The activated protein C (APC) resistance test is a recently described clotting assay that is an important new diagnostic tool to define a cause of hypercoagulability in patients with thrombosis. Defects affecting APC appear to be the most common cause of systemic tendency for excessive clotting. This review will summarize current information as to the incidence and significance of this abnormality.

Protein C, in the presence of its cofactor thrombomodulin and thrombin, is enzymatically cleaved to its active form, Activated Protein C. APC is an important natural anticoagulant which functions by inactivating the critical coagulation factors FVa and FVIIIa.

The many causes of thrombosis include both hereditary and acquired conditions. Inherited predispositions to thrombosis are perhaps the most disturbing clinically, because they affect patients at a younger age. Currently, only about 5-10% of patients with thrombosis have a definable cause of their thrombotic tendency. In the past year, however, groups working independently in California and Europe have found that failure of the APTT to prolong with the addition of activated protein C occurs in 30-40% of patients with an otherwise unknown cause of thrombosis.

Further studies have shown that in 80% of these patients the cause of the APC resistance is a mutant factor V molecule, recently designated factor V Leiden, which is able to clot in the classic coagulation cascade but is resistant to activation by activated protein C.

APC resistance testing is performed on citrated plasma (blue tops) from thrombotic patients with a normal APTT prior to anticoagulant therapy. Briefly, a standard APTT test is performed in the absence and presence of commercially available activated protein C supplied in the APTT activator. In the normal response, the APTT is prolonged in the presence of APC due to the anticoagulant action of this protein. An abnormality is detected by failure to prolong the clotting time resulting from "resistance to APC". The results are reported as a ration of the APC-APTT/APTT with a normal result >2.0 in most laboratories.

Patients with the lowest APC ratios have been described which appear to be homozygous for the abnormal factor V molecule while heterozygotes appear to have ratios intermediate between the normal range and homozygote levels. Further studies are currently underway analyzing whether some other abnormality or group of abnormalities may account for the 20% of positive APC resistance tests not accounted for by the abnormal factor V molecule. 

The finding of an abnormal APC resistance test in a thrombotic patient with an abnormal factor V molecule at present can only be used as an additional piece of information in clinical management. However, knowing this abnormality is present may lower the threshold for placing a patient with a thrombotic tendency on anticoagulants. Currently, replacement of defective factor V is impractical due to its short half-life and the lack of availability of a licensed factor V concentrate. Further clinical implications await additional study.

The activated protein C (APC) resistance test may aid in defining a cause of hypercoagulability in up to 25% of patients with thrombosis and has identified a new congenital cause of thrombosis due to an abnormal factor V molecule. As currently performed, the APC resistance test uses readily available techniques; more specific testing by molecular diagnostic techniques is available. Additional studies may lead to the identification of other causes of hypercoagulability in the near future.