Protein C deficiency

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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: Chandrakala Yannam, MD [2]

Synonyms and Keywords:

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.

Historical Perspective

  • Protein C Deficiency was first discovered by Stenflo a Swedish Chemist, in 1976.
  • 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 made in 1993 and 1994 (Dahlbäcket al 1993; Bertina et al 1994)[1][2][3] .

Classification

Protein C deficiency may be classified according to etiology.

  • Congential Protein C Deficiency
    • Heterozygous Protein Deficiency
      • Type 1 Deficiency
      • Typpe 2 Deficiency
    • Homozygous Protein C Deficiency
  • Acquired Protein C Deficiency

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 thrombine-thrombmomdulin complex when it is bound to endothelial proteoglycan. Synthesis of Gamma carboxylic acid on protein C requires it vit K.The Gla domains bind to calcium leading to structural change that facilitates phospholipid binding which is important for protein.

Protein C after its activation has two main functions.

  • 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. The inhibitory effect of factor Protein C is enhanced by Protein S. Both perform Similar functions.
  • The other role of Protein C is its anti inflammatory effect.[4] 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.[5]
  • The deficiency of protein C results by creating a procoagulant effect generally in areas with slow moving venous blood flow, i.e extremities leading to thrombosis which manifests as Deep Venous Thrombosis.[6]
  • 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 causes decreased the activation of TAFI (thrombin activatable fibrinolysis inhibitor) hence resulting in enhanced profibrinolytic potential.

Causes

The cause of Protein C deficiency is PROC gene mutation in long arm (q) of chromosome 2 at position 14.3. [7]

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

  • The incidence of Protein C deficiency is approximately 142 per 100,000 individuals worldwide.[8]
  • In prevalence of Protein C deficiency was estimated to be 1.45 per 1000 (95% CI, 0.79/1000 to 2.43/1000.[9]

Risk Factors

The most potent risk factor in the development of Protein C deficiency is consanguineous marriage.

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.[10]

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

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].

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

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

OR

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].

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].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

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].

Laboratory Findings

An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].

OR

Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

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

There are no ECG findings associated with [disease name].

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

There are no x-ray findings associated with Protein C deficiency.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

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

There are no CT scan findings associated with Protein C deficiency.

MRI

There are no MRI findings associated with [disease name].

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

There are no other imaging findings associated with [disease name].

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

There are no other diagnostic studies associated with [disease name].

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

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR   The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

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

Surgical intervention is not recommended for the management of Protein C Deficiency.

Primary Prevention

There are no established measures for the primary prevention of [disease name].

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

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

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].

References

  1. 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. 
  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 45799Freely accessible. PMID 8430067. 
  4. Okajima K (December 2001). "Regulation of inflammatory responses by natural anticoagulants". Immunol. Rev. 184: 258–74. PMID 11918684. 
  5. 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. 
  6. Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P (March 1992). "Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies". Chest. 101 (3): 816–23. PMID 1531791. 
  7. 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. 
  8. 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. PMID 3657866. doi:10.1056/NEJM198710153171604. 
  9. Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, Conkie JA, Bertina RM (January 1995). "Prevalence of protein C deficiency in the healthy population". Thromb. Haemost. 73 (1): 87–93. PMID 7740502. 
  10. Khor B, Van Cott EM (June 2010). "Laboratory tests for protein C deficiency". Am. J. Hematol. 85 (6): 440–2. PMID 20309856. doi:10.1002/ajh.21679. 



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