Human Thrombin

Identification

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Name
Human Thrombin
Accession Number
DB11571
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Blood factors
Description

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.

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
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EvithromLiquid1000 [iU]/1mLTopicalEthicon Inc2007-10-27Not applicableUs
Thrombin HumanPowder, for solution2000 [iU]/2mLTopicalEthicon, Inc2009-09-19Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
ArtissHuman Thrombin (4 [iU]/1mL) + Fibrinogen Human (90 mg/1mL)KitBaxalta US Inc.2008-03-212008-03-21Us
ARTISS Fibrin SealantHuman Thrombin (4 [iU]/1mL) + Fibrinogen Human (90 mg/1mL)SolutionTopicalBaxter Healthcare Corporation2008-03-19Not applicableUs
ARTISS FrozenHuman Thrombin (4 [iU]/1mL) + Fibrinogen Human (90 mg/1mL)SolutionTopicalBaxalta US Inc.2009-03-192019-06-30Us
EvarrestHuman Thrombin (37.5 [iU]/1cm2) + Fibrinogen Human (8.6 mg/1cm2)PatchTopicalEthicon, Inc.2013-03-01Not applicableUs
EvicelHuman Thrombin (1200 unit) + Fibrinogen Human (90 mg)Kit; SolutionTopicalOmrix Biopharmaceuticals Ltd2011-03-01Not applicableCanada
EVICEL Fibrin Sealant (Human)Human Thrombin (1200 [iU]/1mL) + Fibrinogen Human (85 mg/1mL)KitEthicon, Inc.2013-03-21Not applicableUs
QuixilHuman Thrombin (1200 unit) + Calcium Chloride (6.2 mg) + Fibrinogen Human (60.0 mg)Kit; SolutionTopicalOmrix Biopharmaceuticals LtdNot applicableNot applicableCanada
RaplixaHuman Thrombin (726 IU/g) + Fibrinogen Human (79 mg/g)PowderTopicalMallinckrodt Pharmaceuticals Ireland Limited2015-03-19Not applicableEu
RaplixaHuman Thrombin (699 [iU]/1g) + Fibrinogen Human (79 mg/1g)PowderTopicalProFibrix BV2015-06-222018-08-03Us
RaplixaHuman Thrombin (726 IU/g) + Fibrinogen Human (79 mg/g)PowderTopicalMallinckrodt Pharmaceuticals Ireland Limited2015-03-19Not applicableEu
Categories
UNII
6K15ABL77G
CAS number
9002-04-4

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.

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
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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.

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

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. [PubMed:24625330]
  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. [PubMed:17635715]
  3. EMEA European Medicines Agency Withdrawal Assessment Report for Recothrom (thrombin alpha) [Link]
External Links
PubChem Substance
347911204
FDA label
Download (1.38 MB)
MSDS
Download (25.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1WithdrawnTreatmentPterygium / Ulcerative keratitis1
2CompletedTreatmentBleeding (Oozing) in Hepatic Resection1
2CompletedTreatmentCardiovascular Disease (CVD)1
2CompletedTreatmentColorectal Anastomosis1
2CompletedTreatmentDura Defects / Pathological Processes in the Posterior Fossa1
2CompletedTreatmentFacial Rhytidectomy (Face-lift)1
2CompletedTreatmentHematoma / Seroma1
2CompletedTreatmentHemostasis1
2RecruitingTreatmentBile Leak / Common Bile Duct Gall Stones / Infection NOS1
2RecruitingTreatmentCerebrospinal Fluid Leaks1
2, 3CompletedPreventionDura Defects1
3CompletedNot AvailableCardiovascular, Neurologic (Spine), and General Surgery1
3CompletedOtherCancer, Breast1
3CompletedPreventionCerebrospinal Fluid Leaks1
3CompletedTreatmentBleeding1
3CompletedTreatmentBlood Loss / Hip Fractures1
3CompletedTreatmentFace-lift / Facial Rhytidectomy1
3CompletedTreatmentHemorrhage1
3CompletedTreatmentLiver Diseases1
3CompletedTreatmentSurgical Bleeding1
3Not Yet RecruitingTreatmentArthroplasty, Replacement, Knee1
3RecruitingTreatmentExcessive Bleeding During Surgery1
3RecruitingTreatmentObesity, Morbid1
3TerminatedTreatmentBlood Loss / Bone Tumour1
4Active Not RecruitingPreventionCervical Cancers / Cervical Intraepithelial Neoplasia (CIN)1
4CompletedTreatmentCardiovascular Surgery / Hemorrhage / Hemostasis1
4CompletedTreatmentHemostasis / Liver Surgery1
4CompletedTreatmentIncisional Hernias1
4Not Yet RecruitingPreventionTotal Blood Loss1
4RecruitingPreventionNeoplasms, Pancreatic / Pancreatic Bordeline Tumor / Pancreatic Periampullary Cancer1
4RecruitingTreatmentAspiration / Cancer, Breast / Seroma1
4RecruitingTreatmentCleft Palates1
4RecruitingTreatmentControlling Mild to Moderate Bleeding During Surgery1
4Unknown StatusSupportive CareThrombotic events1
Not AvailableActive Not RecruitingTreatmentMelanoma1
Not AvailableCompletedPreventionInguinal Hernias1
Not AvailableCompletedSupportive CareGoitre / Neoplasms, Thyroid1
Not AvailableCompletedTreatmentEsophageal Diseases / Gastric Diseases1
Not AvailableCompletedTreatmentKnee Osteoarthritis (Knee OA) / Knee Replacement Surgery / Primary Knee Arthroplasty1
Not AvailableCompletedTreatmentMelanoma1
Not AvailableCompletedTreatmentMinor burns1
Not AvailableTerminatedTreatmentContusions / Recovery Time1
Not AvailableUnknown StatusNot AvailableCompare Ecchymosis and Edema for Fibrin Sealant and no Fibrin Sealant1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionTopical
PatchTopical
Kit; solutionTopical
LiquidTopical1000 [iU]/1mL
PowderTopical
Powder, for solutionTopical2000 [iU]/2mL
Kit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

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. [PubMed:17635715]
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. [PubMed:17635715]
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. [PubMed:17635715]
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. [PubMed:17635715]
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. [PubMed:17635715]
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. [PubMed:17635715]
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. [PubMed:17635715]
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. [PubMed:17635715]

Drug created on April 06, 2016 15:53 / Updated on June 04, 2019 07:24