Human thrombin

Identification

Summary

Human thrombin is a platelet activating factor used to treat minor bleeding.

Brand Names

Artiss, Evarrest, Evicel, Evithrom, Tachosil, Tisseel, Vistaseal

Generic Name

Human thrombin

DrugBank Accession Number

DB11571

Background

Human thrombin is a sterile solution, pH 6.8-7.2, containing highly purified human thrombin for the activation of clotting. Thrombin is a highly specific serine protease encoded by the F2 gene that transforms soluble fibrinogen into insoluble fibrin. This transformation mimics the final coagulation cascade step which involves the clotting mass that adheres to the wound surface and achieves hemostasis and sealing of open tissues.

In particular, while human thrombin products are made from pooled human source plasma, recombinant thrombin is a human coagulation protein produced via recombinant DNA technology from a genetically modified Chinese hamster ovary cell line ^Label. Furthermore, human thrombin is manufactured by chromatographic purification of prothrombin from cryo-poor plasma followed by activation with calcium chloride ^Label.

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Blood factors

Protein Structure

Protein Chemical Formula: Not Available
Protein Average Weight: Not Available

Sequences

>sp|P00734|THRB_HUMAN Prothrombin OS=Homo sapiens OX=9606 GN=F2 PE=1 SV=2
MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLEREC
VEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHV
NITRSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQE
CSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASA
QAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETG
DGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYI
DGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTEN
DLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHP
VCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDST
RIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKY
GFYTHVFRLKKWIQKVIDQFGE

Download FASTA Format

Synonyms

Thrombin (human)
Thrombin human
Thrombin Human Plasma-derived
Trombina humana

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Pharmacology

Indication

Human thrombin is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules are accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical.

In combination with fibrinogen, it is used indicated as an adjunct to hemostasis for mild to moderate bleeding in adults undergoing surgery when control of bleeding by standard surgical techniques (such as suture, ligature, and cautery) is ineffective or impractical.^4,5

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used as adjunct in combination to manage	Bleeding	Combination Product in combination with: Fibrinogen human (DB09222)	••••••••••••	•••••	•••••••••• •••••••• •• •••••••••••• •••••••	•••••
Used as adjunct in combination to manage	Bleeding	Combination Product in combination with: Fibrinogen human (DB09222)	••••••••••••		•••••••••• •••••••• •• •••••••••••• •••••••	•••••
Used as adjunct in combination to manage	Bleeding	Combination Product in combination with: Fibrinogen human (DB09222)	••••••••••••		•••••••••• •••••••• •• •••••••••••• •••••••	•••••
Adjunct therapy in prevention of	Bleeding		••••••••••••
Used in combination for prophylaxis of	Suture rupture	Combination Product in combination with: Aprotinin (DB06692), Calcium chloride (DB01164), Fibrinogen human (DB09222)	••••••••••••		••••••••••••••••••••••• ••••••• •• •••••••• •••• •••••••• •••••••• •••••••••• •••• ••••••• ••••••••• ••• •••••••	••••••

Associated Therapies

Contraindications & Blackbox Warnings

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Pharmacodynamics

Clinical pharmacodynamic studies with human thrombin have not been performed at this time ^Label.

Regardless, commercial human thrombin products are expected to demonstrate activity that is identical to thrombin found endogenously in the body. In the natural blood coagulation pathway of the human body, thrombin functions as a coagulation factor that converts clotting factor XI to XIa, factor VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa ². Specifically, clotting factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between the lysine and glutamine residues found in fibrin. These covalent bonds assist in increasing the stability of the fibrin clot ². Additionally, thrombin also promotes the activation and aggregation of platelets by way of activating protease-activated receptors on the cell membranes of platelets ².

Mechanism of action

Human thrombin (coagulation factor IIa) is a highly specific protease that transforms plasma fibrinogen into fibrin which, in the presence of clotting factor XIII in the patient's plasma, is cross-linked to form a stable clot ^Label. When applied to a surgical wound where bleeding is present, thrombin activates fibrinogen in the patient's plasma to form fibrin, which results in clot formation and hemostasis ^Label. The fibrin clot is stabilized by cross-linking occurring as a result of activation of the patient's endogenous factor XIII, which requires the presence of calcium ^Label.

Human thrombin does not require any intermediate physiological agent because it naturally clots the fibrinogen of the blood directly ^Label. Any failure to clot blood occurs in the rare case where the primary clotting defect is the absence of fibrinogen itself ^Label. The speed with which human thrombin clots blood is dependent upon the concentration of both the human thrombin used and fibrinogen present ^Label.

Target	Actions	Organism
ACoagulation factor V	activator	Humans
ACoagulation factor VIII	activator	Humans
ACoagulation factor XI	activator	Humans
ACoagulation factor XIII A chain	activator	Humans
ACoagulation factor XIII B chain	activator	Humans
AFibrinogen alpha chain	activator	Humans
AFibrinogen beta chain	activator	Humans
AFibrinogen gamma chain	activator	Humans

Absorption

Due to the nature of the product, which is intended for topical application to the surface of the tissue at the surgical site, pharmacokinetic studies were not conducted ^Label. Particularly because the agent is topical, systemic absorption is expected to be small ¹.

Volume of distribution

Due to the nature of the product, which is intended for topical application to the surface of the tissue at the surgical site, pharmacokinetic studies were not conducted ^Label. Precisely because human thrombin is applied only topically, systemic exposure or distribution to other organs and tissues is not expected ¹.

Protein binding

Due to the nature of the product, which is intended for topical application to the surface of the tissue at the surgical site, pharmacokinetic studies were not conducted ^Label. Protein binding data is subsequently not readily available, although human thrombin functions naturally to interact with a very specific set of clotting factors.

Metabolism

Due to the nature of the product, which is intended for topical application to the surface of the tissue at the surgical site, pharmacokinetic studies were not conducted ^Label.

Nevertheless, commercial human thrombin products are expected to be metabolized in the same way as endogenous thrombin is. Endogenous thrombin does not circulate in the blood as a free, active molecule for very long ³. After performing its function it is rapidly inactivated after formation of complexes with various circulating endogenous plasma inhibitors (like antithrombin III) ³. This rapid inactivation prevents the active agent from diffusing into the general circulation. The complexes formed are then generally cleared and eliminated by the liver ³.

Route of elimination

Due to the nature of the product, which is intended for topical application to the surface of the tissue at the surgical site, pharmacokinetic studies were not conducted ^Label.

Nevertheless, commercial human thrombin products are expected to act in much the same way as endogenous thrombin does. Natural bodily thrombin is cleared by two primary separate pathways: (1) through rapid formation of thrombin inhibitor complexes, which are recognized by hepatic receptors and degraded, and (2) via direct binding to thrombomodulin on the endothelium, followed by internalization and degradation ³. Specific thrombin inhibitors include ATIII, alpha-2M and heparin cofactor II ³.

Half-life

Due to the nature of the product, which is intended for topical application to the surface of the tissue at the surgical site, pharmacokinetic studies were not conducted ^Label.

Clearance

Due to the nature of the product, which is intended for topical application to the surface of the tissue at the surgical site, pharmacokinetic studies were not conducted ^Label.

Regardless, commercial human thrombin, like endogenous thrombin, is generally rapidly neutralized by naturally circulating plasma inhibitors limiting its duration of action and preventing the active form from diffusing into the general circulation ³.

Adverse Effects

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Toxicity

No cases of overdose have been reported at this time ^Label. The LD50 value for the mouse model is calculated to be approximately 3 gm/kg ^MSDS.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Evithrom	Liquid	1000 [iU]/1mL	Topical	Ethicon Inc	2007-10-27	Not applicable
Thrombin Human	Powder, for solution	2000 [iU]/2mL	Topical	Ethicon, Inc	2009-09-19	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Artiss	Human thrombin (4 unit / mL) + Aprotinin (3000 kiu / mL) + Calcium chloride (40 mcmol / mL) + Fibrinogen human (125 mg / mL)	Solution	Topical	Baxter Laboratories	2011-12-18	Not applicable
Artiss	Human thrombin (4 [iU]/1mL) + Fibrinogen human (90 mg/1mL)	Kit	Topical	Baxalta US Inc.	2008-03-21	2008-03-21
ARTISS Fibrin Sealant	Human thrombin (4 [iU]/1mL) + Fibrinogen human (86.5 mg/1mL)	Solution	Topical	Baxter Healthcare Corporation	2008-03-19	Not applicable
ARTISS Fibrin Sealant	Human thrombin (4 [iU]/1mL) + Fibrinogen human (86.5 mg/1mL)	Solution	Topical	Baxter Healthcare Corporation	2008-03-19	Not applicable
ARTISS Fibrin Sealant	Human thrombin (4 [iU]/1mL) + Fibrinogen human (86.5 mg/1mL)	Solution	Topical	Baxter Healthcare Corporation	2008-03-19	Not applicable

Chemical Identifiers

UNII: 6K15ABL77G
CAS number: 9002-04-4

References

General References

Mandell SP, Gibran NS: Fibrin sealants: surgical hemostat, sealant and adhesive. Expert Opin Biol Ther. 2014 Jun;14(6):821-30. doi: 10.1517/14712598.2014.897323. Epub 2014 Mar 13. [Article]
Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]
EMEA European Medicines Agency Withdrawal Assessment Report for Recothrom (thrombin alpha) [Link]
DailyMed Label: VISTASEAL (human fibrinogen, human thrombin) kit, for topical use [Link]
FDA Approved Drug Products: EVITHROM (Human Thrombin), for topical use [Link]

External Links

PubChem Substance: 347911204
RxNav: 825006

FDA label

Download (1.38 MB)

MSDS

Download (25.9 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Prevention	Osteoarthritis (OA)	1
4	Completed	Prevention	Osteoarthritis of the Knee	1
4	Completed	Prevention	Prostate or Bladder Cancer	1
4	Completed	Treatment	Aspiration / Breast Cancer / Seroma	1
4	Completed	Treatment	Bloodloss	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Solution	Topical
Solution	Topical	360 -
Solution	Other	70 mg/ml
Solution	Intralesional; Irrigation
Liquid	Topical	1000 [iU]/1mL
Injection, powder, lyophilized, for solution	Intralesional	2500 IU
Powder	Topical
Patch	Topical
Sponge	Topical
Powder, for solution	Topical	2000 [iU]/2mL
Injection, powder, lyophilized, for solution	Topical	1000 IU
Kit	Topical
Kit; powder, for solution	Topical
Kit; solution	Topical

Prices

Not Available

Patents

Not Available

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. Coagulation factor V

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: Copper ion binding
Specific Function: Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.
Gene Name: F5
Uniprot ID: P12259
Uniprot Name: Coagulation factor V
Molecular Weight: 251701.245 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]

Details2. Coagulation factor VIII

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: Oxidoreductase activity
Specific Function: Factor VIII, along with calcium and phospholipid, acts as a cofactor for factor IXa when it converts factor X to the activated form, factor Xa.
Gene Name: F8
Uniprot ID: P00451
Uniprot Name: Coagulation factor VIII
Molecular Weight: 267007.42 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]

Details3. Coagulation factor XI

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: Serine-type endopeptidase activity
Specific Function: Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
Gene Name: F11
Uniprot ID: P03951
Uniprot Name: Coagulation factor XI
Molecular Weight: 70108.56 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]
Oliver JA, Monroe DM, Roberts HR, Hoffman M: Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol. 1999 Jan;19(1):170-7. doi: 10.1161/01.atv.19.1.170. [Article]

Details4. Coagulation factor XIII A chain

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: Protein-glutamine gamma-glutamyltransferase activity
Specific Function: Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl-epsilon-lysine cross-links between fibrin chains, thus stabilizing the fibr...
Gene Name: F13A1
Uniprot ID: P00488
Uniprot Name: Coagulation factor XIII A chain
Molecular Weight: 83266.805 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]

Details5. Coagulation factor XIII B chain

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: The B chain of factor XIII is not catalytically active, but is thought to stabilize the A subunits and regulate the rate of transglutaminase formation by thrombin.
Specific Function: Not Available
Gene Name: F13B
Uniprot ID: P05160
Uniprot Name: Coagulation factor XIII B chain
Molecular Weight: 75510.1 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]

Details6. Fibrinogen alpha chain

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: Structural molecule activity
Specific Function: Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function ...
Gene Name: FGA
Uniprot ID: P02671
Uniprot Name: Fibrinogen alpha chain
Molecular Weight: 94972.455 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]

Details7. Fibrinogen beta chain

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: Structural molecule activity
Specific Function: Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function...
Gene Name: FGB
Uniprot ID: P02675
Uniprot Name: Fibrinogen beta chain
Molecular Weight: 55927.9 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]

Details8. Fibrinogen gamma chain

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Activator

General Function: Structural molecule activity
Specific Function: Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix. Has a major function in hemostasis as one of the primary components of blood clots. I...
Gene Name: FGG
Uniprot ID: P02679
Uniprot Name: Fibrinogen gamma chain
Molecular Weight: 51511.29 Da

References

Crawley JT, Zanardelli S, Chion CK, Lane DA: The central role of thrombin in hemostasis. J Thromb Haemost. 2007 Jul;5 Suppl 1:95-101. doi: 10.1111/j.1538-7836.2007.02500.x. [Article]

Drug created at April 06, 2016 21:53 / Updated at March 17, 2022 22:25

Human thrombin

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References

References

References

References

References

References

References