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The role of fibrin sealants in hemostasis
The American Journal of Surgery 182 (2001) 21S–28S
The role of fibrin sealants in hemostasis Pankaj S. Mankad, M.B.B.S.*, Massimiliano Codispoti, M.D. Department of Cardio-thoracic Surgery, Royal Infirmary, Lauriston Place, Edinburgh, EH3 9YW United Kingdom
Abstract Hemostasis is a prerequisite for wound healing, and under normal physiologic conditions, it is achieved by means of the coagulation cascade. However, there are a number of surgical procedures where there may be considerable benefits to the patient, surgeon, or health-care costs if hemostasis can be achieved more efficiently. The rapid and effective control of bleeding during and after surgery reduces blood loss and can help reduce postoperative complications. These improved outcomes can reduce the need for transfusion, with the associated risk of viral transmission, and have a positive impact on operative and hospital stay times. Fibrin sealants are surgical hemostatic agents derived from human plasma that reproduce the final steps in the coagulation pathway and form a stable fibrin clot. Fibrin sealants are used in a broad range of surgical procedures to assist hemostasis, including cardiovascular, hepatic, and splenic surgery, gastrointestinal hemorrhage, skin grafting, and dental extractions in anticoagulated patients. Patients with coagulopathies are at high risk of prolonged or excessive bleeding during or after invasive surgery, and these patients may also benefit from the use of fibrin sealants. This article reviews the role of fibrin sealants in hemostasis, citing a number of key clinical studies that report a significant reduction in blood loss or chest drain output after surgery with fibrin sealant compared with controls. © 2001 Excerpta Medica, Inc. All rights reserved.
Fibrin sealants (also known as fibrin glues) are surgical hemostatic agents derived from human plasma that are designed to reproduce the final steps of the physiologic coagulation cascade to produce a stable fibrin clot (Fig. 1). Fibrin sealants have a range of uses in many procedures across a wide spectrum of surgical specialties, including hemostasis, wound healing, suture support, and tissue sealing. The range of possible applications is so wide that it is not possible to address all the specifics of sealant use in a single review. However, this article provides an overview of the role of fibrin sealants in hemostasis and gives a number of examples of their use for this indication in a variety of key surgical procedures. Hemostasis depends on the successful balance between the coagulation, complement, and fibrinolytic pathways, with complex interactions between plasma proteins, blood cells, blood flow and viscosity, and the blood vessel endothelium. In order to set the role of fibrin sealants in context, the following brief overview of hemostatic and wound healing mechanisms is provided, based on Mackie [1]. For a more detailed treatment, the reader is referred to specialist texts and reviews.
Overview of hemostasis and wound healing After tissue damage, platelets are activated and adhere rapidly to the blood vessel wall, modifying the vascular tone and forming aggregates. Once activated, platelets produce thromboxane A2, inositol triphosphate, and diacylglycerol, which further up-regulate platelet function and release Ca2⫹ ions, a cofactor essential to several stages of the coagulation cascade. The activated platelets also undergo a transformation of their outer membranes to provide a surface that promotes coagulation, supporting the generation of thrombin and subsequent production of fibrin, leading to clot formation and stablization. The coagulation cascade may be triggered by exposure of blood to foreign or extravascular surfaces, by tissue rupture and the consequent exposure of tissue factor, or by platelet activation. The cascade depends on a number of pro-enzymes, proteins, and cofactors, the final stages of which are completed by thrombin acting on fibrinogen to form fibrin, and factor XIIIa to stabilize the developing fibrin clot. Thrombin, Factor XIII, and the fibrin clot
* Corresponding author. Tel.: ⫹44 131 536 0622; fax: ⫹44 131 536 3482. E-mail address: [email protected]
Thrombin plays a pivotal role in the coagulation mechanism, converting fibrinogen to fibrin in the presence of Ca2⫹ ions. This key final step is common to all the coagu-
0002-9610/01/$ – see front matter © 2001 Excerpta Medica, Inc. All rights reserved. PII: S 0 0 0 2 - 9 6 1 0 ( 0 1 ) 0 0 9 1 1 - 1
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Fig. 1. The mechanism of action of a two-component fibrin sealant (Beriplast P; Aventis Behring, Marburg, Germany). * ⫽ pasteurized. Table 1 Complications of transfusion [3–5] Complication
Incidence
Febrile reaction Hemolytic nonfatal reaction Hemolytic fatal reaction Human T-cell lymphotrophic virus I/II Hepatitis B Hepatitis C Bacterial infection (platelets) Cytomegalo virus infection Immunosuppressed recipient Immunocompetent recipient
1 1 1 1 1 1 1
lation pathways. Fibrinogen is a heterodimer composed of two each of three different polpeptide chains (␣, , and ␥) and two fibrinopeptides (A and B) to give a final structure (A␣, B, ␥)2. Thrombin cleaves the small fibrinopeptides from the ␣- and -polypeptide chains of the fibrinogen to form fibrin monomers. These undergo end-to-end polymerization to form long fibrin strands, which then precipitate to form a fibrin clot [2]. Factor XIII (fibrin-stabilizing factor) is also activated by thrombin, inducing covalent bond formation between the ␥-chains of the fibrin monomers. Polymers then form between the fibrin ␣-chains, imparting tensile strength and stabilizing the fibrin clot. Thrombin also activates platelets trapped in the fibrin mesh: their receptors for fibrin and collagen enhance the stablization of the clot [2]. Cytokines and platelet-derived growth factors enhance wound healing by promoting fibroblast ingrowth along the fibrin strands and subsequent formation of a more permanent collagen fiber network. At this time, the fibrin network (now superfluous) is degraded proteolytically by the action of the plasminogen–plasmin pathway, and the breakdown products are subsequently phagocytosed by macrophages.
in in in in in in in
100 6,000 676,000 640,000 63,000 103,000 2,500
Variable 0.9%
Surgical advantages of achieving hemostasis Wound healing is dependent on achieving hemostasis. As outlined below, rapid and effective control of bleeding can help reduce postoperative complications and lead to improved patient outcomes, reducing the need for transfusions with the attendant increase in risk of blood-borne viral infection, reducing the increased operative and hospitalization times and the increased costs (both direct and indirect). Potential complications associated with blood and blood product transfusions are outlined in Table 1. The role of fibrin sealants in achieving hemostasis Common causes of blood loss after surgery include continuous oozing from the raw surface and suture line or needle hole bleeding, which is usually made worse by additional suturing. Apart from these common factors, other reasons for blood loss can be patient-related factors (eg, the presence of coagulopathy or the patient receiving anticoagulant therapy) and factors related to surgical procedure (eg, liver surgery or open-heart surgery) where the nature of
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Fig. 2. Mean blood loss (⫾ SEM) from experimental arteriotomies is reduced significantly after application of a fibrin sealant dressing. * ⫽ P ⫽ 0.005 vs contralateral control [8].
surgery itself is a risk factor for bleeding. As outlined in the subsequent sections, fibrin sealants have a role to play in almost all situations. In some conditions their hemostatic efficacy has been shown clinically, whereas for others there is overwhelming favorable experimental evidence [6]. The efficacy of fibrin sealants in promoting hemostasis is difficult to quantify directly in patients for practical and ethical reasons, although their effects on blood loss may be inferred from the number of units of blood transfused or from chest drain output during and after surgery. The hemostatic efficacy of fibrin sealants has, however, been quantified in several animal models [7–9]. In a study of the effects of fibrin sealant on femoral bleeding after removal of bilateral femoral catheters in dogs [7], application of fibrin sealant into the periarterial tissue adjacent to the arteriotomy site reduced ecchymosis and hematoma formation significantly in fibrin sealant–treated groins, compared with the contralateral, control groins in the same animal (P ⫽ 0.008 and P ⫽ 0.016, respectively). Gross bleeding after catheter removal in a similarly treated group of heparinized dogs was also reduced significantly by fibrin sealant treatment (P ⫽ 0.016 vs contralateral controls). A prototype fibrin sealant dressing has been shown to be highly effective in maintaining hemostasis in a femoral artery injury model [8]. In a randomized, blinded, placebocontrolled study, 6 pigs received bilateral 4-mm longitudinal femoral arteriotomies after surgical exposure of the arteries. A fibrin sealant dressing was applied to one artery and a control dressing to the contralateral artery. Blood loss was significantly less from the fibrin sealant–treated side compared with the control side (4.9 vs 82.3 mL; P ⬍0.0005; Fig. 2). Complete hemostasis was achieved within 15 minutes in five of six arteriotomies treated with fibrin sealant, but in none of the control arteriotomies even after 1 hour. In a recent study of suture hole bleeding in a pig vascular graft model, Dickneite et al showed that the use of fibrin sealant significantly reduced blood loss (P ⫽ 0.016) and
improved the rate of hemostasis (5 of 5 vs 0 of 4; P ⫽ 0.008), compared with untreated controls. Similarly, when fibrin sealant was compared with gelfoam/thrombin treatment, there was significantly less blood loss in the fibrin sealant–treated group (P ⬍0.01) [9]. The use of fibrin sealants for hemostasis is occasionally criticized on the grounds that it may promote sloppy surgical practice. This is far from the truth. Surgeons are well aware that local hemostatic agents are only an adjunct to achieving hemostasis and can never compensate for inadequate or improper attention to finer details in surgical techniques. Thus, fibrin sealants should not be viewed as an alternative to good surgical practice but as complementary agents to be used judiciously to improve the surgical outcome. Hemostasis in cardiovascular surgery Fibrin sealants have primarily been used in cardiovascular and cardiothoracic surgery as an adjunct to hemostasis, for which they are highly effective in a range of procedures [10]. Fibrin sealants have also been used in cardiovascular surgery to seal suture holes, staple lines, anastomoses, fistulas, and raw surfaces. Optimal application requires a dry operative field, which is often difficult to achieve in cardiovascular surgery, and thus fibrin sealants are frequently used prophylactically while the suture line is dry to prevent anticipated hemorrhage. Fibrin sealants can also be applied by means of a solid matrix, such as collagen fleece, to a specific area where the surgeon requires hemostasis [11], or as a spray, for example, for use in the anterior mediastinum to reduce postoperative hemorrhage from diffuse low-pressure bleeding [12]. In a prospective, randomized clinical trial, Rousou et al [13], established the efficacy of fibrin sealants in reducing time to achieve hemostasis and frequency of postoperative hemorrhage. Fibrin sealant is now frequently used routinely whenever suturing is impossible,
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Fig. 3. Mean chest drain output (⫾ SEM) after open-heart surgery is reduced significantly after spray application of fibrin sealant to the mediastinum [14]. * Cumulative.
dangerous, or difficult, and to save time waiting for spontaneous hemostasis [10]. Mediastinal bleeding during cardiac operations is a troublesome complication. However, spray application of fibrin sealant to the anterior mediastinum in coronary artery bypass graft and valve replacement operations reduced perioperative blood loss significantly, as measured by chest drain output, and also by the number of units of whole blood transfused [14]. In 20 consecutively treated patients undergoing a range of cardiac operations, fibrin sealant was sprayed on the anterior mediastinum before closure of the median sternotomy incision. A matched control group of 20 patients who underwent open-heart operations of the same complexity by the same surgeon during the same period (but without the use of fibrin sealant) was chosen for comparison. Application of fibrin sealant reduced the mean chest drain output at both 12 hours (461 mL vs 731 mL; P ⬍0.05) and 24 hours (714 mL vs 1,016 mL; P ⬍0.05; Fig. 3) [14]. In a review of their experience with fibrin sealants in 689 thoracic and cardiovascular procedures over a 4-year period, Matthew et al [15] reported a 94% success rate in reducing the blood loss associated with various cardiac interventions. Blood loss was reduced from diffuse areas of the mediastinum, specific sites at coronary artery bypass graft anastomoses, and long suture lines. As described above, fibrin sealants also promote hemostasis in the femoral artery after cardiac catheterization [7]. This may be useful in reducing the morbidity, complications, and hospitalization associated with this increasingly common procedure and may promote earlier patient mobilization [7]. Fibrin sealants have also proven to be effective in reducing suture line bleeding in arteriotomy [16] and in maintaining hemostasis by reinforcing the suture line for closure of the aortic stump in cases of possible blowout [17].
Pediatric cardiac surgery The need for perfect hemostasis is even more important in pediatric cardiac surgery because of the high incidence of coagulopathy after open-heart procedures [18] and increased risks associated with the use of blood and blood products. In a prospective randomized control study looking at the safety and efficacy of Beriplast P (Aventis Behring, Marburg, Germany) to achieve hemostasis in pediatric open-heart operations (n ⫽ 50), we found that the treatment group had significantly reduced blood loss measured at 4 and 24 hours after surgery, along with significantly reduced transfusion requirements of red cell concentrates, fresh frozen plasma, and platelets (unpublished observations). The two groups were similar in relation to patient demographic factors, such as age, weight, and so forth, and procedure variables, such as aortic cross clamp time and bypass time. The incidence of post– cardiopulmonary bypass coagulopathy was also similar in the two groups. A number of lessons regarding the use of fibrin sealants were learned during the course of this study. These included the importance of team work in the clinical use of fibrin sealants; a steep, albeit inevitable, learning curve to derive optimum benefit from the use of fibrin sealants; and the need to spray all potential mediastinal sites of bleeding with fibrin sealant. Re-operative procedures Mediastinal bleeding during cardiac operations is a potentially serious complication, and the application of fibrin sealant in cardiac re-operations to the excessive nonsuturable bleeding from adhesions, at the end of surgery reduces postoperative bleeding [14]. These findings are reinforced by the results of a clinical study of 333 patients undergoing cardiac re-operations [13], in which the success rate when using the fibrin sealant Tisseel (Baxter Immuno, Vienna,
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Austria) in controlling bleeding was significantly improved compared with conventional topical hemostatic agents. Bleeding was controlled within 5 minutes in 198 of 214 bleeding episodes (92.6%) treated with fibrin sealant, compared with only 12 of the 97 episodes (12.4%) treated with conventional topical agents (P ⬍0.001). In 64 of 78 episodes (82.0%) in which other topical agents failed to prevent bleeding within 5 minutes, fibrin sealant stopped the bleeding within the next 5 minutes. In addition, emergency resternotomy rates after re-operation were significantly lower in the fibrin sealant group, compared with historic controls (5.6% vs 10%; P ⬍0.0089). When fibrin sealant was used in valve or coronary artery bypass graft re-operations, only one re-exploration for bleeding was needed in 49 cases [15]. Preventing the formation of adhesions is beneficial to the patient, because adhesions cause complications during reoperations and can cause injury to the heart and bypass grafts; they can also lengthen operating times and increase the need for blood transfusion during surgery. Animal models of re-operative cardiac surgery have shown that animals that receive fibrin sealant during open-heart surgery procedures are easier to re-operate because of fewer adhesions [19,20].
was effective in obtaining hemostasis in cases of parenchymal lacerations, despite thrombocytopenia and coagulopathy in some cases [25]. In another report, fibrin sealant was compared with microcrystalline collagen powder for topical hemostasis in elective hepatic resection [26]. A dry cut surface was achieved in 87% and 81% of the collagen powder–treated and fibrin sealant–treated groups, respectively. Both agents showed similar hemostatic effects and comparable results in terms of postoperative bleeding, bile leakage, or morbidity and mortality rates. The authors concluded that fibrin sealant treatment provided a more reliable result postoperatively compared with collagen powder [26]. In a recent study, Davidson et al [27], compared the efficacy of autologous fibrin sealant, regenerated oxidized cellulose gauze and untreated controls in a porcine partial hepatic lobectomy model. Median time to hemostasis was significantly reduced in animals treated with the fibrin sealant (8 minutes) and regenerated oxidized cellulose gauze (10 minutes) compared with untreated controls (31 minutes; P ⬍0.001). Extrapolation of these data to the clinical setting, assuming a resection surface of 70 cm2, translates to the potential saving of 1 hour of operating room time [27].
Other biological sealants Like fibrin sealants, another biological sealant often used in cardiovascular operations is gelatin–resorcinol–formaldehyde (GRF) glue. Sometimes there is confusion surrounding the clinical use of these two sealants. However, these preparations have different biophysical properties and relatively well-defined clinical indications for their use [21]. GRF glue has hemostatic potential but is a much weaker agent compared with fibrin sealants [10]. Both the clot-forming ability and the type of clot formed with fibrin sealants are superior to those achieved by GRF glue. GRF glue is known to cause extensive fibroblastic proliferation, thus stimulating adhesion formation, as opposed to little tissue reaction and possible antiadhesive properties of fibrin sealants [20,22]. Both fibrin sealants and GRF glue have good adhesive qualities, but GRF glue has significantly more tensile strength compared with fibrin sealants. Therefore, it is appropriate to use GRF glue as a tissue-reinforcing agent, for example, in surgery for aortic dissection [10,23,24], whereas a fibrin sealant is the preferred agent for hemostasis and suture support [10].
Upper gastrointestinal hemorrhage, particularly from peptic ulcers, is a relatively common and sometimes lifethreatening emergency, with an estimated incidence of about 100 per 100,000 adults per year [28,29]. The incidence increases with age, from 23 per 100,000 adults per year in those aged under 30 years to 485 per 100,000 in those aged over 70 years [29]. Although bleeding usually ceases spontaneously, persistent or recurrent bleeding occurs in 5% to 30% of patients with gastroduodenal ulcer [30]. The mortality rate reported in one study of over 4,000 cases in the United Kingdom was about 14% (11% in emergency admissions and 33% in hemorrhaging inpatients) [29]. The standard therapy in Europe for such ulcers involves infiltration of the ulcer and surrounding tissue with noradrenaline and sclerotherapy with polidocanol. Although effective, recurrent bleeding is common and gastric or duodenal infarction or other serious complications may occur with such injection treatments. Additionally, the use of polidocanol may be associated with necrosis of the surrounding tissue. In a clinical study of 854 patients with active gastroduodenal bleeding, repeated endoscopic treatment with the fibrin sealant Beriplast P reduced recurrent bleeding significantly more than treatment with polidocanol 1% [31]. The resulting clot forms a physiologic seal that does not cause necrosis of the surrounding tissue. Such prophylactic treatment with fibrin sealant is far less costly than a long hospital stay with surgery and time spent in intensive care, which may be required for an episode of rebleeding.
Hemostasis in hepatic and splenic surgery Hepatic and splenic surgery pose particular problems because of the difficulties in maintaining hemostasis in parenchymal tissue and in suturing these highly vascular organs. Theoretically, fibrin glue may therefore be particularly useful in cases of trauma to these organs. This is borne out by reports in the literature. In one study, fibrin sealant
Treatment of bleeding gastroduodenal ulcers
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Hemostasis in the treatment of burns
Use of fibrin sealants in patients with coagulation disorders
The use of fibrin sealants as an adjunct to surgery in skin grafting has been investigated by several groups. The fibrin sealant promoted both improved adhesion of grafts and considerably improved hemostasis, both in terms of time to establish hemostasis and in terms of blood loss per se [32–34]. In addition, early graft adherence and an improved graft “take” are obtained, leading to shorter hospitalization for isolated burns to the face or hands, with a reduced requirement for postoperative care, a prompt start to physiotherapy, and an earlier return to normal activities [34]. In one study involving thermally injured patients, patients treated with fibrin sealant (n ⫽ 34) did not require packed red blood cell transfusions, albumin infusion, or topical bovine thrombin treatment during excision and grafting procedures, whereas patients who did not receive fibrin sealant (n ⫽ 61) received various quantities of packed red blood cells, albumin infusions, and topical bovine thrombin treatment. Although there was no reported decrease in operating time or hospital stay for patients in this study, fibrin sealant eliminated the need for packed red blood cells and albumin and thrombin kits with an estimated total cost saving of $1,500 per patient [35].
The role of fibrin sealants in surgical procedures performed on patients with coagulopathies has been reviewed by Martinowitz et al [38]. Patients with a bleeding diathesis are at high risk of prolonged or excessive bleeding during or after invasive procedures, despite systemic replacement therapy aimed at replacing the congenital or acquired defect. Martinowitz et al [38] reported their use of fibrin sealant in a total of 356 orthopedic, general, and dental surgical procedures performed on 176 patients with bleeding disorders (106 with hemophilia A, B, or von Willebrand’s disease; 40 undergoing anticoagulant therapy; and 29 with other coagulopathies). Use of fibrin sealant reduced the perioperative blood loss considerably. Fibrin sealants also reduce the incidence of postoperative hemorrhagic complications, so that patients require less factor concentrate and costs can be reduced greatly. The use of fibrin sealants as an adjunct to surgery in patients with hemostatic disorders may also permit multiple surgical procedures to be performed in single sessions, with faster rehabilitation, reduced hospitalization times, and substantial cost savings [38]. Given the clear benefits of fibrin sealants in promoting hemostasis in patients with hemostatic disorders, Martinowitz et al [38] suggest that these products are of sufficient effectiveness that they should be introduced as soon as possible for hemostasis in patients with hemophilia and von Willebrand’s disease. As the authors point out, these patients are already exposed to significant amounts of clotting factor concentrates obtained from multiple donors. The use of fibrin sealant will reduce this exposure, offering a safety and cost advantage in addition to effective hemostasis. It is anticipated that the use of fibrin sealants will reduce hospitalization, medical costs, viral transmission risk, and factor supplementation in patients with hemophilia [39]. Thus, it is most likely that the role of fibrin sealants will amplify significantly in the field of hemophilia and other hemostatic disorders.
Hemostasis in dental patients receiving anticoagulant therapy Long-term anticoagulant therapy is indicated for patients at serious risk of thromboembolism, such as those with artificial heart valves, mitral valve stenosis, or acute myocardial infarction. Tooth extraction is a relatively common and straightforward procedure for most patients with normal blood coagulability. However, dental extractions in anticoagulated patients are difficult and controversial. Continuation of anticoagulant therapy exposes the patient to the risk of serious hemorrhage, whereas reducing or discontinuing therapy, so that the prothrombin time decreases to within the normal range, exposes the patient to the risk of thromboembolism with possible difficulty in re-establishing a therapeutic level of anticoagulation. In a clinical study of the fibrin sealant Beriplast P to induce clot formation at the site of the surgical wound in 40 patients remaining on anticoagulant therapy and undergoing a total of 63 dental extractions, local hemostasis was achieved without postoperative risk of hemorrhage or thromboembolism [36]. Hospitalization and frequent monitoring of prothrombin time were also found not to be required. In a more recent study of 150 patients, local hemostasis with fibrin sealant, gelatin sponge, and sutures (123 extractions) was compared with gelatin sponge and sutures or gelatin sponge, sutures, and tranexamic acid mouthwash. The rate of postoperative bleeding was comparable in all treatment groups [37].
Economic evaluation of fibrin sealants as hemostatic agents Blood transfusion–related costs cannot be underestimated. In an elegant study by Jefferies et al [40] involving 60 university hospitals, 5% to 8.6% of total hospital costs were attributed to all aspects of blood transfusion costs in many surgical specialties and procedures. Thus, any procedure that has the potential to reduce blood transfusion requirements should help reduce total hospital costs. Despite a number of studies showing safety and efficacy of fibrin sealants in achieving hemostasis, there are few reports in the literature addressing the cost-effectiveness equation of their use. In a randomized study that compared the use of fibrin sealant with polidocanol as an endoscopic hemostatic agent in bleeding gastroduodenal ulcer, the investigators showed an improved cost– benefit and cost-effectiveness ratio of the
P.S. Mankad and M. Codispoti / The American Journal of Surgery 182 (2001) 21S–28S Table 2 Potential economic impact 1. 2. 3. 4. 5. 6.
Direct costs of blood and blood product transfusions Reduced stay in critical care unit Reduced hospital stay Decreased operating room time Potential to increase patient through-put due to 2, 3, and 4 above Costs associated with complications of transfusions (outlined in Table 1) 7. Open claim on medical negligence resulting from a complication [43]
fibrin sealant compared with polidocanol [41]. Another study evaluating the health economics of a conventional regimen of post–tooth extraction hemostasis in patients on anticoagulant therapy versus the use of a fibrin sealant concluded that the use of the fibrin sealant was a significantly more cost-effective modality [42]. However, certain limitations do apply in pharmacoeconomic evaluations of the clinical use of fibrin sealants. These include (1) in some parts of the world, for example in the United Kingdom and Canada, the price of blood or blood products is an indirect cost, and one not borne by the health service providers or insurers; and (2) some of the potential benefits of fibrin sealant use cannot be measured in economic terms. For example, it is difficult to measure the psychological benefit to the patient in knowing there will be a reduced use of blood and blood products. Potential economic benefits of improving surgical hemostasis and minimizing transfusions are shown in Table 2. Summary Fibrin sealants can reduce postoperative complications by promoting hemostasis and the avoidance of blood loss. The reduction in hemorrhage also reduces the need for blood transfusions, which may lead to a reduced risk of viral infection. By promoting wound healing, fibrin sealants also reduce the need for repeat procedures, which may involve lengthy hospitalization or intensive care, with the associated increased costs. Future pharmacoeconomic studies are required to better define the place of fibrin sealants as hemostatic agents in surgical practice. References [1] Mackie IJ. The biology of haemostasis and thrombosis. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine, 3rd ed. Oxford: Oxford University Press, 1996:3613–27. [2] Sierra DH. Fibrin sealant adhesive systems: a review of their chemistry, material properties and clinical applications. J Biomater Appl 1993;7:309 –52. [3] Anderson KC, Weinstein H. Transfusion-associated graft versus host disease. N Engl J Med 1990;323:315–21. [4] Klein HG. Risks of perioperative transfusion: the transfusion trigger. In: Wechsler AS, ed. Pharmacologic management of perioperative bleeding. Southampton, NY: CME Network, 1996:1–9.
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[28] Longstreth GF. Epidemiology of hospitalisation for acute upper gastrointestinal hemorrhage: a population based study. Am J Gastroenterol 1995;90:861– 8. [29] Rockall TA, Logan RFA, Devlin HB, et al. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. BMJ 1995;311:222– 6. [30] Terdiman JP. Update on upper gastrointestinal bleeding. Basing treatment decisions on patient’s risk level. Postgrad Med 1998;103:43– 4,51–2,58 –9 passim. [31] Rutgeerts P, Rauws E, Wara P, et al. Randomised trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 1997;350:692– 6. [32] Ihara N, Suzuki K, Tanaka H, et al. Application of fibrin glue to burns: its hemostatic and skin transplant fixation effects in the excised wound. Burns 1984;10:396 – 404. [33] Stuart JD, Kenney JG, Lettieri J, et al. Application of single donor fibrin glue to burns. J Burn Care Rehabil 1988;9:619 –22. [34] Saltz R, Sierra D, Feldman D, et al. Experimental and clinical applications of fibrin glue. Plast Reconstr Surg 1991;88:1005–15. [35] McGill V, Kowal-Vern A, Lee M, et al. Use of fibrin sealant in thermal injury. J Burn Care Rehabil 1997;18:429 –34. [36] Martinowitz U, Mazar AL, Taicher S, et al. Dental extraction for patients on oral anticoagulation therapy. Oral Surg Oral Med Oral Pathol 1990;70:274 –7.
[37] Blinder D, Manor Y, Martinowitz U, et al. Dental extractions in patients maintained on continued oral anticoagulant: comparison of local hemostasis modalities. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:137– 40. [38] Martinowitz U, Schulman S, Horoszowski H, et al. Role of fibrin sealants in surgical procedures on patients with hemostatic disorders. Clin Orthop 1996;328:65–75. [39] Kavakli K. Fibrin glue and clinical impact on haemophilia care. Haemophilia 1999;5:392– 6. [40] Jefferies LC, Sachais BS, Young DS. Blood transfusion costs by diagnosis-related groups in 60 university hospitals in 1995. Transfusion 2001;41:522–9. [41] Salm R, Grund KE, Szucs TD. [Endoscopic hemostasis in bleeding gastroduodenal ulcer—a contribution to the cost aspect.] Endoskopische Blutstillung bei der gastroduodenalen Ulkusblutung—Ein Beitrag zur Kostenproblematik. Zentralbl Chir 1996;121:847–50. [42] Zusman SP, Lustig JP, Bin NG. Cost evaluation of two methods of post tooth extraction hemostasis in patients on anticoagulant therapy. Community Dent Health 1993;10:167–73. [43] Perkins HA. The safety of the blood supply: making decisions in transfusion medicine. In: Nance SJ, ed. Blood Safety: Current Challenges. Bethesda, MD: American Association of Blood Banks, 1992.
The role of fibrin sealants in hemostasis Pankaj S. Mankad, M.B.B.S.*, Massimiliano Codispoti, M.D. Department of Cardio-thoracic Surgery, Royal Infirmary, Lauriston Place, Edinburgh, EH3 9YW United Kingdom
Abstract Hemostasis is a prerequisite for wound healing, and under normal physiologic conditions, it is achieved by means of the coagulation cascade. However, there are a number of surgical procedures where there may be considerable benefits to the patient, surgeon, or health-care costs if hemostasis can be achieved more efficiently. The rapid and effective control of bleeding during and after surgery reduces blood loss and can help reduce postoperative complications. These improved outcomes can reduce the need for transfusion, with the associated risk of viral transmission, and have a positive impact on operative and hospital stay times. Fibrin sealants are surgical hemostatic agents derived from human plasma that reproduce the final steps in the coagulation pathway and form a stable fibrin clot. Fibrin sealants are used in a broad range of surgical procedures to assist hemostasis, including cardiovascular, hepatic, and splenic surgery, gastrointestinal hemorrhage, skin grafting, and dental extractions in anticoagulated patients. Patients with coagulopathies are at high risk of prolonged or excessive bleeding during or after invasive surgery, and these patients may also benefit from the use of fibrin sealants. This article reviews the role of fibrin sealants in hemostasis, citing a number of key clinical studies that report a significant reduction in blood loss or chest drain output after surgery with fibrin sealant compared with controls. © 2001 Excerpta Medica, Inc. All rights reserved.
Fibrin sealants (also known as fibrin glues) are surgical hemostatic agents derived from human plasma that are designed to reproduce the final steps of the physiologic coagulation cascade to produce a stable fibrin clot (Fig. 1). Fibrin sealants have a range of uses in many procedures across a wide spectrum of surgical specialties, including hemostasis, wound healing, suture support, and tissue sealing. The range of possible applications is so wide that it is not possible to address all the specifics of sealant use in a single review. However, this article provides an overview of the role of fibrin sealants in hemostasis and gives a number of examples of their use for this indication in a variety of key surgical procedures. Hemostasis depends on the successful balance between the coagulation, complement, and fibrinolytic pathways, with complex interactions between plasma proteins, blood cells, blood flow and viscosity, and the blood vessel endothelium. In order to set the role of fibrin sealants in context, the following brief overview of hemostatic and wound healing mechanisms is provided, based on Mackie [1]. For a more detailed treatment, the reader is referred to specialist texts and reviews.
Overview of hemostasis and wound healing After tissue damage, platelets are activated and adhere rapidly to the blood vessel wall, modifying the vascular tone and forming aggregates. Once activated, platelets produce thromboxane A2, inositol triphosphate, and diacylglycerol, which further up-regulate platelet function and release Ca2⫹ ions, a cofactor essential to several stages of the coagulation cascade. The activated platelets also undergo a transformation of their outer membranes to provide a surface that promotes coagulation, supporting the generation of thrombin and subsequent production of fibrin, leading to clot formation and stablization. The coagulation cascade may be triggered by exposure of blood to foreign or extravascular surfaces, by tissue rupture and the consequent exposure of tissue factor, or by platelet activation. The cascade depends on a number of pro-enzymes, proteins, and cofactors, the final stages of which are completed by thrombin acting on fibrinogen to form fibrin, and factor XIIIa to stabilize the developing fibrin clot. Thrombin, Factor XIII, and the fibrin clot
* Corresponding author. Tel.: ⫹44 131 536 0622; fax: ⫹44 131 536 3482. E-mail address: [email protected]
Thrombin plays a pivotal role in the coagulation mechanism, converting fibrinogen to fibrin in the presence of Ca2⫹ ions. This key final step is common to all the coagu-
0002-9610/01/$ – see front matter © 2001 Excerpta Medica, Inc. All rights reserved. PII: S 0 0 0 2 - 9 6 1 0 ( 0 1 ) 0 0 9 1 1 - 1
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Fig. 1. The mechanism of action of a two-component fibrin sealant (Beriplast P; Aventis Behring, Marburg, Germany). * ⫽ pasteurized. Table 1 Complications of transfusion [3–5] Complication
Incidence
Febrile reaction Hemolytic nonfatal reaction Hemolytic fatal reaction Human T-cell lymphotrophic virus I/II Hepatitis B Hepatitis C Bacterial infection (platelets) Cytomegalo virus infection Immunosuppressed recipient Immunocompetent recipient
1 1 1 1 1 1 1
lation pathways. Fibrinogen is a heterodimer composed of two each of three different polpeptide chains (␣, , and ␥) and two fibrinopeptides (A and B) to give a final structure (A␣, B, ␥)2. Thrombin cleaves the small fibrinopeptides from the ␣- and -polypeptide chains of the fibrinogen to form fibrin monomers. These undergo end-to-end polymerization to form long fibrin strands, which then precipitate to form a fibrin clot [2]. Factor XIII (fibrin-stabilizing factor) is also activated by thrombin, inducing covalent bond formation between the ␥-chains of the fibrin monomers. Polymers then form between the fibrin ␣-chains, imparting tensile strength and stabilizing the fibrin clot. Thrombin also activates platelets trapped in the fibrin mesh: their receptors for fibrin and collagen enhance the stablization of the clot [2]. Cytokines and platelet-derived growth factors enhance wound healing by promoting fibroblast ingrowth along the fibrin strands and subsequent formation of a more permanent collagen fiber network. At this time, the fibrin network (now superfluous) is degraded proteolytically by the action of the plasminogen–plasmin pathway, and the breakdown products are subsequently phagocytosed by macrophages.
in in in in in in in
100 6,000 676,000 640,000 63,000 103,000 2,500
Variable 0.9%
Surgical advantages of achieving hemostasis Wound healing is dependent on achieving hemostasis. As outlined below, rapid and effective control of bleeding can help reduce postoperative complications and lead to improved patient outcomes, reducing the need for transfusions with the attendant increase in risk of blood-borne viral infection, reducing the increased operative and hospitalization times and the increased costs (both direct and indirect). Potential complications associated with blood and blood product transfusions are outlined in Table 1. The role of fibrin sealants in achieving hemostasis Common causes of blood loss after surgery include continuous oozing from the raw surface and suture line or needle hole bleeding, which is usually made worse by additional suturing. Apart from these common factors, other reasons for blood loss can be patient-related factors (eg, the presence of coagulopathy or the patient receiving anticoagulant therapy) and factors related to surgical procedure (eg, liver surgery or open-heart surgery) where the nature of
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Fig. 2. Mean blood loss (⫾ SEM) from experimental arteriotomies is reduced significantly after application of a fibrin sealant dressing. * ⫽ P ⫽ 0.005 vs contralateral control [8].
surgery itself is a risk factor for bleeding. As outlined in the subsequent sections, fibrin sealants have a role to play in almost all situations. In some conditions their hemostatic efficacy has been shown clinically, whereas for others there is overwhelming favorable experimental evidence [6]. The efficacy of fibrin sealants in promoting hemostasis is difficult to quantify directly in patients for practical and ethical reasons, although their effects on blood loss may be inferred from the number of units of blood transfused or from chest drain output during and after surgery. The hemostatic efficacy of fibrin sealants has, however, been quantified in several animal models [7–9]. In a study of the effects of fibrin sealant on femoral bleeding after removal of bilateral femoral catheters in dogs [7], application of fibrin sealant into the periarterial tissue adjacent to the arteriotomy site reduced ecchymosis and hematoma formation significantly in fibrin sealant–treated groins, compared with the contralateral, control groins in the same animal (P ⫽ 0.008 and P ⫽ 0.016, respectively). Gross bleeding after catheter removal in a similarly treated group of heparinized dogs was also reduced significantly by fibrin sealant treatment (P ⫽ 0.016 vs contralateral controls). A prototype fibrin sealant dressing has been shown to be highly effective in maintaining hemostasis in a femoral artery injury model [8]. In a randomized, blinded, placebocontrolled study, 6 pigs received bilateral 4-mm longitudinal femoral arteriotomies after surgical exposure of the arteries. A fibrin sealant dressing was applied to one artery and a control dressing to the contralateral artery. Blood loss was significantly less from the fibrin sealant–treated side compared with the control side (4.9 vs 82.3 mL; P ⬍0.0005; Fig. 2). Complete hemostasis was achieved within 15 minutes in five of six arteriotomies treated with fibrin sealant, but in none of the control arteriotomies even after 1 hour. In a recent study of suture hole bleeding in a pig vascular graft model, Dickneite et al showed that the use of fibrin sealant significantly reduced blood loss (P ⫽ 0.016) and
improved the rate of hemostasis (5 of 5 vs 0 of 4; P ⫽ 0.008), compared with untreated controls. Similarly, when fibrin sealant was compared with gelfoam/thrombin treatment, there was significantly less blood loss in the fibrin sealant–treated group (P ⬍0.01) [9]. The use of fibrin sealants for hemostasis is occasionally criticized on the grounds that it may promote sloppy surgical practice. This is far from the truth. Surgeons are well aware that local hemostatic agents are only an adjunct to achieving hemostasis and can never compensate for inadequate or improper attention to finer details in surgical techniques. Thus, fibrin sealants should not be viewed as an alternative to good surgical practice but as complementary agents to be used judiciously to improve the surgical outcome. Hemostasis in cardiovascular surgery Fibrin sealants have primarily been used in cardiovascular and cardiothoracic surgery as an adjunct to hemostasis, for which they are highly effective in a range of procedures [10]. Fibrin sealants have also been used in cardiovascular surgery to seal suture holes, staple lines, anastomoses, fistulas, and raw surfaces. Optimal application requires a dry operative field, which is often difficult to achieve in cardiovascular surgery, and thus fibrin sealants are frequently used prophylactically while the suture line is dry to prevent anticipated hemorrhage. Fibrin sealants can also be applied by means of a solid matrix, such as collagen fleece, to a specific area where the surgeon requires hemostasis [11], or as a spray, for example, for use in the anterior mediastinum to reduce postoperative hemorrhage from diffuse low-pressure bleeding [12]. In a prospective, randomized clinical trial, Rousou et al [13], established the efficacy of fibrin sealants in reducing time to achieve hemostasis and frequency of postoperative hemorrhage. Fibrin sealant is now frequently used routinely whenever suturing is impossible,
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Fig. 3. Mean chest drain output (⫾ SEM) after open-heart surgery is reduced significantly after spray application of fibrin sealant to the mediastinum [14]. * Cumulative.
dangerous, or difficult, and to save time waiting for spontaneous hemostasis [10]. Mediastinal bleeding during cardiac operations is a troublesome complication. However, spray application of fibrin sealant to the anterior mediastinum in coronary artery bypass graft and valve replacement operations reduced perioperative blood loss significantly, as measured by chest drain output, and also by the number of units of whole blood transfused [14]. In 20 consecutively treated patients undergoing a range of cardiac operations, fibrin sealant was sprayed on the anterior mediastinum before closure of the median sternotomy incision. A matched control group of 20 patients who underwent open-heart operations of the same complexity by the same surgeon during the same period (but without the use of fibrin sealant) was chosen for comparison. Application of fibrin sealant reduced the mean chest drain output at both 12 hours (461 mL vs 731 mL; P ⬍0.05) and 24 hours (714 mL vs 1,016 mL; P ⬍0.05; Fig. 3) [14]. In a review of their experience with fibrin sealants in 689 thoracic and cardiovascular procedures over a 4-year period, Matthew et al [15] reported a 94% success rate in reducing the blood loss associated with various cardiac interventions. Blood loss was reduced from diffuse areas of the mediastinum, specific sites at coronary artery bypass graft anastomoses, and long suture lines. As described above, fibrin sealants also promote hemostasis in the femoral artery after cardiac catheterization [7]. This may be useful in reducing the morbidity, complications, and hospitalization associated with this increasingly common procedure and may promote earlier patient mobilization [7]. Fibrin sealants have also proven to be effective in reducing suture line bleeding in arteriotomy [16] and in maintaining hemostasis by reinforcing the suture line for closure of the aortic stump in cases of possible blowout [17].
Pediatric cardiac surgery The need for perfect hemostasis is even more important in pediatric cardiac surgery because of the high incidence of coagulopathy after open-heart procedures [18] and increased risks associated with the use of blood and blood products. In a prospective randomized control study looking at the safety and efficacy of Beriplast P (Aventis Behring, Marburg, Germany) to achieve hemostasis in pediatric open-heart operations (n ⫽ 50), we found that the treatment group had significantly reduced blood loss measured at 4 and 24 hours after surgery, along with significantly reduced transfusion requirements of red cell concentrates, fresh frozen plasma, and platelets (unpublished observations). The two groups were similar in relation to patient demographic factors, such as age, weight, and so forth, and procedure variables, such as aortic cross clamp time and bypass time. The incidence of post– cardiopulmonary bypass coagulopathy was also similar in the two groups. A number of lessons regarding the use of fibrin sealants were learned during the course of this study. These included the importance of team work in the clinical use of fibrin sealants; a steep, albeit inevitable, learning curve to derive optimum benefit from the use of fibrin sealants; and the need to spray all potential mediastinal sites of bleeding with fibrin sealant. Re-operative procedures Mediastinal bleeding during cardiac operations is a potentially serious complication, and the application of fibrin sealant in cardiac re-operations to the excessive nonsuturable bleeding from adhesions, at the end of surgery reduces postoperative bleeding [14]. These findings are reinforced by the results of a clinical study of 333 patients undergoing cardiac re-operations [13], in which the success rate when using the fibrin sealant Tisseel (Baxter Immuno, Vienna,
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Austria) in controlling bleeding was significantly improved compared with conventional topical hemostatic agents. Bleeding was controlled within 5 minutes in 198 of 214 bleeding episodes (92.6%) treated with fibrin sealant, compared with only 12 of the 97 episodes (12.4%) treated with conventional topical agents (P ⬍0.001). In 64 of 78 episodes (82.0%) in which other topical agents failed to prevent bleeding within 5 minutes, fibrin sealant stopped the bleeding within the next 5 minutes. In addition, emergency resternotomy rates after re-operation were significantly lower in the fibrin sealant group, compared with historic controls (5.6% vs 10%; P ⬍0.0089). When fibrin sealant was used in valve or coronary artery bypass graft re-operations, only one re-exploration for bleeding was needed in 49 cases [15]. Preventing the formation of adhesions is beneficial to the patient, because adhesions cause complications during reoperations and can cause injury to the heart and bypass grafts; they can also lengthen operating times and increase the need for blood transfusion during surgery. Animal models of re-operative cardiac surgery have shown that animals that receive fibrin sealant during open-heart surgery procedures are easier to re-operate because of fewer adhesions [19,20].
was effective in obtaining hemostasis in cases of parenchymal lacerations, despite thrombocytopenia and coagulopathy in some cases [25]. In another report, fibrin sealant was compared with microcrystalline collagen powder for topical hemostasis in elective hepatic resection [26]. A dry cut surface was achieved in 87% and 81% of the collagen powder–treated and fibrin sealant–treated groups, respectively. Both agents showed similar hemostatic effects and comparable results in terms of postoperative bleeding, bile leakage, or morbidity and mortality rates. The authors concluded that fibrin sealant treatment provided a more reliable result postoperatively compared with collagen powder [26]. In a recent study, Davidson et al [27], compared the efficacy of autologous fibrin sealant, regenerated oxidized cellulose gauze and untreated controls in a porcine partial hepatic lobectomy model. Median time to hemostasis was significantly reduced in animals treated with the fibrin sealant (8 minutes) and regenerated oxidized cellulose gauze (10 minutes) compared with untreated controls (31 minutes; P ⬍0.001). Extrapolation of these data to the clinical setting, assuming a resection surface of 70 cm2, translates to the potential saving of 1 hour of operating room time [27].
Other biological sealants Like fibrin sealants, another biological sealant often used in cardiovascular operations is gelatin–resorcinol–formaldehyde (GRF) glue. Sometimes there is confusion surrounding the clinical use of these two sealants. However, these preparations have different biophysical properties and relatively well-defined clinical indications for their use [21]. GRF glue has hemostatic potential but is a much weaker agent compared with fibrin sealants [10]. Both the clot-forming ability and the type of clot formed with fibrin sealants are superior to those achieved by GRF glue. GRF glue is known to cause extensive fibroblastic proliferation, thus stimulating adhesion formation, as opposed to little tissue reaction and possible antiadhesive properties of fibrin sealants [20,22]. Both fibrin sealants and GRF glue have good adhesive qualities, but GRF glue has significantly more tensile strength compared with fibrin sealants. Therefore, it is appropriate to use GRF glue as a tissue-reinforcing agent, for example, in surgery for aortic dissection [10,23,24], whereas a fibrin sealant is the preferred agent for hemostasis and suture support [10].
Upper gastrointestinal hemorrhage, particularly from peptic ulcers, is a relatively common and sometimes lifethreatening emergency, with an estimated incidence of about 100 per 100,000 adults per year [28,29]. The incidence increases with age, from 23 per 100,000 adults per year in those aged under 30 years to 485 per 100,000 in those aged over 70 years [29]. Although bleeding usually ceases spontaneously, persistent or recurrent bleeding occurs in 5% to 30% of patients with gastroduodenal ulcer [30]. The mortality rate reported in one study of over 4,000 cases in the United Kingdom was about 14% (11% in emergency admissions and 33% in hemorrhaging inpatients) [29]. The standard therapy in Europe for such ulcers involves infiltration of the ulcer and surrounding tissue with noradrenaline and sclerotherapy with polidocanol. Although effective, recurrent bleeding is common and gastric or duodenal infarction or other serious complications may occur with such injection treatments. Additionally, the use of polidocanol may be associated with necrosis of the surrounding tissue. In a clinical study of 854 patients with active gastroduodenal bleeding, repeated endoscopic treatment with the fibrin sealant Beriplast P reduced recurrent bleeding significantly more than treatment with polidocanol 1% [31]. The resulting clot forms a physiologic seal that does not cause necrosis of the surrounding tissue. Such prophylactic treatment with fibrin sealant is far less costly than a long hospital stay with surgery and time spent in intensive care, which may be required for an episode of rebleeding.
Hemostasis in hepatic and splenic surgery Hepatic and splenic surgery pose particular problems because of the difficulties in maintaining hemostasis in parenchymal tissue and in suturing these highly vascular organs. Theoretically, fibrin glue may therefore be particularly useful in cases of trauma to these organs. This is borne out by reports in the literature. In one study, fibrin sealant
Treatment of bleeding gastroduodenal ulcers
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Hemostasis in the treatment of burns
Use of fibrin sealants in patients with coagulation disorders
The use of fibrin sealants as an adjunct to surgery in skin grafting has been investigated by several groups. The fibrin sealant promoted both improved adhesion of grafts and considerably improved hemostasis, both in terms of time to establish hemostasis and in terms of blood loss per se [32–34]. In addition, early graft adherence and an improved graft “take” are obtained, leading to shorter hospitalization for isolated burns to the face or hands, with a reduced requirement for postoperative care, a prompt start to physiotherapy, and an earlier return to normal activities [34]. In one study involving thermally injured patients, patients treated with fibrin sealant (n ⫽ 34) did not require packed red blood cell transfusions, albumin infusion, or topical bovine thrombin treatment during excision and grafting procedures, whereas patients who did not receive fibrin sealant (n ⫽ 61) received various quantities of packed red blood cells, albumin infusions, and topical bovine thrombin treatment. Although there was no reported decrease in operating time or hospital stay for patients in this study, fibrin sealant eliminated the need for packed red blood cells and albumin and thrombin kits with an estimated total cost saving of $1,500 per patient [35].
The role of fibrin sealants in surgical procedures performed on patients with coagulopathies has been reviewed by Martinowitz et al [38]. Patients with a bleeding diathesis are at high risk of prolonged or excessive bleeding during or after invasive procedures, despite systemic replacement therapy aimed at replacing the congenital or acquired defect. Martinowitz et al [38] reported their use of fibrin sealant in a total of 356 orthopedic, general, and dental surgical procedures performed on 176 patients with bleeding disorders (106 with hemophilia A, B, or von Willebrand’s disease; 40 undergoing anticoagulant therapy; and 29 with other coagulopathies). Use of fibrin sealant reduced the perioperative blood loss considerably. Fibrin sealants also reduce the incidence of postoperative hemorrhagic complications, so that patients require less factor concentrate and costs can be reduced greatly. The use of fibrin sealants as an adjunct to surgery in patients with hemostatic disorders may also permit multiple surgical procedures to be performed in single sessions, with faster rehabilitation, reduced hospitalization times, and substantial cost savings [38]. Given the clear benefits of fibrin sealants in promoting hemostasis in patients with hemostatic disorders, Martinowitz et al [38] suggest that these products are of sufficient effectiveness that they should be introduced as soon as possible for hemostasis in patients with hemophilia and von Willebrand’s disease. As the authors point out, these patients are already exposed to significant amounts of clotting factor concentrates obtained from multiple donors. The use of fibrin sealant will reduce this exposure, offering a safety and cost advantage in addition to effective hemostasis. It is anticipated that the use of fibrin sealants will reduce hospitalization, medical costs, viral transmission risk, and factor supplementation in patients with hemophilia [39]. Thus, it is most likely that the role of fibrin sealants will amplify significantly in the field of hemophilia and other hemostatic disorders.
Hemostasis in dental patients receiving anticoagulant therapy Long-term anticoagulant therapy is indicated for patients at serious risk of thromboembolism, such as those with artificial heart valves, mitral valve stenosis, or acute myocardial infarction. Tooth extraction is a relatively common and straightforward procedure for most patients with normal blood coagulability. However, dental extractions in anticoagulated patients are difficult and controversial. Continuation of anticoagulant therapy exposes the patient to the risk of serious hemorrhage, whereas reducing or discontinuing therapy, so that the prothrombin time decreases to within the normal range, exposes the patient to the risk of thromboembolism with possible difficulty in re-establishing a therapeutic level of anticoagulation. In a clinical study of the fibrin sealant Beriplast P to induce clot formation at the site of the surgical wound in 40 patients remaining on anticoagulant therapy and undergoing a total of 63 dental extractions, local hemostasis was achieved without postoperative risk of hemorrhage or thromboembolism [36]. Hospitalization and frequent monitoring of prothrombin time were also found not to be required. In a more recent study of 150 patients, local hemostasis with fibrin sealant, gelatin sponge, and sutures (123 extractions) was compared with gelatin sponge and sutures or gelatin sponge, sutures, and tranexamic acid mouthwash. The rate of postoperative bleeding was comparable in all treatment groups [37].
Economic evaluation of fibrin sealants as hemostatic agents Blood transfusion–related costs cannot be underestimated. In an elegant study by Jefferies et al [40] involving 60 university hospitals, 5% to 8.6% of total hospital costs were attributed to all aspects of blood transfusion costs in many surgical specialties and procedures. Thus, any procedure that has the potential to reduce blood transfusion requirements should help reduce total hospital costs. Despite a number of studies showing safety and efficacy of fibrin sealants in achieving hemostasis, there are few reports in the literature addressing the cost-effectiveness equation of their use. In a randomized study that compared the use of fibrin sealant with polidocanol as an endoscopic hemostatic agent in bleeding gastroduodenal ulcer, the investigators showed an improved cost– benefit and cost-effectiveness ratio of the
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Direct costs of blood and blood product transfusions Reduced stay in critical care unit Reduced hospital stay Decreased operating room time Potential to increase patient through-put due to 2, 3, and 4 above Costs associated with complications of transfusions (outlined in Table 1) 7. Open claim on medical negligence resulting from a complication [43]
fibrin sealant compared with polidocanol [41]. Another study evaluating the health economics of a conventional regimen of post–tooth extraction hemostasis in patients on anticoagulant therapy versus the use of a fibrin sealant concluded that the use of the fibrin sealant was a significantly more cost-effective modality [42]. However, certain limitations do apply in pharmacoeconomic evaluations of the clinical use of fibrin sealants. These include (1) in some parts of the world, for example in the United Kingdom and Canada, the price of blood or blood products is an indirect cost, and one not borne by the health service providers or insurers; and (2) some of the potential benefits of fibrin sealant use cannot be measured in economic terms. For example, it is difficult to measure the psychological benefit to the patient in knowing there will be a reduced use of blood and blood products. Potential economic benefits of improving surgical hemostasis and minimizing transfusions are shown in Table 2. Summary Fibrin sealants can reduce postoperative complications by promoting hemostasis and the avoidance of blood loss. The reduction in hemorrhage also reduces the need for blood transfusions, which may lead to a reduced risk of viral infection. By promoting wound healing, fibrin sealants also reduce the need for repeat procedures, which may involve lengthy hospitalization or intensive care, with the associated increased costs. Future pharmacoeconomic studies are required to better define the place of fibrin sealants as hemostatic agents in surgical practice. References [1] Mackie IJ. The biology of haemostasis and thrombosis. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine, 3rd ed. Oxford: Oxford University Press, 1996:3613–27. [2] Sierra DH. Fibrin sealant adhesive systems: a review of their chemistry, material properties and clinical applications. J Biomater Appl 1993;7:309 –52. [3] Anderson KC, Weinstein H. Transfusion-associated graft versus host disease. N Engl J Med 1990;323:315–21. [4] Klein HG. Risks of perioperative transfusion: the transfusion trigger. In: Wechsler AS, ed. Pharmacologic management of perioperative bleeding. Southampton, NY: CME Network, 1996:1–9.
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