Topical Biologic Agents Pharmacologic Fibrin Sealant

Fibrin sealant may be produced from pooled sources or a single donor. The use of pooled blood products is the current basis for the commercially available fibrin sealant. The single-donor blood can be allogenic or autologous.

Nine fibrin sealants are currently available to urologists worldwide: (i) Tisseel™b; (ii) Crosseal™c; (iii) Hemaseel™d; (iv) Quixil™e; (v) Beriplast P™f; (vi) Bolheal™g; (vii) Biocol™h; (viii) VIGuard F.S™1.; and (ix) CoStasis™j. Tisseel, Crosseal, Hemaseel, VIGuard F.S., and Costasis have Food and Drug Administration approval for sale in the United States.

The primary component of all synthetic fibrin sealants is highly concentrated human fibrinogen mixed with factor XIII and fibronectin. Human thrombin concentrate and an antifibrinolytic constitute the remaining components. Fibrinogen and thrombin are solubilized with antifibrinolytic and calcium chloride solutions, respectively (6).

The primary component of all synthetic fibrin sealants is highly concentrated human fibrinogen mixed with factor XIII and fibronectin. Human thrombin concentrate and an antifibrinolytic constitute the remaining components. Fibrinogen and thrombin are solubilized with antifibrinolytic and calcium chloride solutions, respectively.

bBaxter Healthcare Corporation, Deerfield, IL.

cAmerican Red Cross, Washington, D.C.

dHaemacure Corp., Montreal, Quebec, Canada.

eOmrix Biopharmaceuticals S.A., Rhode St Genese, Belgium.

fAventis Behring, Marburg, Germany.

gKaketsuken Pharmaceuticals, Kumamoto, Japan.

hLFB-Lille, France.

i(itex: VI Technologies, Inc., Watertown, MA.

JAngiotech Pharmaceuticals, Inc., Vancouver, British Columbia.

Fibrin sealants do not rely on the intrinsic/extrinsic clotting pathways and actually function also in the presence of systemic coagulation defects.

Tranexamic acid has caused neurologic symptoms including trembling, involuntary head movements, and clonic contractions in rabbits.

To avoid the possibility of thromboembolic complications, fibrin sealant should be applied with caution and should not be injected directly into large blood vessels.

When the two components are mixed in the presence of ionized calcium, the last step in the coagulation cascade is reproduced beginning with thrombin cleavage of fibrinopeptides Aand B from the fibrinogen molecule. Thrombin also activates factor XIII, which stabilizes fibrin cross-linkage and promotes the formation of an insoluble, nonfri-able clot. The addition of fibronectin helps to cross-link fibrin, and to stimulate cellular migration (12) and fibroblastic growth in the areas where the fibrin sealant was applied.

Fibrin sealants do not rely on the intrinsic/extrinsic clotting pathways and actually function also in the presence of systemic coagulation defects.

An antifibrinolytic, which is a variable ingredient in the fibrin-sealant preparation, is intended to slow the rate of fibrinolysis and thereby preserve the integrity of the fibrin clot. In Tisseel and Hemaseel, aprotinin is the antifibrinolytic agent. Alternatively, the antifibrinolytic in Crosseal is tranexamic acid. Aprotinin, derived from bovine lung, inhibits a number of serine proteases including trypsin, chymotrypsin, kallikrein, elas-tase, urokinase, thrombin, and plasmin (13). Tranexamic acid, a synthetic analogue of the amino acid lysine, prevents the binding of plasminogen and plasmin to fibrinogen and fibrin by competing with lysine for binding sites, and thus helps to suppress fibrinolysis (14). Tranexamic acid also offers a theoretical advantage because it is not bovine derived. In fact, anaphylactic reactions reported in bovine aprotinin did not occur with tranexamic acid (15-20). Crosseal eliminates the risk of bovine spongiform enceph-alopathy transmission and immunologically mediated coagulopathy.

Tranexamic acid has caused neurologic symptoms including trembling, involuntary head movements, and clonic contractions in rabbits (21,22).

Tisseel VH contains four separate vials and its preparation requires approximately 20 minutes prior to reconstitution—all four vials have to be warmed (37°C) using the Fibrinotherm heating and stirring device or a water bath. The bovine aprotinin is aspirated and injected into the fibrinogen vial. This solution is mixed in a magnetic stirring well for one to four minutes depending on the volume of the kit. The calcium chloride is added to the thrombin vial before agitation and further warming of the mixture. Once the preparation process is completed, the Tisseel is best used within four hours. The two components of the fibrin sealant may be applied sequentially or simultaneously. The most common method of application relies on a double-barreled Duploject™ Preparation and Application Systemk enabling simultaneous and equal application of the fibrinogen and thrombin solutions through a blunt-tipped needle. A laparoscopic applicator is also available. Conversely, Crosseal can be prepared in less than one minute and does not require a warming process provided the solutions have been previously thawed (21). Like Tisseel, Crosseal can be applied with a laparoscopic applicator. Both brands of fibrin sealant should be applied with individual drops to the target area. The drops should be allowed to separate from one another and from the applicator tip. Fibrin sealants also can be applied using a source of forced sterile gas (35-45 lb/inch2) to spray equal portions of the solutions onto a desired surface.

■ Proper application is essential for optimal adhesive function.

■ After the sealant application, the two surfaces should be brought into contact prior to polymerization of the sealant.

■ Once polymerization has occurred on one surface, it will act as an antiadhesive and prevent the two surfaces from adhering (23,24).

■ Fibrin sealant is most effective in a "dry" operative field because it does not rely on the presence of blood to develop the fibrin clot.

This differs from other hemostatic agents such as Floseal™k or Gelfoam™', which require blood for optimal hemostasis.

To avoid the possibility of thromboembolic complications, fibrin sealant should be applied with caution and should not be injected directly into large blood vessels (24).

Two additional preparations of fibrin, the absorbable fibrin adhesive bandage and the hemostatic fibrin-sealant powder have been described and utilized in a porcine model. Theabsorbable fibrin adhesive bandagem is made of a concentrated mixture of lyophilized fibrinogen and thrombin on an absorbable Vicryl backing (25). Cornum et al. (25) applied the absorbable fibrin adhesive bandage to porcine kidneys after lower-pole heminephrectomy; by comparing this method of hemostasis to conventional methods of partial nephrectomy bed repair, the authors found significantly less bleeding and kBaxter Healthcare Corporation, Deerfield, IL.

"American Red Cross, Washington, D.C.

The primary advantage of Costasis is that the autologous source of fibrinogen eliminates the potential risks of viral transmission. However, the risk of bovine spongiform encephalopathy and allergic reaction to bovine thrombin remain.

Floseal is a Food and Drug Administration-approved gelatin-matrix hemostatic sealant that has been well described in open cardiac, vascular, spine, and ear-nose-throat surgery.

shorter operative and ischemia times in the absorbable fibrin adhesive bandage group. The same team employed the absorbable fibrin adhesive bandage for the management of grade-4 renal stab wounds in a porcine model and found that the bandage had a promising role in the renal trauma setting (26). However, such a fibrin preparation is not currently applicable to laparoscopy because the bulky nature of the bandage prohibits placement through laparoscopic ports. Furthermore, placement through a handport would be difficult because it will adhere to any moist surface that it comes into contact with. The other additional fibrin preparation, hemostatic fibrin-sealant powder,n consists of lyophilized human fibrinogen and thrombin. Bishoff et al. evaluated the ability of hemostatic fibrin-sealant powder to achieve hemostasis and seal the collecting system of porcine kidneys after laparoscopic heminephrectomy (27). In this study, hemostatic fibrin-sealant powder applied alone with regional ischemia was compared to conventional intracorporeal suturing with vascular control. Follow-up computed tomography was performed at 48 hours and six weeks. Although at 48 hours there were more urinomas in the hemostatic fibrin-sealant powder group, at six weeks there was no evidence of urinoma or hematoma in either group. Unlike the absorbable fibrin adhesive bandage preparation, the hemostatic fibrin-sealant powder preparation holds promise as a possible addition to the laparoscopic armamentarium of hemostatic agents.

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