Identification

Name
Antihemophilic factor human
Accession Number
DB13192
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Blood factors
Description

Antihemophilic factor human, also known as Coagulation Factor VIII or Anti-Hemophilic Factor (AHF), is a non-recombinant, lyophilized concentrate of coagulation factor VIII, an endogenous protein and essential component of the coagulation cascade. Antihemophilic factor is manufactured with reduced amounts of von Willebrand Factor antigen (VWF:Ag) and purified from extraneous plasma-derived protein by affinity chromatography. The small amount of VWF:Ag is used to purify factor VIII complex and then removed from the final preparation. The final purified concentrate contains albumin as a stabilizer.[11]. The complex was developed by CSL Behring or Baxter Healthcare Corporation and approved in the 90s.

Endogenous Factor VIII is essential to the clotting process in the body due to its involvement in the clotting cascade where it is responsible for acting as a co-factor to Factor IX. Activation of Factor IX leads to a cascade of signals that results in activation of Factor X, which then results in the conversion of prothrombin to thrombin, and as a result, leads to the conversion of fibrinogen to fibrin, the fibrous protein that creates the scaffold of the clot. Replacement of Factor VIII is essential for the treatment of Hemophilia A, which is caused by mutations in the Factor VIII gene, leading to a functional deficiency or complete loss of protein. Congenital loss or deficiency of Factor VIII results in the physiologic impairment of the coagulation clotting cascade, and as a result, leads to easy bruising and bleeding. Bleeding can range in severity from minor concerns, such as nosebleeds, to more serious events such as hemorrhaging in the joints, brain, or digestive tract [6].

Exogenous replacement of Factor VIII is currently the cornerstone of Hemophilia treatment and is used for the prophylaxis and control of bleeding episodes. Treatment has drastically improved since the 1960s when Factor VIII protein was primarily purified from human plasma, rather than being produced through recombinant DNA technology. Unfortunately, purification of protein from human plasma carries an increased risk of transmission of blood-borne diseases such as HIV and Hepatitis, which in part contributed to the Tainted Blood Scandal in the 1980s and 1990s [7, 8].

Other drug products with similar structure and function to Antihemophilic factor human include Moroctocog alfa, which is produced by recombinant DNA technology and is identical in sequence to endogenously produced Factor VIII, but does not contain the B-domain, which has no known biological function and Efmoroctocog alfa, which is a fully recombinant factor VIII-Fc fusion protein which has an extended half-life compared with conventional factor VIII due to conjugation to the dimeric Fc domain of human immunoglobulin G1, a long-lived plasma protein [7].

Antihemophilic factor human is approved by the Food and Drug Administration for use in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes [FDA Label].

Protein structure
Db13192
Protein chemical formula
Not Available
Protein average weight
480000.0 Da (active (coagulant activity))
Sequences
>>>antihemophilic factor<<<<
MQIELSTCFFLCLLRFCFSATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFN
TSVVYKKTLFVEFTVHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAV
GVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSH
VDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRD
AASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNH
RQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNE
EAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLA
PDDRSYKSQYLNNGPQRIGRKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTL
LIIFKNQASRPYNIYPHGITDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGP
TKSDPRCLTRYYSSFVNMERDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDE
NRSWYLTENIQRFLPNPAGVQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILS
IGAQTDFLSVFFSGYTFKHKMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRG
MTALLKVSSCDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSQNSRHPSTRQKQFNATTI
PENDIEKTDPWFAHRTPMPKIQNVSSSDLLMLLRQSPTPHGLSLSDLQEAKYETFSDDPS
PGAIDSNNSLSEMTHFRPQLHHSGDMVFTPESGLQLRLNEKLGTTAATELKKLDFKVSST
SNNLISTIPSDNLAAGTDNTSSLGPPSMPVHYDSQLDTTLFGKKSSPLTESGGPLSLSEE
NNDSKLLESGLMNSQESSWGKNVSSTESGRLFKGKRAHGPALLTKDNALFKVSISLLKTN
KTSNNSATNRKTHIDGPSLLIENSPSVWQNILESDTEFKKVTPLIHDRMLMDKNATALRL
NHMSNKTTSSKNMEMVQQKKEGPIPPDAQNPDMSFFKMLFLPESARWIQRTHGKNSLNSG
QGPSPKQLVSLGPEKSVEGQNFLSEKNKVVVGKGEFTKDVGLKEMVFPSSRNLFLTNLDN
LHENNTHNQEKKIQEEIEKKETLIQENVVLPQIHTVTGTKNFMKNLFLLSTRQNVEGSYE
GAYAPVLQDFRSLNDSTNRTKKHTAHFSKKGEEENLEGLGNQTKQIVEKYACTTRISPNT
SQQNFVTQRSKRALKQFRLPLEETELEKRIIVDDTDTQWSKNMKHLTPSTLTQIDYNEKE
KGAITQSPLSDCLTRSHSIPQANRSPLPIAKVSSFPSIRPIYLTRVLFQDNSSHLPAASY
RKKDSGVQESSHFLQGAKKNNLSLAILTLEMTGDQREVGSLGTSATNSVTYKKVENTVLP
KPDLPKTSGKVELLPKVHIYQKDLFPTETSNGSPGHLDLVEGSLLQGTEGAIKWNEANRP
GKVPFLRVATESSAKTPSKLLDPLAWDNHYGTQIPKEEWKSQEKSPEKTAFKKKDTILSL
NACESNHAIAAINEGQNKPEIEVTWAKQGRTERLCSQNPPVLKRHQREITRTTLQSDQEE
IDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNR
AQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASR
PYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDV
DLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRA
PCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGH
VFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKC
QTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMII
HGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFN
PPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFA
TWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFL
ISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRM
EVLGCEAQDLY
Download FASTA Format
Synonyms
  • Antihemophilic factor VIII human
  • Antihemophilic factor, human
  • Antihemophilic factor, human (monoclonal)
  • Antihemophilic factor,human
  • F8 protein, human
  • Factor VIII (antihaemophilic factor)
  • Factor VIII (human)
  • Human coagulation factor VIII
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AlphanateKitIntravenousGrifols2007-01-31Not applicableUs
AlphanateKitIntravenousGrifols2007-01-31Not applicableUs
AlphanateKitIntravenousGrifols2007-01-31Not applicableUs
AlphanateKitIntravenousGrifols2007-01-31Not applicableUs
AlphanateKitIntravenousGrifols2007-01-31Not applicableUs
Hemofil MKitBaxalta Canada Corporation1988-02-23Not applicableUs
Hemofil MKitBaxalta Canada Corporation1988-02-23Not applicableUs
Hemofil MKitBaxalta Canada Corporation1988-02-23Not applicableUs
Hemofil MKitBaxalta Canada Corporation1988-02-23Not applicableUs
KoateKitIntravenousKedrion Biopharma, Inc.1999-05-20Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Humate-PAntihemophilic factor human (300 unit) + Von Willebrand Factor Human (840 unit)Powder, for solutionIntravenousCsl Behring2004-12-06Not applicableCanada
Humate-PAntihemophilic factor human (1200 unit) + Von Willebrand Factor Human (3360 unit)Powder, for solutionIntravenousCsl Behring2004-12-06Not applicableCanada
Humate-PAntihemophilic factor human (600 unit) + Von Willebrand Factor Human (1680 unit)Powder, for solutionIntravenousCsl Behring2004-12-06Not applicableCanada
WilateAntihemophilic factor human (1000 IU/10mL) + Von Willebrand Factor Human (1000 IU/10mL)Powder, for solutionIntravenousOctapharma Pharmazeutika Produktionsges M B H2008-04-29Not applicableCanada
WilateAntihemophilic factor human (500 IU/5mL) + Von Willebrand Factor Human (500 IU/5mL)Powder, for solutionIntravenousOctapharma Pharmazeutika Produktionsges M B H2008-04-29Not applicableCanada
Categories
UNII
839MOZ74GK
CAS number
Not Available

Pharmacology

Indication

The human antihemophilic factor is indicated for the cases of hemophilia A, also known as classical hemophilia for the prevention and control of hemorrhagic episodes.[12] If surgery is needed in patients with hemophilia A there is a need of correction of the clotting abnormality. In this cases, the human antihemophilic factor may be administered followed by intermittent maintenance doses.[11] The hemophilia A is characterized by the deficiency of the coagulation factor VIII that results in prolonged blood flow after injury or surgery as well as recurrent bleeding.[9]

Structured Indications
Pharmacodynamics

The human antihemophilic factor assists in the convertion of prothrombin to thrombin.[10] Its administration generates the formation of a complex constituted by the Factor IXa, Factor X and the antihemophilic factor which triggers the normal coagulation cascade for the formation of blood clots.[1] The human antihemophilic factor is increased in the plasma thus enabling temporary correction of the hemophilia A bleeding.[13] Its effect is reported as the normalization of the partial thromboplastin time.[14]

Mechanism of action

The human antihemophilic factor replaces the coagulation factor VIII. It acts as a co-factor for factor IX to activate factor X in the intrinsic pathway of blood coagulation.[13, 14]

TargetActionsOrganism
ACoagulation factor IX
activator
Human
ACoagulation factor X
activator
Human
Absorption

After intravenous administration of the human antihemophilic factor the values of Cmax, AUC and Tmax were 100 IU/ml, 1450 IU h/ml and 0.43 h respectively. In a second clinical trial, the treatment was administered for six months and the values of Cmax, AUC and Tmax were 99 units/ 100 ml, 1471 units h/ 100ml and 16 h, respectively.[14]

Volume of distribution

The pharmacokinetic profile of the human antihemophilic factor needed to be studied by the two-compartment theory as not all of it stays just in blood plasma. The central and peripheral volume of distribution in adults weight an average of 68 kg were 2.81 L and 1.90 L respectively.[3]

Protein binding

The human antihemophilic factor is retained mainly in the blood as its major function is to start the coagulation cascade.

Metabolism

The metabolism of the human antihemophilic factor is identical to the normal inactivation and elimination pathway of the natural coagulation factor VIII. After activation, the human antihemophilic factor gets metabolized by activated protein C in R336 and R562 and this action inactivates this cofactor. The proteolysis generates two major fragments which are recognized by an anti-factor VIII A2 domain antibody. This process is followed by a further degradation into smaller fragments.[4]

Route of elimination

Intravenous administration of human antihemophilic factor is rapidly eliminated primarly through the reticuloendothelial system.[5]

Half life

The mean half-life of human antihemophilic factor administered in hemophilic A patients is 14.8 hours.[13]

Clearance

The reported clearance for the administration of antihemophilic factor is 0.15 L/h in adults with an average weight of 68 kg. In the same study, there was a separation of the intercompartment clearance which is 0.16 L/h. The clearance rate was reported to be significantly decreased with increasing age and significantly increased in patients that presented a blood type of gourp O.[3]

Toxicity

The highest toxicity is the risk of viral hepatitis transmition as well as intravascular hemolyisis can occur if large or frequent doses are used in blood groups A, B or AB.[10]

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. Nogami K: Bispecific antibody mimicking factor VIII. Thromb Res. 2016 May;141 Suppl 2:S34-5. doi: 10.1016/S0049-3848(16)30361-9. [PubMed:27207420]
  2. Morfini M: The History of Clotting Factor Concentrates Pharmacokinetics. J Clin Med. 2017 Mar 20;6(3). pii: jcm6030035. doi: 10.3390/jcm6030035. [PubMed:28335525]
  3. Hazendonk H, Fijnvandraat K, Lock J, Driessens M, van der Meer F, Meijer K, Kruip M, Gorkom BL, Peters M, de Wildt S, Leebeek F, Cnossen M, Mathot R: A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients. Haematologica. 2016 Oct;101(10):1159-1169. doi: 10.3324/haematol.2015.136275. Epub 2016 Jul 6. [PubMed:27390359]
  4. Warren DL, Morrissey JH, Neuenschwander PF: Proteolysis of blood coagulation factor VIII by the factor VIIa-tissue factor complex: generation of an inactive factor VIII cofactor. Biochemistry. 1999 May 18;38(20):6529-36. doi: 10.1021/bi983033o. [PubMed:10350471]
  5. Bjorkman S, Berntorp E: Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia. Clin Pharmacokinet. 2001;40(11):815-32. doi: 10.2165/00003088-200140110-00003. [PubMed:11735604]
  6. Franchini M, Mannucci PM: Hemophilia A in the third millennium. Blood Rev. 2013 Jul;27(4):179-84. doi: 10.1016/j.blre.2013.06.002. Epub 2013 Jun 28. [PubMed:23815950]
  7. Frampton JE: Efmoroctocog Alfa: A Review in Haemophilia A. Drugs. 2016 Sep;76(13):1281-1291. doi: 10.1007/s40265-016-0622-z. [PubMed:27487799]
  8. Santagostino E: A new recombinant factor VIII: from genetics to clinical use. Drug Des Devel Ther. 2014 Dec 12;8:2507-15. doi: 10.2147/DDDT.S73241. eCollection 2014. [PubMed:25548513]
  9. Konkle B., Huston H. and Fletcher S. (2017). Gene Reviews. University of Washington..
  10. Hodgson B and Kizior R. (2014). Saunders Nursing Drug Handbook. Elsevier.
  11. CSL Behring [Link]
  12. Hemofil M [Link]
  13. Dailymed [Link]
  14. Dailymed [Link]
External Links
PubChem Substance
347911441
ATC Codes
B02BD02 — Coagulation factor viii
FDA label
Download (326 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentVonWillebrand's Disease1
2RecruitingTreatmentHemophilia A, Congenital1
3CompletedNot AvailableHemophilia A1
3CompletedTreatmentHemophilia A2
3CompletedTreatmentSevere Hemophilia A1
3CompletedTreatmentVon Willebrand 's disease Type 11
3RecruitingTreatmentSevere Hemophilia A1
4CompletedBasic ScienceHemophilia A1
4RecruitingTreatmentHemophilia A / Hemophilia A With Inhibitors1
Not AvailableActive Not RecruitingPreventionSevere Hemophilia A1
Not AvailableNot Yet RecruitingNot AvailableHemophilia A1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
KitIntravenous
Kit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
isoelectric point5.5-6United States patent 6953837

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
Human
Pharmacological action
Yes
Actions
Activator
General Function
Serine-type endopeptidase activity
Specific Function
Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholi...
Gene Name
F9
Uniprot ID
P00740
Uniprot Name
Coagulation factor IX
Molecular Weight
51778.11 Da
References
  1. Hemofil M [Link]
  2. Dailymed [Link]
  3. Dailymed [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Activator
General Function
Serine-type endopeptidase activity
Specific Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Hemofil M [Link]
  2. Dailymed [Link]
  3. Dailymed [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Serine-type endopeptidase activity
Specific Function
Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids (PubMed:25618265). Exerts ...
Gene Name
PROC
Uniprot ID
P04070
Uniprot Name
Vitamin K-dependent protein C
Molecular Weight
52070.82 Da
References
  1. Warren DL, Morrissey JH, Neuenschwander PF: Proteolysis of blood coagulation factor VIII by the factor VIIa-tissue factor complex: generation of an inactive factor VIII cofactor. Biochemistry. 1999 May 18;38(20):6529-36. doi: 10.1021/bi983033o. [PubMed:10350471]

Drug created on June 22, 2017 09:32 / Updated on May 02, 2018 00:30