Activated protein C resistance in pregnancy

Factor V Leiden (FVL), the principal inherited cause of activated protein C resistance (APCR), has been linked to the failure of pregnancy with an increased risk of venous thrombosis, fetal loss and pre-eclampsia. Both venous thrombosis and pre-eclampsia are associated with inflammation. In particular pre-eclampsia is associated with a monocyte/macrophage infiltration of the placental bed. That APCR, without FVL, (acquired APCR) may be a marker of thrombotic potential out-with pregnancy has been suggested by the association of venous thrombosis with the combined oral contraceptive pill and more recently by the association of venous thrombosis with a low activated protein C sensitivity ratio (the APC:SR). Changes in sensitivity to APC (assessed by the APC:SR) occur in normal pregnancy. The aetiology and significance of this phenomenon has not been fully characterised. In this thesis, the pattern of change in APC:SR in pregnancy was detailed in FVL negative subjects. The relationship of the APC:SR to other coagulation factors and thrombin generation was investigated. The significance of the APC:SR to the mother and the fetus was also examined. To investigate if a link (via thrombin) exists between the APC:SR and the inflammatory response, the inflammatory marker ICAM-1 was examined on the monocyte. The influence of thrombin on the expression of this marker was examined in vitro and the relationship between the APC:SR in pregnancy and ICAM-1 was examined ex vivo. In a prospective study of 1046 pregnancies, the APC:SR at 7-15 weeks gestation showed a significant relationship with blood group and smoking, with higher APC:SRs observed in non-smokers and blood group 0 subjects. No significant relationship of APC:SR with body mass index, waist circumference, age, alcohol consumption, or family history of venous thrombosis or pregnancy-induced hypertension in a first degree relative was observed. In ~75% of pregnancies, a fall in APC:SR with increasing gestation was seen. Those who showed a fall in APC:SR (i.e. an increase in APCR) with increasing gestation had higher absolute APC:SR values at 7-15 weeks gestation than those who did not show a fall. APC:SR values less than the reference range observed in non-pregnant females were seen in 38% of subjects in the third trimester of pregnancy (28 to 40 weeks gestation) in the absence of FVL or elevated ACAs. In subjects without elevated ACAs or FVL, the APC:SR showed a significant negative relationship with factor VIIIc, factor Vc, and a positive relationship with free protein S. The relationship to factor VIIIc is compatible with the association of APCR and inflammatory disorders and with the association of non-blood group 0, higher factor VIIIc levels and venous thrombosis. The relationship with factor Vc is consistent with in vitro evidence that the APC:SR may be affected by factor V. (Abstract shortened by ProQuest.)