Cryoprecipitate/Fibrinogen concentrate transfusions

Fibrinogen is a critical coagulation protein involved in both primary and secondary hemostasis. Cryoprecipitate preparation was first described by Dr. Judith Graham Pool in 1964 at Stanford University as a product for factor VIII replacement in patients with hemophilia A. Its use for hemophilia A has been superseded by safer, virally inactivated recombinant products. At the present time, cryoprecipitate is only used for fibrinogen replacement for patients with acquired bleeding disorders and hypofibrinogenemia. The product also contains fibrinogen, von Willebrand factor, fibronectin, factor XIII, and platelet microparticles. The hemostatic contribution of these other hemostatic factors in the management of the trauma patient is unknown. Each 10-unit pool must contain typically at least 1.5 g (150 mg per unit) of fibrinogen by regulatory requirements, although may contain substantially more due to donor variability. In contrast, fibrinogen concentrate is a heat-treated, lyophilized fibrinogen powder made from pooled human plasma which must be reconstituted with water prior to injection. Each vial contains between 900 and 1300 mg fibrinogen, as well as 400 and 700 mg human albumin. Hypofibrinogenemia is common in trauma patients on arrival (<1.5 g/L in 14%, <1.0 g/L in 5% and <0.5 g/L in 3% in adult trauma patients) and may be more common in pediatric trauma patients (52% <2.0 g/L, 20% <1.0 g/L, and 11% undetectable). A preserved fibrinogen level on arrival to the hospital is associated with substantially better outcomes (odds of death reduced by 0.22 during the first 28 days for every 1 g/L rise in baseline fibrinogen). The fibrinogen is depleted by a combination of factors including consumption at sites of injury, hemodilution from intravenous fluids, and depletion from hyperfibrinolysis due to activation of protein C and uncontrolled release of tissue plasminogen activator (tPA). Worldwide, approximately 10% of cryoprecipitate distributed to hospitals is transfused to trauma patients. Adult patients on average receive a dose of approximately 10 units of cryoprecipitate at about 3 h after arrival to hospital (at about the eighth unit of red cells), and with a rise in fibrinogen level of 0.5-0.9 g/L posttransfusion. Several retrospective studies and small prospective trials in adult and pediatric, civilian and military, trauma settings suggest that more aggressive use of fibrinogen replacement may improve outcomes. It is unclear what should be the appropriate dose, threshold for administration, or hemostatic target level for fibrinogen. Studies from the settings of cardiac surgery and postpartum hemorrhage suggest that the target of 1.0 g/L in some guidelines may be inadequate for some patients and that a higher target may be necessary (>1.5-2.0 g/L). A large clinical trial in trauma hemorrhage to access the effects of early high dose fibrinogen replacement with cryoprecipitate on survival is currently in progress. While we await better evidence on when and how cryoprecipitate should be used, it is reasonable to administer cryoprecipitate if the fibrinogen is under 2 g/L and the patient has serious ongoing hemorrhage. A dose of 10 units (or 50 mg/kg of fibrinogen in pediatrics) or equivalent does of fibrinogen concentrate (4 g) is a reasonable starting dose as such patients will typically be receiving some fibrinogen replacement with each bag of plasma.