Pregnancy-associated changes in the hemostatic system in  wild-type and factor V Leiden mice.
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.


OBJECTIVE
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.
Tchaikovski
S N
SN
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
van Vlijmen
B J M
BJ
Cleuren
A C A
AC
Thomassen
M C L G D
MC
Tchaikovski
V
V
Tans
G
G
Rosing
J
J
D020016:Activated Protein C Resistance / Q000175:diagnosis / Q000209:etiology*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D005165:Factor V; D005260:Female; D006487:Hemostasis; D008074:Lipoproteins / Q000097:blood*; D051379:Mice; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000097:blood; D017293:Protein S / Q000032:analysis*; D013045:Species Specificity
D015415:Biomarkers; D008074:Lipoproteins; D017293:Protein S; C095381:factor V Leiden; C051928:lipoprotein-associated coagulation inhibitor; D005165:Factor V