Protein C deficiency: Difference between revisions

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'''For patient information click [[Congenital protein C or S deficiency (patient information)|here]]'''
'''For patient information click [[Congenital protein C or S deficiency (patient information)|here]]'''


{{CMG}}; {{AE}} {{CK}}
{{CMG}}; {{AE}} {{Badria}}


{{SK}}  
{{SK}} Protein C deficiency disorder


==Overview==
==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 VIIIa and hence plays role its role in anticoagulation. The manifestations of the disease can be mild which don't develop Deep Venous thrombosis, however it has increased risk of developing [[Warfarin Induced 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 can cause 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.  
Protein C deficiency is hyper-coagulopathy in which a person develops increased tendency of forming abnormal blood [[Clots in the veins|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]] [[Factor V|Va]] and factor [[Factor VIII|VIIIa]] and hence plays role its role as [[Anticoagulants|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 in the veins|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 [[Mutations|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==
==Historical Perspective==
* Protein C Deficiency was first discovered by Stenflo a Swedish Chemist, in 1976.
* 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.
* 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 made in 1993 and 1994 (Dahlbäcket al 1993; Bertina et al 1994)<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><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><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 
* 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
**[[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 1 Deficiency
***Type I disease: Generally mild form. It has decreased levels of [[protein C]].
###Typpe 2 Deficiency 
***Type II disease: It has normal or near normal levels of [[protein C]] but reduced functional activity.
##Homozygous Protein C Deficiency
**[[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,. It circulates as zymogen and is activated to Activated Protein C (APC) is catalyzed by trombone when it is bound to endothelial proteoglycan. SYnthesis off Gamma carboxylic acid requires vit K . ThGla domains bind to calcium leading to structural change that facilitates phospholipid binding which is important for protein.
* 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).
Protein C has two main functions.
* 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" />


d by Protein S.  
* 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.
* 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.
* 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==
Disease name] may be caused by [cause1], [cause2], or [cause3].
* 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>
 
OR
 
Common causes of [disease] include [cause1], [cause2], and [cause3].
 
OR
 
The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].


OR
* 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>


The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click [[Pericarditis causes#Overview|here]].
* Protein C consumption:
**[[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]]
**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]]
**[[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>
**[[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/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
*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>
 
OR
 
In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
 
OR
 
In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.
 
 
 
Patients of all age groups may develop [disease name].
 
OR
 
The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.
 
OR
 
[Disease name] commonly affects individuals younger than/older than [number of years] years of age.
 
OR
 
[Chronic disease name] is usually first diagnosed among [age group].
 
OR
 
[Acute disease name] commonly affects [age group].


 
*The [[prevalence]] of [[protein C]] deficiency was estimated to be 145 per 100,000 annually.<ref name="pmid3657866" />
 
===Age===
There is no racial predilection to [disease 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>
 
OR
 
[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].
 
 
 
[Disease name] affects men and women equally.
 
OR
 
[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.
 
 
 
The majority of [disease name] cases are reported in [geographical region].
 
OR
 
[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].


==Risk Factors==
==Risk Factors==
There are no established risk factors for [disease name].
* 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>
OR
 
The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].
 
OR
 
Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
 
OR
 
Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.


==Screening==
==Screening==
There is insufficient evidence to recommend routine screening for [disease/malignancy].
* 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>
 
OR
 
According to the [guideline name], screening for [disease name] is not recommended.
 
OR
 
According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
* 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.<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>
OR
 
Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].


OR
==== Common complications of protein C deficiency include: ====
**[[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="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<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 excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.
==== 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===
The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].
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>
 
OR
 
The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].
 
OR
 
The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].


OR
* 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>


There are no established criteria for the diagnosis of [disease name].
*[[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.<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.
*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 [disease name] 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>
OR
* 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]].
* 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''']].


The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
* Other symptoms include following:
** [[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]]
** [[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]]


===Physical Examination===
===Physical Examination===
Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].
* 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]].'''
OR
 
Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].


OR
* [[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" />
 
The presence of [finding(s)] on physical examination is diagnostic of [disease name].
 
OR
 
The presence of [finding(s)] on physical examination is highly suggestive of [disease name].


* [[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===
An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
* 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:<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]])
** Clotting time (CT)
** [[Prothrombin time]] ([[PT]])
** [[Partial thromboplastin time|Activated prothrombin time]] ([[aPTT]])


OR
* 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.


Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
* Genetic testing for [[mutations]] in [[PROC gene.]]<ref name="pmid7482420" />
 
OR
 
[Test] is usually normal among patients with [disease name].
 
OR
 
Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
 
OR
 
There are no diagnostic laboratory findings associated with [disease name].


===Electrocardiogram===
===Electrocardiogram===
There are no ECG findings associated with [disease name].
* 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:
OR
 
An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].


===X-ray===
** [[ST segment elevation|ST segment elevations]] in leads II, III, and aVF with reciprocal [[ST depression]] in lead V4–6.
There are no x-ray findings associated with [disease name].
** Loss of R wave


OR
=== X-ray ===
 
* There are no specific [[x-ray]] findings associated with [[protein C]] deficiency.
An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
* For specific x-ray findings seen with [[pulmonary embolism]], [[Pulmonary embolism chest x ray|click here]].
 
OR
 
There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].


===Echocardiography or Ultrasound===
===Echocardiography or Ultrasound===
There are no echocardiography/ultrasound findings associated with [disease name].
* 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]].
OR
* For echocardiography findings associated with [[pulmonary embolism]], [[Pulmonary embolism echocardiography|click here]].
 
Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no echocardiography/ultrasound  findings associated with [disease name]. However, an echocardiography/ultrasound  may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].


===CT scan===
===CT scan===
There are no CT scan findings associated with [disease name].
* 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]].
OR
 
[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].


===MRI===
===MRI===
There are no MRI findings associated with [disease name].
* There are no MRI findings associated with [[protein C]] deficiency.
 
OR
 
[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].


===Other Imaging Findings===
===Other Imaging Findings===
There are no other imaging findings associated with [disease name].
* There are no other imaging findings associated with [[protein C]] deficiency.
 
OR
 
[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].


===Other Diagnostic Studies===
===Other Diagnostic Studies===
There are no other diagnostic studies associated with [disease name].
* There are no other diagnostic studies associated with [[protein C]] deficiency.
 
OR
 
[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].


==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
There is no treatment for [disease name]; the mainstay of therapy is supportive care.
* 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: ====
OR
* <nowiki/>[[Anticoagulation]] is primarily recommended.<ref name="pmid28259509" />
 
* <nowiki/>For longer duration, it is suggested to bridge [[warfarin]] and [[heparin]].
Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].
* <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/>The duration of [[anticoagulation]] varies according to case.
OR
* <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.
The majority of cases of [disease name] are self-limited and require only supportive care.
* For more information related to management of [[Deep vein thrombosis|deep venous thrombosis]], [[Deep venous thrombosis|'''click here''']].
 
OR
 
[Disease name] is a medical emergency and requires prompt treatment.
 
OR
 
The mainstay of treatment for [disease name] is [therapy].


OR
=== 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]].
The optimal therapy for [malignancy name] depends on the stage at diagnosis.
* <nowiki/>For management of [[pulmonary embolism]] <nowiki/>'''[[Pulmonary embolism (Assessment and Plan)|cl]]'''<nowiki/>'''[[Pulmonary embolism (Assessment and Plan)|ick here]].'''


OR
==== Management of warfarin-induced skin necrosis: ====
 
* <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" />
[Therapy] is recommended among all patients who develop [disease name].
** Stop warfarin.
 
** Administer [[vitamin K]] intravenously.
OR
** Administer unfractionated [[heparin]].
 
** 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>
Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
** For skin lesions consult a [[Dermatologist]].
 
*
OR
 
Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
 
OR
 
Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
 
OR
 
Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].


===Surgery===
===Surgery===
Surgical intervention is not recommended for the management of [disease name].
* 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>
 
OR
 
Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]
 
OR
 
The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].
 
OR
 
The feasibility of surgery depends on the stage of [malignancy] at diagnosis.
 
OR


Surgery is the mainstay of treatment for [disease or malignancy].
* [[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 [disease name].
* There are no established measures for the primary prevention of [[protein C]] deficiency.
 
OR
 
There are no available vaccines against [disease name].
 
OR
 
Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
 
OR
 
[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].


===Secondary Prevention===
===Secondary Prevention===
There are no established measures for the secondary prevention of [disease name].


OR
==== 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>
** 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 [[Anticoagulant|anticoagulation]] is achieved. After which [[warfarin]] can be administered again.<ref name="pmid3754407" />


Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].
==== Prophylaxis for recurrent thromboembolism: ====
* [[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" />
*Other effective measures for secondary prevention of [[protein C]] deficiency include:<ref name="pmid28259509" />
** 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

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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]
      • 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.[7]
    • Acquired protein C deficiency.

Pathophysiology

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

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:

For more information on differentiating protein C deficiency, click here.

Epidemiology and Demographics

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

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:

Less common complications include:

Prognosis

Diagnosis

Diagnostic Study of Choice

Following are the two tests that are performed to reach the absolute diagnosis:[29]

History and Symptoms

Physical Examination

Laboratory Findings

  • 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.

Electrocardiogram

  • Protein C deficiency may be associated with development of myocardial infarction in young patients.[34]
  • Following are the ECG findings:

X-ray

Echocardiography or Ultrasound

CT scan

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

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:

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]

Surgery

  • Surgical consultation is recommended for the complication of protein C deficiency such as management of skin lesions in warfarin-induced skin necrosis.[35]

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:

References

  1. ↑ Goldenberg NA, Manco-Johnson MJ (November 2008). "Protein C deficiency". Haemophilia. 14 (6): 1214–21. doi:10.1111/j.1365-2516.2008.01838.x. PMID 19141162.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Reitsma PH (July 1997). "Protein C deficiency: from gene defects to disease". Thromb. Haemost. 78 (1): 344–50. PMID 9198177.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. ↑ 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.
  11. ↑ Joyce DE, Grinnell BW (May 2002). "Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB". Crit. Care Med. 30 (5 Suppl): S288–93. PMID 12004250.
  12. ↑ 12.0 12.1 12.2 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR (May 1995). "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". Thromb. Haemost. 73 (5): 876–89. PMID 7482420.
  13. ↑ Reitsma PH, Poort SR, Allaart CF, Briët E, Bertina RM (August 1991). "The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects". Blood. 78 (4): 890–4. PMID 1868249.
  14. ↑ 14.0 14.1 Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P (March 2005). "Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests". Hepatology. 41 (3): 553–8. doi:10.1002/hep.20569. PMID 15726661.
  15. ↑ Llach F (September 1985). "Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome". Kidney Int. 28 (3): 429–39. PMID 3906225.
  16. ↑ Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, Casey W (November 1997). "Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans". Lancet. 350 (9091): 1590–3. PMID 9393338.
  17. ↑ 17.0 17.1 Mitchell CA, Rowell JA, Hau L, Young JP, Salem HH (December 1987). "A fatal thrombotic disorder associated with an acquired inhibitor of protein C". N. Engl. J. Med. 317 (26): 1638–42. doi:10.1056/NEJM198712243172606. PMID 3683503.
  18. ↑ 18.0 18.1 Miletich J, Sherman L, Broze G (October 1987). "Absence of thrombosis in subjects with heterozygous protein C deficiency". N. Engl. J. Med. 317 (16): 991–6. doi:10.1056/NEJM198710153171604. PMID 3657866.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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. ↑ 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.
  25. ↑ 25.0 25.1 Price VE, Ledingham DL, Krümpel A, Chan AK (December 2011). "Diagnosis and management of neonatal purpura fulminans". Semin Fetal Neonatal Med. 16 (6): 318–22. doi:10.1016/j.siny.2011.07.009. PMID 21839696.
  26. ↑ 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. ↑ 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.
  28. ↑ 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. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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. ↑ 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. ↑ 36.0 36.1 36.2
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.


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