View source for Protein C

{{Short description|Mammalian protein found in Homo sapiens}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Distinguish|C-peptide|C-reactive protein|protein kinase C}}
{{Infobox gene}}

'''Protein&nbsp;C''', also known as '''autoprothrombin IIA''' and '''blood coagulation factor XIV''',<ref name="mather">{{cite book | vauthors = Hall JA, Morton I | title = Concise dictionary of pharmacological agents: properties and synonyms | publisher = Kluwer Academic | year = 1999 | isbn = 978-0-7514-0499-9 }}</ref>{{rp|6822}}<ref name="morton"/> is a [[zymogen]], that is, an inactive enzyme. The activated form plays an important role in regulating [[anticoagulation]], [[inflammation]], and [[apoptosis|cell death]] and maintaining the [[vascular permeability|permeability]] of blood vessel walls in humans and other animals. '''Activated protein&nbsp;C''' ('''APC''') performs these operations primarily by [[proteolysis|proteolytically]] inactivating proteins [[Factor V|Factor V<sub>a</sub>]] and [[Factor VIII|Factor VIII<sub>a</sub>]]. APC is classified as a [[serine protease]] since it contains a [[residue (chemistry)|residue]] of [[serine]] in its [[active site]].<ref name=nicolaes />{{rp|35}} In humans, protein C is encoded by the ''PROC'' [[gene]], which is found on [[chromosome 2 (human)|chromosome 2]].<ref name=foster />

The zymogenic form of protein C is a [[vitamin K]]-dependent [[glycoprotein]] that circulates in [[blood plasma]]. Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a [[disulfide bond]].<ref name=foster />{{rp|4673}} The protein C zymogen is activated when it binds to [[thrombin]], another protein heavily involved in coagulation, and protein C's activation is greatly promoted by the presence of [[thrombomodulin]] and [[endothelial protein&nbsp;C receptor]]s (EPCRs). Because of EPCR's role, activated protein C is found primarily near endothelial cells (i.e., those that make up the walls of blood vessels), and it is these cells and [[white blood cell|leukocyte]]s (white blood cells) that APC affects.<ref name=nicolaes />{{rp|34}}<ref name=mosnier />{{rp|3162}} Because of the crucial role that protein C plays as an [[anticoagulant]], those with deficiencies in protein C, or some kind of [[activated protein C resistance|resistance to APC]], suffer from a significantly increased risk of forming dangerous blood clots ([[thrombosis]]).

Research into the clinical use of a [[recombinant DNA|recombinant]] form of human Activated Protein&nbsp;C (rhAPC) known as [[Drotrecogin alfa|Drotrecogin alfa-activated]], branded Xigris by [[Eli Lilly and Company]], has been surrounded by controversy. Eli Lilly ran an aggressive marketing campaign to promote its use for people with severe [[sepsis]] and septic shock and sponsored the 2004 [[Surviving Sepsis Campaign]] Guidelines.<ref name="pmid17050887"/> However, a 2012 [[Cochrane review]] found that its use cannot be recommended since it does not improve survival and increases bleeding risk.<ref name="pmid23235609"/> In October 2011, Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.<ref name="Kylat"/>

==History==
Protein C's [[anticoagulant]] role in the human body was first noted by Seegers ''et al.'' in 1960,<ref name="seegers"/> who gave protein C its original name, ''autoprothrombin II-a''.<ref name=mather />{{rp|6822}} Protein&nbsp;C was first isolated by [[Johan Stenflo]] from [[cow|bovine]] [[blood plasma|plasma]] in 1976, and Stenflo determined it to be a [[vitamin K-dependent protein]].<ref name="stenflo"/> He named it protein ''C'' because it was the third protein ("peak C") that [[elution|eluted]] from a [[DEAE-Sepharose]] [[Ion chromatography|ion-exchange chromotograph]]. Seegers was, at the time, searching for vitamin K-dependent coagulation factors undetected by [[Coagulation#Medical assessment|clotting assay]]s, which measure global clotting function. Soon after this, Seegers recognised Stenflo's discovery was identical with his own.<ref name=mather />{{rp|6822}} Activated protein&nbsp;C was discovered later that year,<ref name="kisiel"/> and in 1977 it was first recognised that APC inactivates Factor V<sub>a</sub>.<ref name="mosnier2"/>{{rp|2382}}<ref name="kisiel2"/> In 1980, Vehar and Davie discovered that APC also inactivates Factor VIII<sub>a</sub>,<ref name="vehar"/> and soon after, [[Protein S]] was recognised as a [[cofactor (biochemistry)|cofactor]] by Walker.<ref name="walker"/> In 1982, a family study by Griffin ''et al''. first associated [[protein&nbsp;C deficiency]] with symptoms of [[venous thrombosis]].<ref name="griffin"/> Homozygous protein&nbsp;C deficiency and the consequent serious health effects were described in 1984 by several scientists.<ref name=goldenberg />{{rp|1214}} cDNA cloning of protein&nbsp;C was first performed in 1984 by Beckmann ''et al.'' which produced a map of the gene responsible for producing protein&nbsp;C in the liver.<ref name="beckmann"/> In 1987 a seminal experiment was performed (Taylor ''et al.'') whereby it was demonstrated that activated protein&nbsp;C prevented [[coagulopathy]] and death in baboons [[route of administration|infused]] with lethal concentrations of ''[[Escherichia coli|E. coli]].''<ref name=mosnier2 />{{rp|2382}}<ref name="taylor"/>

In 1993, a heritable resistance to APC was detected by [[Björn Dahlbäck|Dahlbäck]] ''et al.'' and associated with familial [[thrombophilia]].<ref name="dahlback2"/>  In 1994, the relatively common genetic mutation that produces [[Factor V Leiden|Factor V<sub>Leiden</sub>]] was noted (Bertina ''et al.'').<ref name="bertina"/> Two years later, Gla-domainless APC was imaged at a resolution of 2.8&nbsp;[[Ångström]]s.{{Cref|α}}<ref name=mather /> <!--In 1998, a study was performed mating mice that were heterozygous for a protein&nbsp;C deficiency after the gene was specifically targeted for inactivation. Their offspring exhibited clear signs of the serious symptoms associated with homozygous deficiencies.<ref name=mosnier2 />{{rp|2382}}<ref name="jalbert"/>--> Beginning with the PROWESS [[clinical trial]] of 2001,<ref name="bernard"/> it was recognised that many of the symptoms of [[sepsis]] may be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased.<ref name=mosnier />{{rp|3161,6}} Near the end of that year, [[Drotrecogin alfa (activated)]], a recombinant human activated protein&nbsp;C, became the first drug approved by the U.S. [[Food and Drug Administration|FDA]]  for treating severe [[sepsis]].<ref name="hosac"/> In 2002, ''[[Science (journal)|Science]]'' published an article that first showed protein&nbsp;C activates [[coagulation factor II receptor|protease-activated receptor-1]] (PAR-1) and this process accounts for the protein's modulation of the immune system.<ref name=mosnier2 />{{rp|2382}}<ref name="riewald"/><!--
par-1 2002 (9)

(1) 2003 cytoprotective benefits are PAR-1 and EPCR dependent-->

==Genetics==
The biologic instructions for synthesising protein&nbsp;C in humans are encoded in the gene officially named "protein&nbsp;C (inactivator of coagulation factors Va and VIIIa)". The gene's symbol approved by the [[HUGO Gene Nomenclature Committee]] is "PROC" from "'''pro'''tein '''C'''". It is located on the second [[chromosome]] (2q13-q14) and comprises nine [[exon]]s.<ref name=foster /><ref name=mosnier2 />{{rp|2383}} The nucleotide sequence that codes for human protein&nbsp;C is approximately 11,000&nbsp;bases long.<ref name=foster />{{rp|4675}}<!--restriction map and sequencing strategy for human protein&nbsp;C on page 4674 of foster; map of protein&nbsp;C on 4676-->

==Structure and processing==
Human protein&nbsp;C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting,<ref name=wildhagen /> such as [[thrombin|prothrombin]], [[Factor VII]], [[Factor IX]] and [[Factor X]].<ref name=goldenberg />{{rp|1215}} Protein&nbsp;C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acid [[N-terminus]] [[signal peptide]] preceding a [[propeptide]].<ref name="dursi"/>{{rp|S11}} Protein&nbsp;C is formed when a [[dipeptide]] of Lys<sup>198</sup> and Arg<sup>199</sup> is removed; this causes the transformation into a [[dimer (chemistry)|heterodimer]] with ''N''-linked carbohydrates on each chain. The protein has one light chain ({{val|21|ul=kDa}}) and one heavy chain (41&nbsp;kDa) connected by a [[disulfide bond]] between Cys<sup>183</sup> and Cys<sup>319</sup>.

[[File:Protein C 1D schematic.png|thumb|410px|alt=A tube diagram representing the linear amino acid sequence of the preproprotein C (461 amino acids long) and mature heterodimer (light + heavy chains) highlighting the locations of the signal (1–32), gla (43–88), EGF-1 (97–132), EGF-2 (136–176), activation peptide (200–211), and serine protease (212–450) domains.  The light (43–197) and heavy (212–461) chains of the heterodimer are joined by a line representing a disulfide bond between cysteine residues 183 and 319.|[[Protein domain|Domain]] structure of preproprotein C (top) and the mature heterodimer (bottom).]]

Inactive protein&nbsp;C comprises 419&nbsp;amino acids in multiple [[protein domain|domains]]:<ref name=mosnier2 />{{rp|2383}} one [[Gla domain]] (residues 43–88); a helical [[aromatic amino acids|aromatic]] segment (89–96); two [[EGF-like domain|epidermal growth factor (EGF)-like domains]] (97–132 and 136–176); an activation peptide (200–211); and a [[trypsin]]-like serine protease domain (212–450). The light chain contains the Gla- and EGF-like domains and the aromatic segment. The heavy chain contains the protease domain and the activation petide. It is in this form that 85–90% of protein&nbsp;C circulates in the plasma as a [[zymogen]], waiting to be activated.<ref name=mather />{{rp|6822}} The remaining protein&nbsp;C zymogen comprises slightly modified forms of the protein.<!--<ref name=mosnier2 />{{rp|2383}} detailed description exists there--> Activation of the enzyme occurs when a thrombin molecule cleaves away the activation peptide from the [[N-terminus]] of the heavy chain.<ref name="foster"/>{{rp|4673}}
<ref name="dursi"/>{{rp|S11}} The active site contains a [[catalytic triad]] typical of serine proteases (His<sup>253</sup>, Asp<sup>299</sup> and Ser<sup>402</sup>).<ref name=mosnier2 />{{rp|2833}}

The Gla domain is particularly useful for binding to negatively charged [[phospholipid]]s for anticoagulation and to EPCR for [[cytoprotection]]. One particular [[Exosite (biology)|exosite]] augments protein&nbsp;C's ability to inactivate Factor V<sub>a</sub> efficiently. Another is necessary for interacting with thrombomodulin.<ref name=mosnier2 />{{rp|2833}}

'''Post-translational modifications'''. Human Protein C has at least five types of [[Post-translational modification|post-translational modifications]]: (1) gamma-[[carboxylation]] on the first nine [[glutamic acid]] residues in the protein sequence. This modification event is performed by a vitamin K-dependent microsomal carboxylase. The full complement of Gla is required to give full activity to protein C. (2) beta-[[Hydroxylation]] of Asp71 in one of the two [[EGF-like domain|EGF-like domains]] to give erythro-L-beta-hydroxy-aspartate (bHA). The modification is required for functional activity as was demonstrated by mutating Asp71 to Glu. (3) N-linked [[glycosylation]] at three possible glycosylation sites. Plasma human Protein C has been reported to be 23% carbohydrate by weight. (4) Disulfide formation. (5) Multiple [[Proteolysis|proteolytic cleavages]] of the polypeptide backbone to remove an 18 amino acid [[signal peptide]], a 24 amino acid propeptide and then cleavages at amino acids 155-156 and 157-158 to yield the two-chain structure of the circulating zymogen.<ref>{{cite journal | vauthors = Yan SC, Grinnell BW, Wold F | title = Post-translational modifications of proteins: some problems left to solve | journal = Trends in Biochemical Sciences | volume = 14 | issue = 7 | pages = 264–268 | date = July 1989 | pmid = 2672445 | doi = 10.1016/0968-0004(89)90060-1 }}</ref>

== Physiology ==
The activation of protein&nbsp;C is strongly promoted by [[thrombomodulin]] and [[endothelial protein&nbsp;C receptor]] (EPCR), the latter of which is found primarily on [[endothelial cells]] (cells on the inside of blood vessels). The presence of thrombomodulin accelerates activation by several orders of magnitude,<ref name=nicolaes />{{rp|34}} and EPCR speeds up activation by a factor of 20. If either of these two proteins is absent in [[mouse|murine]] specimens, the mouse dies from excessive blood-clotting while still in an [[embryo]]nic state.<ref name=weiler-guettler />{{rp|1983}}<ref name=gu />{{rp|43335}} On the endothelium, APC performs a major role in regulating blood clotting, inflammation, and cell death ([[apoptosis]]).<ref name=esmon />{{rp|28S}} Because of the accelerating effect of thrombomodulin on the activation of protein&nbsp;C, the protein may be said to be activated not by thrombin but the thrombin–thrombomodulin (or even thrombin–thrombomodulin–EPCR) complex.<ref name="mosnier2"/>{{rp|2381}} Once in active form, APC may or may not remain bound to EPCR, to which it has approximately the same affinity as the protein zymogen.<ref name=mosnier />{{rp|3162}}

Protein&nbsp;C in [[zymogen]] form is present in normal adult human [[blood plasma]] at concentrations between 65 and 135&nbsp;[[international unit|IU]]/[[decilitre|dL]]. Activated protein&nbsp;C is found at levels approximately 2000 times lower than this.<ref name="mosnier"/>{{rp|3161}}  Mild protein&nbsp;C deficiency corresponds to plasma levels above 20&nbsp;IU/dL, but below the normal range. Moderately severe deficiencies describe blood concentrations between 1 and 20 IU/dL; severe deficiencies yield levels of protein&nbsp;C that are below 1&nbsp;IU/dL or are undetectable. Protein&nbsp;C levels in a healthy [[preterm birth|term infant]] average 40&nbsp;IU/dL. The concentration of protein&nbsp;C increases until six months, when the mean level is 60&nbsp;IU/dL; the level stays low through childhood until it reaches adult levels after [[adolescence]].<ref name=goldenberg />{{rp|1216}} The [[half-life]] of activated protein&nbsp;C is around 15&nbsp;minutes.<ref name=mather />{{rp|6823}}<!--
70,000&nbsp;[[mole (unit)|pmol]]/[[litre|L]]; the activated protein&nbsp;C is found at only 40&nbsp;pM/L--><!--(2.3&nbsp;ng/mL)<ref name="mosnier"/>{{rp|3161}}-->

== Pathways ==
The protein&nbsp;C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body.<ref name=nicolaes />{{rp|34}} Protein&nbsp;C is [[pleiotropism|pleiotropic]], with two main classes of functions: anticoagulation and cytoprotection (its direct effect on cells). Which function protein&nbsp;C performs depends on whether or not APC remains bound to EPCR after it is activated; the anticoagulative effects of APC occur when it does not. In this case, protein&nbsp;C functions as an anticoagulant by irreversibly proteolytically inactivating [[Factor V|Factor V<sub>a</sub>]] and [[Factor VIII|Factor VIII<sub>a</sub>]], turning them into Factor V<sub>i</sub> and Factor VIII<sub>i</sub> respectively. When still bound to EPCR, activated protein&nbsp;C performs its cytoprotective effects, acting on the [[effector (biology)|effector]] [[enzyme substrate|substrate]] PAR-1, [[coagulation factor II receptor|protease-activated receptor-1]]. To a degree, APC's anticoagulant properties are independent of its cytoprotective ones, in that expression of one pathway is not affected by the existence of the other.<ref name=mosnier />{{rp|3162}}<ref name="esmon"/>{{rp|26S}}

The activity of protein&nbsp;C may be [[downregulation and upregulation|down-regulated]] by reducing the amount either of available thrombomodulin or of EPCR. This may be done by inflammatory [[cytokine]]s, such as [[IL1B|interleukin-1β]]  (IL-1β ) and [[tumor necrosis factor-alpha|tumor necrosis factor-α]] (TNF-α). Activated leukocytes release these inflammatory mediators during inflammation, inhibiting the creation of both thrombomodulin and EPCR, and inducing their shedding from the endothelial surface. Both of these actions down-regulate protein&nbsp;C activation. Thrombin itself may also have an effect on the levels of EPCR. In addition, proteins released from cells can impede protein&nbsp;C activation, for example [[eosinophil]], which may explain thrombosis in [[hypereosinophilic syndrome|hypereosinophilic]] heart disease.{{Cref|β}} Protein&nbsp;C may be [[downregulation and upregulation|up-regulated]] by [[platelet factor 4]]. This cytokine is conjectured to improve activation of protein&nbsp;C by forming an [[salt bridge (protein and supramolecular)|electrostatic bridge]] from protein&nbsp;C's Gla domain to the [[glycosaminoglycan]] (GAG) domain of thrombomodulin, reducing the [[Michaelis constant]] (K<sub>M</sub>) for their reaction.<ref name=mosnier2 />{{rp|2386}}<ref name=esmon />{{rp|29S}} In addition, Protein&nbsp;C is inhibited by [[protein&nbsp;C inhibitor]].<ref name="espana"/>{{rp|369}}

=== Anticoagulative effects ===
[[Image:Coagulation full.svg|right|thumb|360px|alt=Schematic diagram of the blood coagulation (thrombin; left) and protein C (right) pathways. In the blood coagulation pathway, thrombin acts to convert factor Xi to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin. In addition, thrombin promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet. Thrombin also cross over into the protein C pathway by converting protein C into APC. APC in turn converts factor V into Vi, and VIIIa into VIIIi. Finally APC activates PAR-1 and EPCR. | Blood coagulation and the protein&nbsp;C anticoagulation pathway]]
Protein&nbsp;C is a major component in anticoagulation in the human body. It acts as a [[serine protease]] [[zymogen]]: APC proteolyses peptide bonds in activated [[Factor V]] and [[Factor VIII]] (Factor V<sub>a</sub> and Factor VIII<sub>a</sub>), and one of the amino acids in the bond is [[serine]].<ref name=mosnier2 />{{rp|2381}} These proteins that APC inactivates, Factor V<sub>a</sub> and Factor VIII<sub>a</sub>, are highly procoagulant cofactors in the generation of [[thrombin]], which is a crucial element in blood clotting; together they are part of the [[prothrombinase|prothrombinase complex]].<ref name=esmon />{{rp|26S}} Cofactors in the inactivation of Factor V<sub>a</sub> and Factor VIII<sub>a</sub> include [[protein S]], Factor V, [[high-density lipoprotein]], anionic [[phospholipid]]s and [[glycosphingolipid]]s.<ref name="mosnier"/>{{rp|3161}}
<!--pg. 3166: all about how APC and PAR-1 interact-->

Factor V<sub>a</sub> binds to [[prothrombin]] and Factor X<sub>a</sub>, increasing the rate at which thrombin is produced by four orders of magnitude (10,000x). Inactivation of Factor V<sub>a</sub> thus practically halts the production of thrombin. Factor VIII, on the other hand, is a cofactor in production of activated Factor X, which in turn converts prothrombin into thrombin. Factor VIII<sub>a</sub> augments Factor X activation by a factor of around 200,000. Because of its importance in clotting, Factor VIII is also known as anti-haemophilic factor, and deficiencies of Factor VIII cause [[haemophilia A]].<ref name=mosnier2 />{{rp|2382,3}}

APC inactivates Factor V<sub>a</sub> by making three cleavages (Arg<sup>306</sup>, Arg<sup>506</sup>, Arg<sup>679</sup>). The cleavages at both Arg<sup>306</sup> and Arg<sup>506</sup> diminish the molecule's attraction to Factor X<sub>a</sub>, and though the first of these sites is slow to be cleaved, it is entirely necessary to the functioning of Factor V. Protein S aids this process by catalysing the proteolysis at Arg<sup>306</sup>, in which the A2 domain of Factor V is dissociated from the rest of the protein.<ref name=nicolaes3 /> Protein S also binds to Factor X<sub>a</sub>, inhibiting the latter from diminishing APC's inactivation of Factor V<sub>a</sub>.<ref name=mosnier2 />{{rp|2386}}

The inactivation of Factor VIII<sub>a</sub> is not as well understood. The half-life of Factor VIII<sub>a</sub> is only around two minutes unless Factor IX<sub>a</sub> is present to stabilise it. Some have questioned the significance of APC's inactivation of Factor VIII<sub>a</sub>, and it is unknown to what degree Factor V and protein S are cofactors in its proteolysis. It is known that APC works on Factor VIII<sub>a</sub> by cleaving at two sites, Arg<sup>336</sup> and Arg<sup>562</sup>, either of which is sufficient to disable Factor VIII<sub>a</sub> and convert it to Factor VIII<sub>i</sub>.<ref name=mosnier2 />{{rp|2387}}

=== Cytoprotective effects ===
When APC is bound to EPCR, it performs a number of important cytoprotective (i.e. cell-protecting) functions, most of which are known to require EPCR and PAR-1. These include regulating gene expression, anti-inflammatory effects, antiapoptotic effects and protecting endothelial barrier function.<ref name=mosnier />{{rp|3162}}

Treatment of cells with APC demonstrates that its gene expression modulation effectively controls major pathways for inflammatory and apoptotic behaviour. There are about 20 genes that are up-regulated by protein&nbsp;C, and 20 genes that are down-regulated: the former are generally anti-inflammatory and antiapoptotic pathways, while the latter tend to be proinflammatory and proapoptotic. APC's mechanisms for altering gene expression profiles are not well understood, but it is believed that they at least partly involve an inhibitory effect on [[transcription factor]] activity.<ref name=mosnier />{{rp|3162,4}}<!--complete table exists{{rp|3163}}--> Important proteins that APC up-regulates include [[Bcl-2]], [[Endothelial NOS|eNOS]] and [[Inhibitor of apoptosis|IAP]]. APC effects significant down-regulation of [[p53]] and [[Bax (biochemistry)|Bax]].<ref name=mosnier2 />{{rp|2388}}

APC has anti-inflammatory effects on [[endothelium|endothelial]] cells and [[white blood cell|leukocytes]]. APC affects endothelial cells by inhibiting [[inflammation|inflammatory mediator release]] and down-regulating [[cell adhesion molecule|vascular adhesion molecules]]. This reduces leukocyte adhesion and infiltration into tissues, while also limiting damage to underlying tissue. APC supports endothelial barrier function and reduces [[chemotaxis]]. APC inhibits the release of inflammatory-response mediators in leukocytes as well as endothelial cells, by reducing cytokine response, and maybe diminishing systemic inflammatory response, such as is seen in [[sepsis]]. Studies on both rats and humans have demonstrated that APC reduces [[endotoxin]]-induced pulmonary injury and inflammation.<ref name=mosnier />{{rp|3164}}

Scientists recognise activated protein&nbsp;C's antiapoptotic effects, but are unclear as to the exact mechanisms by which apoptosis is inhibited. It is known that APC is [[neuroprotection|neuroprotective]]. Antiapoptosis is achieved with diminished activation of [[caspase 3]] and [[caspase 8]], improved Bax/Bcl-2 ratio and down-regulation of p53.<ref name=mosnier2 />{{rp|2388}}

Activated protein&nbsp;C also provides much protection of endothelial barrier function. Endothelial barrier breakdown, and the corresponding increase in endothelial permeability, are associated with [[swelling (medical)|swelling]], [[hypotension]] and inflammation, all problems of sepsis. APC protects endothelial barrier function by inducing PAR-1 dependent [[sphingosine kinase 1|sphingosine kinase-1]] activation and up-regulating [[sphingosine-1-phosphate]] with [[sphingosine kinase]].<ref name=mosnier />{{rp|3165}}

Several studies have indicated that the proteolytic activity of APC contributes to the observed cytoprotective properties of APC, but variants that are proteolytically inactive also are able to regulate formation of PAR-activators thrombin and factor Xa and express cytoprotective properties in vitro and in vivo.<ref name=nicolaes2 /><ref name=wildhagen2 />

== Role in disease ==
A genetic [[protein&nbsp;C deficiency]], in its mild form associated with [[Heterozygosity|simple heterozygosity]], causes a significantly increased risk of [[venous thrombosis]] in adults. If a fetus is [[homozygous]] or [[compound heterozygous]] for the deficiency, there may be a presentation of [[purpura fulminans]], severe [[disseminated intravascular coagulation]] and simultaneous [[venous thromboembolism]] in the womb;<ref name="goldenberg"/>{{rp|1214}}  this is very severe and usually fatal.<ref name="Ansell_2008"/>{{rp|211s}} Deletion of the protein&nbsp;C gene in mice causes fetal death around the time of birth. Fetal mice with no protein&nbsp;C develop normally at first, but experience severe bleeding, [[coagulopathy]], deposition of [[fibrin]] and [[necrosis]] of the liver.<ref name=mosnier />{{rp|3161}}

The frequency of protein&nbsp;C deficiency among asymptomatic individuals is between 1 in 200 and 1 in 500. In contrast, significant symptoms of the deficiency are detectable in 1 in 20,000 individuals. No racial nor ethnic biases have been detected.<ref name=goldenberg />{{rp|1215}}

At least 177 disease-causing mutations in this gene have been discovered.<ref name = "Šimčíková_2019 - supplementary table S7">{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | article-number = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4 | bibcode = 2019NatSR...918577S }}</ref> [[Activated protein&nbsp;C resistance]] occurs when APC is unable to perform its functions. This disease has similar symptoms to protein&nbsp;C deficiency. The most common mutation leading to activated protein&nbsp;C resistance among Caucasians is at the cleavage site in Factor V for APC. There, Arg<sup>506</sup> is replaced with Gln, producing [[Factor V Leiden]]. This mutation is also called a R506Q.<ref name=mosnier2 />{{rp|2382}} The mutation leading to the loss of this cleavage site actually stops APC from effectively inactivating both Factor V<sub>a</sub> and Factor VIII<sub>a</sub>. Thus, the person's blood clots too readily, and he is perpetually at an increased risk for thrombosis.<ref name="dahlback"/>{{rp|3}} Individuals heterozygous for the Factor V<sub>Leiden</sub> mutation carry a risk of venous thrombosis 5–7 times higher than in the general population. Homozygous subjects have a risk 80 times higher.<ref name=nicolaes />{{rp|40}} This mutation is also the most common hereditary risk for venous thrombosis among [[Caucasian (race)|Caucasian]]s.<ref name=mosnier2 />{{rp|2382}}

Around 5% of APC resistance are not associated with the above mutation and Factor V<sub>Leiden</sub>. Other genetic mutations cause APC resistance, but none to the extent that Factor V<sub>Leiden</sub> does. These mutations include various other versions of Factor V, spontaneous generation of [[autoantibody|autoantibodies]] targeting Factor V, and dysfunction of any of APC's cofactors.<ref name=mosnier2 />{{rp|2387}} Also, some acquired conditions may reduce the efficacy of APC in performing its anticoagulative functions.<ref name="nicolaes"/>{{rp|33}} Studies suggest that between 20% and 60% of thrombophilic patients suffer from some form of APC resistance.<ref name=nicolaes />{{rp|37}}

[[Warfarin necrosis]] is an acquired protein&nbsp;C deficiency due to treatment with [[warfarin]], which is a vitamin K antagonist and an anticoagulant itself. However, warfarin treatment may produce paradoxical skin lesions similar to those seen in purpura fulminans. A variant of this response presents as venous limb [[gangrene]] when warfarin is used to treat deep vein thrombosis associated with cancer. In these situations, warfarin may be restarted at a low dosage to ensure that the protein&nbsp;C deficiency does not present before the vitamin K coagulation factors II, IX and X are suppressed.<ref name="Ansell_2008"/>{{rp|211s}}

Activated protein C cleaves ''[[Plasmodium falciparum]]'' [[histone]]s which are released during infection: cleavage of these histones eliminates their pro inflammatory effects.<ref name=Gillrie2012>{{cite journal | vauthors = Gillrie MR, Lee K, Gowda DC, Davis SP, Monestier M, Cui L, Hien TT, Day NP, Ho M | title = Plasmodium falciparum histones induce endothelial proinflammatory response and barrier dysfunction | journal = The American Journal of Pathology | volume = 180 | issue = 3 | pages = 1028–1039 | date = March 2012 | pmid = 22260922 | pmc = 3448071 | doi = 10.1016/j.ajpath.2011.11.037 }}</ref>

== Role in medicine ==
{{see also|drotrecogin alfa}}

In November 2001, the [[Food and Drug Administration]] approved [[Drotrecogin alfa|Drotrecogin alfa-activated]] (DrotAA) for the clinical treatment of adults suffering from severe sepsis and with a high risk of death.<ref name="abraham"/>{{rp|1332}} Drotrecogin alfa-activated is a [[recombinant DNA|recombinant]] form of human activated protein&nbsp;C (rhAPC). It is marketed as Xigris by [[Eli Lilly and Company]],<ref name=hosac />{{rp|224}}

Drotrecogin alfa-activated was the subject of significant controversy while it was approved for clinical use as it was found to increase bleeding and not to reduce mortality.<ref name="apc">{{cite journal | vauthors = Martí-Carvajal AJ, Solà I, Lathyris D, Cardona AF | title = Human recombinant activated protein C for severe sepsis | journal = The Cochrane Database of Systematic Reviews | issue = 3 | article-number = CD004388 | date = March 2012 | pmid = 22419295 | doi = 10.1002/14651858.CD004388.pub5 | veditors = Martí-Carvajal AJ }}</ref>{{Update inline|reason=Updated version https://www.ncbi.nlm.nih.gov/pubmed/23235609|date = October 2024}} In October 2011 rhAPC (Xigris) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.<ref name="Kylat"/><ref name="apc" />

APC has been studied as way of treating [[lung]] injury, after studies showed that in patients with lung injury, reduced APC levels in specific parts of the lungs correlated with worse outcomes.<ref name=mosnier />{{rp|3167,8}} APC also has been considered for use in improving patient outcome in cases of [[ischemic stroke]], a medical emergency in which arterial blockage deprives a region of brain of oxygen, causing tissue death. Promising studies suggest that APC could be coupled with the only currently approved treatment, [[tissue plasminogen activator]] (tPA), to protect the brain from tPA's very harmful [[side effect]]s, in addition to preventing cell death from lack of oxygen ([[hypoxia (medical)|hypoxia]]).<ref name="griffin_2006"/>{{rp|211}} Clinical use of APC has also been proposed for improving the outcome of [[islet cell transplantation|pancreatic islet transplantation]] in treating [[type I diabetes]].<ref name=mosnier2 />{{rp|2392}}

Ceprotin was approved for medical used in the European Union in July 2001.<ref name="Ceprotin EPAR">{{cite web | title=Ceprotin EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ceprotin | access-date=29 November 2020}}</ref> Ceprotin is indicated in purpura fulminans and coumarin-induced skin necrosis in people with severe congenital protein C deficiency.<ref name="Ceprotin EPAR" />

== See also ==
* [[Activated protein C–protein C inhibitor]]

== Notes ==
* {{Cnote|α|GLA-domainless protein&nbsp;C is produced by selective proteolysis between residues 82 and 83 to remove the [[N-terminal]] portion of the protein that includes essentially all of the [[GLA domain]] (residues 47–88). The N-terminus was removed in order to make crystallization of the protein easier.<ref name=esmon2 />{{rp|5548}}}}
* {{Cnote|β|In hypereosinophilia, excess eosinophil-specific granule proteins (such as [[major basic protein]], [[erythropoietin]] and [[eosinophil cationic protein]]) on the endothelial surface bind to thrombomodulin and inhibit its participation in the activation of protein&nbsp;C by electrostatic interaction on the surface of thrombomodulin.<ref name=slungaard />{{rp|1728}}}}

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}}

== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.218 S01.218] {{Webarchive|url=https://web.archive.org/web/20070916202727/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.218 |date=2007-09-16 }}
* {{PDBe-KB2|P04070|Vitamin K-dependent protein C}}

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[[Category:Coagulation system]]
[[Category:Peripheral membrane proteins]]
[[Category:EC 3.4.21]]
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