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Most people are familiar with blood clotting and its importance in the proper functioning of the body. Too much clotting is not healthy and can lead to blocking the blood vessels, causing conditions like stroke, and too little clotting can result in hemorrhage, or internal bleeding. One key compound in the blood’s ability to properly clot is known as plasminogen activator inhibitor-1 or PAI-1.

PAI-1 is a pro-inflammatory adipocytokine, so elevated PAI-1 levels are associated with a pro-thrombotic, inflammatory state, making it a promising marker to potentially be used in clinical medicine as a prognostic and treatment marker for inflammatory conditions such as atherosclerosis and insulin resistance, to name a few. Already, it’s on functional medicine-based lab assessments for providers to incorporate into their patient treatment and in research studies, although it hasn’t quite made it to conventional medicine at this early stage.

Let’s take a look at what PAI is, what roles it plays in the body, how it may relate to various disease states, and why it may be important for your health outcomes.

What Is PAI-1 and What Roles Does It Play?

PAI-1 is a single-chain glycoprotein that’s secreted by endothelial cells (which line the inside of blood and lymphatic vessels) and is involved in the process of blood clotting.

Specifically, it’s inhibiting the action of the plasminogen activator proteins, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA), which are responsible for converting plasminogen—the inactive precursor enzyme—to its active enzyme form, plasmin.

Plasmin is involved in the breakdown of blood clots (i.e., fibrinolysis) by cleaving fibrin for degradation. Therefore, PAI-1 is responsible for the suppression of fibrinolysis activity, making sure blood clots stay intact until they are no longer needed to stop blood loss. As you might imagine, we need PAI-1 activity, but the right amount.

PAI-1 Variants 4G/5G Polymorphisms and Disease

I came to learn more about PAI-1 when I had my genes tested for variants. The most studied PAI-1 genetic variant (or allele) is the 4G/5G polymorphism located on the promoter region of DNA. In this polymorphism, one allele contains a sequence of four guanosine (4G), and the other contains a sequence of 5 guanosine (5G). Both the 4G and 5G alleles have binding sites to activate transcription, whereas the 5G allele has an additional binding site to repress transcription.

What does all this genetic talk mean? Essentially, having the 4G/4G polymorphism (which you can find out by doing a test that will measure gene variants) produces more PAI-1, resulting in reduced fibrinolysis (so more clots) and increased risk for cardiovascular events. Findings in the literature are inconsistent when considering the effects of 4G/5G polymorphisms on chronic disease. Most likely, that’s because of the many other factors that go into whether or not we get disease, like age, gender, environmental factors, and other interacting genetic predispositions, are considered.

Stroke and Venous Thromboembolism:

Reduced fibrinolysis due to 4G/5G polymorphisms increases the risk for ischemic stroke and venous thromboembolism (or VTE, a condition when blood clots form in the deep veins of the leg, groin, or arm). The risk of VTE is significantly increased in individuals with a 4G/5G polymorphism and is even higher for 4G/4G polymorphic individuals. This associated risk is especially evident in Asian populations. In contrast, the 5G/5G polymorphism produces relatively low amounts of PAI-1 and is seen to have a protective effect.

Coronary Artery Disease:

According to a 2015 meta-analysis, PAI-1 4G/5G carriers also have an increased risk for developing coronary artery disease (CAD), especially in Asian, Caucasian, male, and younger populations. These populations may be at increased risk due to gene-environment interactions, but more studies are needed to be sure. CAD is associated with atherosclerotic plaque lesions and enhanced expression of PAI-1 in the vascular wall. Therefore, PAI-1 4G/5G polymorphisms may play a role in the pathology of CAD.

Hypertension:

In a prospective cohort study of black South Africans, PAI-1 4G/5G variants had an increased risk for developing hypertension (high blood pressure) compared to 5G/5G individuals with the highest risk found with 4G/4G individuals. This association was mediated by central obesity and its effect on genetic expression, as evidenced by obese South African women having higher PAI-1 activity and more hypertension than men.

Visceral adipose tissue (commonly referred to as belly fat) is one of the main sites for PAI-1 production, which may explain why increased PAI-1 activity is found with obesity. Elevated PAI-1 activity was also associated with elevated brachial systolic and central blood pressure in both men and women, which supports the association between 4G/5G PAI-1 polymorphisms and hypertension. This relationship makes sense considering angiotensin-converting enzyme (which is responsible for converting angiotensin I to angiotensin II to increase blood pressure) increases PAI-1 activity.

Cancer:

PAI-1 expression is increased in cancer. Therefore, it is biologically plausible that 4G/5G polymorphisms may curb the development and progression of cancer due to its role in cellular adhesion, detachment, and migration. Evidence from a meta-analysis found that PAI-1 4G/4G and 4G/5G polymorphisms were associated with an increased risk for colorectal and endometrial cancer, especially in Caucasians. However, we know that type and severity of cancer is highly dependent on genetic and environmental factors as well.

How Does Dietary Fat Impact PAI-1 Activity?

To determine if 4G/5G polymorphisms play a role in postprandial triglyceride levels, researchers measured fibrinolytic activity (via dilute clot lysis time) in men > 52 years old after a high-oleate, high-palmitate, or low-fat meal. Results indicated that the high-fat meal raised postprandial triglyceride levels but did not affect fibrinolytic activity any more than the low-fat meal.

However, stratification for PAI-1 polymorphisms revealed that 4G/4G and 4G/5G had higher plasma triglyceride levels and PAI-1 activity at baseline (fasting) and after the high-oleate meal compared to 5G/5G individuals. Therefore, fibrinolytic activity is not affected by the fat content of meals, but fasting triglycerides, PAI-1 activity, and blood coagulation are affected with a high-fat meal in 4G allele carriers.

The relationship between dietary fat and PAI-1 may be dependent on the type of fat consumed. In a cross-over study, 4G/4G, 4G/5G, and 5G/5G individuals were randomly assigned a diet either high in saturated fat, monounsaturated fat, or carbohydrates for 28 days. Results showed a significant decrease in PAI-1 activity in 4G/4G and 4G/5G individuals on the monounsaturated fat diet (composed of 80% virgin olive oil) compared to the saturated fat and high-carb diets. Despite the cross-over change in diet and dietary fat, 5G/5G individuals still had the lowest concentrations of PAI-1.

Even more reason to be considering genotype when trying to select the best diet for an individual. Some people may be more primed to respond to certain macronutrients like fat due to genetic variation.

Diet and Lifestyle Changes for Those with PAI-1 Variability and Increased Risk of Cardiovascular Disease

As you can imagine, it would be helpful from a health perspective to know whether you have genetic variability in how your blood clots through the action of PAI-1. Unfortunately, there are too few studies examining people with gene variants and certain modalities. Therefore, these are some food and lifestyle methods that have been assessed for overall lowering of PAI-1 (which would seem to be beneficial in those with gene variants that increase its activity). Once I found out I had variability in how my body expresses PAI-1, I made sure to take extra good care of my blood vessels with a number of these strategies:

• Low-glycemic index diet: A low-glycemic index (GI) diet consisting of whole grains of wheat and rye breads, long-grain rice, and pasta for a daily weighted glycemic index of 72 decreases fasting plasma PAI-1 activity in overweight women.
• Vitamin D: Low levels of vitamin D (<20 ng/mL) are inversely related to PAI-1 concentrations. Vitamin D supplementation to bring serum vitamin D levels up to >30 ng/mL may help reduce PAI-1 levels. Of course, best to have vitamin D levels measured and have a practitioner determine what level of supplementation would be optimal.
• Prebiotic fiber: Foods that contain nondigestible prebiotic fibers like inulin and oligofructose (i.e., onions, garlic, bananas, chicory root, leeks, asparagus) help reduce inflammation and PAI-1 in overweight and obese adults.
• Move around: A sedentary lifestyle relates to higher levels of PAI-1. Engaging in a form of light- to moderate-intensity exercise is beneficial for reducing PAI-1 levels as well as total cholesterol, LDL-cholesterol, and triglycerides.
• Eat colorful, whole foods: This is a strategy I can surely get behind! Consuming a well-rounded, colorful diet of whole foods will ensure adequate consumption of polyphenols, which are associated with lower levels of pro-inflammatory adipocytokines like PAI-1.
• Resveratrol: In cell culture, this antioxidant reduces the expression of PAI-1 through its ability to suppress nuclear factor kappa b (NF-kB), a transcription factor involved in inflammation.
• Omega-3 fatty acids: The research on omega-3 fatty acid supplementation and PAI-1 concentrations is mixed. A fish oil supplement containing 1.08 g of EPA and 0.72 grams of DHA reduced PAI-1 concentrations in type II diabetics but did not reduce PAI-1 gene expression. Increased PAI-1 and prothrombotic activity has also seen with high-dose (4 grams EPA) omega-3 fatty acid intake. This may be due to the nature of PAI-1 looking to counteract excessive inhibition of the coagulation cascade. In general, however, omega-3 fatty acids are thought to reduce blood clotting, which is why they are often stopped pre-surgery.
• Nattokinase: An enzyme found in soybeans fermented with Bacillus nato, native to Japan, nattokinase has been used to increase fibrinolysis and antithrombosis activity for thousands of years by inactivating PAI-1. After a single dose of nattokinase (2,000 FU), fibrinolysis and anti-coagulation mechanisms were enhanced. These findings suggest nattokinase may be a useful intervention for 4G/5G PAI-1 individuals.
• Don’t smoke: Nicotine increases PAI-1 expression from central nervous system endothelial cells and thus increases prothrombotic effects. Individuals with a PAI-1 4G allele are likely more susceptible to the cardiovascular fatalities of smoking.
• Reduce stress: Chronic stress raises PAI-1 levels, decreases fibrinolytic activity, and increases the risk for thrombosis.
• What about OCPs? Despite their link to increased incidence risk of blood clots, low-estrogen oral contraceptive pills are not associated with increased PAI-1 activity. In fact, OCPs have shown to increase fibrinolysis to preserve hemostasis. However, the risk may be elevated in women taking OCPs who are obese, smoke cigarettes, and contain a 4G allele.

Because of the potential health risks associated with the 4G/5G polymorphic variation, it’s a promising marker for the future in clinical medicine. People with this variation will likely benefit from lifestyle changes to decrease these risks. Best to take charge of your health and meet with a healthcare practitioner who can assess your PAI-1 and other genotypes to evaluate a personalized approach for you.

Content contributed by Taylor Groff. Review by Deanna Minich, PhD.