Nattokinase

• Supports cardiovascular health by breaking down fibrin and blood clots
• May help maintain healthy blood pressure levels
• Potential to reduce risk of thrombosis and related cardiovascular events
• May improve blood circulation and reduce hypercoagulation

• May help reduce inflammation associated with cardiovascular disease
• Potential to support overall vascular health
• May help reduce fibrinogen levels in the blood
• Possible neuroprotective effects
• May support healthy lipid profiles

Nattokinase (NK) is a serine protease enzyme produced by Bacillus subtilis during the fermentation of soybeans to create natto, a traditional Japanese food. Its primary mechanism of action centers on its potent fibrinolytic (fibrin-dissolving) and antithrombotic properties. Nattokinase works through multiple pathways to affect blood coagulation and fibrinolysis. First, it directly hydrolyzes fibrin, the insoluble protein that forms the structural scaffold of blood clots.

This direct fibrinolytic activity allows nattokinase to break down existing blood clots and prevent the excessive formation of new ones. Second, nattokinase enhances the body’s endogenous fibrinolytic system by converting plasminogen to plasmin, which is the body’s primary fibrin-degrading enzyme. It increases tissue plasminogen activator (tPA) activity while simultaneously decreasing plasminogen activator inhibitor-1 (PAI-1) activity, thereby enhancing the body’s natural clot-dissolving mechanisms. This dual action—both direct fibrinolysis and enhancement of the body’s own fibrinolytic system—makes nattokinase particularly effective.

Third, nattokinase has been shown to decrease the activity of specific coagulation factors, including Factor VIII (anti-hemophilic factor) and Factor VII (proconvertin), which are involved in the intrinsic and extrinsic coagulation pathways, respectively. By modulating these factors, nattokinase helps maintain a balanced coagulation state. Fourth, nattokinase has demonstrated the ability to reduce plasma levels of fibrinogen, a soluble protein that is converted to fibrin during the clotting process. Elevated fibrinogen is a risk factor for cardiovascular disease, and its reduction may contribute to nattokinase’s cardioprotective effects.

Fifth, research suggests that nattokinase may have antihypertensive properties through the inhibition of angiotensin-converting enzyme (ACE) and the production of vasodilating compounds. This may contribute to its overall cardiovascular benefits beyond its thrombolytic effects. Sixth, nattokinase appears to inhibit platelet aggregation and activation, which are early steps in the clotting cascade. This antiplatelet activity further contributes to its antithrombotic effects.

Seventh, some studies indicate that nattokinase may have anti-inflammatory properties, potentially reducing the production of pro-inflammatory cytokines associated with cardiovascular disease. Unlike some pharmaceutical thrombolytics, nattokinase can be effective when taken orally, with research demonstrating that it can be absorbed from the gastrointestinal tract into the bloodstream in its enzymatically active form. This oral bioavailability is a significant advantage for its use as a dietary supplement. It’s important to note that while nattokinase shares some mechanisms with pharmaceutical anticoagulants and thrombolytics, its effects are generally milder and it works through multiple pathways rather than targeting a single specific factor in the coagulation cascade.

Nattokinase dosage is typically measured in Fibrinolytic Units (FU), which quantify the enzyme’s activity rather than simply its weight. The standard dosage range for general cardiovascular support is typically 1,000-4,000 FU per day. Most commercial supplements provide between 1,000-2,000 FU per capsule or tablet. For preventive purposes, a common recommendation is 2,000 FU once daily, while therapeutic applications may use 2,000-4,000 FU daily, often divided into two doses.

It’s important to note that nattokinase should typically be taken on an empty stomach (at least 30 minutes before meals or 2 hours after) to maximize absorption and effectiveness, as food may interfere with its enzymatic activity. Enteric-coated or delayed-release formulations are preferred to protect the enzyme from degradation by stomach acid.

Nattokinase faces significant bioavailability challenges as a protein-based enzyme. When taken orally, it is vulnerable to degradation by stomach acid and digestive proteases in the gastrointestinal tract. Despite these challenges, research has demonstrated that nattokinase can be absorbed from the intestinal tract in its active form, though the exact bioavailability rate has not been precisely determined in comprehensive human studies. A landmark study by Fujita et al.

(1995) using a rat model demonstrated that nattokinase can be absorbed from the intestinal tract into the bloodstream, maintaining its enzymatic activity. A human pharmacokinetic study by Ero et al. (2013) detected nattokinase activity in human serum after oral administration, confirming its absorption. The peak activity was observed approximately 13 hours after ingestion, with detectable activity persisting for up to 24 hours.

This relatively long half-life suggests that once-daily dosing may be sufficient for maintaining therapeutic levels. To overcome the bioavailability limitations, most commercial nattokinase supplements are formulated with enteric coatings or delayed-release technologies that protect the enzyme from stomach acid, allowing it to reach the small intestine where absorption can occur. The timing of administration (on an empty stomach) also significantly impacts bioavailability, as food can trigger increased production of digestive enzymes that may degrade nattokinase.

Enteric coating or delayed-release capsule technology to protect the enzyme from stomach acid degradation, Taking on an empty stomach (30-60 minutes before meals or 2 hours after meals) to minimize exposure to food-stimulated digestive enzymes, Standardized enzyme activity units (FU) to ensure adequate active enzyme delivery despite bioavailability limitations, Consistent timing of doses to maintain therapeutic levels, Some formulations include additional compounds that may help stabilize the enzyme during digestion, Avoiding simultaneous consumption of proteolytic enzyme inhibitors found in certain foods

For optimal absorption and effectiveness, nattokinase should be taken on an empty stomach, typically 30-60 minutes before meals or at least 2 hours after meals. This timing minimizes the presence of food-stimulated digestive enzymes that could degrade the nattokinase before absorption. When used for cardiovascular support or hypercoagulation, consistent daily dosing is important to maintain therapeutic effects. Due to nattokinase’s relatively long half-life (with activity detectable up to 24 hours after ingestion), once-daily dosing is often sufficient for most preventive applications.

For those taking higher daily doses (3,000-4,000 FU), dividing into morning and evening doses (both on empty stomach) may help maintain more consistent blood levels. It’s important to note that nattokinase should not be taken simultaneously with blood-thinning medications unless specifically directed and monitored by a healthcare provider. For individuals undergoing surgical procedures, nattokinase is typically discontinued at least 1-2 weeks before surgery due to its anticoagulant effects, and should only be resumed under medical supervision.

• Increased risk of bleeding or bruising due to anticoagulant effects
• Gastrointestinal discomfort, including nausea, bloating, or diarrhea (uncommon)
• Allergic reactions, particularly in individuals with soy allergies (rare)
• Skin rash or itching (rare)
• Headache (rare)
• Dizziness (rare)
• Potential for hypotension in sensitive individuals (rare)

• Active bleeding disorders or conditions with high bleeding risk
• Recent or planned surgery (within 2 weeks)
• Severe liver or kidney disease
• History of hemorrhagic stroke
• Severe uncontrolled hypertension
• Pregnancy and breastfeeding (due to insufficient safety data)
• Known allergy or hypersensitivity to nattokinase, soybeans, or other soy products
• Concurrent use of multiple anticoagulant medications without medical supervision
• Peptic ulcer disease or other conditions with risk of gastrointestinal bleeding

• Anticoagulant medications (warfarin, heparin, direct oral anticoagulants): May increase bleeding risk
• Antiplatelet drugs (aspirin, clopidogrel): May have additive effects on platelet inhibition and increase bleeding risk
• Fibrinolytic drugs (tPA, streptokinase): May enhance fibrinolytic effects and increase bleeding risk
• NSAIDs (ibuprofen, naproxen): May increase bleeding risk, especially with long-term use
• Herbs with anticoagulant properties (ginkgo biloba, garlic supplements, fish oil): May have additive effects on blood thinning
• Antihypertensive medications: Theoretical risk of enhanced blood pressure lowering effects
• Supplements that affect platelet function (high-dose vitamin E, ginger): May have additive effects on bleeding risk

The upper limit for safe nattokinase dosage has not been definitively established through comprehensive safety studies. Most clinical studies have used dosages ranging from 1,000-4,000 FU daily without reporting significant adverse effects. However, higher dosages increase the theoretical risk of bleeding complications, especially in vulnerable individuals or those taking other anticoagulants. As a general precaution, it is advisable not to exceed 4,000 FU per day without medical supervision.

A comprehensive toxicological assessment published by Lampe and English (2016) found that nattokinase derived from Bacillus subtilis var. natto was safe at the doses typically used in supplements. However, individual tolerance and response can vary significantly, and some sensitive individuals may experience side effects even at standard dosages. The risk-benefit profile should be carefully considered for each individual, particularly for those with pre-existing bleeding disorders or those taking other medications that affect blood coagulation.

In the United States, nattokinase is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. It has not been approved by the FDA as a drug for treating, curing, or preventing any disease. As a dietary supplement, nattokinase products cannot legally make specific disease claims on their labels or in marketing materials. Manufacturers are responsible for ensuring the safety of their products before marketing, but pre-market approval is not required by the FDA.

The FDA can take action against unsafe products or those making unsubstantiated health claims after they reach the market. In 2015, the FDA acknowledged a Generally Recognized as Safe (GRAS) notification for nattokinase (NSK-SD) for use as an ingredient in certain foods, though this does not constitute formal approval. Nattokinase has not undergone the FDA’s New Drug Application (NDA) process, which would be required for it to be marketed as a pharmaceutical with specific therapeutic claims.

Japan: In Japan, where nattokinase originated, it is regulated as a Food for Specified Health Uses (FOSHU) when certain criteria are met. FOSHU products can make specific health claims that have been approved by Japanese regulatory authorities based on scientific evidence. Nattokinase is also available as a general dietary supplement in Japan.

Eu: In the European Union, nattokinase is regulated as a food supplement. The European Food Safety Authority (EFSA) has not approved any specific health claims for nattokinase products. In 2012, the EFSA issued a scientific opinion stating that a cause-and-effect relationship had not been established between nattokinase consumption and maintenance of normal blood pressure. Regulations may vary somewhat between individual EU member states.

Canada: Health Canada regulates nattokinase as a Natural Health Product (NHP). Products containing nattokinase must have a Natural Product Number (NPN) to be legally sold in Canada. Health Canada has approved certain claims for nattokinase products, including ‘helps support cardiovascular health’ under specific conditions.

Australia: The Therapeutic Goods Administration (TGA) regulates nattokinase as a complementary medicine. Products containing nattokinase must be listed on the Australian Register of Therapeutic Goods (ARTG) before they can be legally supplied in Australia. In 2019, the TGA updated its regulations to require additional warning statements on nattokinase products regarding potential interactions with blood-thinning medications.

China: In China, nattokinase is regulated as a health food ingredient. Products containing nattokinase must obtain health food approval from the China Food and Drug Administration (CFDA) before they can be marketed with specific health claims.

South Korea: The Korean Food and Drug Administration (KFDA) regulates nattokinase as a health functional food ingredient. Certain health claims are permitted for nattokinase products that meet specific standards.

Moderate to High

Nattokinase supplements typically cost between $0.30 and $1.00 per day for a standard dose of 2,000 FU, depending on the brand, quality, and whether it’s purchased in bulk. This translates to approximately $9 to $30 per month. Higher-quality products with standardized potency, enteric coating, and third-party testing tend to be at the upper end of this price range. Products using the proprietary NSK-SD form of nattokinase, which has been used in many clinical studies, are typically more expensive than generic nattokinase supplements.

Some specialized formulations that combine nattokinase with other cardiovascular support ingredients may cost up to $1.50 per day. The extraction and purification process for nattokinase is relatively complex, contributing to its moderate to high cost compared to many other dietary supplements.

The value proposition of nattokinase depends largely on the specific health concern being addressed and individual response. For cardiovascular applications, particularly in individuals with hypercoagulation or those at risk of thrombotic events who cannot tolerate conventional medications, nattokinase may offer good value despite its moderate to high cost. When compared to pharmaceutical anticoagulants, nattokinase is generally more expensive than generic medications like warfarin but may be comparable to or less expensive than newer direct oral anticoagulants (DOACs). However, pharmaceuticals have the advantage of insurance coverage in many cases, while supplements are typically paid out-of-pocket.

The scientific evidence supporting nattokinase’s cardiovascular benefits is relatively strong compared to many other supplements, which may justify its cost for those seeking evidence-based natural approaches to cardiovascular health. For blood pressure support, nattokinase may offer reasonable value compared to other natural approaches, with clinical studies showing significant reductions in both systolic and diastolic blood pressure. When comparing different nattokinase products, higher-priced options from established manufacturers often provide better standardization of enzyme activity and more reliable enteric coating, potentially offering better value despite the higher upfront cost. Products using the NSK-SD form of nattokinase, while more expensive, have the advantage of being used in most clinical studies, providing greater confidence in their efficacy.

For preventive use in generally healthy individuals, the cost-benefit ratio may be less favorable, and other lifestyle interventions (such as diet, exercise, and stress management) may offer better value for cardiovascular health. The cost-effectiveness of nattokinase may be enhanced when used as part of a comprehensive approach to cardiovascular health rather than as a standalone intervention.

Nattokinase, being a protein-based enzyme, has inherent stability challenges. In properly formulated and packaged supplements, nattokinase typically has a shelf life of 2-3 years from the date of manufacture when stored according to recommendations. However, once the container is opened, the shelf life may be reduced due to potential exposure to moisture, air, and temperature fluctuations. The enzyme activity can gradually decrease over time, even in unopened packages, which is why most manufacturers include an expiration date.

Some manufacturers use specialized processing techniques and stabilizing agents to extend shelf life. For example, NSK-SD is a proprietary form of nattokinase that has been processed to enhance stability. It’s important to note that the actual enzyme activity may decrease before visible signs of degradation appear, so adhering to expiration dates is particularly important for enzymatic supplements like nattokinase.

Store nattokinase supplements in a cool, dry place away from direct sunlight, ideally at temperatures between 59-77°F (15-25°C). Avoid storing in bathrooms or kitchens where humidity levels can fluctuate significantly. Keep the container tightly closed when not in use to protect from moisture, which can accelerate enzyme degradation. If the product comes with a desiccant packet, leave it in the container to continue absorbing moisture.

Refrigeration is generally not necessary and may actually introduce moisture through condensation when the container is opened, unless specifically recommended by the manufacturer. Freezing is not recommended as freeze-thaw cycles can denature the enzymes. If traveling with nattokinase, keep it in its original container and protect from extreme temperatures. For long-term storage, consider using airtight containers with desiccants if the original packaging is not resealable.

Exposure to moisture, which can activate the enzymes prematurely and lead to self-degradation, High temperatures (above 86°F/30°C), which can denature the protein structure of the enzymes, Acidic environments, such as stomach acid, which is why enteric coating is essential for oral supplements, Proteolytic enzymes in the digestive tract, which can break down nattokinase if not protected, Oxidation from prolonged exposure to air, which can alter the enzyme structure and reduce activity, UV light and direct sunlight, which can degrade the protein components, Microbial contamination, which can occur if the product is exposed to moisture, Chemical interactions with certain minerals or compounds in multi-ingredient formulations, Freeze-thaw cycles, which can disrupt the protein structure, Extended storage beyond the expiration date, as enzyme activity naturally decreases over time

Synthesis Methods

Natural Sources

Quality Considerations

Nattokinase has its origins in natto, a traditional Japanese fermented soybean food that has been consumed for over 1,000 years. Natto itself has a long history in Japanese culture, dating back to the Jomon period (10,000-300 BCE), though it became more widely consumed during the Edo period (1603-1867). Traditionally, natto was made by wrapping cooked soybeans in rice straw, which naturally contained the bacterium Bacillus subtilis var. natto, and allowing them to ferment.

The resulting food was valued not only as a protein source but also for its perceived health benefits. While natto has been consumed for centuries, the specific enzyme nattokinase was not identified until much more recently. In 1980, Dr. Hiroyuki Sumi, a researcher at the University of Chicago Medical School, was searching for a natural substance that could dissolve blood clots.

He tested various foods on artificial thrombi (blood clots) and discovered that natto had a remarkable ability to dissolve the clots. Further investigation led to the isolation of the enzyme responsible for this effect, which Dr. Sumi named ‘nattokinase.’ The first scientific paper on nattokinase was published in 1987, describing its fibrinolytic properties. Following this discovery, research on nattokinase expanded in Japan and later internationally.

By the 1990s, methods for extracting and purifying nattokinase were developed, leading to the first commercial nattokinase supplements in Japan. These early supplements were primarily marketed for cardiovascular health based on nattokinase’s fibrinolytic properties. In the early 2000s, nattokinase began to gain popularity in Western countries as interest in traditional Asian remedies and natural approaches to cardiovascular health increased. The first standardized form of nattokinase, NSK-SD, was developed by Japan Bio Science Laboratory Co., Ltd.

and has been used in many clinical studies. Throughout the 2000s and 2010s, scientific research on nattokinase expanded beyond its fibrinolytic effects to include potential benefits for blood pressure, inflammation, and other aspects of cardiovascular health. This research has helped establish nattokinase as one of the better-studied natural supplements for cardiovascular support. In recent years, interest in nattokinase has continued to grow, with new applications being explored, including its potential role in addressing biofilms in chronic infections and possible neuroprotective effects.

The COVID-19 pandemic also sparked renewed interest in nattokinase due to concerns about hypercoagulation associated with the disease, though it’s important to note that nattokinase has not been approved for treating or preventing COVID-19. Today, nattokinase is widely available as a dietary supplement globally, with Japan, the United States, and various European and Asian countries being major markets. It represents an interesting case of traditional food wisdom being validated and expanded upon by modern scientific research.

Clinical trials investigating nattokinase’s effects on cardiovascular outcomes in various at-risk populations, Studies examining the potential of nattokinase as an adjunctive therapy for individuals with established cardiovascular disease, Research on nattokinase’s effects on specific markers of coagulation and inflammation in different populations, Investigations into the potential synergistic effects of nattokinase with other natural compounds for cardiovascular health