Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors

Abstract

During pregnancy the plasma concentration of two different inhibitors of plasminogen activators (PAIs) increases. The only one found in the plasma of nonpregnant women (PAI1) is immunologically related to a PAI of endothelial cells; its plasma activity, as deduced from the inhibition of single-chain tissue-type plasminogen activator (t-PA), increased from 3.4 +/- 2.3 U/mL (mean +/- 95% confidence limits) in the plasma of nonpregnant women to 29 +/- 7 U/mL at term, and its antigen level, measured by a radioimmunoassay, increased from 54 +/- 17 ng/mL to 144 +/- 25 ng/mL. In pregnancy plasma a second PAI (PAI 2) related to a PAI found in placenta extracts was observed. Its level, quantified with a radioimmunoassay, increased from below the detection limit (approximately 10 ng/mL) in normal plasma to 260 ng/mL at term. One hour after delivery, PAI 1 activities and antigen decreased sharply, but the PAI 2 antigen levels remained constant. Three days later, the PAI 1 antigen levels had fallen to normal levels, but the PAI 2 antigen levels were still at least eightfold above the nonpregnant values. During pregnancy, the t-PA and prourokinase (u-PA) antigen concentrations increased 50% and 200%, respectively, whereas the plasminogen and alpha 2-antiplasmin levels remained constant. Despite the large variations in the levels of PAs and PAIs, the overall fibrinolytic activity as measured in diluted plasma by a radioiodinated fibrin plate assay did not change significantly. Just after delivery, a great increase in the t-PA antigen levels was observed. Three to five days after delivery most parameters of the fibrinolytic system were normal again. Our results demonstrate that during pregnancy and in the puerperium profound alterations of the fibrinolytic system occur that are characterized by increases in PAs and their inhibitors, but these alterations do not affect the overall fibrinolytic activity.

Plasminogen activator inhibitors (PAI-1 and PAI-2) in normal pregnancies, pre-eclampsia and hydatidiform mole

“…Bonnar et al (1971) reported that overall plasma fibrinolytic activity was decreased and that this was accompanied by an increase of an inhibitor of urokinase-induced lysis in subjects with the disorder; Chmielewska et al (1983) reported an increase in fast acting inhibitor activity against t-PA in plasma from women with pre-eclampsia. It is now known that in pregnancy two distinct inhibitors of plasminogen activator (PAI-1 and PAI-2) exist in circulating blood (Kruithof et al 1987;Booth et al 1988b;Reith et al 1989). PAI-1 is present in nonpregnant individuals in significant quantities in both plasma and platelets (Booth et al 1988a) and plasma levels are altered in a variety of disease states whereas platelet levels tend not to vary (Simpson etal.…”

“…plasma, while PAI-1 normally circulates at about 20 ng/ml (Booth et al 1988a). The profile of these inhibitors in normal pregnancy has been established (Kruithof et al 1987;Booth et al 1988b). In normal pregnancy, levels of both inhibitors in plasma rise, PAI-1 to maximum levels of over 100 ng/ml and PAI-2 to 200 ng/ml at 30-35 weeks gestation.…”

Regulation of the plasminogen activator inhibitor-2 (PAI-2) gene in murine macrophages. Demonstration of a novel pattern of responsiveness to bacterial endotoxin

“…The most studied physiological regulator of PAI-2 gene expression in macrophages is bacterial endotoxin, lipopolysaccharide (LPS), which induces PAI-2 mRNA and protein in both primary human monocytes and human monocyte-like cell lines [17][18][19][20][21]. Endotoxin is an archetypal inflammatory mediator and it is the actions of this compound on macrophages that induces the symptoms of toxic shock in septicemia: fever, hypotension, disseminated intravascular coagulation (DIC), and hypoxia.…”

The undecided serpin

“…One of the most physiologically striking observations for PAI-2 concerns its association with pregnancy. Plasma levels of PAI-2 increase impressively during the third trimester of pregnancy (up to 250 ngAEmL )1 ) and are maintained at these levels for up to 1 week postpartum and then rapidly decline [10]. The tissue source of plasma PAI-2 is the placenta itself.…”

“…General biology of PAI-2 PAI-2 was defined as a placental tissue-derived uPA inhibitor over three decades ago [8], which was subsequently verified by others [9,10]. Human PAI-2 consists of a single chain protein of 415 amino acids encoded by a 1900 bp PAI-2 transcript and is highly homologous with mouse and rat PAI-2.…”