Cryoprecipitate and Fibrinogen Concentrates

Fibrinogen Replacement

Hypofibrinogenemia occurs in patients with disseminated intravascular coagulopathy (DIC), with liver failure, after cardiac surgery, during the anhepatic phase of liver transplantation surgery, and during massive transfusion. In an actively bleeding patient or before surgery, fibrinogen product should be given when fibrinogen levels fall below 100 mg/dL, although more evidence and guidelines recommend a trigger of 150–200 mg/dL, as clot strength increases linearly with a minimum of 200 mg/dL required in vitro for optimal rate of clot formation. Early intervention can reduce the amount of red blood cells (RBCs) transfused. When the fibrinogen does fall below 100 mg/dL, there is a prolongation of the prothrombin test (PT) and activated partial thromboplastin time (aPTT) that cannot be corrected by the infusion of plasma products. Once the PT and aPTT are critically abnormal and with significant bleeding in the patient, it can be more important to intervene with the transfusion of a fibrinogen product than to await fibrinogen levels. In cardiac surgery, transplant surgery, and trauma, rather than wait for lab testing, the viscoelasticity of the clot is assessed periodically during the procedure to determine the appropriate needs for transfusion. Postoperative fibrinogen levels in cardiac surgery may be an independent predictor of severe bleeding postoperatively. Mathematical modeling would suggest a prophylactic trigger of 115 mg/dL with a target of 280 mg/dL. For those with severe bleeding already, a trigger of 215 mg/dL should be used with a target of 375 mg/dL. Fibrinogen products are also used for fibrinogen replacement in patients with congenital or acquired abnormalities in fibrinogen, such as afibrinogenemia, hypofibrinogenemia, or dysfibrinogenemia. It may also be used preprocedure in plasma exchange to keep the intraprocedure fibrinogen level >50 mg/dL and replenish fibrinogen lost in daily procedures with albumin replacement fluid.

Massive Transfusion

Massive transfusion, defined as the replacement of one blood volume with RBC units (i.e., 10 units in an adult), is often complicated by both a primary and secondary coagulopathy, resulting in thrombocytopenia, hypofibrinogenemia, and low coagulation factor levels. Fibrinogen is the earliest of the factors to be exhausted in the trauma coagulopathy. Low levels of fibrinogen are early predictors of mortality in trauma patients. Fibrinogen levels do not normalize during damage control resuscitation despite high ratios of plasma:RBCs. Therefore, fibrinogen product use should be incorporated into the treatment of massively transfused patients, either as part of a massive transfusion protocol or as replacement once fibrinogen levels reach a predefined threshold through measuring fibrinogen level or by thromboelastography (see Chapter 58 ).

Women with postpartum hemorrhage (PPH) and fibrinogen levels <200 mg/dL go on to develop severe hemorrhage. Women with levels ≥400 mg/dL rarely develop severe PPH. Given normally elevated fibrinogen levels in pregnancy and the progression to PPH, fibrinogen levels should be kept at or above 200 mg/dL.

Fibrin Glue/Sealant

Fibrin glue/sealant results from the mixture of a fibrinogen source (from plasma or heterologous/autologous cryoprecipitate) with a thrombin source (bovine, human, or recombinant). Fibrin glue is a non–FDA-approved thrombin/preparation, and it has been widely used in Europe for many years. Fibrin sealants are FDA-approved alternatives to fibrin glue and have some advantages, such as standardization of production, over locally made fibrin glues, but are more expensive. Fibrin glues/sealants can be used for multiple surgical purposes, including as topical hemostat, sealant, or adhesive. They are not a substitute to stop active arterial bleeding when a suture is required. Multiple fibrin or thrombin-containing products are FDA-approved for use.

The safety profile of each product differs depending on the product components and source. Bovine thrombin has been reported to cause anaphylaxis (due to bovine allergies), coagulopathy through formation of antibodies to factor V or II, and, rarely, death due to severe systemic hypotensive reactions. Consequently, bovine products have an FDA-mandated black box warning on their package inserts. Pooled human plasma sources have the potential risk of viral or prion disease transmission. It is recommended that patients be counseled about this risk although it is greatly reduced via screening donors, testing for viruses, and inactivating or removing viruses. Some human plasma products also contain synthetic aprotinin, which is a potential source of allergic reactions. Recombinant products, although eliminating the risk of infectious transmission or antibody formation, may cause allergic reactions owing to the hamster or snake proteins used to manufacture the product. Lastly, autologous fibrin glue preparations have been used; the infectious risks associated with the use of heterologous fibrin glue are eliminated by replacement with the autologous source.

Factor XIII Deficiency

Factor XIII deficiency is a rare autosomal recessive congenital deficiency. Factor XIII plays an important role in the cross-linking of polymerized fibrin. Patients present with bleeding and delayed wound healing usually first noted at the umbilical stump or after circumcision. They have normal PT and aPTT tests but increased clot solubility. The half-life of factor XIII is 9–15 days. Factor XIII concentrate is the preferred therapy, and if unavailable, cryoprecipitate can be used. Prophylactic replacement is standard of care with factor activity <1%. It may be considered with factor activity <4%–5% in severe bleeding phenotypes.