Evaluation of patients with incident or recurrent venous thromboembolism

Evaluation of individuals with a family history of venous thromboembolism

Evaluation of women with recurrent miscarriage or complications of

pregnancy (eg, severe preeclampsia, abruptio placentae, intrauterine

growth restriction, and stillbirth)

Possibly useful for evaluation of individuals with a history of arterial

thrombosis (eg, stroke, acute myocardial infarction, or other acute

coronary syndromes), especially among young patients (ie, <50 years)

or patients with no other risk factors for arthrosclerosis

Protein C is a vitamin K-dependent protein zymogen (MW = 62,000 da)

that is synthesized in the liver and circulates at a plasma concentration

of approximately 5 ug/mL. Protein C is part of the natural anticoagulant

system. Protein C is activated to activated protein C (APC) via

proteolytic cleavage by thrombin bound to thrombomodulin, an

endothelial cell surface membrane protein. APC down-regulates

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 (APTT) clotting test fails to prolong significantly after the addition

of APC.

The 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.

APCRV RATIO

      > 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 >6 months.

REPORTABLE RANGE

1.0-10.0

An APC-R ratio of <2.3 suggests abnormal resistance to APC of

hereditary origin.

DNA-based testing for the factor V Leiden mutation (#81419, "Factor

V Leiden [R506Q] Mutation, Blood”) may be helpful in confirming or

excluding hereditary APC-resistance, after initial screening with the

APC-resistance test.

This assay is highly sensitive and specific for inherited 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.

This test will not detect patients with acquired APC-resistance.

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, APTT) 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.

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 #550 "Coagulation

Consultation, Thrombosis/Hypercoagulability, Blood and Plasma", which

is employed for Mayo Medical Laboratories or #83093 "Thrombophilia

Profile” for Mayo Clinic.

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