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    Hemophilia B

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    Apr.18.2023

    Hemophilia B

    Synopsis

    Key Points

    • Hemophilia B is a blood disorder characterized by spontaneous bleeding episodes (eg, deep muscles, joints) and excessive and/or prolonged bleeding after injury
    • Caused by deficiency of coagulation factor IX due to pathogenic variation of F9 gene on X chromosome
    • Categorized as severe, moderate, or mild by measurement of clotting factor activity in the blood r1
    • Severe form is characterized by abnormal bleeding in infancy and childhood; bleeding may be prolonged and difficult to stop, and it may restart after initial control; spontaneous bleeding into joints and deep muscles is common and can be life-threatening
    • Laboratory features of hemophilia B include a prolonged activated partial thromboplastin time which corrects when mixed with normal plasma immediately and after incubation; diagnosis is confirmed by reduced levels of factor IX activity
    • Treatment of hemophilia B involves replacement of factor IX, either prophylactically or on demand (for bleeding episodes)
      • 2% of patients with hemophilia B develop factor IX inhibitors that render factor IX replacement therapy ineffective; these patients require bypass agents (which trigger the coagulation cascade beyond the factor IX step) or immune tolerance induction r2
    • Repeated bleeds into joints and muscles result in musculoskeletal damage (eg, progressive cartilage deterioration, muscle atrophy, loss of function), one of the most disabling complications of the disease; intracranial hemorrhage may be a fatal complication in patients with severe disease
    • If prophylaxis is started before the second joint bleed, patients have better long-term outcomes with respect to joint preservation r3
    • Primary medical care from a multidisciplinary team at a recognized hemophilia treatment center improves outcomes r4
    • Prophylactic dosing with recombinant factor IX is important for any patient undergoing a scheduled procedure or surgery

    Urgent Action

    • Empiric emergency administration of factor IX (or alternative agent if patient is known to have inhibitors) is necessary for acute bleeding
      • Severe bleeding in head, neck, chest, or gastrointestinal tract
      • Forearm or calf bleeding with evidence of compartment syndrome
      • Bleeding into abdomen, thigh, or inguinal area
      • Undiagnosed abdominal pain
      • Persistent or painful hematuria
      • Bleeds causing severe pain
      • Suspicion of a severe bleed: when in doubt, treat

    Pitfalls

    • Clinical evidence of an acute bleed may lag, even in severe bleeds; clinicians must have a low threshold of suspicion and treat quickly and empirically
    • Production of inhibitors (alloantibodies) may make recombinant factor IX treatments ineffective and make bleeds difficult to control

    Terminology

    Clinical Clarification

    • Hemophilia B is a blood disorder characterized by spontaneous bleeding episodes (eg, deep muscles, joints) and disproportionate or prolonged bleeding after injury r5
    • Caused by deficiency of coagulation factor IX
    • Results from variants in F9 gene (coagulation factor IX) on X chromosome r6
      • Variants are usually hereditary; sometimes spontaneous

    Classification

    • Disease is characterized by severity of bleeding and clotting factor activity level detected in blood r1r7
      • Severe disease
        • Clotting factor activity level less than 1% of normal (less than 1 unit/dL) r1r7
        • Characterized by frequent, spontaneous bleeding episodes and bleeding after minor injury
        • 2 to 5 spontaneous bleeds per month r8
        • About 40% of patients with hemophilia B have severe disease r9
      • Moderate disease
        • Clotting factor activity level 1% to 5% of normal (1-5 units/dL) r1r7
        • Characterized by severe bleeding after trauma and bleeding after minor injury
        • Frequency of bleeds varies from 1 per month to 1 per year r8
      • Mild disease
        • Clotting factor activity level more than 5% but less than 40% of normal (more than 5 but less than 40 units/dL) r1r7
        • Characterized by severe bleeding after major trauma
        • Bleeding episodes may occur as often as once a year or as infrequently as once a decade r8

    Diagnosis

    Clinical Presentation

    History

    • Bleeding history may begin at birth (with severe disease), later in childhood, or in adulthood (with mild disease); bleeding may be prolonged and difficult to stop, and it may restart after initial control c1c2
      • Abnormal bleeding at birth or in early childhood
        • Bleeding in head of infant (intracranial, cephalohematoma) c3c4
        • Severe or prolonged bleeding after circumcision or heel stick c5c6
        • Hematomas after vaccinations c7
        • Easy bruising c8
        • Prolonged bleeding after loss of a deciduous tooth may occur but is uncommon c9
      • Deep spontaneous bleeds may be seen with increasing mobility and weight-bearing; patients or caregivers may report pain and/or swelling in affected areas or, in the case of intracranial bleeds, altered mental status, focal or diffuse weakness, and even seizures r5c10c11c12c13c14c15c16
        • Joints (70%-80%) c17
        • Muscle (10%-20%) c18
        • Other (5%-10%)
        • Central nervous system (less than 5%) c19
      • Blood in urine or stool c20c21
      • Frequent and prolonged nosebleeds that are difficult to stop c22
      • Prolonged bleeding after surgery or trauma
      • Menorrhagia in female carriers (many are asymptomatic, but some have mild hemophilia, and a few have severe disease) c23
    • Assessment of an acute bleeding episode r5
      • Some patients report a premonitory symptom, a tingling or bubbling sensation before clinical manifestations appear; this is often called an aura, by analogy with epileptic auras r5c24
      • Internal bleeding may take some time to become apparent, but history may provide clues

    Physical examination

    • Bleeding of mouth and gums c31c32
    • Epistaxis (may be bilateral) c33
    • Ecchymoses c34
    • Hemarthroses are most commonly seen in ankles, knees, and elbows, presenting as effusions; the affected joint is usually flexed and there is increased pain on extension; there may be ecchymotic discoloration over the joint c35c36c37c38c39c40
    • Signs of deep muscle bleeding (commonly occurs in iliopsoas muscle); may be associated with a psoas sign (pain elicited on passive hip extension of the affected side, performed as the patient lies in the lateral decubitus position on the opposite side) c41c42
    • There may be evidence of damage from previous bleeds: stiffened and/or deformed joints, muscle contractures, or neurologic deficits c43c44c45c46
    • There may be signs of anemia
      • Pallor c47
      • Tachycardia c48
      • Orthostatic hypotension c49

    Causes and Risk Factors

    Causes

    • Pathogenic variations of F9 gene on X chromosome (coagulation factor IX), resulting in factor IX deficiency or dysfunction c50c51

    Risk factors and/or associations

    Age
    • Although the genetic variation is present from birth (whether inherited or de novo), mild or moderate disease may not be recognized until mid to late childhood or adolescence c52c53
    Sex
    • Severe disease occurs almost exclusively in males; about 30%r8 of female carriers may have mild but clinically significant bleeding c54c55
    • On rare occasions, clinical manifestations in female carriers may be greater, owing to certain karyotypic and genetic factors (eg, skewed X-inactivation, especially in twinning; Turner syndrome) r10
    Genetics
    • Pathogenic variations of F9 gene (coagulation factor IX at Xq27); most are of the missense type c56
      • A rare point variant in the promoter region results in hemophilia B Leyden r11
        • Clinical significance of this variant is that although it causes severe hemophilia in childhood, disease resolves with puberty
    • Most people with hemophilia B have family history of the disease in a pattern consistent with X-linked inheritance c57c58
    • About 8% of hemophilia B cases are caused by spontaneous variants of F9r6c59
    Ethnicity/race
    • Occurs in all races and ethnicities
    • Black people with hemophilia B may have a higher risk of developing inhibitors against factor IX replacement r12c60

    Diagnostic Procedures

    Primary diagnostic tools

    • If history and physical examination findings suggest a bleeding disorder, investigate further with CBC, prothrombin time with INR, and activated partial thromboplastin time r13c61
    • If initial activated partial thromboplastin time is prolonged, a mixing test should be ordered, in which normal plasma is mixed in a 1:1 ratio with patient plasma to determine if coagulation normalizes r13
      • Activated partial thromboplastin time is tested immediately and again after a 2-hour incubation period
      • Normal values suggest that a missing factor has been supplied by the normal plasma
    • Identify the missing factor using factor assays; if hemophilia B is suspected, a factor IX assay is appropriate r5
    • Offer genetic testing to all people with hemophilia B and to their at-risk female family members r5
    • Imaging studies are not useful in the initial diagnosis of hemophilia, but may be needed to evaluate bleeding events (eg, hemarthrosis, retroperitoneal bleeds) r5

    Laboratory

    • Coagulation analysis
      • Activated partial thromboplastin time c62
        • Clotting time is up to 3 times longer than normal in severe disease r14
        • May be normal or only slightly prolonged in mild disease (ie, normal value does not rule out hemophilia B)
      • Mixing test r5c63
        • Immediate correction of activated partial thromboplastin time that is sustained even after 2-hour incubation suggests deficiency of a coagulation factor (eg, factor IX in the case of hemophilia B) that has been repleted by the normal plasma
        • Prolonged activated partial thromboplastin time after 1- to 2-hour incubation indicates presence of an inhibitor, even if immediate result was normal (the activity of some inhibitors is time dependent)
          • Inhibitors to numerous blood factors exist and are usually not pertinent to the initial diagnosis of hemophilia B; however, factor IX replacement therapy is sometimes complicated by the development of inhibitors, with important implications for treatment
          • These inhibitors are further identified and quantified by a Bethesda assay
            • Result of more than 0.5 Bethesda units is diagnostic of inhibitor presence
      • Factor assay r1r7c64
        • Severe disease
          • Factor IX activity level less than 1% of normal (less than 1 unit/dL)
        • Moderate disease
          • Factor IX activity level 1% to 5% of normal (1-5 units/dL)
        • Mild disease
          • Factor IX activity level more than 5% but less than 40% of normal (more than 5 but less than 40 units/dL)
    • Genetic testing r8c65
      • Single gene testing involves sequence analysis of F9 with or without more specific deletion/duplication analysis
      • Multigene panels are available, including analysis of F9 and various arrays of other genes related to bleeding disorders

    Differential Diagnosis

    Most common

    • Hemophilia B is fundamentally a laboratory diagnosis based on demonstration of inadequate levels of factor IX; whereas other bleeding diatheses may have similar presentations, the distinction is made primarily on the basis of laboratory findings
    • Clinically similar conditions include:
      • von Willebrand disease c66
        • Results from deficiency or abnormality of von Willebrand factor, which initiates platelet adhesion in primary clot formation and also binds to and stabilizes factor VIII to prevent proteolytic destruction thereof
          • Deficiency or dysfunction may result in low levels of factor VIII
        • Several subtypes exist, and clinical manifestations vary; some patients experience recurrent and prolonged episodes of spontaneous epistaxis, severe gingival bleeding associated with dental work, menorrhagia, and/or excessive bleeding with trauma or surgery
        • Unlike with hemophilia, deep spontaneous bleeds are uncommon, but they may occur if factor VIII declines to low levels
        • Differentiated by serum analysis showing low levels of von Willebrand factor antigen (less than 30 units/dL) r15
      • Other coagulation factor deficiencies r11
        • As with hemophilia B, bleeding is often out of proportion to injury; deep and/or spontaneous bleeds are common features in many of these conditions; prolonged bleeding and rebleeding after initial control may be seen
        • Factor VIII deficiency (hemophilia A) and factor IX deficiency (hemophilia B) can be virtually identical in presentation, although some debate exists as to whether overall severity may be less in hemophilia B r16c67d1
        • Spontaneous bleeds are less common in factor XI deficiency (hemophilia C) as opposed to bleeding from injury or surgery c68d2
        • In deficiencies of high-molecular-weight kininogen, prekallikrein, or factors XII and XI, activated partial thromboplastin time is prolonged (as with hemophilia B), although only factor XI deficiency results in a bleeding diathesis c69c70c71
        • In factor VII deficiency, prothrombin time is prolonged and activated partial thromboplastin time is normal (unlike with hemophilia B)
        • Deficiencies of factors V, X, II, and I (fibrinogen) result in prolongation of both prothrombin time and activated partial thromboplastin time c72c73c74c75
        • Antibodies (inhibitors) against various factors result in the same patterns
        • Normalization of result with addition of normal plasma (mixing test) confirms factor deficiency
        • Assays for the factor(s) suspected to be deficient confirm diagnosis
      • Thrombocytopenia or platelet dysfunction c76c77
        • As with hemophilia, easy and disproportionate bleeding occurs
        • Unlike with hemophilia, deep spontaneous bleeds are not common; manifestations generally include easy bruising, petechiae, and disproportionate bleeding after injury and dental or surgical procedures
        • Unlike with hemophilia, activated partial thromboplastin time is normal
        • Further differentiated by platelet count and platelet function test results
      • Vitamin K deficiency c78c79
        • Uncommon condition after neonatal period; human vitamin K supply relies in part on colonic bacterial metabolism, so deficiency occurs in some neonates (because initial gut microbiome colonization is unfinished) and occurs rarely at later ages owing to malabsorption or malnutrition, usually in conjunction with alterations in gut microbiome (eg, with use of antibiotics)
        • As with hemophilia, pattern of excessive bleeding occurs
        • Unlike with hemophilia, prolonged prothrombin time with elevated INR is the hallmark laboratory finding, and improvement with vitamin K administration is characteristic
        • Diagnosis is usually clinical

    Treatment

    Goals

    • Prevent and treat bleeding
    • Prevent long-term complications of deep bleeds (eg, joint destruction, contractures, neurologic deficits)

    Disposition

    Admission criteria

    Severe bleeding or bleeding refractory to standard outpatient care

    • Severe bleeding in head, neck, chest, or gastrointestinal tract
    • Forearm or calf bleed with evidence of compartment syndrome
    • Undiagnosed abdominal pain in a patient with hemophilia
    • Persistent hematuria
    • Bleeds causing severe pain

    Patients with hemophilia B who are being newly treated or who have developed inhibitors to factor IX are at risk for anaphylaxis or other severe allergic manifestations; therefore, it is recommended that blood or factor IX products to which the patient has not been exposed be administered for the first 10 to 20 times in a hospital or other supervised medical setting in which severe allergic reactions can be adequately managed r5

    Criteria for ICU admission
    • Prolonged bleeding and hemodynamic instability
    • Intracranial bleeding
    • Bleeding from nose, mouth, or throat that threatens airway
    • Gastrointestinal bleeding

    Recommendations for specialist referral

    • Management of all patients with hemophilia should be directed by a comprehensive multidisciplinary team associated with a recognized hemophilia treatment center r5
      • Team should include a hematologist, musculoskeletal specialist(s) (ie, orthopedic surgeon, rheumatologist, physiatrist), and laboratory (hematology/blood bank) expert
      • Additional referrals or consultation may be needed:
        • Geneticist to guide genetic testing to identify the specific pathogenic variation involved and to provide genetic counselling
        • Pain management specialist for patients who have chronic joint pain due to recurrent hemarthroses
        • Dentist with expertise caring for patients with bleeding disorders (to manage all dental care)
        • Gynecologist/obstetrician to manage menorrhagia in female carriers
        • Maternal-fetal health specialist to handle pregnancy and delivery for female carriers, especially if fetus is known to have hemophilia
        • Neonatologist for care of infant with known or suspected hemophilia

    Treatment Options

    Mainstay of treatment consists of replacing factor IX, though the approval of gene therapy may alter the landscape of treatment in upcoming years

    Factor IX replacement

    • Several factor replacement preparations are available
    • Treatment consists of 2 main strategies: episodic (on demand) control of bleeding and prophylaxis to reduce the incidence of bleeding; additional consideration required in the perioperative setting r5
      • Episodic treatment to control active bleeding
        • Clinical manifestations of bleed may lag; begin treatment if a bleed is suspected; do not wait for documentation; when in doubt, treat r17
        • In patients with severe hemophilia B, factor IX replacement often must be administered urgently (within 1r8 to 2 hoursr5) and empirically, before diagnostic imaging and other studies are done r17
        • Indications for factor replacement include: r17
          • Suspected bleeding into a joint or muscle
          • Any significant injury to head, neck, eyes, or mouth, or evidence of bleeding in these areas
          • New or unusual headache, particularly after trauma
          • Severe pain or swelling at any site
          • History of accident or trauma that might result in internal bleeding
          • Heavy or persistent bleeding from any site
          • Gastrointestinal bleeding
          • Acute musculoskeletal injury (eg, sprain, dislocation, fracture)
          • Surgery or any other invasive procedure (eg, lumbar puncture, interventional radiology)
        • Goal plasma concentration of factor IX and duration of treatment depend on bleeding severity and site r5
          • Factor concentration may be expressed as a percentage factor IX activity or as international units per deciliter r5
          • Central nervous system or head bleeds
            • Maintain titer of 60 to 80 international units/dL for days 1 through 7
            • Maintain titer of 30 international units/dL for days 8 through 21
          • Throat and neck bleeds
            • Maintain titer of 60 to 80 international units/dL for days 1 through 7
            • Maintain titer of 30 international units/dL as maintenance for days 8 through 14
          • Gastrointestinal bleeds
            • Maintain titer of 60 to 80 international units/dL for 7 to 14 days or until bleeding has stopped and source control obtained
            • Further dosing should aim to maintain levels of 30 international units/dL; duration unspecified
          • Deep muscle bleeds
            • Maintain titer of 60 to 80 international units/dL for first 1 to 2 days
            • Maintain titer of 30 to 60 international units/dL as maintenance for days 3 to 5 or beyond (eg, in conjunction with physical therapy)
          • Superficial muscle bleeds
            • Maintain titer of 40 to 60 international units/dL for 2 to 3 days
          • Joint bleeds
            • Maintain titer of 40 to 60 international units/dL for 1 to 2 days
          • Renal bleeds
            • Maintain titer of 40 international units/dL for 3 to 5 days
          • Deep lacerations
            • Maintain titer of 40 international units/dL for 5 to 7 days
      • Prophylaxis
        • Entails regular administration of factor IX to maintain levels that will prevent bleeding; these regimens result in fewer bleeds and fewer long-term musculoskeletal complications, and are now the favored approach in children and adolescents with severe hemophilia (factor IX activity less than 1%) r5
        • Goal of prophylaxis is to maintain consistent factor IX activity levels above the threshold of severe manifestations: more than 1% of normal (more than 1 international units/dL), though many clinicians prefer to maintain trough level of 3% to 5% due to continued risk of bleeding r5
        • It is recommended that prophylaxis begin early in childhood, before a second clinically significant joint bleed and before age 3 years r5
          • Prophylactic regimens are typically described as low, intermediate, or high where dose/intensity incorporates both the number of units administered and the dosing frequency r5
          • Prophylactic regimens should be individualized to allow escalation of regimens (ie, increased dose, frequency, or both) in patients who continue to experience bleeds despite prophylaxis r5
          • When initiating prophylactic factor replacement, may switch to using a low-frequency approach to improve patient and family acceptance of regimen; escalation may occur gradually or more quickly dependent on patient factors (ie, presence or absence of bleeding) r5
        • Because of the risk of allergic reactions, the first 10 to 20 doses after starting or changing therapy should be administered in a medical setting r5
        • Whether and when patients can stop prophylaxis (eg, after adolescence) is unclear, and the decision is individualized to the patient and available resources r5
        • In circumstances of short supply or limited economic resources, use of smaller doses and/or longer intervals may provide some benefit r5
        • Half-life of many factor IX products require infusions twice a week;r5 several techniques have been used to develop products with a longer half-life to allow for once-weekly dosing to decrease infusion burden r16
      • Perioperative management of surgical bleeding r5
        • Perioperative factor replacement should occur a minimum of 3 days for minor procedures and 7 to 10 days for major procedures r5
        • Major surgery
          • Preoperative goal is plasma level of 60 to 80 international units/dL
          • Postoperative goals
            • 40 to 60 international units/dL for days 1 to 3
            • 30 to 50 international units/dL for days 4 to 6
            • 20 to 40 international units/dL for days 7 to 14
        • Minor surgery
          • Preoperative goal is plasma level of 50 to 80 international units/dL
          • Postoperative goal is 30 to 80 international units/dL for 1 to 5 days

    Gene therapy

    • Adenoviral vector–based gene therapy delivers the Padua gene variant of factor IX to promote generation of factor IX protein r18
    • Etranacogene dezaparvovec-drlb
      • Approved for the treatment of adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historic life-threatening hemorrhage, or have repeated, serious, spontaneous bleeding episodes
      • HOPE-B study enrolled male patients 18 years or older with factor IX activity level of 2% or less of normal r19
        • Factor IX activity level increased to 39 international units/dL at 6 months and 36.9 international units/dL at 18 months in patients receiving etranacogene dezaparvovec-drlb
        • Factor IX-treated bleeds were reduced by 77%
        • 98% of patients who received etranacogene dezaparvovec-drlb discontinued use of prophylactic factor IX therapy
      • Immune-mediated hepatotoxicity has been reported; corticosteroid therapy should be administered concomitantly

    Management of factor IX inhibitors r5

    • Some patients with hemophilia B who have been treated with factor IX (2%-5%) may develop alloantibodies to the factor (inhibitors) r11
      • Not a common problem in hemophilia B (whereas factor VIII inhibitors are common in hemophilia A)
      • More likely to occur in patients with severe disease r20
    • Inhibitors are categorized as follows:
      • High-titer inhibitors (5 or more Bethesda units)
      • Low-titer inhibitors (less than 5 Bethesda units)
        • High responders, characterized by a rapid anamnestic rise in titer after infusion
          • Represent about 80% of patients with hemophilia B who develop inhibitors r20
        • Low responders, characterized by a slower antibody response
    • There are several approaches to this problem
      • Immune tolerance induction to eradicate inhibitor production r16r20
        • Most data on immune tolerance induction are in patients with factor VIII inhibitors in hemophilia A; many patients receive upfront immunomodulatory agents, given the difficulty with inhibitor eradication r20
        • Such therapy for hemophilia B is less effective than for hemophilia A, and it carries greater risk of adverse effects (eg, allergic reaction, kidney injury) r20
        • When used, therapy involves frequent exposure to high doses of factor IX over the course of many months r20
        • Ongoing exposure to factor IX—and at high doses in particular—is often not a viable approach
      • Low responders with low titers can sometimes be treated effectively with higher doses of factor IX for both prophylaxis and episodic bleeds r16
      • Bypassing agents can be used for both prophylaxis r22and episodicr23 treatment r20r21
        • Activated factors whose role in the coagulation cascade occurs after that of factor IX
          • Recombinant factor VIIa
            • Favored over activated prothrombin complex concentrate, because the latter contains a substantial amount of factor IX, which may spur further inhibitor production and/or trigger an allergic reaction r16
          • Activated prothrombin complex concentrate

    Additional considerations for bleeding episodes

    • Antifibrinolytic agents r5
      • Indicated for mucosal bleeding or before oral or dental surgery, as well as for menorrhagia and epistaxis
      • Tranexamic acid
        • Contraindicated in patients with the following:
          • Subarachnoid hemorrhage
          • Hematuria due to risk of obstructive uropathy
      • Aminocaproic acid (also known as epsilon aminocaproic acid)
        • Contraindicated in patients with hematuria of upper urinary tract origin due to risk of obstructive uropathy
      • Both agents are commonly used and appear to be effective, but data (particularly comparative) are scant r24
    • Other measures r5
      • For severe bleeds, monitor hemoglobin level and hemodynamic stability (pulse, blood pressure) and transfuse as necessary
      • Apply ice and compression to accessible bleeds (joints, muscles)
      • Elevate affected joint and consider immobilizing; avoid weight-bearing
        • Consider arthrocentesis if the joint remains tensely swollen after 24 hours, there is refractory pain, or there is evidence of neurovascular compromise or joint infection
      • After bleeding has ceased and patient is stable, institute physical therapy for patients who have had joint or muscle bleeds
      • In pain management, avoid intramuscular injection as well as use of aspirin and most NSAIDs
        • Cyclooxygenase-2 inhibitors can be prescribed for joint pain if acetaminophen is not effective
        • For severe pain (eg, postoperative), IV morphine may be given initially before transitioning to oral opioids

    All patients with hemophilia B should be immunized against hepatitis A and B r5

    • Use of blood products increases the likelihood of exposure to these viruses
    • Administer vaccinations if not already current

    Drug therapy

    • Replacement of coagulation factor IX (recombinant or human plasma–derived) r5c80
      • Episodic treatment to control active bleeding r17
        • General dosing is described below; for specific product information, refer to individual drug monographs
          • Recombinant factor IX
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Infants, Children, and Adolescents younger than 15 years: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 0.7 International Units/dL. Use following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal) x 1.43. Joint bleeding: required factor IX activity is 40% to 60% for 1 to 2 days or longer if response inadequate. Superficial muscle without neurovascular compromise: required factor IX activity is 40% to 60% for 2 to 3 days or longer if response inadequate. Iliopsoas and deep muscle with neurovascular compromise or substantial blood loss: required factor IX activity is 60% to 80% for 1 to 2 days, then 30% to 60% for 3 to 5 days. CNS/head bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 21 days. Throat and neck bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 14 days. Gastrointestinal bleeding: required factor IX activity is 60% to 80% for 7 to 14 days, then 30% (duration unspecified). Renal bleeding: required factor IX activity is 40% for 3 to 5 days. Deep lacerations: required factor IX activity is 40% for 5 to 7 days. Titrate dose based on clinical response and individual pharmacokinetics.
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Adolescents 15 to 17 years: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 0.8 International Units/dL. Use following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal) x 1.25. Joint bleeding: required factor IX activity is 40% to 60% for 1 to 2 days or longer if response inadequate. Superficial muscle without neurovascular compromise: required factor IX activity is 40% to 60% for 2 to 3 days or longer if response inadequate. Iliopsoas and deep muscle with neurovascular compromise or substantial blood loss: required factor IX activity is 60% to 80% for 1 to 2 days, then 30% to 60% for 3 to 5 days. CNS/head bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 21 days. Throat and neck bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 14 days. Gastrointestinal bleeding: required factor IX activity is 60% to 80% for 7 to 14 days, then 30% (duration unspecified). Renal bleeding: required factor IX activity is 40% for 3 to 5 days. Deep lacerations: required factor IX activity is 40% for 5 to 7 days. Titrate dose based on clinical response and individual pharmacokinetics.
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Adults: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 0.8 International Units/dL. Use following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal) x 1.25. Joint bleeding: required factor IX activity is 40% to 60% for 1 to 2 days or longer if response inadequate. Superficial muscle without neurovascular compromise: required factor IX activity is 40% to 60% for 2 to 3 days or longer if response inadequate. Iliopsoas and deep muscle with neurovascular compromise or substantial blood loss: required factor IX activity is 60% to 80% for 1 to 2 days, then 30% to 60% for 3 to 5 days. CNS/head bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 21 days. Throat and neck bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 14 days. Gastrointestinal bleeding: required factor IX activity is 60% to 80% for 7 to 14 days, then 30% (duration unspecified). Renal bleeding: required factor IX activity is 40% for 3 to 5 days. Deep lacerations: required factor IX activity is 40% for 5 to 7 days. Titrate dose based on clinical response and individual pharmacokinetics.
          • Plasma-derived factor IX
            • Coagulation Factor IX (Pooled Human Plasma), High Purity Solution for injection; Infants, Children, and Adolescents: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 1 International Unit/dL. Use following formula to estimate initial dose: Dose (International Units) = Body Weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal). Joint bleeding: required factor IX activity is 40% to 60% for 1 to 2 days or longer if response inadequate. Superficial muscle without neurovascular compromise: required factor IX activity is 40% to 60% for 2 to 3 days or longer if response inadequate. Iliopsoas and deep muscle with neurovascular compromise or substantial blood loss: required factor IX activity is 60% to 80% for 1 to 2 days, then 30% to 60% for 3 to 5 days. CNS/head bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 21 days. Throat and neck bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 14 days. Gastrointestinal bleeding: required factor IX activity is 60% to 80% for 7 to 14 days, then 30% (duration unspecified). Renal bleeding: required factor IX activity is 40% for 3 to 5 days. Deep lacerations: required factor IX activity is 40% for 5 to 7 days. Titrate dose based on clinical response and individual pharmacokinetics.
            • Coagulation Factor IX (Pooled Human Plasma), High Purity Solution for injection; Adults: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 1 International Unit/dL. Use following formula to estimate initial dose: Dose (International Units) = Body Weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal). Joint bleeding: required factor IX activity is 40% to 60% for 1 to 2 days or longer if response inadequate. Superficial muscle without neurovascular compromise: required factor IX activity is 40% to 60% for 2 to 3 days or longer if response inadequate. Iliopsoas and deep muscle with neurovascular compromise or substantial blood loss: required factor IX activity is 60% to 80% for 1 to 2 days, then 30% to 60% for 3 to 5 days. CNS/head bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 21 days. Throat and neck bleeding: required factor IX activity is 60% to 80% for 1 to 7 days, then 30% for 8 to 14 days. Gastrointestinal bleeding: required factor IX activity is 60% to 80% for 7 to 14 days, then 30% (duration unspecified). Renal bleeding: required factor IX activity is 40% for 3 to 5 days. Deep lacerations: required factor IX activity is 40% for 5 to 7 days. Titrate dose based on clinical response and individual pharmacokinetics.
      • Routine prophylaxis
        • General dosing is described below; for specific product information, refer to individual drug monographs
          • High-dose prophylaxis
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Infants, Children, and Adolescents requiring more than 4,000 International Units/kg/year (high-dose) of clotting factor concentrate: 40 to 60 International units/kg/dose IV twice weekly.
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Adults requiring more than 4,000 International Units/kg/year (high-dose) of clotting factor concentrate: 40 to 60 International Units/kg/dose IV twice weekly.
          • Intermediate-dose prophylaxis
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Infants, Children and Adolescents requiring 2,000 to 4,000 International Units/kg/year (intermediate-dose) of clotting factor concentrate: 20 to 40 International Units/kg/dose IV twice weekly.
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Adults requiring 2,000 to 4,000 International Units/kg/year (intermediate-dose) of clotting factor concentrate: 20 to 40 International Units/kg/dose IV twice weekly.
          • Low-dose prophylaxis with escalation of dose-intensity as needed
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Infants, Children and Adolescents requiring 1,000 to 1,500 International Units/kg/year (low-dose) of clotting factor concentrate: 10 to 15 International Units/kg/dose IV twice weekly.
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Adults requiring 1,000 to 1,500 International Units/kg/year (low-dose) of clotting factor concentrate: 10 to 15 International Units/kg/dose IV twice weekly.
      • Perioperative management of surgical bleeding
        • General dosing is described below; for specific product information, refer to individual drug monographs
          • Recombinant factor IX
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Infants, Children, and Adolescents younger than 15 years: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 0.7 International Units/dL. Use the following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal) x 1.43. Minor surgery: required factor IX activity preoperatively is 50% to 80% and postoperatively is 30% to 80% for 1 to 5 days, depending on type of procedure. Major surgery: required factor IX activity preoperatively is 60% to 80% and postoperatively is 40% to 60% for 1 to 3 days, then 30% to 50% for 4 to 6 days, then 20% to 40% for 7 to 14 days. Titrate dose based on clinical response and individual pharmacokinetics.
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Adolescents 15 to 17 years: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 0.8 International Units/dL. Use the following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal) x 1.25. Minor surgery: required factor IX activity preoperatively is 50% to 80% and postoperatively is 30% to 80% for 1 to 5 days, depending on type of procedure. Major surgery: required factor IX activity preoperatively is 60% to 80% and postoperatively is 40% to 60% for 1 to 3 days, then 30% to 50% for 4 to 6 days, then 20% to 40% for 7 to 14 days. Titrate dose based on clinical response and individual pharmacokinetics.
            • Coagulation Factor IX (Recombinant)(Hamster) Solution for injection; Adults: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 0.8 International Units/dL. Use the following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal) x 1.25. Minor surgery: required factor IX activity preoperatively is 50% to 80% and postoperatively is 30% to 80% for 1 to 5 days, depending on type of procedure. Major surgery: required factor IX activity preoperatively is 60% to 80% and postoperatively is 40% to 60% for 1 to 3 days, then 30% to 50% for 4 to 6 days, then 20% to 40% for 7 to 14 days. Titrate dose based on clinical response and individual pharmacokinetics.
          • Plasma-derived factor IX
            • Coagulation Factor IX (Pooled Human Plasma), High Purity Solution for injection; Infants, Children, and Adolescents: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 1 International Unit/dL. Use following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal). Minor surgery: required factor IX activity preoperatively is 50% to 80% and postoperatively is 30% to 80% for 1 to 5 days, depending on type of procedure. Major surgery: required factor IX activity preoperatively is 60% to 80% and postoperatively is 40% to 60% for 1 to 3 days, then 30% to 50% for 4 to 6 days, then 20% to 40% for 7 to 14 days. Titrate dose based on clinical response and individual pharmacokinetics.
            • Coagulation Factor IX (Pooled Human Plasma), High Purity Solution for injection; Adults: Dose and duration depend on severity of factor IX deficiency, location/extent of bleeding, and clinical condition. Generally, 1 International Unit/kg increases the circulating concentration of factor IX by 1 International Unit/dL. Use following formula to estimate initial dose: Dose (International Units) = Body weight (kg) x Desired Factor IX Rise (International Units/dL or % of normal). Minor surgery: required factor IX activity preoperatively is 50% to 80% and postoperatively is 30% to 80% for 1 to 5 days, depending on type of procedure. Major surgery: required factor IX activity preoperatively is 60% to 80% and postoperatively is 40% to 60% for 1 to 3 days, then 30% to 50% for 4 to 6 days, then 20% to 40% for 7 to 14 days. Titrate dose based on clinical response and individual pharmacokinetics.
    • Gene therapy
      • Etranacogene Dezaparvovec Suspension for injection; Adults: 2 x 10 to the 13th power genome copies/kg (or 2 mL/kg) IV as a single dose.
    • Bypassing agents
      • Recombinant factor VIIa is generally preferred over activated prothrombin complex concentrate as it does not contain factor IX, thus minimizing the risk of anaphylaxis in patients with allergy to exogenous factor IX r5
      • Episodic treatment to control bleeding r17
        • Recombinant factor VIIa r25c81
          • Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Infants, Children, and Adolescents: 90 mcg/kg/dose IV every 2 hours (adjustable based on severity of bleeding) until hemostasis is achieved or the treatment deemed inadequate. For severe bleeds, continue 90 mcg/kg/dose IV every 3 to 6 hours thereafter.
          • Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Adults: 90 mcg/kg/dose IV every 2 hours (adjustable based on severity of bleeding) until hemostasis is achieved or the treatment deemed inadequate. For severe bleeds, continue 90 mcg/kg/dose IV every 3 to 6 hours thereafter.
        • Activated prothrombin complex concentrate (eg, Feiba) r26
          • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Infants, Children, and Adolescents: 100 units/kg/dose IV every 6 to 12 hours until resolution of bleeding.
          • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Adults 18 to 64 years: 100 units/kg/dose IV every 6 to 12 hours until bleeding resolved.
      • Prophylaxis r21
        • 2017 Cochrane Review concluded that prophylaxis with bypassing agents may be effective in reducing bleeding rates in patients with hemophilia though optimal dosing is not established r22
        • Recombinant factor VIIa c82c83
          • 2 dosages have been used in studies, with similar safety and efficacy
            • Coagulation Factor VIIA Recombinant Human Solution for injection; Adults, Adolescents, and Children: 90 mcg/kg or 270 mcg/kg IV daily r27
        • Activated prothrombin complex concentrate (eg, Feiba)
          • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Infants, Children, and Adolescents: 85 units/kg/dose IV every other day.
          • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Adults 18 to 64 years: 85 units/kg/dose IV every other day.
      • Perioperative management of surgical bleeding
        • Recombinant factor VIIa
          • Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Infants, Children, and Adolescents: Minor surgery: 120 to 150 mcg/kg/dose IV preoperatively, then every 3 to 6 hours for 24 hours. Intermediate surgery: 150 mcg/kg/dose IV preoperatively and every 2 hours through surgery, followed by 90 to 120 mcg/kg/dose IV every 2 hours thru day 1, every 3 hours on day 2, every 4 hours on days 3 thru 5, and every 6 hours on days 6 thru 14. Major surgery: follow intermediate surgery intermittent infusion dosing or 15 to 50 mcg/kg/hour continuous IV infusion through postoperative day 14.
          • Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Adults: Minor surgery: 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery and for 48 hours postoperatively, then every 2 to 6 hours until healing occurs. Major surgery: 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery and for 5 days postoperatively, then every 4 hours or by continuous infusion at 50 mcg/kg/hour until healing occurs.
        • Activated prothrombin complex concentrate (eg, Feiba)
          • Preoperative dosing
            • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Infants, Children, and Adolescents: 50 to 100 units/kg/dose IV as a single dose immediately prior to surgery.
            • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Adults 18 to 64 years: 50 to 100 units/kg/dose IV as single dose immediately prior to surgery.
          • Postoperative dosing
            • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Infants, Children, and Adolescents: 50 to 100 units/kg/dose IV every 6 to 12 hours until resolution of bleeding and healing are achieved.
            • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Adults 18 to 64 years: 50 to 100 units/kg IV every 6 to 12 hours until bleeding resolved and healing achieved.
    • Antifibrinolytic agents
      • Aminocaproic acid c84
        • Must be preceded by a dose of factor IX concentrate to establish clot r28
          • Oral
            • Aminocaproic Acid Oral tablet; Children and Adolescents: 50 to 100 mg/kg/dose PO every 6 hours until mucosal healing is complete (10 to 14 days). Max: 24 g/day.
            • Aminocaproic Acid Oral tablet; Adults: 100 mg/kg/dose PO every 4 to 6 hours until mucosal healing is complete (10 to 14 days). Max: 2 g/dose and 24 g/day.
          • IV
            • Aminocaproic Acid Solution for injection; Adults: 100 mg/kg/dose IV every 4 to 6 hours until mucosal healing is complete (10 to 14 days). Max: 4 g/dose and 24 g/day.
      • Tranexamic acid r28c85
        • For menorrhagia
          • Tranexamic Acid Oral tablet; Children and Adolescents 12 to 17 years: 1,300 mg PO 3 times daily for 5 days during monthly menstruation.
          • Tranexamic Acid Oral tablet; Adults: 1,300 mg PO 3 times daily for 5 days during monthly menstruation.
        • For the treatment of epistaxis
          • Tranexamic Acid Oral tablet; Adults: 1 to 4.5 g/day PO in 2 to 4 divided doses.

    Nondrug and supportive care

    Avoid drug products containing aspirin or NSAIDs c86c87

    • May cause or exacerbate bleeding

    Avoid long-term opioid use r5

    Administer hepatitis A and B vaccines to all nonimmune patients with hemophilia r5

    • Intramuscular injection may be given with a small-gauge needle shortly after factor replacement; apply an ice pack to the area for 5 minutes before the injection, and apply pressure for at least 5 minutes after the injection
    Procedures
    Arthrocentesis r5c88
    General explanation
    • Aspiration to remove blood from joints and prevent long-term joint damage after factor replacement therapy
    • Should be done within 48 hours of bleeding onset
    Indication
    • Persistent tense swelling after 24 hours
    • Refractory pain
    • Neurovascular compromise
    • Evidence of joint infection (fever, unremitting pain, calor over the joint)
    Physiotherapy r5c89
    General explanation
    • Adjunctive treatment after factor replacement therapy to maintain joint function; begin as soon as possible after bleeding has stopped and should include:
      • Range of motion to improve flexibility and attain full extension
      • Active exercise to prevent muscle atrophy
      • Proprioceptive training
    Indication
    • Indicated for acute or chronic joint bleeding

    Comorbidities

    • With improved survival, management of comorbidities associated with aging is part of essential care of patients with hemophilia and may require some adaptations r5
      • Osteoporosis is common and may be managed conventionally (ie, calcium and vitamin D supplementation, bisphosphonates); weight-bearing activity can be encouraged to the extent possible without bleeding, as assessed individually c90d3
      • Hypertension is more common in patients with hemophilia; because of the associated risk of secondary bleeding, close monitoring of blood pressure and vigorous efforts to keep it under 140/90 mm Hg are recommended c91d4
      • Patients with diabetes may use subcutaneous insulin as indicated c92
      • Acute coronary syndrome c93d5
        • Patients who require percutaneous coronary intervention should receive factor replacement before the procedure and for 48 hours after, but excessive factor levels should be avoided to prevent pathologic thrombosis; radial access is preferred if feasible
        • Heparin and glycoprotein IIb/IIIa inhibitors may be administered; prolonged aspirin is not recommended for patients with severe hemophilia
        • Factor concentrates should be given for the period of dual antiplatelet activity
      • Renal failure r5
        • Patients with hemophilia B are 50 times more likely to die from complications of renal failure than the general population r5

    Special populations

    • Female carriers r5
      • Usually have factor IX levels about 50% normal and are essentially asymptomatic
        • Carriers with 50% normal levels may experience mildly abnormal bleeding with injury or invasive procedures
      • Some have lower factor IX levels (in the mild hemophilia ranges and occasionally in more severe categories) owing to certain karyotypic and genetic factors (eg, skewed X-inactivation, especially in twinning; Turner syndrome) r10
        • Significant menorrhagia may occur
      • Genetic counseling should be offered to all females with known bleeding disorders and to possible carriers who desire pregnancy r29
      • Female and their partners should receive information on all embryo and fetal diagnostic methods to make an informed decision r29
        • Methods include preimplantation diagnosis and invasive fetal tests such as chorionic villus sampling, amniocentesis, and cordocentesis r29
        • Noninvasive ultrasound can determine fetal sex, though female sex of the fetus does not exclude a bleeding diathesis r29
      • Factor IX levels do not rise during pregnancy (unlike factor VIII levels); factor IX levels should be measured in the third trimester to determine whether replacement is indicated r16
        • Delivery should be accomplished by the least traumatic means to prevent bleeding in both mother and infant r5
        • Avoid forceps, vacuum extraction, and fetal scalp monitoring r5
        • Females with factor IX levels less than 50% should receive replacement r29
        • Females with factor IX levels more than 50% may undergo epidural anesthesia r29
        • Factor IX levels may drop in the postpartum period and should be monitored r29
      • Females with known bleeding disorders should be managed by a team of specialists during pregnancy and labor and delivery, including an obstetrician/gynecologist, a hematologist, and an anesthesiologist r29

    Monitoring

    • Patients with hemophilia should undergo a standardized review every 12 months and should be evaluated by the multidisciplinary hemophilia care team after every major bleeding episode; evaluations should include: r5
      • Adequacy of venous access and presence of related complications c94
      • Record of interim bleeding episodes c95
      • Use of replacement products and response to them (efficacy, adverse events)
      • Presence of inhibitors c96
      • Musculoskeletal status c97
      • Oral health/hygiene c98
      • Psychosocial issues c99
    • Patients with hemophilia who receive factor replacement should be monitored for the development of inhibitors r5
      • Children beginning treatment: test for inhibitors after every 5 exposure days up to 20 exposure days, then every 10 exposure days up to 50 exposure days, and then at least twice a year until 150 exposure days c100
        • Exposure day is defined as a day during which 1 or more infusions of factor replacement are given
      • Adults with more than 150 exposure days: screen once or twice yearly (or as clinically indicated) c101
      • Patients who have been intensely treated for more than 5 days within 4 weeks of the most recent infusion (eg, spontaneous episode control, perioperative control): rescreen
    • Regular dental examinations and careful attention to routine daily maintenance are essential to avoid periodontal disease and associated bleeding r5c102
    • Patients receiving plasma-derived products that are not virus inactivated should undergo testing for HIV, hepatitis B (HBsAg, anti‐HBc, anti‐HBe, anti‐HBs), and hepatitis C (anti‐HCV) every 6 to 12 months r5c103c104c105c106c107c108

    Complications and Prognosis

    Complications

    • Musculoskeletal complications r5
      • Chronic hemophilic arthropathy c109
        • Repeated bleeds into joints and muscles cause progressive cartilage deterioration, muscle atrophy, and loss of function
        • Physiotherapy after joint and muscle bleeds helps preserve function
        • Other treatment options include:
          • Serial casting
          • Bracing and orthotics
          • Walking aids
    • Pseudotumors c110
      • Repeated soft tissue bleeds can form an encapsulated mass of clotted blood and necrotic tissue
      • Pseudotumors can be limb- and/or life-threatening
      • Treatment options include:
        • 6-week course of factor replacement to shrink pseudotumor r5
        • Surgical removal of pseudotumor
        • Aspiration of pseudotumor contents
        • Arterial embolization r30
        • Radiotherapy r30
        • Limb amputation
    • Intracranial bleeds r8c111
      • Most common cause of bleeding-related death
    • Complications related to treatment
      • Venipuncture complications
        • Precautions must be taken to prevent excess bleeding
          • 23- to 25-gauge butterfly needles are recommended r5
          • Avoid cutting down into a vein, except in emergencies
          • Apply pressure for 3 to 5 minutes after venipuncture r5
      • Alloantibodies against coagulation factor IX (ie, inhibitors) can develop after start of replacement therapy
        • These occur in about 2% of patients with hemophilia B r2
          • Patients with large-deletion F9 variants are at greater risk of inhibitor development r31
          • Inhibitors make factor replacement therapy ineffective and make bleeds difficult to control
          • Lack of response to factor replacement therapy may indicate presence of inhibitors
        • Patients with certain circumstances should be screened for inhibitors r5
          • Poor response or treatment failure with factor replacement therapy
          • Intensive treatment for more than 5 days within 4 weeks of the most recent infusion r32
          • Preparation for surgery
          • A switch to a new factor replacement product
        • Presence of inhibitors is detected with the Nijmegen-modified Bethesda assay
          • Patients with low inhibitor levels (less than 5 Bethesda units/mL) may be treated with higher doses of replacement therapy r5
          • Patients with high inhibitor levels (5 or more Bethesda units/mL) require different therapies for prophylactic and episodic treatment; some of these patients may be candidates for immune tolerance induction therapy to try to decrease inhibitor production r5
      • Anaphylactic reactions to factor IX administration
        • Patients with inhibitors are at greater risk for anaphylactic response to factor IX concentrate
        • Patients with severe disease (who are more likely to develop inhibitors) should be monitored over their first 10 to 20 infusions in a facility capable of treating anaphylactic shock r5
        • Patients with a history of anaphylaxis to FIX-containing clotting factor concentrates should receive recombinant activated factor VIIa r5
      • Nephrotic syndrome r5
        • May occur in patients who have developed factor IX inhibitors and who have had allergic reactions to factor replacement
      • Bloodborne disease
        • In the past, infectious complications from bloodborne viruses (eg, HIV, hepatitis B, hepatitis C) have been a major cause of death and chronic comorbidities r5
        • Availability of recombinant products essentially eliminates the risk; in addition, use of screened blood from volunteer (rather than paid) donors and viral inactivation procedures for blood products have reduced the incidence significantly in areas where these measures are used

    Prognosis

    • Prophylactic factor replacement therapy
      • Patients with severe hemophilia on prophylactic regimens
        • Have less joint damage by age 6 years than patients with episodic treatments (normal MRI evaluation of index joints in 93% versus 53%) r33
        • Have 50% lower probability of needing to undergo major surgery r34
        • Risk of intracranial bleeding is reduced by 50% r35
      • Outcomes are better if prophylaxis is started before the second joint bleed r3
        • Patients experience fewer bleeds and are at lower risk for arthropathy
    • Median life expectancy for patients with hemophilia B depends on disease severity r36
      • Median life expectancy is 63 years for severe disease
      • Median life expectancy is 75 years for moderate or mild disease
    • Mortality rates are higher than for the general population; increases correlate with disease severity r36
      • Severe disease mortality rates are increased by a factor of 2.69
      • Mild and moderate disease mortality rates are increased by a factor of 1.19
    • Primary medical care from a hemophilia treatment center (recognized by the National Hemophilia Foundation) improves outcomes r4
      • Reduces mortality rates by 40%

    Screening and Prevention

    Screening

    At-risk populations

    • Fetuses or newborns with family history of hemophilia B r8
    • Immediate female relatives of a person with hemophilia B r5

    Screening tests

    • Prenatal or newborn genetic testing for variants in F9 gene c112
      • Perform chorionic villus sampling, amniocentesis, or umbilical cord blood sampling r8
      • Polymerase chain reaction amplification and sequencing r6
    • First-degree female relatives r5
      • May wish to undergo genetic testing if planning pregnancy
      • Should have factor IX levels measured before invasive procedures c113
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