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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 3.4.21.69) 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.

Contents

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]

Pharmacology

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]

Genetics

edit
Protein C (inactivator of coagulation factors Va and VIIIa)

PDB rendering based on 1aut.
Available structures
1aut, 1lqv
Identifiers
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
Orthologs
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]

Interactions

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

See also

References

  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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