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Identification
Name Drotrecogin alfa
Accession Number DB00055 (BIOD00068, BTD00068)
Type biotech
Groups approved
Description

Drotrecogin alfa is activated human protein C that is synthesized by recombinant DNA technology. It is a glycoprotein of approximately 55 kilodalton molecular weight, consisting of a heavy chain and a light chain linked by a disulfide bond.
Protein structure Db00055
Display: 3D Structure
Protein chemical formula C1786H2779N509O519S29
Protein average weight 55000.0000
Sequences 
>Heavy chain
LIDGKMTRRGDSPWQVVLLDSKKKLACGAVLIHPSWVLTAAHCMDESKKLLVRLGEYDLR
RWEKWELDLDIKEVFVHPNYSKSTTDNDIALLHLAQPATLSQTIVPICLPDSGLAERELN
QAGQETLVTGWGYHSSREKEAKRNRTFVLNFIKIPVVPHNECSEVMSNMVSENMLCAGIL
GDRQDACEGDSGGPMVASFHGTWFLVGLVSWGEGCGLLHNYGVYTKVSRYLDWIHGHIRD
KEAPQKSWAP

>Light chain
SKHVDGDQCLVLPLEHPCASLCCGHGTCIXGIGSFSCDCRSGWEGRFCQREVSFLNCSLD
NGGCTHYCLEEVGWRRCSCAPGYKLGDDLLQCHPAVKFPCGRPWKRMEKKRSHL

FASTA
Synonyms
Anticoagulant protein C
Autoprothrombin IIA
Blood coagulation factor XIV
Vitamin K-dependent protein C precursor
Salts Not Available
Brand names
Name Company
Xigris
Xigris (Eli Lilly & Co)
Brand mixtures Not Available
Categories
  • Antisepsis Agents
CAS number 60202-16-6
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For reduction of mortality in patients with severe sepsis.
Pharmacodynamics Drotrecogin alfa is activated human protein C that is synthesized by recombinant DNA technology. It is a glycoprotein of approximately 55 kilodalton molecular weight, consisting of a heavy chain and a light chain linked by a disulfide bond. Drotrecogin alfa inhibits factor Va and VIIIa, thereby reducing the coagulability of blood.
Mechanism of action Activated protein C combines with protein S on platelet surfaces and then degrades factor Va and factor VIIIa, thereby reducing blood coagulability.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism Not Available
Route of elimination Not Available
Half life 5.5 hours (mammalian reticulocytes, in vitro).
Clearance
  • 40 L/hr [severe sepsis adults]
  • 30 +/- 8 L/hr [patients without sepsis undergoing hemodialysis]
  • 28 +/- 9 L/hr [heathy]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Xigris 20 mg vial 1481.66 USD vial
Xigris 5 mg vial 370.42 USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
Canada 2139468 2007-08-21 2015-01-03
Canada 2036894 2002-01-15 2011-02-22
Properties
State liquid
Experimental Properties
Property Value Source
hydrophobicity -0.291 Not Available
isoelectric point 6.78 Not Available
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
UniProt P04070 Link_out
Genbank M11228 Link_out
PharmGKB PA131548935 Link_out
Drug Product Database 2247130 Link_out
RxList http://www.rxlist.com/cgi/generic/drotrecogin.htm Link_out
Drugs.com http://www.drugs.com/cdi/drotrecogin-alfa.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Drotrecogin_alfa Link_out
ATC Codes
  • B01AD10
AHFS Codes
  • 20:12.20
PDB Entries
FDA label show (241 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Clopidogrel Antiplatelet agents such as clopidogrel may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Increase monitoring for signs/symptoms of bleeding during concomitant therapy. If possible, avoid use of drotrecogin within 7 days of use of any IIb/IIIa antagonists, higher dose aspirin (more than 650 mg/day), or use of other antiplatelet agents.
Dalteparin Low molecular weight heparin (LMWH) such as dalteparin may enhance the adverse/toxic effect of drotrecogin alfa. Bleeding may occur.
Enoxaparin Combination should be used with caution after weighing advantages and disadvantages. Low molecular weight heparins such as enoxaparin may increase the adverse effects of drotrecogin. Monitor for bleeding if used concomitantly.
Fondaparinux sodium Drotrecogin alfa may increase the adverse effects of fondaparinux, resulting in excessive bleeding. Concomitant use should be avoided.
Heparin The potential benefits of drotrecogin alfa should be weighed against an increased risk of bleeding in patients receiving therapeutic doses of heparin. Monitor for bleeding during concomitant therapy, and immediately stop infusion of drotrecogin if clinically important bleeding occurs. In patients receiving prophylactic heparin doses, consider continuing this during drotrecogin.
Ketoprofen The antiplatelet effect of ketoprofen may increase the bleed risk associated with drotrecogin alfa. Consider spacing use of the two agents by at least 7 days. Increase monitoring for signs and symptoms of bleeding during concomitant therapy.
Nadroparin The potential benefits of drotrecogin alfa should be weighed against an increased risk of bleeding in patients receiving therapeutic doses of low molecular weight heparins such as nadroparin. Monitor for bleeding during concomitant therapy, and immediately stop infusion of drotrecogin if clinically important bleeding occurs. In patients receiving prophylactic heparin doses, consider continuing this during drotrecogin.
Tenecteplase Increased risk of bleeding.
Tinzaparin Low molecular weight heparins (LMWHs) such as tinzaparin may enhance the adverse/toxic effects of drotrecogin alfa. Bleeding may occur. The potential benefits of drotrecogin alfa should be weighed against the increased risk of bleeding in patients on therapeutic doses of LMWHs.
Tolmetin Increased risk of bleeding. Monitor for increased bleeding during concomitant therapy.
Treprostinil The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Drotrecogin alfa. Monitor for increased bleeding during concomitant thearpy.
Urokinase Increased risk of bleeding.
Vilazodone Increase monitoring for signs/symptoms of bleeding during concomitant therapy. If possible, avoid use of drotrecogin within 7 days of use of any IIb/IIIa antagonists, higher dose aspirin (more than 650 mg/day), or use of other antiplatelet agents.
Warfarin Increased risk of bleeding.
Food Interactions Not Available
Targets

1. Coagulation factor VIII

Pharmacological action: yes
Actions: multitarget

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

Organism class: human
UniProt ID: P00451 Link_out
Gene: F8 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Geng JP, Castellino FJ: Properties of a recombinant chimeric protein in which the gamma-carboxyglutamic acid and helical stack domains of human anticoagulant protein C are replaced by those of human coagulation factor VII. Thromb Haemost. 1997 May;77(5):926-33. Pubmed
  2. Colin G, Annane D: Corticosteroids and human recombinant activated protein C for septic shock. Clin Chest Med. 2008 Dec;29(4):705-12, x. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Coagulation factor V

Pharmacological action: yes
Actions: multitarget

Coagulation factor V is a cofactor that participates with factor Xa to activate prothrombin to thrombin

Organism class: human
UniProt ID: P12259 Link_out
Gene: F5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. Pubmed
  2. Kanji S, Devlin JW, Piekos KA, Racine E: Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. Pharmacotherapy. 2001 Nov;21(11):1389-402. Pubmed
  3. Lyseng-Williamson KA, Perry CM: Drotrecogin alfa (activated). Drugs. 2002;62(4):617-30; discussion 631-2. Pubmed
  4. Joyce DE, Grinnell BW: Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med. 2002 May;30(5 Suppl):S288-93. Pubmed
  5. Poe K: Drotrecogin alfa (activated) approved for treatment of severe sepsis. J Am Pharm Assoc (Wash). 2002 May-Jun;42(3):520-2. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Plasminogen activator inhibitor 1

Pharmacological action: unknown

This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, and protein C. Its rapid interaction with TPA may function as a major control point in the regulation of fibrinolysis

Organism class: human
UniProt ID: P05121 Link_out
Gene: SERPINE1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. Pubmed
  2. Cerchiara E, Tirindelli MC, Giannetti B, Dicuonzo G, Avvisati G: [The numerous properties of the anticoagulant protein C] Clin Ter. 2007 Mar-Apr;158(2):181-7. Pubmed
  3. Idell S: Endothelium and disordered fibrin turnover in the injured lung: newly recognized pathways. Crit Care Med. 2002 May;30(5 Suppl):S274-80. Pubmed
  4. Dhainaut JF, Yan SB, Margolis BD, Lorente JA, Russell JA, Freebairn RC, Spapen HD, Riess H, Basson B, Johnson G 3rd, Kinasewitz GT: Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis. Thromb Haemost. 2003 Oct;90(4):642-53. Pubmed

4. Thrombomodulin

Pharmacological action: unknown

Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated

Organism class: human
UniProt ID: P07204 Link_out
Gene: THBD Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Gresele P, Agnelli G: Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci. 2002 Jan;23(1):25-32. Pubmed
  2. Pineda AO, Chen ZW, Caccia S, Cantwell AM, Savvides SN, Waksman G, Mathews FS, Di Cera E: The anticoagulant thrombin mutant W215A/E217A has a collapsed primary specificity pocket. J Biol Chem. 2004 Sep 17;279(38):39824-8. Epub 2004 Jul 13. Pubmed
  3. McCachren SS, Diggs J, Weinberg JB, Dittman WA: Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. Blood. 1991 Dec 15;78(12):3128-32. Pubmed
  4. Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, Maruyama I, Suzuki K: Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C. J Biochem (Tokyo). 1988 Feb;103(2):281-5. Pubmed
  5. Boffa MC, Burke B, Haudenschild C: [Different localization of thrombomodulin] Ann Biol Clin (Paris). 1987;45(2):191-7. Pubmed

5. Vitamin K-dependent protein S

Pharmacological action: unknown

Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis

Organism class: human
UniProt ID: P07225 Link_out
Gene: PROS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W: Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res. 2002 Mar 1;105(5):433-9. Pubmed
  2. Hesselvik JF, Malm J, Dahlback B, Blomback M: Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost. 1991 Feb 12;65(2):126-9. Pubmed
  3. Cosio FG, Harker C, Batard MA, Brandt JT, Griffin JH: Plasma concentrations of the natural anticoagulants protein C and protein S in patients with proteinuria. J Lab Clin Med. 1985 Aug;106(2):218-22. Pubmed

6. Ceruloplasmin

Pharmacological action: unknown

Ceruloplasmin is a blue, copper-binding (6-7 atoms per molecule) glycoprotein. It has ferroxidase activity oxidizing iron(II) to iron(III) without releasing radical oxygen species. It is involved in iron transport across the cell membrane

Organism class: human
UniProt ID: P00450 Link_out
Gene: CP Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

7. Prothrombin

Pharmacological action: unknown

Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C

Organism class: human
UniProt ID: P00734 Link_out
Gene: F2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Omar MN, Shouk TA, Khaleq MA: Activity of blood coagulation and fibrinolysis during and after hydroxyethyl starch (HES) colloidal volume replacement. Clin Biochem. 1999 Jun;32(4):269-74. Pubmed
  2. Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W: Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res. 2002 Mar 1;105(5):433-9. Pubmed
  3. Gruber A, Cantwell AM, Di Cera E, Hanson SR: The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo. J Biol Chem. 2002 Aug 2;277(31):27581-4. Epub 2002 Jun 17. Pubmed
  4. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese A, Weitz JI, Weiler H, Hellings PW, Schaeffer P, Herbert JM, Collen D, Theilmeier G: The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med. 2002 Sep 2;196(5):565-77. Pubmed
  5. Levi M, De Jonge E, van der Poll T: Recombinant human activated protein C (Xigris). Int J Clin Pract. 2002 Sep;56(7):542-5. Pubmed

8. Platelet factor 4

Pharmacological action: unknown

Platelet factor 4, non-covalently bound to a proteoglycan molecule, is released during platelet aggregation. PF4 neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. Chemotactic for neutrophils and monocytes

Organism class: human
UniProt ID: P02776 Link_out
Gene: PF4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. Pubmed

9. Plasma serine protease inhibitor

Pharmacological action: unknown

Inhibits activated protein C as well as plasminogen activators

Organism class: human
UniProt ID: P05154 Link_out
Gene: SERPINA5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Shen L, Villoutreix BO, Dahlback B: Involvement of Lys 62(217) and Lys 63(218) of human anticoagulant protein C in heparin stimulation of inhibition by the protein C inhibitor. Thromb Haemost. 1999 Jul;82(1):72-9. Pubmed
  2. He X, Shen L, Bjartell A, Malm J, Lilja H, Dahlback B: The gene encoding vitamin K-dependent anticoagulant protein C is expressed in human male reproductive tissues. J Histochem Cytochem. 1995 Jun;43(6):563-70. Pubmed
  3. Kobayashi H, Gabazza EC, Taguchi O, Wada H, Takeya H, Nishioka J, Yasui H, Kobayashi T, Hataji O, Suzuki K, Adachi Y: Protein C anticoagulant system in patients with interstitial lung disease. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1850-4. Pubmed
  4. Hayashi T, Suzuki K: [Molecular biology of protein C-thrombomodulin pathway. Structure and function, and basic studies on its clinical application] Nippon Rinsho. 1993 Jun;51(6):1610-9. Pubmed
  5. Berg DT, Gerlitz B, Shang J, Smith T, Santa P, Richardson MA, Kurz KD, Grinnell BW, Mace K, Jones BE: Engineering the proteolytic specificity of activated protein C improves its pharmacological properties. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4423-8. Epub 2003 Apr 1. Pubmed

10. Serpin B6

Pharmacological action: unknown

Inhibits thrombin

Organism class: human
UniProt ID: P35237 Link_out
Gene: SERPINB6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

11. Vitamin K-dependent gamma-carboxylase

Pharmacological action: unknown

Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium binding gamma-carboxyglutamate (Gla) residues with the concomitant convertion of the reduced hydroquinone form of vitamin K to vitamin K epoxide

Organism class: human
UniProt ID: P38435 Link_out
Gene: GGCX Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

12. Endothelial protein C receptor

Pharmacological action: unknown

Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation

Organism class: human
UniProt ID: Q9UNN8 Link_out
Gene: PROCR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, Mizokami H, Kimoto M: Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med. 1998 Apr 6;187(7):1029-35. Pubmed
  2. Ruf W, Dorfleutner A, Riewald M: Specificity of coagulation factor signaling. J Thromb Haemost. 2003 Jul;1(7):1495-503. Pubmed
  3. Castellino FJ, Liang Z, Volkir SP, Haalboom E, Martin JA, Sandoval-Cooper MJ, Rosen ED: Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge. Thromb Haemost. 2002 Sep;88(3):462-72. Pubmed
  4. Cerchiara E, Tirindelli MC, Giannetti B, Dicuonzo G, Avvisati G: [The numerous properties of the anticoagulant protein C] Clin Ter. 2007 Mar-Apr;158(2):181-7. Pubmed
  5. Liaw PC: Endogenous protein C activation in patients with severe sepsis. Crit Care Med. 2004 May;32(5 Suppl):S214-8. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on September 29, 2010 14:34