Protein C deficiency: Difference between revisions
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==Historical Perspective== | ==Historical Perspective== | ||
* Protein C deficiency was first discovered by Stenflo, a Swedish chemist, in 1976.<ref name=" | * Protein C deficiency was first discovered by Stenflo, a Swedish chemist, in 1976.<ref name="pmid19141162">{{cite journal |vauthors=Goldenberg NA, Manco-Johnson MJ |title=Protein C deficiency |journal=Haemophilia |volume=14 |issue=6 |pages=1214–21 |date=November 2008 |pmid=19141162 |doi=10.1111/j.1365-2516.2008.01838.x |url=}}</ref> | ||
* In 1982, Bertina was the first to discover the association between thrombosis and protein C deficiency.<ref name="pmid6897135">{{cite journal |vauthors=Bertina RM, Broekmans AW, van der Linden IK, Mertens K |title=Protein C deficiency in a Dutch family with thrombotic disease |journal=Thromb. Haemost. |volume=48 |issue=1 |pages=1–5 |date=August 1982 |pmid=6897135 |doi= |url=}}</ref> | * In 1982, Bertina was the first to discover the association between thrombosis and protein C deficiency.<ref name="pmid6897135">{{cite journal |vauthors=Bertina RM, Broekmans AW, van der Linden IK, Mertens K |title=Protein C deficiency in a Dutch family with thrombotic disease |journal=Thromb. Haemost. |volume=48 |issue=1 |pages=1–5 |date=August 1982 |pmid=6897135 |doi= |url=}}</ref> | ||
* The association between thrombosis and protein C deficiency was again confirmed in 1993 by Dahlbäck et al and 1994 by Bertina et al 1994.<ref name="pmid8430067">{{cite journal |vauthors=Dahlbäck B, Carlsson M, Svensson PJ |title=Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=3 |pages=1004–8 |date=February 1993 |pmid=8430067 |pmc=45799 |doi= |url=}}</ref> | * The association between thrombosis and protein C deficiency was again confirmed in 1993 by Dahlbäck et al and 1994 by Bertina et al 1994.<ref name="pmid8430067">{{cite journal |vauthors=Dahlbäck B, Carlsson M, Svensson PJ |title=Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=3 |pages=1004–8 |date=February 1993 |pmid=8430067 |pmc=45799 |doi= |url=}}</ref> | ||
==Classification== | ==Classification== | ||
Protein C deficiency may be classified according to etiology | Protein C deficiency may be classified according to etiology:<ref name="pmid8208728">{{cite journal |vauthors=Greengard JS, Fisher CL, Villoutreix B, Griffin JH |title=Structural basis for type I and type II deficiencies of antithrombotic plasma protein C: patterns revealed by three-dimensional molecular modelling of mutations of the protease domain |journal=Proteins |volume=18 |issue=4 |pages=367–80 |date=April 1994 |pmid=8208728 |doi=10.1002/prot.340180407 |url=}}</ref> | ||
* Congential protein C deficiency:<ref name="pmid9198177">{{cite journal |vauthors=Reitsma PH |title=Protein C deficiency: from gene defects to disease |journal=Thromb. Haemost. |volume=78 |issue=1 |pages=344–50 |date=July 1997 |pmid=9198177 |doi= |url=}}</ref> | |||
* | **[[Heterozygous]] protein deficiency<ref name="pmid2521802">{{cite journal |vauthors=Bovill EG, Bauer KA, Dickerman JD, Callas P, West B |title=The clinical spectrum of heterozygous protein C deficiency in a large New England kindred |journal=Blood |volume=73 |issue=3 |pages=712–7 |date=February 1989 |pmid=2521802 |doi= |url=}}</ref> | ||
***Type I disease: Generally mild form. It has decreased levels of [[protein C]]. | |||
** | ***Type II disease: It has normal or near normal levels of [[protein C]] but reduced functional activity. | ||
**[[Homozygous]] protein C deficiency: It is severe form of disease. It presents with neonatal purpura fulminans.<ref name=" | **[[Homozygous]] protein C deficiency: It is severe form of disease. It presents with neonatal purpura fulminans.<ref name="pmid7556318">{{cite journal |vauthors=Baliga V, Thwaites R, Tillyer ML, Minford A, Parapia L, Allgrove J |title=Homozygous protein C deficiency--management with protein C concentrate |journal=Eur. J. Pediatr. |volume=154 |issue=7 |pages=534–8 |date=July 1995 |pmid=7556318 |doi= |url=}}</ref> | ||
* Acquired protein C deficiency | **Acquired protein C deficiency. | ||
==Pathophysiology== | ==Pathophysiology== | ||
* The protein C is a vitamin K dependent [[glycoprotein]], 62 kD, synthesized in the liver.<ref name=" | * The [[protein C]] is a [[vitamin K]] dependent [[glycoprotein]], 62 kD, synthesized in the [[liver]].<ref name="pmid2991859">{{cite journal |vauthors=Beckmann RJ, Schmidt RJ, Santerre RF, Plutzky J, Crabtree GR, Long GL |title=The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs |journal=Nucleic Acids Res. |volume=13 |issue=14 |pages=5233–47 |date=July 1985 |pmid=2991859 |pmc=321861 |doi= |url=}}</ref> | ||
* It circulates as [[zymogen]] and is activated to activated protein C (APC) | * It circulates as [[zymogen]] and is activated to activated protein C (APC). | ||
* Synthesis of gamma-carboxylic acid on protein C requires [[vitamin K]]. The [[Gla domain|Gla]] domains bind to calcium leading to structural change that facilitates [[phospholipid]] binding which is important for protein function. | * Synthesis of gamma-carboxylic acid on [[protein C]] requires [[vitamin K]]. The [[Gla domain|Gla]] domains bind to [[calcium]] leading to structural change that facilitates [[phospholipid]] binding which is important for protein function.<ref name="pmid2538457">{{cite journal |vauthors=Esmon CT |title=The roles of protein C and thrombomodulin in the regulation of blood coagulation |journal=J. Biol. Chem. |volume=264 |issue=9 |pages=4743–6 |date=March 1989 |pmid=2538457 |doi= |url=}}</ref> | ||
* Activated [[protein C]] is catalyzed by thrombine-thrombmomdulin complex when it is binds to [[endothelial]] [[proteoglycan]]. | |||
[[Protein C]] after its activation has following functions:<ref name="pmid2975409" /> | |||
* The primary role of protein C is to inactivate [[Factor V|factor Va]] and [[factor VIII]]<nowiki/>a, both of these factors are essential for activation of [[thrombin]] and [[factor Xa]] which forms clots. The inhibitory effect of factor [[protein C]] is enhanced by [[protein S]]. Both perform similar functions. | * The primary role of protein C is to inactivate [[Factor V|factor Va]] and [[factor VIII]]<nowiki/>a, both of these factors are essential for activation of [[thrombin]] and [[factor Xa]] which forms clots. | ||
* Activated [[protein C]] indirectly increases the profibrinolytic activity by<nowiki/> activating to [[tissue plasminogen activator]] (tPA) after binding to [[plasminogen activator inhibitor]] (PAI). The reduced [[thrombin]] generation thus decreases the activation of TAFI (thrombin activatable fibrinolysis inhibitor) hence resulting in enhanced profibrinolytic potential | * When protein C is deficient or inactive it leads to uncontrolled clot f<nowiki/>ormation. | ||
* The inhibitory effect of factor [[protein C]] is enhanced by [[protein S]]. Both<nowiki/> perform similar functions. | |||
* The deficiency of protein C creates procoagulant effect generally in areas with slow moving venous blood flow, such as extremities leading to [[thrombosis]] which | * Activated [[protein C]] indirectly increases the profibrinolytic activity by<nowiki/> activating to [[tissue plasminogen activator]] (tPA) after binding to [[plasminogen activator inhibitor]] (PAI). The reduced [[thrombin]] generation thus decreases the activation of TAFI (thrombin activatable fibrinolysis inhibitor) hence resulting in enhanced profibrinolytic potential.<ref name="pmid2975409">{{cite journal |vauthors=de Fouw NJ, de Jong YF, Haverkate F, Bertina RM |title=Activated protein C increases fibrin clot lysis by neutralization of plasminogen activator inhibitor--no evidence for a cofactor role of protein S |journal=Thromb. Haemost. |volume=60 |issue=2 |pages=328–33 |date=October 1988 |pmid=2975409 |doi= |url=}}</ref> | ||
* The other role of [[protein C]] is its anti inflammatory effect. The reactions are mediated by epithelial protein cell receptors (EPCR) and protease activated receptor 1 (PAR -1) that play primary role in cytoprotective, anti [[inflammatory]] effects and [[Barrier to autointegration factor 1|barrier]] stabilizing effects.<ref name="pmid12004250">{{cite journal |vauthors=Joyce DE, Grinnell BW |title=Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB |journal=Crit. Care Med. |volume=30 |issue=5 Suppl |pages=S288–93 |date=May 2002 |pmid=12004250 |doi= |url=}}</ref> | |||
* The deficiency of protein C creates procoagulant effect generally in areas with slow moving [[venous blood]] flow, such as [[extremities]] leading to [[thrombosis]] which manifest as [[deep venous thrombosis]]. | |||
==Causes== | ==Causes== | ||
* The cause of protein C deficiency is PROC miss sense or [[Nonsense mutation|nonsense]] [[mutation]] gene mutation of [[chromosome]] 2 at 14q3.<ref name="pmid7482420">{{cite journal |vauthors=Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR |title=Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH |journal=Thromb. Haemost. |volume=73 |issue=5 |pages=876–89 |date=May 1995 |pmid=7482420 | * The cause of [[protein C]] deficiency is PROC miss sense or [[Nonsense mutation|nonsense]] [[mutation]] [[Mutation|gene mutation]] of [[chromosome]] 2 at 14q3.<ref name="pmid7482420">{{cite journal |vauthors=Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR |title=Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH |journal=Thromb. Haemost. |volume=73 |issue=5 |pages=876–89 |date=May 1995 |pmid=7482420 |doi= |url=}}</ref> | ||
* Other types of mutations have also been described, including [[promoter]] mutations, [[Splice site mutation|splice site]] abnormalities, in-frame deletions, [[Frameshift mutation|frameshift]] deletions, in-frame insertions, and [[Frameshift mutation|frameshift]] insertions.<ref name="pmid1868249">{{cite journal |vauthors=Reitsma PH, Poort SR, Allaart CF, Briët E, Bertina RM |title=The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects |journal=Blood |volume=78 |issue=4 |pages=890–4 |date=August 1991 |pmid=1868249 |doi= |url=}}</ref> | * Other types of mutations have also been described, including [[promoter]] mutations, [[Splice site mutation|splice site]] abnormalities, in-frame deletions, [[Frameshift mutation|frameshift]] deletions, in-frame insertions, and [[Frameshift mutation|frameshift]] insertions.<ref name="pmid1868249">{{cite journal |vauthors=Reitsma PH, Poort SR, Allaart CF, Briët E, Bertina RM |title=The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects |journal=Blood |volume=78 |issue=4 |pages=890–4 |date=August 1991 |pmid=1868249 |doi= |url=}}</ref> | ||
* Protein C consumption: | * Protein C consumption: | ||
**[[Disseminated intravascular coagulation]] | **[[Disseminated intravascular coagulation]]<ref name="pmid15726661">{{cite journal |vauthors=Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P |title=Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests |journal=Hepatology |volume=41 |issue=3 |pages=553–8 |date=March 2005 |pmid=15726661 |doi=10.1002/hep.20569 |url=}}</ref> | ||
**[[Surgery]] | **[[Surgery]] | ||
**Decreased synthesis of protein C in [[liver disease]]<ref name="pmid15726661">{{cite journal |vauthors=Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P |title=Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests |journal=Hepatology |volume=41 |issue=3 |pages=553–8 |date=March 2005 |pmid=15726661 |doi=10.1002/hep.20569 |url=}}</ref> | **Decreased synthesis of protein C in [[liver disease]]<ref name="pmid15726661">{{cite journal |vauthors=Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P |title=Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests |journal=Hepatology |volume=41 |issue=3 |pages=553–8 |date=March 2005 |pmid=15726661 |doi=10.1002/hep.20569 |url=}}</ref> | ||
**[[Vitamin K deficiency]] | **[[Vitamin K deficiency]] | ||
**[[Nephrotic syndrome]]<ref name=" | **[[Nephrotic syndrome]]<ref name="pmid3906225">{{cite journal |vauthors=Llach F |title=Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome |journal=Kidney Int. |volume=28 |issue=3 |pages=429–39 |date=September 1985 |pmid=3906225 |doi= |url=}}</ref> | ||
**[[Infection]]<ref name="pmid9393338">{{cite journal |vauthors=Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, Casey W |title=Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans |journal=Lancet |volume=350 |issue=9091 |pages=1590–3 |date=November 1997 |pmid=9393338 |doi= |url=}}</ref> | **[[Infection]]<ref name="pmid9393338">{{cite journal |vauthors=Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, Casey W |title=Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans |journal=Lancet |volume=350 |issue=9091 |pages=1590–3 |date=November 1997 |pmid=9393338 |doi= |url=}}</ref> | ||
**[[Autoantibodies]]<ref name="pmid3683503">{{cite journal |vauthors=Mitchell CA, Rowell JA, Hau L, Young JP, Salem HH |title=A fatal thrombotic disorder associated with an acquired inhibitor of protein C |journal=N. Engl. J. Med. |volume=317 |issue=26 |pages=1638–42 |date=December 1987 |pmid=3683503 |doi=10.1056/NEJM198712243172606 |url=}}</ref> | **[[Autoantibodies]]<ref name="pmid3683503">{{cite journal |vauthors=Mitchell CA, Rowell JA, Hau L, Young JP, Salem HH |title=A fatal thrombotic disorder associated with an acquired inhibitor of protein C |journal=N. Engl. J. Med. |volume=317 |issue=26 |pages=1638–42 |date=December 1987 |pmid=3683503 |doi=10.1056/NEJM198712243172606 |url=}}</ref> | ||
**[[Cancer]]<ref name="pmid3683503">{{cite journal |vauthors=Mitchell CA, Rowell JA, Hau L, Young JP, Salem HH |title=A fatal thrombotic disorder associated with an acquired inhibitor of protein C |journal=N. Engl. J. Med. |volume=317 |issue=26 |pages=1638–42 |date=December 1987 |pmid=3683503 |doi=10.1056/NEJM198712243172606 |url=}}</ref> | |||
==Differentiating Protein C deficiency from Other Diseases== | ==Differentiating Protein C deficiency from Other Diseases== | ||
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==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
*The incidence of | *The [[incidence]] of [[protein C]] deficiency is approximately 142 per 100,000 individuals, worldwide.<ref name="pmid3657866">{{cite journal |vauthors=Miletich J, Sherman L, Broze G |title=Absence of thrombosis in subjects with heterozygous protein C deficiency |journal=N. Engl. J. Med. |volume=317 |issue=16 |pages=991–6 |date=October 1987 |pmid=3657866 |doi=10.1056/NEJM198710153171604 |url=}}</ref> | ||
*The prevalence of | *The [[prevalence]] of [[protein C]] deficiency was estimated to be 145 per 100,000 annually.<ref name="pmid3657866" /> | ||
===Age=== | ===Age=== | ||
*The median age of a first episode is typically in third to fourth decade with family history; while, individuals without a family history tend develop first episode in their fourth to fifth decade.<ref name=" | *The median age of a first episode is typically in third to fourth decade with family history; while, individuals without a family history tend to develop first episode in their fourth to fifth decade.<ref name="pmid9607123">{{cite journal |vauthors=Mustafa S, Mannhalter C, Rintelen C, Kyrle PA, Knöbl P, Lechner K, Pabinger I |title=Clinical features of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden |journal=Blood Coagul. Fibrinolysis |volume=9 |issue=1 |pages=85–9 |date=January 1998 |pmid=9607123 |doi= |url=}}</ref> | ||
==Risk Factors== | ==Risk Factors== | ||
* The most potent risk factor in the development of protein C deficiency is consanguineous marriage.<ref name="pmid27081530">{{cite journal |vauthors=Tairaku S, Taniguchi-Ikeda M, Okazaki Y, Noguchi Y, Nakamachi Y, Mori T, Kubokawa I, Hayakawa A, Shibata A, Emoto T, Kurahashi H, Toda T, Kawano S, Yamada H, Morioka I, Iijima K |title=Prenatal genetic testing for familial severe congenital protein C deficiency |journal=Hum Genome Var |volume=2 |issue= |pages=15017 |date=2015 |pmid=27081530 |pmc=4785544 |doi=10.1038/hgv.2015.17 |url=}}</ref | * The most potent risk factor in the development of [[protein C]] deficiency is [[consanguineous]] marriage.<ref name="pmid7482420">{{cite journal |vauthors=Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR |title=Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH |journal=Thromb. Haemost. |volume=73 |issue=5 |pages=876–89 |date=May 1995 |pmid=7482420 |doi= |url=}}</ref> | ||
* [[Hereditary]] variant is associated with [[Mutations|mutation]] in PROC gene, which is transmitted in an [[autosomal dominant]] pattern.<ref name="pmid27081530">{{cite journal |vauthors=Tairaku S, Taniguchi-Ikeda M, Okazaki Y, Noguchi Y, Nakamachi Y, Mori T, Kubokawa I, Hayakawa A, Shibata A, Emoto T, Kurahashi H, Toda T, Kawano S, Yamada H, Morioka I, Iijima K |title=Prenatal genetic testing for familial severe congenital protein C deficiency |journal=Hum Genome Var |volume=2 |issue= |pages=15017 |date=2015 |pmid=27081530 |pmc=4785544 |doi=10.1038/hgv.2015.17 |url=}}</ref> | |||
==Screening== | ==Screening== | ||
* There is insufficient evidence to recommend routine screening for protein C deficiency, however in patients with positive family history, it is recommended to check protein C activity (functional) assay which is either clotting time based or chromogenic.<ref name=" | * There is insufficient evidence to recommend routine screening for protein C deficiency, however in patients with positive family history, it is recommended to check [[protein C]] activity (functional) assay which is either clotting time based or chromogenic.<ref name="pmid2521802">{{cite journal |vauthors=Bovill EG, Bauer KA, Dickerman JD, Callas P, West B |title=The clinical spectrum of heterozygous protein C deficiency in a large New England kindred |journal=Blood |volume=73 |issue=3 |pages=712–7 |date=February 1989 |pmid=2521802 |doi= |url=}}</ref> | ||
==Natural History, Complications, and Prognosis== | ==Natural History, Complications, and Prognosis== | ||
* If left untreated, the patients of protein C deficiency manifest as unprovoked episodes of [[venous thromboembolism]].<ref name=" | * If left untreated, the patients of protein C deficiency manifest as unprovoked episodes of [[venous thromboembolism]].<ref name="pmid98420422">{{cite journal |vauthors=Massicotte MP, Dix D, Monagle P, Adams M, Andrew M |title=Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications |journal=J. Pediatr. |volume=133 |issue=6 |pages=770–6 |date=December 1998 |pmid=9842042 |doi= |url=}}</ref> | ||
* The probability of manifestation of disease is enhanced in presence of the precipitating factors such as [[immobility]], prolonged use of [[oral contraceptives]], and pelvic surgery. | * The probability of manifestation of disease is enhanced in presence of the precipitating factors such as [[immobility]], prolonged use of [[oral contraceptives]], and pelvic surgery.<ref name="pmid9842042">{{cite journal |vauthors=Massicotte MP, Dix D, Monagle P, Adams M, Andrew M |title=Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications |journal=J. Pediatr. |volume=133 |issue=6 |pages=770–6 |date=December 1998 |pmid=9842042 |doi= |url=}}</ref> | ||
==== Common complications of protein C deficiency include: ==== | |||
**[[Deep vein thrombosis|Deep venous thrombosis]]<ref name=" | **[[Deep vein thrombosis|Deep venous thrombosis]]<ref name="pmid6688122">{{cite journal |vauthors=Broekmans AW, Veltkamp JJ, Bertina RM |title=Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families |journal=N. Engl. J. Med. |volume=309 |issue=6 |pages=340–4 |date=August 1983 |pmid=6688122 |doi=10.1056/NEJM198308113090604 |url=}}</ref> | ||
**Warfarin-induced skin necrosis<ref name=" | **[[Warfarin]]-induced skin necrosis<ref name="pmid6547283">{{cite journal |vauthors=McGehee WG, Klotz TA, Epstein DJ, Rapaport SI |title=Coumarin necrosis associated with hereditary protein C deficiency |journal=Ann. Intern. Med. |volume=101 |issue=1 |pages=59–60 |date=July 1984 |pmid=6547283 |doi= |url=}}</ref> | ||
**Neonatal purpura fulminans | **Neonatal purpura fulminans<ref name="pmid21839696">{{cite journal |vauthors=Price VE, Ledingham DL, Krümpel A, Chan AK |title=Diagnosis and management of neonatal purpura fulminans |journal=Semin Fetal Neonatal Med |volume=16 |issue=6 |pages=318–22 |date=December 2011 |pmid=21839696 |doi=10.1016/j.siny.2011.07.009 |url=}}</ref> | ||
**P[[Pulmonary embolism|ulmonary embolism]] and thrombosis in unusual sites such as [[cerebral]], [[mesenteric]], [[splenic]] and [[hepatic veins]].<ref name="pmid2164313">{{cite journal |vauthors=Wysokinski W, Verhaeghe R, Arnout J, Vermylen J |title=Protein C deficiency associated with venous thromboembolism |journal=Acta Clin Belg |volume=45 |issue=2 |pages=78–84 |date=1990 |pmid=2164313 |doi= |url=}}</ref> | |||
* | |||
* Prognosis is generally good with [[anticoagulation|anticogulation]] therapy survival rate of patients with protein C deficiency is improved. | ==== Less common complications include: ==== | ||
*Impaired [[fetal]] growth and [[miscarriage]] has also been reported with [[homozygous]] protein C deficiency.<ref name="pmid8843809">{{cite journal |vauthors=Preston FE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ |title=Increased fetal loss in women with heritable thrombophilia |journal=Lancet |volume=348 |issue=9032 |pages=913–6 |date=October 1996 |pmid=8843809 |doi= |url=}}</ref> | |||
*Neonatal purpura fulminans is observed with [[homozygous]] variant of [[protein C]] deficiency.<ref name="pmid21839696" /> | |||
*Severe complications such as [[arterial thrombosis]] is seen resulting in [[ischemic stroke]] in young patient with [[heterozygous]] protein C deficiency.<ref name="pmid9724011">{{cite journal |vauthors=Douay X, Lucas C, Caron C, Goudemand J, Leys D |title=Antithrombin, protein C and protein S levels in 127 consecutive young adults with ischemic stroke |journal=Acta Neurol. Scand. |volume=98 |issue=2 |pages=124–7 |date=August 1998 |pmid=9724011 |doi= |url=}}</ref> | |||
==== Prognosis ==== | |||
* Prognosis of [[protein C]] deficiency is generally good with [[anticoagulation|anticogulation]] therapy survival rate of patients with [[protein C]] deficiency is improved. | |||
==Diagnosis== | ==Diagnosis== | ||
===Diagnostic Study of Choice=== | ===Diagnostic Study of Choice=== | ||
Following are the two tests that are performed to reach the absolute diagnosis:<ref name=" | Following are the two tests that are performed to reach the absolute diagnosis:<ref name="pmid3511097">{{cite journal |vauthors=Vigano D'Angelo S, Comp PC, Esmon CT, D'Angelo A |title=Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states |journal=J. Clin. Invest. |volume=77 |issue=2 |pages=416–25 |date=February 1986 |pmid=3511097 |pmc=423361 |doi=10.1172/JCI112319 |url=}}</ref> | ||
* Functional assays such as [[aPTT]] based assay, [[factor Xa]] based (enzymatic assay that uses a [[chromogenic]] [[substrate]] to check the amidolytic cleavage of a synthetic [[protein]] ([[Snake venoms|snake venom]]) are used to determine function of protein C.<ref name="pmid6547008">{{cite journal |vauthors=Bertina RM, Broekmans AW, Krommenhoek-van Es C, van Wijngaarden A |title=The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency |journal=Thromb. Haemost. |volume=51 |issue=1 |pages=1–5 |date=February 1984 |pmid=6547008 |doi= |url=}}</ref> | |||
*[[Antigenic]] determination of [[protein C]] levels. This can detect low levels of [[protein C]] as well as the [[anticoagulant]] effects. | *[[Antigenic]] determination of [[protein C]] levels. This can detect low levels of [[protein C]] as well as the [[anticoagulant]] effects. | ||
*Clotting based assays ([[aPTT]] and [[Factor X|factor Xa]]) may be used; however, the results may be affected [[heparin]] and other anticoagulants. Hence chromogenic assays are preferred. The only exception is when the patient is using [[vitamin K antagonists]] which lowers the activity of [[protein C]] activity in any assay. | *Clotting based assays ([[aPTT]] and [[Factor X|factor Xa]]) may be used; however, the results may be affected [[heparin]] and other [[anticoagulants]]. Hence chromogenic assays are preferred. The only exception is when the patient is using [[vitamin K antagonists]] which lowers the activity of [[protein C]] activity in any assay.<ref name="pmid6317087">{{cite journal |vauthors=Comp PC, Nixon RR, Esmon CT |title=Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex |journal=Blood |volume=63 |issue=1 |pages=15–21 |date=January 1984 |pmid=6317087 |doi= |url=}}</ref> | ||
*If functional assays do not reveal the reduced function of protein C especially when clinical suspicion is high, alternative methods should be considered. | *If functional assays do not reveal the reduced function of [[protein C]] especially when clinical suspicion is high, alternative methods should be considered. | ||
*Some people have normal levels of [[protein C]] with reduced or near normal anticoagulant function, but normal or near normal amidolytic activity, this indicates reduced ability of [[protein C]] to interact with substrate such as [[factor V]], [[Platelet membrane glycoprotein|platelet membrane]] and [[factor VIII]]. | *Some people have normal levels of [[protein C]] with reduced or near normal anticoagulant function, but normal or near normal amidolytic activity, this indicates reduced ability of [[protein C]] to interact with substrate such as [[factor V]], [[Platelet membrane glycoprotein|platelet membrane]] and [[factor VIII]]. | ||
===History and Symptoms=== | ===History and Symptoms=== | ||
* The majority of patients with protein C deficiency are asymptomatic. | * The majority of patients with protein C deficiency are asymptomatic. | ||
* <nowiki/>The probability of developing venous [[thromboembolism]] is especially increased in patients with [[protein C]] defici<nowiki/>ency in the presence of risk factors such as, [[factor V Leiden mutation]], prolonged [[immobility]], [[surgery]], and prolonged use of [[oral contraceptives]].<ref name="pmid177266842">{{cite journal |vauthors=Pomp ER, Rosendaal FR, Doggen CJ |title=Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use |journal=Am. J. Hematol. |volume=83 |issue=2 |pages=97–102 |date=February 2008 |pmid=17726684 |doi=10.1002/ajh.21059 |url=}}</ref> | |||
* <nowiki/>The probability of developing venous [[thromboembolism]] is especially increased in patients with protein C defici<nowiki/>ency in the presence of risk factors such as, [[factor V Leiden mutation]], prolonged [[immobility]], [[surgery]], and prolonged use of [[oral contraceptives]]. | * Initial episode of [[venous thromboembolism]] is spontaneous in 2/3rd of cases, however, it tends to be [[Recurrent DVT|recurrent]]. | ||
* Initial episode of [[venous thromboembolism]] is spontaneous in 2/3rd of cases, however, it tends to be [[Recurrent DVT|recurrent]]. In deep venous thrombosis, a clot is formed in [[Deep vein|deep veins]] of leg with potential to ascend upwards to [[right heart]] and [[pulmonary arteries]], if dislodged may manifest as [[pulmonary embolism]]. | * In deep venous thrombosis, a clot is formed in [[Deep vein|deep veins]] of leg with potential to ascend upwards to [[right heart]] and [[pulmonary arteries]], if dislodged may manifest as [[pulmonary embolism]]. | ||
* The patients with acquired disease tend to develop [[skin changes]] after the use of [[anticoagulants]] such as warfarin.<ref name="pmid6547283" /> | |||
* For symptoms of [[deep venous thrombosis]] '''[[Deep vein thrombosis|click here]].''' | |||
* For symptoms of [[pulmonary embolism]] [[Pulmonary embolism|'''click here''']]. | |||
* Other symptoms include following: | * Other symptoms include following: | ||
** [[Purpura]] and [[skin changes]] | ** [[Purpura]] and [[skin changes]]<ref name="pmid6688122">{{cite journal |vauthors=Broekmans AW, Veltkamp JJ, Bertina RM |title=Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families |journal=N. Engl. J. Med. |volume=309 |issue=6 |pages=340–4 |date=August 1983 |pmid=6688122 |doi=10.1056/NEJM198308113090604 |url=}}</ref> | ||
** Abnormal [[pigmentation]] | ** Abnormal [[pigmentation]] | ||
** [[Neurologic disease|Neurologic]] abnormalities<ref name="pmid8843809">{{cite journal |vauthors=Preston FE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ |title=Increased fetal loss in women with heritable thrombophilia |journal=Lancet |volume=348 |issue=9032 |pages=913–6 |date=October 1996 |pmid=8843809 |doi= |url=}}</ref> | |||
** [[Thrombophlebitis|Superficial thrombophlebitis]] | |||
** [[Neurologic disease|Neurologic]] abnormalities | |||
** [[ | |||
===Physical Examination=== | ===Physical Examination=== | ||
* | * For physical signs related to [[Deep vein thrombosis|deep venous thrombosis]] '''[[Deep vein thrombosis|click here]].''' | ||
* | * For physical signs related to [[pulmonary embolism]] '''[[Pulmonary embolism|click here]].''' | ||
* | * [[Warfarin]]-induced necrosis can present with [[erythematous]] [[macules]] which begins on the [[torso]] and extremities which can become [[Purpura|purpuric]] and [[necrotic]].<ref name="pmid6547283" /> | ||
* [[Homozygous]] cases may present with more severe disease such as neonatal [[purpura]] fulminans which is seen as diffuse [[Ecchymoses|ecchymoses,]] if left untreated it can progress to [[necrotic]] [[bullae]].<ref name="pmid6546411">{{cite journal |vauthors=Seligsohn U, Berger A, Abend M, Rubin L, Attias D, Zivelin A, Rapaport SI |title=Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn |journal=N. Engl. J. Med. |volume=310 |issue=9 |pages=559–62 |date=March 1984 |pmid=6546411 |doi=10.1056/NEJM198403013100904 |url=}}</ref> | |||
===Laboratory Findings=== | ===Laboratory Findings=== | ||
* The diagnosis of protein C deficiency is based on the clinical presentation in addition to strong familial history. | * The diagnosis of [[protein C]] deficiency is based on the clinical presentation in addition to strong [[familial]] history. | ||
* Various tests are conducted to document protein C deficiency in addition to baseline clotting profile including: | * Various tests are conducted to document [[protein C]] deficiency in addition to baseline clotting profile including:<ref name="pmid3511097">{{cite journal |vauthors=Vigano D'Angelo S, Comp PC, Esmon CT, D'Angelo A |title=Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states |journal=J. Clin. Invest. |volume=77 |issue=2 |pages=416–25 |date=February 1986 |pmid=3511097 |pmc=423361 |doi=10.1172/JCI112319 |url=}}</ref> | ||
** Bleeding time ([[Bleeding time|BT]]) | ** [[Bleeding time]] ([[Bleeding time|BT]]) | ||
** Clotting time (CT) | ** Clotting time (CT) | ||
** Prothrombin time ([[PT]]) | ** [[Prothrombin time]] ([[PT]]) | ||
** Activated prothrombin time ([[aPTT]]) | ** [[Partial thromboplastin time|Activated prothrombin time]] ([[aPTT]]) | ||
* It is important to mention that testing should be done after the episode has settled because it can lead to falsely lower protein C measurements. | * It is important to mention that testing should be done after the episode has settled because it can lead to falsely lower [[protein C]] measurements. | ||
* The diagnostic tests of choice | * The diagnostic tests of choice have been described above. | ||
* Genetic testing for [[mutations]] in [[PROC gene.]]<ref name=" | * Genetic testing for [[mutations]] in [[PROC gene.]]<ref name="pmid7482420" /> | ||
===Electrocardiogram=== | ===Electrocardiogram=== | ||
* Protein C deficiency may be associated with development of myocardial infarction in young patients. | * Protein C deficiency may be associated with development of [[myocardial infarction]] in young patients.<ref name="pmid10026361">{{cite journal |vauthors=Bux-Gewehr I, Nacke A, Feurle GE |title=Recurring myocardial infarction in a 35 year old woman |journal=Heart |volume=81 |issue=3 |pages=316–7 |date=March 1999 |pmid=10026361 |pmc=1728956 |doi= |url=}}</ref> | ||
* Following are the ECG findings: | |||
**ST segment elevations in leads II, III, and aVF with reciprocal ST depression in lead V4–6 | ** [[ST segment elevation|ST segment elevations]] in leads II, III, and aVF with reciprocal [[ST depression]] in lead V4–6. | ||
**Loss of R wave | ** Loss of R wave | ||
=== X-ray === | === X-ray === | ||
* There are no specific [[x-ray]] findings associated with protein C deficiency. | * There are no specific [[x-ray]] findings associated with [[protein C]] deficiency. | ||
* For specific x-ray findings seen with [[pulmonary embolism]], [[Pulmonary embolism chest x ray|click here]]. | * For specific x-ray findings seen with [[pulmonary embolism]], [[Pulmonary embolism chest x ray|click here]]. | ||
===Echocardiography or Ultrasound=== | ===Echocardiography or Ultrasound=== | ||
* There are no specific | * There are no specific echocardiography or ultrasound findings associated with [[protein C]] deficiency. | ||
* For ultrasound findings related to [[deep vein thrombosis]], [[Deep vein thrombosis ultrasound|click here]]. | * For ultrasound findings related to [[deep vein thrombosis]], [[Deep vein thrombosis ultrasound|click here]]. | ||
* For echocardiography findings associated with [[pulmonary embolism]], [[Pulmonary embolism echocardiography|click here]]. | * For echocardiography findings associated with [[pulmonary embolism]], [[Pulmonary embolism echocardiography|click here]]. | ||
===CT scan=== | ===CT scan=== | ||
* There are no specific [[CT scan]] findings associated with protein C deficiency. | * There are no specific [[CT scan]] findings associated with [[protein C]] deficiency. | ||
* For CT scan findings related to [[pulmonary embolism]], [[Pulmonary embolism CT|click here]]. | * For CT scan findings related to [[pulmonary embolism]], [[Pulmonary embolism CT|click here]]. | ||
===MRI=== | ===MRI=== | ||
* There are no MRI findings associated with protein C deficiency. | * There are no MRI findings associated with [[protein C]] deficiency. | ||
===Other Imaging Findings=== | ===Other Imaging Findings=== | ||
* There are no other imaging findings associated with protein C deficiency. | * There are no other imaging findings associated with [[protein C]] deficiency. | ||
===Other Diagnostic Studies=== | ===Other Diagnostic Studies=== | ||
* There are no other diagnostic studies associated with protein C deficiency. | * There are no other diagnostic studies associated with [[protein C]] deficiency. | ||
==Treatment== | ==Treatment== | ||
===Medical Therapy=== | ===Medical Therapy=== | ||
* Pharmacologic medical therapy is recommended among patients with warfarin-induced skin necrosis, neonatal purpura fulminans | * Pharmacologic medical therapy is recommended among patients with [[warfarin]]-induced skin [[necrosis]], neonatal [[purpura]] fulminans and [[pulmonary embolism]].<ref name="pmid3754407">{{cite journal |vauthors=Zauber NP, Stark MW |title=Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis |journal=Ann. Intern. Med. |volume=104 |issue=5 |pages=659–60 |date=May 1986 |pmid=3754407 |doi= |url=}}</ref> | ||
==== Management of venous thromboembolism: ==== | ==== Management of venous thromboembolism: ==== | ||
* <nowiki/>[[Anticoagulation]] is primarily | * <nowiki/>[[Anticoagulation]] is primarily recommended.<ref name="pmid28259509" /> | ||
* <nowiki/>For longer duration, it is suggested to bridge [[warfarin]] and [[heparin]]. | * <nowiki/>For longer duration, it is suggested to bridge [[warfarin]] and [[heparin]]. | ||
* <nowiki/>However, [[Anticoagulants|oral anticoagulants]] such as [[Factor X|factor Xa]] inhibitors can also be used<nowiki/> d<nowiki/>epending on compliance of patient in<nowiki/> a<nowiki/>ddition to severity of disease. | * <nowiki/>However, [[Anticoagulants|oral anticoagulants]] such as [[Factor X|factor Xa]] inhibitors can also be used<nowiki/> d<nowiki/>epending on compliance of patient in<nowiki/> a<nowiki/>ddition to severity of disease. | ||
* <nowiki/> | * <nowiki/>The duration of [[anticoagulation]] varies according to case. | ||
* <nowiki/> In case of u<nowiki/>np<nowiki/>rovoked episode of [[thromboembolism]] o<nowiki/>r <nowiki/>once the diagnosis of<nowiki/> p<nowiki/>rotein C has been established, life <nowiki/>lo<nowiki/>ng anticoagulation therapy is suggested. | |||
* For provoked episodes and in presence of precipitating factors 6 months of [[warfarin]] therapy bridged with heparin is recommended. | * For provoked episodes and in presence of precipitating factors 6 months of [[warfarin]] therapy bridged with heparin is recommended. | ||
* For more information related to management of [[Deep vein thrombosis|deep venous thrombosis]], [[Deep venous thrombosis|'''click here''']]. | |||
=== Management of pulmonary embolism: === | |||
*<nowiki/><nowiki/><nowiki/><nowiki/><nowiki/><nowiki/><nowiki/><nowiki/><nowiki/><nowiki/>Warfarin is suggested for patients wi<nowiki/>th<nowiki/> complicated disease such as in case of [[pulmonary embolism]]. | |||
* <nowiki/>For management of [[pulmonary embolism]] <nowiki/>'''[[Pulmonary embolism (Assessment and Plan)|cl]]'''<nowiki/>'''[[Pulmonary embolism (Assessment and Plan)|ick here]].''' | |||
==== Management of warfarin-induced skin necrosis ==== | ==== Management of warfarin-induced skin necrosis: ==== | ||
* Once the episode of [[Warfarin detailed information|warfarin]] induced skin necrosis sets in, it needs immediate therapy to prevent the further complications.<ref name="pmid3754407" /> | * <nowiki/><nowiki/><nowiki/>Once the episode of [[Warfarin detailed information|warfarin]] induced skin necrosis sets in, it needs immediate therapy to prevent the further complications.<ref name="pmid3754407" /> | ||
** Stop warfarin | ** Stop warfarin. | ||
** Administer [[vitamin K]] intravenously | ** Administer [[vitamin K]] intravenously. | ||
** Administer unfractionated [[heparin]] | ** Administer unfractionated [[heparin]]. | ||
** Administer a source of protein C such as protein C concentrate or [[fresh frozen plasma]]<ref name=" | ** Administer a source of protein C such as protein C concentrate or [[fresh frozen plasma]].<ref name="pmid1245477">{{cite journal |vauthors=Stenflo J |title=A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization |journal=J. Biol. Chem. |volume=251 |issue=2 |pages=355–63 |date=January 1976 |pmid=1245477 |doi= |url=}}</ref> | ||
** For skin lesions consult a [[Dermatologist]] | ** For skin lesions consult a [[Dermatologist]]. | ||
* | * | ||
===Surgery=== | ===Surgery=== | ||
* Surgical consultation is recommended for the complication of protein C deficiency such as management of skin lesions in warfarin-induced skin necrosis. | * Surgical consultation is recommended for the complication of [[protein C]] deficiency such as management of skin lesions in warfarin-induced skin necrosis.<ref name="pmid3754407">{{cite journal |vauthors=Zauber NP, Stark MW |title=Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis |journal=Ann. Intern. Med. |volume=104 |issue=5 |pages=659–60 |date=May 1986 |pmid=3754407 |doi= |url=}}</ref> | ||
* Liver transplantation was performed in neonatal purpura fulminans that resulted in permanent cure.<ref name="pmid18482214">{{cite journal |vauthors=Lee MJ, Kim KM, Kim JS, Kim YJ, Lee YJ, Ghim TT |title=Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation |journal=Pediatr Transplant |volume=13 |issue=2 |pages=251–4 |date=March 2009 |pmid=18482214 |doi=10.1111/j.1399-3046.2008.00972.x |url=}}</ref> | * [[Liver transplantation]] was performed in neonatal purpura fulminans that resulted in permanent cure.<ref name="pmid18482214">{{cite journal |vauthors=Lee MJ, Kim KM, Kim JS, Kim YJ, Lee YJ, Ghim TT |title=Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation |journal=Pediatr Transplant |volume=13 |issue=2 |pages=251–4 |date=March 2009 |pmid=18482214 |doi=10.1111/j.1399-3046.2008.00972.x |url=}}</ref> | ||
===Primary Prevention=== | ===Primary Prevention=== | ||
* There are no established measures for the primary prevention of protein C deficiency. | * There are no established measures for the primary prevention of [[protein C]] deficiency. | ||
===Secondary Prevention=== | ===Secondary Prevention=== | ||
** Start warfarin at a low dose, gradually increase from 2 mg to therapeutic dose | ==== Prophylaxis of warfarin-induced skin necrosis: ==== | ||
** Start [[warfarin]] at a low dose, gradually increase from 2 mg to therapeutic dose.<ref name="pmid8507079">{{cite journal |vauthors=Schramm W, Spannagl M, Bauer KA, Rosenberg RD, Birkner B, Linnau Y, Schwarz HP |title=Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate |journal=Arch Dermatol |volume=129 |issue=6 |pages=753–6 |date=June 1993 |pmid=8507079 |doi= |url=}}</ref> | |||
** Overlapping of warfarin with heparin during the first several days of warfarin administration is recommended. | ** Other anticoagulants such as [[dabigatran]], [[rivaroxaban]], apaxaban, or edoxaban may be used. | ||
** Use of [[warfarin]] in patients of protein C deficiency: Protein C concentrate should be used unless the required level of [[Anticoagulant|anticoagulation]] is achieved. After which warfarin can be administered again.<ref name="pmid3754407" /> | ** Overlapping of [[warfarin]] with heparin during the first several days of [[warfarin]] administration is recommended. | ||
* [[Prophylactic]] anticoagulation should be considered in patients having risk factors for venous [[thromboembolism]] such as recurrent episodes of VTE, prolonged use of [[Oral contraceptive|oral contraceptives]], and [[surgeries]]. | ** Use of [[warfarin]] in patients of [[protein C]] deficiency: Protein C concentrate should be used unless the required level of [[Anticoagulant|anticoagulation]] is achieved. After which [[warfarin]] can be administered again.<ref name="pmid3754407" /> | ||
* | ==== Prophylaxis for recurrent thromboembolism: ==== | ||
* Avoid prolonged use of oral contraceptives | * [[Prophylactic]] [[Anticoagulant|anticoagulation]] should be considered in patients having risk factors for venous [[thromboembolism]] such as recurrent episodes of [[VTE]], prolonged use of [[Oral contraceptive|oral contraceptives]], and [[surgeries]].<ref name="pmid28259509" /> | ||
* Avoid immobilization | *Other effective measures for secondary prevention of [[protein C]] deficiency include:<ref name="pmid28259509" /> | ||
* Education concerning signs and symptoms of [[Venous thrombosis|venous thromboembolic events]] | ** Avoid prolonged use of oral contraceptives. | ||
** Avoid immobilization. | |||
** Education concerning signs and symptoms of [[Venous thrombosis|venous thromboembolic events]]. | |||
==References== | ==References== | ||
Latest revision as of 22:20, 21 December 2018
| Protein C deficiency | |
| ICD-9 | 289.81 |
|---|---|
| OMIM | 176860 |
| DiseasesDB | 10807 |
| MedlinePlus | 000559 |
| MeSH | D020151 |
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2]
Synonyms and keywords: Protein C deficiency disorder
Overview
Protein C deficiency is hyper-coagulopathy in which a person develops increased tendency of forming abnormal blood clots, especially in peripheral extremities (legs and arms). These clots can dislodge and ascend into the lungs, causing a life threatening condition, pulmonary embolism. Protein C is one of vitamin K dependent anticoagulants, which upon activation inactivates the clotting factors Va and factor VIIIa and hence plays role its role as anticoagulant. The manifestations of the disease can be mild which don't develop deep venous thrombosis; however, it has an increased risk of developing warfarin-induced skin necrosis and neonatal purpura fulminans in which widespread clots are formed in the body leading to necrosis and after utilization of all the clotting factors leads to massive bleeding. Protein C deficiency can be hereditary or acquired. Hereditary variant is associated with mutation in PROC gene, which is transmitted in an autosomal dominant pattern. People carrying two alleles of the mutant gene tend to develop more aggressive disease.
Historical Perspective
- Protein C deficiency was first discovered by Stenflo, a Swedish chemist, in 1976.[1]
- In 1982, Bertina was the first to discover the association between thrombosis and protein C deficiency.[2]
- The association between thrombosis and protein C deficiency was again confirmed in 1993 by Dahlbäck et al and 1994 by Bertina et al 1994.[3]
Classification
Protein C deficiency may be classified according to etiology:[4]
- Congential protein C deficiency:[5]
- Heterozygous protein deficiency[6]
- Homozygous protein C deficiency: It is severe form of disease. It presents with neonatal purpura fulminans.[7]
- Acquired protein C deficiency.
Pathophysiology
- The protein C is a vitamin K dependent glycoprotein, 62 kD, synthesized in the liver.[8]
- It circulates as zymogen and is activated to activated protein C (APC).
- Synthesis of gamma-carboxylic acid on protein C requires vitamin K. The Gla domains bind to calcium leading to structural change that facilitates phospholipid binding which is important for protein function.[9]
- Activated protein C is catalyzed by thrombine-thrombmomdulin complex when it is binds to endothelial proteoglycan.
Protein C after its activation has following functions:[10]
- The primary role of protein C is to inactivate factor Va and factor VIIIa, both of these factors are essential for activation of thrombin and factor Xa which forms clots.
- When protein C is deficient or inactive it leads to uncontrolled clot formation.
- The inhibitory effect of factor protein C is enhanced by protein S. Both perform similar functions.
- Activated protein C indirectly increases the profibrinolytic activity by activating to tissue plasminogen activator (tPA) after binding to plasminogen activator inhibitor (PAI). The reduced thrombin generation thus decreases the activation of TAFI (thrombin activatable fibrinolysis inhibitor) hence resulting in enhanced profibrinolytic potential.[10]
- The other role of protein C is its anti inflammatory effect. The reactions are mediated by epithelial protein cell receptors (EPCR) and protease activated receptor 1 (PAR -1) that play primary role in cytoprotective, anti inflammatory effects and barrier stabilizing effects.[11]
- The deficiency of protein C creates procoagulant effect generally in areas with slow moving venous blood flow, such as extremities leading to thrombosis which manifest as deep venous thrombosis.
Causes
- The cause of protein C deficiency is PROC miss sense or nonsense mutation gene mutation of chromosome 2 at 14q3.[12]
- Other types of mutations have also been described, including promoter mutations, splice site abnormalities, in-frame deletions, frameshift deletions, in-frame insertions, and frameshift insertions.[13]
- Protein C consumption:
- Disseminated intravascular coagulation[14]
- Surgery
- Decreased synthesis of protein C in liver disease[14]
- Vitamin K deficiency
- Nephrotic syndrome[15]
- Infection[16]
- Autoantibodies[17]
- Cancer[17]
Differentiating Protein C deficiency from Other Diseases
Protein C deficiency must be differentiated from other diseases that cause symptoms of DVT and pulmonary embolism such as:
- Factor V Leiden mutation
- Antithrombin III deficiency
- Protein S deficiency
- Prothrombin gene mutation
- Disseminated intravascular coagulation (DIC)
- Antiphospholipid antibody syndrome
For more information on differentiating protein C deficiency, click here.
Epidemiology and Demographics
- The prevalence of protein C deficiency was estimated to be 145 per 100,000 annually.[18]
Age
- The median age of a first episode is typically in third to fourth decade with family history; while, individuals without a family history tend to develop first episode in their fourth to fifth decade.[19]
Risk Factors
- The most potent risk factor in the development of protein C deficiency is consanguineous marriage.[12]
- Hereditary variant is associated with mutation in PROC gene, which is transmitted in an autosomal dominant pattern.[20]
Screening
- There is insufficient evidence to recommend routine screening for protein C deficiency, however in patients with positive family history, it is recommended to check protein C activity (functional) assay which is either clotting time based or chromogenic.[6]
Natural History, Complications, and Prognosis
- If left untreated, the patients of protein C deficiency manifest as unprovoked episodes of venous thromboembolism.[21]
- The probability of manifestation of disease is enhanced in presence of the precipitating factors such as immobility, prolonged use of oral contraceptives, and pelvic surgery.[22]
Common complications of protein C deficiency include:
- Deep venous thrombosis[23]
- Warfarin-induced skin necrosis[24]
- Neonatal purpura fulminans[25]
- Pulmonary embolism and thrombosis in unusual sites such as cerebral, mesenteric, splenic and hepatic veins.[26]
Less common complications include:
- Impaired fetal growth and miscarriage has also been reported with homozygous protein C deficiency.[27]
- Neonatal purpura fulminans is observed with homozygous variant of protein C deficiency.[25]
- Severe complications such as arterial thrombosis is seen resulting in ischemic stroke in young patient with heterozygous protein C deficiency.[28]
Prognosis
- Prognosis of protein C deficiency is generally good with anticogulation therapy survival rate of patients with protein C deficiency is improved.
Diagnosis
Diagnostic Study of Choice
Following are the two tests that are performed to reach the absolute diagnosis:[29]
- Functional assays such as aPTT based assay, factor Xa based (enzymatic assay that uses a chromogenic substrate to check the amidolytic cleavage of a synthetic protein (snake venom) are used to determine function of protein C.[30]
- Antigenic determination of protein C levels. This can detect low levels of protein C as well as the anticoagulant effects.
- Clotting based assays (aPTT and factor Xa) may be used; however, the results may be affected heparin and other anticoagulants. Hence chromogenic assays are preferred. The only exception is when the patient is using vitamin K antagonists which lowers the activity of protein C activity in any assay.[31]
- If functional assays do not reveal the reduced function of protein C especially when clinical suspicion is high, alternative methods should be considered.
- Some people have normal levels of protein C with reduced or near normal anticoagulant function, but normal or near normal amidolytic activity, this indicates reduced ability of protein C to interact with substrate such as factor V, platelet membrane and factor VIII.
History and Symptoms
- The majority of patients with protein C deficiency are asymptomatic.
- The probability of developing venous thromboembolism is especially increased in patients with protein C deficiency in the presence of risk factors such as, factor V Leiden mutation, prolonged immobility, surgery, and prolonged use of oral contraceptives.[32]
- Initial episode of venous thromboembolism is spontaneous in 2/3rd of cases, however, it tends to be recurrent.
- In deep venous thrombosis, a clot is formed in deep veins of leg with potential to ascend upwards to right heart and pulmonary arteries, if dislodged may manifest as pulmonary embolism.
- The patients with acquired disease tend to develop skin changes after the use of anticoagulants such as warfarin.[24]
- For symptoms of deep venous thrombosis click here.
- For symptoms of pulmonary embolism click here.
- Other symptoms include following:
- Purpura and skin changes[23]
- Abnormal pigmentation
- Neurologic abnormalities[27]
- Superficial thrombophlebitis
Physical Examination
- For physical signs related to deep venous thrombosis click here.
- For physical signs related to pulmonary embolism click here.
- Warfarin-induced necrosis can present with erythematous macules which begins on the torso and extremities which can become purpuric and necrotic.[24]
- Homozygous cases may present with more severe disease such as neonatal purpura fulminans which is seen as diffuse ecchymoses, if left untreated it can progress to necrotic bullae.[33]
Laboratory Findings
- The diagnosis of protein C deficiency is based on the clinical presentation in addition to strong familial history.
- Various tests are conducted to document protein C deficiency in addition to baseline clotting profile including:[29]
- Bleeding time (BT)
- Clotting time (CT)
- Prothrombin time (PT)
- Activated prothrombin time (aPTT)
- It is important to mention that testing should be done after the episode has settled because it can lead to falsely lower protein C measurements.
- The diagnostic tests of choice have been described above.
- Genetic testing for mutations in PROC gene.[12]
Electrocardiogram
- Protein C deficiency may be associated with development of myocardial infarction in young patients.[34]
- Following are the ECG findings:
- ST segment elevations in leads II, III, and aVF with reciprocal ST depression in lead V4–6.
- Loss of R wave
X-ray
- There are no specific x-ray findings associated with protein C deficiency.
- For specific x-ray findings seen with pulmonary embolism, click here.
Echocardiography or Ultrasound
- There are no specific echocardiography or ultrasound findings associated with protein C deficiency.
- For ultrasound findings related to deep vein thrombosis, click here.
- For echocardiography findings associated with pulmonary embolism, click here.
CT scan
- There are no specific CT scan findings associated with protein C deficiency.
- For CT scan findings related to pulmonary embolism, click here.
MRI
- There are no MRI findings associated with protein C deficiency.
Other Imaging Findings
- There are no other imaging findings associated with protein C deficiency.
Other Diagnostic Studies
- There are no other diagnostic studies associated with protein C deficiency.
Treatment
Medical Therapy
- Pharmacologic medical therapy is recommended among patients with warfarin-induced skin necrosis, neonatal purpura fulminans and pulmonary embolism.[35]
Management of venous thromboembolism:
- Anticoagulation is primarily recommended.[36]
- For longer duration, it is suggested to bridge warfarin and heparin.
- However, oral anticoagulants such as factor Xa inhibitors can also be used depending on compliance of patient in addition to severity of disease.
- The duration of anticoagulation varies according to case.
- In case of unprovoked episode of thromboembolism or once the diagnosis of protein C has been established, life long anticoagulation therapy is suggested.
- For provoked episodes and in presence of precipitating factors 6 months of warfarin therapy bridged with heparin is recommended.
- For more information related to management of deep venous thrombosis, click here.
Management of pulmonary embolism:
- Warfarin is suggested for patients with complicated disease such as in case of pulmonary embolism.
- For management of pulmonary embolism click here.
Management of warfarin-induced skin necrosis:
- Once the episode of warfarin induced skin necrosis sets in, it needs immediate therapy to prevent the further complications.[35]
- Stop warfarin.
- Administer vitamin K intravenously.
- Administer unfractionated heparin.
- Administer a source of protein C such as protein C concentrate or fresh frozen plasma.[37]
- For skin lesions consult a Dermatologist.
Surgery
- Surgical consultation is recommended for the complication of protein C deficiency such as management of skin lesions in warfarin-induced skin necrosis.[35]
- Liver transplantation was performed in neonatal purpura fulminans that resulted in permanent cure.[38]
Primary Prevention
- There are no established measures for the primary prevention of protein C deficiency.
Secondary Prevention
Prophylaxis of warfarin-induced skin necrosis:
- Start warfarin at a low dose, gradually increase from 2 mg to therapeutic dose.[39]
- Other anticoagulants such as dabigatran, rivaroxaban, apaxaban, or edoxaban may be used.
- Overlapping of warfarin with heparin during the first several days of warfarin administration is recommended.
- Use of warfarin in patients of protein C deficiency: Protein C concentrate should be used unless the required level of anticoagulation is achieved. After which warfarin can be administered again.[35]
Prophylaxis for recurrent thromboembolism:
- Prophylactic anticoagulation should be considered in patients having risk factors for venous thromboembolism such as recurrent episodes of VTE, prolonged use of oral contraceptives, and surgeries.[36]
- Other effective measures for secondary prevention of protein C deficiency include:[36]
- Avoid prolonged use of oral contraceptives.
- Avoid immobilization.
- Education concerning signs and symptoms of venous thromboembolic events.
References
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- ↑ Bertina RM, Broekmans AW, van der Linden IK, Mertens K (August 1982). "Protein C deficiency in a Dutch family with thrombotic disease". Thromb. Haemost. 48 (1): 1–5. PMID 6897135.
- ↑ Dahlbäck B, Carlsson M, Svensson PJ (February 1993). "Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C". Proc. Natl. Acad. Sci. U.S.A. 90 (3): 1004–8. PMC 45799. PMID 8430067.
- ↑ Greengard JS, Fisher CL, Villoutreix B, Griffin JH (April 1994). "Structural basis for type I and type II deficiencies of antithrombotic plasma protein C: patterns revealed by three-dimensional molecular modelling of mutations of the protease domain". Proteins. 18 (4): 367–80. doi:10.1002/prot.340180407. PMID 8208728.
- ↑ Reitsma PH (July 1997). "Protein C deficiency: from gene defects to disease". Thromb. Haemost. 78 (1): 344–50. PMID 9198177.
- ↑ 6.0 6.1 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B (February 1989). "The clinical spectrum of heterozygous protein C deficiency in a large New England kindred". Blood. 73 (3): 712–7. PMID 2521802.
- ↑ Baliga V, Thwaites R, Tillyer ML, Minford A, Parapia L, Allgrove J (July 1995). "Homozygous protein C deficiency--management with protein C concentrate". Eur. J. Pediatr. 154 (7): 534–8. PMID 7556318.
- ↑ Beckmann RJ, Schmidt RJ, Santerre RF, Plutzky J, Crabtree GR, Long GL (July 1985). "The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs". Nucleic Acids Res. 13 (14): 5233–47. PMC 321861. PMID 2991859.
- ↑ Esmon CT (March 1989). "The roles of protein C and thrombomodulin in the regulation of blood coagulation". J. Biol. Chem. 264 (9): 4743–6. PMID 2538457.
- ↑ 10.0 10.1 de Fouw NJ, de Jong YF, Haverkate F, Bertina RM (October 1988). "Activated protein C increases fibrin clot lysis by neutralization of plasminogen activator inhibitor--no evidence for a cofactor role of protein S". Thromb. Haemost. 60 (2): 328–33. PMID 2975409.
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- ↑ Llach F (September 1985). "Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome". Kidney Int. 28 (3): 429–39. PMID 3906225.
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- ↑ Mustafa S, Mannhalter C, Rintelen C, Kyrle PA, Knöbl P, Lechner K, Pabinger I (January 1998). "Clinical features of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden". Blood Coagul. Fibrinolysis. 9 (1): 85–9. PMID 9607123.
- ↑ Tairaku S, Taniguchi-Ikeda M, Okazaki Y, Noguchi Y, Nakamachi Y, Mori T, Kubokawa I, Hayakawa A, Shibata A, Emoto T, Kurahashi H, Toda T, Kawano S, Yamada H, Morioka I, Iijima K (2015). "Prenatal genetic testing for familial severe congenital protein C deficiency". Hum Genome Var. 2: 15017. doi:10.1038/hgv.2015.17. PMC 4785544. PMID 27081530.
- ↑ Massicotte MP, Dix D, Monagle P, Adams M, Andrew M (December 1998). "Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications". J. Pediatr. 133 (6): 770–6. PMID 9842042.
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- ↑ 23.0 23.1 Broekmans AW, Veltkamp JJ, Bertina RM (August 1983). "Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families". N. Engl. J. Med. 309 (6): 340–4. doi:10.1056/NEJM198308113090604. PMID 6688122.
- ↑ 24.0 24.1 24.2 McGehee WG, Klotz TA, Epstein DJ, Rapaport SI (July 1984). "Coumarin necrosis associated with hereditary protein C deficiency". Ann. Intern. Med. 101 (1): 59–60. PMID 6547283.
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- ↑ Wysokinski W, Verhaeghe R, Arnout J, Vermylen J (1990). "Protein C deficiency associated with venous thromboembolism". Acta Clin Belg. 45 (2): 78–84. PMID 2164313.
- ↑ 27.0 27.1 Preston FE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ (October 1996). "Increased fetal loss in women with heritable thrombophilia". Lancet. 348 (9032): 913–6. PMID 8843809.
- ↑ Douay X, Lucas C, Caron C, Goudemand J, Leys D (August 1998). "Antithrombin, protein C and protein S levels in 127 consecutive young adults with ischemic stroke". Acta Neurol. Scand. 98 (2): 124–7. PMID 9724011.
- ↑ 29.0 29.1 Vigano D'Angelo S, Comp PC, Esmon CT, D'Angelo A (February 1986). "Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states". J. Clin. Invest. 77 (2): 416–25. doi:10.1172/JCI112319. PMC 423361. PMID 3511097.
- ↑ Bertina RM, Broekmans AW, Krommenhoek-van Es C, van Wijngaarden A (February 1984). "The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency". Thromb. Haemost. 51 (1): 1–5. PMID 6547008.
- ↑ Comp PC, Nixon RR, Esmon CT (January 1984). "Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex". Blood. 63 (1): 15–21. PMID 6317087.
- ↑ Pomp ER, Rosendaal FR, Doggen CJ (February 2008). "Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use". Am. J. Hematol. 83 (2): 97–102. doi:10.1002/ajh.21059. PMID 17726684.
- ↑ Seligsohn U, Berger A, Abend M, Rubin L, Attias D, Zivelin A, Rapaport SI (March 1984). "Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn". N. Engl. J. Med. 310 (9): 559–62. doi:10.1056/NEJM198403013100904. PMID 6546411.
- ↑ Bux-Gewehr I, Nacke A, Feurle GE (March 1999). "Recurring myocardial infarction in a 35 year old woman". Heart. 81 (3): 316–7. PMC 1728956. PMID 10026361.
- ↑ 35.0 35.1 35.2 35.3 Zauber NP, Stark MW (May 1986). "Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis". Ann. Intern. Med. 104 (5): 659–60. PMID 3754407.
- ↑ 36.0 36.1 36.2
- ↑ Stenflo J (January 1976). "A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization". J. Biol. Chem. 251 (2): 355–63. PMID 1245477.
- ↑ Lee MJ, Kim KM, Kim JS, Kim YJ, Lee YJ, Ghim TT (March 2009). "Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation". Pediatr Transplant. 13 (2): 251–4. doi:10.1111/j.1399-3046.2008.00972.x. PMID 18482214.
- ↑ Schramm W, Spannagl M, Bauer KA, Rosenberg RD, Birkner B, Linnau Y, Schwarz HP (June 1993). "Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate". Arch Dermatol. 129 (6): 753–6. PMID 8507079.