Case 360°™: Appropriate Management of Patients With Hemophilia B


Hemophilia, a bleeding disorder, occurs in approximately 1 of every 5000 live births and the estimated prevalence in the United States is 20,000.[1] Globally, the estimated prevalence is believed to be >400,000, and three-quarters of those patients do not receive adequate care.[2]

Hemophilia A, also referred to as classic hemophilia or factor VIII deficiency, is a genetic disorder caused by a missing or defective clotting protein called factor VIII (FVIII).[1] Hemophilia B results from a missing or defective factor IX (FIX) protein. [NHF Hem B] Hemophilia B, the focus of this 360°™ case study, is referred to as Christmas disease or factor IX (FIX) deficiency.[3] It is 75% less prevalent than hemophilia A, with an occurrence of approximately 1 in 25,000 male births.[3,4] The prevalence of hemophilia B does not appear to be related to a specific country or race.[5]


Hemophilia treatment centers (HTC) provide multidisciplinary care to patients with hemophilia. Their integration with the Health Resources and Services Administration (HRSA) and the US Centers for Disease Control and Prevention (CDC) allows for the collection of aggregate data to assess the hemophilia population and service characteristics. In a report capturing data from 1990 through 2010, the HTC population grew 90% from 17,177 to 36,612. Specifically, the number of patients with factor IX deficiency increased by 66% from 2531 to 4209. In 2002, records began tracking diagnosis by gender, which allowed for a more accurate data collection regarding women affected by bleeding disorders. In 2010, women accounted for 31% of the HTC population, up 13% from in 1990. The percentage of females with hemophilia (A and B) remained steady at 7%, while their absolute numbers grew by 62% to 1165.[6]

Figure 1. Hemophilia A and B Patients (1990–2010)

Source: Baker JR, Riske B, Drake JH, et al. US hemophilia treatment center population trends 1990–2010: patient diagnoses, demographics, health services utilization. Haemophilia. 2013;19:21-26. Adapted with permission.

Figure 2. Hemophilia Patients by Gender (2002–2010)

Source: Baker JR, Riske B, Drake JH, et al. US hemophilia treatment center population trends 1990–2010: patient diagnoses, demographics, health services utilization. Haemophilia. 2013;19:21-26. Adapted with permission.


In patients with hemophilia, the severity of bleeding is dependent upon the levels of factor in the blood and is characterized based on the clotting activity that results in prolonged bleeding after injuries, tooth extractions, surgery, and delayed/recurrent bleeding during the wound healing process.[5] The diagnosis and frequency of bleeding episodes is related to the level of clotting activity, as shown in Table 1 below.

Table 1. Clinical Characteristics of Hemophilia B[4,5,7]

aAs patients with hemophilia B age, bleeding episodes may become more infrequent compared to early childhood and adolescence.

Children with severe hemophilia B are often diagnosed soon after birth or, frequently, within the first year of life. Head bumps and mouth injuries are common and often are presenting symptoms in younger children with hemophilia B. Presenting children often have subcutaneous hematomas and have an increased likelihood of spontaneous joint bleeds or deep-muscle hematomas. As joint bleeding is the most common site of spontaneous bleeding, children may have pain and begin limping before signs of swelling appear.[5]

Additional bleeding sites known to occur in patients with hemophilia B include the muscles, kidneys, gastrointestinal tract, brain, and nose.[5] If left untreated, long-term damage may result including inflammation of the synovium, muscle weakness/swelling, tightness, and restricted movement in the affected joint.[4] A major cause of disability in patients with hemophilia is chronic joint disease that results from excessive bleeding into joints.[8] Intracranial hemorrhage, the leading cause of death related to bleeding, may manifest with symptoms such as headache, stiff neck, vomiting, seizures, or mental status changes.[4,5]

Figure 3. The Effects of Hemophilia on Different Parts of the Body


Hemophilia B results from a mutation of the Factor 9 (F9) gene, which is mapped at chromosome Xq27.1, mainly expressed by hepatocytes. More than 1000 mutations causing hemophilia B have been identified globally, and >70% of the mutations are point mutations. Approximately 16% are deletions, while the remaining are insertions, duplications, and combinations of deletions and insertions. Severe hemophilia B disease is most often a result of large deletions, nonsense variants, and frameshift variants in the F9 gene, while missense mutations are associated with mild, moderate, and some cases of severe hemophilia B.[9]

A study reviewing molecular genotyping from male hemophilia B individuals was conducted in 17 US HTCs to determine the mutations that account for hemophilia B. Individuals were enrolled in the federally funded Hemophilia Inhibitor Research Study to gain insight into mutation identification, frequency, and risk for inhibitor development.[9] Based on samples gathered between 2006 and 2012, 87 unique mutations in the F9 gene were identified in 225 (99.6%) of the 226 patients, as shown in Table 2.

Table 2. Frequencies of Mutation Type and Inhibitors in US Hemophilia B Patients

Source: Li T, Miller CH, Driggers J, Payne AB, Ellingsen D, Hooper WC. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol. 2014;89:375-379. Adapted with permission.

Table 3. Associations Between Severity and Mutation Type

Source: Li T, Miller CH, Driggers J, Payne AB, Ellingsen D, Hooper WC. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol. 2014;89:375-379. Adapted with permission.


Genetic mutations as a predictor of clinical severity
The clinical severity of hemophilia appears to have at least some correlation with the type of genetic mutation. For example, the severity of hemophilia B correlates with the type of mutation, and missense mutations often led to different severities of hemophilia B.[9] Bleeding severity varies among clinical phenotypes in patients with hemophilia who have identical mutations in the FIX gene. Mild bleeding tendencies have even been reported in patients with severe hemophilia. Santagostino, et al reported on a study that evaluated the roles of genetic mutations, thrombophilic polymorphisms, and thrombin generated in platelet-rich and platelet-poor plasma to determine if these variables could be used as determinants in the clinical phenotype of patients with severe hemophilia. The results (see Table 4) showed that patients with hemophilia B who had non-null mutations (defined as the ability to synthesize some protein, as opposed to null mutations, which prevent the synthesis of any protein), detectable factor IX antigen levels, and higher levels of endogenous thrombin potential in platelet-rich plasma were more likely to demonstrate a mild clinical phenotype, as expected. The study went on to report that only non-null mutations were confirmed as an independent predictor of clinical severity.[10]

Table 4. Factors Associated with a Mild Clinical Phenotype of Severe Hemophilia

Source: Santagostino E, Mancuso ME, Tripodi A, et al. Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile. J Thromb Haemost. 2010;8:737-743. Adapted with permission.

Development of a composite score

In an effort to provide a more comprehensive measurement of clinical severity for patients with hemophilia, a composite score was developed and validated in patients with both hemophilia A and B. During the validation study, the Hemophilia Severity Score (HSS) was lower in patients with severe hemophilia B than in those with hemophilia A (P =.031) indicating a less severe bleeding phenotype in severe hemophilia B patients overall. This difference was variably demonstrated in the bleed score (not statistically significant), joint score (not statistically significant), and factor score (P =.040). In patients with mild hemophilia, those with hemophilia B had a higher HSS (P =.027) with a statistically significant difference in the bleeding score (P =.006). [Schulman 2008] These findings validate the HSS as providing a comprehensive representation of the clinical severity of hemophilia in adult patients.[11]

Table 5. The Hemophilia Severity Score (HSS) in Hemophilia Subtypes

Source: Schulman S, Eelde A, Homstrom M, Stahlberg G, Odeberg J, Blombacks M. Validation of a composite score for clinical severity of hemophilia. J Thromb Haemost. 2008;6:1113-1121. Adapted with permission.

Rate of joint arthroplasty
A main complication of hemophilia A and B is the development of chronic arthropathy. Joint arthroplasty has been a mainstay of treatment for patients with hemophilia to improve quality of life and relieve severe joint pain associated with the disease. As more research begins to surface regarding the clinical severity of hemophilia A and B, a retrospective analysis and systematic review of the literature was conducted that actively reviewed the number, scope, and outcomes of patients with hemophilia who underwent arthroscopic surgery. By performing retrospective analyses and then comparing the results to a systematic search of the literature, the authors were able to account for the uneven distribution of patients with hemophilia A and B and provide a more definitive analysis. The authors included arthroplasties of the knee, hip, ankle, and elbow. Based on data provided by Italian HTCs, the rate of arthroplasty in the entire population of Italians with hemophilia was calculated using data from the Italian National Registry: 253 of 1770 patients with severe hemophilia A (14.3%; 95% CI: 12.7%, 15.9%) and 15 of 319 patients with severe hemophilia B (4.7%; 95% CI: 2.4%, 7.0%) underwent arthroplasty. The risk of undergoing arthroplasty was expressed as an overall risk (OR) of 3.38 (95% CI: 1.97, 5.77; P <.001). This analysis provides evidence that patients with hemophilia A are 3 times more likely to require arthroplasty than those with hemophilia B, thus indicating a more severe bleeding phenotype in hemophilia A.[12]

Incidence of bleeding episodes
An institutional retrospective chart review of patients with severe hemophilia A and B yielded interesting results in terms of bleed frequency. When comparing the average number of bleeds per year, hemophilia A patients had 14.4 bleeds per year vs 8.63 for patients with hemophilia B, a 40% difference, suggesting that patients with hemophilia B are less likely to experience bleeds. Additionally, 14.7% of patients with hemophilia A underwent surgical procedures for musculoskeletal complications compared to 4.7% of patients with hemophilia B, representing a 3.2-fold higher incidence in hemophilia A patients. These data corroborate the increased need for arthroplasty procedures in patients with hemophilia A. However, no statistical difference was noted in the amount of factor replacement used.[13]

Another study reviewing on-demand vs prophylactic therapy in patients with severe hemophilia A and B also noted that patients with severe hemophilia B had fewer bleeding episodes compared to their severe hemophilia A counterparts. In this review, patients with severe hemophilia A had a yearly bleed rate of 10.8 bleeding episodes a year vs 8.4 bleeding episodes per year for those with severe hemophilia B. As shown in Table 6, adolescents aged 13 to 17 years and young adults aged 18 to 24 had the most bleeding episodes of the age ranges studied.[14]

Figure 4. Incidence of Bleeding Episodes Across Patient Age Groups

Source: Zappa S, McDaniel M, Marandola J, Allen G. Treatment trends for haemophilia A and haemophilia B in the United States: results from the 2010 practice patterns survey. Haemophilia. 2012;18:e140-e153. Adapted with permission.

Is there any utility in genotyping previously untreated patients with severe hemophilia B? And if so, when is the appropriate time?

Chirs Guelcher


Quality of life in patients with hemophilia has only recently been documented in the literature[15–20] as has the psychological health of parents coping with children suffering from hemophilia.[21,22] A recent review of the literature examined data from questionnaire studies, qualitative studies, medical examinations, retrospective case reviews, and surveillance programs to explore social and psychosocial outcomes in patients with hemophilia. Among the issues commonly identified were stress; family relationships and parenting competence; stigma/discrimination/disclosure; self-esteem and psychological/emotional well-being; concerns about carrier testing and reproductive choices; and education, lifestyle, and career choices. The availability of psychological support is essential to help patients with hemophilia and their caregivers, because it offers information assistance, clarifies doubts, and teaches coping strategies to help minimize the impact of the disease and its related disabilities.[15]

At all ages, patients with hemophilia must manage differing aspects of the disease. For example, adult patients need to deal with frequent spontaneous and trauma-related bleeding, while elderly patients may face the consequences of years of suboptimal treatment and the resulting joint damage.[18] Parents of children with hemophilia are confronted with more diverse issues such as the immediate response to emergencies, financial concerns, social restrictions, conversations with family members, emotional issues, and possible feelings of abandonment in other siblings or relatives.[21] Each of these populations has different coping strategies.

In a study conducted from 2003 to 2005, patients with severe hemophilia (A and B) aged 18 to 68 years were invited to complete a Coping Inventory for Stressful Situations (CISS-21) questionnaire during their routine checkup. This questionnaire identifies coping methods and delineates them into 3 main categories; task-oriented coping, emotion-oriented coping, and avoidance coping. Problem-focused coping is generally considered to be the most effective approach to dealing with chronic diseases, even though emotion-focused coping may be a more effective method to deal with acute, stressful situations. Avoidance coping, characterized by the effort to avoid or deny an illness, may negatively impact health outcomes and diminish quality of life.[18]

As the coping strategies of patients with hemophilia had not yet been examined, this study was undertaken to explore coping strategies that would allow for more focused and positive, outcome-oriented responses to hemophilia situations. A total of 86 patients with severe hemophilia (15% with hemophilia B) were analyzed and compared to a control group of Dutch working men. Findings demonstrated that patients with severe hemophilia were more likely to use emotion-oriented and avoidance coping, compared to controls. (see Figure 3). The high use of emotional-oriented coping was strongly correlated with poor psychological health (r=0.67) while good psychological health was correlated with low use of emotional-oriented coping. High use of emotional-oriented coping also demonstrated a weak correlation with low participation (r=0.32) and lack of social interaction (r=0.29).[18]

Figure 5. Coping Strategies in Patients With Hemophilia

Source: Binnema M, Schrijvers LH, Bos R, Schuurmans MJ, Fischer K. Coping in adult patients with severe haemophilia. Haemophilia. 2014;20:513-518. Adapted with permission.

Can you describe a negative psychosocial effect you have seen in one of your patients with hemophilia B? What you did to remedy the situation?

Michelle Witkop


The incorporation of prophylactic therapy is the first choice for treatment recommended by both the World Health Organization (WHO) and the World Federation of Hemophilia (WFH) in resource-rich countries. Prophylaxis is effective in minimizing joint bleeds at an early age and prevents and reduces muscle-skeletal impairment (ie, arthropathy). However, factor prophylaxis is a very broad term and can reflect a wide spectrum of clinical conditions and objectives of treatment in patients with hemophilia. Prophylactic therapy can be used to reduce the frequency of bleeds and to prevent severe or life-threatening hemorrhagic events. The focus of primary prophylaxis is the avoidance of any joint abnormality (or significant delay of serious arthropathy) while the objective of secondary prophylaxis is to avoid or delay the progression of arthropathy. It should be noted that earlier treatment results in in better outcomes and improved quality of life. [23]

Figure 6. Primary and Secondary Prophylaxis for Patients With Hemophilia

Source: Coppola A, DiCapua M, DeSimone C. Primary prophylaxis in children with haemophilia. Primary prophylaxis in haemophilia. Blood Transfus. 2008;6(Suppl 2):s4-s11. Adapted with permission.

Special Considerations for the Treatment of Children

Prophylactic regimens for children with hemophilia may vary in terms of amount and frequency. Clinicians must consider issues such as cost, access, effectiveness, resources, and individualization of therapy to achieve optimal treatment outcomes in children.[23]


Factor Trough Levels

One concept that has been gaining traction in the literature is the optimal factor trough level. This concept focuses on the need to maintain factor activity above a trough baseline of 1% to minimize the frequency of bleeds. In other words, an increased amount of time below the trough level is associated with an increased rate of breakthrough bleeding, whereas maintaining levels above the trough would decrease or minimize bleeding episodes. Recent models suggest that a more appropriate baseline for factor should be at a higher target trough of 15% to eliminate all spontaneous joint bleeds, but no hard evidence is available at this time.[24] 

Baseline trough percentages vary between individual patients due to limitations such as resources, access, and other factors. There are 4 primary strategies for increasing the trough level: 1) daily prophylactic dosing, 2) increased dosing, 3) pharmacokinetic-tailored prophylactic dosing, and 4) use of new molecules with an extended half-life.[24] Unfortunately, limited data are available on pharmacokinetics in patients with hemophilia B.

Figure 7. Optimal Trough Levels

Source: Jimenez-Yuste V, Auerswald G, Benson G, et al. Achieving and maintaining an optimal trough level for prophylaxis in haemophilia: the past, the present and the future. Blood Transfus. 2014;12:314-319.
Adapted with permission.