall mutation rate was 4.1 x 10(-6) and that the ratio of male to female specific mutation rates was 11. Three of 13 isolated cases had a new mutation, whereas the other 10 had mothers who carried a new mutation. Kling et al. (1992) found that 24 of 45 hemophilia B patients in Malmo, Sweden, had no affected family members. Three of 13 families with 1 patient available for study had a do novo mutation, whereas the defect was inherited from a carrier mother in the remaining 10. All 10 of these carrier mothers had de novo mutation, as their fathers were phenotypically normal and the grandmothers were noncarriers. In all 6 of the 10 cases in whom RFLP patterns were informative, the mutation was of paternal origin, and the average age of the father at the birth of the new carrier female was 41.5 years. These data supported a paternal age effect and a higher mutation rate in males than in females regarding factor IX mutations. Among 43 families with hemophilia B, Ketterling et al. (1993) found that 25 had a mutation in the female germline and 18 in the male germline. The excess of germline origins in females did not imply an overall excess mutation rate per basepair, because when the mother and maternal grandparents were analyzed, the excess of X chromosomes in females, 4:1, skewed the data in favor of female origins. Bayesian analysis corrected for this bias and indicated that the 25:18 ratio actually represented a predominance of mutations in males. Transitions at the dinucleotide CpG, estimated to account for 36% of mutations in the F9 gene (Koeberl et al., 1990), showed the most striking male predominance of mutation, 11:1. This finding was comparable with previous data suggesting that methylation at CpG dinucleotides is reduced or absent in the female germline (Driscoll and Migeon, 1990). This effect, rather than an increased number of replications in the male germ cells, likely accounted for the male excess. In studies of the patterns of independent mutation resulting in hemophilia B in 127 Caucasian and 44 non-Caucasian patients, Gostout et al. (1993) could find no differences, suggesting either predominance of endogenous processes or common mutagen exposure rather than mutagen exposure specifically associated with non-Caucasian status or non-Western life style. Green et al. (1999) conducted a population-based study of hemophilia B mutations in the United Kingdom in order to construct a national confidential database of mutations and pedigrees to be used for the provision of carrier and prenatal diagnoses based on mutation detection. This allowed the direct estimate of overall mutation rate, male mutation rate, and female mutation rate for hemophilia B. The values obtained per gamete per generation and the 95% confidence intervals were 7.73 (6.29-9.12) x 10(-6) for overall mutation rate; 18.8 (14.5-22.9) x 10(-6) for male mutation rate; and 2.18 (1.44-3.16) x 10(-6) for female mutation rate. The ratio of male-to-female mutation rates was 8.64 (95% CI, 5.46-14.5). Attempts to detect evidence of gonadal mosaicism for hemophilia B mutation in suitable families did not detect any instances of ovarian mosaicism in 47 available opportunities. This suggested that the risk of a noncarrier mother manifesting as a gonadal mosaic by transmitting the mutation to a second child should be less than 0.062. Giannelli et al. (1999) also estimated the rates per base per generation of specific types of mutations, using their direct estimate of the overall mutation rate for hemophilia B and information on the mutations present in the U.K. population as well as those reported year by year in the hemophilia B world database. These rates were as follows: transitions at CpG sites, 9.7 x 10(-8); other transitions, 7.3 x 10(-9); transversions at CpG sites, 5.4 x 10(-9); other transversions, 6.9 x 10(-9); and small deletions/insertions causing frameshifts, 3.2 x 10(-10). Ketterling et al. (1999) estimated the male:female ratio of mutations in the F9 gene by Bayesian analysis of 59 families. The overall ratio was estimated at 3.75. It varied with the type of mutation, from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (more than 1 kb), respectively. The value for the 2 subsets of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of the 45 'origin individuals' for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately 1 part in 20). Four of the 5 defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 U.S. Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen; however, an advanced maternal age effect was observed (P = 0.03) and was particularly prominent in transversions. This suggested that an increased maternal age results in a higher rate of transmitted mutations, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation. Liu et al. (2000) found that the pattern of germline mutations in 66 hemophilia B patients from mainland China was similar to that in U.S. Caucasians, blacks, and Mexican Hispanics. The existence of a ubiquitous mutagen or the possibility that multiple mutagens could produce the same pattern of mutation was considered unlikely; the findings were compatible with the inference that endogenous processes predominate in germline mutations. Ljung et al. (2001) found that the ratio of male to female mutation rates was 5:3 and that the overall mutation rate per gamete per generation was 5.4 x 10(-6).
Giannelli et al. (1983) stated that 798 cases of Christmas disease were known in the U.K., corresponding to a frequency of 1 in 30,000 males.
Connor et al. (1985), by total ascertainment, found 28 families with ... Giannelli et al. (1983) stated that 798 cases of Christmas disease were known in the U.K., corresponding to a frequency of 1 in 30,000 males. Connor et al. (1985), by total ascertainment, found 28 families with hemophilia B in the west of Scotland (prevalence = 1/26,870 males). Of 26 living obligate carriers, 42% were heterozygous for a TaqI polymorphism recognized by the factor IX genomic probe. Linkage disequilibrium was apparent for this RFLP and hemophilia B in the west of Scotland. This surprising finding suggested that some of these families might be related. Soucie et al. (1998) studied the frequency of hemophilia A and hemophilia B in 6 U.S. states: Colorado, Georgia, Louisiana, Massachusetts, New York, and Oklahoma. The age-adjusted prevalence of hemophilia in all 6 states in 1994 was 13.4 cases per 100,000 males (10.5 hemophilia A and 2.9 hemophilia B). The prevalence by race/ethnicity was 13.2 cases per 100,000 white, 11.0% among African American, and 11.5% among Hispanic males. Application of age-specific prevalence rates from the 6 surveillance states to the U.S. population resulted in an estimated national population of 13,320 cases of hemophilia A and 3,640 cases of hemophilia B. For the 10-year period 1982 to 1991, the average incidence of hemophilia A and B in the 6 surveillance states was estimated to be 1 in 5,032 live male births.
The diagnosis of hemophilia B cannot be made on clinical findings. A coagulation disorder is suspected in individuals with any of the following: ...
DiagnosisClinical DiagnosisThe diagnosis of hemophilia B cannot be made on clinical findings. A coagulation disorder is suspected in individuals with any of the following: Hemarthrosis, especially with mild or no antecedent trauma Deep-muscle hematomas Intracranial bleeding in the absence of major trauma Neonatal cephalohematoma or intracranial bleeding Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *Prolonged or delayed bleeding or poor wound healing following surgery or trauma *Unexplained GI bleeding or hematuria *Menorrhagia, especially with onset at menarche (in symptomatic carriers) *Prolonged nosebleeds, especially recurrent and bilateral *Excessive bruising, especially with firm, subcutaneous hematomas * Any severity, or especially in more severely affected personsTestingCoagulation screening tests. Evaluation of an individual with a suspected bleeding disorder includes: platelet count and bleeding time or platelet function analysis (PFA closure times), activated partial thromboplastin time (APTT), and prothrombin time (PT). Thrombin time and/or plasma concentration of fibrinogen can be useful for rare disorders. In individuals with hemophilia B, the above screening tests are normal, with the following exceptions: The APTT is prolonged in severe and moderate hemophilia B. Prolongations that correct on mixing with an equal volume of normal plasma indicate an intrinsic system clotting factor deficiency, including factor IX, without an inhibitor. Note: It is important to confirm the diagnosis of hemophilia B and to exclude other deficiencies with a specific factor IX clotting activity which is available in most hospital laboratories or coagulation reference laboratories. The APTT may be normal but is usually mildly prolonged n mild hemophilia B. The prothrombin time (PT), a screen for the extrinsic clotting system, should be normal except with some reagents and certain Crm+ missense genotypes, unless there is another hemostatic defect such as acquired liver disease.Note: In some clinical laboratories, the APTT is not sensitive enough to diagnose a mild bleeding disorder.Coagulation factor assays. Individuals with a history of a lifelong bleeding tendency should have specific coagulation factor assays performed, even if all the coagulation screening tests are in the normal range: The normal range for factor IX clotting activity is approximately 50% to 150% [Khachidze et al 2006]. Individuals with factor IX clotting activity higher than 30% usually have normal coagulation in vivo. However, some increased bleeding can occur with low to low-normal factor IX clotting activity in hemophilia B carrier females [Plug et al 2006]. In hemophilia B, the factor IX clotting activity is usually less than 30%. Classification of hemophilia B based on in vitro clotting activity: Severe hemophilia B: <1% factor IX Moderate hemophilia B: 1%-5% factor IX Mild hemophilia B: >5%-30% factor IX Carrier females Coagulation factor assays. Approximately 10% of carrier females have a factor IX clotting activity below 30%, regardless of the severity of hemophilia B in their family. Bleeding may also be more severe in those with low-normal factor IX activity [Plug et al 2006]. Note: The majority of obligate carriers, even of severe hemophilia B, have normal factor IX clotting activities.Molecular Genetic Testing Gene. F9 is the only gene in which mutations are known to cause hemophilia B. Clinical testing Sequence analysis of amplified fragments that include all eight exons of F9 can identify a mutation in more than 99% of individuals with hemophilia B. Direct sequencing is the usual approach, although several screening strategies have been used [Mitchell et al 2005]. In some instances, it is appropriate to include F9 promoter mutations that cause hemophilia B Leyden, an uncommon variant that results from one of several mutations from base pairs -23 through +13 (numbered according to Yoshitake et al 1985 [see Bajaj & Thompson 2006]; see also Genotype-Phenotype Correlations; Table A, Locus-Specific Databases). In males, a presumptive diagnosis of a large or partial-gene deletion occurs from failure to amplify one or more exon fragments. Deletion/duplication analysisIn affected males, deletion/duplication analysis detects and/or confirms exonic, multiexonic, or complete F9 deletions suspected on sequence analysis in males with severe hemophilia B. In carrier females deletion duplication analysis can detect gene deletions and rearrangements not detectable by sequence analysis. Guidelines for laboratory practice for molecular analysis of F9 have been established in the UK [Mitchell et al 2005 (click for full text)]. Table 1. Summary of Molecular Genetic Testing Used in Hemophilia B View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMalesCarrier FemalesF9Sequence analysisSequence variants 2, 3~100% 4, 5, 697% 7ClinicalDeletion / duplication analysis 8Deletion / duplication of one or more exons or the whole gene 3%3%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations, and changes in the 5’ or 3’ untranslated portions of F9.3. Includes ~1% with hemophilia B Leyden with specific 5' base substitutions in an "androgen-responsive element" in which the bleeding tendency becomes milder after puberty4. Lack of amplification by PCRs prior to sequence analysis suggests a deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis including use of additional sets of amplification primers. 5. Includes the mutation detection frequency using deletion/duplication analysis.6. Somatic mosaicism occurs and could lower the mutation detection frequency in males with hemophilia B [Ketterling et al 1999].7. Sequence analysis of genomic DNA cannot detect deletion or duplication of one or more exons or the entire X-linked gene in a carrier female.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Linkage analysis can be used to track an unidentified F9 disease-causing allele in a family and to identify the origin of de novo mutations: Tracking an unidentified F9 mutation. When a disease-causing mutation of F9 is not identified in an affected family member by direct DNA testing, linkage analysis can be considered to obtain information for genetic counseling in families in which more than one family member has the unequivocal diagnosis of hemophilia B. Linkage studies are always based on accurate clinical diagnosis of hemophilia B in the affected family members and accurate understanding of the genetic relationships in the family. In addition, linkage analysis depends on the availability and willingness of family members to be tested and on the presence of informative heterozygous polymorphic markers. The markers used for hemophilia B linkage are intragenic and are informative with greater than 99% accuracy in approximately 95% of African American families, 85%-90% of families of European origin, and 60% of Asian/Native American families with hemophilia B [Bajaj & Thompson 2006]. Identifying the origin of a de novo mutation. Among the nearly 50% of families with a simplex case of hemophilia B (i.e., occurrence in one family member only), the origin of a de novo mutation can often be identified by performing molecular genetic testing in conjunction with linkage analysis. The presence of the mutation on the affected individual's factor IX haplotype is tracked back through the parents and, if necessary, through maternal grandparents to identify the individual in whom the mutation originated. Testing StrategyTo confirm/establish the diagnosis in a proband requires measurement of factor IX clotting activity. Molecular genetic testing is performed on a proband to detect the family-specific mutation in F9 in order to obtain information for genetic counseling of at-risk family members. If an affected individual is not available, an obligate carrier female can be tested.In individuals who represent a simplex case, identification of the specific F9 mutation can help predict the clinical phenotype and assess the risk of developing a factor IX inhibitor. (See Genotype-Phenotype Correlations). For individuals with (a) hemophilia B or (b) females with a family history of hemophilia B in whom the family-specific mutation is not known, molecular genetic testing is generally performed in the following sequence until a mutation (or linkage) is identified: Sequence analysis of the eight exons in F9Deletion/duplication analysis Linkage analysisNote: When carrier testing is performed on an at-risk relative without previous identification of the F9 mutation in the family, a negative result does not necessarily exclude a potential carrier. Carrier testing for at-risk relatives is most informative after identification of the disease-causing mutation in the family. See above for testing of at-risk females when the family specific mutation is not known.Note: Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersCertain missense mutations within the propeptide portion of factor IX enhance sensitivity to warfarin by altering the binding of a gamma-carboxylase responsible for post-translational Gla residue formation [Bajaj & Thompson 2006]. One family has been described in which a missense change, p.Arg338Leu, is associated with markedly elevated circulating levels of factor IX and venous thrombosis at a young age [Simioni et al 2009].
Hemophilia B in the untreated individual is characterized by prolonged oozing after injuries, tooth extractions, or surgery or renewed bleeding after initial bleeding has stopped [Kessler & Mariani 2006]. 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 symptom. ...
Natural HistoryHemophilia B in the untreated individual is characterized by prolonged oozing after injuries, tooth extractions, or surgery or renewed bleeding after initial bleeding has stopped [Kessler & Mariani 2006]. 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 symptom. 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 during the first two years of life. On rare occasions, infants with severe hemophilia have extra- or intracranial bleeding following birth. 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. Carrier females with a factor IX clotting activity level lower than 30% 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 activities between 30% and 60% [Plug et al 2006].Table 2. Symptoms Related to Severity of Untreated Hemophilia BView in own windowClinical Severity Factor IX Clotting Activity 1 Symptoms Usual Age of Diagnosis Severe <1% Frequent spontaneous bleeding; excessive and/or prolonged bleeding after minor injuries, surgery, or tooth extractions Age ≤2 yearsModerate 1%-5%Spontaneous bleeding rare; excessive and/or prolonged bleeding after minor injuries, surgery, or tooth extractions Age <5-6 years Mild >5%-30% No spontaneous bleeding; excessive and/or prolonged bleeding after major injuries, surgery, or tooth extractions Often later in life, depending on hemostatic challenges 1. Clinical severity does not always correlate with the in vitro assay result.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 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 is 63 years [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 a risk of 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]. HIV transmission from concentrates essentially 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 3% of individuals with severe hemophilia B develop alloimmune inhibitors to factor IX. These individuals usually have partial or complete gene deletions or certain nonsense mutations (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 CorrelationsDisease severityLarge gene deletions, nonsense mutations, and most frameshift mutations cause severe disease. Missense mutations can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved. Alloimmune inhibitorsAlloimmune inhibitors occur with the greatest frequency (~20%) in individuals with large partial- or whole-gene deletions.Among individuals with the p.Arg29* mutation approximately 20% have developed inhibitors and/or anaphylaxis in response to factor IX infusion.Missense mutations are rarely associated with inhibitors.Unlike hemophilia A, severe hemophilia B is often caused by a missense mutation and several of these are associated with normal CRM (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 [Bajaj & Thompson 2006] (see Management).In hemophilia B Leyden (caused by mutations in a restricted 5’ UT promoter region of F9) the severity of disease decreases after puberty; mild disease disappears and severe disease becomes mild, depending on the specific mutation.
When an individual presents with bleeding or the history of being a "bleeder," the first task is to determine if he/she truly has abnormal bleeding. "Bleeding a lot" during or immediately after major trauma, after a tonsillectomy, or for a few hours following tooth extraction may not be significant. In contrast, prolonged or intermittent oozing that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or development of a wound hematoma several days after surgery almost always indicates a coagulation problem. A careful history of bleeding episodes can help determine if the individual has a lifelong, inherited bleeding disorder or an acquired (often transient) bleeding disorder. ...
Differential DiagnosisWhen an individual presents with bleeding or the history of being a "bleeder," the first task is to determine if he/she truly has abnormal bleeding. "Bleeding a lot" during or immediately after major trauma, after a tonsillectomy, or for a few hours following tooth extraction may not be significant. In contrast, prolonged or intermittent oozing that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or development of a wound hematoma several days after surgery almost always indicates a coagulation problem. A careful history of bleeding episodes can help determine if the individual has a lifelong, inherited bleeding disorder or an acquired (often transient) bleeding disorder. Physical examination provides few specific diagnostic clues. An older individual with severe or moderate hemophilia B may have joint deformities and muscle contractures. Large bruises and subcutaneous hematomas for which no trauma can be identified may be present, but individuals with a mild bleeding disorder usually have no outward signs except during an acute bleeding episode. Petechial hemorrhages indicate severe thrombocytopenia and are not a feature of hemophilia B. A family history with a pattern of autosomal dominant, autosomal recessive, or X-linked inheritance provides clues to the diagnosis but is not definitive. At least 10% of women who carry hemophilia B of any severity have low enough factor IX activity levels to have mild bleeding themselves, which in some families may erroneously suggest autosomal rather than X-linked inheritance. Hemophilia B is only one of several lifelong bleeding disorders, and coagulation factor assays are the main tools for determining the specific diagnosis. Other bleeding disorders associated with a low factor IX clotting activity include the following: Combined vitamin K-dependent factor deficiencies (prothrombin and factors VII, IX, and X and proteins C and S), usually caused by a γ-carboxylase or epoxide reductase deficiency [Weston & Monahan 2008] Common acquired deficiencies of these factors in individuals with vitamin K disorders, including warfarin treatment or liver disease Other bleeding disorders with normal factor IX levels include the following: Hemophilia A is clinically indistinguishable from hemophilia B. Diagnosis is based on a factor VIII clotting activity level lower than 35% in the presence of a normal von Willebrand factor (VWF) level. Mutations in F8 are causative. Inheritance is X-linked. von Willebrand disease (VWD) type 1 or type 2 is characterized predominantly by mucous membrane bleeding. Eighty percent of individuals with VWD have a quantitative deficiency of von Willebrand factor (low VWF antigen, factor VIII activity, and ristocetin cofactor activity). Essentially all individuals with hemophilia B have a normal VWF level and a normal factor VIII activity. VWD types 2A and 2B are characterized by a qualitative deficiency of VWF, with a decrease of the high molecular-weight multimers. Type 2B VWD is caused by a gain of function in platelet binding and is often accompanied by thrombocytopenia. Type 2M VWD is caused by a similar gain of function in platelet binding as with type 2B although it is associated with a normal multimer pattern. Molecular genetic testing can aid in the diagnosis. VWF antigen and factor VIII clotting activity may be low-normal to mildly decreased. Functional VWF level is low in a ristocetin cofactor assay. Inheritance of VWD is autosomal dominant with the exception of some variants including 2N, which is autosomal recessive. Severe, type 3 VWD is characterized by frequent episodes of mucous membrane bleeding and joint and muscle bleeding similar to that seen in individuals with hemophilia B. The VWF level is lower than 1% and the factor VIII clotting activity level is 2%-8%. Inheritance is autosomal recessive. Factor XI deficiency [Thompson 2006] is inherited in an autosomal recessive manner with heterozygotes showing a factor XI coagulant activity level of 25% to 75% of normal, while homozygotes have activity of less than 1% to 15%, depending on their genotype. Two mutations are common among individuals of Ashkenazi Jewish descent. Both compound heterozygotes and homozygotes may exhibit bleeding similar to that seen in mild or moderate hemophilia B. Specific factor assays establish the diagnosis. Factor XII, prekallekrein, or high-molecular-weight kininogen deficiencies do not cause clinical bleeding, but can cause a long activated partial thromboplastin time (APTT). Prothrombin (factor II), factor V, factor X, and factor VII deficiency are rare bleeding disorders inherited in an autosomal recessive manner. Affected individuals may display easy bruising and hematoma formation, epistaxis, menorrhagia, and bleeding after trauma and surgery. Hemarthroses are uncommon. Spontaneous intracranial bleeding can occur. Factor VII deficiency should be suspected if the PT is prolonged with a normal APTT. Individuals with factors II, V, or X deficiency usually have prolonged PT and APTT, but specific factor assays establish the diagnosis of these rare bleeding tendencies. Fibrinogen disorders include severe, mild, and asymptomatic variants [Thompson 2006]: Congenital afibrinogenemia is a rare disorder inherited in an autosomal recessive manner with manifestations similar to those observed in hemophilia B, except that bleeding from minor cuts is prolonged because of the lack of fibrinogen to support platelet aggregation. Hypofibrinogenemia can be inherited in either an autosomal dominant or autosomal recessive manner and is usually asymptomatic but may be combined with dysfibrinogenemia. Dysfibrinogenemia is inherited in an autosomal dominant manner. Individuals with hypofibrinogenemia or dysfibrinogenemia have mild-to-moderate bleeding symptoms or may be asymptomatic; some individuals with dysfibrinogenemia are at risk for thrombosis. Diagnosis is based on kinetic and antigenic protein levels, although the thrombin time is usually prolonged and is a simple screening test. Factor XIII deficiency is a rare autosomal recessive disorder [Thompson 2006]. Umbilical stump bleeding is common (>80% of individuals). Intracranial bleeding that occurs spontaneously or following minor trauma occurs in 30% of affected individuals. Subcutaneous hematomas, muscle hematomas, defective wound healing, and recurrent spontaneous abortion are also seen. Joint bleeding is rare. All the kinetic coagulation screening tests are normal; a specific test for clot solubility must be performed. Platelet function disorders cause bleeding problems similar to those seen in individuals with thrombocytopenia. Affected individuals have skin and mucous membrane bleeding, recurring epistaxis, gastrointestinal bleeding, menorrhagia, and excessive bleeding during or immediately after trauma and surgery. Joint, muscle, and intracranial bleeding are rare. Diagnosis is made utilizing platelet aggregation assays and flow cytometry.Bernard-Soulier syndrome, inherited in an autosomal recessive manner, involves the VWF receptor, the platelet membrane GPIb-IX complex. Glanzmann's thrombasthenia, also autosomal recessive, involves the GPIIb-IIIa receptor necessary for platelet aggregation. Abnormal platelet function is usually associated with a prolonged bleeding time or prolonged closure times on platelet function analysis. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Hemophilia B: malesHemophilia B: female heterozygotes
To establish the extent of disease in an individual diagnosed with hemophilia B, the following evaluations are recommended: ...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hemophilia B, the following evaluations are recommended: Identification of the specific F9 mutation in an individual to aid in determining: disease severity; the likelihood of inhibitor development; and the risk of anaphylaxis if an inhibitor does develop [Chitlur et al 2009]A personal and family history of bleeding to help predict severity A joint and muscle evaluation, particularly if the individual describes a past hemarthrosis or muscle hematoma Screening for hepatitis A, B, and C and HIV, particularly if blood products or plasma-derived clotting factors were administered prior to 1985Baseline CBC and platelet count, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding, or, in women, menorrhagia or postpartum hemorrhageTreatment of ManifestationsIn developed countries, life expectancy for individuals with hemophilia B has greatly increased over the past four decades [Darby et al 2007]; disability has decreased with the intravenous infusion of factor IX concentrates, home infusion programs, prophylactic treatment, and improved patient education. Individuals with hemophilia B benefit from referral for assessment, education, and genetic counseling at one of the approximately 140 federally funded hemophilia treatment centers (HTCs) in the USA that can be located through the National Hemophilia Foundation. Worldwide, treatment centers can be found through the World Federation of Haemophilia. The treatment centers establish appropriate treatment plans and referrals or direct care for individuals with inherited bleeding disorders. They are also a resource for current information on new treatment modalities for hemophilia. An assessment at one of these centers usually includes extensive patient education, genetic counseling, and laboratory testing. Intravenous infusion of factor IX concentrate. A recombinant factor IX concentrate that has no human- or animal-derived proteins is available [Kessler & Mariani 2006]. Additional preparations including fusion proteins (to prolong half-life) are undergoing clinical trials [Monahan & Di Paola 2010]. Virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV transmission since 1985, and of hepatitis B and C viruses since 1990. Bleeding episodes are controlled rapidly after intravenous infusions of factor IX concentrate. Fast, effective treatment of bleeding episodes prevents pain, disability, and reduces the risk of chronic joint disease. Ideally, the affected individual should receive clotting factor within an hour of noticing symptoms or trauma. Knowing the previous in vivo recovery of a patient with hemophilia B helps estimate the proper dose [Björkman et al 2007]:Arranging efficient, effective treatment for infants and toddlers is especially challenging. Because frequent venipunctures may be necessary, it is important to identify staff members who are expert in performing venipunctures in small children. It is recommended that the parents of children age two to five years with severe hemophilia B be trained to administer the infusions as soon as is feasible. Home treatment allows for prompt treatment after symptoms occur and facilitates prophylactic therapy. Pediatric issues. Special considerations for care of infants and children with hemophilia B include the following [Chalmers et al 2005]: Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure to prevent delayed oozing and poor wound healing. Intramuscular injections should be avoided; immunizations should be administered subcutaneously. Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children. Inhibitors. Alloimmune inhibitors to factor IX, seen in 1%-3% of persons with severe hemophilia B, greatly compromise the ability to manage bleeding episodes [Hay et al 2006]. Their onset can be associated with anaphylactic reactions to factor IX infusion and nephrotic syndrome [DiMichele 2007, Chitlur et al 2009]. Prevention of Primary ManifestationsChildren with severe hemophilia B are often given "primary" prophylactic infusions of factor IX concentrate two to three times a week to maintain factor IX clotting activity above 1%; these infusions prevent spontaneous bleeding and decrease the number of bleeding episodes. As shown for hemophilia A [Manco-Johnson et al 2007], prophylactic infusions almost completely eliminate spontaneous joint bleeding, decreasing chronic joint disease, although complications of venous access ports in young children can occur. Prevention of Secondary ComplicationsPrevention of chronic joint disease is a major concern. Controversy still exists as to indications for beginning primary prophylaxis in individuals with severe hemophilia B, especially whether the benefits of primary prophylaxis justify the risk of an indwelling venous catheter in a young child."Secondary" prophylaxis is often used for several weeks, even in adults, if recurrent bleeding in a "target" joint or synovitis occurs, or for longer periods in adults with frequent bleeding. SurveillancePersons with hemophilia followed at hemophilia treatment centers (HTCs) (see Resources) have lower mortality than those who are not [Soucie et al 2000]. It is recommended that young children with severe or moderate hemophilia B have assessments at an HTC (accompanied by the parents) every six to 12 months to review and evaluate signs and symptoms of possible bleeding episodes and to adjust treatment as needed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, and a discussion of any other problems related to the individual's hemophilia and family and community support.Screening for alloimmune inhibitors is usually done in those with severe hemophilia B after treatment with factor IX concentrates has been initiated either for bleeding or prophylaxis; additional screening is usually performed up to a few years of age when the genotype is a large partial or complete F9 deletion or a nonsense mutation at p.Arg29* (c.85C>T) (see Genotype-Phenotype Correlations; see Molecular Genetics: Normal allelic variants and Normal gene product for reference sequences). Testing for inhibitors should also be performed in any individual with hemophilia whenever a suboptimal clinical response to treatment is suspected, regardless of disease severity; with hemophilia B, the onset may be heralded by an allergic reaction to infused factor IX concentrate.Older children and adults with severe or moderate hemophilia B benefit from contact with an HTC (see Resources) and periodic assessments to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for an inhibitor, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia.Individuals with mild hemophilia B can benefit by maintaining a relationship with an HTC and having regular assessments every two to three years.Agents/Circumstances to AvoidAvoid the following:Activities that involve a high risk of trauma, particularly head injury Aspirin and all aspirin-containing products Cautious use of other medications and herbal remedies that affect platelet function is indicated. Older, intermediate purity plasma-derived “prothrombin complex” concentrates should be used cautiously (if at all) in hemophilia B because of their thrombogenic potential. Evaluation of Relatives at RiskIdentification of at-risk relatives. A thorough family history may identify other male relatives who are at risk but have not been tested (particularly in families with mild hemophilia B). Early determination of the genetic status of males at risk. Either assay of factor IX clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue) or molecular genetic testing for the family-specific F9 mutation can establish or exclude the diagnosis of hemophilia B in newborn males at risk. Infants with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, factor IX concentrate is administered immediately before and after the procedure to prevent delayed oozing and poor wound healing. Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one-tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1%, but is equivocal in an infant with moderately low (15%-20%) activity.Determination of genetic status of females at risk. Approximately 10% of carriers have factor IX clotting activity lower than 30% and may have abnormal bleeding themselves. In a recent Dutch survey of hemophilia carriers, bleeding symptoms correlated with baseline factor clotting activity; there was suggestion of a very mild increase in bleeding even in those with 40% to 60% factor IX clotting activity [Plug et al 2006]. Therefore, all daughters and mothers of an affected male and other at-risk females should have a baseline factor IX clotting activity assay to determine if they are at increased risk for bleeding unless they are known on the basis of molecular genetic testing to be non-carriers. Very occasionally, a woman will have particularly low factor IX clotting activity that may result from heterozygosity for an F9 mutation associated with skewed X-chromosome inactivation or, on rare occasion, compound heterozygosity for two F9 mutations.It is recommended that the carrier status of a woman at risk be established prior to pregnancy or as early in a pregnancy as possible.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Obstetric issues. It is recommended that the carrier status of a woman at risk be established prior to pregnancy or as early in a pregnancy as possible [Lee et al 2006]. In some carriers, postpartum hemorrhage has been a prominent feature, despite the absence of menorrhagia [Yang & Ragni 2004]. If the mother is a symptomatic carrier (i.e., has a baseline factor IX clotting activity below ~30%), she may be at risk for excessive bleeding, particularly post partum, and may require therapy with factor IX concentrate [Yang & Ragni 2004].Newborn males. Controversy remains as to indications for Cesarean section versus vaginal delivery [James & Hoots 2010, Ljung 2010]. For elective deliveries, the relative risks of Cesarean section versus vaginal delivery should be considered, especially if a male has been diagnosed with hemophilia B prenatally.At birth or in the early neonatal period, intracranial hemorrhage is uncommon (<1%-2%), even in males with severe hemophilia B who are delivered vaginally. Therapies Under InvestigationAdditional recombinant factor IX proteins show promise in improving treatment [Monahan & Di Paola 2010]. One recombinant factor IX, with a higher yield from cultured cells, will hopefully lower the cost of therapy. Another preparation in which recombinant factor IX is fused to a portion of the immunoglobulin Fc protein shows prolonged survival and efficacy in animal models [Peters & Bitonti 2007, Shapiro et al 2011] as is a factor IX that is N-glycoPEGylated [Ostergaard et al 2011]. Phase III clinical trials are in progress. A factor IX fused to albumin also appears to have prolonged survival. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherClinical trials for gene therapy in hemophilia B were discontinued because of complications and failure to achieve significant factor IX expression in humans with hemophilia B. The hemophilia community remains hopeful, but many obstacles remain [Pierce et al 2007]. As recently reviewed, two clinical trials have been initiated using AAV vectors with strategies to avoid immune responses to capsid proteins that limited success in previous trials [Mingozzi & High 2011]. Vitamin K does not prevent or control bleeding caused by hemophilia B.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hemophilia B: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDF9Xq27.1Coagulation factor IXHemobase: Hemophilia B mutation registry F9 @ LOVD Factor IX Mutation DatabaseF9Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hemophilia B (View All in OMIM) View in own window 300746COAGULATION FACTOR IX; F9 306900HEMOPHILIA B; HEMBNormal allelic variants. F9 (reference sequence NM_000133.3) is 34 kb in length and comprises eight exons. Normal variants are uncommon in F9, but several have been identified [Mitchell et al 2005, Bajaj & Thompson 2006, Khachidze et al 2006]. Normal allelic variants (and their dbSNP identifier) that are useful for linkage analysis include an MseI site 5' (rs378815) and an HhaI site (rs3117459) 3' to the gene in all populations, a 50-bp intron 1 insert and an exon 6 MnlI site (rs6048) in blacks and whites, a 5' BamHI (rs4149657) and an intron 4 MspI (rs408567) site in blacks, and an intron 1 transition in Asians and Native Americans. The MnlI site is the only known exonic polymorphism and codes for Thr at codon 148 (see Note) or (less frequently) Ala, and is in strong linkage disequilibrium with a TaqI site (rs398101) in intron 4; however, it is not polymorphic in East Asians or Native Americans. See Table A, Locus-Specific Databases; Bajaj & Thompson [2006]; Khachidze et al [2006]. Note: Assuming that the initiating Met is the first of three within the first seven codons of the signal peptide, this would be residue 194 in the translated protein.Pathologic allelic variants. Severe hemophilia B is caused by gross gene alterations, frameshift or splice junction changes, or nonsense or missense mutations. Mild or moderate hemophilia B is predominantly associated with missense changes (see Table A, Locus-Specific Databases). Occasionally, individuals with severe hemophilia B have exonic, multiexonic, or complete F9 deletions. Mild to moderate hemophilia is most often caused by missense mutations. Approximately half of the missense mutations are recurrent, and some clearly represent founder effects (see Table A, Locus-Specific Databases). Normal gene product. The factor IX gene product (reference sequence NP_000124.1) includes several distinct domains [Bajaj & Thompson 2006]. The first and second domains are a signal peptide and a propeptide (respectively) that are cleaved to yield the mature protein, which is secreted as a single-chain peptide with 415 amino acid residues. Post-translational modifications include glycosylation, sulfation, phosphorylation, β-hydroxylation, and γ-carboxylation. A γ-carboxylase binds to the propeptide before cleavage and, in a vitamin K-dependent step, converts the first 12 glutamic acid residues (near the amino-terminus) to γ-carboxyglutamic residues or Gla. This Gla domain then binds calcium ions and adopts a conformation capable of binding to a phospholipid surface where the clotting cascade occurs. Adjacent to the Gla domain are two domains homologous with epidermal growth factor. The next domains are a connecting sequence that includes the activation peptide, and finally the catalytic domain. The latter is typical of serine proteases. Crystal structures are consistent with other data that show the catalytic domain elevated above a lipid surface. Factor IX is homologous with clotting factors VII and X and protein C. Factor IX is synthesized in hepatocytes and circulates as a zymogen at 90 nmol/L (5 µg/mL). During coagulation in vivo, it is activated by factor VIIa tissue factor in a reaction in which the activation peptide is cleaved. Activated factor IX is the intrinsic factor X activator, requiring its cofactor, activated factor VIII, a lipid surface, and calcium. Sites of interaction of the active enzyme and cofactor are being identified [Bajaj & Thompson 2006]. Factor X activation is a critical early step that can regulate the overall rate of thrombin generation in coagulation.Abnormal gene product. Different genotypes are associated with either absolute or relative lack of factor IX protein. Several missense mutations are associated with dysfunctional protein (see Table A, Locus-Specific Databases).