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Hemophilia C

Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

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 ^c2^c3^c4^c5
- 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 ^c12^c13^c14
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 ^r5^r6
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 ^c16^c17
- 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) ^r7^r8^c21
- Most are autosomal recessive with variable penetrance, although some appear to be dominant ^r7^r9^c22^c23
- 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 ^r8^c24

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 ^r10^c25
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 ^c27^c28
- 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 ^c31^c32
  - 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) ^c34^c35^c36^c37
  - 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 ^c38^c39^c40^c41
  - 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 ^c43^c44
  - 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 ^c45^c46
  - 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: ^r11^r17

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 bleeding^r17

Appropriate treatment of hemophilia C in various situations.
Clinical situation	Appropriate treatment
Minor bleeds or minor surgery in patients with higher bleeding risk	Tranexamic acid
All bleeds and all surgery in patients with lower bleeding risk	Tranexamic acid
Severe bleeding or major surgery in patients with higher bleeding risk	A 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 challenge	Tranexamic 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 history	A 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 bleeding	Manage 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 ^r11^c51
    - 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) ^c53^c54
  - 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 ^c55^c56
- 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 ^r4^c57

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%) ^r2^c59

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 ^r4^c60
  - 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 ^c61^c62
- 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 ^r9^r22^c63

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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Hemophilia C

Synopsis

Key Points

Urgent Action

Pitfalls

Terminology

Clinical Clarification r3

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Genetics

Ethnicity/race

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Differential Diagnosis

Most common

Treatment

Goals

Disposition

Admission criteria

Criteria for ICU admission

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening

At-risk populations

Screening tests

Clinical Clarification ^r3