Thrombin (Human) (Monograph)

Drug class: Hemostatics
VA class: BL116

Introduction

Thrombin (human), a preparation of human plasma-derived thrombin, is a topical hemostatic agent.

Uses for Thrombin (Human)

Hemorrhage

Thrombin (human) is used topically as an aid in achieving hemostasis at accessible sites of oozing blood and minor bleeding from capillaries and small venules when control of bleeding using standard surgical techniques (e.g., suture, ligature, electrocautery) is ineffective or impractical. The drug should not be used for the treatment of massive or brisk arterial bleeding. In various types of surgery, topical thrombin (human) may be used alone or in conjunction with an absorbable gelatin sponge to establish hemostasis. Thrombin (human) also is used as a component of some commercially available fibrin sealants.

The current indication for thrombin (human) is based principally on results of a phase 3 randomized, multicenter double-blind, active-controlled study comparing the hemostatic effects of human thrombin with bovine thrombin in 305 adults undergoing elective cardiovascular, neurologic (spinal), or general surgical procedures. Patients with one or more bleeding sites of mild (defined as oozing or capillary bleeding) or moderate (defined as gradual or steady bleeding) severity that could not be controlled using standard surgical techniques were randomized to receive human thrombin 800–1200 units/mL or bovine thrombin 1000 units/mL. Thrombin was applied directly to surfaces of bleeding tissue with an absorbable gelatin sponge in variable amounts depending on the size and total number of target bleeding sites. Hemostasis, defined as complete cessation of accumulating blood at the target site, was evaluated at 3, 6, and 10 minutes following drug application. Human thrombin and bovine thrombin were equally effective in establishing surgical hemostasis; in both treatment groups, hemostasis was achieved in 97.4% of patients within 10 minutes of thrombin application (primary outcome). The percentage of patients achieving hemostasis within 3 and 6 minutes of product application also were equivalent between the 2 thrombin preparations.

Thrombin is ineffective when the primary clotting defect is the rare absence of fibrinogen.

Thrombin (Human) Dosage and Administration

Reconstitution and Administration

Thrombin (human) is applied topically to surfaces of bleeding tissue. The drug must not be injected into the circulatory system because of the risk of thrombosis and even death. Topical thrombin solution should be separated from parenteral preparations to avoid inadvertent injections. (See Cautions: Contraindications.)

Commercially available thrombin (human) is supplied as a frozen solution that must be thawed prior to administration. Thrombin (human) may be thawed at 20–25°C (room temperature) or 2–8°C (under refrigeration). Vials usually thaw within 1 hour at 20–25°C or within 1 day at 2–8°C. Alternatively, the 2- and 5-mL vials may be thawed at 37°C for up to 10 minutes; care must be taken to ensure that the drug is not left at this temperature for more than 10 minutes or exposed to temperatures exceeding 37°C. Once thawed, thrombin (human) solutions should not be refrozen. Thawed solutions of thrombin (human) are stable for up to 24 hours at 20–25°C and for up to 30 days at 2–8°C.

Thawed thrombin (human) solutions may be applied directly to bleeding tissue with a sterile syringe and small gauge needle or with an absorbable gelatin sponge. If drawn into a syringe, an auxiliary label indicating that the product is for topical use only should be applied to the syringe. Thrombin (human) should never be left in a syringe as an intermediate step. When used in conjunction with an absorbable gelatin sponge, the solution should be transferred from the original vial into a sterile container. Sponge strips of the desired size are then immersed in the thrombin solution and kneaded vigorously with moistened, gloved fingers to remove trapped air and facilitate saturation of the sponge. The saturated sponge is applied to the bleeding area using moderate pressure and held in place with gauze or a cotton pledget until hemostasis occurs. The manufacturer’s information should be consulted for detailed information on use of absorbable gelatin sponge preparations.

Before thrombin is applied, the recipient surface should be sponged (not wiped) or suctioned free of blood. After thrombin is applied, sponging of treated areas should be avoided so that the clot is not disturbed.

Dosage

The volume of thrombin (human) required to achieve hemostasis varies depending on the size of the bleeding area and method of application. In clinical studies, volumes of up to 10 mL were used in conjunction with absorbable gelatin sponge preparations.

Cautions for Thrombin (Human)

Contraindications

Thrombin (human) should not be injected directly into the circulatory system. (See Thrombosis under Warnings/Precautions: Warnings, in Cautions.)

Treatment of massive or brisk arterial bleeding.

Known hypersensitivity (i.e., anaphylaxis) or severe systemic reaction to human blood products.

Warnings/Precautions

Warnings

Risk of Transmissible Agents in Plasma-derived Preparations

Plasma-derived products such as thrombin (human) are potentially capable of transmitting human viruses (i.e., hepatitis A [HAV], B [HBV] or C virus [HCV]; human immunodeficiency virus [HIV-1 or HIV-2]; parvovirus B19) or other infectious agents such as the causative agent of Creutzfeldt-Jakob disease (CJD). Although the risk of transmitting an infectious agent has been substantially reduced with current donor screening practices and viral eliminating/reducing procedures, there is still a possibility for disease transmission. Any suspected infections thought to be associated with thrombin (human) should be reported to the manufacturer at 877-384-4266. Clinicians should discuss the risks of viral transmission versus the benefits of thrombin (human) with their patients.

Thrombosis

Potential risk of thrombosis if thrombin (human) is absorbed systemically. Thrombin (human) should not be injected directly into the circulatory system; serious complications, including death, may result. Precautionary measures should be taken to avoid of inadvertent injection. (See Cautions: Contraindications.)

Sensitivity Reactions

Hypersensitivity

Although anaphylactic reactions were not reported in clinical trials with thrombin (human), the possibility that such hypersensitivity-type reactions could occur should be considered. Antihistamines may be used to manage mild reactions; if severe hypotension occurs, immediate intervention including standard treatment for shock should be instituted.

Antibody Formation

Antibody formation has been reported in patients receiving thrombin (human); however, the clinical importance of such antibodies is unknown. In contrast, antibody development in patients receiving bovine-derived thrombin preparations has occasionally been associated with hemostatic abnormalities ranging from asymptomatic alterations in hemostatic indices (e.g., prolonged prothrombin time [PT], partial thromboplastin time [PTT]) to thrombosis, bleeding, and/or death.

Current evidence suggests that the risk of antibody development with thrombin (human) is lower than that associated with bovine-derived thrombin. In a comparative study of patients who received human or bovine thrombin for surgical hemostasis, substantially more patients in the bovine thrombin group demonstrated seroconversion for at least one of the 4 antibodies assayed (human thrombin, bovine thrombin, bovine factor V/Va, human factor V/Va) versus those who received human thrombin (12.7% versus 3.3%, respectively). A few patients in the bovine thrombin treatment group developed cross-reacting antibodies to human thrombin; however, no detectable antibodies to human thrombin or human factor V/Va were found in patients treated with thrombin (human). Because of methodologic differences in antibody assays and other factors (e.g., timing of sample collection, manner in which samples are handled, concomitant drug therapy, underlying diseases), such results cannot be directly compared to those of other immunogenicity studies.

Specific Populations

Pregnancy

Category C.

Pediatric Use

Safety and efficacy of thrombin (human) in pediatric patients is based on extrapolation of data from adults and also on limited experience from controlled clinical studies in which 8 patients 12 years of age or younger received a human thrombin-containing fibrin sealant product while undergoing liver surgery.

Geriatric Use

No overall differences in efficacy or safety observed relative to younger adults, but the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Common Adverse Effects

The most common adverse effects reported in patients receiving thrombin (human) in clinical trials were procedure-related complications (e.g., wound infection), nausea, pruritus, and laboratory abnormalities (e.g., decreased hematocrit, hemoglobin, lymphocytes, and red blood cells; increased neutrophils and leukocytes). Such effects are common in a postoperative population and have not been directly attributed to the drug.

Drug Interactions

There are no known drug interactions with thrombin (human).

Description

Thrombin (human) is a highly purified preparation of thrombin derived from pooled human plasma. Thrombin is prepared from its precursor, prothrombin, through a series of separation and purification steps followed by activation with calcium chloride. Manufacturing pools and individual units of plasma used in the preparation of thrombin (human) are screened for human viruses (e.g., hepatitis, HIV, parvovirus B19). Additional viral inactivation and purification steps (e.g., solvent/detergent, nanofiltration) are employed to further reduce the risk of pathogen transmission.

Thrombin promotes hemostasis principally by converting fibrinogen to fibrin, the final step in the coagulation cascade. However, thrombin’s effects in hemostasis are complex and include several other mechanisms (e.g., platelet activation and aggregation, activation of factor XIII leading to fibrin crosslinking and clot stabilization). Thrombin is capable of converting fibrinogen directly to fibrin at the site of vessel injury without the addition of other substances, thus providing a rationale for its use as a topical hemostatic agent. Failure of thrombin to clot blood occurs in the rare instance when the primary clotting defect is the absence of fibrinogen. The rate at which thrombin clots blood depends on the concentration of thrombin and fibrinogen.

Thrombin (human) is stable for up to 2 years when stored at -18°C or colder. Unopened vials may be stored under refrigeration (2–8°C) for up to 30 days or up to the manufacturer’s labeled expiration date, whichever comes first.

Advice to Patients

Risk of transmission of certain viruses, including parvovirus B19 and/or hepatitis A; importance of patient informing clinician if symptoms of parvovirus B19 infection (e.g., fever, drowsiness, chills, runny nose followed approximately 2 weeks later by rash and joint pain) or hepatitis A infection (e.g., several days to weeks of low grade fever, poor appetite, and fatigue followed by nausea, vomiting, and abdominal pain; jaundice; dark urine) occur.

Risk of blood clotting disorders if absorbed systemically; importance of contacting a clinician if any new or unusual symptoms of thrombosis occur.

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

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Biological Products Related to thrombin topical

Find detailed information on biosimilars for this medication.

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