Clinical applications of fibrin sealants

CURRENT THERAPY J Oral Maxillofac Surg 62:218-224, 2004

Clinical Applications of Fibrin Sealants Tirbod Fattahi, DDS, MD,* Maneesh Mohan, DMD,† and Gregory T. Caldwell, DMD, MD‡ dures.5 Although widespread use of synthetic and homologous fibrin sealants in Europe, Canada, and Japan was common, the Food and Drug Administration (FDA) banned the sale and use of homologous fibrin glue in the United States in 1978, fearing widespread viral transmission. The discovery of the human immunodeficiency virus (HIV) in the early 1980s added more credence to the FDA’s position. Finally, in May 1998, the FDA approved the clinical application of synthetic fibrin sealants in the United States. Currently, the 2 synthetic fibrin sealants available to surgeons in the United States are Tisseel (Baxter Healthcare, Deerfield, IL) and Hemaseel (Haemacure Corp, Sarasota, FL).

Fibrin sealant, also known as “fibrin glue” and “fibrin tissue adhesive,” is a natural or synthetic hemostatic agent derived from plasma coagulation proteins. It is usually a combination of fibrinogen (factor I), fibrinstabilizing factor (factor XIII), thrombin (responsible for conversion of fibrinogen to fibrin in the presence of calcium chloride), and aprotinin (an inhibitor of fibrinolysis). Tissue adhesive has been defined as “any substance with characteristics that allow for polymerization, holding tissues together or serving as a barrier to leakage.”1 Natural and synthetic fibrin sealants are the most effective tissue adhesives and hemostatic agents available to surgeons. The concept of applying clotting factors for hemostasis has been considered for almost 100 years. In 1909, fibrin was used for the first time for hemostatic purposes by Bergel.2 As years passed, the biochemical and adhesive properties of fibrinogen became well known, leading to widespread use of “home-made” fibrin glue by surgeons. The combination of homologous fibrinogen and thrombin was used during World War II to improve skin graft adhesion in burn patients.3 Although initially promising, this application was met with skepticism due to the possibility of transmission of viral hepatitis. Further development in technology allowed substitution of human thrombin with bovine thrombin, thereby reducing the risk of viral transmission. However, use of first-generation bovine proteins leads to documented cases of iatrogenic coagulopathies secondary to the formation of factor V and thrombin inhibitors.4 In the 1970s, Matras and colleagues used autologous cryoprecipitate solutions in animals to perform nerve anastomosis and microvascular proce-

Classification and Mechanism of Action The inappropriate use of terms such as “cryoprecipitate,” “homologous fibrin glue,” “autologous fibrin sealant,” and “synthetic/commercial tissue glue” has created some confusion in the surgical literature about the specific ingredients of fibrin sealants. In essence, there are 3 basic types of fibrin sealants: 1) autologous, 2) homologous (both obtained from cryoprecipitate), and 3) synthetic/commercial. Although there might be minor differences in the individual components of each type, all fibrin sealants essentially mimic the final stages of the coagulation cascade (Fig 1). The stable fibrin “glue” or “gel” can act as a hemostatic agent, a sealing agent, an adhesive agent, and a targeted delivery system for specific medications, growth factors, and cell lines.1 Targeted delivery system via fibrin sealants is the least documented use of the material at this time but may have the greatest potential in the future.1,6 Laboratory studies and histologic evaluations have consistently shown that fibrin adhesives do not interfere with the healing process and may in fact promote healing.7,8

*Assistant Professor and Director of Residency Program, Department of Surgery, Division of Maxillofacial Surgery, University of Florida, Jacksonville, FL. †Resident, Division of Maxillofacial Surgery, University of Florida, Jacksonville, FL. ‡Private Practice, Lexington, MA. Address correspondence and reprint requests to Dr Fattahi: Department of Surgery, Division of Maxillofacial Surgery, University of Florida, Jacksonville, FL 32209; e-mail: [email protected]

CRYOPRECIPITATE

Cryoprecipitate is a human blood component obtained from fresh frozen plasma rich in fibrinogen, factor VIII, von Willebrand factor (vWF), factor XIII, and fibronectin. Fibronectin, a plasma glycoprotein, aids in anchoring of the platelet plug to the site of injury as well as playing an integral role in promoting

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use of cryoprecipitate.11,12 The FDA ban in 1978, along with the introduction of recombinant factor VIII, vWF, and commercially available clotting factor concentrates, has obviated the need for homologous cryoprecipitate. These synthetic products undergo extensive viral inactivation procedures, including heat inactivation with solvent detergents, which virtually eliminates the transmission risk of HIV, hepatitis B, and hepatitis C. A typical adult dose for treatment of factor VIII deficiency or von Willebrand disease is 10 to 15 bags of cryoprecipitate. AUTOLOGOUS AND HOMOLOGOUS FIBRIN SEALANTS

FIGURE 1. Intrinsic and extrinsic coagulation cascades.

the migration of fibroblasts into the clot.9,10 Cryoprecipitate can be prepared from the plasma of a single volunteer donor, from multiple volunteers, or from an autologous source, if blood has been donated in advance. After plasma is procured, it is frozen at ⫺80°C and then thawed at 4°C, thereby allowing most of the factor VIII, fibronectin, vWF, and fibrinogen to remain as a precipitate while all other plasma proteins dissolve. This “cold precipitate” is separated from the supernatant plasma by the process of centrifugation, after which the supernatant is discarded and the cryoprecipitate is refrozen, and stored, ready for use. Just before its use, cryoprecipitate has to be thawed at 37°C in a water bath. Approximately 10 to 20 mL of normal saline is added to each cryoprecipitate bag to reconstitute it before use. Each bag of cryoprecipitate is about 15 to 20 mL in volume and has on average 80 to 120 units of factor VIII and vWF, 150 mg of fibrinogen, and small amounts of fibronectin. The necessary number of bags are grouped together and transfused. Cryoprecipitate became the mainstay for the therapy of hemophilia A and von Willebrand disease due to its high concentration of factor VIII and vWF. Transfusion of large volumes of cryoprecipitate from multiple plasma donors was common practice until the early 1980s when documented cases of hepatitis B virus transmission were traced back to the injudicious

Because cryoprecipitate has a high concentration of fibrinogen, a well-known hemostatic sealing agent, surgeons are able to use this product in various surgical settings for a variety of purposes.1 Natural fibrin sealants, derived from cryoprecipitate from the patient’s plasma (autologous) or from another donor’s plasma (homologous), can be used for tissue adhesive purposes. Autologous donation can be performed before surgery as a preplanned donation or in the operating room environment just before surgery. Autologous donation, whether preplanned or at the time of surgery, eliminates the chance of transmission of infectious agents as long as clerical errors have not been made. If cryoprecipitate is being used solely for its fibrinogen activity, a single bag will be adequate for about 10 mL of fibrin glue. Ten milliliters of fibrin glue is more than adequate for most clinical applications.12 Bovine thrombin is added to the cryoprecipitate just before its use to accommodate the formation of the “glue” or “gel.” Multiple different “recipes” are available to obtain the correct mixture of fibrinogen, fibronectin, calcium, and bovine thrombin.12-15 Average laboratory time to prepare autologous cryoprecipitate is about 30 minutes in most urban level I trauma centers. The average cost of autologous cryoprecipitate for fibrin glue purposes is about $100.00 at our institution. There are some inherent problems in using autologous cryoprecipitate. Some hospitals require autologous donations of at least 1 unit of whole blood up to 2 days before surgery to prepare it. Donation of 1 unit of blood may certainly increase the need for red blood cell transfusion perioperatively. Furthermore, it is not practical to rely on autologous blood donation in multiorgan trauma patients or in cases of unanticipated emergencies. To bypass these potential shortcomings, fibrin glue preparation from a single, known-donor plasma cryoprecipitate has been advocated by some.12,16,17 With the exception of the source of plasma, single-donor cryoprecipitate, also known as homologous cryoprecipitate, has the same

220 ingredients as an autologous preparation. The single donor’s blood has been extensively tested for viral transmission. The major advantage of a single donor for fibrin sealant formation is the fact that the donor’s cryoprecipitate is readily available and can be stored at 4°C for up to 2 weeks. Before its use, bovine thrombin is mixed with this product to form the adhesive clot. This method of preparation, although not used routinely since the inception of synthetic fibrin glues, is also available at our institution at an average cost of $30 to $40 per bag. Each unit of single-donor cryoprecipitate yields about 150 mg of fibrinogen. Equal amounts of topical bovine thrombin (Thrombinar; Armour Pharmaceutical Co, Kankakee, IL) are mixed with fibrinogen for the final product. The rate of fibrin clot formation is dependent on the concentration of bovine thrombin. A mixture of equal amounts of bovine thrombin at a concentration of 500 U/mL and fibrinogen forms a clot within 15 seconds, whereas the use of a more concentrated form of thrombin (1,000 U/mL) accelerates the clot formation to about 5 seconds.12 The 2 major disadvantages of the use of cryoprecipitate for preparation of fibrin sealants are the possibility of viral transmission and the presence of bovine thrombin. The estimated risk of transfusiontransmitted infection from a single unit of a properly screened blood or blood components is reported to be 1:63,000 and 1:103,000 for hepatitis B and C, respectively, and 1:450,000 to 1:660,000 for HIV.18,19 Since 1955, there have been 126 documented cases of acquired factor V antibodies in patients who have been exposed to bovine thrombin.4,20-22 Thirty-three percent of these patients developed bleeding complications.4 Studies clearly indicate that bovine thrombin can be a potent antigen, capable of eliciting a marked antibody formation against factor V and possibly other coagulation factors.4,23 The exact mechanism or predisposing factors for the formation of iatrogenic factor V inhibitors have not been well elucidated.4,22,23 SYNTHETIC/COMMERCIAL FIBRIN SEALANTS

Currently, there are 2 FDA-approved synthetic or commercial fibrin sealants available to surgeons in the United States: Tisseel (Baxter Healthcare) and Hemaseel (Haemacure Corp). Both of these products are identical with no difference in clinical use. Synthetic or commercial fibrin sealants have the following ingredients: 1) vapor-heated, freeze-dried pooled human fibrinogen concentrate and factor XIII, 2) bovine fibrinolysis inhibitor (aprotinin), 3) vapor-heated, freeze-dried pooled human thrombin, and 4) calcium chloride. These components, when mixed together according to the manufacturer’s recommendations, mimic the final stage of the coagulation cascade (Fig 2). Tisseel, commonly used at our institution, is sup-

FIBRIN SEALANT CLINICAL APPLICATIONS

FIGURE 2. Final steps in the coagulation cascade. Items in bold are specific ingredients of commercial fibrin sealants.

plied in 4 different package sizes of 0.5, 1.0, 2.0, and 5.0 mL. The smallest amount of fibrin sealants (0.5 mL), after reconstitution, will yield 1.0 mL total solution containing between 37.5 and 57.5 mg of fibrinogen. The largest amount (5.0 mL), after reconstitution, can yield up to 575 mg of fibrinogen.24 A single bag of cryoprecipitate has only about 150 mg of fibrinogen. The rate of clot formation is dependent on the concentration of thrombin, whereas the shear adhesive tensile strength of the clot is mainly a function of the fibrinogen concentration.12,25 The cost of 2.0 mL of Tisseel is about $200 at our institution. The term “synthetic” might best be replaced by the term “commercial” because the fibrinogen concentrate and the thrombin concentrate are actually derived from pooled human plasma. Viral elimination in the manufacturing process is quite rigorous and includes chromatography, pH treatment, filtration, pasteurization, vapor heating, solvent detergent treatment, and the routine blood screening assays as set forth by the FDA.25 To date, more than 2.5 million administrations of synthetic fibrin sealants have occurred in this country, and there has yet to be a single documented case of hepatitis B or C or HIV transmission.26,27 Tisseel is available in a 2-syringe system attached to a Y-shaped hand plunger or to an aerosolized apparatus. The sealer protein, consisting of fibrinogen, factor XIII, and aprotinin, is in 1 syringe while calcium chloride and thrombin are in the other syringe. All 4 components are applied to the surgical site simultaneously, allowing the thrombin to interact with the fibrinogen, forming the fibrin “gel.” Similar to cryoprecipitate,

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the addition of a higher concentration of thrombin will accelerate the gel formation.12,24 The major advantage of commercial fibrin sealants is their availability and ease of use. Although these products are slightly more expensive than autologous and homologous fibrin sealants, widespread use of commercial fibrin sealants will undoubtedly reduce their prices in the near future.

Clinical Applications Fibrin sealants have been used as an adjunct in a wide variety of surgical procedures. The widespread availability of commercial sealants has led to the increased use of this product. More than 2,300 clinical abstracts have been published on the clinical application of fibrin sealants, with the greatest experience in cardiothoracic surgery and neurologic surgery.27-29 CRANIOMAXILLOFACIAL APPLICATIONS

Multiple publications have reported use of fibrin sealants in the maxillofacial region.15,26,30-46 These applications include areas of dentoalveolar, sinus lift and implant surgery, bony reconstruction, flap elevation, fistula closure, head and neck pathology, microneurosurgical procedures, middle ear surgery, endoscopic surgery, and facial aesthetic surgery. Up to date, one of the larger single studies included 71 patients who underwent a variety of reconstructive, aesthetic, and dentoalveolar procedures with the aid of Tisseel.26 Patients were followed for a period of 6 months and 70 patients had successful outcomes with 1 recurrent oral-antral fistula. Tayapongsak et al15 reported 33 cases of mandibular reconstruction with particulate cancellous bone and marrow using autologous fibrin sealants. The fibrin sealant held the bony particles together firmly and allowed the remodeling process of the bone graft to begin about 50% earlier by providing scaffolding for migration of progenitor cells. Martinowitz et al37 successfully treated 40 patients on anticoagulant therapy requiring dental extraction with commercial fibrin sealants injected on the surgical site. Sullivan et al31 and Khoury32 used autologous fibrin adhesives to manage sinus membrane perforations while elevating maxillary sinus floor. Intraesional fibrin glue injection during surgical excision of intraoral and extraoral cavernous lymphangioma has been used over a period of 10 years in 27 patients with no recurrence.34 This technique is helpful in preventing rupture of the thin epithelial lining of the lymphangioma, ensuring successful and complete surgical excision. Low-flow venous malformations of the cheek have also been injected with fibrin glue with the intent that the fibrin glue would act as a space-occupying mass and, more important, would increase the connective tissue to the vascular

component ratio as more fibroblast colonize the fibrin thrombus.35 Murray et al46 used fibrin sealants in facial nerve reanastomosis in rats and found no difference in results when using fibrin glue compared with a collagen conduit. The use of fibrin sealants in facial aesthetic surgery appears very promising. One of the most common complications after a face-lift procedure, regardless of the plane of dissection (superficial, superficial musculoaponeurosis system [SMAS], sub-SMAS, etc), is the development of a hematoma. Many surgeons routinely use drains during rhytidectomy to minimize this occurrence. Application of fibrin adhesives under the skin or SMAS flap can directly affect the development of a hematoma and may obviate the need for drain placement. Fezza et al36 conducted a prospective study on 48 consecutive face-lift patients. Twentyfour patients received aerosolized fibrin glue and no drains while the other 24 patients did not receive fibrin glue but had drains placed. The patients in whom fibrin glue was used had significantly less bruising and swelling, more rapid healing response, decreased operating time, and no hematoma. Risk of hematoma formation, however, was not statistically significant between the 2 groups. However, others have shown a statistically significant difference in the formation of hematomas and postoperative ecchymosis and edema when comparing face lifts with and without use of fibrin glue.41,44,45 Mommaerts et al,40 in a prospective study, showed that the use of fibrin glue in lower transcutaneous blepharoplasty did not affect the final appearance of the scar but reduced the operating time and postoperative ecchymosis and allowed a quicker return to daily life. Marchac et al42 performed 206 cases of endoscopic brow lift using fibrin glue as the main fixation device without any plates or screws. In severe cases of “forehead sagging,” a 3-0 suture was used as an adjunctive support. The authors reported an 86% satisfactory result with no complications associated with the use of fibrin sealants. Next to cardiothoracic surgery, fibrin sealants are used most frequently in neurosurgical procedures. Closure of possible dural leaks and cerebrospinal fistulas, elimination of dead space after transcortical intraventricular neurosurgical manipulations, and reinforcement of vessel walls surrounding a cerebral aneurysm have been accomplished using fibrin sealants.29,47-50 OTHER SURGICAL APPLICATIONS

The concept of tissue adhesives and fibrin glue is a growing trend in surgical literature, with more than 2,300 articles dealing with this issue.27 Fibrin sealants are used literally in every surgical specialty, including trauma, cardiothoracic, vascular, endoscopy, gastro-

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intestinal, urologic, and obstetrics. Buckley et al51 have used fibrin glue as an adhesive in fixation of skin grafts to the back and trunk, without using staples or sutures. This method was successfully used in 50 cases without any complications and was found to be cost effective as well. Management of burn patients has also benefited from the application of fibrin sealants.8,48 Fibrin adhesives have been successfully applied to coronary artery anastomoses and ventricular suture lines in cardiovascular surgery.16 Pulmonary air leaks and bronchopleural fistulas have been effectively treated with fibrin glue.25 Rate of resternotomy in cardiothoracic surgery has declined from 10% to 5.6% with the use of fibrin sealants.27 Raw, bleeding surfaces of hepatic and pancreatic tissues, which are difficult to isolate and secure with conventional methods, can now be treated successfully with aerosolized fibrin sealants.25,27,52 The risk of seroma formation after mastectomy has also decreased after the application of fibrin sealants.27 European surgeons have implemented a protocol for the treatment of upper gastrointestinal hemorrhage using sclerotherapy and repeated fibrin sealant injections via an endoscopic approach. In a clinical study of 854 patients with active gastrointestinal bleed treated with this protocol, the rate of rebleed was reduced to 1%.53 A novel application of fibrin sealants was recently used in pregnant patients who develop premature rupture of membranes as a result of amniocentesis.54 A combination of maternal platelets and fibrin sealants was applied to uterine surfaces under direct fetoscopic visualization to seal the puncture sites from amniocentesis.

Since the publications of the report by Hino et al, many manufacturers have started to use polymerase chain reaction to test for parvovirus. Today, in most hospitals, commercial and autologous fibrin adhesives have virtually eliminated the need for homologous fibrin glue. However, there are several potential problems associated with the ingredients of commercial fibrin sealants and their methods of application. Beriplast P (Aventis Behring, Marburg, Germany), a common European fibrin sealant, with more than 5 million applications, has been associated with 29 reported cases of bovine hypersensitivity due to bovine aprotinin.57 This has occurred in repeated applications of the product. There are reports of flap necrosis and seroma formation after the improper use of fibrin sealants during face-lift procedures.44,45 This has been attributed to a nonhomogeneous application of fibrinogen and thrombin as well as an excessively thick sealant layer. Ischemia occurs as the thick layer of sealant begins to act as a mechanical barrier, preventing capillary neovascularization under the skin flap. It is recommended that fibrin sealants are applied as a thin layer, on the surface of the surgical site, only after major bleeding has been controlled, and with minimal pooling of the product in dependent areas, thereby minimizing a nonhomogeneous and possibly an excessively thick application.45 The only true contraindications to the use of commercial fibrin sealants are the presence of allergic hypersensitivity to bovine proteins and intravascular application of the product.24

Adverse Events

Future Applications

Unfavorable results from application of fibrin sealants can be broadly divided into 2 categories: those directly related to the product ingredients and those related to its clinical use. Fibrin sealants have an excellent safety record. As previously mentioned, there have been no reports of hepatitis B or C or HIV transmission associated with commercial fibrin glues.26,27 However, before the implementation of strict hematologic testing of donated blood and blood products in this country, documented cases of viral transmission were reported.55 Recently, Hino et al56 reported 3 cases of iatrogenic parvovirus B19 transmission associated with commercial sealants. This has been attributed to the use of dry-heat viral inactivation, which appears to be ineffective against parvoviruses. Fortunately, most adults have antibodies to parvoviruses, and if infection does occur, it is usually mild. This infection, however, can be life threatening in neonates and pregnant patients.

With the recent approval of commercial fibrin sealants by the FDA, and the tremendous number of clinical applications of these products, several companies are currently exploring new ways to improve and use fibrin sealants.52 The absorbable fibrin adhesive bandage is a resorbable wound dressing impregnated with fibrin glue that can be applied to wounds, or even packed directly into them to provide local hemorrhage control until definitive care can be rendered.58 This application may be beneficial in battlefield wounds. The most promising and least documented use of tissue adhesives lies in the ability to deliver medications and specific cell lines to a target site.1,59,60 Because tissue adhesives are biodegradable, they can be bioengineered for slow release of medications such as chemotherapeutic drugs at the specific target organ, thereby bypassing the systemic deleterious side effects of the medication.

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223 28. Kjacrgard HK, Fairbrother JE: Controlled clinical studies of fibrin sealant in cardiothoracic surgery—A review. Eur J Cardiothorac Surg 10:727, 1996 29. Floris R, Salvatore C, Fraioli B, et al: Trans-sphenoidal treatment of postsurgical cerebrospinal fluid fistula: CT-guided closure. Neuroradiolgoy 40:690, 1998 30. Meijer HJ, Steen WH, Bosman F, et al: Radiographic evaluation of mandibular augmentation with prefabricated hydroxylapatite/fibrin glue implant. J Oral Maxillofac Surg 55: 138, 1997 31. Sullivan SM, Bulard RA, Meaders R, et al: The use of fibrin adhesives in sinus lift procedures. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:616, 1997 32. Khoury F: Augmentation of the sinus floor with mandibular bone block and simultaneous implantation: A 6-year clinical investigation. Int J Oral Maxillofac Implants 14:557, 1999 33. Whitman DH, Berry RL, Green DM: Platelet gel: An autologous alternative to fibrin glue with applications in oral and maxillofacial surgery. J Oral Maxillofac Surg 55:1294, 1997 34. Honig JF, Merten HA: Surgical removal of intra- and extraoral cavernous lymphangiomas using intraoperative-assisted intralesional fibrin glue injections. J Craniofac Surg 11:42, 2000 35. Jemec B, Sanders R: A facial low-flow venous malformation treated with fibrin glue. Br J Plast Surg 53:73, 2000 36. Fezza JP, Cartwright M, Mack W, et al: The use of aerosolized fibrin glue in face-lift surgery. Plast Reconstr Surg 110:658, 2002 37. Martinowitz U, Mazar AL, Taicher S, et al: Dental extraction for patients on oral anticoagulation therapy. Oral Surg Oral Med Oral Pathol 70:274, 1990 38. Bento RF, De Almeida ER, Minit A: Anastomosis of intratemporal facial nerve with fibrin tissue adhesive. Eur Arch Otorhinolaryngol Dec:S387, 1994 39. Weber R, Keerl R, Draf W, et al: Management of dural lesions occurring during endonasal sinus surgery. Arch Otolaryngol Head Neck Surg 122:732, 1996 40. Mommaerts MY, Beirne JC, Jacobs WI, et al: Use of fibrin glue in lower blepharoplasties. J Craniomaxillofac Surg 24:78, 1996 41. Sandor G, Marchac D: Face lifts and sprayed fibrin glue: An outcome analysis of 200 patients. J Craniomaxillofac Surg 22: 25, 1994 (suppl 1) 42. Marchac D, Ascherman J, Arnaud E: Fibrin glue fixation in forehead endoscopy: Evaluation of our experience with 206 cases. Plast Reconstr Surg 100:704, 1997 43. Vogel A, O’Grady K, Toriumi DM: Surgical tissue adhesives in facial plastic and reconstructive surgery. Facial Plast Surg 9:49, 1993 44. Flemming I: Fibrin glue in face lifts. Facial Plast Surg 8:79, 1992 45. Grossman JA, Capraro PA, Burneikis V: Minimizing complications in the use of fibrin sealant in aesthetic facial procedures. Anesth Surg J 21:32, 2001 46. Murray JA, Willins M, Mountain RE: A comparison of glue and a tube as an anastomotic agent to repair the divided buccal branch of the rat facial nerve. Clin Otolaryngol 19:190, 1994 47. Brandt MT, Jenkins WS, Fattahi TT, et al: Cerebrospinal fluid: Implications in oral and maxillofacial surgery. J Oral Maxillofac Surg 60:1049, 2002 48. Saltz R, Dimick A, Harris C, et al: Application of autologous fibrin glue in burn wounds. J Burn Care Rehab 10:504, 1989 49. Al-Yamany A, Del Macstro RF: Prevention of subdural fluid collection following transcortical intraventricular and/or paraventricular procedures by using fibrin sealant. J Neurosurg 92:406, 2000 50. Lee KC, Park SK, Lee KS: Neurosurgical application of fibrin adhesive. Yonsei Med J 32:53, 1991 51. Buckley RC, Breazeale EE, Edmond JA, et al: A simple preparation of autologous fibrin glue for skin-graft fixation. Plast Reconstr Surg 103:202, 1999 52. Jackson M: New and potential uses of fibrin sealants as an adjunct to surgical hemostasis. Am J Surg 182:36S, 2001

224 53. Rutgeerts P, Rauws E, Wara P, et al: Randomized trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 350:692, 1997 54. Young BK, Roque H, Abdelhak YE, et al: Minimally invasive endoscopy in the treatment of preterm premature rupture of membranes by application of fibrin sealant. J Perinat Med 28:326, 2000 55. Wilson SM, Pell P, Donegan EA: HIV-1 transmission following the use of cryoprecipitated fibrinogen as gel/adhesive. Transfusion 31S:51S, 1991 56. Hino M, Ishiko O, Honda KI, et al: Transmission of symptomatic parvovirus B19 infection by fibrin sealant used during surgery. Br J Haematol 108:194, 2000

FIBRIN SEALANT CLINICAL APPLICATIONS 57. Joch C, Witzke G, Groner A, et al: Clinical safety of fibrin sealants. Poster presentation at the IX World Congress of Cardiothoracic Surgeons. Lisbon, Portugal, November 14-17, 1999 58. Holcomb JB, Pusateri AE, Hess JR, et al: Implications of new fibrin sealant technology for trauma surgery. Surg Clin North Am 77:943, 1997 59. Fujimoto K, Yamamura K, Osada T, et al: Subcutaneous tissue distribution of vancomycin from a fibrin glue/Dacron graft carrier. J Biomed Mater Res 36:692, 1997 60. Kaiser HW, Stark GB, Kopp J, et al: Cultured autologous keratinocytes in fibrin glue suspension, exclusively and combined with STS-allograft (preliminary clinical and histological report of a new technique). Burns 20:23, 1994