VA Class:BL116
Thrombin (bovine), a protein produced via limited proteolysis of bovine prothrombin, is a topical hemostatic agent.100, 112
Thrombin (bovine) is used topically as an aid in achieving hemostasis at accessible sites of oozing blood and minor bleeding from capillaries and small venules.100 Thrombin (bovine) alone does not control arterial bleeding. In various types of surgery, thrombin (bovine) solutions may be used in conjunction with an absorbable gelatin sponge to establish hemostasis.100
Reconstitution and Administration
Thrombin (bovine) is applied topically as a dry powder or as a solution.100 The drug must not be injected or otherwise allowed to enter large blood vessels since intravascular thrombosis and death may result .100, 102
Solutions of thrombin (bovine) should be prepared and administered according to the manufacturer's recommendations.100 When the drug is to be used as a solution, the lyophilized powder is reconstituted by adding the appropriate volume of isotonic saline diluent (0.9% sodium chloride) to a vial labeled as containing 5000 or 20,000 units of thrombin (bovine); concentations of 1000-2000 units/mL usually are recommended.100 Reconstituted solutions may be applied as a spray using a sterile syringe, spray pump, or nasal delivery device (available as part of the syringe spray, pump spray, or epistaxis kit supplied by the manufacturer) or with an absorbable gelatin spon the reconstituted solution should not be left in a syringe as an intermediate step when preparing the spray delivery device.102 Alternatively, surfaces may be flooded with the solution using a sterile syringe and small gauge needle. To avoid inadvertent intravascular administration, syringes containing reconstituted solutions of thrombin (bovine) should be labeled with a warning against IV injection and kept separate from parenteral preparations. 100, 102
When used in conjunction with an absorbable gelatin sponge, thrombin (bovine) is reconstituted to the desired concentration.100 Sponge strips of the desired size are then immersed in the thrombin (bovine) solution and kneaded vigorously with moistened, gloved fingers to remove trapped air and facilitate saturation of the sponge.100 The saturated sponge is applied to the bleeding area and held in place with a cotton pledget or small gauze sponge until hemostasis occurs.100 The manufacturer's information should be consulted for detailed information on use of absorbable gelatin sponge preparations.100
Topical thrombin (bovine) can be applied directly to bleeding sites as a dry powder, and in many cases, may be the preferred method of application to oozing surfaces.100, 102 Thrombin (bovine) also may be used in conjunction with a bovine gelatin-based hemostatic matrix (FloSeal® NT) according to instructions provided by the manufacturer.100
Before thrombin (bovine) is applied, the recipient surface should be sponged (not wiped) free of blood; otherwise, thrombin (bovine) may clot surface layers of blood and bleeding may continue underneath the clot.100 After thrombin (bovine) is applied, sponging of treated areas should be avoided so that the clot is not disturbed.100
The concentration of thrombin (bovine) solutions used depends on the severity of bleeding.100, 109 Thrombin (bovine) is reconstituted to the desired concentration using 0.9% sodium chloride; solutions should be used promptly following removal from the container.100, 102 (See Chemistry and Stability: Stability.) For general use such as in plastic surgery, dental extractions, or skin grafting, thrombin (bovine) solutions containing approximately 100 units/mL are usually used.100 Where bleeding is profuse (e.g., from cut surfaces of the liver or spleen), concentrations as high as 1000 units/mL may be required.100
Hemostatic abnormalities ranging from asymptomatic alterations in coagulation test results (e.g., prolonged prothrombin time [PT] and partial thromboplastin time [PTT]) to severe bleeding and thrombosis have been reported in patients receiving topical thrombin (bovine) preparations; death has occurred rarely.100, 103, 105, 106, 108, 109, 110, 111, 112 Such effects may be associated with the development of antibodies to thrombin (bovine) and/or bovine factor V, a contaminant found in some of the preparations.100, 103, 104, 105, 106, 107, 109, 111, 112 (See Antibody Formation under Cautions: Sensitivity Reactions.)
Cross-reactivity between antibodies to bovine factor V and human coagulation factor V may result in factor V deficiency and potential bleeding complications; paradoxical thrombotic events have occurred occasionally in patients with factor V antibodies, although a causal relationship between such antibodies and thrombosis has not been conclusively established.100, 103, 105, 106, 107, 109, 111, 112
The possibility of an immune-mediated reaction should be considered in any patient who exhibits abnormal coagulation test results, bleeding, or thrombosis following exposure to topical thrombin (bovine); consultation with an expert in coagulation disorders is recommended.100, 106
Antibodies to thrombin (bovine), factor V, or other protein contaminants have developed in patients receiving bovine-derived thrombin preparations.100, 103, 104, 105, 106, 109, 110, 111, 112 Such antibodies have been detected as early as several days following initial exposure to thrombin (bovine) and can persist for months, sometimes years.103, 105, 106, 111 The incidence of antibody formation varies substantially in clinical studies and published case reports, and may be related to differences in patient-specific factors (e.g., prior exposure to thrombin [bovine], type of surgery), antibody detection techniques, or purity among various thrombin (bovine) preparations.103, 105, 106, 107, 109, 110, 111 In one prospective study, elevated antibody titers were detected in more than 90% of patients who received a topical thrombin (bovine) preparation during cardiac surgery; however, lower rates (e.g., 10-20%) have been reported in other studies.103, 105, 106, 107, 108, 109, 110, 111 Studies comparing the relative immunogenicity of the various thrombin preparations have reported substantially higher rates of antibody development with bovine-derived thrombin compared with plasma-derived or recombinant preparations.107, 108, 109 It is not known whether highly purified preparations of thrombin (bovine) containing factor Va concentrations below the limits of detection are associated with a reduced risk of immunogenicity.100, 109
Adverse hemostatic effects (e.g., severe bleeding) have occurred in association with the presence of antibodies and have been attributed to the drug's immunogenicity.100, 105, 106, 107, 109, 111, 112 (See Cautions: Hemostatic Effects.) Because of the risk of immune-mediated adverse efffects, some experts recommend that use of topical hemostatic agents containing thrombin (bovine) be avoided or minimized;104, 111 others state additional studies are needed to clearly elucidate the clinical importance of antibody development with thrombin (bovine).105, 109, 110 Patients with existing antibodies to thrombin (bovine) should not be reexposed to the drug because of an increased risk of antibody formation and a potentially greater likelihood of adverse effects.100, 103, 104, 105, 107, 109, 111
Anaphylactic reactions have been reported rarely following use of topical preparations containing thrombin (bovine).101, 110 In at least one patient, anaphylaxis with profound bradycardia and hypotension occurred within minutes following topical application of surgical gelatin sponge soaked with thrombin (bovine).101 This reaction appeared to be mediated by antithrombin IgE antibodies, and it was suggested that the patient may have been previously sensitized to thrombin (bovine) from use of the drug during prior surgeries.101 An allergic-type reaction following the use of thrombin (bovine) for the treatment of epistaxis has been reported.
Febrile reactions have occurred following the use of thrombin (bovine) in some surgical procedures, but a causal relationship to the drug has not been conclusively established.
Precautions and Contraindications
Thrombin (bovine) has caused hypersensitivity reactions, including anaphylaxis, when used topically in humans.101 Allergic reactions may occur if thrombin (bovine) is used in individuals sensitive to material of bovine origin.100 Thrombin (bovine) is contraindicated in individuals with known sensitivity to any ingredient in the formulation and/or to material of bovine origin.100
When thrombin (bovine) is used in conjunction with an absorbable gelatin sponge, the prescribing information for absorbable gelatin sponge preparations should be consulted for complete information regarding their concomitant use.100
Because of its hemostatic activity, thrombin (bovine) must not be injected or otherwise allowed to enter large blood vessels; extensive intravascular clotting and even death may result. 100, 102
Safety and efficacy of topical thrombin (bovine) in children have not been established.100
Animal reproduction studies have not been performed with topical thrombin (bovine).100 It is also not known whether topical thrombin (bovine) can cause fetal harm when administered to pregnant women.100 Topical thrombin (bovine) should be used during pregnancy only when clearly needed.100
Thrombin is a hemostatic agent capable of causing the clotting of whole blood, plasma, or a solution of fibrinogen without the addition of other substances.100, 112 Thrombin affects hemostasis principally by converting fibrinogen to fibrin, the final step in the coagulation cascade.109, 112 However, thrombin's effects in hemostasis are complex and include several other mechanisms (e.g., stimulation of platelet release reaction, aggregation and adherence of platelets, activation of factor XIII leading to fibrin cross-linking).109, 112 Failure of thrombin to clot blood occurs in the rare instance when the primary clotting defect is the absence of fibrinogen.100 The rate at which thrombin clots blood depends on the concentration of both thrombin and fibrinogen.100
Thrombin (bovine) is a hemostatic agent.100 Thrombin (bovine) is commercially available as a sterile, lyophilized powder containing the protein substance prepared from prothrombin of bovine origin through interaction with added thromboplastin in the presence of calcium.100 The manufacturing process for currently available thrombin (bovine) includes chromatography and ultrafiltration steps to remove contaminating proteins; the resulting product is a highly purifed preparation with concentrations of factor Va below detectable limits (less than 92 ng/mL by semiquantitative Western blot assay).100, 109 Commercially available thrombin (bovine) preparations meet standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. Commercially available thrombin (bovine) preparations also may contain mannitol and sodium chloride.100 Diluents provided with commercially available thrombin (bovine) preparations contain sterile isotonic saline (0.9% sodium chloride).100
Lyophilized thrombin (bovine) preparations should be stored at 2-25°C.100 Following reconstitution, thrombin (bovine) solutions should be used promptly upon removal from the container; if the reconstituted solution will not be used immediately, it may be stored at 2-8°C for up to 24 hours or at room temperature for up to 8 hours.100 (See Reconstitution and Administration under Dosage and Administration regarding caution about storage in syringes.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Powder | 5000 units | Thrombin-JMI® (with 0.9% sodium chloride diluent) | |
Thrombin-JMI® (with 0.9% sodium chloride diluent; epistaxis kit also contains nasal delivery device and syringe) | King | |||
20,000 units | Thrombin-JMI® (with 0.9% sodium chloride diluent) | King | ||
Thrombin-JMI® (with 0.9% sodium chloride diluent; syringe spray kit also contains sterile syringe with transfer device and spray tip) | King | |||
Thrombin-JMI® (with 0.9% sodium chloride diluent; pump spray kit also contains spray pump and actuator) | King |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions December 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
100. King Pharmaceuticals, Inc. Thrombin-JMI® (thrombin, topical USP) bovine origin prescribing information. Bristol, TN; 2007 Nov.
101. Rothenberg DM, Moy JN. Anaphylactic reaction to topical bovine thrombin. Anesthesiology . 1993; 78:779-82. [PubMed 8096685]
102. Cohen MR, Smetzer JL. ISMP medical error report analysis: Danger of giving topical thrombin intravascularly. Hosp Pharm. 2007; 42:284-5.
103. Winterbottom N, Kuo JM, Nguyen K et al. Antigenic responses to bovine thrombin exposure during surgery: a prospective study of 309 patients. J Applied Research . 2002; 2:1-11.
104. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Ferraris SP et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg . 2007; 83:S27-86. [PubMed 17462454]
105. Ortel TL, Mercer MC, Thames EH et al. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Ann Surg . 2001; 233:88-96. [PubMedCentral][PubMed 11141230]
106. Streiff MB, Ness PM. Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure. Transfusion . 2002; 42:18-26. [PubMed 11896308]
107. Doria C, Fischer CP, Wood CG et al. Phase 3, randomized, double-blind study of plasma-derived human thrombin versus bovine thrombin in achieving hemostasis in patients undergoing surgery. Curr Med Res Opin . 2008; 24:785-94. [PubMed 18241525]
108. Chapman WC, Singla N, Genyk Y et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg . 2007; 205:256-65. [PubMed 17660072]
109. Cheng CM, Meyer-Massetti C, Kayser SR. A review of three stand-alone topical thrombins for surgical hemostasis. Clin Ther . 2009; 31:32-41. [PubMed 19243705]
110. Clark J, Crean S, Reynolds MW. Topical bovine thrombin and adverse events: a review of the literature. Curr Med Res Opin . 2008; 24:2071-87. [PubMed 18549663]
111. Dorion RP, Hamati HF, Landis B et al. Risk and clinical significance of developing antibodies induced by topical thrombin preparations. Arch Pathol Lab Med . 1998; 122:887-94. [PubMed 9786349]
112. Lundblad RL, Bradshaw RA, Gabriel D et al. A review of the therapeutic uses of thrombin. Thromb Haemost . 2004; 91:851-60. [PubMed 15116244]