Hemophilia B (Factor IX Deficiency) Treatment & Management

The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilic synovitis.

Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have better access to care, less morbidity, and better overall outcome.

Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability.

Dose calculations are directed toward achieving a factor IX (FIX) activity level of 30% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or for prophylaxis of major dental surgery or major surgery, and 80-100% in life-threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work.

Patients may be treated with prophylaxis or with intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints. ^{[21, 22]} According to a review of six randomized controlled trials, preventive therapy started early in childhood, as compared with on-demand treatment, can reduce total bleeds and bleeding into joints, thus decreasing overall joint deterioration and improving patients' quality of life. ^[23]

In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity. ^[24]  In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has been established to prevent worsening of the joint) is instituted for a defined period. ^{[25, 26]}

Dosing is designed to maintain trough levels greater than 2%. With the development of FIX preparations that have extended half-lives, dosing for routine prophylaxis may be as infrequent as every 10 days.

In the future, oral administration of FIX for prophylaxis may become possible, through the use of hydrogel carriers that protect FIX from destruction in the stomach and release it in the intestines. ^[16] Gene therapy offers the potential for a definitive cure, and has now entered clinical practice, with US Food and Drug Administration (FDA) approval of the first product in November 2022. ^[27]

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Prehospital providers should address the emergency ABCs (airway, breathing, circulation) while rapidly transporting the patient to a definitive care facility. In the prehospital setting, providers should do the following:

• Apply aggressive hemostatic techniques
• Assist patients capable of self-administered factor therapy
• Gather focused historical data if the patient is unable to communicate

Before a patient with hemophilia is treated, the following information should be obtained:

• The type and severity of factor deficiency
• The nature of the hemorrhage or the planned procedure
• The patient's previous treatments with blood products
• Whether inhibitors are present and if so, their probable titer

Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.

If admission is indicated, disposition (intensive care unit versus floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose the attending service based on hemorrhage site and etiology. Hematology/ blood bank/pathology consultation is mandatory.

Further outpatient care for patients with minor hemorrhage (not life-threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandaging). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring.

If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the patient's CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections.

Various FIX concentrates are available to treat hemophilia B. Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload. Cryoprecipitate contains no FIX and is not appropriate for hemophilia ​B therapy.

Various purification techniques are used in plasma-based FIX concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a potential problem.

Recombinant FIX products (eg, BeneFIX, Rixubis, Alprolix, Ixinity) are commercially available and have a lower risk of viral contamination. All the products are approved by the FDA for control and prevention of bleeding episodes, and for perioperative management in adults and children. Rixubis, Ixinity, and Alprolix are also approved for routine prophylaxis in adults and children.

Idelvion, a long-acting recombinant FIX albumin fusion protein (rIX-FP, albutrepenonacog alfa) was approved in 2016 for on-demand control and prevention of bleeding episodes, management of postoperative bleeding, and as prophylaxis to reduce the frequency of bleeding episodes. Approval was based on open-label trials in children and adults (n=90) with FIX activity < 2%. Mean trough levels of FIX activity were 20 IU/dL on prophylaxis with rIX-FP 40 IU/kg weekly and 12 IU/dL FIX on prophylaxis with 75 IU/kg every 2 weeks. The switch from on-demand treatment to prophylaxis with rIX-FP resulted in a 100% reduction in the median annualized spontaneous bleeding rate and 100% resolution of target joints (P < 0.0001). ^[28]

Rixubis approval for adults was based on a study demonstrating that twice-weekly prophylactic treatment for 6 months achieved a median annualized bleed rate of 2.0 with 43% of patients experiencing no bleeds. ^{[29, 30]}

Rebinyn (nonacog beta pegol) is a recombinant glycopegylated FIX with an extended half-life. Pegylation slows removal of FIX from the blood circulation. Rebinyn was approved by the FDA in 2017 for control and prevention of bleeding episodes and for perioperative management in adults and children. ^[31]

Doses of FIX concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FIX 1 U/kg increases FIX plasma levels by 1%. The reaction half-time is 16 hours.

Target levels by hemorrhage severity are as follows:

• Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain a FIX level of 30%

• Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain a FIX level of 50%

• Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain a FIX level of 80-90%. Plasma levels are maintained above 40-50% for a minimum of 7-10 days

Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia B (Open Table in a new window)

Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels. Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.

Musculoskeletal bleeding

The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.

Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.

Early infusion upon the recognition of pain may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.

Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply.

Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. Administer adequate replacement therapy for at least 3 days.

Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely replacement therapy is important to prevent such disabilities.

Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension.

Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.

Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These occur in the upper arm, forearm, wrist, and palm of the hand. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FIX.

Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.

Oral bleeding

Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva.

Combine adequate replacement therapy with an antifibrinolytic agent (e-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity.

Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used. ^[32]

Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.

Administer prophylactic factor infusion therapy before an oral surgical procedure to prevent the need for further treatment.

Gastrointestinal bleeding

GI bleeds are unusual compared with those associated with von Willebrand disease and, therefore, require an evaluation for an underlying cause. Depending on their location, they may be confused with acute abdomen or appendicitis. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FIX.

Intracranial bleeding

Intracranial hemorrhage is often trauma induced; in the pediatric population, spontaneous intracranial hemorrhages are more common than those related to trauma. If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established. Late-onset bleeding has been reported at up to 4 weeks.

All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI. If the patient is not hospitalized, instruct the patient and family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion.

Inhibitors are antibodies that neutralize FIX and can render replacement therapy ineffective. FIX inhibitors are less common than FVIII inhibitors; they occur found in only 1-3% of patients with severe hemophilia B. These inhibitors typically appear after the first infusions of FIX concentrate. Patients with FIX inhibitors can have anaphylactic reactions to FIX infusions, and may develop steroid-resistant nephrotic syndrome due to immune complex formation; this typically occurs in individuals with complete gene deletions.

The relatively low frequency of FIX inhibitors has lead to a dearth of experience in its treatment. Early hematology consultation for these patients is essential.

Low-titer inhibitors and, occasionally, high-titer inhibitors can be overcome with high doses of FIX concentrate. Recombinant human coagulation factor VIIa (rFVIIa) is indicated for the treatment of patients with bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in patients with inhibitors to FIX. ^[33]

Activated prothrombin complex concentrate (PCC) has shown promise, although it may trigger disseminated intravascular coagulopathy (DIC) at doses greater than 200 IU/kg/d. Desensitization and immune-tolerance strategies in those with identified inhibitors have been successful as well.

Recombinant activated FVIIa

Recombinant activated FVIIa (rFVIIa) is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa. ^[34] It is manufactured by using DNA biotechnology. Intravenous recombinant FVIIa has also been studied for treating bleeding episodes and for providing hemostasis during surgery in patients with particular bleeding diathesis.

Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia.

To date, recombinant activated FVIIa has proven to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product has precluded its use as prophylaxis in patients with FIX inhibitors. In addition, when recombinant activated FVIIa has been used for this indication, select patients have had severe complications related to bleeding.

In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of patients subjectively classified as responders. Clinical context and pH values before administration were independently associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients. ^[35]

Desensitization

Desensitization in nonemergency situations also may be feasible. This therapy includes large doses of FIX along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening bleeding, methods to quickly remove the inhibiting antibody have been tried, such as vigorous plasmapheresis in conjunction with immunosuppression and infusion of FIX with or without antifibrinolytic therapy.

Immune tolerance induction

In immune tolerance induction (ITI), patients are rendered tolerant to FIX by means of daily exposure to FIX over several months to years. ^[36] The overall likelihood of success with ITI is 70% ± 10%. In patients with high-titer FIX inhibitors, ITI is less successful than it is in patients with FVIII inhibitors.

First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FIX and with or without immunosuppressive therapy. This technique is well established in acquired hemophilia but not in congenital hemophilia.

Rituximab, a chimeric human-mouse monoclonal antibody against CD20, has been used with success in patients with hemophilia B and high titer inhibitors. ^[37] Reports describe durable complete responses with brief courses of rituximab and prednisone with or without cyclophosphamide in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU. ^[38] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia. ^{[39, 40]}

In several small trials, a 4-week course of weekly rituximab has resulted in durable and complete responses. The addition of prednisone with or without cyclophosphamide has increased response rates.

An international immune tolerance study was started in 2002 to compare the efficiency, morbidity, and cost-effectiveness of low- versus high-dose ITI. For information, please see the study Web site Immune Tolerance Induction Study.

Concizumab

Concizumab is a subcutaneously administered monoclonal IgG4 antibody that promotes thrombin generation by binding to tissue factor pathway inhibitor (TFPI); TFPI is the primary inhibitor of the initiation of coagulation. In phase II trials, concizumab has demonstrated benefit for prophylaxis in patients with hemophilia B with inhibitors. ^{[41, 42]} Phase III trials of concizumab were paused after the occurrence of thromboembolic events in 3 patients, but the trials have since been restarted with risk mitigation in place. ^[42] The European Commission has granted orphan drug designation to concizumab for the treatment of hemophilia B. ^[43] The US Food and Drug Administration granted concizumab Breakthrough Therapy designation for treatment of patients with hemophilia B with inhibitors. ^[44]

Most of the care for children with severe forms of hemophilia now takes place at home, in the community, and at school, allowing children with hemophilia to participate in normal activities that are otherwise impossible. This resulted from the development of prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent.

The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilic arthropathy that results from recurrent or target joint bleeding can be prevented by this method.

Prophylaxis is not universally accepted, with only about one third of children with hemophilia B receiving this treatment modality in the United States. Reasons cited for the lack of acceptance of this modality include need for venous access, factor availability, repeated venipunctures, cost, and others.

Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule. Tools have now been developed to assess long-treatment effects.

The long-acting recombinant FIX albumin fusion protein (Idelvion) was approved in 2016 for prophylaxis to reduce the frequency of bleeding episodes. Adults who respond to once-weekly prophylaxis may be switched to a slightly higher dose administered every 2 weeks. Clinical trial results demonstrated a 100% reduction in the median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < 0.0001). ^[28]

In 2013, the FDA approved the first recombinant coagulation factor IX (Rixubis) specifically indicated for the routine prevention of bleeding in patients with hemophilia B in children and adults. ^{[45, 46]} In addition to routine prophylaxis (prevention or reduction in frequency of bleeding episodes), Rixubis is indicated for the control of bleeding episodes and perioperative management in these patients. This purified protein is supplied in single-use vials of freeze-dried powder, and it is injected intravenously after reconstitution with sterile water. For routine prophylaxis, Rixubis is administered twice a week. ^{[45, 46]}

Approval of Rixubis was based on a multicenter study of 73 males (age range, 12-65 years) who received the drug for routine prophylaxis or as needed for hemostasis. Patients taking this agent prophylactically had a 75% lower annual rate of bleeding relative to those who had received on-demand therapy. ^{[45, 46]} The most common side effects associated with Rixubis in clinical studies included distorted taste, pain in an extremity, and atypical blood test results. Life-threatening anaphylaxis occurred less commonly. ^{[45, 46]}

In 2014, Rixubis was approved for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative management in children with hemophilia B. Approval was based on the results of a clinical trial in 23 previously-treated male patients aged < 12 years with severe or moderately severe hemophilia B. The tiral used a twice-weekly prophylaxis regimen (mean dose 56 IU/kg; mean treatment duration 6 months, mean of 54 exposure days). The median annualized bleeding rate was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients in the study (39.1%) experienced no bleeds and 23 bleeding episodes (88.5%) were treated with 1-2 infusions. There were no reports of inhibitor development, no severe allergic reactions, and no thrombotic or treatment-related adverse events among the study participants. ^[30]

The long-acting recombinant Fc fusion factor IX (rFIXFc), Alprolix, was approved by the FDA in 2014 for patients with hemophilia B. It is the first treatment designed to require less frequent injections for routine prophylaxis. The safety and efficacy were evaluated in a multicenter clinical trial that compared each of 2 prophylactic treatment regimens with on-demand treatment. A total of 123 individuals with severe hemophilia B, aged 12-71 years, were followed for up to 18 months. The studies demonstrated effectiveness in preventing and treating bleeding episodes and during perioperative management of patients undergoing surgical procedures. ^{[47, 48]}

Another long-acting recombinant, Ixinity, gained approval for routine prophylaxis for patients aged 12 years and older in 2020, in addition to its previous indications for on-demand usage and perioperative management. 

In 2013, the FDA expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors. The approval was based on data from a pivotal Phase III study in which treatment with a prophylactic regimen showed a 72% reduction in median annual bleed rate (ABR) compared to treatment with an on-demand regimen. ^[49] An earlier study showed a 62% reduction in all bleeding episodes with anti-inhibitor coagulant complex prophylaxis compared with an on-demand regimen. ^[50]

Assessing adherence to prophylaxis

The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries). ^[51]

Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be extremely painful. This requires immediate analgesic relief.

Hemophilic chronic arthropathy is associated with pain. Narcotic agents have been used, but frequent use of these drugs may result in addiction. Nonsteroidal anti-inflammatory drugs may be used instead because their effects on platelet function are reversible and because these drugs can be effective in managing acute and chronic arthritic pain. Avoid aspirin because of its irreversible effect on platelet function.

Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.

Appropriate preoperative evaluation includes an activated partial thromboplastin time (aPTT) mixing test after incubation for 1-2 hours at 37°C with pooled normal plasma to exclude an inhibitor, followed by administration of an appropriate preoperative dose of concentrate, followed by appropriate postoperative treatment.

A review by Hazendonk et al of perioperative management in hemophilia B recommends the following perioperative target ranges for FIX ^[52] :

• Day 1  (0-24 hours) -  0.80-1.00 IU/mL ⁻¹
• Days 2-5 (24-120 hours) - 0.50-0.80 IU/mL ⁻¹
• Days ≥6 (> 120 hours) - 0.30-0.50 IU/mL ⁻¹

These authors note that targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. In their review of 255 surgical procedures in 118 patients with hemophilia B, 60% of FIX levels within 24 hours of surgery were below target, while > 6 days after surgery, 59% of FIX levels were above target. However, clinically relevant bleeding complications occurred in only 7 procedures (2.7%). During the first 24 hours postoperatively, only bolus infusion was predictive of lower FIX levels, compared with continuous infusion. ^[52]

Long-acting FIX products have proved effective for surgical hemostasis, with nearly all patients requiring only a single preoperative dose and infrequent postoperative doses. ^{[53, 54]} In patients with FIX inhibitors, recombinant FVIIa has consistently demonstrated effectiveness, and with only rare thrombotic events. ^[55]

The use of fibrin sealants (ie, fibrin glue, fibrin adhesive), which consist of fibrinogen and thrombin with variable incorporation of factor XIII (FXIII) and fibrinolytic inhibitors, has helped improve surgical hemostasis markedly, thereby permitting necessary high-risk surgery (eg, pseudocyst removal, surgery in patients with hemophilia with inhibitors). This technology reduces or eliminates the need for prolonged replacement using expensive clotting factor concentrates and may eliminate or reduce the need for hospitalization.

HIV-associated immune thrombocytopenia is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to more than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.

Allergic reactions are occasionally reported with the use of factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem.

Do not circumcise male infants born to mothers who are known or thought to be carriers of hemophilia until disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FIX with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.

Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous route (rather than deep intramuscular route) with a fine-gauge needle.

Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.

In severe hemophilia, consider prophylactic or scheduled FIX infusions. Prophylactic replacement is used to maintain a measurable FIX level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis. ^[56] This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at age 1-2 years.

Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period.

Phenotypic and genotypic (ie, restriction fragment–length polymorphism) methods have advantages and disadvantages.

Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases. ^{[57, 58, 59]} The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination.

With the cloning of FIX and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived. Preclinical studies in mice and dogs with hemophilia resulted in long-term correction of the bleeding disorders, and in some cases a permanent cure. However, the induction of neutralizing antibodies often precluded stable phenotypic correction.

In addition, the relatively high prevalence of antibodies against adeno-associated virus serotype 8 (AAV8), which has been used as a vector for the normal FIX gene, has limited enrollment of clinical trial subjects. ^[60] Nevertheless, Nathwani and colleagues reported sustained long-term expression of therapeutic levels of FIX in 10 men with severe hemophilia B after a single intravenous infusion of an AAV8 vector expressing a codon-optimized FIX transgene. ^[61]

Other AAV serotypes have also proved effective as vectors. In November 2022, the FDA approved etranacogene dezaparvovec, an AAV5-based gene therapy, for the treatment of adults with hemophilia B who currently use FIX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes. ^[27]  

The approval was supported by the single-arm, open-label HOPE-B trial in 54 men who relied on FIX replacement therapy. Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = 0.0002), and FIX-treated bleeds fell 77% (P < 0.0001). Additionally, 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued FIX prophylaxis. Durability remains uncertain, but mean FIX activity was 39 IU/dL at 6 months (39% of normal) and 36.9 IU/dL at 18 months (approximately 37% of normal). To date, no patient has developed inhibitors against the infusion. ^[62]

In a phase 1-2 trial of AAVS3 gene therapy with FLT180a (verbrinacogene setparvovec), 9 of 10 men with severe or moderately severe hemophilia B (FIX level, ≤2% of normal) maintained FIX activity at a median follow-up of 27.2 months and no longer required FIX injections. In the patients who responded, FIX levels ranged from 23-260%, depending on their gene therapy dose. This protocol requires immunosuppression (with glucocorticoids, with or without tacrolimus) to decrease the risk of vector-related immune responses; of reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. ^[63]

Other gene therapies for hemophilia B include lentiviral and CRISPR (clustered regulatory interspaced short palindromic repeats)/Cas-9 gene therapy approaches. ^[64] A proof-of-principle study by Morishige et al demonstrated that gene repair in hemophilia B can be accomplished with CRISPR  technology. Using CRISPR/Cas9 on patient-derived induced pluripotent stem cells, these researchers repaired an in-frame deletion in exon 2 of the factor IX gene. ^[65] Chen et al reported long-term correction of hemophilia B in a rat model, using CRISPR/Cas9-induced homology-independent targeted integration. ^[66]

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improving psychosocial functioning.

Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help prevent bleeding during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity.

Consultations may be indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended.

A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.

Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and healing period.

Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis in relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint.

Management should be provided in coordination with a comprehensive hemophilia care center.