Nattokinase for Cardiovascular Health & Fibrinolysis

Nattokinase was discovered in 1987 by Dr. Hiroyuki Sumi while he was a postdoctoral researcher at the University of Chicago, screening over 200 traditional foods for fibrinolytic activity. He dropped natto onto a fibrin plate (the standard agar substrate for testing clot-dissolving enzymes), expected to see the cleared zone characteristic of a strong fibrinolytic agent over a span of hours — and instead got the largest clear zone of any food he had ever tested, within just minutes. The enzyme he isolated and named "nattokinase" is unusual: unlike tPA, urokinase, and streptokinase — the three principal pharmaceutical thrombolytics, all of which work indirectly by activating plasminogen to plasmin — nattokinase acts directly on fibrin. It is also unusual in that it appears to retain measurable activity after oral absorption, one of the very few proteolytic enzymes for which this has been documented in human pharmacokinetic studies. This deep-dive walks through the discovery, the unique mechanism, the deep-vein-thrombosis prevention pilot data including the Cesarone long-flight trial, fibrinogen and clotting-factor reductions in randomized trials, comparison with aspirin and warfarin, and the practical question of when nattokinase is and is not the right cardiovascular intervention.

The Sumi 1987 Discovery — Natto on a Fibrin Plate
The Direct-Fibrin-Cleavage Mechanism (vs. tPA / Urokinase / Streptokinase)
Dual Pathway: tPA Up, PAI-1 Down
Fibrinogen, Factor VII, and Factor VIII Reduction
Deep Vein Thrombosis Prevention — The Cesarone Long-Flight Trial
The Oral-Bioavailability Question
Comparison with Aspirin and Warfarin
Whole-Blood Viscosity and Erythrocyte Deformability
Endothelial Function and Flow-Mediated Dilation
Practical Cardiovascular Dosing Protocols
Cautions — Anticoagulants, Antiplatelets, Surgery, Bleeding Disorders
Key Research Papers
Connections

The Sumi 1987 Discovery — Natto on a Fibrin Plate

The discovery of nattokinase is one of the more memorable stories in natural-product chemistry. Hiroyuki Sumi, a Japanese postdoctoral researcher at the University of Chicago Medical School in the early 1980s, was working in a lab studying thrombolysis — the dissolution of blood clots, which was becoming a clinically central problem as the developed world's leading cause of death shifted firmly to cardiovascular disease. tPA, urokinase, and streptokinase were the available pharmaceutical agents, all intravenous, all expensive, all with significant bleeding risk and short half-lives.

Sumi had a sideline interest: he was systematically screening traditional foods for fibrinolytic activity, on the theory that long-traditional foods that humans had selected for over centuries might contain useful bioactive compounds. The screening method was straightforward: a fibrin plate (purified fibrin polymerized on agar in a Petri dish) is the standard substrate for testing clot-dissolving activity. A drop of test material is placed on the surface; a clear zone develops over time as the fibrin polymer is dissolved. The diameter and rate of the clear zone, compared to a standard, gives the activity in fibrinolytic units (FU).

Sumi had screened over 200 traditional foods with mostly negative or weakly-positive results. Then he dropped natto — the sticky, stringy fermented soybean breakfast staple from his native Japan, an acquired-taste food he ate regularly — onto a fibrin plate. The clear zone developed within minutes, and was larger than any food he had previously tested. The 1987 Experientia paper reporting this finding launched the modern nattokinase literature.

Sumi isolated the active enzyme, named it "nattokinase" (the Greek suffix –kinase, indicating an enzyme), and characterized it as a 275-amino-acid serine protease produced during fermentation by Bacillus subtilis var. natto, the specific bacterial strain that converts cooked soybeans into the traditional natto food. The enzyme was assigned EC number 3.4.21.62 in the Enzyme Commission nomenclature, classifying it as a subtilisin-family serine endopeptidase.

What made the discovery particularly interesting was that natto had been a staple food in Japan for at least 1,000 years — documented in records back to the Heian period (794–1185 CE), with origin legends placing it considerably earlier — and Japan has long been notable for one of the world's lowest rates of cardiovascular mortality. The convergence of these facts — a uniquely concentrated dietary fibrinolytic enzyme, in a population with uniquely low cardiovascular disease — immediately raised the question of whether natto consumption was contributing causally to Japanese cardiovascular longevity. That question is still not fully resolved, but the epidemiologic data (Takayama study, JACC cohort) discussed in the stroke prevention deep-dive are consistent with a meaningful contribution.

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The Direct-Fibrin-Cleavage Mechanism (vs. tPA / Urokinase / Streptokinase)

Most clinically used fibrinolytic agents do not actually dissolve fibrin themselves. They are plasminogen activators — they convert the inactive plasma zymogen plasminogen into the active enzyme plasmin, and it is plasmin that does the actual fibrin-cleaving work. The pharmaceutical thrombolytics fall into this category:

Tissue plasminogen activator (tPA, alteplase) — recombinant human enzyme, the standard-of-care for acute ischemic stroke if administered within ~4.5 hours of symptom onset. Activates plasminogen specifically at fibrin surfaces.
Urokinase — originally isolated from human urine, also activates plasminogen, but with less fibrin-specificity than tPA.
Streptokinase — bacterial protein from Streptococcus, forms a complex with plasminogen that has plasminogen-activator activity. Cheap, used widely outside the US for myocardial infarction.

Nattokinase is different. It cleaves fibrin directly, in a manner similar to plasmin itself, without requiring plasminogen as an intermediate. It also activates plasminogen (more on that in the next section), but the direct fibrin-cleavage activity is the more distinctive feature. The cleavage sites on the fibrin alpha- and beta-chains are different from those preferred by plasmin, and the cleavage kinetics are different, but the net effect — depolymerization of the fibrin clot — is similar.

From a mechanistic standpoint this matters because direct fibrin cleavage proceeds even in conditions where plasminogen is depleted or where plasminogen activator inhibitor-1 (PAI-1) is elevated — both of which can limit the effectiveness of tPA and similar agents. From a clinical standpoint it matters because the direct cleavage mechanism is what allows oral nattokinase to have any plausible effect at all (an orally-absorbed plasminogen activator would face daunting bioavailability problems; an orally-absorbed enzyme that cleaves fibrin directly faces fewer).

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Dual Pathway: tPA Up, PAI-1 Down

The second mechanism — complementary to direct fibrin cleavage — is that nattokinase modulates the endogenous plasminogen-activator system in the direction of more fibrinolysis. Two specific changes are well-documented:

tPA activity increases — oral nattokinase raises plasma tissue plasminogen activator activity in human studies. The Kurosawa 2015 single-dose pharmacokinetic study showed measurable increases within 6–8 hours of oral administration.
PAI-1 activity decreases — plasminogen activator inhibitor-1 is the body's principal endogenous brake on fibrinolysis. PAI-1 binds and inactivates tPA. Elevated PAI-1 is independently associated with cardiovascular events, particularly myocardial infarction. Oral nattokinase reduces PAI-1 activity in human studies, removing the brake on endogenous fibrinolysis.

The net effect of these two changes is a shift of the entire fibrinolytic balance toward more endogenous clot dissolution. This is mechanistically distinct from the direct-fibrin-cleavage activity of nattokinase itself: even after the nattokinase molecules have been cleared from circulation, the elevated tPA and reduced PAI-1 continue to support endogenous fibrinolysis.

The clinical relevance: morning cardiovascular events (myocardial infarction, sudden cardiac death) are partly driven by the natural circadian peak of PAI-1 activity, which is highest in the early morning. Some practitioners suggest evening dosing of nattokinase specifically to support fibrinolytic activity through the high-risk pre-dawn hours; the evidence for this is suggestive rather than definitive.

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Fibrinogen, Factor VII, and Factor VIII Reduction

The Hsia 2009 Nutrition Research paper is one of the more important nattokinase human trials. Hsia and colleagues randomized 45 patients into three groups (healthy controls, cardiovascular-disease patients, dialysis patients) and gave each group 2,000 FU/day nattokinase for 2 months. The endpoints were not just fibrinolytic activity but the underlying coagulation cascade itself. The findings:

Plasma fibrinogen decreased by approximately 7–9% across all three groups. Fibrinogen is the substrate from which clots are made; lower fibrinogen means less raw material for thrombus formation, lower blood viscosity, and lower cardiovascular risk (elevated fibrinogen is an independent cardiovascular risk factor).
Factor VII activity decreased by approximately 14%. Factor VII is part of the extrinsic coagulation pathway and is activated by tissue factor exposed at sites of vascular injury.
Factor VIII activity decreased by approximately 17%. Factor VIII is part of the intrinsic coagulation pathway, the same factor that is deficient in hemophilia A.

The interpretation: nattokinase has effects on the coagulation cascade itself, not just on already-formed fibrin clots. The mechanism for these effects is not fully established — they may reflect direct proteolytic effects on the clotting factors themselves, indirect effects via the plasmin system, or hepatic-synthesis-rate effects via signaling. What matters clinically is the net direction: lower fibrinogen, lower factor VII, lower factor VIII, all of which trend in the direction of reduced thrombotic tendency.

This is also the source of the safety concern: a patient already on an anticoagulant or antiplatelet drug, which is suppressing coagulation through one mechanism, who adds nattokinase, which is suppressing coagulation through additional mechanisms, may end up at significantly elevated bleeding risk. See the cautions section below for the specific drug interactions and the pre-surgical discontinuation guidance.

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Deep Vein Thrombosis Prevention — The Cesarone Long-Flight Trial

The single best-known clinical use case for nattokinase is venous thromboembolism prevention, particularly in the long-haul-flight setting. The Cesarone 2003 trial published in Angiology (an Italian-led study, sometimes called the Flite Tabs trial after the branded preparation used) is the pivotal study.

Design: 204 high-risk passengers on flights longer than 7 hours were randomized to placebo or to a single-dose pre-flight Flite Tabs preparation containing 150 mg nattokinase plus 300 mg pycnogenol (French maritime pine bark extract). Passengers wore standard graduated compression stockings (the standard mechanical preventive intervention). Doppler ultrasound of the lower extremity venous system was performed pre-flight and within 4 hours post-flight.

Results:

Placebo group: 5 deep vein thromboses (in calf veins, mostly asymptomatic) and 2 superficial thromboses detected post-flight.
Nattokinase + pycnogenol group: 0 deep vein thromboses, 0 superficial thromboses.
The difference was statistically significant (P < 0.025).

The Cesarone trial has been criticized on several grounds — the use of a combined product means the contribution of nattokinase alone vs. pycnogenol alone cannot be cleanly separated; the sample size is modest; the endpoint (asymptomatic Doppler-detected calf thrombi) is a surrogate for clinically meaningful pulmonary embolism. But it remains the best randomized human evidence for nattokinase in venous thrombosis prevention, and the result has informed the off-label use of nattokinase as a long-haul-flight prophylactic in many integrative-medicine practices.

Practical protocol: 2,000–4,000 FU nattokinase taken 30–60 minutes before a long flight, plus standard mechanical measures (compression stockings, hourly ambulation, hydration). Patients with known hypercoagulable conditions (factor V Leiden, prothrombin G20210A, antiphospholipid syndrome) should not substitute nattokinase for prescribed pharmaceutical anticoagulation when the latter is indicated; for those patients nattokinase is at most an adjunct under physician supervision.

For more on deep vein thrombosis itself, see our Deep Vein Thrombosis page.

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The Oral-Bioavailability Question

The single most-asked question about nattokinase is whether an enzyme this large — a 275-amino-acid protein with a molecular weight around 27.7 kDa — can possibly survive gastric digestion and reach the systemic circulation in active form. Most ingested proteins are denatured by gastric acid and degraded by pepsin in the stomach, then further degraded by pancreatic proteases (trypsin, chymotrypsin) in the small intestine. The end products of normal dietary protein digestion are short peptides and free amino acids, which are absorbed via PEPT1 and amino-acid transporters in the small intestine.

For nattokinase to act systemically, intact (or at least catalytically active) enzyme must reach the circulation in measurable amounts. The evidence that this actually happens, while not as definitive as one would like, is reasonably strong:

Pharmacokinetic studies measure changes in serum fibrinolytic activity, tPA, PAI-1, and D-dimer within 2–6 hours of oral nattokinase administration in human subjects. These are downstream functional markers, not direct measurement of nattokinase in serum, but the time-course is consistent with absorption of active enzyme.
Rat absorption studies show measurable absorption of intact nattokinase through the intestinal wall, with detection in the lymphatic system and in serum.
Enteric-coated formulations outperform uncoated formulations in head-to-head studies of downstream fibrinolytic markers, consistent with the interpretation that protecting the enzyme from gastric pH preserves activity.
The enzyme is structurally robust — it is stable across a wide pH range (6–12), tolerates temperatures up to ~60°C, and has a structure (subtilisin family) known for resistance to proteolytic degradation.

The honest position is that the magnitude of absorption is small and probably highly variable from person to person and from formulation to formulation. But there is enough mechanistic and PK evidence to conclude that the downstream effects observed in clinical trials are not entirely placebo — some active enzyme does reach the systemic circulation, and that fraction is enhanced by enteric coating and proper formulation.

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Comparison with Aspirin and Warfarin

Patients (and integrative-medicine practitioners) frequently ask whether nattokinase can substitute for low-dose aspirin or warfarin in their specific situation. The honest answer requires distinguishing several distinct clinical scenarios:

Primary cardiovascular disease prevention in healthy adults with no atherosclerotic disease. The current consensus is that low-dose aspirin should NOT routinely be used for primary prevention in this population, given the bleeding risk roughly offsets the cardiovascular benefit. Nattokinase may be a reasonable option in this setting for an individual who wants some pro-fibrinolytic support without the GI bleeding risk profile of aspirin. The evidence base is weaker than for aspirin but the safety profile is more favorable.
Secondary prevention after established cardiovascular disease (post-MI, post-PCI, established CAD). Low-dose aspirin (and often clopidogrel for a period after stent placement) are evidence-based and life-saving in this population. Nattokinase is NOT a substitute. Nattokinase as an ADJUNCT to prescribed antiplatelet therapy raises bleeding risk and should only be done with explicit physician supervision and monitoring.
Atrial fibrillation with elevated stroke risk (CHADS–VASc ≥ 2). Warfarin or DOAC (apixaban, rivaroxaban, edoxaban, dabigatran) is the standard of care and reduces stroke risk by approximately 60–70%. Nattokinase is NOT remotely a substitute. Patients who want to try discontinuing warfarin in favor of "natural alternatives" need to understand they are accepting a stroke risk approximately 3x higher than continued therapy. This is not a defensible substitution.
Deep vein thrombosis prophylaxis in long-distance travel. This is the one situation where nattokinase has direct head-to-head supportive evidence (the Cesarone trial above). It is a reasonable alternative or adjunct to aspirin for this specific use.
Active treatment of established DVT or pulmonary embolism. Therapeutic anticoagulation with heparin or DOAC is the standard. Nattokinase is NOT a treatment for established VTE.

The simplest summary: nattokinase is a reasonable pro-fibrinolytic supplement for healthy adults without cardiovascular disease who want some pro-fibrinolytic support, and a reasonable VTE prophylactic for long-distance travelers. It is not a substitute for evidence-based pharmaceutical anticoagulation in patients with atrial fibrillation, mechanical heart valves, established VTE, or recent acute coronary syndrome.

For more on aspirin and its evolving evidence base in primary vs. secondary prevention, see our Aspirin page.

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Whole-Blood Viscosity and Erythrocyte Deformability

The Pais 2006 study in Clinical Hemorheology and Microcirculation measured the effect of nattokinase on whole-blood viscosity and on red-blood-cell aggregation in vitro. Findings:

Whole-blood viscosity decreased modestly but significantly at therapeutic nattokinase concentrations
Erythrocyte aggregation (a measure of how readily red cells clump together at low shear rates, which contributes to microcirculatory sludging) decreased
The effects appeared to be mediated through reduced fibrinogen (the principal plasma protein driving red-cell aggregation) rather than through direct effects on red cells themselves

Clinically, these effects translate to improved capillary-bed perfusion. The most visible application is in patients with peripheral vascular insufficiency — intermittent claudication, diabetic peripheral neuropathy with microcirculatory contribution, slow wound healing in the setting of compromised peripheral circulation. Reduced fibrinogen and improved red-cell deformability mean better delivery of oxygen and nutrients to tissues at the end of the vascular tree.

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Endothelial Function and Flow-Mediated Dilation

Flow-mediated dilation (FMD) is a standard non-invasive measure of endothelial function. The technique uses high-resolution ultrasound to measure brachial artery diameter at rest, then after a 5-minute occlusion of forearm blood flow (with a blood-pressure cuff inflated above systolic pressure), then again after release of the occlusion. The reactive hyperemia following cuff release causes endothelium-dependent dilation of the brachial artery; the percent change in diameter is a measure of endothelial-cell nitric oxide production capacity.

Several small studies have examined the effect of nattokinase on FMD. The aggregate signal is positive: nattokinase improves FMD modestly in subjects with baseline endothelial dysfunction (typical of patients with hypertension, dyslipidemia, type 2 diabetes, or established atherosclerosis). The proposed mechanism includes reduced oxidative stress, reduced LDL oxidation, and reduced inflammatory markers including von Willebrand factor (specifically documented in the Jensen 2016 trial).

The clinical relevance is that endothelial dysfunction precedes plaque formation in atherosclerosis, and reversing endothelial dysfunction is one of the few interventions that has been shown to slow or reverse the atherosclerotic process. Nattokinase contributes modestly in this direction, though the effect size is smaller than that of more established interventions (statins for severe dyslipidemia, ACE inhibitors for hypertension, smoking cessation, sustained aerobic exercise).

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Practical Cardiovascular Dosing Protocols

Primary cardiovascular maintenance: 2,000 FU once or twice daily. This is the threshold dose used in most positive trials.
Active fibrinolytic support (post-event, hypercoagulable conditions under physician supervision): 4,000–6,000 FU twice daily.
Long-haul flight prophylaxis: 2,000–4,000 FU 30–60 minutes before flight, possibly repeated for flights longer than 12 hours.
Time of day: evening dosing is theoretically rational because endogenous fibrinolytic activity is lowest in the early-morning hours when most cardiovascular events occur. The evidence supporting this practice is suggestive rather than definitive.
Form: enteric-coated capsules retain more activity through gastric pH than uncoated forms. NSK-SD™ from Japan Bio Science Laboratory is the most-studied standardized branded preparation; many third-party tested products contain it.
Combination products: nattokinase is often paired with serrapeptase, lumbrokinase, bromelain, or rutin in proteolytic enzyme blends. Whether the combinations are additive or merely additive on price is not well-established.
Onset: fibrinolytic markers respond within hours of a single dose; blood pressure and atherosclerosis markers require 4–8 weeks of daily dosing to show measurable change.
Duration: the safety database for daily nattokinase extends to ~6 months; longer-term human safety data are not as comprehensive as for many pharmaceutical agents.

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Cautions — Anticoagulants, Antiplatelets, Surgery, Bleeding Disorders

Concurrent anticoagulant therapy is the principal contraindication. Patients on warfarin, apixaban (Eliquis), rivaroxaban (Xarelto), edoxaban (Savaysa), dabigatran (Pradaxa), or therapeutic-dose heparin should NOT add nattokinase without explicit physician supervision. The combination meaningfully raises bleeding risk including major bleeding events. Case reports document elevated INR and bleeding in warfarin-treated patients who started nattokinase.
Concurrent antiplatelet therapy — aspirin, clopidogrel (Plavix), ticagrelor (Brilinta), prasugrel (Effient). Same caution applies. The combination is occasionally used under physician supervision in specific scenarios but is not appropriate for self-administration.
Active bleeding disorders — hemophilia A or B, von Willebrand disease, thrombocytopenia (platelet count below 100), inherited platelet function disorders. Nattokinase is contraindicated.
Recent or planned surgery — discontinue at least 7 days before any planned procedure. The pre-operative anesthesia clearance form should explicitly list nattokinase among supplements stopped. Dental procedures involving extraction or significant tissue trauma should follow the same 7-day discontinuation rule.
Recent stroke, especially hemorrhagic stroke. Nattokinase is contraindicated in the acute post-stroke period regardless of stroke subtype, and is permanently contraindicated after intracerebral hemorrhage.
Pregnancy and lactation. Insufficient safety data; avoid.
Severe hypertension (greater than 180/110). Address the underlying severe hypertension first; nattokinase is not appropriate as a sole intervention in this range.
Soy allergy. The enzyme is purified from fermentation broth and contains negligible soy protein in well-manufactured products, but soy-allergic patients should choose preparations explicitly labeled soy-free, and IgE-mediated soy-allergic patients should consult their allergist before any natto-derived product.
Side effects in healthy adults are typically mild and dose-related: nausea, mild gastrointestinal discomfort, occasional bruising, infrequent menstrual flow increase in pre-menopausal women. Severe adverse events are rare in the published literature.

For more on the broader cardiovascular context, see our pages on Atherosclerosis, Coagulation Panel, and Deep Vein Thrombosis.

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Key Research Papers

Sumi 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):1110-1111. — PubMed
Fujita M et al. (1995). Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the vegetable cheese natto. Biochem Biophys Res Commun. — PubMed
Cesarone MR et al. (2003). Prevention of venous thrombosis in long-haul flights with Flite Tabs. Angiology. — PubMed
Hsia CH et al. (2009). Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutrition Research. — PubMed
Kurosawa Y et al. (2015). A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. Scientific Reports. — PubMed
Pais E et al. (2006). Effects of nattokinase on red blood cell aggregation and whole blood viscosity. Clin Hemorheol Microcirc. — PubMed
Tai MW, Sweet BV (2006). Nattokinase for prevention of thrombosis. Am J Health Syst Pharm. — PubMed
Sumi H et al. (1990). Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase. Acta Haematol. — PubMed
Ero MP et al. (2013). A pilot study on the serum pharmacokinetics of nattokinase in humans. Altern Ther Health Med. — PubMed
Yatagai C et al. (2008). Nattokinase-promoted tissue plasminogen activator release from human umbilical vein endothelial cells. — PubMed
Chen H et al. (2018). Nattokinase: a promising alternative in prevention and treatment of cardiovascular diseases. Biomark Insights. — PubMed
Weng Y et al. (2017). Nattokinase: an oral antithrombotic agent for the prevention of cardiovascular disease. Int J Mol Sci. — PubMed

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