A comparison of antifibrinolytic agents used in hemostatic fibrin sealants.

Abstract

Fibrin sealants used as hemostatic and adhesive surgical adjuncts invariably combine fibrinogen and thrombin. The use of plasma-derived products to facilitate hemostasis was first described in 1909. Because the approach relied on in vivo concentrations of fibrinogen and thrombin the quality of the resulting fibrin clot was poor. During the 1940s human fibrinogen and thrombin became available in large quantities as byproducts of plasma fractionation. Fibrinogen and thrombin, derived from plasma supplied by the American Red Cross, were used to enhance adhesion of skin grafts in soldiers who had sustained severe burn injuries. In the years after World War II bovine thrombin came to replace human thrombin because of concerns about the potential of human thrombin to transmit hepatitis. During the 1960s a method for the cryoprecipitation of fibrinogen led to the availability of a sealant with a high concentration of fibrinogen. This improved product was used in skin grafting to promote wound healing and dural sealing, to obtain hemostasis in microvascular surgery and parenchymal injury, and to serve as a matrix in the repair of bone defects; but fibrinogen concentrates were found to transmit hepatitis and all US licenses for commercially prepared fibrinogen (human) concentrates were revoked in 1977. Commercial concentrates containing clottable human fibrinogen and factor XIII (fibrin stabilizing factor) plus bovine thrombin became available in Europe in the late 1970s and have been used extensively since then for hemostasis and other indications. These products all contained an antifibrinolytic agent. The risk of viral transmission was reduced through careful donor selection followed by heat treatment of the human fibrinogen component. Virally inactivated human thrombin has now replaced bovine thrombin in most European products. During the 1980s and 1990s, before the availability of fibrin sealants approved by the US Food and Drug Administration (FDA), US surgeons used so-called homemade sealants, a practice that may still continue to some extent. These homemade formulations combined bovine thrombin and human fibrinogen from pooled cryoprecipitate or autologous fibrinogen. The cryoprecipitate was not subjected to viral inactivation and had a variable fibrinogen concentration. Bovine thrombin was obtained as a commercial preparation but was not regulated with respect to factor V content or other impurities. A number of investigators described the development of antibodies to bovine thrombin in postoperative patients. For these reasons regulators and manufacturers considered homemade fibrin sealants to be suboptimal. The first so-called new generation of virus-inactivated or virus-removed fibrin sealant marketed in the United States (US) was Tisseel (Baxter Healthcare), approved by the FDA in 1998. A second-generation product, Crosseal (American Red Cross), received FDA approval in March 2003. Crosseal is marketed as Quixil (Omrix Biopharmaceuticals) outside of the US. Both Tisseel and Crosseal consist of human fibrinogen and human thrombin, which are combined at the time of use to form a crosslinked fibrin matrix at the site of bleeding. The respective formulations differ in an important way: Tisseel contains bovine aprotinin (BA), while Crosseal contains tranexamic acid (TA). BA and TA are antifibrinolytic agents added to the respective formulations of these products to slow the natural dissolution of the clot that is produced at the site of application. The differences between these antifibrinolytics warrant a detailed discussion. No competing interests declared. Supported by an unrestricted educational grant from the American Red Cross.