What is nattokinase and its use in preventing or treating conditions associated with blood clotting?

Nattokinase: A Fibrinolytic Enzyme from Fermented Soybeans

What Nattokinase Is

Nattokinase is a serine protease enzyme with fibrinolytic activity derived from natto, a traditional Japanese fermented soybean food, that directly cleaves fibrin and has been studied as a potential oral thrombolytic agent, though it lacks formal guideline endorsement and carries significant bleeding risks when combined with other antithrombotic medications. 1, 2

• Nattokinase is produced by Bacillus subtilis during the fermentation of soybeans and has been consumed in Asian populations for over 1000 years 2
• The enzyme has a molecular weight of approximately 27 kDa and functions as a fibrinolytic protease 3
• Unlike tissue plasminogen activator (tPA), which converts plasminogen to plasmin indirectly, nattokinase directly degrades fibrin and fibrinogen 4

Mechanism of Action

• Nattokinase cleaves cross-linked fibrin directly, distinguishing it from conventional plasminogen activators like tPA, urokinase, or streptokinase that work through plasminogen conversion 4
• In animal models, nattokinase demonstrated stronger thrombolytic activity than plasmin or elastase on a molar basis, with 62% recovery of arterial blood flow compared to 15.8% with plasmin 4
• The enzyme exhibits both fibrinolytic and thrombolytic properties in vitro and in vivo 1, 3

Clinical Evidence and Safety Concerns

Real-World Safety Data

• A 2021 observational study in 153 vascular surgery patients (ages 22-92) using nattokinase 100 mg/day showed clinical symptom improvement without adverse drug reactions when used alone or combined with fondaparinux or enoxaparin 1
• However, this study emphasized that "attention to patients' clinical evolution, monitoring of the INR, and timely and frequent adjustment of dosages represent the cornerstones of the safety of care" 1

Critical Bleeding Risk

The most concerning evidence comes from a case report of acute cerebellar hemorrhage in a patient taking nattokinase 400 mg daily for 7 days combined with aspirin, who had underlying cerebral microbleeds. 5

• This case demonstrates that nattokinase may increase intracerebral hemorrhage risk in patients with bleeding-prone cerebral microangiopathy, particularly when combined with other antithrombotic agents 5
• The patient had been using aspirin for secondary stroke prevention, highlighting the danger of combining nattokinase with antiplatelet or anticoagulant medications 5

Absence from Clinical Guidelines

Notably, nattokinase is completely absent from major evidence-based clinical practice guidelines for antithrombotic therapy, including the American College of Chest Physicians guidelines and American Heart Association statements. 6

• The 2012 ACCP guidelines on new antithrombotic drugs discuss novel fibrinolytic agents like alfimeprase, V10153, plasmin, and desmoteplase, but make no mention of nattokinase 6
• Established thrombolytic agents endorsed by guidelines include tPA (alteplase), reteplase, tenecteplase, streptokinase, and urokinase 6

Clinical Positioning and Limitations

Comparison to Guideline-Endorsed Agents

• tPA converts plasminogen to plasmin with 1000-fold enhanced activity when bound to fibrin, providing targeted fibrinolysis 7
• tPA has a short half-life of approximately 5 minutes and is rapidly inhibited by PAI-1, allowing for controlled therapeutic use 8, 7
• Newer variants like tenecteplase have longer half-lives and enhanced fibrin specificity with resistance to PAI-1 inhibition 6

Current Status

• Nattokinase is marketed as a dietary supplement or nutraceutical rather than an FDA-approved pharmaceutical agent 2
• It lacks the rigorous phase 3 clinical trial data required for guideline inclusion 6
• Production involves fermentation optimization, with recent studies achieving enzyme activities of 1874.94 IU/mL under optimal conditions 3

Critical Clinical Caveats

Avoid combining nattokinase with any antiplatelet agents (aspirin, clopidogrel) or anticoagulants (warfarin, heparin, DOACs) due to additive bleeding risk. 5

• Patients with cerebral microbleeds or other bleeding-prone microangiopathies should not use nattokinase 5
• The lack of standardized dosing, quality control, and pharmacokinetic data makes clinical use unpredictable 1, 2
• No established monitoring parameters exist, unlike warfarin (INR) or heparin (aPTT, anti-Xa levels) 1

For patients seeking thromboembolic disease prevention or treatment, guideline-endorsed therapies with established safety profiles and monitoring protocols should be prioritized over nattokinase. 6