Prepared by: Kamil Khoury
Date: October 7, 2025
Intended Use: Research‑use only; not medical advice.
Disclaimer: Educational content for research‑use only. This document does not provide medical advice, diagnosis, treatment, or dosing guidance.
Introduction
Nattokinase and lumbrokinase are two naturally derived enzymes that have garnered significant attention in the field of cardiovascular health and alternative medicine. Nattokinase, a serine protease enzyme, is produced during the fermentation of soybeans by the bacterium Bacillus subtilis natto, a process integral to the traditional Japanese food natto. This enzyme was first isolated in 1987 by Dr. Hiroyuki Sumi, who discovered its potent fibrinolytic properties, earning it the nickname “the enzyme of enzymes” for its ability to dissolve blood clots. Lumbrokinase, on the other hand, is a complex of fibrinolytic enzymes extracted from earthworms, specifically species like Lumbricus bimastus or Eisenia fetida. It has been used in traditional Chinese medicine for centuries to treat conditions related to blood stagnation and has been studied scientifically since the 1990s.
Both enzymes are classified as fibrinolytic agents, meaning they break down fibrin, the protein mesh that forms blood clots. However, their applications extend beyond thrombolysis to include anti-inflammatory, antihypertensive, and potentially neuroprotective effects. In recent years, interest has surged due to their potential roles in managing post-viral syndromes like Long COVID, where microclots and vascular inflammation are implicated. This research brief explores their mechanisms of action, with a particular focus on vasodilation effects, the advantages of combining them, clinical evidence from human studies, applications in cardiovascular health and related conditions such as erectile dysfunction (ED), and safety profiles. Drawing from over 50 sources including clinical trials, reviews, and mechanistic studies, this brief aims to provide a comprehensive overview while highlighting gaps in current knowledge.
The relevance of these enzymes stems from the global burden of cardiovascular diseases (CVD), which account for nearly 18 million deaths annually worldwide. Traditional treatments like anticoagulants (e.g., warfarin) or antiplatelets (e.g., aspirin) carry risks of bleeding and gastrointestinal issues, prompting exploration of natural alternatives. Nattokinase and lumbrokinase offer promising, orally bioavailable options with potentially fewer side effects, though rigorous large-scale trials are still needed. Furthermore, their indirect links to conditions like ED through improved blood flow and vascular health tie into broader discussions on penile enlargement and sexual health, where vasodilation plays a key role. This brief will delve into these aspects, ensuring a balanced view supported by evidence.
Mechanisms of Action
Nattokinase Mechanisms
Nattokinase exerts its effects through multiple pathways, primarily fibrinolysis, anticoagulation, and antiplatelet activity. As a subtilisin-like serine protease, it directly degrades fibrin and fibrinogen, the building blocks of clots, while also enhancing endogenous fibrinolytic systems by increasing tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) levels. This dual action direct and indirect distinguishes it from pharmaceutical fibrinolytics like alteplase, which are typically administered intravenously.
Beyond clot dissolution, nattokinase modulates inflammatory pathways by inhibiting pro-inflammatory cytokines such as TNF-α and IL-6, reducing oxidative stress via antioxidant properties, and improving lipid profiles by lowering LDL cholesterol and triglycerides. In terms of vasodilation, nattokinase inhibits angiotensin-converting enzyme (ACE), a key enzyme in the renin-angiotensin-aldosterone system (RAAS) that promotes vasoconstriction. By blocking ACE, it reduces angiotensin II production, leading to vessel relaxation and decreased blood pressure. Animal studies in hypertensive rats have shown dose-dependent BP reductions, with mechanisms involving enhanced nitric oxide (NO) production, a potent vasodilator.
Additionally, nattokinase influences coagulation factors by decreasing levels of factor VII and VIII, further preventing thrombus formation. Its neuroprotective effects, observed in cerebral ischemia models, involve increased cyclic AMP (cAMP) levels and activation of JAK1/STAT1 signaling, which protect against neuronal damage.
Lumbrokinase Mechanisms
Lumbrokinase is a mixture of six or more proteolytic enzymes, making it more complex than nattokinase. Its primary mechanism is selective fibrinolysis: it directly hydrolyzes fibrin without significantly affecting other proteins, and it activates plasminogen to plasmin while inhibiting plasminogen activator inhibitor-1 (PAI-1). This specificity reduces the risk of systemic bleeding compared to broader-acting agents.
Unlike nattokinase, lumbrokinase has less direct impact on ACE or RAAS, but it indirectly supports vasodilation by reducing blood viscosity and preventing microthrombi that could impair endothelial function. In myocardial ischemia-reperfusion models, it attenuates injury via Sirt1 signaling, promoting anti-apoptotic effects and vascular integrity. Lumbrokinase also degrades amyloid fibrils, suggesting potential in neurodegenerative diseases, and inhibits fibroblast motility to prevent adhesions in post-surgical.
Vasodilation Effects
Nattokinase’s Vasodilation
Nattokinase’s vasodilatory effects are well-documented and multifaceted. By inhibiting ACE, it mimics the action of ACE inhibitors like lisinopril, leading to reduced vasoconstriction. A 2008 randomized trial with 73 prehypertensive participants showed significant reductions in systolic (5.55 mmHg) and diastolic (2.84 mmHg) BP after 8 weeks of 2000 FU daily nattokinase supplementation. This effect is independent of renin levels, indicating alternative pathways like enhanced endothelial NO synthase (eNOS) activity.
In human studies, nattokinase has been associated with improved peripheral blood flow, as measured by skin temperature increases post-ingestion. For CVD prevention, it reduces intima-media thickness in carotid arteries, a marker of atherosclerosis, by improving vascular elasticity. In a large observational study with 1062 participants, nattokinase intake correlated with lower CVD mortality, partly due to its antihypertensive and lipid-lowering effects.
Lumbrokinase’s Vasodilation
Lumbrokinase’s vasodilation is more indirect, stemming from its superior fibrinolytic potency (up to 30 times that of nattokinase in some assays). By dissolving microclots, it restores normal blood flow, reducing shear stress on vessel walls and promoting endothelial health. Clinical trials for secondary stroke prevention show improved Ankle Brachial Index (ABI), indicating better peripheral circulation. In combination with aspirin, lumbrokinase reduced ischemic stroke recurrence more effectively than aspirin alone in a trial of 310 patients.
However, direct BP-lowering data for lumbrokinase is sparse compared to nattokinase, with effects more pronounced in ischemic models rather than hypertension.
Benefits of Combining Nattokinase and Lumbrokinase
Combining these enzymes leverages their complementary strengths for enhanced efficacy. Nattokinase’s ACE inhibition and broader anti-inflammatory effects pair with lumbrokinase’s potent fibrinolysis, potentially offering superior clot management and vascular support. In lab settings, conjugated forms have shown improved thrombolytic activity on nanoparticle membranes, suggesting synergistic potential.
For microclots in Long COVID, user surveys report >60% symptom improvement with the combo, attributed to comprehensive fibrin degradation and circulation restoration. In cardiovascular contexts, the combination may reduce amyloid fibrils more effectively, benefiting neurodegeneration. Commercial products like those with red yeast rice claim versatile benefits for flow and wellness.
Evidence from indirect studies suggests reduced blood viscosity and inflammation, potentially lowering CVD risk more than either alone. However, direct human trials on the combination are limited, with most data from in vitro or animal models.
Clinical Evidence and Human Studies
Human studies on nattokinase include the Nattokinase Atherothrombotic Prevention Study (ongoing as of 2025), measuring carotid stiffness. A 90-day double-blind trial with nattokinase and red yeast rice showed improved cardiometabolic parameters in dyslipidemia patients. BP-focused trials like NCT02886507 confirmed reductions without coagulation changes in healthy subjects.
For lumbrokinase, trials demonstrate efficacy in stroke prevention and PAD, with one showing reduced recurrence when combined with aspirin. Amyloid degradation studies highlight potential for Alzheimer’s.
In ED and penile health, indirect benefits arise from improved vasodilation; nattokinase’s NO enhancement could support erectile function, though no direct trials exist. For penile enlargement, claims are anecdotal, with no evidence linking these enzymes to tissue growth beyond vascular improvements.
Lipid studies show nattokinase reduces atherosclerotic plaques.
Applications in Cardiovascular Health, ED, and Related Conditions
In CVD, both enzymes reduce mortality risk through anti-atherosclerotic effects. Nattokinase lowers lipids and BP, while lumbrokinase excels in thrombolysis for acute events.
For ED, enhanced blood flow via vasodilation may improve erectile quality, as seen in general vascular supplements. Penile enlargement claims lack support; any perceived increases would be from better engorgement, not permanent growth.
In post-viral care, the combo addresses microclots.
Safety and Side Effects
Nattokinase is generally safe, with no major adverse events in trials at doses up to 400 mg/day. Side effects include mild bleeding risk when combined with anticoagulants. Lumbrokinase may cause GI discomfort, nausea, or bleeding.
Combination increases bleeding potential; avoid pre-surgery or with blood thinners without supervision.
Conclusion
Nattokinase and lumbrokinase represent promising natural interventions for vascular health, with nattokinase offering direct vasodilation and lumbrokinase potent fibrinolysis. Their combination amplifies benefits, though more trials are needed. While useful for CVD and potentially ED, they are not proven for penile enlargement. Safety is high, but caution is advised. Future research should focus on long-term outcomes and synergies.