Test Catalog

Test ID: APCRR    
Activated Protein C Resistance V, with Reflex to Factor V Leiden, Blood and Plasma

Useful For Suggests clinical disorders or settings where the test may be helpful

Evaluation of patients with incident or recurrent venous thromboembolism (VTE)


Evaluation of individuals with a family history of VTE

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

If the assay ratio is abnormal, then factor V Leiden variant analysis will be performed at an additional charge.


When the activated protein C resistance V is abnormal or indeterminate and the factor V Leiden variant assay is performed, a summary interpretation will be provided.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Protein C, a part of the natural anticoagulant system, is a vitamin K-dependent protein zymogen (molecular weight=62,000 Da) that is synthesized in the liver and circulates at a plasma concentration of approximately 5 mcg/mL. Protein C is activated to activated protein C (APC) via proteolytic cleavage by thrombin bound to thrombomodulin, an endothelial cell surface membrane protein. APC downregulates the procoagulant system by proteolytically inactivating procoagulant factors Va and VIIIa. Protein S, another vitamin K-dependent coagulation protein, catalyzes APC inactivation of factors Va and VIIIa. APC interacts with and proteolyzes factors V/Va and VIII/VIIIa at specific APC binding and cleavage sites, respectively. Resistance to activated protein C (APC resistance) is a term used to describe abnormal resistance of human plasma to the anticoagulant effects of human APC. APC resistance is characterized by a reduced anticoagulant response of patient plasma after adding a standard amount of APC. For this assay, the activated partial thromboplastin time fails to prolong significantly after the addition of APC.


The vast majority of individuals with familial APC resistance have a specific alteration in the procoagulant factor V gene (F5) encoding for a p.Arg534Gln substitution in the heavy chain of factor V (formerly R506Q). This glutamine to arginine amino acid change alters an APC cleavage site on factor V such that factor V/Va is partially resistant to inactivation by APC. The carrier frequency for the factor V Leiden variant varies depending on the population. Approximately 5% of asymptomatic white Americans of non-Hispanic ancestry are heterozygous carriers, while the carrier frequency among African Americans, Asian Americans, and Native Americans is less than 1%, and the carrier frequency for Hispanics is intermediate (2.5%). The carrier frequency can be especially high (up to 14%) among whites of Northern European or Scandinavian ancestry. Homozygosity for factor V Leiden is much less common but may confer a substantially increased risk for thrombosis. The degree of abnormality of the APC-resistance assay correlates with heterozygosity or homozygosity for the factor V Leiden variant; homozygous carriers have a very low APC-resistance ratio (eg, 1.1-1.4), while the ratio for heterozygous carriers is usually 1.5 to 1.8.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.


> or =2.3

Pediatric reference range has neither been established nor is available in scientific literature. The adult reference range likely would be applicable to children older than 6 months.

Interpretation Provides information to assist in interpretation of the test results

An activated protein C (APC) resistance ratio below 2.3 suggests abnormal resistance to APC of hereditary origin.


If the screening APC resistance test is abnormal, DNA-based testing for the factor V Leiden variant (p.Arg534Gln, formerly R506Q) is performed to confirm or exclude hereditary APC-resistance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This assay is highly sensitive and specific for inherited activated protein C (APC) resistance, most commonly due to the factor V Leiden variant but will not detect patients with acquired APC resistance. Persons with acquired APC resistance are at similar risk for venous thromboembolism.


Preanalytical conditions of the patient and the blood specimen are extremely important for reliable performance and interpretation of testing for APC resistance. Plasma specimens demonstrating prolongation of clotting times (prothrombin time, activated partial thromboplastin time) for reasons other than anticoagulant effects (eg, lupus-like anticoagulants or specific coagulation factor inhibitors) generally cannot be reliably tested for the presence or absence of APC resistance. Proper preparation of the plasma specimen is extremely important to help ensure accuracy of results and interpretation.


This assay has greater than 99% sensitivity for detecting the presence of the factor V Leiden variant. Discrepant results of plasma-based activated protein C resistance ratio (APCRV) and DNA-based factor V Leiden testing may occur in recipients of liver or allogeneic hematopoietic stem cell transplants, or due to anticoagulant effects such as excess heparin, direct thrombin inhibitors argatroban (Acova), bivalirudin (Angiomax) or dabigatran (Pradaxa); or direct factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa); or a sample mix up. Suggest clinical correlation. If DNA-based testing for the factor V Leiden variant is clinically indicated, call 800-533-1710.


Although the APC-resistance assay can be performed in the absence of other coagulation tests and clinical information, it is most reliably performed as part of a consultative coagulation test panel with interpretive reporting (including appropriate testing of the same specimen to evaluate for the presence or absence of coagulation abnormalities or conditions that may affect interpretation of the APC-resistance assay). This test is included among a panel of tests designated AATHR / Thrombophilia Profile, Plasma and Whole Blood.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Nichols WL, Heit JA: Activated protein C resistance and thrombosis. Mayo Clin Proc. 1996;71:897-898

2. Dahlback B: Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol. 1997;34(3):217-234

3. Rodeghiero F, Tosetto A: Activated protein C resistance and Factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med. 1999;130:643-650. doi: 10.7326/0003-4819-130-8-199904200-00004.

4. Grody WW, Griffin JH, Taylor AK, et al: American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001;3:139-148. doi: 10.1097/00125817-200103000-00009. 

5. Press RD, Bauer KA, Kujovich JL, Heit JA: Clinical utility of factor V Leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med. 2002;126:1304-1318. doi: 10.5858/2002-126-1304-CUOFVL.

6.  Yohe S, Olson J: Thrombophilia: Assays and interpretation. In: Kottke-Marchant K, ed: Laboratory Hematology Practice. Wiley Blackwell Publishing; 2012:492-508

Special Instructions Library of PDFs including pertinent information and forms related to the test