Pregnancy-associated Changes in the Hemostatic System in Wild-Type and Factor V Leiden Mice

J Thromb Haemost. 2009 Feb;7(2):312-8. doi: 10.1111/j.1538-7836.2008.03240.x.

Abstract

Background: Pregnancy, oral contraceptive (OC)use and hormone replacement therapy (HRT) are established risk factors for venous thrombosis. Acquired resistance to activated protein C (APC) has been proposed to contribute to the increased thrombosis risk. Mouse models are often used for preclinical testing of newly developed hormone preparations. However, it is not known whether hormone-induced APC resistance is also observed in laboratory animals.

Objectives: To investigate whether hormonal changes modulate APC resistance in mice, we used pregnant mice as a model of hormone-induced APC resistance. The effect of pregnancy on APC resistance was studied in wild-type and factor (F)V Leiden mice.

Methods: APC resistance was determined in mouse plasma using a thrombin generation-based APC resistance test. APC resistance determinants,i.e. prothrombin, FV, FX, antithrombin and protein S levels,and of tissue factor pathway inhibitor (TFPI) activity were evaluated in plasma from non-pregnant and pregnant mice.

Results: In contrast to humans, pregnancy induced a decrease in APC resistance in wild-type and in FV Leiden mice.Pregnant mice had higher levels of prothrombin, FV, FX,protein S and TFPI activity as compared with non-pregnant mice.

Conclusions: Pregnancy causes a decrease in APC resistance in mice, which can be explained by the elevation of protein S levels and increased TFPI activity in plasma. Our findings show species specificity in the effects of pregnancy on the major determinants of the protein C system and suggest that protein S and TFPI play an important role in the development of pregnancy-induced APC resistance in humans.

MeSH terms

  • Activated Protein C Resistance / diagnosis
  • Activated Protein C Resistance / etiology*
  • Animals
  • Biomarkers / blood
  • Factor V*
  • Female
  • Hemostasis*
  • Lipoproteins / blood*
  • Mice
  • Pregnancy
  • Pregnancy Complications, Hematologic / blood
  • Protein S / analysis*
  • Species Specificity

Substances

  • Biomarkers
  • Lipoproteins
  • Protein S
  • factor V Leiden
  • lipoprotein-associated coagulation inhibitor
  • Factor V