Thrombin alfa

Identification

Summary

Thrombin alfa is a platelet activating factor used to treat minor bleeding.

Brand Names
Recothrom
Generic Name
Thrombin alfa
DrugBank Accession Number
DB11572
Background

Thrombin Alfa is a human coagulation protein produced via recombinant DNA technology from a genetically modified CHO cell line. Thrombin Alfa is identical in amino acid sequence and structurally similar to naturally occurring human thrombin. Thrombin Alfa precursor is secreted to culture medium as single chain form that is proteolytically converted to a two-chain active form (using a protein derived from snakes) and is purified by a chromatographic process that yields a product having hemostatic activities similar to native human thrombin. The cell line used to manufacture Thrombin Alfa has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of Thrombin Alfa employs no additives of human or animal origin. The purification process includes solvent-detergent treatment and nano-filtration steps dedicated to viral clearance. The thrombin alfa product ultimate comes from recombinant human prethrombin-1 2.

Nevertheless, because the incidence of hemostasis within a timely manner is relatively comparable between the use of thrombin alfa and the placebo treatment in patient subjects, thrombin alfa is not currently approved by certain organizations like the European Medicines Agency 2.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Blood factors
Protein Structure
Db11572
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
  • Human Thrombin (recombinant, glycosylated)
  • Thrombin (synthetic human)
  • Thrombin alfa

Pharmacology

Indication

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 (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age Label.

Additionally, thrombin alfa can be used in conjunction with an absorbable gelatin sponge, USP Label.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

As thrombin alfa, a recombinant thrombin, is considered to be identical in amino acid sequence and structural similarity to naturally occurring human thrombin, it is believed that thrombin alfa shares the same pharmacodynamics as endogenous or natural human thrombin coagulation factor 2.

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 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

Specifically, thrombin alfa is a human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding Label. In particular, thrombin alfa activates platelets and cleaves fibrinogen to fibrin, leading directly to clot formation. It also activates clotting factor XIII, leading to fibrin cross-linking and clot stability Label,2. The ability of thrombin alfa to bypass the initial enzymatic steps of the coagulation pathway provides a clear rationale as to why thrombin alfa may be used as a topical haemostatic agent Label,2.

TargetActionsOrganism
ACoagulation factor V
activator
Humans
ACoagulation factor VIII
activator
Humans
AFibrinogen alpha chain
activator
Humans
AFibrinogen beta chain
activator
Humans
AFibrinogen gamma chain
activator
Humans
Absorption

Traditional absorption, distribution, metabolism, and excretion studies were not/have not been performed for thrombin alfa 2.

Nevertheless, observations of a subcutaneous administration of 350 U rhThrombin/kg resulted in a bioavailability of approximately 95% in male cynomolgus monkeys 2.

Volume of distribution

Traditional absorption, distribution, metabolism, and excretion studies were not/have not been performed for thrombin alfa 2. Volume of distribution data is subsequently not readily available.

Protein binding

Traditional absorption, distribution, metabolism, and excretion studies were not/have not been performed for thrombin alfa 2. Protein binding data is subsequently not readily available, although thrombin alfa functions predominantly to interact with a very specific set of clotting factors - a function that endogenous thrombin (of which thrombin alfa is a recombinant replica of) is naturally designed to perform.

Metabolism

Much like endogenous thrombin, thrombin alfa does not circulate in the blood as a free, active molecule for very long Label. After performing its function it is rapidly inactivated after formation of complexes with various circulating endogenous plasma inhibitors (like antithrombin III) Label,2. 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 Label,2.

Route of elimination

Thrombin alfa, like endogenous 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 2. Specific thrombin inhibitors include ATIII, alpha-2M and heparin cofactor II 2.

Half-life

Following intravenous administration, thrombin alfa exhibited an initial half-life of 0.17 hours (10.2 min) 2. Following either intravenous or subcutaneous administration, the agent demonstrated a terminal half-life of about 15 hours 2. This data follows administration of thrombin alfa to cynomolgus monkeys.

Clearance

Traditional absorption, distribution, metabolism, and excretion studies were not/have not been performed for thrombin alfa 2. Regardless, thrombin alfa, like natural thrombin, is known to be rapidly neutralized by naturally circulating plasma inhibitors limiting its duration of action and preventing the active form from diffusing into the general circulation 2.

Adverse Effects
Medicalerrors
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Toxicity

Traditional absorption, distribution, metabolism, and excretion studies were not/have not been performed for thrombin alfa 2. Data regarding overdosage are not available. The predominant adverse reaction associated with thrombin alfa is the possibility of thrombosis or other thromboembolic events occurring Label.

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

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RecothromKit1000 [iU]/1mLTopicalZymo Genetics2008-01-292016-11-30US flag
RecothromPowder, for solution6000 unitTopicalBaxter Laboratories2010-03-24Not applicableCanada flag
RecothromKit1000 [iU]/1mLTopicalMallinckrodt Hospital Products Inc.2008-01-292019-09-21US flag
RecothromKit1000 [iU]/1mLTopicalBaxter Healthcare Corporation2008-01-29Not applicableUS flag
RecothromKit1000 [iU]/1mLTopicalThe Medicines Company2008-06-09Not applicableUS flag
RecothromPowder, for solution24000 unitTopicalBaxter LaboratoriesNot applicableNot applicableCanada flag
RecothromKit1000 [iU]/1mLTopicalBaxter Healthcare Corporation2008-06-09Not applicableUS flag
RecothromKit1000 [iU]/1mLTopicalZymo Genetics2008-06-092015-08-30US flag
RecothromKit1000 [iU]/1mLTopicalThe Medicines Company2008-01-29Not applicableUS flag
RecothromKit1000 [iU]/1mLTopicalMallinckrodt Hospital Products Inc.2008-06-092019-09-21US 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
SCK81AMR7R
CAS number
869858-13-9

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. [Article]
  2. EMEA European Medicines Agency Withdrawal Assessment Report for Recothrom (thrombin alpha) [Link]
PubChem Substance
347911205
RxNav
1367075
AHFS Codes
  • 20:28.16 — Hemostatics
FDA label
Download (201 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
KitTopical1000 [iU]/1mL
Powder, for solutionTopical24000 unit
Powder, for solutionTopical6000 unit
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. Ustinov NB, Zav'yalova EG, Kopylov AM: Effect of Thrombin Inhibitors on Positive Feedback in the Coagulation Cascade. Biochemistry (Mosc). 2016 Mar;81(3):242-8. doi: 10.1134/S0006297916030068. [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. Ustinov NB, Zav'yalova EG, Kopylov AM: Effect of Thrombin Inhibitors on Positive Feedback in the Coagulation Cascade. Biochemistry (Mosc). 2016 Mar;81(3):242-8. doi: 10.1134/S0006297916030068. [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. Ustinov NB, Zav'yalova EG, Kopylov AM: Effect of Thrombin Inhibitors on Positive Feedback in the Coagulation Cascade. Biochemistry (Mosc). 2016 Mar;81(3):242-8. doi: 10.1134/S0006297916030068. [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. Ustinov NB, Zav'yalova EG, Kopylov AM: Effect of Thrombin Inhibitors on Positive Feedback in the Coagulation Cascade. Biochemistry (Mosc). 2016 Mar;81(3):242-8. doi: 10.1134/S0006297916030068. [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. Ustinov NB, Zav'yalova EG, Kopylov AM: Effect of Thrombin Inhibitors on Positive Feedback in the Coagulation Cascade. Biochemistry (Mosc). 2016 Mar;81(3):242-8. doi: 10.1134/S0006297916030068. [Article]

Drug created on April 06, 2016 22:25 / Updated on May 07, 2021 21:05