In our last post, we reviewed several studies that would lend support to the hypothesis that women with elevated levels of plasminogen activator inhibitor-1 (PAI-1), and a genetic predisposition for the same, are at increased risk for adverse pregnancy outcome later in pregnancy. Let me make it quite clear that these studies do not prove that increased PAI-1 causes preeclampsia (or any of the other conditions discussed), but they do suggest that PAI-1 may be a contributor to expression of the disease and particularly the more severe forms of preeclampsia. In today’s post, I would like to begin to build a case with the support of the published scientific literature over the years for an association of increased PAI-1 expression/activity (resulting in decreased fibrinolytic – clot breakdown - activity) with recurrent early pregnancy loss…
In 1993, Gris and colleagues (J Lab Clin Med 1993;122:606-15) evaluated the fibrinolytic system in 116 women who had recurrent early pregnancy loss (RPL) of unknown etiology matched with a group of 90 women who had never had an early miscarriage. Seventy-four of these 116 women with recurrent losses were found to have at least one abnormal test for fibrinolysis compared to none of the control group. A subgroup of 56 women who were shown to have decreased fibrinolytic activity in blood samples taken from veins that were intentionally occluded were selected for further evaluation. Seventeen of these women produced about half the amount of tissue plasminogen activator (t-PA) compared to the controls, 21 had elevated levels of PAI-1 activity, and 16 had both low t-PA and high PAI-1. Other abnormalities that were found among the RPL women were elevated levels of PAI-2 (like that made by the placenta) in nine and decreased urokinase-like plasminogen activator (u-PA) in six. The bottomline is that with these imbalances in the fibrinolytic system, decreased PA activity and/or increased PAI activity, there would be an increased tendency for blood clots to form and not be broken down. These findings led the authors to conclude that “activators and inhibitors of the fibrinolytic system are frequently abnormal in primary habitual aborters” and that “impaired plasmin dependent proteolysis (fibrin clot breakdown) in women might favor recurrent abortion by promoting fibrin deposition in early placental circulation or by limiting trophoblast development.”
Subsequent studies have supported and extended the findings and conclusions above. In 1999, Glueck and colleagues (Metabolism 1999;48:1589-95) found a significant correlation in women with polycystic ovary syndrome (PCOS) between elevated levels of PAI-1, early pregnancy loss, and no live births. These authors concluded it “is a predominant independent significant positive reversible risk factor for miscarriage in women with PCOS.” In 2003, Dossenabch-Glaninger, et al. (Clin Chem 2003;49:1081-6) evaluated 49 women with a history of two consecutive, or 3 to 6 nonconsecutive, early pregnancy losses compared to 48 women without a history of pregnancy loss for several genetic variants of the coagulation system. They found that homozygosity for PAI-1 or the factor XIII 34 Leu polymorphisms or compound heterozygous status (both of these polymorphisms in the same individual) of these same mutations significantly increased the risk for early pregnancy loss (OR = 2.4; 95% CI, 1.1-5.5).
In our last post, we mentioned that PAI-1 produced by vascular endothelial cells is induced by angiotensin II which is generated by the action of angiotensin I converting enzyme (ACE) and that autoantibodies directed against the angiotensin II type 1 receptor (AT1) found in preeclamptic women was associated with associated with increased production of PAI-1 (Xia, et al., J Soc Gynecol Invest 2003;10:82-93). Along the same lines, Buchholz and colleagues (Hum Reprod 2003;18:2473-7) studied the ACE deletion(D)/insertion(I) and the PAI-1 4G/5G polymorphisms in women with RPL, both of which are associated with increased ACE and PAI-1 expression, respectively. Comparing 184 women with a history of two or more consecutive spontaneous abortions with 127 women who had term pregnancies and no early losses, they found that homozygosity for the D allele of the ACE gene (D/D) was significantly correlated with RPL and the presence of the PAI-1 4G/4G homozygous state further increased PAI-1 levels and risk for early pregnancy loss. As a consequence of these findings, the authors recommended “the incorporation of these two polymorphisms into the spectrum of thrombophilic mutations which should be analyzed in individuals with recurrent spontaneous miscarriages.”
In more recent studies, Glueck and colleagues (Metabolism 2005;54:1345-9) reported that even among women who had had live births, if they had also had a spontaneous abortion, they were at greater risk than women who had never lost a pregnancy for having elevated levels of PAI-1 (33% vs 18%) and for the presence of other aberrations of the coagulation cascade: presence of factor V Leiden homozygosity (15.2% vs 1.6%) and elevated levels of factor VIII (31% vs 18%). These findings carried over to similar observations in women with PCOS (Glueck, et al., Metabolism 2006;55:345-52). In this study they assessed the association of PAI-1 levels in 430 women with PCOS who were divided into the following groups: 1) women who had live births only (n = 208); 2) women who had one or more live births and one or more first trimester losses (n = 111); 3) women who had only had first trimester miscarriages (n = 71). They found that “PAI-1 activity was positively associated with first-trimester miscarriage (p = 0.004)” … and “for each 5 IU/mL increment in PAI-1 activity, the risk being in an adverse first-trimester miscarriage …increased (OR, 1.12; 95% CI, 1.04-1.20).” In the same study, they also evaluated the association of the PAI-1 4G polymorphism in 921 women with PCOS compared to 126 normal females and again demonstrated (although the difference was not as dramatic in these women with a more heterogeneous obstetrical history – 78% in the PCOS group compared to 69% in controls) the 4G allele “is more common in women with PCOS than in normal women and, in concert with obesity, hyperinsulinemia, and hypertriglyceridemia, contributes to treatable, hypofibrinolytic, miscarriage-promoting, high PAI-1 activity.”
Coulam and colleagues (Reprod Biomed Online 2006;12:322-7) compared the prevalence of ten thrombophilic gene mutations in 42 women with a history of recurrent implantation failure after IVF embryo transfer with 20 fertile women. They found that the women with implantation failure had a significantly higher prevalence of PAI-1 4G/5G polymorphisms than controls (P = 0.007). Although they found no significant differences in the prevalence of any other single gene mutation, they did find “the prevalence of total gene mutations among patients with implantation failure was significantly higher than among controls. More than 3 gene mutations among the 10 genes studied were observed in 74% of women with implantation failure” compared to 20% of controls (P = 0.0004). They “concluded that inherited thrombophilias are associated with implantation failure” and this highly significant “association is manifest by totatl number of mutations as well as with PAI-1 mutations.”
Using the same approach, Coulam’s group also reported (Am J Reprod Immunol 2006;55:360-5) a comparison between 150 women with two or more recurrent pregnancy losses and 20 fertile women with no history of pregnancy losses. In this study they also found that there were “no differences in the frequency of specific gene mutations…however, the prevalence of homozygous mutations (59% vs 10%) and total gene mutations among patients with recurrent miscarriage was significantly higher than among controls.” As in their previous report, more than 3 mutations among the 10 genes studied were observed in a significantly higher percentage of women with recurrent miscarriage than controls (68% vs 21%). Subsequently, they reported on 550 women with RPL and among the polymorphisms they investigated they found that PAI-1 4G/5G (P = 0.009), factor XIII V34L (P < 0.0001), and homozygous MTHFR C677T (P < 0.0001) correlated significantly with RPL compared to controls.
To summarize today’s post, despite the heterogeneity of findings detailed in the studies referenced above, there seems to be a common thread: recurrent pregnancy loss, in the absence of other explanations (e.g., chromosomal abnormalities, uterine anomalies, chronic maternal disease) is frequently accompanied by imbalances in the fibrinolytic system. These imbalances are uniformly those that lead, theoretically, to decreased fibrinolysis and may include genetic defects of the coagulation system and are frequently accompanied by conditions that lead to increased production of PAI-1. The mechanism by which these factors might actually contribute to an increased risk for recurrent early pregnancy loss will be discussed in the next post…