Protein C deficiency

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) .

Classification

Protein C deficiency may be classified according to etiology.

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

Differentiating Protein C deficiency from Other Diseases

Protein C deficiency must be differentiated from other diseases that cause symptoms of DVT and pulmonary embolism such as:

• Factor V Leiden mutation
• Antithrombin III deficiency
• Protein S deficiency
• Prothrombin gene mutation
• Disseminated intravascular coagulation (DIC)
• Antiphospholipid antibody syndrome

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

Epidemiology and Demographics

The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

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In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

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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].

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The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.

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[Disease name] commonly affects individuals younger than/older than [number of years] years of age.

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[Chronic disease name] is usually first diagnosed among [age group].

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[Acute disease name] commonly affects [age group].

There is no racial predilection to [disease name].

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[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.

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[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].

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[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Risk Factors

There are no established risk factors for [disease name].

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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].

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Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

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Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.

Screening

There is insufficient evidence to recommend routine screening for [disease/malignancy].

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According to the [guideline name], screening for [disease name] is not recommended.

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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

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

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

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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

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The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

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The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

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

History and Symptoms

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

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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].

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

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The presence of [finding(s)] on physical examination is diagnostic of [disease name].

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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].

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

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[Test] is usually normal among patients with [disease name].

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Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].

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There are no diagnostic laboratory findings associated with [disease name].

Electrocardiogram

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

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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

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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].

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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

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

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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].

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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 [disease name].

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[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].

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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

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

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[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].

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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].

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[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].

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[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].

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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.

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

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

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

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

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

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

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Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

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Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

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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 [disease name].

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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]

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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].

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The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

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Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

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

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There are no available vaccines against [disease name].

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Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

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[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].

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

References

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