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    Hemophilia C

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    Dec.16.2022

    Hemophilia C

    Synopsis

    Key Points

    • Hemophilia C is a rare bleeding disorder characterized by disproportionate bleeding after injury or surgery, especially in mucous membranes
    • Caused by mutation in F11 gene, which encodes coagulation factor XI; most mutations are autosomal recessive with variable penetrance
    • Characterized by prolonged activated partial thromboplastin time that corrects when the patient sample is mixed with normal plasma; assay finds low levels of factor XI activity
    • 49% of patients are asymptomatic; in symptomatic patients, excess bleeding is usually associated with trauma or surgery involving the nasal, oropharyngeal, or urogenital mucosa r1
    • Women with factor XI deficiency are at increased risk for postpartum hemorrhage compared with general population (16% versus 5%) r2
    • Episodic bleeding can be treated with factor XI concentrate (available only in parts of Europe), fresh frozen plasma, or antifibrinolytic agents
    • Prophylaxis with these agents can be given in advance of scheduled procedures and intrapartum once labor is established

    Urgent Action

    • Severe bleeding is unusual but requires prompt administration of factor XI replacement

    Pitfalls

    • Hemophilia C can be categorized by level of deficiency, but that level does not predict bleeding likelihood or severity
    • Factor replacement therapy can induce development of inhibitors (alloantibodies) to factor XI, rendering subsequent administration ineffective; this happens most commonly in patients with certain F11 mutations and in those with very low factor XI levels

    Terminology

    Clinical Clarification r3

    • Hemophilia C is a rare bleeding disorder characterized by disproportionate bleeding after injury or surgery, especially in mucous membranes
    • Caused by deficiency or dysfunction of coagulation factor XI due to mutations of the gene that encodes it, F11

    Classification

    • Classified as a rare bleeding disorder r1
    • Can be categorized by level of deficiency, but that level does not predict bleeding likelihood or severity
      • Severe deficiency
        • Factor XI activity level less than 20 units/dL r3
      • Partial deficiency
        • Factor XI activity level of 20 to 60 units/dL r4

    Diagnosis

    Clinical Presentation

    History

    • Symptoms are variable, and bleeding tendency may vary over time
      • Many affected persons are asymptomatic c1
    • Excessive bleeding may occur after surgical or accidental trauma, most commonly involving mucosa of oral and nasal cavities or urogenital tract c2c3c4c5
      • Epistaxis (may appear spontaneous or associated with minor provocation such as dryness) c6
      • Dental procedures c7
      • Tonsillectomy c8
      • Menstruation (menorrhagia) c9
      • Childbirth c10
      • Hysterectomy c11
    • Spontaneous bleeds (eg, in joints or deep muscles) are uncommon c12c13c14
    • Efforts should be made to characterize and quantify bleeding in some manner, to determine whether it is disproportionate
      • Various tools have been developed to identify trigger (trauma versus spontaneous) and to ascertain timing (immediate versus delayed), quantity and duration of bleeding, and response to treatment r5r6
    • Family history of excessive bleeding, including triggers, sites, and bleeding duration, may be helpful c15

    Physical examination

    • Physical examination is likely to be unrevealing except during a bleeding episode
      • Blood visible in mouth (eg, along gingiva) or nose c16c17
      • Continuous oozing at surgical site or traumatic wound c18
    • Ecchymoses may be observed at sites of known or unrecognized trauma c19

    Causes and Risk Factors

    Causes

    • Mutations of F11 gene (coagulation factor XI) resulting in deficient or dysfunctional proenzyme c20

    Risk factors and/or associations

    Age
    • Condition is present from birth, but it may not become evident until there is a need for surgery or a significant traumatic injury occurs
    Genetics
    • Nearly 200 mutations of F11, which is located on chromosome 4 (4q35.2), have been described (OMIM *264900) r7r8c21
      • Most are autosomal recessive with variable penetrance, although some appear to be dominant r7r9c22c23
      • Certain mutations are associated with increased likelihood of developing an inhibitor
    • In Ashkenazi Jews, in whom there is an increased prevalence, 2 mutations predominate: r9
      • Type II (Glu117Stop)
        • About 30% of homozygous patients develop inhibitors to factor XI r4
      • Type III (Phe283Leu)
    • In other populations, a wider variety of mutations is observed r9
    • Clotting factor deficiency is more profound in homozygotes than heterozygotes, although it may be significant in compound heterozygotes r8
    Ethnicity/race
    • Common in (but not limited to) Ashkenazi Jews, among whom about 5% are carriers, with severe deficiency present in about 1 of 450 persons r8c24

    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 r10c25
    • If initial tests of coagulation (prothrombin time with INR, activated partial thromboplastin time) yield abnormal results, a mixing test is indicated r10
      • Normal plasma is added to patient plasma in a 1:1 ratio
      • Correction of the abnormal value implies that a missing coagulation factor has been supplied by the normal plasma
    • Missing factor (eg, factor XI) can be identified by the appropriate antigen assay and by exclusion of other deficiencies or inhibitors (ie, antibodies against coagulation factors) r9
    • Genetic testing may be done to further characterize the mutation, which may aid in identifying affected family members and in genetic counseling r9

    Laboratory

    • Activated partial thromboplastin time c26
      • Usually but not invariably prolonged r11
      • When clinical suspicion for factor XI deficiency is strong, a factor XI assay should be considered regardless of normal activated partial thromboplastin time r11
    • Mixing test c27c28
      • Activated partial thromboplastin time is tested immediately after patient and normal plasma samples are mixed, and again after 1- to 2-hour incubation
      • Prolonged activated partial thromboplastin time after 1- to 2-hour incubation (even if initial result was normal) suggests the presence of a clotting factor inhibitor, the activity of which may be delayed r12
        • Inhibitors to numerous factors exist, and they are usually not pertinent to initial diagnosis of hemophilia C; however, exposure to factor XI through factor replacement therapy or other blood products may induce development of a factor XI inhibitor, with important implications for treatment
        • Such inhibitors are further identified and quantified by a Bethesda assay
    • Factor XI assay c29
      • Severe deficiency of factor XI activity
        • Less than 20 units/dL r13
      • Partial deficiency of factor XI activity
        • 20 to 60 units/dL r13
    • Genetic testing c30
      • Polymerase chain reaction can identify a number of known mutations r9

    Differential Diagnosis

    Most common

    • Hemophilia C is fundamentally a laboratory diagnosis based on demonstration of inadequate levels of factor XI activity; whereas other bleeding diatheses may have similar presentations, the distinction is made primarily on the basis of laboratory findings
    • Clinically similar conditions include:
      • Congenital hemophilia A and B c31c32
        • Blood disorders due to deficiencies of coagulation factors VIII and IX, respectively d1
        • Hemophilia A and B may be virtually indistinguishable from each other in clinical presentation of disproportionate and prolonged bleeding d2
        • Unlike hemophilia C, these conditions are characterized by deep and spontaneous bleeding
        • All are characterized by prolonged activated partial thromboplastin time that corrects when mixed with normal plasma, normal prothrombin time and INR, and normal platelet count
      • von Willebrand disease c33
        • 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; similar to hemophilia C, some patients experience recurrent and prolonged episodes of spontaneous epistaxis, severe gingival bleeding associated with dental work, menorrhagia, and/or excessive bleeding after trauma or surgery
        • Differentiated by demonstrating low Willebrand factor antigen levels (less than 30 units/dL) r14
      • Other coagulation factor deficiencies r15
        • May present with a variety of bleeding patterns; may be spontaneous or out of proportion to injury; prolonged bleeding and rebleeding after initial control may be observed
        • In deficiencies of high-molecular-weight kininogen, prekallikrein, factor XII, and factor VII, activated partial thromboplastin time is prolonged (as with hemophilia C) c34c35c36c37
        • In factor VII deficiency, prothrombin time is prolonged and activated partial thromboplastin time is normal, unlike with hemophilia C
        • Deficiencies of factors V, X, II, and I (fibrinogen) result in prolongation of both prothrombin time and activated partial thromboplastin time c38c39c40c41
        • Normalization of result with addition of normal plasma (mixing test) confirms factor deficiency
        • Assays for the possibly deficient factor(s) confirm the diagnosis
        • Inhibitors (antibodies against specific coagulation factors) may present with bleeding tendencies similar to congenital deficiencies, although usually not until mid-life or later c42
          • They can be distinguished from congenital factor deficiency by failure of normal plasma to correct prolonged coagulation result either immediately or (more commonly) after incubation for 2 hours; detection of inhibitor by Bethesda assay confirms the diagnosis
      • Thrombocytopenia or platelet dysfunction c43c44
        • As with hemophilia C, characterized by disproportionate bleeding after injury and dental or surgical procedures
        • Unlike with hemophilia C, petechiae are characteristic physical findings
        • Unlike with most cases of hemophilia C, activated partial thromboplastin time is normal
        • Differentiation is made by platelet count and platelet function studies
      • Vitamin K deficiency c45c46
        • 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 predictable bleeding
      • Scheduled surgery or dental work; childbirth
    • Treat episodic bleeding
      • Trauma
      • Procedure-related in setting of emergency or previously unrecognized bleeding disorder

    Disposition

    Admission criteria

    Admission may be required if bleeding is not readily controlled with outpatient or emergency department care; length of stay for invasive procedures (or childbirth) may be increased

    Criteria for ICU admission
    • Oropharyngeal bleeding that threatens the airway
    • May be necessary in the unlikely event of prolonged or profuse bleeding resulting in hemodynamic instability

    Recommendations for specialist referral

    • Patients with hemophilia C should be managed in conjunction with a hematologist
    • Dental care (even routine care) should be provided by a dentist with expertise in managing oral care of patients with bleeding disorders
    • Refer to a gynecologist for management of menorrhagia
    • Consider consulting a maternal-fetal medicine specialist to help manage pregnancy and delivery of pregnant patients with hemophilia C
    • Refer to a geneticist to guide genetic testing to identify the specific mutation involved and to provide genetic counseling

    Treatment Options

    Prophylaxis (periprocedural) and treatment include replacement of factor XI and/or use of antifibrinolytic drugs (ie, tranexamic acid, aminocaproic acid) r5

    • Virus-inactivated factor XI concentrate is available in some European countries; elsewhere, factor XI replacement is provided through administration of fresh frozen plasma (preferably pathogen-inactivated product if available)
      • Factor XI concentrates have been associated with thrombotic events; use of these agents in conjunction with systemic antifibrinolytic therapy or in patients with preexisting risk factors for thrombosis should generally be avoided r11
    • Use of recombinant factor VIIa (eg, eptacog alfa) may be considered in patients who have factor XI inhibitors or who are at high risk for developing them; this is a bypassing agent that activates the coagulation cascade at a point beyond the factor XI step r4
    • Desmopressin has been used, although efficacy is unclear r4

    Determining the need for prophylaxis is problematic r8

    • Quantitative measures of factor XI activity do not predict bleeding tendency; some patients with very low levels do not experience excessive bleeding, and some patients with higher levels do
    • Researchers are investigating global coagulation assays to provide a more precise measure of bleeding tendencies in people with decreased factor XI activity r16
    • Negative bleeding history does not preclude the possibility of excessive bleeding during surgery
    • Exposure of patients who are homozygous for the Glu117Stop mutation to factor XI presents a significant risk for development of factor XI inhibitors r4
    • However, some considerations favor prophylaxis, as follows:
      • Procedures at certain sites generate more bleeding in patients with hemophilia C: nasal, dental, oropharyngeal, or genitourinary
      • Procedures at certain sites are inherently more risky and excessive bleeding, if it occurs, poses significant threat: neurosurgery; head and neck surgery; and cardiothoracic, abdominal, or pelvic procedures
    • Some experts support an expectant approach for procedures that are unlikely to result in profuse bleeding, such as circumcision, appendectomy, certain orthopedic procedures, and normal vaginal delivery (unless epidural anesthesia is planned)

    There are few published guidelines with specific recommendations for management of hemophilia C; UK Haemophilia Centre Doctors' Organisation offers the following: r11r17

    • Higher risk of bleeding is likely if:
      • Factor XI activity is less than 1 unit/dL
      • There is another coagulopathy present
      • There is personal history of excessive bleeding
      • Proposed surgery involves dental extraction or other procedure on oropharyngeal mucosa
      • Proposed surgery involves urogenital mucosa
    • Patients with factor XI activity less than 1 unit/dL are at high risk for developing factor XI inhibitors; they should be screened for inhibitors before childbirth or surgery if they have received factor replacement before
    • For minor bleeds or minor surgery in patients with higher bleeding risk, and for all bleeds and all surgery in patients with lower bleeding risk, consider tranexamic acid
    • For severe bleeding or major surgery in patients with higher bleeding risk, consider a dose of factor XI concentrate (if available), or a combination of fresh frozen plasma and tranexamic acid
    • For labor and delivery of women with recent factor XI level of less than 15 units/dL, consider a dose of factor XI concentrate (if available), fresh frozen plasma, or recombinant-activated factor VIIa
    • For labor and delivery of women with recent factor XI level of 15 to 70 units/dL and a history of excessive bleeding or no relevant hemostatic challenge, consider tranexamic acid
    • For labor and delivery of women with recent factor XI level of 15 to 70 units/dL and a history of relevant hemostatic challenge without excessive bleeding, manage expectantly. Consider tranexamic acid in women who have a history of excessive bleedingr17
    • Appropriate treatment of hemophilia C in various situations.Data from Mumford AD et al: Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol. 167(3):304-26, 2014; and Wheeler AP et al: The clinical management of factor XI deficiency in pregnant women. Expert Rev Hematol. 13(7):719-29, 2020
      Clinical situationAppropriate treatment
      Minor bleeds or minor surgery in patients with higher bleeding riskTranexamic acid
      All bleeds and all surgery in patients with lower bleeding riskTranexamic acid
      Severe bleeding or major surgery in patients with higher bleeding riskA dose of factor XI concentrate (if available), or a combination of fresh frozen plasma and tranexamic acid
      Labor and delivery of women with recent factor XI level of 15 to 70 units/dL and a history of excessive bleeding or no relevant hemostatic challengeTranexamic acid
      Labor and delivery of women with recent factor XI level of less than 15 units/dL and a bleeding history or an unknown bleeding historyA dose of factor XI concentrate (if available), fresh frozen plasma, or rFVIIa
      Labor and delivery of women with recent factor XI level of 15 to 70 units/dL and a history of relevant hemostatic challenge without excessive bleedingManage expectantly; consider tranexamic acid in women with history of excessive bleeding

    Menorrhagia can be controlled with antifibrinolytic agents; an intrauterine device or oral contraceptives may be considered r4

    World Federation of Hemophilia recommends immunization against hepatitis A and B for all patients with hemophilia r18

    • Exposure to blood products may increase the risk of acquiring these viruses, although viral inactivation processes applied to blood products are highly effective

    Drug therapy

    • Factor replacements
      • Factor XI concentration may be expressed as a percentage or as international units per deciliter
      • Factor XI concentrate c47
        • Currently available only in some European countries
        • For prophylaxis or episodic treatment: initial dose of 10 to 15 units/kg r11
          • After surgery, repeat as needed to maintain trough levels of 45 units/dL for 5 to 7 days r4
        • May be associated with increased risk of pathologic thrombosis r5
      • Fresh frozen plasma c48
        • For prophylaxis or episodic treatment: initial dose of 15 to 25 mL/kg r11
        • After surgery, repeat as needed to maintain trough levels of 45 units/dL for 5 to 7 days r4
        • Large volumes may result in fluid overload and increased risk of pathologic clotting r5
    • Antifibrinolytic agent
      • Tranexamic acid c49
        • For menorrhagia c50
          • 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 postpartum hemorrhage r11c51
          • Tranexamic Acid Solution for injection; Adults: 1000 mg IV given once within 3 hours of procedure. If bleeding continued after 30 minutes, or stopped but restarted within 24 hours of the first dose, a second dose of 1000 mg may be given. r19
        • For prophylaxis during surgery c52
          • Tranexamic Acid Solution for injection; Adults: 10 or 15 mg/kg IV bolus before start of procedure followed by second bolus 3 hours later or 1 mg/kg/hour continuous IV infusion until skin closure or for 6 hours after surgery.
        • Do not use to treat hematuria, owing to risk of clot formation and tubular obstruction r9
    • Bypassing agent
      • Recombinant factor VIIa (eg, eptacog alfa) c53c54
        • Factor VIIa Recombinant Solution for injection; Adults: 15 mcg/kg as a single dose immediately before surgery has been reported. r4

    Nondrug and supportive care

    • Avoid drug products containing aspirin or NSAIDs c55c56
      • May cause or exacerbate bleeding
    • Administer hepatitis A and hepatitis B vaccine to all nonimmune patients with hemophilia r18
      • 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

    Special populations

    • Pregnant patients r11
      • Obtain Factor XI levels before conception and during the third trimester r17
      • Need for factor replacement or fibrinolytic therapy for delivery is individualized by third trimester factor XI level and personal bleeding history r11
        • With a third trimester factor XI level less than 15 units/dL and a positive or unknown bleeding history, consider factor XI concentrate, fresh frozen plasma, or recombinant-activated factor VIIa in labor and delivery for both vaginal births and C-sections r17
        • With a third trimester factor XI level less than 15 units/dL and no bleeding history, consider tranexamic acid in labor and delivery r17
        • With factor XI level of 15 to 70 units/dL and history of excessive bleeding or no relevant hemostatic challenge, consider tranexamic acid r17
        • If recent factor XI level is 15 to 70 units/dL and there is history of relevant hemostatic challenge without excessive bleeding, manage expectantly. Consider tranexamic acid for women with a history of excessive bleeding r8
      • Delivery should be accomplished by the least traumatic means to prevent bleeding in both mother and infant r20
      • Avoid forceps, vacuum extraction, and fetal scalp monitoring r20
      • Anesthesiologists should make individual determinations of risks and benefits of epidural anesthesia r17

    Monitoring

    • Postoperatively, monitor factor XI levels of patients who have received factor replacement so that repeat doses may be administered as needed to maintain effective factor XI levels; goal is to keep trough levels higher than 45 units/dL and peak below 70 units/dL r4c57

    Complications and Prognosis

    Complications

    • Alloantibodies against exogenous factor XI (ie, inhibitors) can develop after factor replacement therapy, rendering subsequent administration ineffective c58
      • About 4% of patients with hemophilia C develop inhibitors r21
        • Happens most commonly in patients with certain F11 mutations and in those with very low factor XI levels
      • Lack of response to factor replacement may indicate presence of inhibitors
      • Diagnosis is suggested by mixing test results indicating failure of normal plasma to correct coagulation defect after incubation; a Bethesda assay can identify and quantify the inhibitor
      • Patients with inhibitors who need treatment or prophylaxis require administration of a bypass agent that triggers coagulation at a further point in the cascade r4
    • Women with factor XI deficiency are at increased risk for postpartum hemorrhage compared with general population (16% versus 5%) r2c59

    Prognosis

    • Bleeding severity is not correlated with factor XI activity r1
      • 49% of patients are asymptomatic
      • 19% of patients have bleeding after trauma
      • 29% of patients have minor bleeding
      • 3% of patients have spontaneous major bleeding

    Screening and Prevention

    Screening

    At-risk populations

    • There are no well-established guidelines for screening. Circumstances in which it may be considered include:
      • Newborns with family history of hemophilia C, if early circumcision is desired r4c60
        • Neonates have relatively low levels of factor XI, and levels rise for about 6 months r11
          • Use age-appropriate reference range
          • Retest after age 6 months
          • Consider delaying circumcision and other invasive procedures r17
      • Relatives of a person with factor XI deficiency
        • Screening may be appropriate in asymptomatic persons who are contemplating pregnancy or surgery c61c62
      • Prenatal screening of fetus of affected parents
        • There is disagreement about this indication; some argue that the usual low morbidity of this condition does not warrant the risks associated with amniocentesis or chorionic villus sampling, although a guideline by the UK Haemophilia Centre Doctors' Organisation suggests that it be offered in potentially severe cases r9r22c63

    Screening tests

    • In the absence of guideline recommendations, a reasonable initial test is activated partial thromboplastin time
    • For prenatal screening, testing for the implicated gene, if known (eg, F11 for hemophilia C), is suggested r22
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