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    Hemophilia A

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    Mar.13.2023

    Hemophilia A

    Synopsis

    Key Points

    • Hemophilia A 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 VIII through mutations of F8 gene (located on X chromosome) or through development of autoantibodies against the factor
    • 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 inherited hemophilia A include a prolonged activated partial thromboplastin time that corrects when mixed with normal plasma (ie, corrects immediately and remains corrected after incubation); diagnosis is confirmed by reduced levels of factor VIII activity r2
      • Failure of activated partial thromboplastin time to remain corrected after incubation suggests presence of an inhibitor (autoantibody) and the possibility of acquired hemophilia; confirmation of diagnosis is through a Nijmegen-modified Bethesda assay, which quantifies inhibitors
    • Treatment of hereditary hemophilia A involves replacement of factor VIII, either prophylactically (preferred approach for children with severe hemophilia) and/or on demand (for bleeding episodes), as well as emicizumab
      • Up to 40% of treated patients with severe hereditary hemophilia A develop inhibitors interfering with the efficacy of factor VIII replacement; these patients require bypass agents (which trigger the coagulation cascade beyond the factor VIII step) or immune tolerance induction to attempt inhibitor eradication r3
    • Treatment of acquired hemophilia A involves use of bypass agents or recombinant porcine factor VIII (which eludes most inhibitors) for bleeding episodes and efforts to eradicate the inhibitor through immunosuppression and treatment of the triggering condition if identified
    • 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; pseudotumors may also cause limb-threatening complications
    • Primary medical care from a multidisciplinary team at a recognized hemophilia treatment center improves outcomes r4

    Urgent Action

    • Empiric emergency administration of factor VIII (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
    • Inhibitors make exogenous factor VIII treatments ineffective

    Terminology

    Clinical Clarification

    • Hemophilia A 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 VIII r6
    • Can be hereditary or acquired r6
      • Hereditary disease stems from mutations of F8 gene (coagulation factor VIII) on X chromosome
      • Acquired disease is due to development of an autoantibody to factor VIII

    Classification

    • By bleeding severity 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
        • Approximately 60% of patients with hemophilia A 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
        • 15% of patients with hemophilia A have moderate disease r9
      • 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
        • 25% of patients with hemophilia A have mild disease r9
    • By pattern of causation r6
      • Inherited
        • Caused by hereditary variants of F8 gene, located on X chromosome
        • Clinically evident disease affects males primarily, with typical pattern of X-linked inheritance
      • Acquired
        • Caused by spontaneous development of autoantibodies to factor VIII

    Diagnosis

    Clinical Presentation

    History

    • Bleeding history
      • Hereditary hemophilia A
        • Severe form may present with abnormal bleeding in infancy and childhood; bleeding may be prolonged and difficult to stop, and it may restart after initial control c1
          • Intracranial bleed or cephalohematoma in infant after difficult delivery c2c3
          • Umbilical stump bleeding c4
          • Persistent bleeding after circumcision c5
          • Easy bruising with formation of large hematomas c6c7
          • Bleeding after vaccinations c8
          • Some children have excessive or prolonged bleeding after shedding deciduous teeth 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
        • Patients with less severe disease may present later, with a variety of abnormal bleeding episodes (which may also be seen in patients with severe hemophilia): r8
          • Nosebleeds, which are often bilateral, difficult to stop, and recurrent c20
          • Menorrhagia c21
            • Ascertain an estimate of amount of blood loss (duration of menstrual period and number of pads or tampons per day)
            • Although inherited hemophilia mutations are often clinically silent in carrier females, some carriers experience a degree of abnormal bleeding
          • Prolonged bleeding after surgery or trauma c22
          • Blood in urine, semen, or stool c23c24c25
        • 66% of patients have family history of hemophilia A r5c26
      • Acquired hemophilia A
        • Typically presents in middle age or later, when patient presents with a significant bleed r10c27
        • Bleeding tends to be mucocutaneous or subcutaneous (ecchymosis) rather than deep; involvement of trunk is common r6c28
        • However, severe life- or limb-threatening bleeding may occur either spontaneously or after surgery or trauma r11
        • 40% of patients have history of associated pregnancy or disease r10r12c29
          • Rheumatoid arthritis c30
          • Systemic lupus erythematosus c31
          • Polymyalgia rheumatica c32
          • Malignancies c33
          • Dermatologic disease c34
    • Family history
      • For hereditary hemophilia A, there may be one or more known individuals with hemophilia in a family
        • Daughters of fathers with hemophilia A are obligate carriers
        • Women with at least one male who has hemophilia in their maternal pedigree are possible carriers
    • Evaluating an acute bleed
      • 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 r5c35
      • Because bleeding is often internal, it is important to inquire about symptoms and events that might have triggered a bleed, which may help to localize the source:
        • Head, chest, back, or abdominal pain c36c37c38c39
        • Fall or other injury c40c41
        • Participation in sports or other physical activities c42

    Physical examination

    • In either hereditary or acquired hemophilia, any of the following may be seen:
      • Bleeding of mouth and gums c43c44
      • Epistaxis (often bilateral) c45
      • Ecchymoses, which may be widespread c46
      • Signs of anemia c47
        • Pallor c48
        • Tachycardia c49
        • Orthostatic hypotension c50
    • In patients with hereditary hemophilia, there may be signs of deep bleeding c51
      • Commonly occurs in iliopsoas muscle; may be associated with a psoas sign (pain elicited on passive hip extension of the affected side, performed as patient lies in the lateral decubitus position on the opposite side) c52c53
      • Hemarthroses are most commonly seen in ankles, knees, and elbows;r13 presentation includes effusions, flexed joints with increased pain on extension, and sometimes ecchymotic discoloration c54c55c56c57c58c59c60c61
      • There may be evidence of damage from previous bleeds: stiffened and/or deformed joints, muscle contractures, or neurologic deficits c62c63c64c65

    Causes and Risk Factors

    Causes

    • Hereditary hemophilia A
      • Recessive pathogenic variants of F8 gene on X chromosome (coagulation factor VIII), resulting in factor VIII deficiency or dysfunction c66c67
    • Acquired hemophilia A
      • Production of autoantibodies against coagulation factor VIII c68
        • May be associated with pregnancy, an autoimmune disorder, or other underlying condition

    Risk factors and/or associations

    Age
    • All patients with inherited hemophilia have the condition from birth; however, they may present at different times depending on severity r8
      • Patients with severe disease present within the first 2 years of life c69c70c71
      • Those with moderate hemophilia are usually diagnosed by school age c72
      • Mild disease may not be recognized until adolescence or adulthood c73c74
    • Acquired disease usually occurs in older adults (median age, 77 yearsr11), but it may be seen in younger people with certain triggering conditions (eg, pregnancy, autoimmune diseases) r6c75c76c77
    Sex
    • Clinical manifestations of hereditary hemophilia A are more common in males c78c79
    • Approximately 30% of female carriers have less than 40% clotting activity and may experience clinically relevant abnormal bleeding r8
    Genetics
    • Mutations of F8 gene (coagulation factor VIII at Xq28) cause hereditary hemophilia by X-linked recessive inheritance (OMIM #306700) r14c80
      • More than 2000 different mutations of F8 gene have been identified; the most common is an intron 22 inversion r13
        • Specific mutations may correlate with severity of phenotype; the intron 22 inversion results in severe disease r15
        • Likelihood that a person with hemophilia will develop inhibitors (alloantibodies) after exposure to blood products or recombinant replacement factor also correlates with certain types of mutations; the common intron 22 inversion is associated with a 20% to 25% risk of developing an inhibitor r15
      • Approximately 70% of patients have family history of hemophilia r6c81
        • Approximately 30% of cases result from a de novo mutation r14
    • Gene variants are also thought to be implicated in the development of factor VIII autoantibodies in some cases of acquired hemophilia r16c82
    Ethnicity/race
    • Inherited hemophilia A has not been associated with any particular ethnic or racial group r17
    • Black and Hispanic people are more likely to acquire factor VIII inhibitors c83c84
    Other risk factors/associations
    • Acquired hemophilia A is often associated with another, underlying condition; approximately 50% of cases are idiopathic r10

    Diagnostic Procedures

    Primary diagnostic tools

    • Scenarios that should prompt consideration a new diagnosis of hemophilia A include: r19
      • Positive family history of the disease
      • Personal history of abnormal bleeding, history of bleeding in close family members
      • Unexpected finding of abnormal coagulation tests
    • If history and physical examination findings suggest a bleeding disorder, investigate further with CBC, prothrombin time with INR, and activated partial thromboplastin time r6c88
    • If initial tests of coagulation (prothrombin time with INR, activated partial thromboplastin time) yield abnormal results, a mixing test is indicated r6
      • Normal plasma is mixed with patient plasma and activated partial thromboplastin time is tested, both immediately and after incubation for 1 to 2 hours at 37°C r11
      • Immediate correction of coagulation test results suggests a factor deficiency that has been repleted by the normal plasma r11
        • For patients in whom hemophilia A is a possibility based on history and preliminary blood test results (eg, abnormal activated partial thromboplastin time that corrects upon mixing test), obtain a coagulation factor VIII activity level r2
        • A diagnosis of hemophilia A requires a factor VIII activity level less than 40% of normal r19
      • Failure of activated partial thromboplastin time to correct after incubation (even if the result immediately after mixing was normal) suggests the presence of an inhibitor (autoantibody) and the possibility of acquired hemophilia r11
        • For patients in whom acquired hemophilia is suspected based on history and laboratory results, Nijmegen-modified Bethesda assay is indicated r2
    • Genetic testing to identify the responsible mutation (in an individual with no family history) is routine for moderate and severe hemophilia A r19
      • Genetic testing offers several advantages, including providing useful clinical information regarding prognosis (likely phenotype, severity of disease, and potential for development of inhibitors) as well as facilitating screening of affected family members
      • In mild cases, genetic analysis is less often performed, because prognostic implications are much less relevant r19
      • Genetic testing is the preferred method for carrier detection in cases where a mutation has already been identified in an affected family member r19
    • Imaging has no role in diagnosis of hemophilia per se, but it may be necessary in evaluating bleeding events (eg, hemarthrosis, retroperitoneal bleeds)

    Laboratory

    • Activated partial thromboplastin time is prolonged in hemophilia r8c89
      • Clotting time up to 3 times longer than normal r20
    • Prothrombin time, INR, and platelet count are normal in hemophilia r8c90c91c92
    • Mixing test c93
      • Immediate correction of activated partial thromboplastin time (with normal prothrombin time) indicates a factor deficiency (VIII, IX, XI, or XII)
      • Failure of mixing to correct activated partial thromboplastin time after 1 to 2 hours of incubation indicates presence of factor inhibitor r11
        • Some inhibitors are time dependent
    • Factor VIII activity level c94
      • Several methods are available; local laboratory availability may determine specific assay used
      • Quantitative levels are reported
        • Severe disease
          • Clotting factor activity level less than 1% of normal (less than 1 units/dL) r1r7
        • Moderate disease
          • Clotting factor activity level 1% to 5% of normal (1 to 5 units/dL) r1r7
        • 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
    • Genetic testing c95
      • Factor VIII intron 22 inversion and intron 1 mutations are most common in severe disease r15
      • Point mutations in the F8 gene are common in mild to moderate disease
    • Bethesda assay c96
      • Quantification of inhibitor that neutralizes coagulation factor VIII in normal plasma
        • Nijmegen-modified Bethesda assay is used to determine inhibitor levels
      • Result of more than 0.5 Bethesda units is diagnostic of inhibitor presence r21
        • Inhibitor titer less than 5 Bethesda units/mL: classified as a low immunologic response to factor VIII replacement r22
        • Inhibitor titer of 5 or more Bethesda units/mL: classified as a high immunologic response to factor VIII replacement r22
      • This test is also used to detect antibodies that sometimes arise in patients with known hemophilia who have received exogenous factor VIII for treatment

    Differential Diagnosis

    Most common

    • Hemophilia A is fundamentally a laboratory diagnosis based on demonstration of inadequate levels of factor VIII or of autoantibodies to it; 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 c97
        • 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) r23
      • Other coagulation factor deficiencies r13
        • As with hemophilia A, 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 r24c98d1
        • Spontaneous bleeds are less common in hemophilia C (as opposed to bleeding from injury or surgery) c99d2
        • In deficiencies of high-molecular-weight kininogen, prekallikrein, or factors XII, XI, or IX, activated partial thromboplastin time is prolonged (as with hemophilia A); however, deficiencies of factor XII, high-molecular-weight kininogen, or prekallikrein are not associated with abnormal bleeding phenotypes c100c101c102
        • In factor VII deficiency, activated partial thromboplastin time is normal and prothrombin time is prolonged (unlike with hemophilia A) c103
        • Deficiencies of factors V, X, II, and I (fibrinogen) result in prolongation of both prothrombin time and activated partial thromboplastin time c104c105c106c107
        • 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 c108c109
        • 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 c110c111
        • 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 consequences 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
    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 r5r8
      • Team should include hematologist, musculoskeletal specialist(s) (ie, orthopedic surgeon, rheumatologist, physiatrist), and laboratory (coagulation/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 counseling
        • 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 infants with known or suspected hemophilia

    Treatment Options

    Hereditary hemophilia A

    • Historically, treatment was limited to managing bleeds by administering factor VIII replacement therapy and replacing lost blood; such episodic (ie, on-demand) therapy remains necessary for bleeding that occurs despite other measures and for prevention of bleeding in anticipation of surgery or other invasive procedures r16
      • In patients with severe hemophilia A, factor VIII replacement often must be administered urgently (within 1 hourr8 or 2 hoursr5) and empirically, before diagnostic imaging and other studies are done. Indications for factor replacement therapy include: r25
        • 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)
      • Clinical manifestations may lag; begin treatment if a bleed is suspected, without waiting for documentation. When in doubt, treat r25
    • Prophylactic treatment entails regular administration of factor VIII to maintain levels that will prevent bleeding; these regimens result in fewer bleeds and fewer long-term musculoskeletal complications, and they are now the standard of care in patients of all ages with severe hemophilia (factor VIII level less than 1%)
      • It is recommended that prophylaxis begin early in childhood, before a second clinically significant joint bleed and before age 3 years r5
      • Goal of prophylaxis is to maintain factor VIII level at higher than 1% of general reference range and prevent bleeding r5
      • Half-life of factor VIII requires infusions every 2 to 3 days; several techniques (eg, pegylation) have been used to develop products with a longer half-life, with modest success r26
    • Several factor replacement preparations for both prophylaxis and treatment of bleeding in patients with inherited hemophilia A are available: r5r27r28
      • Recombinant factor VIII
        • Current (third-generation) products contain no human or animal proteins
        • Felt to be safest regarding the possibility of disease transmission (eg, HIV, viral hepatitis)
        • A small study of a novel von Willebrand–independent factor VIII product showed promising efficacy and safety results r29r30
      • Plasma-derived factor VIII concentrate
        • Current products are derived from screened donors and treated to inactivate or remove viruses
        • Guidelines differ as to whether plasma-derived factor is equivalent to recombinant factor in safety from infection; National Hemophilia Foundationr28 and United Kingdom Haemophilia Centre Doctors' Organisationr27 favor recombinant over plasma-derived factor VIII, but World Federation of Hemophiliar5 does not express a preference
      • Cryoprecipitate r5r27r28
        • Not recommended unless no alternatives are available
    • Patients with inherited hemophilia who have been treated with factor VIII (either recombinant or plasma-derived) commonly develop alloantibodies to the factor (also called inhibitors); these are identified with laboratory tests (eg, Bethesda assay)
      • Inhibitors occur more commonly in severe hemophilia (20%-30% of patients) than in nonsevere disease (5%-10% of patients), and in patients treated with recombinant factor VIII versus plasma-derivedr31 products r5
      • Inhibitors are characterized as follows: r16
        • High-titer inhibitor (5 or more Bethesda units)
        • Low-titer inhibitor (more than 0.5 but less than 5 Bethesda units)
          • High responders: characterized by a rapid anamnestic rise in titer after infusion
          • Low responders: do not exhibit a rapid rise in inhibitor titer
      • There are several approaches to this problem:
        • Immune tolerance induction r16
          • Involves frequent exposure to high doses of factor VIII over the course of many months
            • Effective in approximately 65% to 70% of patients
            • Most likely to be effective in patients with titers less than 10 Bethesda units r32
        • Bypass agents can be used for both prophylaxisr30 and episodic treatmentr34 in patients who have high titers of inhibitors despite immune tolerance induction (or in those who have not started it) r16r33
          • Administration of activated factors that follow factor VIII in the coagulation cascade
            • Activated prothrombin complex concentrate
            • Recombinant factor VIIa (eg, eptacog alfa)
            • Both agents are effective in both episodic and prophylactic treatment; overall safety and efficacy of the 2 agents appear to be similar, although some patients appear to have better response with one versus the other r16r34
            • Emicizumab is a recently developed monoclonal antibody that substitutes for activated factor VIII (ie, VIIIa), triggering activation of the tenase complex (factor Xa) r35
              • Indicated for and effective as prophylaxis in persons of all ages with inherited hemophilia A, withr36 or withoutr37 inhibitors; however, has been studied only in patients with severe hemophilia
                • May be particularly beneficial for patients with inhibitors, and it has largely replaced other agents for prophylaxis (ie, activated prothrombin complex concentrate, recombinant factor VIIa) in this population
    • Gene therapy is under study, but it has not been as effective for hemophilia A as for hemophilia B owing to technical challenges related to the length of the gene fragment that must be inserted r38

    Acquired hemophilia A

    • Episodic treatment may be required to control bleeding episodes; definitive treatment consists of eradicating the antibody by treatment of the underlying disease and/or immunosuppression r39r40
      • Bleeding control
        • First line treatment to control bleeding is through use of bypass agents
          • Recombinant factor VIIa (eg, eptacog alfa) r28
            • Can also be used as preoperative treatment to prevent bleeding
          • Activated prothrombin complex concentrates r41
            • Considered off-label use for controlling bleeding in patients with acquired hemophilia A
            • Product is derived from human plasma and carries a minimal risk of human virus transmission
        • Recombinant porcine factor VIII r28
          • Approved only for use in acquired hemophilia A
          • Acquired antibodies to human factor VIII often do not cross-react with the porcine factor
      • Eradication therapy is intended to control factor VIII inhibitor production and prevent bleeding r40r41
        • Control of triggering condition, if possible, is fundamental r40
        • Initiate immunosuppressive therapy as soon as diagnosis of acquired hemophilia A is made
          • Prednisone or prednisolone is recommended to begin, alone or with cyclophosphamide
          • Although efficacy data are limited, rituximab may be used as an alternative therapy, alone or in combination with other agents, if there is a contraindication to first line agents or if they are ineffective r42r43
          • Calcineurin inhibitors
            • Both cyclosporine and tacrolimus have been used, usually in combination with prednisone
          • Efficacy is defined as titer less than 0.6 Bethesda units and persistent factor VIII levels higher than 70% of normal; efficacy rates are variable but have been as high as 70% to 90% in some studies; recurrence occurs in 10% to 20% r40
        • In refractory cases, immunosuppression may be combined with immune tolerance induction

    Additional considerations for bleeding episodes

    • Other agents that may be appropriate to control bleeding in certain circumstances include:
      • Desmopressin r5
        • Indicated to control mild or moderate bleeding episodes in patients with hemophilia if they have previously demonstrated an adequate response
        • May also be used as preoperative prophylaxis to prevent excessive bleeding
        • It is recommended that patients who might be suitable candidates for desmopressin treatment undergo a test dose during a nonbleeding period to assess response as determined by a 3- to 6-fold rise in factor VIII level 60 minutes after administration
      • Antifibrinolytic agents r5
        • Indicated for mucosal bleeding or before oral or dental surgery, as well as for menorrhagia
        • Tranexamic acid
          • Contraindicated in patients with:
            • Subarachnoid hemorrhage
            • Hematuria
        • Aminocaproic acid (also known as epsilon aminocaproic acid)
          • Contraindicated in patients with hematuria of upper urinary tract origin
        • Both agents appear to be effective, but data (particularly comparative) are scant r44
    • 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
      • Pain management must avoid intramuscular injection and 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, transitioning to oral opioids
        • Avoid long-term opioids for pain management r5

    All patients with hemophilia should be immunized against hepatitis A and B; administer vaccinations if not already current r5

    • Use of blood products increases the likelihood of exposure to these viruses

    Drug therapy

    • Replacement coagulation factor VIII (recombinant or human plasma–derived) c112
      • Prophylaxis
        • Long-term prophylaxis involves continuous dosing (46 or more weeks/year) of replacement coagulation factor VIII r5
          • Dosing and frequency is individualized; 2 regimens are commonly used:
            • Malmö protocol: Adults, Adolescents, Children, and Infants: 25 to 40 International Units/kg/dose IV 3 times per week. c113
            • Utrecht protocol: Adults, Adolescents, Children, and Infants: 15 to 30 International Units/kg/dose IV 3 times per week.
          • In circumstances of constrained resources, smaller doses at longer intervals may still provide benefit
      • Episodic treatment
        • Antihemophilic Factor VIII (Recombinant) (Bovine) (Hamster) (Murine) Solution for injection; Infants, Children, and Adolescents: Dosage not established. Initially, 50 to 100 International Units/kg IV may be required. Repeat doses PRN until desired factor VIII activity concentration is reached, then continue every 8 to 12 hours to maintain factor VIII activity.
        • Antihemophilic Factor VIII (Recombinant) (Bovine) (Hamster) (Murine) Solution for injection; Adults: Dosage not established. Initially, 50 to 100 International Units/kg IV may be required. Repeat doses PRN until desired factor VIII activity concentration is reached, then continue every 8 to 12 hours to maintain factor VIII activity.
        • Goal plasma concentration of factor VIII and duration of treatment depend on bleeding severity and site r5
          • Factor concentration may be expressed as a percentage or as international units per deciliter
          • Gastrointestinal bleeds
            • Initial dose to maintain levels of 80 to 100 units/dL for days 1 through 7 or until bleeding has stopped and source identified and addressed
            • Lower dose to maintain 50 units/dL, duration unspecified
          • Central nervous system or head bleeds
            • Maintain level of 80 to 100 units/dL for days 1 through 7
            • Maintain level of 50 units/dL as maintenance for days 8 through 21
          • Throat and neck bleeds
            • Maintain level of 80 to 100 units/dL for days 1 through 7
            • Maintain level of 50 units/dL as maintenance for days 8 through 14
          • Deep muscle bleeds
            • Maintain level of 80 to 100 units/dL for 1 to 2 days
            • Maintain level of 30 to 60 units/dL as maintenance through day 5 or longer (eg, in conjunction with physical therapy)
          • Superficial muscle bleeds
            • Maintain level of 40 to 60 units/dL for 2 to 3 days
          • Joint bleeds
            • Maintain level of 40 to 60 units/dL for 1 to 2 days
          • Renal bleeds
            • Maintain level of 50 units/dL for 3 to 5 days
          • Deep lacerations
            • Maintain level of 50 units/dL for 5 to 7 days
        • Surgical prophylaxis and postoperative maintenance
          • Major surgery
            • Preoperative goal is plasma level of 80 to 100 units/dL
            • Postoperative goals
              • Maintain level of 60 to 80 units/dL for days 1 to 3
              • Maintain level of 40 to 60 units/dL for days 4 to 6
              • Maintain level of 30 to 50 units/dL for days 7 to 14
          • Minor surgery
            • Preoperative goal is plasma level of 50 to 80 units/dL
            • Postoperative goal is 30 to 80 units/dL for 1 to 5 days
    • Bypassing agents
      • Prophylaxis r33
        • Activated prothrombin complex concentrate (eg, Feiba) c114c115
          • Anti-Inhibitor Coagulant Complex (Human) Solution for injection; Adults, Adolescents, Children, and Infants: 85 units/kg IV every other day.
            • Alternative dosing frequency: give on 3 nonconsecutive days a week.
        • Recombinant factor VIIa (eg, eptacog alfa) c116c117
          • 2 dosages have been used in studies, with similar efficacy:
            • Factor VIIa (Recombinant Solution for injection); Adults, Adolescents, and Children: Optimal dosing has not been determined; either 90 mcg/kg IV daily or 270 mcg/kg IV daily; both dosages were found to be safe and effective. r33
      • Bleeding control r25
        • Activated prothrombin complex concentrate (eg, Feiba) r45
          • 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.
        • Recombinant factor VIIa (eg, eptacog alfa) r46c118
          • 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.
          • Higher dosing is required for patients with inhibitors (antibodies)
    • Recombinant porcine factor VIII c119
      • Bleeding control r47c120
        • Antihemophilic Factor VIII (Recombinant), Porcine Sequence Solution for injection; Adults: 200 units/kg IV initially. Subsequent dose, frequency, and duration of treatment depend on severity of factor VIII deficiency, location and extent of bleeding, and patient's clinical condition. Doses may be administered every 4 to 12 hours. For minor and moderate bleeding, required circulating factor VIII concentration is 50% to 100% of normal. For major bleeding, required circulating factor VIII concentration is 100% to 200% of normal for acute bleed and 50% to 100% of normal after bleed is controlled, if needed. Max plasma concentration of factor VIII: 200% of normal or 200 units/dL.
    • Vasopressin synthetic analogues
      • Desmopressin c121
        • IV
          • Desmopressin Acetate Solution for injection; Infants, Children, and Adolescents 3 months to 17 years: 0.3 mcg/kg/dose (Max: 20 mcg/dose) IV once. Determine need for repeat dosage based on laboratory response and patient's clinical condition.
          • Desmopressin Acetate Solution for injection; Adults: 0.3 mcg/kg/dose (Max: 20 mcg/dose) IV once. Determine need for repeat dosage based on laboratory response and patient's clinical condition.
        • Nasal
          • Desmopressin Acetate Nasal spray, solution; Infants, Children, and Adolescents 11 months to 17 years weighing less than 50 kg: 150 mcg into 1 nostril once for a total dose of 150 mcg. Determine need for repeat dosage based on laboratory response and patient's clinical condition.
          • Desmopressin Acetate Nasal spray, solution; Children and Adolescents weighing 50 kg or more: 150 mcg into each nostril once for a total dose of 300 mcg. Determine need for repeat dosage based on laboratory response and patient's clinical condition.
          • Desmopressin Acetate Nasal spray, solution; Adults weighing less than 50 kg: 150 mcg into 1 nostril once for a total dose of 150 mcg. Determine need for repeat dosage based on laboratory response and patient's clinical condition.
          • Desmopressin Acetate Nasal spray, solution; Adults weighing 50 kg or more: 150 mcg into each nostril once for a total dose of 300 mcg. Determine need for repeat dosage based on laboratory response and patient's clinical condition.
    • Antifibrinolytic agents
      • Aminocaproic acid r28c122
        • Oral
          • Aminocaproic Acid Oral tablet: Adults, Adolescents, and Children: 50 to 100 mg/kg PO every 6 hours to preserve the clot until healing has taken place (10-14 days).
        • IV
          • For prevention of bleeding after dental or otolaryngologic surgery
          • Aminocaproic Acid Solution for injection; Adults: 1 g/hour IV as continuous infusion for 8 hours or until therapeutic response is achieved (Max 30 g/day), followed by 50 to 100 mg/kg PO every 6 hours to preserve the clot until healing has taken place (10-14 days).
      • Tranexamic acid
        • For menorrhagia c123
          • 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 c124
          • Tranexamic Acid Oral tablet; Adults: 1 to 4.5 g/day PO in 2 to 4 divided doses.
    • Autoantibody eradication therapy for acquired hemophilia
      • Prednisone c125
        • Prednisone Oral tablet; Adults: 1 to 2 mg/kg/day PO for 4 to 6 weeks. r40r41
      • Cyclophosphamide c126
        • Cyclophosphamide Oral capsule; Adults: 1 to 2 mg/kg/day PO for up to 5 weeks. r40r41
      • Rituximab c127
        • Rituximab (Murine) Solution for injection; Children and Adolescents: 375 mg/m2 IV once weekly for 4 doses.
        • Rituximab (Murine) Solution for injection; Adults: 375 mg/m2 IV once weekly for 4 doses.
    • Monoclonal antibody
      • Discontinue prophylactic use of bypassing agents the day before starting emicizumab prophylaxis c128
      • Prophylactic use of factor VIII products may be continued during the first week of emicizumab prophylaxis
        • Emicizumab Solution for injection; Infants, Children, and Adolescents: 3 mg/kg/dose subcutaneously once weekly for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg/dose once every week, 3 mg/kg/dose once every 2 weeks, or 6 mg/kg/dose once every 4 weeks. Base maintenance dose selection on healthcare provider preference and patient adherence.
        • Emicizumab Solution for injection; Adults: 3 mg/kg/dose subcutaneously once weekly for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg/dose once every week, 3 mg/kg/dose once every 2 weeks, or 6 mg/kg/dose once every 4 weeks. Base maintenance dose selection on healthcare provider preference and patient adherence.

    Nondrug and supportive care

    Avoid drug products containing aspirin or NSAIDs c129c130

    • May cause or exacerbate bleeding

    Administer hepatitis A and hepatitis 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 r5c131
    General explanation
    • Aspiration to remove blood from joint and prevent long-term joint damage after factor replacement therapy
    • Perform within 48 hours of bleeding onset
    • Assess for inhibitors; may need to use other hemostatic agents if present r5
    Indication
    • Persistent tense swelling after 24 hours
    • Refractory pain
    • Neurovascular compromise
    • Evidence of joint infection (fever, unremitting pain, calor over the joint)
    Physiotherapy r5c132
    General explanation
    • Adjunctive treatment after factor replacement therapy to maintain joint function; begin as soon as possible after bleeding has stopped and 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 c133d3
      • 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 c134d4
      • Patients with diabetes may use subcutaneous insulin as indicated c135
      • Acute coronary syndrome c136d5
        • 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
        • Give factor concentrates for the period of dual antiplatelet activity

    Special populations

    • Female carriers r5
      • Usually have factor VIII levels approximately 50% of normal; commonly minimally symptomatic
        • However, may have mildly increased bleeding tendency
        • Consider genetic testing in girls and women with menorrhagia and a family history of a bleeding disorder r48
      • Some have lower levels and bleeding manifestations consistent with mild hemophilia
      • Offer genetic testing to possible carriers and genetic counseling to known carriers
      • For pregnant carriers, prenatal diagnosis may be offered
        • Fetal gender can be determined at 7 to 9 weeks of gestation by polymerase chain reaction on maternal blood, or around 11 weeks by ultrasonography
        • Chorionic villus sampling or amniocentesis can be done for genetic testing of fetus at 9 to 14 weeks and 15 to 17 weeks of gestation, respectively
      • Monitor factor VIII levels during third trimester in pregnant carriers, and if levels are below 50 units/dL, make arrangements for factor replacement therapy during delivery
        • Delivery should be accomplished by the least traumatic means to prevent bleeding in both mother and infant
        • Avoid forceps, vacuum extraction, and fetal scalp monitoring
        • Women with factor levels higher than 50% may undergo epidural anesthesia during labor and delivery r49
      • A team of specialists, including a neonatologist, should manage pregnant carriers r49

    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 c137
      • Record of interim bleeding episodes c138
      • Use of replacement products and response to them (efficacy, adverse events)
      • Presence of inhibitors c139
      • Musculoskeletal status c140
      • Oral health/hygiene c141
      • Psychosocial status c142
    • Monitor patients with hemophilia who receive factor replacement therapy for 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 c143
        • 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) c144
      • 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 r5c145
    • For patients receiving plasma-derived products that are not virus-inactivated: test for HIV, hepatitis B (HBsAg, anti‐HBc, anti‐HBe, anti‐HBs), and hepatitis C (anti‐HCV) every 6 to 12 months r5c146c147c148c149c150c151

    Complications and Prognosis

    Complications

    • Musculoskeletal complications
      • Chronic hemophilic arthropathy c152
        • 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 c153
      • 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 r50
        • Radiotherapy r50
        • Limb amputation
    • Treatment complications
      • Development of inhibitors (alloantibodies against coagulation factor VIII)
        • Approximately 40% of patients with hereditary hemophilia A develop inhibitors r3
          • More common in patients with severe hemophilia A
        • High-titer inhibitors make factor VIII replacement ineffective and make bleeds difficult to control
          • Lack of response to factor replacement therapy may indicate presence of inhibitors
        • Presence of factor VIII 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 factor replacement therapy r5
          • Patients with high inhibitor levels (5 or more Bethesda units/mL) require bypassing therapies instead r5
            • Bypassing agents that trigger the coagulation cascade at a point beyond factor VIII for episodic or prophylactic therapy
              • Activated prothrombin complex concentrates
              • Recombinant factor VIIa (eg, eptacog alfa)
              • Emicizumab
            • Immune tolerance induction therapy, given for a prolonged period, may result in loss of inhibitor
        • Routine screening for inhibitors is recommended in patients who are treated with replacement factor r5
          • Children beginning treatment: screen once every 5 exposure days up to 20 exposure days, then every 10 exposure days up to 50 exposure days, and then twice a year until 150 exposure days
            • Exposure day is defined as a day during which 1 or more infusions of factor VIII are given
          • Adults with more than 150 exposure days: screen annually
          • Patients who have been intensely treated for more than 5 days within 4 weeks of last infusion: rescreen
        • In addition to routine monitoring, certain circumstances should prompt testing for factor VIII inhibitors in patients with hereditary hemophilia A who have received factor replacement therapy r39
          • Poor response or treatment failure with factor replacement therapy
          • Intensive treatment for more than 5 days within 4 weeks of the most recent infusion r51
          • Preparation for surgery
          • A switch to a new factor replacement product
      • 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
      • In the past, infectious complications from bloodborne viruses (eg, HIV, hepatitis B virus, hepatitis C virus) have been a major cause of death and chronic comorbidities r5
        • Availability of recombinant products essentially eliminates the risk; additionally, 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
      • Thrombosis and thromboembolism may occur with the use of certain products (eg, prothrombin complex concentrates, vasopressin, emicizumab) and in some clinical situations (eg, indwelling central lines, critical illness) r28

    Prognosis

    • Hereditary hemophilia A
      • Prophylactic factor replacement therapy
        • If prophylaxis is started before the second joint bleed, patients have better outcomes r52
          • Patients experience fewer bleeds and are at lower risk for arthropathy
      • Median life expectancy for patients with hemophilia A depends on disease severity r53
        • Median life expectancy is 63 years for severe disease
        • Median life expectancy is 75 years for moderate or mild disease
        • Children who receive regular care with access to appropriate treatment have normal life expectancy
      • Mortality rates are higher than for the general population; increases correlate with disease severity r53
        • 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%
        • Increases use of home factor-infusion practices by a factor of 2.4
    • Acquired hemophilia A
      • Immunosuppressive therapy
        • Approximately 60% to 80% of patients reach remission r11r54
          • Patients treated with a steroid alone r54
            • 58% reach complete remission
            • Undetectable inhibitor levels are achieved in 17 to 76 days
            • 48% reach stable remission
            • 18% have relapse
          • Patients treated with a steroid and cyclophosphamide r54
            • 80% reach complete remission
            • Undetectable inhibitor levels are achieved in 12 to 77 days
            • 70% reach stable remission
            • 12% have relapse
          • Patients treated with steroids and rituximab r54
            • 64% reach complete remission
            • Undetectable inhibitor levels are achieved in 28 to 109 days
            • 64% reach stable remission
            • Relapse is uncommon
      • Mortality rates for acquired hemophilia A are 28% to 42% r55
        • Underlying cause and/or complications of immunosuppressive treatment often contribute

    Screening and Prevention

    Screening

    At-risk populations

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

    Screening tests

    • Ascertain the carrier status through molecular diagnosis of the causative mutation in F8r19
      • Prenatal or newborn genetic testing for mutations in F8 gene r8c154
        • Perform chorionic villus sampling, amniocentesis, or umbilical cord blood sampling
        • Polymerase chain reaction amplification and sequencing
          • Inversion of intron 1 or 22 in F8 accounts for approximately 40% of cases of severe hemophilia A r19
          • Point mutations in coding region of F8 account for the remaining cases r19
      • First-degree female relatives r5
        • May wish to undergo genetic testing if planning pregnancy
        • Should have factor VIII levels measured before invasive procedures c155
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