Resistance to activated protein C in women using oral contraceptives

Abstract

Resistance to activated protein C (APC resistance) is an important and common risk factor for deep vein thrombosis. The majority of patients with APC resistance carry a mutation on the factor V gene at nucleotide position 1691 (G/A), called factor V Leiden mutation. Besides the factor V Leiden mutation several acquired risk factors like lupus anticoagulant, elevated levels of acute phase proteins (increased plasma levels of factor VIII and fibrinogen), pregnancy, or the use of oral contraceptives are known to induce APC resistance in plasma. We studied the effect of oral contraceptives (OC) on hemostasis variables known to be risk factors for venous thromboembolism, especially looking for acquired APC resistance and the plasmatic factors of the protein C system. We studied 821 women, who were randomly selected and enrolled in the BATER- cohort study (Bavarian Thromboembolic Risk Study), which was carried out in Bavaria (Germany) from 1996 to 1997. Current use of any OC type compared with noncurrent use showed a significantly impaired response to APC. There was no difference in APC response among women currently using OCs of different generations. Coagulation factor VIII was the only factor of the protein C pathway that was not altered under OC use. All other plasmatic factors of the protein C system changed in the expected range as described before. On the other hand, coagulation factor VIII was the only factor of the protein C system which negatively correlated with the APC response in the assays applied. Thus, APC resistance is significantly lower in OC users than in nonusers but cannot be attributed to increased factor VIII levels. Whether a decreased response to APC in OC users is of clinical relevance has to be proven in further studies.

PIP: Activated protein C (APC) resistance has been identified in many studies as a major cause of venous thromboembolism. The most common genetic polymorphism of clinical relevance causing APC resistance is the factor V Leiden mutation (FVL). Besides the FVL mutation, several acquired risk factors like lupus anticoagulant or elevated levels of acute phase proteins are known to induce APC resistance in plasma. Oral contraceptive (OC) users are known to be at higher risk for deep vein thrombosis than nonusers. Therefore, this BATER-cohort study (Bavarian Thromboembolic Risk Study) was conducted in Bavaria, Germany, during 1996-97. A total of 821 women were randomly selected and enrolled in the study to examine the effects of OCs on hemostasis variables known to be risk factors for venous thromboembolism, especially looking for acquired APC resistance and the plasmatic factors of the protein C system. Findings revealed that APC resistance was significantly lower in OC users in comparison with nonusers and was not attributable to the increased factor VIII:C levels. APC methods applied in this study revealed no significant difference between OC users of any type. Therefore, an increase of the risk related to OC use and/or FVL mutation was statistically insignificant.