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
Db11571
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

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 Label.

Pharmacology
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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
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
Medicalerrors
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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
Not Available

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EvithromLiquid1000 [iU]/1mLTopicalEthicon Inc2007-10-27Not applicableUS flag
Thrombin HumanPowder, for solution2000 [iU]/2mLTopicalEthicon, Inc2009-09-19Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ArtissHuman thrombin (4 [iU]/1mL) + Fibrinogen human (90 mg/1mL)KitTopicalBaxalta US Inc.2008-03-212008-03-21US flag
ArtissHuman thrombin (4 unit / mL) + Aprotinin (3000 kiu / mL) + Calcium chloride (40 mcmol / mL) + Fibrinogen human (125 mg / mL)SolutionTopicalBaxter Laboratories2011-12-18Not applicableCanada flag
ARTISS Fibrin SealantHuman thrombin (4 [iU]/1mL) + Fibrinogen human (90 mg/1mL)SolutionTopicalBaxter Healthcare Corporation2008-03-19Not applicableUS flag
ARTISS FrozenHuman thrombin (4 [iU]/1mL) + Fibrinogen human (90 mg/1mL)SolutionTopicalBaxalta US Inc.2009-03-192019-06-30US flag
EvarrestHuman thrombin (37.5 [iU]/1cm2) + Fibrinogen human (8.6 mg/1cm2)PatchTopicalEthicon, Inc.2013-03-01Not applicableUS flag
EvicelHuman thrombin (1000 iU/ml) + Fibrinogen human (70 mg/ml)TopicalOmrix Biopharmaceuticals N. V.2016-09-08Not applicableEU flag
EvicelHuman thrombin (1000 iU/ml) + Fibrinogen human (70 mg/ml)TopicalOmrix Biopharmaceuticals N. V.2016-09-08Not applicableEU flag
EvicelHuman thrombin (1000 iU/ml) + Fibrinogen human (70 mg/ml)TopicalOmrix Biopharmaceuticals N. V.2016-09-08Not applicableEU flag
EvicelHuman thrombin (1200 unit / mL) + Fibrinogen human (90 mg / mL)Kit; SolutionTopicalOmrix Biopharmaceuticals Ltd2011-03-01Not applicableCanada flag
EVICEL Fibrin Sealant (Human)Human thrombin (1200 [iU]/1mL) + Fibrinogen human (85 mg/1mL)TopicalEthicon Inc2013-03-21Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
6K15ABL77G
CAS number
9002-04-4

References

General References
  1. 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]
  2. 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]
  3. EMEA European Medicines Agency Withdrawal Assessment Report for Recothrom (thrombin alpha) [Link]
  4. DailyMed Label: VISTASEAL (human fibrinogen, human thrombin) kit, for topical use [Link]
  5. FDA Approved Drug Products: EVITHROM (Human Thrombin), for topical use [Link]
PubChem Substance
347911204
RxNav
825006
FDA label
Download (1.38 MB)
MSDS
Download (25.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionOsteoarthritis (OA)1
4CompletedPreventionProstate or Bladder Cancer1
4CompletedTreatmentAspiration / Breast Cancer / Seroma1
4CompletedTreatmentBlood Loss2
4CompletedTreatmentCardiovascular Surgery / Hemorrhage / Hemostasis1
4CompletedTreatmentCervical Cancers / Endometrial Cancer / Lymphoceles1
4CompletedTreatmentHemorrhage / Soft tissue haemorrhage1
4CompletedTreatmentHemostasis / Liver Surgery1
4CompletedTreatmentIncisional Hernias1
4CompletedTreatmentIntraoperative Bleeding / Post-operative Bleeding1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SolutionTopical
Kit; solutionTopical
SolutionIntralesional; Irrigation
LiquidTopical1000 [iU]/1mL
Injection, powder, lyophilized, for solutionIntralesional
PowderTopical
PatchTopical
SpongeTopical
Powder, for solutionTopical2000 [iU]/2mL
Injection, powder, lyophilized, for solutionTopical
KitTopical
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets
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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
  1. 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]
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
  1. 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]
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
  1. 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]
  2. 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]
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
  1. 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]
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
  1. 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]
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
  1. 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]
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
  1. 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]
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
  1. 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 on April 06, 2016 21:53 / Updated on January 08, 2021 01:05