Hemophilia C 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. Recombinant activated factor VII is useful for patients with inhibitors.

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. Although not in factor Xi deficiency, 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.

Class Summary

FFP is the first product used to treat patients with hemophilia C. The main advantage of FFP is its availability. Disadvantages to 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.

Fresh frozen plasma

This is the product of choice when factor XI concentrates are not available. FFP is easily available. It can be infused over a short period. Disadvantages include large infusion volumes to achieve appropriate control of bleeding, a potential for transmitting infective agents, and the possibility of allergic reactions.

Human coagulation factor Xl (Hemoleven)

Factor XI concentrates provide the best source for factor XI replacement. Two products available in Europe 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 are not expected to transmit the human immunodeficiency virus (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 of the attendant disadvantages of any plasma-derived product.

Several issues are encountered with the use of factor XI concentrates. 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 studied 229 treatment episodes with factor XI concentrate (BPL) 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. The 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. 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%, with a half-life of 46 hours (range, 32-52 h). Thromboembolic events occurred as complication in 3 infusions exceeding 30 U/kg.

Hemoleven and factor XI concentrate (BPL) are heat treated and are therefore not expected to transmit HIV or hepatitis viruses.

Fibrin sealant (Tisseel, Artiss, Evicel)

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) approved a fibrin sealant (Tisseel VH; Baxter Healthcare Corporation, Westlake Village, Calif) for adjunctive topical hemostasis. Fibrin sealant contains fibrinogen (sealer protein) as the main active ingredient and fibrinolysis inhibitor (aprotinin) of bovine origin. Two reconstituted components, sealer protein, and thrombin solutions are mixed and applied topically. The viscous solution quickly sets into an elastic coagulum.

Class Summary

Antifibrinolytic agents are important adjuncts in patients undergoing surgery in areas of the body prone to increased fibrinolysis (oral cavity, 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)

This agent's antifibrinolytic effects result primarily from the inhibition of plasminogen activators and, to lesser degree, antiplasmin activity.