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Blood coagulation and protein C pathway

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. Its actions are related to development of thrombosis and ischemic stroke. The protein C pathway of the coagulation of the blood involves the influences of lipids and lipoproteins and the study of the strong epidemiologic association between hyperlipidemia and hypercoagulability.^[1]

See: detailed diagram of Blood Coagulation (Thrombin) and Protein C Pathways

Role in disease

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. 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^[2]

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.^[3]

Pharmacology

Drotrecogin alpha(activated) is recombinant activated protein C from Ely Lilly Co, USA. It is used in the treatment of severe sepsis, septic shock and disseminated intravascular coagulation.

Genetics

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

Protein C (inactivator of coagulation factors Va and VIIIa)
PDB rendering based on 1aut.
Available structures: 1aut, 1lqv
Identifiers
Symbols	PROC; PROC1
External IDs	OMIM: 176860 MGI: 97771 HomoloGene: 37288
Gene ontology Molecular function: • protein C (activated) activity • calcium ion binding • peptidase activity Cellular component: • extracellular region Biological process: • proteolysis • blood coagulation • negative regulation of blood coagulation • negative regulation of apoptosis
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	5624	19123
Ensembl	ENSG00000115718	ENSMUSG00000024386
Uniprot	P04070	P33587
Refseq	NM_000312 (mRNA) NP_000303 (protein)	XM_984063 (mRNA) XP_989157 (protein)
Location	Chr 2: 127.89 - 127.9 Mb	Chr 18: 32.27 - 32.28 Mb
Pubmed search	[1]	[2]

See also

• Activated protein C resistance
• Protein C inhibitor
• Hemostasis
• Thrombosis
• Coagulation
• Anticoagulants

Notes

1. ^ Thrombosis, Blood Coagulation and the Antithrombotic Protein C Pathway - John H. Griffin, TSRI
2. ^ Activated protein C resistance
3. ^ Blood review by Mosnier, Zlokovic and Griffin 2006 ePub

External links

• Relative antithrombotic and antihemostatic effects of protein C activator versus low molecular weight heparin in primates, Gruber A, Marzec UM, Bush L, Di Cera E, Fernandez JA, Berny MA, Tucker EI, McCarty OJ, Griffin JH, Hanson SR., Blood (2007) - 310 articles by Griffin, et al. are represented at this link
• The cytoprotective protein C pathway, Mosnier LO, Zlokovic BV, Griffin JH., Blood (2006)
• The Protein C Pathway- John H. Griffin, retired, TSRI, La Jolla, California
• Diagram of The Blood Coagulation Pathway and Protein C Pathway

Wikipedia content modification information:

• This page was last modified on 2 October 2008, at 20:34.

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