Number 812
ACOG Committee on Gynecologic Practice
This Committee Opinion was developed by the American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice in collaboration with committee member Kathryn P. Pennington, MD and liaison Gena Dunivan, MD.
ABSTRACT: There are three broad categories of hemostatic agents: 1) caustic, 2) physical, and 3) biologic. Because of the paucity of data on the use of topical hemostatic agents in gynecologic and obstetric surgery, indications for use are extrapolated from data on the use of these agents in other types of surgeries and are based on expert opinion. Topical hemostatic agents can be a useful adjunct to assist in the management of intraoperative bleeding in select circumstances. Topical hemostatic agents most commonly are used in situations where the use of electrocautery or sutures for hemostatic control of surgical bleeding is not ideal or safe, including bleeding in areas with nearby vulnerable structures or in the presence of diffuse bleeding from peritoneal surfaces or cut surfaces of solid organs. When managing intraoperative bleeding, there is no substitute for meticulous surgical technique. When possible, the surgeon should attempt to control intraoperative bleeding with sutures, clips, or electrosurgery before the use of hemostatic agents. It is essential for surgeons to understand the appropriate use, contraindications, and cost of these agents in order to make the most informed decision for patient care.
Recommendations and Conclusions
The American College of Obstetricians and Gynecologists makes the following recommendations and conclusions regarding the use of topical hemostatic agents:
Data on the use of topical hemostatic agents in gynecologic and obstetric surgery are limited and, therefore, recommendations largely are based on findings extrapolated from studies on the use of these agents in nongynecologic and nonobstetric surgeries.
When managing intraoperative bleeding, there is no substitute for meticulous surgical technique. When possible, the surgeon should attempt to control intraoperative bleeding with sutures, clips, or electrosurgery before the use of hemostatic agents.
Topical hemostatic agents most commonly are used in situations where the use of electrocautery or sutures for hemostatic control of surgical bleeding is not ideal or safe, including bleeding in areas with nearby vulnerable structures (eg, ureters or nerves) or in the presence of diffuse bleeding from peritoneal surfaces or cut surfaces of solid organs.
Topical hemostatic agents should not be used for routine prophylaxis of postoperative bleeding because these agents may increase the risk of infection, adhesion formation, and other complications.
Topical hemostatic agents have distinct mechanisms of action, different potential adverse effect profiles, and varying costs. An understanding of these differences is essential to making the most appropriate and cost-effective decisions regarding their use.
Physical agents are more likely to be effective in patients without coagulation abnormalities and in less severe bleeding situations. When bleeding is more active or in the presence of coagulopathy, biologically active agents such as topical thrombin and fibrin sealants may be considered.
Introduction
When managing intraoperative bleeding, there is no substitute for meticulous surgical technique. When possible, the surgeon should attempt to control intraoperative bleeding with sutures, clips, or electrosurgery before the use of hemostatic agents. However, topical hemostatic agents can be a useful adjunct to assist in the management of intraoperative bleeding in select circumstances. Topical hemostatic agents most commonly are used in situations where the use of electrocautery or sutures for hemostatic control of surgical bleeding is not ideal or safe, including bleeding in areas with nearby vulnerable structures (eg, ureters or nerves) or in the presence of diffuse bleeding from peritoneal surfaces or cut surfaces of solid organs. They should not be used prophylactically. Data on the use of topical hemostatic agents in gynecologic and obstetric surgery are limited and, therefore, recommendations largely are based on findings extrapolated from studies on the use of these agents in nongynecologic and nonobstetric surgeries.
The use of intravenous tranexamic acid is outside of the scope of this article; for guidance on the use of intravenous tranexamic acid for the prevention and treatment of obstetric hemorrhage related to vaginal and cesarean delivery, see Practice Bulletin No. 183, Postpartum Hemorrhage 1. This Committee Opinion does not apply to individuals with known bleeding disorders. For guidance for those populations, see Committee Opinion No. 785, Screening and Management of Bleeding Disorders in Adolescents With Heavy Menstrual Bleeding, and Committee Opinion No. 580, Von Willebrand Disease in Women 2 3.
General Overview of the Clotting Cascade
An understanding of the clotting cascade pathway is necessary to understand the role of topical hemostatic agents. Briefly, the intrinsic pathway and extrinsic pathway involve a variety of factors that eventually join to activate factor X in the common pathway. Activated factor X (Factor Xa) is needed to convert prothrombin to thrombin. Thrombin then can convert fibrinogen to fibrin. Fibrin becomes cross-linked and serves as a scaffold for platelets, ultimately resulting in a stable fibrin clot Figure 1.
Categories of Topical Hemostatic Agents
There are three broad categories of hemostatic agents: 1) caustic, 2) physical, and 3) biologic. See Table 1 for details on physical and biologic topical hemostatic agents. Brand names referenced in the document are used purely for product identification purposes and do not imply endorsement.
Caustic Agents
Topical caustic agents include aluminum chloride, ferric subsulfate 20% (Monsel’s solution), silver nitrate, and zinc chloride paste. They coagulate proteins leading to tissue necrosis and eschar formation, enhancing thrombus formation and hemostasis 4. Although used in the cervix and vagina, they are not for intraabdominal use 5.
Physical Agents
Physical agents use a substrate, such as cellulose, gelatin, starch, or collagen, to form a matrix at the site of bleeding which activates the extrinsic coagulation cascade and serves as a scaffold for clot formation. Thus, physical agents are not appropriate in patients with severe coagulopathy because the agents require an intact coagulation cascade to function 6. Physical agents are available in a variety of forms, including powder, sponges, a woven mesh, or foam.
Gelatin matrix (eg, Gelfilm, GelFoam, Surgifoam) is available in a powder or sponge form, is porcine-derived, and is absorbed over 4–6 weeks. It absorbs the surrounding blood and fluid, substantially increasing its size and weight; this may be useful for mechanical hemostasis in addition to concentrating platelets and blood proteins at the site of bleeding. Sterile compressed gelatin sponge (GelFoam), in particular, can expand up to two times its size; caution is warranted because of associated complications such as compressive necrosis if used in confined spaces near fragile structures (eg, nerves) or within bony cavities 7 8 9. Gelatin matrix products have a neutral pH and therefore can be used with topical thrombin or other pH-neutral topical hemostatic agents 7.
Oxidized regenerated cellulose (eg, Surgicel) is plant-derived and is available as powder or a loose knit mesh that can be trimmed as needed as well as placed through laparoscopic ports 10. It generally is absorbed over 1–2 weeks, although a published report has documented persistent material present at up to 15 months after surgery 11. Oxidized regenerated cellulose has a low pH which helps to form an artificial clot and enhances surface interactions between platelets, collagen, coagulation factors, and small vessel vasoconstriction 10 12 13. In addition, its acidic nature provides theoretical antibacterial properties 7 10 14. Notably, the low pH can inactivate topical thrombin; thus, oxidized regenerated cellulose and topical thrombin should not be used together.
Microporous polysaccharide hemospheres (eg, Arista) are a plant-derived polysaccharide powder hemostat. The powder absorbs water and therefore concentrates platelets and other proteins to accelerate clot formation 15. Because the powder is absorbed in approximately 48 hours, it theoretically may be less likely to cause foreign body reaction or to serve as a nidus for infection when compared with other physical agents 15.
Microfibrillar collagen (eg, Avitene) is made from purified bovine collagen, and comes as a powder or foam. It provides a large surface area to facilitate platelet aggregation and thrombus formation 15. It is absorbed in 8–12 weeks.
Biologic Agents
Biologic agents, such as topical thrombin and fibrin sealant, bypass the initial steps of the coagulation cascade (the extrinsic pathway) to promote hemostasis through the common pathway. Thrombin at the bleeding site cleaves fibrinogen to produce a fibrin clot 7. Unlike physical agents, topical thrombin can be used in patients who have impaired coagulation cascade but adequate fibrinogen levels; so, it is useful in patients with mild coagulopathy 16. It is less likely to be effective in patients with severe coagulopathy, especially if hypofibrinogenemia is present. Topical thrombins (eg, Thrombin-JMI, Recothrom, Evithrom) can be derived from either bovine, human, or recombinant sources, and each type has a different safety profile. These agents usually are applied with a syringe or through a spray. Thrombin can be used alone, but often is combined with gelatin matrix, such as gelatin granules, to create a “flowable” hemostatic agent (eg, Floseal). It also can be combined with gelatin sponge or combined with human fibrinogen (see fibrin sealant below for more information). Many surgeons may not know that topical thrombin should not be combined with oxidized regenerated cellulose because the acidity of oxidized regenerated cellulose can neutralize the effectiveness of topical thrombin 12.
Fibrin sealants (eg, Tisseel, Evicel) are a two-component system that combines thrombin solution with a concentrated human fibrinogen solution that is applied directly to the bleeding site, allowing formation of a fibrin clot. Some products also contain aprotinin, an antifibrinolytic agent, to help maintain stable fibrin clots 16. Fibrin sealants can be used in patients with coagulopathy, even in those with deficient fibrinogen. One potential drawback of fibrin sealants is that they take longer to prepare compared with other topical hemostatic agents. This includes at least 10–20 minutes to allow thawing, depending on the specific product 17. They also are among the most expensive of all topical hemostatic agents.
Tranexamic acid exerts an antifibrinolytic effect by displacing plasminogen from the fibrin surface and by inhibiting the proteolytic activity of plasmin. Intravenous administration of tranexamic acid reduces bleeding during surgery, but because of concerns about possible thromboembolic events, topical tranexamic acid has also been studied. Tranexamic acid can be mixed with sterile water and directly applied to bleeding surfaces. Plasma concentrations following topical application of tranexamic acid are less than one-tenth the level after intravenous administration. Topical tranexamic acid has been shown to reduce blood loss in a variety of surgery types including cardiac, spinal, otolaryngologic, and knee arthroplasty. Its effect on thromboembolic events is uncertain 18.
Indications for Use
Because of the paucity of data on the use of topical hemostatic agents in gynecologic and obstetric surgery, indications for use are extrapolated from data on the use of these agents in other types of surgeries and are based on expert opinion. When possible, the surgeon should attempt to control intraoperative bleeding with sutures, clips, or electrosurgery before the use of hemostatic agents. Topical hemostatic agents should not be used for routine prophylaxis of postoperative bleeding because these agents may increase the risk of infection, adhesion formation, and other complications.
In general, any topical hemostatic agent is more likely to be effective for low pressure, low velocity venous bleeding. Microporous polysaccharide hemospheres (Arista) is the only topical hemostatic agent approved for arterial bleeding. Physical agents are often used as a first-line approach to control minimal bleeding because of their rapid availability. Additionally, they generally are less expensive than biologic agents. Physical agents are more likely to be effective in patients without coagulation abnormalities and in less severe bleeding situations. When bleeding is more active or in the presence of coagulopathy, biologically active agents such as topical thrombin and fibrin sealants may be considered.
Efficacy
In general, high-quality data comparing the efficacy of different topical hemostatic agents are lacking. However, a small number of randomized controlled clinical trials comparing topical agents have been conducted. Randomized controlled trials comparing fibrin sealant with oxidized regenerated cellulose 19 20 or with another topical hemostatic agent singly or in combination, including oxidized regenerated cellulose, gelatin matrix, gelatin matrix with thrombin, and microfibrillar collagen 21 22, demonstrated that fibrin sealant had the highest success rate in achieving hemostasis, did so more quickly than other agents, and could be effective when other hemostatic agents had failed. However, they are more expensive and take longer to prepare.
Gelatin matrix often is combined with topical thrombin. Little is known about the relative effectiveness of the gelatin-thrombin combination compared with gelatin alone, although it has been shown to be more effective than gelatin alone in animal studies 23. Several randomized trials comparing the flowable combination liquid thrombin and gelatin granules (Floseal) to gelatin sponge (Gelfoam) soaked in thrombin demonstrated that the flowable liquid thrombin and gelatin granules combination (Floseal) was superior 24 25. Head-to-head comparisons of bovine thrombin versus pooled human plasma thrombin 26 and of bovine thrombin versus recombinant thrombin 27 suggest that all three forms of topical thrombin have similar efficacy.
Potential Complications
Infection is the most commonly reported complication associated with topical hemostatic agents. However, it is important to note that uncontrolled bleeding during surgery is associated with other risk factors for infection, including prolonged operative time, transfusion, and other characteristics that may confound the association between infection and the use of hemostatic agents. Nonetheless, any product with delayed absorption can serve as a potential nidus for infection. Generally, using the minimum required amount of topical hemostatic agent needed and removing any excess topical agent once adequate hemostasis is achieved should be done in order to reduce the risk of infection as much as possible. Oxidized regenerated cellulose may have a lower risk of infection compared with other physical hemostatic agents 28 29 and has some bactericidal activity because of its acidic pH 30; however, excessive use still may cause infection 28. There is some evidence that physical hemostatic agents may mimic an abscess on imaging, even in the absence of infection 31.
Foreign body reactions such as granuloma formation and fibrosis have been reported with physical agents, including microfibrillar collagen 32, oxidized regenerated cellulose 33, and gelatin-based agents 34 35 36 37. Adhesions and small bowel obstruction at the site of previous application also have been reported with flowable thrombin-gelatin matrix products used alone 38 39 or in combination with oxidized regenerated cellulose 40. According to the manufacturer’s instructions for a thrombin-gelatin product, excess substance that is not incorporated into the hemostatic clot should be removed by gentle irrigation 41.
Pooled human thrombin and fibrin sealants, which contain human fibrinogen in addition to thrombin, have a theoretical risk of viral transmission. Because of stringent screening techniques, the overall risk is quite low, with the risk of human immunodeficiency virus (HIV) and hepatitis estimated to be less than 1 in 1015 for both thrombin and fibrinogen, and the risk of parvovirus slightly higher, but still low, at less than 1 in 107 per vial of thrombin, and less than 1 in 500,000 for fibrinogen 42. A case report of parvovirus infection after use of fibrin sealant during hysterectomy has been described 43.
Allergic reactions and immunologic events can occur. Most reactions occur with the use of biologic agents. Bovine-derived thrombin can induce severe antibody-mediated reactions, which can result in the development of antibodies against thrombin and factor V, and have led to immune-mediated coagulopathy with severe postoperative bleeding on re-exposure 44 45. A U.S. Food and Drug Administration black box warning cautions against re-exposure to bovine-derived thrombin for patients with antibodies to bovine thrombin preparations 46. It may be prudent for surgeons to avoid using bovine-derived thrombin in patients who have previously been exposed to the agent because routine clinical testing for antibodies to bovine-derived thrombin typically is not performed. Antibody production also can occur in patients exposed to pooled human thrombin and recombinant thrombin but occurs at a much lower incidence compared with bovine-derived thrombin 47. Postoperatively, patients who were treated with bovine-derived thrombin should be counseled about potential risks associated with re-exposure during future surgical procedures.
There also is a theoretical risk of allergic reactions to recombinant thrombin in patients who are allergic to hamster cell lines or snake proteases used to manufacture the product. Fibrin sealants can cause allergic reactions depending on the type of thrombin used. Some fibrin sealants also contain the antifibrinolytic agent aprotinin; anaphylactic reactions have been reported on aprotinin re-exposure 48. Fibrin sealants prepared from plasma or cryoprecipitate should not be used in individuals who have had previous anaphylaxis with the use of plasma products or who have an immunoglobulin A deficiency. Products of animal origin, including gelatin matrix (porcine) and microfibrillar collagen (bovine), also can theoretically cause allergic reactions; however, gelatin matrix is not considered to be antigenic. One case of a severe systemic allergic response after the use of microfibrillar collagen in a laparoscopic cholecystectomy has been reported 49.
Gas embolism, including death, has been reported with spray fibrin sealants 50 51. Risk may increase if the sealant is sprayed too close to the tissue or when the maximum recommended spray pressure is exceeded. One case report described intravascular thromboembolism of thrombin-gelatin mixture inadvertently exposed to the intravascular space when applied to a briskly bleeding venous pedicle 52. The intravascular use of hemostatic agents is contraindicated given the risk of embolization. In addition, the use of topical hemostatic agents in conjunction with cell salvage systems remains controversial, because of concern about causing blood in the intraoperative salvage reservoirs to clot. Cases of pulmonary embolism after reinfusion of recovered blood have been reported 53. The American Association of Blood Banks recommends when using a blood recovery system to avoid aspiration in the area in which topical hemostatic agents are being used 54.
Other Considerations
The use of hemostatic agents often cannot be predicted as they are used in situations of unanticipated bleeding; therefore, it is not necessarily feasible to consent patients preoperatively for the potential use of the various products. However, obstetrician–gynecologists and other clinicians should be sensitive to religious objections or secular concerns related to hemostatic agents and engage in an informed consent conversation about the potential use when practical. This conversation may occur when a patient informs the clinician that they refuse blood products or object to bovine-derived or porcine-derived products. For patients who refuse blood products, the obstetrician–gynecologist should engage in an informed consent conversation about plasma-derived topical hemostatic agents before surgery 55. In lieu of plasma-derived thrombin, recombinant thrombin is an effective alternative. If a patient brings up concerns about animal-derived products, the obstetrician–gynecologist should inform the patient of alternative hemostatic agents. It is important to note that religious leaders from around the world support the use of animal-derived products if no other alternatives are available or in the case of an emergent situation 56. Additionally, the cost of specific hemostatic agents varies and obstetrician–gynecologists are encouraged to understand the costs at their respective institutions.
Conclusion
Because use of topical hemostatic agents may increase the risk of complications, they should not be used for routine prophylaxis of postoperative bleeding. Topical hemostatic agents have distinct mechanisms of action, different potential adverse effect profiles, and varying costs. An understanding of these differences is essential to making the most appropriate and cost-effective decisions regarding their use. Physical agents can be considered in patients without coagulation abnormalities and in less severe bleeding situations. Physical agents generally are less expensive than biologic agents, but infection and foreign-body reactions may occur. In contrast, when more active bleeding occurs, coagulopathy is present, or if physical agents are not effective, biologic agents may be considered. Biologic agents or combination agents tend to be more expensive and may be associated with risk of blood-borne pathogens, immunologic events, or allergic reactions, depending on the agent. Although fibrin sealants are the most expensive type of biologic agent, they are associated with higher rates of control and may be appropriate to consider when bleeding does not respond to other agents or in the presence of severe coagulopathy. It is essential for surgeons to understand the appropriate use, contraindications, and cost of these agents in order to make the most informed decision for patient care.