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: 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.
Blood Coagulation and Protein C Pathways.jpg

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

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  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. 
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