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Laboratory issues in diagnosing abnormalities of protein C, thrombomodulin, and endothelial cell protein C receptor
Kandice Kottke-Marchant1, Philip Comp
1Department of Clinical Pathology, Cleveland Clinic Foundation, Ohio 44195, USA. marchak@ccf.org
Insights
Protein C deficiency is a rare genetic cause of thrombophilia. Initial testing for protein C deficiency should use functional assays after excluding acquired causes, confirming results with repeat testing.
Area of Science:
- Hematology
- Genetics
- Clinical Pathology
Background:
- Protein C deficiency is an uncommon genetic disorder.
- It can contribute to thrombophilia, often alongside other risk factors.
- Understanding its pathophysiology is crucial for diagnosis and management.
Purpose of the Study:
- To review the pathophysiology of protein C deficiency.
- To provide recommendations for diagnostic testing of protein C function and concentration.
- To discuss the role of related proteins like thrombomodulin and endothelial protein C receptor.
Main Methods:
- Literature review of published medical studies.
- Consensus opinions from experts in thrombophilia.
- Recommendations presented and voted on at a scientific conference.
Main Results:
- Functional amidolytic protein C assay is recommended for initial testing.
- Diagnosis requires exclusion of acquired causes and confirmation with repeat testing.
- Antigenic assays may aid in subtyping protein C deficiency.
Conclusions:
- Protein C deficiency is a rare contributor to thrombophilia.
- Proper diagnostic testing involves functional assays and exclusion of acquired causes.
- Diagnostic testing for thrombomodulin and endothelial protein C receptor is not currently recommended.
Objective:
To review the current understanding of the pathophysiology of protein C deficiency and its role in congenital thrombophilia. Recommendations for diagnostic testing for protein C function and concentration, derived from the medical literature and consensus opinions of recognized experts in the field, are included, specifying whom, how, and when to test. The role of related proteins, such as thrombomodulin and endothelial protein C receptor, is also reviewed. Data Sources.-Review of the published medical literature.
Data Extraction And Synthesis:
A summary of the medical literature and proposed testing recommendations were prepared and presented at the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. After discussion at the conference, consensus recommendations presented in this manuscript were accepted after a two-thirds majority vote by the participants.
Conclusions:
Protein C deficiency is an uncommon genetic abnormality that may be a contributing cause of thrombophilia, often in conjunction with other genetic or acquired risk factors. When assay of protein C plasma levels is included in the laboratory evaluation of thrombophilia, a functional amidolytic protein C assay should be used for initial testing. The diagnosis of protein C deficiency should be established only after other acquired causes of protein C deficiency are excluded. A low protein C level should be confirmed with a subsequent assay on a new specimen. Antigenic protein C assays may be of benefit in subclassification of the type of protein C deficiency. The role of thrombomodulin and endothelial cell protein C receptor in thrombosis has yet to be clearly established, and diagnostic testing is not recommended at this time.