Thrombin

Identification

Name
Thrombin
Accession Number
DB11300
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors
Description

Also known as coagulation factor II, thrombin is a serine protease that plays a physiological role in regulating hemostasis and maintaining blood coagulation. Once converted from prothrombin, thrombin converts fibrinogen to fibrin, which, in combination with platelets from the blood, forms a clot.

Medical thrombin is a protein substance produced through a conversion reaction in which prothrombin of bovine origin is activated by tissue thromboplastin in the presence of calcium chloride. Thrombin requires no intermediate physiological agent for its action. It clots the fibrinogen of the blood directly. Failure to clot blood occurs in the rare case where the primary clotting defect is the absence of fibrinogen itself.

Bovine thrombin however, is capable of causing fatal severe bleeding or thrombosis [Label]. This thrombosis may result from the development of antibodies against bovine thrombin [Label]. Bleeding may result from the development of antibodies against bovine factor V [Label]. These antibodies may subsequently cross-react with endogenous human factor V and lead to its deficiency [Label]. Patients who are know or suspected to have antibodies to bovine thrombin and/or bovine factor V should not be re-exposed to the product [Label]. Patients who are administered bovine thrombin should be monitored for abnormal coagulation laboratory values, bleeding, or indeed, thrombosis [Label].

A variety of human thrombin and recombinant thrombin (ie. thrombin alfa) products are available as alternatives to using bovine thrombin.

Protein structure
Db11300
Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
>sp|P00735|THRB_BOVIN Prothrombin OS=Bos taurus OX=9913 GN=F2 PE=1 SV=2
MARVRGPRLPGCLALAALFSLVHSQHVFLAHQQASSLLQRARRANKGFLEEVRKGNLERE
CLEEPCSREEAFEALESLSATDAFWAKYTACESARNPREKLNECLEGNCAEGVGMNYRGN
VSVTRSGIECQLWRSRYPHKPEINSTTHPGADLRENFCRNPDGSITGPWCYTTSPTLRRE
ECSVPVCGQDRVTVEVIPRSGGSTTSQSPLLETCVPDRGREYRGRLAVTTSGSRCLAWSS
EQAKALSKDQDFNPAVPLAENFCRNPDGDEEGAWCYVADQPGDFEYCDLNYCEEPVDGDL
GDRLGEDPDPDAAIEGRTSEDHFQPFFNEKTFGAGEADCGLRPLFEKKQVQDQTEKELFE
SYIEGRIVEGQDAEVGLSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNF
TVDDLLVRIGKHSRTRYERKVEKISMLDKIYIHPRYNWKENLDRDIALLKLKRPIELSDY
IHPVCLPDKQTAAKLLHAGFKGRVTGWGNRRETWTTSVAEVQPSVLQVVNLPLVERPVCK
ASTRIRITDNMFCAGYKPGEGKRGDACEGDSGGPFVMKSPYNNRWYQMGIVSWGEGCDRD
GKYGFYTHVFRLKKWIQKVIDRLGS
Download FASTA Format
Synonyms
  • coagulation factor II
  • Thrombin bovine
  • Thrombin, Topical (Bovine)
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Thrombin-jmiKit5000 [iU]/5mLPfizer Laboratories Div Pfizer Inc.1995-02-24Not applicableUs
Thrombin-jmiKit20000 [iU]/20mLPfizer Laboratories Div Pfizer Inc.1995-02-24Not applicableUs
Thrombin-jmiKit5000 [iU]/5mLPfizer Laboratories Div Pfizer Inc.1995-02-24Not applicableUs
Thrombin-jmiKit5000 [iU]/5mLPfizer Laboratories Div Pfizer Inc.1995-02-24Not applicableUs
Thrombinar Pws 5000unit/vialPowder, for solution5000 unitTopicalArmour Pharmaceutical Co.1984-12-311999-12-15Canada
Thrombostat 10000unitsPowder10000 unitTopicalPfizer1954-12-312004-07-26Canada
Thrombostat 1000unitsPowder1000 unitTopicalParke Davis Division, Warner Lambert Canada Inc.1960-12-311997-04-25Canada
Thrombostat 5000unitsPowder, for solution5000 unitTopicalPfizer1951-12-312004-07-26Canada
Categories
UNII
25ADE2236L
CAS number
Not Available

Pharmacology

Indication

Bovine thrombin is a topical thrombin indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (like suture, ligature, or cautery) is ineffective or impractical [Label]. Additionally, topical bovine thrombin can also be used in combination with an absorbable gelatin sponge, USP [Label].

Associated Conditions
Pharmacodynamics

Little has been reported about the systemic pharmacodynamics and pharmacokinetics of bovine thrombin preparations [2], but it is expected that bovine thrombin elicits similar activities as endogenous thrombin. Subsequently, it is believed that bovine thrombin, like endogenous 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 [1]. 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 [1]. Additionally, thrombin also promotes the activation and aggregation of platelets by way of activating protease-activated receptors on the cell membranes of platelets [1].

Mechanism of action

Bovine thrombin requires no intermediate physiological agent for its action [Label]. It activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are essential steps for clot formation [Label]. Failure to clot blood occurs in the case where the primary clotting defect is the absence of fibrinogen itself [Label]. The speed with which the bovine thrombin clots blood is dependent upon the concentration of both the bovine thrombin and the fibrinogen present [Label].

TargetActionsOrganism
UProteinase-activated receptor 1Not AvailableHumans
UProteinase-activated receptor 4Not AvailableHumans
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
ACoagulation factor V
activator
Humans
ACoagulation factor VIII
activator
Humans
Absorption

Little has been reported about the systemic pharmacokinetics of bovine thrombin preparations [2], but owing to its topical mode of administration, it is expected that any kind of systemic absorption would be minimal.

Volume of distribution

Little has been reported about the systemic pharmacokinetics of bovine thrombin preparations [2], but owing to its topical mode of application, systemic exposure or distribution to other organs and tissues is not expected.

Protein binding

Little has been reported about the systemic pharmacokinetics of bovine thrombin preparations [2]. Protein binding data is subsequently not readily available, although thrombin functions naturally to interact with a very specific set of clotting factors [1].

Metabolism

Although little has been reported about the systemic pharmacokinetics of bovine thrombin preparations [2], such 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

Although little has been reported about the systemic pharmacokinetics of bovine thrombin preparations [2], they 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

Unfortunately, little has been reported about the systemic pharmacokinetics of bovine thrombin preparations [2].

Clearance

Although little has been reported about the systemic pharmacokinetics of bovine thrombin preparations [2], it is expected that they are 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

With regards to bovine thrombin, no cases of overdose have been reported so far [2]. Bovine thrombin however, is capable of causing fatal severe bleeding or thrombosis [Label]. This thrombosis may result from the development of antibodies against bovine thrombin [Label]. Bleeding may result from the development of antibodies against bovine factor V [Label]. These antibodies may subsequently cross-react with endogenous human factor V and lead to its deficiency [Label]. Patients who are know or suspected to have antibodies to bovine thrombin and/or bovine factor V should not be re-exposed to the product [Label]. Patients who are administered bovine thrombin should be monitored for abnormal coagulation laboratory values, bleeding, or indeed, thrombosis [Label].

LD50 values are available for rat and mouse models where rat subcutaneous LD50 > 40mg/kg, rat IP LD50 > 40mg/kg, and mouse subcutaneous LD50 > 50 mg/kg (in which the greater than symbol indicates that the toxicity endpoint being tested was not achievable at the highest dose used in the test) [MSDS].

Regardless, the most common adverse reactions following administration of bovine thrombin include hypersensitivity, bleeding, anemia, post-operative wound infection, thromboembolic events, hypotension, pyrexia, tachycardia, and/or thrombocytopenia [Label].

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. 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]
  2. Richard C. Dart (2004). Medical Toxicology Third Edition (3rd ed.). Lippincott Williams & Wilkins. [ISBN:0781728452]
  3. EMEA European Medicines Agency Withdrawal Assessment Report for Recothrom (thrombin alpha) [Link]
External Links
PubChem Substance
347911181
Wikipedia
Thrombin
ATC Codes
B02BC06 — ThrombinB02BD30 — Thrombin
FDA label
Download (51.2 KB)
MSDS
Download (36.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2, 3WithdrawnTreatmentMinor burns1
3CompletedTreatmentMaintenance of surgical hemostasis therapy1
3Unknown StatusTreatmentRebleeding From Gastric Varices / Ulcer, on Gastric Varices1
Not AvailableTerminatedTreatmentNasal Bleeding1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit20000 [iU]/20mL
Kit5000 [iU]/5mL
PowderTopical10000 unit
PowderTopical1000 unit
Powder, for solutionTopical5000 unit
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
Unknown
General Function
Thrombin receptor activity
Specific Function
High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation and in vascular development.
Gene Name
F2R
Uniprot ID
P25116
Uniprot Name
Proteinase-activated receptor 1
Molecular Weight
47439.83 Da
References
  1. Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK, Andrade-Gordon P, Covic L, Kuliopulos A: Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation. 2006 Mar 7;113(9):1244-54. Epub 2006 Feb 27. [PubMed:16505172]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Receptor for activated thrombin or trypsin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation.
Specific Function
G-protein coupled receptor activity
Gene Name
F2RL3
Uniprot ID
Q96RI0
Uniprot Name
Proteinase-activated receptor 4
Molecular Weight
41132.43 Da
References
  1. Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK, Andrade-Gordon P, Covic L, Kuliopulos A: Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation. 2006 Mar 7;113(9):1244-54. Epub 2006 Feb 27. [PubMed:16505172]
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
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
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
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
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

Drug created on December 03, 2015 09:52 / Updated on November 02, 2018 07:08