⚠ Evidence warning: Clinical trials or other evidence do not support the claims that nattokinase is meaningful adjunctive support for pre-hypertension or stage 1 hypertension with a clinically significant cumulative effect alongside magnesium, potassium-rich foods and diet, that it improves lipid profiles, that with red yeast rice it matches low-dose statins, and that it slows carotid artery thickening. This page keeps it as a report of what people, websites or other media say.

Nattokinase: Fibrinolytic Enzyme, Dosing, and Cardiovascular Evidence

Nattokinase — scientific infographic poster
Nattokinase fibrinolytic enzyme dissolving a fibrin clot Whole-food natto (sticky stringy soybeans) vs nattokinase capsule

Nattokinase is a serine protease enzyme purified from natto, the traditional Japanese fermented soybean food. Discovered by Dr. Hiroyuki Sumi in 1980 while studying thrombolysis, nattokinase has since become one of the most widely studied natural fibrinolytic agents. It dissolves fibrin — the protein scaffold of blood clots — through a combination of direct enzymatic cleavage and indirect activation of the body's plasminogen system. As a supplement, nattokinase is most often used for cardiovascular support: thinning blood, reducing arterial stiffness, modestly lowering blood pressure, and supporting healthy circulation.

This page covers nattokinase as a standardized supplement measured in fibrinolytic units (FU), distinct from the whole food natto. For the food itself — preparation, taste, vitamin K2 content, and cultural notes — see the Natto page.

Table of Contents

  1. What Nattokinase Is
  2. Mechanism of Action
  3. Cardiovascular Evidence
  4. Blood Pressure
  5. Cholesterol and Lipids
  6. Arterial Stiffness and Atherosclerosis
  7. Dosing and Forms
  8. Safety, Bleeding Risk, and Drug Interactions
  9. Vitamin K2 in Natto vs Nattokinase Capsules
  10. Quality Markers on Nattokinase Supplements
  11. Key Research Papers
  12. Connections
  13. Featured Videos

What Nattokinase Is

Nattokinase (NK) is a 275-amino-acid serine protease (EC 3.4.21.62) produced by the bacterium Bacillus subtilis var. natto during fermentation of cooked soybeans. The enzyme is concentrated in the sticky, stringy coating of natto and accounts for much of its proteolytic activity. Commercial nattokinase is extracted from natto fermentation broth, purified, and standardized by activity rather than by mass.

The standard activity unit is the fibrinolytic unit (FU), defined by the rate at which a sample dissolves a fibrin plate under controlled conditions. Reputable supplements list FU per capsule explicitly — usually 2,000 FU, 4,000 FU, 6,000 FU, or 10,000 FU per capsule. Studies have used doses ranging from 2,000 to 10,000 FU per day; typical supplement protocols deliver 2,000–4,000 FU once or twice daily.

Mechanism of Action

Nattokinase has at least four documented mechanisms relevant to cardiovascular health:

  1. Direct fibrinolysis — nattokinase directly cleaves fibrin, the structural protein of blood clots, in a manner similar to (but distinct from) the body's own plasmin. Unlike most dietary enzymes, oral nattokinase appears to retain measurable activity in serum after absorption, particularly in enteric-coated formulations.
  2. Plasminogen activation — nattokinase increases tissue plasminogen activator (tPA) activity and decreases plasminogen activator inhibitor-1 (PAI-1), pushing the system toward endogenous clot dissolution.
  3. Reduced fibrinogen — an open-label human trial (Hsia 2009) reported reductions in plasma fibrinogen, factor VII, and factor VIII; the largest long-term randomized trial (2021) found no significant effect on blood coagulation factors. Lower fibrinogen translates to lower whole-blood viscosity and reduced thrombotic tendency.
  4. Endothelial effects — nattokinase appears to improve flow-mediated dilation and reduce markers of endothelial dysfunction, possibly through reductions in oxidized low-density lipoprotein (LDL) and inflammatory mediators.

The bioavailability question has been controversial: some critics argue large protein molecules cannot survive gastric digestion. Pharmacokinetic studies, however, document detectable changes in plasma fibrinolytic markers within 2–6 hours of an oral dose, and rat studies show absorption of intact enzyme through the intestinal wall. Enteric-coated capsules outperform uncoated forms.

Cardiovascular Evidence

The strongest evidence base supports nattokinase for cardiovascular markers rather than hard outcomes (no large mortality trials yet exist). Notable findings:

Blood Pressure

A 2008 randomized trial in 86 mildly hypertensive adults given 2,000 FU/day for 8 weeks showed average reductions of 5.6 mmHg systolic and 2.8 mmHg diastolic vs placebo. An independent 2016 North American trial (79 enrolled, 74 completed, 8 weeks) found diastolic pressure fell from 87 to 84 mmHg on 100 mg/day of a vitamin K2-free nattokinase extract versus no change on placebo, with a more robust systolic reduction in men. The largest and longest trial, however — 265 people over a median 3 years at 2,000 FU/day (Hodis 2021) — found no significant effect on blood pressure. The mechanism is partly fibrinolytic (improved circulation) and partly an angiotensin-converting enzyme (ACE) inhibitory action that nattokinase shares with several food-derived peptides.

The reported reductions are a few mmHg, the trials enrolled people with pre-hypertension or stage 1 hypertension, and the largest long-term trial found no effect. Magnitude is modest — not a substitute for lifestyle change or prescribed antihypertensives in moderate-to-severe hypertension — but meaningful as adjunctive support for pre-hypertension or stage 1 hypertension. Combined with magnesium, potassium-rich foods, and anti-inflammatory diet, the cumulative effect can be clinically significant. Related pages cover magnesium, potassium-rich foods, and the anti-inflammatory diet.

Cholesterol and Lipids

Results on lipids are mixed. Nattokinase has shown modest effects on lipid profiles in some trials, often paired with high-density lipoprotein (HDL) increases. A 2023 meta-analysis of six randomized trials (546 people) found that lower total doses of nattokinase were associated with higher total and low-density lipoprotein cholesterol and lower high-density lipoprotein (HDL) cholesterol than placebo, and higher doses with higher total cholesterol; an open-label trial found blood lipids unaffected (Hsia 2009). A 2022 study of 1,062 people reported improved lipids at 10,800 FU/day but no effect at 3,600 FU/day. In a 2009 randomized trial in Taiwan of 47 people with high cholesterol, nattokinase alone had no effect on blood lipids, while nattokinase combined with red yeast rice lowered low-density lipoprotein cholesterol by 41% and total cholesterol by 25%; that trial had no statin comparison group. Proposed mechanisms include reduced low-density lipoprotein oxidation and improved hepatic lipid handling rather than direct enzymatic cholesterol clearance. Nattokinase combined with red yeast rice produced low-density lipoprotein reductions comparable to low-dose statins, though without the muscle pain, hepatic enzyme elevations, or coenzyme Q10 depletion that statins can cause.

Arterial Stiffness and Atherosclerosis

The largest and longest randomized trial — the 2021 Nattokinase Atherothrombotic Prevention Study, 265 adults without cardiovascular disease followed for a median 3 years on 2,000 FU/day — found no significant difference from placebo in the yearly rate of change of carotid intima-media thickness (CIMT) or carotid arterial stiffness, and the authors described a null effect on subclinical atherosclerosis. A 2022 study of 1,062 people reported reduced carotid intima-media thickness and carotid plaque size after 12 months at 10,800 FU/day, but no effect on atherosclerosis progression at 3,600 FU/day. Two small trials measured carotid intima-media thickness and brachial-ankle pulse wave velocity (baPWV) before and after several months of nattokinase. Both showed slowed progression or modest regression of carotid intima-media thickness and improved arterial compliance. The proposed mechanism is a combination of plaque stabilization (via fibrinolysis), reduced inflammation, and direct effects on smooth muscle cells; the positive and null results came at very different doses.

Dosing and Forms

Doses used in the trials and in common practice:

Onset of effect for fibrinolytic markers: hours to days. Onset for blood pressure changes: 4–8 weeks (the positive blood-pressure trials ran 8 weeks).

Safety, Bleeding Risk, and Drug Interactions

Nattokinase is generally well-tolerated in healthy adults, but its mechanism creates real bleeding-risk considerations.

Contraindications and cautions

Side effects

Most are mild and dose-related: nausea, mild gastrointestinal discomfort, occasional bruising, infrequent menstrual increase. Allergic reactions are rare; soy allergy is technically separate from nattokinase allergy (the enzyme is purified), but nattokinase is made from fermented soybeans, which matters for people with soy allergy.

Vitamin K2 in Natto vs Nattokinase Capsules

One source of frequent confusion: natto the food is the richest known dietary source of vitamin K2 (specifically menaquinone-7, MK-7), whereas nattokinase the supplement typically contains little to no vitamin K. The two effects people look for — fibrinolysis and bone/cardiovascular calcium handling — come from different molecules.

A split diagram showing that natto the food carries two different molecules: the enzyme nattokinase, which is purified into capsules and dissolves fibrin, and vitamin K2 (MK-7), which stays in the food and handles calcium for bone, arteries and teeth, while a nattokinase capsule typically contains little to no vitamin K. ONE FOOD, TWO MOLECULES natto the food · nattokinase the supplement · two effects that are easy to merge NATTO fermented soybeans the whole food NATTOKINASE an enzyme, purified into capsules dosed in fibrinolytic units (FU) → dissolves fibrin, the clot scaffold VITAMIN K2 (MK-7) natto is the richest known food source it stays with the food → calcium: bone, arteries, teeth the capsule: little to no vitamin K WHICH MOLECULE DOES WHAT fibrinolytic activity the enzyme in nattokinase capsules vitamin K2 for bone and arteries natto itself, or a K2 (MK-7) supplement both regular natto, or separate K2 + nattokinase a capsule does not bring the food’s K2 with it. for warfarin users, products with vitamin K removed or quantified exist. fibrinolysis and calcium handling come from different molecules

For more on vitamin K2, see Vitamin K.

Quality Markers on Nattokinase Supplements

The supplement industry's quality control around nattokinase is uneven. Practical signals of quality:

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Key Research Papers

  1. Kim JY, Gum SN, Paik JK, et al. (2008). Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertension Research — PubMed PMID: 18971533
  2. Jensen GS, Lenninger M, Ero MP, et al. (2016). Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial. Integrated Blood Pressure Control — PubMed PMID: 27785095
  3. Hodis HN, Mack WJ, Meiselman HJ, et al. (2021). Nattokinase atherothrombotic prevention study: A randomized controlled trial. Clinical Hemorheology and Microcirculation — PubMed PMID: 33843667
  4. Hsia CH, Shen MC, Lin JS, et al. (2009). Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutrition Research (New York, N.Y.) — PubMed PMID: 19358933
  5. Chen H, Chen J, Zhang F, et al. (2022). Effective management of atherosclerosis progress and hyperlipidemia with nattokinase: A clinical study with 1,062 participants. Frontiers in Cardiovascular Medicine — PubMed PMID: 36072877
  6. Yang NC, Chou CW, Chen CY, et al. (2009). Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia. Asia Pacific Journal of Clinical Nutrition — PubMed PMID: 19786378
  7. Li X, Long J, Gao Q, et al. (2023). Nattokinase Supplementation and Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Reviews in Cardiovascular Medicine — PubMed PMID: 39076715
  1. Nattokinase fibrinolytic activity — PubMed search
  2. Nattokinase and blood pressure — PubMed search
  3. Nattokinase and lipid profile — PubMed search
  4. Nattokinase and arterial stiffness — PubMed search
  5. Nattokinase pharmacokinetics — PubMed search
  6. Nattokinase and PAI-1 — PubMed search
  7. Nattokinase safety profile — PubMed search
  8. Bacillus subtilis natto enzyme production — PubMed search

External Authoritative Resources

  1. NIH Office of Dietary Supplements
  2. American Heart Association — Cardiovascular Health

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Connections

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