Hemophilia B is an inherited disease, mainly caused by the deficiency of factor IX. It mostly affects males, but carrier females may show some signs of bleeding. It has an X-linked recessive inherited mode of inheritance, but some acquired form has also been reported due to the development of autoantibodies toward factor IX. This activity highlights the role of the interprofessional team in the evaluation and treatment of hemophilia B.
Describe the etiology of hemophilia B.
Summarize the evaluation of patients with hemophilia B.
Describe the treatment considerations for patients with hemophilia B.
Summarize how to counsel patients with hemophilia B
Hemophilia B, also known as Christmas disease, is the second most common type of hemophilia. The disease was named after Stephen Christmas, who was the first person diagnosed with the condition in 1952. The disorder was ubiquitous in the royal families of Spain, Germany, and Russia. One of the most famous families with this condition was that of Queen Victoria of England; thus, it is known as the "Royal disease." It is a hereditary hemorrhagic disorder resulting from congenital deficit or scarcity of factor IX, which manifests either spontaneously or after traumatic events.
Hemophilia is an inherited condition caused by a deficiency of one of the clotting factors in the blood. It may be due to a defect in the gene for the clotting factor. The genes for factors VIII and factor IX are present in the X chromosome. Hemophilia B is inherited via an X-linked recessive pattern, thus affecting mostly males, where affected males will have 100% carrier daughters while none of their sons would be affected. Female carriers will have a 50% chance of delivering affected sons and a 50% chance of delivering carrier daughters. Females could be affected if they received the mutated alleles from both their parents or through the process of Lyonization, where there is inactivation of the other X chromosome.
Acquired hemophilia B is a rare autoimmune disorder that occurs in patients with no family history of bleeding disorders or hemorrhage due to autoantibodies developing against coagulation factors. Patients with acquired hemophilia usually have pre-existing underlying autoimmune diseases, malignancies, or infections like HIV and hepatitis B or C.
The prevalence of hemophilia B is 1 in 40,000 live males which is about 15% of cases of hemophilia, while that of hemophilia A is 1 in 5,000 live males which is about 85% of cases of hemophilia and 1 in 100,000 live births for hemophilia C which is about 1% of hemophilia cases. It is equal among all ethnic groups. Consanguinity plays a major role in increasing frequencies in specific communities like Egyptian and Ashkenazi Jews.
Any disruption in the continuity of a vessel wall will generate a series of cascades to form a hemostatic plug. Any injury to the vessel will induce vasoconstriction by the release of endothelin and neural stimulation reflex. Exposed collagen will interact with vWF (Von Willbrand factor) released from nearby endothelial cells and the platelets. Platelets will bind to vWF through the GpIb receptors. Fibrinogen attaches the platelets to each other through GpIIb/IIIa receptors, forming an unstable plug eventually.
The formation of fibrin mesh to stabilize the platelet plug will require the activation of two pathways. An intrinsic pathway, which is activated by collagen, basement membrane, activated platelets, and high molecular weight kininogen (HMWK), which includes factor XII, XI, IX, and VIII and an extrinsic pathway which is activated by tissue factor (TF) which includes factor VII. Both will lead to activating the combined pathway, which consists of factor X, V, II, and I, which eventually will lead to a stable fibrin mesh formation.
Factor IX is synthesized by the hepatocytes and considered to be part of the intrinsic pathway, and its deficiency will result in the defective coagulation cascade and insufficient fibrin mesh formation.
History and Physical
Hemophilia B is clinically less severe than hemophilia A. The disease manifestations can be categorized according to the degree of factor IX deficiency in the blood. In mild hemophilia, bleeding will present only after significant trauma or surgery, spontaneous bleeding is uncommon, and typically the diagnosis is made incidentally. In moderate hemophilia, bleeding usually presents after trauma, injury, dental work, or surgery. Recurrent joint bleeding may be present in up to 25% of cases, and the diagnosis usually gets delayed until late childhood or adulthood. While in severe hemophilia, bleeding will present spontaneously and will appear early in life due to a lack of transmission of coagulation factors transplacentally. In the neonatal period, the presentation usually started when the infant starts walking or crawling, or after circumcision or getting IM vaccinations.
The hallmark clinical presentation of hemophilia B is joint involvement (hemarthroses), which typically presents in severe disease. The joints will become swollen, inflamed, painful, warm, with a limited range of movement. Recurrent hemarthrosis eventually causes erosion of joint cartilage and Charcot joints of hemophilic arthropathy. Other presentations of recurrent joint arthropathy are contractures, compartment syndrome, and pseudotumors. The most commonly affected joints are knees, elbows, ankles, shoulders, wrist, and hips.
Patients with severe hemophilia are at risk of developing occult organ bleeding such as in the liver, spleen, bladder, kidneys, and spinal cord. Intracranial hemorrhage represents the most immediately life-threatening manifestation that could present as headache, vomiting, meningism, and lethargy; however, it could be silent and detected through routine imaging. It occurs in 1-4% of cases with the potential for chronic neurological disability. Extracranial bleeds such as subgaleal bleed and cephalohematoma can also be the initial presentation after delivery.
In about two-thirds of cases, there is a family history of hemophilia. Any patient with a known family history of hemophilia and bleeding that is out of proportion after a traumatic injury or abnormal blood levels during routine tests will require a test for coagulation factors defects. Patients with hemophilia B will present with decreased factor IX level.
The patient could also present with prolonged activated partial thromboplastin time (aPTT), which indicated an intrinsic pathway disruption, but a normal aPTT does not exclude hemophilia and a normal Pt (prothrombin time). Complete blood count could show normal or low hemoglobin levels with normal platelet levels. After blood tests suggest hemophilia, then a coagulation factor VIII and IX should be the next step.
Factor IX is present in plasma in a concentration of 4-5 µg/mL. Thus the disease is categorized according to the scarcity of factor IX. Mild hemophilia: If 5% to 50% of factor IX is present. Moderate hemophilia: If only 1% to 5% of the factor IX activity of normal is present. And severe hemophilia: if less than 1% of factor IX is present. Molecular genotyping should then be offered to confirm the diagnosis. In patients with an established diagnosis of hemophilia B, periodic laboratory evaluation include screening for the presence of FIX antibodies and testing for transfusion-related infections such as hepatitis and HIV.
Treatment / Management
Management of acute bleeding of hemophilia B patients:
Replacement of factor IX remains the mainstay of treatment for hemophilia B patients. The dose is calculated according to the desired percentage of the factor with a goal of 30% in patients with mild hemorrhages, 50% in patients with severe bleed after trauma or prophylaxis of major dental surgery or major surgery, and 80% to 100% in patients with life-threatening conditions. It is calculated with this formula : Initial dose = body weight (kg) x desired factor IX increase (% or IU/dL) x reciprocal of observed recovery (IU/dL per IU/kg). It there is no available factor IX then prothrombin complex concentrate can be given at a dose of IU/kg.
Monoclonal antibodies (e.g., rituximab), tranexamic acid, and epsilon aminocaproic acid are anti-fibrinolytic agents that could be used in cases of mucosal bleeds and dental extractions in patients with hemophilia.
Future treatment considerations:
The novel treatments like genetic therapy, through introducing exogenous DNA into a person's cells that can be used to produce a missing protein. Also, cellular therapy, through injecting intact cells into the patient rather than the manipulation of coagulation factor genes have been under testing, and monoclonal antibodies like concizumab which is an antibody directed against the tissue factor pathway inhibitor (TFPI), which inhibits the coagulation cascade by blocking the function of factor Xa. Blocking the inhibitor allows the generation of factor Xa and, in turn, thrombin, even in the absence of factors VIII and IX.
The main goal of factor IX prophylaxis therapy is to improve the quality of life through reducing hemarthrosis episodes, its development into hemophilic arthropathy, and the need for surgeries and minimizing the episodes of cerebral and muscle bleeds. The goal of dosing has been to maintain factor IX level above 1 to 2 percent, mainly converting the patient from a severe to a moderate hemophilia phenotype. Factor IX dosing, either 25 to 40 units/kg of body weight, given two times per week (Malmo protocol) or 15 to 30 units/kg two times per week (Utrecht protocol). Longer lasting products allow for once per week or once every two-week dosing.
A significant complication in patients getting a replacement of factor IX is the development of antibodies (IgG) that block the activity of the replaced factor. These inhibitory antibodies develop in response to exogenous factors. They occur in approximately 3 to 5 percent with severe hemophilia B. Inhibitors are much less common in patients with mild or moderate disease, mainly because the infused factor does not get recognized as foreign protein in these individuals. Inhibitors complicate bleeding episodes because they decrease responsiveness to factor infusions. The presence of inhibitors should be suspected if bleeding does not stop after clotting factors replacement in a previously responsive patient. Also, anaphylactic reactions can occur with factor IX inhibitors.
These inhibitors are managed by:
Recombinant activated FVIIa administration: these contain an activated form of a downstream clotting factor in the coagulation cascade.
Plasmapheresis: it may be useful in patients with a high titer inhibitor to acutely lower the inhibitor titer and allow transient use of replacement factor. That intervention is reserved for an individual with life-threatening or limb-threatening bleeding.
High-dose factor infusion: A final option for an individual with bleeding, and an inhibitor is to provide high-dose factor infusion.
Many diseases that present similarly with bleeding episodes should be excluded and put into consideration. These include:
Other coagulation factor defects: Hemophilia A (factor VIII) and hemophilia C (factor XI) are differentiated through coagulation factor assay study and genetic testing, while hemophilia A and B are X-linked recessive. Hemophilia C is an autosomal recessive inheritance.
Von Willebrand factor deficiency: This is the most common internal bleeding deficiency, with a defect in platelet plug formation. The patient has an increase in bleeding time, normal/increase PTT, and normal platelets. It has an autosomal dominant inheritance.
Platelet dysfunctions (quantitative or qualitative): bleeding is usually mucocutaneous, unlike hemophilia. Usually, these disorders are diagnosed by platelet aggregation studies or platelet electron microscopy. Typically there is increase bleeding time and a decrease in platelet count. E.g., immune thrombocytopenia, thrombotic thrombocytopenia, hemolytic uremic syndrome.
Disseminated intravascular coagulation: usually, there is a precipitating event (sepsis, trauma, obstetric complications, acute pancreatitis, acute promylogenous leukemia, and transfusion). Diagnosis is usually carried out by blood tests that show decreased platelet count, increase PT and PTT, increase fibrin degradation (D-dimer), and decreased fibrinogen levels.
Vitamin K deficiency occurs in neonates and patients with prolonged antibiotic use. It presents with increased PT and PTT, decreased factor II, VII, IX, X, protein C, and S, with normal platelet counts.
Scurvy: There is a deficiency of vitamin C. It presents with swollen gums, perifollicular and subperiosteal hemorrhage, hemarthrosis, and poor wound healing.
Ehlers-Danlos syndrome: occurs due to defect in collagen synthesis, and mainly presents with mucosal bleeding with hyperextensible skin and hypermobile joints.
Fabry disease: Patients may have angiokeratomas with other organs being affected, including kidneys and heart.
Child abuse: It can sometimes be misidentified and confused with hemophilia. It needs a high index of suspicion, and it is essential to find the inconsistencies in the history of how trauma has occurred. Other signs of abuse include different stages of wound healing, malnourishment, subdural hematoma, retinal hemorrhage, and signs of sexual abuse like STIs and UTIs.
The life expectancy for patients with hemophilia was 11 to 13 years until 1970 through the introduction of the first coagulation factors. Before that, the patients used to receive whole blood or fresh frozen plasma. Until 1964 a noble prize winner, American physician Judith Graham Pool extracted cryoprecipitate from the plasma, which contained higher amounts of coagulation factors and made a significant improvement in the patients with this condition. In 1970, the first coagulation factor could be extracted from the plasma, which made a significant improvement in the quality of life and the prognosis of the patients.
By the beginning of 1980, patients receiving factors replacements started getting infected with HIV and hepatitis C, which reached 80% to 85% of the patients till 1992 with the development of new screening techniques, and this improved the safety of plasma-derived products and their transmission to these patients.
Nowadays, patients have a regular life span in developed countries after an early replacement of factor deficiency with prophylaxis started earlier by age 1 to 2 years in cases of severe hemophilia. While in developing countries, the mortality rate for patients with hemophilia remains twice that of the average healthy male population due to inadequate health systems and diminished health resources.
The most common complication of hemophilia is due to bleeding episodes. Recurrent hemarthrosis, which leads to synovial membrane inflammation and hypertrophy, eventually leads to destructive arthropathy. Other complications include intracranial hemorrhages after minor trauma, hypovolemic shock events due to iliopsoas muscle bleeding, and airway compromise due to retropharyngeal bleedings.
Patients treated with factors in the late 1970s and early 1980s were known to have a high risk for infection with HIV, HCV, which reached 80% to 85%. But after 1992, and due to the combination of effective blood screening with viral inactivation protocols, the risk of infection was extremely low.
Psychosocial impairments, depression, and functional impairments in patients with hemophilia have been reported to have a higher incidence than normal healthy individuals. In children, maturational delays were reported.
Deterrence and Patient Education
Patient education about the nature of the disease plays a vital role in improving the prognosis of patients, reducing morbidity and mortality, and improving their lifestyles. Ideally, early detection, follow up, and adequate treatment helps decrease the burden of the disease on the patients and their families. Hemophilia patients should use cold packs, immobilization, splinting, acetaminophen, and codeine for pain. It is necessary to prevent the use of anticoagulants, aspirin, and NSAIDs to avoid complications.
For children undergoing vaccination, special precautions should be taken by using 23 gauge needle and applying ice packs for five minutes with a factor replacement to be given soon after the procedure. Appropriate dental care should be encouraged for all children with at least two times per day dental cleaning with flossing, and physical activity is a recommendation in all children with hemophilia.
There is no data that shows a preference of either cesarean or vaginal delivery in a pregnant woman with a child diagnosed with hemophilia in utero. But the use of operative vaginal delivery (use of forceps, vacuum extraction) should be avoided due to increased risk of intracranial bleeding and cephalohematoma. Circumcision should be deferred until the diagnosis is confirmed or excluded.
Enhancing Healthcare Team Outcomes
Improvement in the quality of life and life expectancy remains the main goal in patients with hemophilia. Designated hemophilia treatment centers (HTCs) have been established in many parts of the world. These centers should include a multidisciplinary team of doctors (pain specialists, geneticists, hematologists, immunologists, etc.), nurses, musculoskeletal experts, laboratory specialists, pharmacists, and psychology experts. Education should be provided to the patients to monitor their symptoms and seek treatment as soon as possible. Pharmacists should examine the patient's medication profile frequently and to avoid any drugs that could precipitate any bleeding events.
Home therapies should be established promptly after diagnoses and as soon as families have the required education and training. The patient and family should be comfortable with hemophilia management since it provides the most immediate access to early treatment and decreases overall pain, dysfunction, disability, and hospital admission.
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