Fruit of the Womb
Fruit of the Womb

Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 1 - Introduction

In a post at the end of September, we summarized a series of questions from a 26 year old, otherwise healthy, reader who had had recurrent early first trimester pregnancy losses. Her ‘work-up’ to date had been relatively unremarkable, however, she was found to be a carrier for the plasminogen activator inhibitor-1 (PAI-1) 4G/4G polymorphism and her queries revolved around the possible role of PAI-1 polymorphisms in recurrent pregnancy loss (RPL), options for ‘therapy’, and the utility and safety of such therapy. In the last comment from her cited in that earlier post, she notified us that she had actually conceived again, but unfortunately, a few days later, she again miscarried. Is her PAI-1 polymorphism contributing to her early losses? To be honest with you, I don’t know at this point. I can think of other possibilities that may be just as likely, but her questions are very good ones, and it was well worth my time to look into the literature on the issue and perhaps draw some conclusions that may help her or another reader who is in a similar situation...

First of all, what is PAI-1? The best way to explain PAI-1 is to describe what it does. The blood clotting system is made up of many different factors, some which cause a clot to form and others which cause the clot to breakdown, and these coexist in a very delicate balance. When the blood clotting pathways are activated, fibrinogen, a soluble plasma glycoprotein, is polymerized to form fibrin which is then cross-linked by the action of factor XIII to form the ‘clot’. Under normal circumstances, as soon as a clot forms, it begins to be broken down by other plasma factors. Specifically, a substance called tissue plasminogen activator (tPA) converts an inactive plasma protein, plasminogen, to the active substance, plasmin, which then plays a critical role in the breakdown of fibrin (fibrinolysis), thereby ‘dissolving’ the clot. (Interestingly, and perhaps germane to our discussion at some later point, plasmin also plays important roles in ovulation, cell migration, and epithelial cell differentiation).

PAI-1 fits into this balance as the primary inhibitor of tPA and other ‘plasminogen activators’ in the blood. To put its role in perspective, by inhibiting tPA, PAI-1 prevents the activation of plasminogen, thereby controlling the rate and extent of fibrin degradation (clot break down, or fibrinolysis) that occurs. Overactivity of PAI-1 will therefore lead to a tendency to form (or maintain) clots and an underactivity will result in an increased risk for bleeding. (With regard to other known functions of plasmin mentioned above, overactivity of PAI-1 might then also impair ovulation, cell migration, and epithelial cell differentiation).

Control of PAI-1 production is complex, but it is at least partly determined on a genetic basis. Certain polymorphisms of PAI-1, 4G/4G and 4G/5G, are associated with increased blood concentrations of PAI-1. Elevated PAI-1 levels have been correlated with risk for both arterial and venous thromboembolic conditions (e.g., deep venous thrombosis, pulmonary embolism, and stroke) and atherosclerotic disease (.eg., coronary and carotid artery disease), especially if other genetic (e.g., factor V Leiden; prothrombin G20210A; MTHFR polymorphisms; protein C, protein S, and antithrombin III deficiencies) or inherited (e.g., antiphospholipid antibodies; lupus anticoagulant; anti-beta-1-glycoprotein) thrombophilias are also present. Individuals with insulin resistance syndromes and diabetes mellitus frequently have elevated PAI-1 levels. Obesity and hyperlipidemia are also associated with elevated PAI-1 and under certain circumstances, weight reduction and/or reduction in cholesterol and triglycerides, can lead to reduction in PAI-1 levels.

In our next post on this subject, we will begin to explore the possible association and mechanisms of PAI-1 activity with adverse pregnancy outcome and recurrent pregnancy loss…
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