eMedicine Specialties > Pediatrics: General Medicine > Hematology
Hemophilia C: Treatment & Medication
Updated: Mar 10, 2009
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Treatment
Medical Care
Treatment of patients with factor XI deficiency is a challenge. Patients with severe deficiency are clearly and commonly at risk of bleeding from surgical procedures. Bleeding in these patients can start at the time of injury, or it can be delayed for several hours and persists until specific treatment is administered. Bleeding is much more likely in relation to surgery in areas of high fibrinolytic activity and is less common in other procedures.8 Therefore, patients with severe factor XI deficiency usually require replacement therapy before they undergo a surgical procedure, even if they have never bled after surgery before. Patients with partial deficiency can also have bleeding episodes similar to these, and plans for replacement therapy depend on previous history and site of surgery.
The basic principle of management consists of altering the balance between bleeding and clotting. Therapy consists of replacing the deficient factor and using other measures, such as fibrin glue and antifibrinolytics.
Surgical Care
Patients with factor XI deficiency who require surgery are at risk of excessive bleeding. The management should be discussed jointly between surgeon, hematologist and anesthesiologist, and a management plan set out in writing. Generally the use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided.
Consultations
Consult a pediatric or adult hematologist when the patient presents with excessive bleeding or when a preoperative laboratory evaluation reveals a prolonged activated partial thromboplastin time (aPTT).
Diet
No diet restrictions are necessary.
Activity
Advise patients to participate in only age-appropriate activities. Physical activity precautions also apply to patients with factor XI deficiency who have a bleeding tendency. Advise them against participating in contact sports if patient has severe disease.
Medication
Bleeding may not require specific treatment. When therapy is required, available options for patients with factor XI deficiency include antifibrinolytics, fresh-frozen plasma (FFP), ideally pathogen-inactivated (eg, solvent-detergent treated FFP), and factor XI concentrates. Factor XI concentrates are available in Europe but not in the United States.
Antifibrinolytics are particularly useful and may be sufficient for dental extractions even in patients with severe deficiency.
Adjunctive measures include the use of fibrin glue and desmopressin (DDAVP). Desmopressin is a synthetic antidiuretic hormone with actions that mimic those of vasopressin. It also increases levels of factor VIII and von Willebrand factor. DDAVP has widely been used as an adjunct to control bleeding during surgery since its discovery in various congenital bleeding disorders. To date, little documentation addresses the use of DDAVP in factor XI deficiency and the evidence is not very convincing.
Although some patients may not bleed during surgery, the physician has no way to ascertain which patients will not bleed. A history of clinically significant surgery without therapy and without excessive bleeding strongly suggests, but does not guarantee, satisfactory hemostasis with subsequent surgery. In the United States, patients with factor XI deficiency should be given plasma products before surgery when their risk is in doubt.
Replacement therapy during and/or after vaginal delivery is not mandatory in women with severe deficiency, and it can be restricted to patients in whom severe hemorrhage occurs. For women undergoing cesarean delivery, the same policy can be advocated, but additional observations are required. Tooth extractions can be managed by using only antifibrinolytic agents without replacement therapy. Epidural anesthesia without replacement therapy is not recommended in these patients.
Development of inhibitors is a known complication of therapy in patients with hemophilia A or B. Factor XI inhibitors may develop in patients with severe congenital deficiency, particularly with mutations leading to chain termination. One reason for the infrequent presence of inhibitors may be that many patients with factor XI deficiency never receive treatment with plasma products. However, when inhibitors do develop, they may cause clinically significant inhibition and clinical problems similar to those occurring in hemophilia A or B. Development of factor XI inhibitors may be treated successfully with plasma products, prothrombin complex concentrates, or recombinant factor VIIa. Before patients with hemophilia C undergo elective surgery in which plasma products will be used, they should be screened for inhibitors, as is done in patients with hemophilia A or B.
Plasma products
FFP is the first product used to treat patients with hemophilia C. The main advantage of FFP is its availability. Disadvantages of its use include the large volumes required, the potential for transmission of infective agents, and the possibility of allergic reactions.
Solvent-detergent–treated FFP has a factor XI half-life similar to FFP (mean, 45 h). It is safer than regular FFP because it reduces the transmission of known enveloped viral agents. However, it is not protective against nonenveloped viruses, such as hepatitis A virus (HAV).
Fresh frozen plasma
Product of choice when factor XI concentrates are not available. Easily available. Can be infused over short period. Disadvantages include large infusion volumes to achieve appropriate control of bleeding, potential for transmitting infective agents, and possibility of allergic reactions.
Adult
15-20 mL/kg IV loading dose, then 3-6 mL/kg q12h until hemostasis achieved; maintain target levels of 30-40 U/dL for about 7 d after surgery
Pediatric
Administer as in adults
Do not administer in same IV line as drugs
Documented hypersensitivity; in patients with allergic reaction and no clinical contraindications, weigh risks (eg, infusion with concurrent antihistamines, steroids) vs benefit (control of bleeding)
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Monitor young children for fluid overload; watch for allergic reactions during infusions; premedication with acetaminophen and antihistamine (eg, diphenhydramine) may reduce frequency of allergic reactions
Factor XI concentrates
Factor XI concentrates provide the best source for factor XI replacement. Since 1984, 3 products were developed and used in Europe, 2 of which currently are available there. The 2 products are Hemoleven (Laboratoire français du Fractionnement et des Biotechnologies [LFB], Les Ulis, France) and factor XI concentrate (Bio Products Laboratory [BPL], Elstree, Hertfordshire, United Kingdom). Both are heat treated and not expected to transmit HIV or hepatitis viruses. Both products also contain antithrombin III and heparin in different concentrations. These products appear to provide good treatment for selected patients.
The typical dose is 30 U/kg or less.
Advantages of factor XI concentrates include selective delivery of the deficient factor, a reduced volume of infusion, and viral safety. However, they are plasma-derived products; therefore, they can have all the attendant disadvantages of any plasma-derived product.
Several issues are encountered with the use of factor XI concentrates. In reports from Israel, 2 of 3 patients who received transfusions of a locally available concentrate and had activation of the coagulation system with D-dimer production and died.9 This product has been withdrawn from the market. The 2 previously mentioned concentrates, Hemoleven (LFB) and factor XI concentrate (BPL) are hemostatically effective and virally safe but are associated with evidence of activation of the coagulation system and some thrombotic events, especially in patients with preexisting vascular disease.
Briggs et al reported their experience with factor XI concentrate (BPL). They studied 229 treatment episodes in 161 patients aged 3-88 years and observed 21 adverse events in 19 patients, 12 of whom were probably or definitely thrombotic. Good hemostatic efficacy was reported in all. No transmission of HIV or hepatitis was reported. Mean factor XI recovery was 91% of the injected dose, and the mean half-life was 52 hours.
BPL was also used in the United States in a study of elective surgery in 12 patients aged 24-81 years.10 Only 1 patient developed anaphylaxis, and laboratory (not clinical) evidence of disseminated intravascular coagulation (DIC) was present. In all other patients, BPL was used successfully. Hemoleven, (LFB) produced results similar to those of factor XI concentrate from BPL. Thirty-one patients aged 5-76 years undergoing 33 procedures received Hemoleven (LFB). Recovery was 80% ± 16%, with a half-life of 46 hours (range, 32-52 h). Thromboembolic events occurred as complication in 3 infusions exceeding 30 U/kg.
Factor XI concentrate (Hemoleven, factor XI concentrate [BPL])
Heat-treated factor XI concentrates; hence, not expected to transmit HIV or hepatitis viruses. See discussion above.
Adult
Not to exceed 30 U/kg/d IV
Pediatric
Administer as in adults
None reported
Documented hypersensitivity; previous history of DIC with use of these products
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in elderly persons with preexisting cardiovascular disease and in preexisting activation of coagulation system (pregnant or puerperal women, patients with malignancy); if benefit outweighs risk of thromboembolic events, combine concentrates with low-molecular-weight heparin
Avoid doses >30 U/kg; avoid peak factor XI levels of >50-70 U/dL in patients with severe deficiency; avoid concurrent use of antifibrinolytic agents (aminocaproic acid [Amicar], tranexamic acid); administer concentrates only in centers experienced in managing bleeding disorders; monitor thrombotic markers
Fibrin glue
Fibrin glue is sometimes used as an adjunct to or substitute for plasma products. Centeon glue (Beriplast) has been used successfully in Israel in patients with congenital bleeding disorders who are undergoing dental extractions without blood product replacement. The glue is applied with a pair of syringes, one containing calcium and thrombin and one containing fibrinogen, factor XIII, and aprotinin.
The US Food and Drug Administration (FDA) recently approved a fibrin sealant (Tisseel VH; Baxter Healthcare Corporation, Westlake Village, CA) for adjunctive topical hemostasis.
Fibrin sealant (Tisseel VH)
Contains fibrinogen (sealer protein) as main active ingredient and fibrinolysis inhibitor (aprotinin) of bovine origin. Two reconstituted components, sealer protein, and thrombin solutions are mixed and applied topically. Viscous solution quickly sets into an elastic coagulum.
Adult
Apply topically; amount depends on surface area to be treated and method of application
Pediatric
Administer as in adults
Systemic heparin may reduce efficacy because of thrombin inhibition
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Denatured by contact with solutions containing alcohol, iodine, or heavy-metal ions; do not apply before wound surface is cleaned; some patients develop antifactor V antibodies, which can result in bleeding
Antifibrinolytic agents
Antifibrinolytic agents are important adjuncts in patients undergoing surgery in areas of the body prone to increased fibrinolysis (oral cavity, bladder, uterus). These agents may be effective when used alone in patients who have severe factor XI deficiency and who are undergoing dental extractions.
Aminocaproic acid (Amicar)
Antifibrinolytic effects result primarily from inhibition of plasminogen activators and, to lesser degree, antiplasmin activity.
Adult
Loading dose: 5 g PO/IV
Maintenance dose: 1 g q6h PO/IV for 7 d
Pediatric
Loading dose: 100 mg/kg PO/IV
Maintenance dose: 75-100 mg/kg/dose PO/IV q6h for 7 d
Coadministration with estrogens may cause increase in clotting factors, leading to hypercoagulable state
Documented hypersensitivity; evidence of active intravascular clotting process; because drug can be fatal in patients with DIC, important to differentiate between hyperfibrinolysis and DIC
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Injection contains benzyl alcohol as preservative and not recommended for use in newborns; rapid IV administration may induce hypotension, bradycardia, and/or arrhythmia; do not administer concomitantly with prothrombin complex concentrates or activated prothrombin concentrate unless anticipated clinical benefit outweighs increased risk of thrombosis
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References
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Further Reading
Keywords
hemophilia C, plasma thromboplastin antecedent deficiency, factor XI deficiency, factor XIC, factor XIc, clotting, deficiency of factor XI, clotting activity, blood coagulation, thrombin-activatable fibrinolysis inhibitor, TAFI, bleeding tendency, excessive bleeding, ischemic stroke, von Willebrand disease, menorrhagia, tonsillectomy, massive hemothorax, cerebral hemorrhage, subarachnoid hemorrhage, spinal epidural hematoma, systemic lupus erythematosus, Noonan syndrome
