What Is Nattokinase and How Does It Work?

Introduction

Nattokinase occupies an unusual position in cardiovascular medicine. It is a potent fibrinolytic enzyme derived from a traditional Japanese food, backed by decades of laboratory research, yet it remains outside mainstream clinical practice. For patients interested in evidence-based approaches to cardiovascular health, understanding what nattokinase actually is and how it works provides the foundation for evaluating whether it might have a role in their care.

This article addresses the fundamental questions about nattokinase: its origins, its proposed mechanisms of action, how it compares to pharmaceutical thrombolytics, whether it survives digestion, and how long its effects persist. The answers reveal both genuine biological activity and significant gaps in clinical evidence. Subsequent articles in this series examine the cardiovascular evidence, effects on atherosclerosis, drug interactions, and practical considerations for those considering nattokinase.

What is nattokinase and how is it derived from natto?

Nattokinase is a serine protease enzyme produced during the fermentation of soybeans by the bacterium Bacillus subtilis var. natto. The enzyme was first identified and characterized in 1987 by Japanese researcher Hiroyuki Sumi, who discovered its potent fibrinolytic activity while searching for natural thrombolytic agents. The name “nattokinase” reflects its origin in natto, a traditional Japanese food with a distinctive sticky texture and strong flavor that has been consumed for over a thousand years (Sumi et al., 1987).

The fermentation process creates nattokinase as a byproduct of bacterial metabolism. Bacillus subtilis secretes the enzyme extracellularly, meaning it accumulates in the fermented soybean matrix rather than remaining trapped inside bacterial cells. This makes extraction relatively straightforward compared to intracellular enzymes. Commercial nattokinase supplements are produced either by extracting and purifying the enzyme from fermented soybeans or through recombinant production methods.

Nattokinase belongs to the subtilisin family of proteases, which explains its alternative scientific name, subtilisin NAT. It consists of 275 amino acids with a molecular weight of approximately 28 kDa. The enzyme’s structure has been well characterized, and its active site contains the serine-histidine-aspartate catalytic triad typical of serine proteases. This biochemical foundation provides the basis for understanding its mechanism of action.

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What is the proposed mechanism of action?

Nattokinase exerts its fibrinolytic effects through multiple complementary pathways. The enzyme directly cleaves cross-linked fibrin, the protein meshwork that forms the structural scaffold of blood clots. This direct fibrinolytic activity distinguishes nattokinase from tissue plasminogen activator (tPA), which requires conversion of plasminogen to plasmin before fibrin degradation can occur. Animal studies have demonstrated that nattokinase restores blood flow in experimentally induced arterial thrombi through this direct mechanism (Fujita et al., 1995).

Beyond direct fibrin degradation, nattokinase enhances the body’s endogenous fibrinolytic system through several indirect mechanisms. Research has shown that nattokinase cleaves and inactivates PAI-1, the primary inhibitor of tissue plasminogen activator. By reducing PAI-1 activity, nattokinase amplifies the body’s natural clot-dissolving capacity (Urano et al., 2001). Additionally, cell culture studies suggest that nattokinase promotes tPA release from endothelial cells, further enhancing fibrinolytic potential (Yatagai et al., 2008).

Recent research has identified additional mechanisms beyond fibrinolysis. Nattokinase appears to inhibit platelet aggregation through effects on thromboxane B2 formation, and it may interrupt inflammatory pathways that contribute to thrombosis. These anti-inflammatory and antiplatelet properties suggest the enzyme’s cardiovascular effects may extend beyond simple clot dissolution, though the clinical significance of these mechanisms remains to be established in human trials (Wu et al., 2020).

How does nattokinase differ from pharmaceutical thrombolytics?

Pharmaceutical thrombolytics like tPA, streptokinase, and tenecteplase are administered intravenously in hospital settings for acute thrombotic emergencies such as myocardial infarction and ischemic stroke. These agents work primarily by activating plasminogen, which then degrades fibrin. Their potency requires careful dosing and monitoring because excessive fibrinolysis can cause life-threatening bleeding. In contrast, nattokinase is taken orally as a supplement for cardiovascular maintenance rather than acute treatment (Weng et al., 2017).

The pharmacological profiles differ substantially. Pharmaceutical thrombolytics have half-lives measured in minutes, requiring continuous infusion for sustained effect. Their activity is largely systemic, affecting fibrinolysis throughout the body. Nattokinase, by contrast, has a longer duration of action following oral dosing and appears to have more modest effects on systemic fibrinolytic markers. This makes nattokinase unsuitable for treating acute clot emergencies but potentially safer for long-term prophylactic use.

The evidence base also differs dramatically. Pharmaceutical thrombolytics have been evaluated in large randomized trials with hard clinical endpoints including mortality and major cardiovascular events. Nattokinase research has been limited to smaller studies with surrogate endpoints such as biomarker changes and imaging outcomes. No trial has demonstrated that nattokinase reduces heart attacks, strokes, or cardiovascular death. This evidence gap represents the fundamental limitation in comparing nattokinase to proven pharmaceutical interventions (Kotb, 2014).

What is the bioavailability of oral nattokinase?

Whether nattokinase survives gastrointestinal digestion and reaches the bloodstream in active form was initially questioned because most dietary proteins are degraded by stomach acid and digestive enzymes. However, pharmacokinetic studies have demonstrated that nattokinase is absorbed intact following oral administration. Using enzyme-linked immunosorbent assay (ELISA) specific for nattokinase, researchers detected the enzyme in human serum after a single 2000 FU oral dose, with peak concentrations occurring approximately 13 hours after ingestion (Ero et al., 2013).

The mechanism of absorption remains incompletely understood. Nattokinase’s relatively large molecular size (28 kDa) would typically preclude intestinal absorption of intact protein. Some researchers hypothesize that nattokinase may be absorbed through M cells in Peyer’s patches or via other transcellular transport mechanisms. The enzyme’s resistance to acid denaturation and some proteases may preserve its structure during transit through the upper gastrointestinal tract.

Bioavailability appears sufficient to produce measurable effects on fibrinolytic markers. Human studies have documented changes in D-dimer, fibrinogen, and euglobulin clot lysis time following oral nattokinase administration, confirming that enough active enzyme reaches the circulation to influence coagulation and fibrinolysis parameters. However, the absolute bioavailability has not been precisely quantified, and individual variation in absorption likely exists (Kurosawa et al., 2015).

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How long does nattokinase remain active in the bloodstream?

The pharmacokinetic profile of nattokinase suggests prolonged activity compared to pharmaceutical thrombolytics. Following a single oral dose, serum nattokinase concentrations peak at approximately 13 hours and remain detectable for at least 48 hours. The elimination half-life has not been precisely characterized, but the extended detection window suggests relatively slow clearance from circulation (Ero et al., 2013).

Functional effects on coagulation parameters mirror this extended time course. In a crossover trial of healthy volunteers, fibrinolytic activity increased within hours of nattokinase ingestion and remained elevated at eight hours post-dose. Markers including D-dimer and factor VIII showed sustained changes consistent with enhanced fibrinolysis. This duration of effect supports once-daily dosing for those choosing to take nattokinase supplements (Kurosawa et al., 2015).

The practical implication is that nattokinase’s anticoagulant and fibrinolytic effects persist between doses when taken daily. This extended activity may be beneficial for prophylactic use but also means that effects do not dissipate quickly if bleeding occurs or surgery is needed. Anyone taking nattokinase should consider discontinuing it well before elective procedures, though optimal washout periods have not been formally established in clinical studies.

Conclusion

Nattokinase is a well-characterized enzyme with demonstrated fibrinolytic activity through multiple mechanisms. It dissolves fibrin directly, inhibits PAI-1, promotes tPA release, and may have antiplatelet and anti-inflammatory effects. Unlike pharmaceutical thrombolytics, it is absorbed after oral administration and produces sustained effects over many hours.

These biological properties are established. What remains unproven is whether these mechanisms translate into clinical benefits for cardiovascular disease prevention or treatment. The fundamental science provides a rationale for interest in nattokinase, but the evidence base for clinical decision-making requires examination of actual trial data, which the next article addresses in detail.