Protein C deficiency: Difference between revisions

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'''Protein C deficiency''' is a rare genetic trait that predisposes to [[thrombosis|thrombotic disease]]. It was first described in 1981.<ref name="pmid6895379">{{cite journal |author=Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C |title=Deficiency of protein C in congenital thrombotic disease |journal=J. Clin. Invest. |volume=68 |issue=5 |pages=1370–3 |year=1981 |pmid=6895379 |doi=10.1172/JCI110385 |pmc=370934}}</ref> The disease belongs to a group of genetic disorders known as [[thrombophilia]]s. The prevalence of protein C deficiency has been estimated to about 0.2% to 0.5% of the general population. Protein C deficiency is associated with an increased incidence of [[thrombosis|venous thromboembolism]] (relative risk 8-10), whereas no association with arterial thrombotic disease has been found.<ref name="pmid16968541">{{cite journal |author=Khan S, Dickerman JD |title=Hereditary thrombophilia |journal=Thromb J |volume=4 |issue= 1|pages=15 |year=2006 |pmid=16968541 |doi=10.1186/1477-9560-4-15 |url=http://www.thrombosisjournal.com/content/4/1/15 |pmc=1592479}}</ref>
'''Protein C deficiency''' is a rare genetic trait that predisposes to [[thrombosis|thrombotic disease]]. It was first described in 1981.<ref name="pmid6895379">{{cite journal |author=Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C |title=Deficiency of protein C in congenital thrombotic disease |journal=J. Clin. Invest. |volume=68 |issue=5 |pages=1370–3 |year=1981 |pmid=6895379 |doi=10.1172/JCI110385 |pmc=370934}}</ref> The disease belongs to a group of genetic disorders known as [[thrombophilia]]s. Protein C deficiency is associated with an increased incidence of [[thrombosis|venous thromboembolism]] (relative risk 8–10), whereas no association with arterial thrombotic disease has been found.<ref name="pmid16968541">{{cite journal |author=Khan S, Dickerman JD |title=Hereditary thrombophilia |journal=Thromb J |volume=4 |issue= 1|pages=15 |year=2006 |pmid=16968541 |doi=10.1186/1477-9560-4-15 |url=http://www.thrombosisjournal.com/content/4/1/15 |pmc=1592479}}</ref>



==Pathophysiology==
==Pathophysiology==
Line 17: Line 18:
* '''Type II''': ''Qualitative'' defects, in which interaction with other molecules is abnormal. Defects in interaction with [[thrombomodulin]], phospholipids, factors V/VIII and others have been described.
* '''Type II''': ''Qualitative'' defects, in which interaction with other molecules is abnormal. Defects in interaction with [[thrombomodulin]], phospholipids, factors V/VIII and others have been described.


The majority of people with protein C deficiency lack only one of the functioning genes, and are therefore [[heterozygous]]. Before 1999, only sixteen cases of ''[[homozygous]]'' protein C deficiency had been described (two abnormal copies of the gene, leading to absence of functioning protein C in the bloodstream). This may manifest itself as [[purpura fulminans]] in the newborn.<ref name="pmid16968541"/>
The majority of people with protein C deficiency lack only one copy of the functioning genes, and are therefore [[heterozygous]]. Before 1999, only sixteen cases of ''[[homozygous]]'' protein C deficiency had been described (two abnormal copies of the gene, leading to absence of functioning protein C in the bloodstream). This may manifest itself as [[purpura fulminans]] in newborn babies.<ref name="pmid16968541"/>

==Diagnostic testing==
There are two main types of protein C assays, activity and antigen (immunoassays).<ref name="pmid20309856">{{cite journal |author=Khor B, Van Cott EM |title=Laboratory tests for protein C deficiency |journal=Am J Hematol |volume=85 |issue=6|pages=440-442 |year=2010 |pmid=20309856 |doi=10.1002/ajh.21679}}</ref> Commercially available activity assays are based on [[chromogenic]] assays that use activation by snake venom in an activating reagent, or clotting and enzyme-linked immunosorbant assays.<ref name="Goldenberg" /> Repeated testing for protein C functional activity allows differentiation between transient and congenital deficiency of protein C.<ref name="pmid21233082"></ref><ref name=pmid20309856></ref>

Initially, a protein C activity (functional) assay can be performed, and if the result is low, a protein C antigen assay can be considered to determine the deficiency subtype (Type I or Type II). In type I deficiencies, normally functioning protein C molecules are made in reduced quantity. In type II deficiencies normal amounts of dysfunctional protein C are synthesized.<ref name=pmid20309856></ref>

Antigen assays are immunoassays designed to measure the quantity of protein C regardless of its function. Type I deficiencies are therefore characterized by a decrease in both activity and antigen protein C assays whereas type II deficiencies exhibit normal protein C antigen levels with decreased activity levels.<ref name=pmid20309856></ref>

The human protein C gene (PROC) comprises 9 exons, and protein C deficiency has been linked to over 160 mutations to date.<ref name="pmid17430555">{{cite journal |author=D'Ursi P, Marino F, Caprera A, Milanesi L, Faioni EM, Rovida E |title=ProCMD: a database and 3D web resource for protein C mutants |journal=BMC Bioinformatics |volume=8 |issue=Suppl 1|pages=S11 |year=2007 |pmid=17430555 |pmc=1885840}}</ref><ref name="pmid17152060">{{cite journal |author=Rovida E, Merati G, D'Ursi P, Zanardelli S, Marino F, Fontana G, Castaman G, Faioni EM |title=Identification and computationally-based structural interpretation of naturally occurring variants of human protein C |journal=Hum Mutat |volume=28 |issue=4 |pages=345-55 |year=2007 |pmid=17152060}}</ref> Therefore, DNA testing for protein C deficiency is generally not available outside of specialized research laboratories.<ref name=pmid20309856></ref>

Manifestation of purpura fulminans as it is usually associated with reduced protein C plasma concentrations of <5 mg IU/dL.<ref name="pmid21233082">{{cite journal |author=Chalmers E, Cooper P, Forman K, Grimley C, Khair K, Minford A, Morgan M, Mumford A D |title=Purpura fulminans: recognition, diagnosis and management |journal=Arch Dis Child |volume=96 |issue=11 |pages=1066-1071 |year=2011 |pmid=21233082 |doi=10.1136/adc.2010.199919}}</ref> The normal concentration of plasma protein C is 70 nM (4 µg/mL) with a half live of approximately 8 hours.<ref name="pmid6895379"></ref> Healthy term neonates, however, have lower (and more variable) physiological levels of protein C (ranging between 15-55 IU/dL) than older children or adults, and these concentrations progressively increase throughout the first 6 months of life.<ref name="pmid12406062">{{cite journal |author=Williams MD, Chalmers EA, Gibson BE |title=The investigation and management of neonatal haemostasis and thrombosis |journal=Br J Haematol |volume=119 |issue=2 |pages=295-309 |year=202 |pmid=12406062}}</ref> Protein C levels may be <10 IU/dL in preterm or twin neonates or those with respiratory distress without manifesting either purpura fulminans or [[disseminated intravascular coagulation]].<ref name="pmid1834822">{{cite journal |author=Manco-Johnson MJ, Abshire TC, Jacobson LJ, Marlar RA |title=Severe neonatal protein C deficiency: prevalence and thrombotic risk |journal=J Pediatr |volume=119 |issue=5 |pages=793-798 |year=1991 |pmid=1834822}}</ref>


==Complications==
==Complications==
Protein C is vitamin K-dependent. Patients with Protein C deficiency are at an increased risk of developing skin necrosis while on warfarin. Protein C has a short half life (6hrs) compared with other vitamin K-dependent factors and therefore is rapidly depleted with warfarin initiation, resulting in a transient hypercoagulable state.
Protein C is vitamin K-dependent. Patients with Protein C deficiency are at an increased risk of developing skin necrosis while on warfarin. Protein C has a short half life (8 hour) compared with other vitamin K-dependent factors and therefore is rapidly depleted with warfarin initiation, resulting in a transient hypercoagulable state.


==Treatment==
==Treatment==
Primary prophylaxis with low-molecular weight heparin, heparin, or warfarin is often considered in known familial cases. Anticoagulant prophylaxis is given to all who develop a venous clot regardless of underlying cause.<ref name="Goldenberg">Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia. 2008 Nov;14(6):1214-21</ref>
Primary prophylaxis with low-molecular weight heparin, heparin, or warfarin is often considered in known familial cases. Anticoagulant prophylaxis is given to all who develop a venous clot regardless of underlying cause.<ref name="Goldenberg">{{cite journal |author=Goldenberg NA, Manco-Johnson MJ |title=Protein C deficiency |journal=Haemophilia |volume=14 |issue=6 |pages=1214-1221 |year=2008 |pmid=19141162}}</ref>


Studies have demonstrated an increased risk of recurrent venous thromboembolic events in patients with protein C deficiency. Therefore, long-term anticoagulation therapy with [[warfarin]] may be considered in these patients.<ref name="Goldenberg" />
Studies have demonstrated an increased risk of recurrent venous thromboembolic events in patients with protein C deficiency. Therefore, long-term anticoagulation therapy with [[warfarin]] may be considered in these patients.<ref name="Goldenberg" />


Homozygous protein C defect constitutes a potentially life-threatening disease, and warrants the use of supplemental protein C concentrates.{{fact|date=April 2008}}
Homozygous protein C defect constitutes a potentially life-threatening disease, and warrants the use of supplemental protein C concentrates.<ref name="pmid20376174">{{cite journal |author=Kroiss S, Albisetti M |title=Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency |journal=Biologics |volume=24 |issue=5|pages=51-60 |year=2010 |pmid= 20376174 |pmc=2846144}}</ref>

Liver transplant may be considered curative for homozygous protein C deficiency.<ref name="pmid20376174">{{cite journal |author=Kroiss S, Albisetti M |title=Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency |journal=Biologics |volume=24 |issue=5|pages=51-60 |year=2010 |pmid= 20376174 |pmc=2846144}}</ref>

==Epidemiology==
[[Heterozygous]] protein C deficiency occurs in 0.14–0.50% of the general population.<ref name="pmid3657866">{{cite journal |author=Miletich J, Sherman L, Broze G, Jr |title=Absence of thrombosis in subjects with heterozygous protein C deficiency |journal=N Engl J Med |volume=317 |issue=16|pages=991-996 |year=1987 |pmid=3657866 |doi=10.1056/NEJM198710153171604}}</ref><ref name="pmid7740502">{{cite journal |author=Tait RC, Walker ID, Reitsma PH. Islam SI, McCall F, Poort, SR, Conkie, JA, Bertina, RM |title=Prevalence of protein C deficiency in the healthy population |journal=Thromb Haemost |volume=73|issue=1|pages=87-93 |year=1995 |pmid=7740502}}</ref> Based on an estimated carrier rate of 0.2%, a [[homozygous]] or compound heterozygous protein C deficiency incidence of 1 per 4 million births could be predicted, although far fewer living patients have been identified.<ref name="Goldenberg" /> This low prevalence of patients with severe genetic protein C deficiency may be explained by excessive fetal demise, early postnatal deaths before diagnosis, heterogeneity in the cause of low concentrations of protein C among healthy individuals and under-reporting.<ref name="Goldenberg" />



The incidence of protein C deficiency in individuals who present with clinical symptoms has been reported to be estimated at 1 in 20,000.<ref name="pmid7701473">{{cite journal |author=Dahlback B. |title=The protein C anticoagulant system: inherited defects as basis for venous thrombosis |journal=Thromb Res |volume=77 |issue=1 |pages=1-43|year=1995 |pmid=7701473}}</ref>
Liver transplant may be considered curative for homozygous protein C deficiency.<ref>Pediatr Transplant. 2009 Mar;13(2):251-4. Epub 2008 May 11. Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation.</ref>{{npsn|date=September 2012}}{{or|date=September 2012}}


==References==
==References==

Revision as of 17:16, 2 April 2014

Protein C deficiency
SpecialtyHematology Edit this on Wikidata

Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981.[1] The disease belongs to a group of genetic disorders known as thrombophilias. Protein C deficiency is associated with an increased incidence of venous thromboembolism (relative risk 8–10), whereas no association with arterial thrombotic disease has been found.[2]


Pathophysiology

The main function of protein C is its anticoagulant property as an inhibitor of coagulation factors V and VIII. A deficiency results in a loss of the normal cleaving of Factors Va and VIIIa. There are two main types of protein C mutations that lead to protein C deficiency:[2]

  • Type I: Quantitative defects of protein C (low production or short protein half life)
  • Type II: Qualitative defects, in which interaction with other molecules is abnormal. Defects in interaction with thrombomodulin, phospholipids, factors V/VIII and others have been described.

The majority of people with protein C deficiency lack only one copy of the functioning genes, and are therefore heterozygous. Before 1999, only sixteen cases of homozygous protein C deficiency had been described (two abnormal copies of the gene, leading to absence of functioning protein C in the bloodstream). This may manifest itself as purpura fulminans in newborn babies.[2]

Diagnostic testing

There are two main types of protein C assays, activity and antigen (immunoassays).[3] Commercially available activity assays are based on chromogenic assays that use activation by snake venom in an activating reagent, or clotting and enzyme-linked immunosorbant assays.[4] Repeated testing for protein C functional activity allows differentiation between transient and congenital deficiency of protein C.[5][3]

Initially, a protein C activity (functional) assay can be performed, and if the result is low, a protein C antigen assay can be considered to determine the deficiency subtype (Type I or Type II). In type I deficiencies, normally functioning protein C molecules are made in reduced quantity. In type II deficiencies normal amounts of dysfunctional protein C are synthesized.[3]

Antigen assays are immunoassays designed to measure the quantity of protein C regardless of its function. Type I deficiencies are therefore characterized by a decrease in both activity and antigen protein C assays whereas type II deficiencies exhibit normal protein C antigen levels with decreased activity levels.[3]

The human protein C gene (PROC) comprises 9 exons, and protein C deficiency has been linked to over 160 mutations to date.[6][7] Therefore, DNA testing for protein C deficiency is generally not available outside of specialized research laboratories.[3]

Manifestation of purpura fulminans as it is usually associated with reduced protein C plasma concentrations of <5 mg IU/dL.[5] The normal concentration of plasma protein C is 70 nM (4 µg/mL) with a half live of approximately 8 hours.[1] Healthy term neonates, however, have lower (and more variable) physiological levels of protein C (ranging between 15-55 IU/dL) than older children or adults, and these concentrations progressively increase throughout the first 6 months of life.[8] Protein C levels may be <10 IU/dL in preterm or twin neonates or those with respiratory distress without manifesting either purpura fulminans or disseminated intravascular coagulation.[9]

Complications

Protein C is vitamin K-dependent. Patients with Protein C deficiency are at an increased risk of developing skin necrosis while on warfarin. Protein C has a short half life (8 hour) compared with other vitamin K-dependent factors and therefore is rapidly depleted with warfarin initiation, resulting in a transient hypercoagulable state.

Treatment

Primary prophylaxis with low-molecular weight heparin, heparin, or warfarin is often considered in known familial cases. Anticoagulant prophylaxis is given to all who develop a venous clot regardless of underlying cause.[4]

Studies have demonstrated an increased risk of recurrent venous thromboembolic events in patients with protein C deficiency. Therefore, long-term anticoagulation therapy with warfarin may be considered in these patients.[4]

Homozygous protein C defect constitutes a potentially life-threatening disease, and warrants the use of supplemental protein C concentrates.[10]

Liver transplant may be considered curative for homozygous protein C deficiency.[10]

Epidemiology

Heterozygous protein C deficiency occurs in 0.14–0.50% of the general population.[11][12] Based on an estimated carrier rate of 0.2%, a homozygous or compound heterozygous protein C deficiency incidence of 1 per 4 million births could be predicted, although far fewer living patients have been identified.[4] This low prevalence of patients with severe genetic protein C deficiency may be explained by excessive fetal demise, early postnatal deaths before diagnosis, heterogeneity in the cause of low concentrations of protein C among healthy individuals and under-reporting.[4]


The incidence of protein C deficiency in individuals who present with clinical symptoms has been reported to be estimated at 1 in 20,000.[13]

References

  1. ^ a b Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C (1981). "Deficiency of protein C in congenital thrombotic disease". J. Clin. Invest. 68 (5): 1370–3. doi:10.1172/JCI110385. PMC 370934. PMID 6895379.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b c Khan S, Dickerman JD (2006). "Hereditary thrombophilia". Thromb J. 4 (1): 15. doi:10.1186/1477-9560-4-15. PMC 1592479. PMID 16968541.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ a b c d e Khor B, Van Cott EM (2010). "Laboratory tests for protein C deficiency". Am J Hematol. 85 (6): 440–442. doi:10.1002/ajh.21679. PMID 20309856.
  4. ^ a b c d e Goldenberg NA, Manco-Johnson MJ (2008). "Protein C deficiency". Haemophilia. 14 (6): 1214–1221. PMID 19141162.
  5. ^ a b Chalmers E, Cooper P, Forman K, Grimley C, Khair K, Minford A, Morgan M, Mumford A D (2011). "Purpura fulminans: recognition, diagnosis and management". Arch Dis Child. 96 (11): 1066–1071. doi:10.1136/adc.2010.199919. PMID 21233082.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ D'Ursi P, Marino F, Caprera A, Milanesi L, Faioni EM, Rovida E (2007). "ProCMD: a database and 3D web resource for protein C mutants". BMC Bioinformatics. 8 (Suppl 1): S11. PMC 1885840. PMID 17430555.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Rovida E, Merati G, D'Ursi P, Zanardelli S, Marino F, Fontana G, Castaman G, Faioni EM (2007). "Identification and computationally-based structural interpretation of naturally occurring variants of human protein C". Hum Mutat. 28 (4): 345–55. PMID 17152060.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Williams MD, Chalmers EA, Gibson BE (202). "The investigation and management of neonatal haemostasis and thrombosis". Br J Haematol. 119 (2): 295–309. PMID 12406062.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Manco-Johnson MJ, Abshire TC, Jacobson LJ, Marlar RA (1991). "Severe neonatal protein C deficiency: prevalence and thrombotic risk". J Pediatr. 119 (5): 793–798. PMID 1834822.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b Kroiss S, Albisetti M (2010). "Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency". Biologics. 24 (5): 51–60. PMC 2846144. PMID 20376174.
  11. ^ Miletich J, Sherman L, Broze G, Jr (1987). "Absence of thrombosis in subjects with heterozygous protein C deficiency". N Engl J Med. 317 (16): 991–996. doi:10.1056/NEJM198710153171604. PMID 3657866.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Tait RC, Walker ID, Reitsma PH. Islam SI, McCall F, Poort, SR, Conkie, JA, Bertina, RM (1995). "Prevalence of protein C deficiency in the healthy population". Thromb Haemost. 73 (1): 87–93. PMID 7740502.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Dahlback B. (1995). "The protein C anticoagulant system: inherited defects as basis for venous thrombosis". Thromb Res. 77 (1): 1–43. PMID 7701473.

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