(Thrombin and Fibrinogen)

Cross ref: See the entries below for fibrin products, includingTisseel and Hemaseel APR. See also the Thrombin Products entry (#919), and related bovine thrombin product entries.

Description: Fibrin sealants are glue-like products applied topically to help control bleeding. The main active ingredient of fibrin sealant products is fibrinogen, a protein from human blood that forms insoluble fibrin, the major structural component of blood clots, when it comes into contact with thrombin, another blood protein that facilitates blood clotting. Fibrin sealants work by forming a flexible material over oozing blood vessels and can often control bleeding within five minutes. Fibrin sealants can be used to stop oozing from small, sometimes inaccessible, blood vessels during surgery when conventional surgical techniques are not feasible.

Fibrin sealants are two component tissue adhesive systems that are in a relatively viscous liquid form until both components are mixed together and polymerize at the surgical application site into a relatively dense gel. Thrombin in combination with calcium ion (Ca2+) catalyzes the polymerization of fibrinogen, converting the fibrinogen into fibrin polymer. Further, thrombin and Ca2+ activate coagulation Factor XIII, which effects covalent cross-linking of fibrin. Fibrin establishes a mesh-like structure that traps and holds platelets, small cells in the blood that contribute to the clotting process, at the site of blood vessel lesions. The fibrin mesh also traps additional fibrin that forms at the site of bleeding. The rate of proteolytic degradation of the fibrin polymer clot is decreased and mechanical stability is increased as a result of the covalent cross-linking of the polymer. The resulting fibrin polymer clot is porous, but only at a range of 1 to 5 micron (µm) in mean diameter, too small to permit passage of cells or cellular ingrowth.

Commercial fibrin sealants available worldwide are composed of purified, virus-inactivated/removed, human fibrinogen derived from Plasma plus human or bovine thrombin, with or without added components such as virus-inactivated/removed human Factor XIII and/or aprotinin. However, only two fibrin sealant products, Tisseel Kit VH and Hemaseel APR, are currently approved in the U.S., these are actually the same products, and only one is currently marketed. [See the related entries below]. Another product is awaiting approval.

Fibrin is particularly difficult to manufacture from human plasma, because its components/precursors, thrombin, and Factor XIII cofractionate (separate out together).

Autologous (patient’s own) fibrin sealants (not commercial products) are often produced by blood banks/hospitals for onsite or local use. These “home brew” fibrin sealants involve combination during surgery of fibrinogen-rich plasma cryoprecipitate (clotting Factors derived from the patient’s Plasma; see the Cryoprecipitate AHF entry, #716) combined with bovine thrombin (See Thrombin Products, #919; and Thrombin/GenTrac, #920). Use of autologous fibrinogen eliminates the risks involved in using cryoprecipitate from another donor. However, this method is costly and complex, and requires predonation of blood, so it can’t be used in emergencies. The bovine thrombin component is relatively inexpensive but may elicit an antibody response and may contain bovine pathogens. There is only one bovine Thrombin product currently approved and marketed in the U.S. – Thrombin, Topical (Bovine Origin) from GenTrac, Inc., approved as a medical device in 1987. Fibrinogen-rich cryoprecipitate may also be collected from a single donor who is not the patient (single source allogeneic fibrinogen). This reduces risk of virus transmission compared to pooled human cryoprecipitate, but this often has suboptimal bonding strength. Pooled allogeneic fibrinogen is produced from the pooled Plasma of multiple donors. This entails an increased potential risk of virus transmission, but provides a more uniform, higher bonding strength product, and is useful for emergencies.

     The CryoSeal Fibrin Sealant System (see related entry #739) is an automated device for the production of autologous fibrin sealant components from a single unit of a patient’s blood plasma in about 60 minutes. Once prepared, CryoSeal Fibrin Sealant applicator kits can be stored frozen and thawed in minutes, requiring no needle transfers, no reconstitution, and no mixing.

Other, non-biopharmaceutical, tissue sealant products are available. For example, Focal, Inc. (merged into Genzyme Biosurgery in mid-2001) received PMA approval in May 2000 for FocalSeal-L, a synthetic, absorbable, liquid polymer to seal air leaks following lung surgery. The product is marketed in Europe as AdvaSeal. CoSeal from Angiotech Pharmaceuticals Inc. (Vancouver, BC), manufactured and marketed worldwide (except for Japan) by Baxter Healthcare Corp., involves two synthetic derivatized polyethylene glycol (PEG) polymers which are mixed together and extruded onto tissue. CoSeal is indicated for use in vascular reconstruction surgical procedures.

History: Traditional approaches to halt serious bleeding include sutures, cauterization (burning), and tying off of blood vessels. As early as 1909, surgeons were reporting the hemostatic properties of fibrin powder. In the 1940s, combinations of fibrinogen and thrombin were first utilized. The development of the Cohn method for fractionation of plasma in the 1940s, and methods for cryoprecipitation of fibrinogen in the 1960s, led to the development of fibrin sealants in the 1970s. However, fibrinogen concentrates were found to transmit viral hepatitis and all U.S. licenses for Fibrinogen (Human) were revoked on Dec. 7, 1977. Many surgeons/hospitals have and continue to legally prepared (not FDA-regulated) their own “home brew” fibrin sealants on-site.

Companies previously licensed by FDA for manufacture of Fibrinogen (Human) with dates of approval and revocation: Baxter Healthcare Corp. (Sept. 1961-Dec. 1977); Bayer Corp. (Jan. 1947-Dec. 1977); E.R. Squibb & Sons, Inc. (Aug. 1957-Dec. 1977); Merck & Co., Inc. (Aug. 1957-Dec. 1977); and Michigan Biologic Products Inst. (Aug. 1954-Dec. 1977).

In 1994, the FDA cosponsored a conference on the characteristics and clinical uses of fibrin sealants, held at the Uniformed Services University of the Health Sciences, Bethesda, Maryland (summarized in Transfusion 35:783-790, 1995). Despite FDA’s requests for well-controlled clinical trials with patient clinical outcomes (e.g., survival) as endpoints, many companies and clinicians had been reluctant to conduct placebo-controlled trials with manufactured plasma-derived products in settings where they view the minimal standard-of-care to be the use of fibrin sealant prepared on-site from commercial bovine thrombin and various sources of fibrinogen. These clinicians consider the use of locally-prepared fibrin sealant to be of such benefit in controlling bleeding in confined or nearly inaccessible areas that a placebo-controlled trial not using these as the control would put the control patients at significant and unnecessary risk. However, locally-prepared fibrin sealants are not standardized or consistent, making it difficult to approve a product based on comparison with these, and the fibrinogen products available at that time were not treated to inactivate/remove viruses.

The first fibrin sealant product currently available was approved by FDA in May 1998. In May 1999, the Center for Biologics Evaluation and Research (CBER), FDA, issued “Guidance for Industry: Efficacy Studies to Support Marketing of Fibrin Sealant Products manufactured for Commercial Use.”

Market: Plasma-derived thrombin (fibrin sealants) is used in about 750,000 (also reported as over 500,000) cardiovascular operations performed annually in the U.S., and over 1 million surgeries worldwide. Fibrin sealant products are expected to eventually replace cryoprecipitate-based sealants used in more than one million surgical procedures annually.

In Jan. 2009, it was reported, " The current market for active topical haemostats in surgical applications alone is estimated at EUR 700 - 800 million per year [$992 million-$1.134 billion], and this is expected to grow to approx. EUR 1.3 billion the next 3-4 years."

According to a report by Easton Associates, LLC commissioned by OMRIX, the active biosurgical hemostats market in the U.S. currently represents ~$275 million of a $500 million worldwide market. Based on market trends, the company expects the world market to grow to $1.3 billion by 2015.

OMRIX, manufacturer of CROSSEAL/Quixil (see related entry, #736), which uses human thrombin, based on revenues reported by its competitors, estimates the current market for thrombin at $220 million per year in the U.S. (apparently referring to human- and animal-derived thrombin).

In Jan 2005, Frost & Sullivan reported that the European tissue sealants (including synthetics/non-biopharmaceuticals) market is $90 million, with slow growth expected “due to sluggish technological advancements, the slow pace of collecting clinical evidence and unclear product demarcations;” “Over 2005-2011, the market is poised to grow at an annual rate of 17.3 per cent to reach USD 276 million;” “in 2004, the well-established pooled fibrin sealants segment is forecast to account for 80 per cent of the overall European tissue sealants market trailed by synthetic sealants with 17 per cent and autologous fibrin sealants with the remainder;” and the overall low use of tissue sealants in procedures where they could be used. A Frost & Sullivan report, “U.S. Markets for Hemostats, Tissue Sealants and Adhesives, and Adhesion Prevention Products,” Sept. 1999, reported that these various products collectively achieved worldwide sales of $195 million in 1998, and sales are expected to grow at a compound annual rate of nearly 26% through 2005.

In 2005 ThermoGenesis, manufacturer of the CryoSeal Fibrin Sealant device, estimated the U.S. fibrin sealant market to be $125 million, and the worldwide market to exceed $450 million per year. In mid-2000, Haemacure, a manufacturer/marketer of a fibrin sealant (Haemaseel), estimated the U.S. tissue sealant market at $140 million. These estimates include polymeric sealants, which dominate the market.

In a Jan. 2005 report, MedMarket Diligence estimated the worldwide surgical sealants market (including synthetics) at $1 billion, with three million procedures using surgical sealants annually (with the market for conventional hemostats, including sutures, staples, tapes and other products that work through mechanical action is ~$4.6 billion).

According to a survey conducted by Stephens Inc. published in May 1999, “A very large clinical need exists, we believe, for surgical sealants and adhesives in a wide variety of (surgical) procedures. The total number of procedures for which one or more surgical sealants or adhesives would be applicable is, we estimate, 35 million in the U.S.” This includes about 750,000 cardiovascular operations performed annually in the U.S.

R&D: PPL Therapeutics plc (Roslin, U.K.) is developing a plasma-derived fibrin surgical sealant, with manufacture by Instituto Grifols S.A., Probitas Pharma, and with Smith & Nephew plc as marketing partner.

V.I. Technologies Inc. has been developing fibrin subjected to a two-step viral inactivation process (solvent-detergent and UV radiation), now in Phase III trials.

In Oct. 2003, ZymoGenetics, Inc. concluded an agreement with Abbott Labs. for mammalian cell culture manufacture of recombinant human thrombin (rhThrombin) as an alternative to bovine plasma-derived thrombin for fibrin sealant products. Th product is in late-stage trials.

In Sept. 2004, Pharming Group NV entered a Cooperative R&D Agreement (CRADA) with the U.S. Army for the development of recombinant transgenic animal-expressed human fibrinogen (rhFIB) for fibrin glues. In Sept. 2005, the U.S. Army signed an agreement with Pharming Group N.V. for supply and co-development recombinant human fibrinogen for use in fibrin bandages.

In Jan. 2005, Biocoral, Inc received a European patent for its process for preparing a fibrin glue by addition of calcium ions for “biological autologous surgical glue”, and for skin replacement and skin grafts (eliminating the need for protein-based skin grafts).