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Blood coagulation and protein C pathway
The Protein C Anticoagulant Pathway: Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the intact cell surface. As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of protein C. Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and VIIIa.[1] This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular injury. T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= Protein S (see also activated protein C resistance).

Protein C is a protein that in humans is encoded by the PROC gene.[2][3] Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme (EC that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. It should not be confused with C peptide or c-reactive protein or protein kinase C.

The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits both anti-inflammatory and anti-apoptotic activities.[4][5] It also plays a role in the development of thrombosis and ischemic stroke.


Role in disease

Protein C deficiency is a rare genetic disorder that predisposes to venous thrombosis and habitual abortion. If homozygous, this presents with a form of disseminated intravascular coagulation in newborns termed purpura fulminans; it is treated by replacing the defective protein C.

Activated protein C resistance is the inability of protein C to cleave factors V and/or VIII. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations.

Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K inhibitor anticoagulant warfarin. In initial stages of action, inhibition of protein C may be stronger than inhibition of the vitamin K-dependent coagulation factors (II, VII, IX and X), leading to paradoxical activation of coagulation and necrosis of skin areas.

HDL and the effects of activated protein C (APC) on cells is very important.[6]


Drotrecogin alpha(activated) is recombinant activated protein C from Eli Lilly Co, USA. It is used in the treatment of severe sepsis, septic shock and disseminated intravascular coagulation. Its use has been very controversial[7] since the results of clinical studies have been markedly varied.[8] A new clinical trial of activated protein C for severe sepsis is currently underway.[1]


Protein C (inactivator of coagulation factors Va and VIIIa)

PDB rendering based on 1aut.
Available structures
1aut, 1lqv
Symbols PROC; PROC1
External IDs OMIM176860 MGI97771 HomoloGene37288 GeneCards: PROC Gene
RNA expression pattern
PBB GE PROC 206259 at tn.png
More reference expression data
Species Human Mouse
Entrez 5624 19123
Ensembl ENSG00000115718 ENSMUSG00000024386
UniProt P04070 P33587
RefSeq (mRNA) NM_000312 XM_984063
RefSeq (protein) NP_000303 XP_989157
Location (UCSC) Chr 2:
127.89 - 127.9 Mb
Chr 18:
32.27 - 32.28 Mb
PubMed search [1] [2]

The PROC gene is located on the second chromosome (2q13-q14).[9]


Protein C has been shown to interact with Protein C inhibitor.[10][11]

See also


  1. ^ a b Baillie JK (November 2007). "Activated protein C: controversy and hope in the treatment of sepsis". Curr Opin Investig Drugs 8 (11): 933–8. PMID 17979027.  
  2. ^ Foster DC, Yoshitake S, Davie EW (July 1985). "The nucleotide sequence of the gene for human protein C". Proc. Natl. Acad. Sci. U.S.A. 82 (14): 4673–7. PMID 2991887.  
  3. ^ Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vicente V, Mannucci PM, Bertina R, Peschle C (May 1987). "Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene". Proc. Natl. Acad. Sci. U.S.A. 84 (9): 2829–32. PMID 2437584.  
  4. ^ Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV (March 2003). "Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective". Nat. Med. 9 (3): 338–42. doi:10.1038/nm826. PMID 12563316.  
  5. ^ Mosnier LO, Griffin JH (July 2003). "Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor". Biochem. J. 373 (Pt 1): 65–70. doi:10.1042/BJ20030341. PMID 12683950.  
  6. ^ Griffin JH, Fernández JA, Mosnier LO, Liu D, Cheng T, Guo H, Zlokovic BV (2006). "The promise of protein C". Blood Cells Mol. Dis. 36 (2): 211–6. doi:10.1016/j.bcmd.2005.12.023. PMID 16464623.  
  7. ^ Eichacker PQ, Natanson C (March 2007). "Increasing evidence that the risks of rhAPC may outweigh its benefits". Intensive Care Med 33 (3): 396–9. doi:10.1007/s00134-007-0556-8. PMID 17325833.  
  8. ^ Baillie JK, Murray G (January 2006). "Drotrecogin alfa (activated) in severe sepsis". N. Engl. J. Med. 354 (1): 94–6; author reply 94–6. PMID 16395834.  
  9. ^ Rocchi M, Roncuzzi L, Santamaria R, Archidiacono N, Dente L, Romeo G (September 1986). "Mapping through somatic cell hybrids and cDNA probes of protein C to chromosome 2, factor X to chromosome 13, and alpha 1-acid glycoprotein to chromosome 9". Hum. Genet. 74 (1): 30–3. PMID 3463531.  
  10. ^ España F, Berrettini M, Griffin JH (August 1989). "Purification and characterization of plasma protein C inhibitor". Thromb. Res. 55 (3): 369–84. PMID 2551064.  
  11. ^ Strandberg K, Kjellberg M, Erb EM, Persson U, Mosher DF, Villoutreix BO, Stenflo J (December 2000). "Activated protein C-protein C inhibitor complex formation: characterization of a neoepitope provides evidence for extensive insertion of the reactive center loop". Biochemistry 39 (51): 15713–20. PMID 11123896.  

Further reading

External links

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