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Test Code APCRR Activated Protein C Resistance V (APCRV), with Reflex to Factor V Leiden, Plasma

Useful For

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


Evaluation of individuals with a family history of VTE

Profile Information

Test ID Reporting Name Available Separately Always Performed
APCRV Activated Protein Resistance V, P Yes Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
F5DNA Factor V Leiden (R506Q) Mutation, B Yes No
F5DNI APCRV/F5DNA Summary Interpretation No No

Testing Algorithm

If the assay ratio is abnormal, then R506Q mutation will be performed at an additional charge.

When the activated protein C resistance V is abnormal or indeterminate and R506Q mutation assay is reflexed, then a summary interpretation will be provided.

Method Name

Clot-Based Assay

Reporting Name

APCRV, w/Reflex, P

Specimen Type

Plasma Na Cit
Whole blood

Specimen Required

See Coagulation Studies in Special Instructions.


Blood and plasma are required.


Specimen Type: Whole blood


Preferred: Yellow top (ACD)

Acceptable: EDTA or sodium citrate

Specimen Volume: Full tube

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Additional Information: Each molecular coagulation test requested must have its own tube.


Specimen Type: Platelet-poor plasma

Collection Container/Tube: Light-blue top (citrate)

Submission Container/Tube: Polypropylene vial

Specimen Volume: 1 mL

Collection Instructions:

1. Spin down, remove plasma

2. Spin plasma again; remove plasma aliquot without disturbing bottom 0.5 mL

3. Freeze specimen aliquots immediately at or below -40 degrees C if possible, but no longer than 4 hours after collection.

Additional Information:

1. Double-centrifuged specimen is critical for accurate results as platelet contamination may cause spurious results.

2. If priority specimen, mark request form, give reason, and request a call-back.

3. Each coagulation assay requested should have its own vial.

Specimen Minimum Volume

Plasma: 0.5 mL
Whole Blood: 3 mL

Specimen Stability Information

Specimen Type Temperature Time
Plasma Na Cit Frozen 14 days
Whole blood Ambient (preferred) 7 days
  Frozen  14 days
  Refrigerated  14 days

Reject Due To


Mild OK; Gross reject


Mild OK; Gross reject


Mild OK; Gross reject



Clinical Information

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 proteolyses 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 clotting test fails to prolong significantly after the addition of APC.


The vast majority of individuals with familial APC resistance have a specific point mutation in the procoagulant factor V gene (1691G->A, factor V Leiden) encoding for a glutamine (Q) substitution for arginine (R)-506 in the heavy chain of factor V (factor V R506Q). This 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 mutation 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 <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 mutation; 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



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.


An activated protein C (APC) resistance ratio of 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 mutation F5DNA / Factor V Leiden (R506Q) Mutation, Blood is performed to confirm or exclude hereditary APC-resistance.


This assay is highly sensitive and specific for inherited activated protein C (APC) resistance, most commonly due to the factor V Leiden mutation, 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. Plasmas 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 blood (plasma) specimen is extremely important to help insure accuracy of results and interpretation.


This assay has greater than 99% sensitivity for detecting presence of factor V Leiden mutation. 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 mutation is clinically indicated, contact Mayo Medical Laboratories at 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 THRMP / Thrombophilia Profile.

Clinical Reference

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

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

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

Method Description

This assay is performed using the HemosIL Factor V Leiden (APC Resistance V) Kit on the ACL TOP instrument. The method uses a modified activated partial thromboplastin time (APTT) test to detect APC resistance. The plasma specimen is prediluted in factor V-deficient plasma. Then the APTT test is performed by incubating patient plasma with a standardized amount of platelet-like phospholipids and activator of the contact factors of the intrinsic coagulation pathway, followed by recalcification of plasma and measurement of clotting time. The ratio of the APTT test with and without added APC is reported as the APC resistance (or sensitivity) ratio.(Package insert: HemosIL Factor V Leiden [APC Resistance V]. Instrumentation Laboratory Company, Bedford, MA, Rev 10/2012)

Day(s) and Time(s) Performed

Monday through Friday

Analytic Time

4-7 days

Specimen Retention Time

7 days

Performing Laboratory

Mayo Medical Laboratories in Rochester

CPT Code Information


LOINC Code Information

Test ID Test Order Name Order LOINC Value
APCRR APCRV, w/Reflex, P 13590-5


Result ID Test Result Name Result LOINC Value
APCR APCRV Ratio 13590-5
INT55 Interpretation 48591-2


1. Coagulation Patient Information (T675) in Special Instructions

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

Test Classification

See Individual Test IDs