eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Protein C Deficiency: Differential Diagnoses & Workup

Author: Adam Cuker, MD, Fellowship in Hematology/Oncology, Hospital of the University of Pennsylvania
Coauthor(s): Eleanor S Pollak, MD, Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania
Contributor Information and Disclosures

Updated: Jun 11, 2009

Differential Diagnoses

Antithrombin Deficiency
Hypercoagulability: Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli
Cerebral Venous Thrombosis
Mesenteric Venous Thrombosis
Deep Venous Thrombosis
Protein S Deficiency
Dysfibrinogenemia
Pulmonary Embolism

Workup

Laboratory Studies

Assays

 A variety of immunologic and functional protein C assays are available.

Immunologic assays

 Immunologic methods for the measurement of protein C antigen include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and electroimmunoassays.50 Logarithms of protein C antigen levels in the healthy, nonpregnant, adult population show a Gaussian distribution.51  The protein C antigen reference range is defined as the mean +/- 2 standard deviations (SDs) of this distribution and approximates 70-140% of the protein C antigen level of normal pooled plasma.13  As noted earlier, neonates and infants have lower levels of protein C than their adult counterparts, and age-based normal ranges must therefore be derived separately for these populations.45

Functional assays

 Functional protein C assays make use of the venom of the southern copperhead snake (Agkistrodon contortrix), which activates the protein C zymogen to activated protein C (aPC).52 Activated protein C (aPC) activity can then be measured by means of a clotting assay or a chromogenic substrate. The adult reference range for protein C activity tends to be slightly lower than the immunologic normal range. 

Screening
A decreased protein C activity level is required to make the diagnosis of protein C deficiency. However, owing to the broad normal ranges of protein C antigen and activity, diagnosis of heterozygous protein C deficiency can be challenging. Patients with levels less than 50% are likely to have a true hereditary deficiency, whereas levels between 55% and 65% may reflect heterozygous deficiency or the low end of the normal distribution.13 A functional protein C assay should be employed for screening purposes, as it will identify both type I and type II defects. In the event of a low protein C activity, a reflexive immunologic assay should be performed to distinguish between these types. 

As described in Causes, above, there are a number of acquired causes of protein C deficiency. To the extent possible, laboratory testing should be performed in the absence of such causes to confirm that deficiency, when identified, is due to a genetic defect rather than an acquired cause. The timing of testing with respect to acute thrombosis and warfarin therapy deserves special mention.

Acute thrombosis

 The levels of protein C, protein S, and antithrombin are reduced in the setting of acute thrombosis. Therefore, these levels should generally not be performed at the time of presentation with acute VTE. However, a normal protein C activity in this setting essentially rules out hereditary protein C deficiency.

Warfarin

 Because protein C is a vitamin K-dependent protein, its levels are reduced with warfarin administration. Therefore, it is recommended that protein C testing not be performed unless the patient has been off vitamin K antagonist therapy for at least 2 weeks. If the patient has a severe thrombotic diathesis that does not permit discontinuation of anticoagulation, the patient may be temporarily transitioned to low molecular weight heparin (LMWH) for testing purposes or, alternatively, the diagnosis may be inferred through testing of family members.
 
Several investigators have developed ratio methods for diagnosing protein C deficiency in the context of warfarin therapy by comparing the protein C level with that of other vitamin K-dependent clotting factors.53,54 However, such methods have not been broadly validated.

More on Protein C Deficiency

Overview: Protein C Deficiency
Differential Diagnoses & Workup: Protein C Deficiency
Treatment & Medication: Protein C Deficiency
Follow-up: Protein C Deficiency
Multimedia: Protein C Deficiency
References
Further Reading
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References

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Further Reading

Related eMedicine Topics

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National Guideline Clearinghouse

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Keywords

protein C deficiency, thrombophilia, hypercoagulability, venous thromboembolism, VTE, acquired protein C deficiency, warfarin-induced skin necrosis, WISN, neonatal purpura fulminans, NPF, activated protein C resistance, aPC, inherited blood coagulation disorders, inherited blood protein disorders

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Contributor Information and Disclosures

Author

Adam Cuker, MD, Fellowship in Hematology/Oncology, Hospital of the University of Pennsylvania
Adam Cuker, MD is a member of the following medical societies: American Society of Hematology, Hemophilia and Thrombosis Research Society, International Society on Thrombosis and Haemostasis, and National Hemophilia Foundation
Disclosure: Nothing to disclose.

Coauthor(s)

Eleanor S Pollak, MD, Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania
Eleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Medical Editor

David Aboulafia, MD, Medical Director, Bailey-Boushay House; Clinical Professor, Department of Medicine, Division of Hematology, University of Washington
David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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