(c) 2026 E. Yarnell
Nattokinase Overview
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Nattokinase is a serine protease derived from the traditional Japanese fermented soy food known as nattō 納豆. It was first identified in 1987. Its name is somewhat misleading as it is not a kinase; instead it derives from the Japanese word for the bacterium that creates nattō, Bacillus subtilis var natto, nattōkin 納豆 菌. It is also known as subtilisin NAT.
Nattokinase's primary action is inhibition of plasminogen activator inhibitor-1 (PAT-1). Normally PAT-1 inhibits tissue plasminogen (tPA) activator and urokinase plasminogen activator (uPA), two enzymes critical for activating plasminogen and thus breaking down fibrin. This degrades blood clots. By inhibiting the inhibitor, nattokinase enhances fibrinolysis. This reduces pathological clotting, but does not seem to disturb normal hemostasis as will be demonstrated below. |
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Nattokinase Efficacy
There have been quite a few large clinical trials on the effects of nattokinase in patients with a range of conditions. These trials demonstrate several critical points:
Atherosclerosis:
The largest retrospective trial involved 1,062 Chinese adults with mild dyslipidemia (all subjects) and, in 683 participants, mild atherosclerosis based on carotid intimal medial thickness readings measured by ultrasound (Chen, et al. 2022). After taking nattokinase 540 mg (potency 10,800 FU) daily for 1 yr (except for 61 subjects who took only 3,600 FU daily), there was a significant reduction in total and LDL cholesterol levels and triglyceride levels compared to baseline. HDL cholesterol levels rose significantly compared to baseline. Carotid plaques decreased by an average of 36% (from 1.33 to 1.04 mm), a significant improvement compared to baseline. Those who took the lower nattokinase dose did not have any benefits. In 181 subjects who also took 181 mcg of vitamin K2 per day, improvements in lipid levels were superior to those who took nattokinase alone. In 96 subjects who also took 100 mg of aspirin per day, regression of atherosclerotic plaques was augmented beyond that seen with nattokinase alone, though between-group statistical analysis was not provided so it is not known if this difference was significant. There were no significant adverse effects. No coagulation-related blood parameters were monitored.
The largest double-blind trial was conducted in 265 American adults with asymptomatic atherosclerosis and compared nattokinase 2,000 FU in 100 mg qd to placebo over 3 yr (Hodis, et al. 2021). Based on carotid intimal medial thickness and carotid artery stiffness measurements, there was no difference between the groups, with both showing slow progression of their disease. Clearly this dose of nattokinase is ineffective. In light of the results of the much higher doses used in the retrospective trial above that appeared to be helpful in actually reducing plaques, a randomized trial is warranted to determine if more would be better. It is very unfortunate this trial did not do some work to assess whether the dose tested was appropriate, but other preliminary studies suggested it would be. It is also very important that nattokinase be tested in combination with statins, garlic, tadalafil, and other treatments that have shown the ability to regress atherosclerotic plaques to assess the potential synergy. In the meantime, if a patient has asymptomatic atherosclerosis, it is recommended they be treated with at least 6,000 FU in 300 mg of nattokinase, if not 10,000 FU in 500 mg, per day, along with a Mediterranean, pescovegeterian or pescovegan diet, with carotid artery ultrasounds (and serum lipid tests) every 6 months for at least 18 months to decide on whether the treatment is working. If not, then it should be combined with other plaque-regressing therapies for another 12 months.
Deep Vein Thrombosis Prevention:
Only one trial could be identified that tested whether nattokinase could prevent blood clots forming, in this case during long-haul airplane flights. It used a combination of proanthocyanidins and nattokinase (amounts of potency undisclosed) 2 caps (300 mg) 2 hours before flying and another 2 capsules 6 hours later compared to placebo in 224 European adults flying between New York and London, each flight 7--8 hours (Cesarone, et al. 2003). All subjects were instructed to get up and walk around for 5–10 min every hour during flight and to drink at least 100–150 ml of water every hour. There were five episodes of DVT in the placebo group, and two of superficial thromboses, compared to none in the treatment group, a significant difference. All thrombotic events were asymptomatic and were detected based on ultrasound. D-Dimer and fibrinogen levels were within normal limits in all subjects before and after the test, with no significant difference between the groups. Edema increased by an average of 12% in the placebo group while it was reduced an average of 15% in the proanthocyanidins/nattokinase group, a significant difference. There were no adverse effects with the supplement. This appears to be a reasonable way to reduce or prevent thrombotic events in people on long airplane flights, with a suggested dose of at least 4,000 FU in 200 mg 2 hours before flying and the same dose approximately 4 hours into the flight.
Stroke:
In a single-blind randomized trial, 61 Vietnamese adults undergoing in patient care while recovering from ischemic strokes were treated with either nattokinase 300 FU or placebo for 60 days (Pham, et al. 2020). All patients received piracetamin 1 g IV qd and electroacupuncture for 30 min qd. Hemiplegia was improved to a greater degree in significantly more patients in the nattokinase group compared to controls. Recovery of speech, motor function, and ability to perform activities of daily living was also faster and more extensive in the nattokinase group compared to controls. There were no adverse effects of therapy. This provides preliminary evidence that even low doses of nattokinase might help patients recover from ischemic strokes. Larger, more rigorous trials are warranted, and higher doses need to be tested, but this treatment seems promising as an adjunct to other more established treatments.
Hypertension:
In a meta-analysis of 6 trials (n=546), nattokinase reduced systolic and diastolic blood pressure significantly compared to placebo (Li, et al. 2023).
- The dose of nattokinase matters immensely (and it is generally underdosed)
- Used properly, it is clinically effective for several indications
- Nattokinase is safe and does not cause bleeding
Atherosclerosis:
The largest retrospective trial involved 1,062 Chinese adults with mild dyslipidemia (all subjects) and, in 683 participants, mild atherosclerosis based on carotid intimal medial thickness readings measured by ultrasound (Chen, et al. 2022). After taking nattokinase 540 mg (potency 10,800 FU) daily for 1 yr (except for 61 subjects who took only 3,600 FU daily), there was a significant reduction in total and LDL cholesterol levels and triglyceride levels compared to baseline. HDL cholesterol levels rose significantly compared to baseline. Carotid plaques decreased by an average of 36% (from 1.33 to 1.04 mm), a significant improvement compared to baseline. Those who took the lower nattokinase dose did not have any benefits. In 181 subjects who also took 181 mcg of vitamin K2 per day, improvements in lipid levels were superior to those who took nattokinase alone. In 96 subjects who also took 100 mg of aspirin per day, regression of atherosclerotic plaques was augmented beyond that seen with nattokinase alone, though between-group statistical analysis was not provided so it is not known if this difference was significant. There were no significant adverse effects. No coagulation-related blood parameters were monitored.
The largest double-blind trial was conducted in 265 American adults with asymptomatic atherosclerosis and compared nattokinase 2,000 FU in 100 mg qd to placebo over 3 yr (Hodis, et al. 2021). Based on carotid intimal medial thickness and carotid artery stiffness measurements, there was no difference between the groups, with both showing slow progression of their disease. Clearly this dose of nattokinase is ineffective. In light of the results of the much higher doses used in the retrospective trial above that appeared to be helpful in actually reducing plaques, a randomized trial is warranted to determine if more would be better. It is very unfortunate this trial did not do some work to assess whether the dose tested was appropriate, but other preliminary studies suggested it would be. It is also very important that nattokinase be tested in combination with statins, garlic, tadalafil, and other treatments that have shown the ability to regress atherosclerotic plaques to assess the potential synergy. In the meantime, if a patient has asymptomatic atherosclerosis, it is recommended they be treated with at least 6,000 FU in 300 mg of nattokinase, if not 10,000 FU in 500 mg, per day, along with a Mediterranean, pescovegeterian or pescovegan diet, with carotid artery ultrasounds (and serum lipid tests) every 6 months for at least 18 months to decide on whether the treatment is working. If not, then it should be combined with other plaque-regressing therapies for another 12 months.
Deep Vein Thrombosis Prevention:
Only one trial could be identified that tested whether nattokinase could prevent blood clots forming, in this case during long-haul airplane flights. It used a combination of proanthocyanidins and nattokinase (amounts of potency undisclosed) 2 caps (300 mg) 2 hours before flying and another 2 capsules 6 hours later compared to placebo in 224 European adults flying between New York and London, each flight 7--8 hours (Cesarone, et al. 2003). All subjects were instructed to get up and walk around for 5–10 min every hour during flight and to drink at least 100–150 ml of water every hour. There were five episodes of DVT in the placebo group, and two of superficial thromboses, compared to none in the treatment group, a significant difference. All thrombotic events were asymptomatic and were detected based on ultrasound. D-Dimer and fibrinogen levels were within normal limits in all subjects before and after the test, with no significant difference between the groups. Edema increased by an average of 12% in the placebo group while it was reduced an average of 15% in the proanthocyanidins/nattokinase group, a significant difference. There were no adverse effects with the supplement. This appears to be a reasonable way to reduce or prevent thrombotic events in people on long airplane flights, with a suggested dose of at least 4,000 FU in 200 mg 2 hours before flying and the same dose approximately 4 hours into the flight.
Stroke:
In a single-blind randomized trial, 61 Vietnamese adults undergoing in patient care while recovering from ischemic strokes were treated with either nattokinase 300 FU or placebo for 60 days (Pham, et al. 2020). All patients received piracetamin 1 g IV qd and electroacupuncture for 30 min qd. Hemiplegia was improved to a greater degree in significantly more patients in the nattokinase group compared to controls. Recovery of speech, motor function, and ability to perform activities of daily living was also faster and more extensive in the nattokinase group compared to controls. There were no adverse effects of therapy. This provides preliminary evidence that even low doses of nattokinase might help patients recover from ischemic strokes. Larger, more rigorous trials are warranted, and higher doses need to be tested, but this treatment seems promising as an adjunct to other more established treatments.
Hypertension:
In a meta-analysis of 6 trials (n=546), nattokinase reduced systolic and diastolic blood pressure significantly compared to placebo (Li, et al. 2023).
Dose and Potency
Like all enzymes, nattokinase must be dosed based on both the milligram amount and the potency of the material used. Good quality nattokinase has 2,000 fibrinolytic units (FU) per 100 mg of material. Though many studies have used a dose of 2,000 FU in 100 mg per day, or double this, there is evidence this may be far too low a dose to see major clinical effects, as discussed in particular in the admittedly retrospective trial in China that found only 10,800 FU in 540 mg per day reverse atherosclerosis, while 3,600 FU per day did not (Chen, et al. 2022). In one case study, switching from warfarin to nattokinase 100 mg (2000 FU) qd in a 53-yr-old man with a mechanical heart valve over one year was ineffective and resulted in clotting of the valve sufficient to require a replacement of the valve (Elahi, et al. 2015). This does not mean nattokinase cannot be effective in such a situation, but clearly this dose is insufficient. Until and unless this question is answered in a clinical trial though, switching to nattokinase is not recommended in people with artificial heart valves without very close monitoring.
Safety
Summary: Nattokinase has not caused any problems with excessive or unexpected bleeding in any published clinical trials. It is safe and effective to combine with most anticoagulant and antiplatelet drugs. It is safe and effective in helping patients recover after surgery.
No Need to Monitor Serum Coagulation Tests:
Those that have monitored various blood tests related to coagulation have found that while there are statistically significant changes, they have not led to these values moving out of the normal range and are not associated with excessive bleeding. For example, in one double-blind trial, nattokinase 2000 FU qd in 76 Korean adults with dyslipidemia for 8 wk did significantly raise collagen-epinephrine closure time, prothrombin time, and activated partial thromboplastin time compared to placebo (Yoo, et al. 2019). However, the levels of none of these were raised out of the normal range, and there were no reports of inappropriate bleeding.
Anticoagulant Drug Combination Safety:
The combination of nattokinase with anticoagulant drugs has not been rigorously evaluated in randomized clinical trials. However, open trials confirm it is safe and effective when combined with at least some anticoagulants and antiplatelet drugs:
One open, retrospective trial found that combining 10,800 FU (in 540 mg) of nattokinase with 100 mg of aspirin per day had only synergistic benefits with no observable serious side effects, most notably no increase in bleeding of any kind (Chen, et al. 2022).
One open trial in 50 Italian adults with deep vein thrombosis found 2,000 FU (in 100 mg) of nattokinase safe and effective when combined with fondaparinux 7.5 mg IM qd for 30 days (Gallelli, et al. 2021).
One open trial in 57 Italian adults with superficial vein thrombosis found 2,000 FU (in 100 mg) of nattokinase safe and effective when combined with enoxaparin 6,000 IU subQ qd daily for 30 days (Gallelli, et al. 2021).
Safety After Surgery:
One open trial followed 46 Italian adults after surgery for venous insufficiency, all of whom were treated with nattokinase 2,000 FU (in 100 mg) qd for 30 days (Gallelli, et al. 2021). There were no adverse effects, notably no problem with bleeding or wound healing, and postsurgical symptoms in fact resolved quickly and completely in all patients.
No Need to Monitor Serum Coagulation Tests:
Those that have monitored various blood tests related to coagulation have found that while there are statistically significant changes, they have not led to these values moving out of the normal range and are not associated with excessive bleeding. For example, in one double-blind trial, nattokinase 2000 FU qd in 76 Korean adults with dyslipidemia for 8 wk did significantly raise collagen-epinephrine closure time, prothrombin time, and activated partial thromboplastin time compared to placebo (Yoo, et al. 2019). However, the levels of none of these were raised out of the normal range, and there were no reports of inappropriate bleeding.
Anticoagulant Drug Combination Safety:
The combination of nattokinase with anticoagulant drugs has not been rigorously evaluated in randomized clinical trials. However, open trials confirm it is safe and effective when combined with at least some anticoagulants and antiplatelet drugs:
One open, retrospective trial found that combining 10,800 FU (in 540 mg) of nattokinase with 100 mg of aspirin per day had only synergistic benefits with no observable serious side effects, most notably no increase in bleeding of any kind (Chen, et al. 2022).
One open trial in 50 Italian adults with deep vein thrombosis found 2,000 FU (in 100 mg) of nattokinase safe and effective when combined with fondaparinux 7.5 mg IM qd for 30 days (Gallelli, et al. 2021).
One open trial in 57 Italian adults with superficial vein thrombosis found 2,000 FU (in 100 mg) of nattokinase safe and effective when combined with enoxaparin 6,000 IU subQ qd daily for 30 days (Gallelli, et al. 2021).
Safety After Surgery:
One open trial followed 46 Italian adults after surgery for venous insufficiency, all of whom were treated with nattokinase 2,000 FU (in 100 mg) qd for 30 days (Gallelli, et al. 2021). There were no adverse effects, notably no problem with bleeding or wound healing, and postsurgical symptoms in fact resolved quickly and completely in all patients.
References
Cesarone MR, Belcaro G, Nicolaides AN, Ricciet al. (2003) "Prevention of venous thrombosis in long-haul flights with Flite Tabs: the LONFLIT-FLITE randomized, controlled trial" Angiology 54(5):531–9.
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" Front Cardiovasc Med 9:964977.
Elahi MM, Choi CH, Konda S, Shake JG (2015) "Consequence of patient substitution of nattokinase for warfarin after aortic valve replacement with a mechanical prosthesis" Proc (Bayl Univ Med Cent) 28(1):81–2.
Gallelli G, Di Mizio G, Palleria C, et al. (2021) "Data recorded in real life support the safety of nattokinase in patients with vascular diseases" Nutrients 13(6):2031.
Hodis HN, Mack WJ, Meiselman HJ, et al. (2021) "Nattokinase atherothrombotic prevention study: A randomized controlled trial" Clin Hemorheol Microcirc 78(4):339–53.
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" Rev Cardiovasc Med 24(8):234.
Pham PT, Han B, Hoang BX (2020) "Nattospes as effective and safe functional supplements in management of stroke" J Med Food 23(8):879–85.
Sumi H, Hamada H, Tsushima H, et al. (1987) "A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet" Experientia 43(10):1110–1.
Urano T, Ihara H, Umemura K, et al. (2001) "The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type 1" J Biol Chem 276(27):24690–6.
Yoo HJ, Kim M, Kim M, et al. (2019) "The effects of nattokinase supplementation on collagen-epinephrine closure time, prothrombin time and activated partial thromboplastin time in nondiabetic and hypercholesterolemic subjects" Food Funct 10(5):2888–93.
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" Front Cardiovasc Med 9:964977.
Elahi MM, Choi CH, Konda S, Shake JG (2015) "Consequence of patient substitution of nattokinase for warfarin after aortic valve replacement with a mechanical prosthesis" Proc (Bayl Univ Med Cent) 28(1):81–2.
Gallelli G, Di Mizio G, Palleria C, et al. (2021) "Data recorded in real life support the safety of nattokinase in patients with vascular diseases" Nutrients 13(6):2031.
Hodis HN, Mack WJ, Meiselman HJ, et al. (2021) "Nattokinase atherothrombotic prevention study: A randomized controlled trial" Clin Hemorheol Microcirc 78(4):339–53.
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" Rev Cardiovasc Med 24(8):234.
Pham PT, Han B, Hoang BX (2020) "Nattospes as effective and safe functional supplements in management of stroke" J Med Food 23(8):879–85.
Sumi H, Hamada H, Tsushima H, et al. (1987) "A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet" Experientia 43(10):1110–1.
Urano T, Ihara H, Umemura K, et al. (2001) "The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type 1" J Biol Chem 276(27):24690–6.
Yoo HJ, Kim M, Kim M, et al. (2019) "The effects of nattokinase supplementation on collagen-epinephrine closure time, prothrombin time and activated partial thromboplastin time in nondiabetic and hypercholesterolemic subjects" Food Funct 10(5):2888–93.