Approach Considerations
A study by Nagler et al looking at the long-term clinical course and laboratory data associated with four patients with congenital afibrinogenemia indicated that regular fibrinogen replacement or orthotopic liver transplantation can produce long-term remission. Arterial thrombi were found to have resolved after 6-12 months in the two patients who underwent such treatment, while the two who received infrequent fibrinogen replacement had recurrent thromboembolic events. [23]
Medical Care
Hemorrhage
Fibrinogen administration may offer a prophylactic benefit to patients with afibrinogenemia. The level of fibrinogen activity should be maintained at over 0.5 to 1.0 g/L via adjustment of dosage and how frequently the agent is taken. Pregnant women with afibrinogenemia must receive prophylaxis as early as possible, with such treatment continuing through pregnancy and after delivery. [24] For patients with clinical bleeding associated with afibrinogenemia or dysfibrinogenemia, replacement of fibrinogen to a level of more than 0.8 g/L is usually adequate to maintain hemostasis, although levels greater than 1 g/L have been recommended for CNS hemorrhage. Plasma-derived fibrinogen concentrates have the advantage of virus inactivation. [25, 26] Plasma recovery of fibrinogen with the use of fibrinogen concentrate is 1.8 mg/mL per mg/kg infused. Replacement with 70 mg/kg is recommended prior to surgical procedures and severe bleeding episodes, and 40 mg/kg for mild to moderate bleeding.
The half-life of fibrinogen is approximately 3.5 days, and afibrinogenemic patients can usually be managed postoperatively with infusion of replacement therapy every 2-3 days for major surgery.
Children have more rapid plasma fibrinogen clearance and may require higher and more frequent dosing for surgery and major bleeding. The therapeutic goal is to achieve a plasma fibrinogen activity level of 100-150 mg dL-1 prior to surgery that is maintained until hemostasis is achieved and wound healing is complete. [27]
Cryoprecipitate has been used as a source of fibrinogen; each bag of cryoprecipitate contains 100-250 mg of fibrinogen. The guidelines for dysfibrinogenemia are not standardized due to a lack of sufficient data in bleed management.
A study by Khayat et al indicated that in patients with inherited afibrinogenemia, a standard fibrinogen concentrate infusion dose (defined in the report as 40-100 mg/kg) does not induce hypercoagulability. While a statistically significant rise in endogenous thrombin potential and thrombin peak was found at 1 hour post infusion, the increases were nonetheless lower than those seen in healthy controls. The investigators also determined that at 1 hour the fibrin polymerization parameters “were comparable to those of patients with inherited hypofibrinogenemia matched for fibrinogen plasma levels.” [28]
Fibrinogen dosage calculation [9]
Dose (g) = desired increment in g/L x plasma volume (plasma volume is 0.07 x (1-hematocrit) x weight (kg)
The patient's personal and family history of bleeding and thrombosis should be taken into consideration for appropriate dosing of replacement therapy. In addition, the pharmacokinetics of fibrinogen after replacement therapy widely varies, and individual dose adjustment is recommended.
Thrombosis
Patients who present with thrombosis associated with dysfibrinogenemia should receive anticoagulation therapy. The duration of therapy has not been established for this particular group of patients; the decision depends on the clinical situation and the presence of other contributing factors. If the patient has had multiple thromboembolic events, a single life-threatening event, or has additional inherited risk factors, protracted anticoagulation therapy is recommended.
Spontaneous abortion
Recurrent spontaneous abortion may be prevented by routine prophylaxis with fibrinogen concentrates starting early in pregnancy.
Acquired inhibitors
Acquired inhibitors have been reported after replacement therapy and should be considered in previously treated patients who demonstrate poor hemostasis with usual therapies.
Surgical Care
To prevent excessive bleeding during surgical procedures, prophylactic treatment to raise fibrinogen levels to 1-1.5 g/L during the procedure is recommended. Replacement should be continued for 4-14 days following surgery, depending on the nature of the surgical procedure and time to complete healing.
Consultations
Consultation with a hematologist/hemostasis specialist is advisable for patients who require fibrinogen replacement therapy. Genetic counseling and family studies should be part of a complete evaluation.
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The conversion of soluble fibrinogen to insoluble fibrin.
