When it comes right down to it, blood clots are the top cause of death worldwide (heart attacks and strokes). We do all kinds of things to live a long, healthy life, but what if there were more that we could do to ‘stop the clot’?
This article digs into the research and clinical trials on two natural ways to reduce clotting: nattokinase and lumbrokinase. Included is information on genetic variants that increase blood clot risk.
Talk with your doctor for medical advice on whether natural fibrinolytics are the right choice for you. Everyone is different, and the information here is just a recap of peer-reviewed research studies.
What is Nattokinase?
Nattokinase is a powerful serine protease enzyme, which means it can cleave the bonds in certain proteins.
Nattokinase is produced by the bacteria Bacillus subtilis natto and is found in the traditional Japanese fermented soybean food called natto. Natto has been used for centuries in Japan as a remedy for heart disease.[ref]
Nattokinase acts as a fibrinolytic. It means that it breaks down a fibrin clot by cutting the fibrin mesh.[ref]
Let’s dig into how this works and when it could be important…
Coagulation: How does blood clot?
Let me give you some quick background on how clots are made so that you can understand the process of breaking down the clot.
Coagulation, or clotting, begins very quickly when the lining of the blood vessel, the endothelium, is injured. Exposure to the collagen in the sub-endothelium of the blood vessels triggers platelet changes, causing them to clump together at the injury. At the same time, coagulation factors such as factor VII and tissue factor start forming fibrin strands which bind together and strengthen the clot.
Fibrin is a fibrous protein made when fibrinogen encounters thrombin. Fibrinogen is a protein made in the liver that circulates in the bloodstream, ready to be converted to fibrin in an instant when needed. Thrombin is an enzyme that catalyzes the reaction causing fibrinogen to turn into insoluble fibrin strands. The gene that encodes thrombin is the F2 (factor 2) gene.
Related article: F2 and thrombin genetic variants that increase the risk of blood clots.
Here’s a graphical overview of the clotting process, starting with platelet activation:
The clotting process eventually forms a stable blood clot, and then it kind of starts all over again. Clots are partly broken down and reformed continually until the injury is resolved.
Fibrinolysis: breaking down clots
Blood clots break down by a process called fibrinolysis, a term that means to cut up fibrin. Plasmin is the enzyme the body makes to break down fibrin in clots. But it isn’t as simple as just having plasmin come along to cut the fibrin. Instead, a series of actions take place to activate plasmin.
Plasminogen is the inactive form of plasmin. It is produced in the liver and circulates until it is needed. When plasminogen is converted by either tissue plasminogen activator (tPA) or urokinase, it becomes plasmin.
Here’s a visual overview of fibrinolysis, the process of breaking down clots:
Plasminogen activator inhibitor 1 (PIA-1) regulates fibrinolytic activity in the clotting cascade. PIA-1 regulates the formation of plasmin through inhibiting tPA or urokinase. (Read about PIA1/A2 and blood clot risk)
The breakdown of fibrin creates soluble parts called fibrin degradation products. D-dimer is one fibrin degradation product, and it is often measured to see how much clotting action is taking place in the body.
Clots Created by Immune System Activation:
Coagulation is used in the body for more than just injuries to blood vessels. Pathogens (viruses, bacteria) can be physically trapped in blood clots, and platelets play an active role in the immune system.
In addition to their role in plugging leaks in blood vessels, platelets express pathogen recognition receptors on their cell membranes. These receptors can trigger platelet activation when a virus or bacteria circulates in the bloodstream.
Platelets are created and destroyed constantly. We create about 100 billion platelets each day, and they have a lifespan of 7-10 days. They circulate through the bloodstream as tiny cells but when activated, undergo massive spreading and can bind to other platelets or white blood cells. Additionally, they can bind to and sequester anything identified as a pathogen (bacteria, viruses, other particles). Finally, platelets can also release antimicrobial payloads to destroy pathogens.[ref]
Covid-19, Spike protein, and Clots:
The SARS-CoV-2 virus can cause micro-clots to form throughout the small blood vessels in the body in severe COVID-19 cases. Research shows that platelets can internalize SAR-CoV-2 virions and destroy them. This function also leads to platelet activation, though, which could trigger the formation of clots.[ref]
A recent preprint study from King’s College London explains that the SARS-CoV-2 spike protein alone causes platelet activation and adhesion. From the study: “Spike was effective both as a sole agonist or by enhancing the effect of known platelet activators, such as collagen and collagen-related peptide. In particular, Spike exerted a noticeable effect on the procoagulant phenotype of platelets, by enhancing calcium flux, phosphatidylserine externalisation, and thrombin generation. Eventually, this resulted in a striking increase in thrombin-induced clot formation and retraction.”[ref]
Case studies, which are published by doctors, show that the Covid vaccines which deliver the spike protein are also linked to cases of clotting. Examples include cases of pulmonary embolisms, deep vein thrombosis, myocardial infarction, cerebral venous sinus thrombosis, and stroke. Additionally, analysis of data by WHO shows increased clot risk (ischemic stroke, CVST) after the mRNA spike protein vaccines that is significantly higher in comparison to the flu vaccine. [ref][ref][ref][ref][ref][ref][ref][ref][ref][ref][ref][ref]
Related article: Spike Protein, Mast cells in your heart
How does Nattokinase work?
First, let’s clear up a bit of the naming confusion. Nattokinase isn’t a kinase, which is an enzyme that catalyzes reactions where a phosphate group is transferred from ATP to another protein. Instead, nattokinase is a serine protease – an enzyme that breaks apart peptide bonds in proteins.
Nattokinase is a naturally occurring fibrinolytic which breaks down fibrin in clots. It is about four times more potent than plasmin as a fibrinolytic , which the body makes to break down fibrin.[ref]
After nattokinase is absorbed in the intestines, it retains its protease (protein break-down) activity. It works to break down clots and decrease clotting through a couple of different mechanisms.
- Dissolves or cleaves fibrin in blood clots.
- Increases tPA (tissue plasminogen activator), which is an endogenous protein that breaks down fibrin. (see image above)
- Increases urokinase levels. Urokinase leads to more plasmin, another endogenous protein involved in fibrinolysis.
- Inactivates PIA-1, which is an inhibitor of plasmin.
- Acts to inhibit platelet aggregation by blocking thromboxane formation.
Why would you want to break down fibrin?
Clotting is essential and completely necessary when you are wounded.
But blood clots that block the blood vessels of the heart cause heart attacks. Blood clots in the brain cause strokes. Additionally, fibrin is part of the atherosclerotic plaque that can clog blood vessels, which causes elevated blood pressure.
While clotting is essential to keep you from bleeding to death, ironically, blood clots are also your most likely cause of death.
Clinical Trials on Nattokinase:
Studies on any supplement are interesting, but to truly know what happens in the body, you need to look at clinical trials to see both the significance of the supplement as well as any adverse events that occured.
A clinical trial of healthy volunteers and cardiovascular disease patients investigated the effect of nattokinase on cardiovascular endpoints. The participants took two capsules of nattokinase (2000 fibrinolysis units per capsule) daily for two months. There was a statistically significant decrease in fibrinogen, factor VII, and factor VIII (coagulation factors) in healthy and cardiovascular disease participants. No adverse events were noted.[ref]
A study in healthy young adult males to determine bioavailability showed that nattokinase starts to work about two hours after taking it. Blood antithrombin levels rose at two hours and stayed elevated for another two hours. Factor VIII levels dropped significantly by four hours after ingestion. All the changes, though, were still within the normal range. In other words, it didn’t cause so much of a change that excess bleeding would occur.[ref]
A clinical trial of 100 mg of nattokinase for eight weeks in adults showed that it reduces blood pressure (a little bit). The nattokinase arm of the trial reduced both systolic and diastolic blood pressure, with no change noted in the placebo group.[ref]
In China, a randomized controlled clinical trial found that nattokinase (6,000 fibrinolysis units per day) reduced carotid plaque size by 36%. This reduction was statistically quite a bit better than the reduction seen in patients taking statins instead of nattokinase.[ref]
A study also shows that nattokinase supplementation decreased scar tissue formation in heart surgery.[ref]
Safety and Side Effects:
Most clinical trials use 100 mg (2,000 fibrinolytic units) either once or twice a day, with no adverse effects. Keep in mind that the clinical trial participants are screened for things like medication interactions or bleeding risks.
- A safety trial of 153 patients with deep vein thrombosis or venous insufficiency after surgery found that nattokinase improved clinical symptoms without adverse drug reactions.[ref] All the patients’ bleeding times were being monitored, and their doctors adjusted their medications as needed.
- Animal studies show that high doses of nattokinase can cause hemorrhaging. But it was less likely to cause hemorrhages than other drugs commonly used as fibrinolytics.[ref]
- A case study explained that a 92-year-old woman taking nattokinase developed bleeding in the abdomen (hemoperitoneum) and passed away. The patient, who also had chronic kidney disease, atrial fibrillation, hypertension, and hypothyroidism, wasn’t sure how much nattokinase she took but said it was “sometimes a handful”. The physician thinks that the bleeding was, at least in part, due to the nattokinase.[ref]
Nattokinase has the potential for reducing amyloid beta in the brain, which is associated with Alzheimer’s disease. The problem is that nattokinase doesn’t cross the blood-brain barrier very well. Researchers are looking at various ways of combining nattokinase with lipid nanoparticles to overcome the blood-brain barrier issue.[ref]
In an animal model of Alzheimer’s, researchers used a combination of nattokinase with serrapeptase (another serine protease) to see if it would help clear out amyloid-beta. The study showed that the proteases increased levels of certain genes in the brain tissue related to shifting away from the production of amyloid beta.[ref]
A lot more research is needed here, but the idea of reducing amyloid beta with a serine protease is interesting.
Lumbrokinase vs. Nattokinase:
Another natural fibrinolytic, lumbrokinase, is derived from an earthworm species called Lumbricus rubellus. This type of worm has been used historically in traditional Chinese medicine for rheumatoid diseases and heart health.
Lumbrokinase has fibrinolytic activity and reduces platelet activation.[ref]
There isn’t nearly as much research on lumbrokinase, but it is available as a supplement online and in health stores.
Another animal study showed that lumbrokinase ameliorates the effects of secondhand smoke on the heart.[ref]
Clinical trials on Lumbrokinase:
A clinical trial on one of the components of lumbrokinase, called DLBS1022, showed that it helped ischemic stroke patients improve a little faster. There were no adverse events from lumbrokinase.[ref]
A clinical trial using 490mg/day to determine the half-life of lumbrokines noted no serious adverse events due to lumbrokinase.[ref]
Another small study of Lumbrokinase DLBS1033 also showed that it was “safe and tolerable in healthy adults.” The study looked at liver and kidney function, lipid profile, hemorrhagic symptoms, and allergic reactions.[ref]
My two-cents: There really isn’t a lot of research on lumbrokinase yet. While it seems likely safe for most healthy people, personally, I would like to see more clinical trials or even animal trials on it before taking it as a supplement.
The rest of this article is for Genetic Lifehacks members only. It includes information on what to look for in a nattokinase supplement as well as a genetics overview of clot-related variants.
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Bhatt, Prakash Chandra, et al. “Development of Surface-Engineered PLGA Nanoparticulate-Delivery System of Tet1-Conjugated Nattokinase Enzyme for Inhibition of Aβ40 Plaques in Alzheimer’s Disease.” International Journal of Nanomedicine, vol. 12, 2017, p. 8749. www.ncbi.nlm.nih.gov, https://doi.org/10.2147/IJN.S144545.
Cappelletto, Ambra, et al. SARS-CoV-2 Spike Protein Activates TMEM16F-Mediated Platelet pro-Coagulant Activity. bioRxiv, 16 Dec. 2021, p. 2021.12.14.472668. bioRxiv, https://www.biorxiv.org/content/10.1101/2021.12.14.472668v2.
Chen, Hongjie, et al. “Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases.” Biomarker Insights, vol. 13, July 2018, p. 1177271918785130. PubMed Central, https://doi.org/10.1177/1177271918785130.
Fadl, Nn, et al. “Serrapeptase and Nattokinase Intervention for Relieving Alzheimer’s Disease Pathophysiology in Rat Model.” Human & Experimental Toxicology, vol. 32, no. 7, July 2013, pp. 721–35. DOI.org (Crossref), https://doi.org/10.1177/0960327112467040.
Feng, Rui, et al. “Preparation and Toxicity Evaluation of a Novel Nattokinase-Tauroursodeoxycholate Complex.” Asian Journal of Pharmaceutical Sciences, vol. 13, no. 2, Mar. 2018, p. 173. www.ncbi.nlm.nih.gov, https://doi.org/10.1016/j.ajps.2017.11.001.
Gallelli, Giuseppe, et al. “Data Recorded in Real Life Support the Safety of Nattokinase in Patients with Vascular Diseases.” Nutrients, vol. 13, no. 6, June 2021. www.ncbi.nlm.nih.gov, https://doi.org/10.3390/nu13062031.
Gayatri, Anggi, et al. “A Clinical Trial on Biological Half Life of Bioactive Protein from Lumbricus Rubellus, DLBS1033 in Healthy Volunteers.” Acta Medica Indonesiana, vol. 50, no. 3, July 2018, pp. 208–14.
Guo, Haiyu, et al. “Comparative Anti-Thrombotic Activity and Haemorrhagic Adverse Effect of Nattokinase and Tissue-Type Plasminogen Activator.” Food Science and Biotechnology, vol. 28, no. 5, Oct. 2019, p. 1535. www.ncbi.nlm.nih.gov, https://doi.org/10.1007/s10068-019-00580-1.
Guo, Li, and Matthew T. Rondina. “The Era of Thromboinflammation: Platelets Are Dynamic Sensors and Effector Cells During Infectious Diseases.” Frontiers in Immunology, vol. 10, Sept. 2019, p. 2204. PubMed Central, https://doi.org/10.3389/fimmu.2019.02204.
Hsia, Chien-Hsun, et al. “Nattokinase Decreases Plasma Levels of Fibrinogen, Factor VII, and Factor VIII in Human Subjects.” Nutrition Research (New York, N.Y.), vol. 29, no. 3, Mar. 2009, pp. 190–96. PubMed, https://doi.org/10.1016/j.nutres.2009.01.009.
Jensen, Gitte S., et al. “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, vol. 9, 2016, p. 95. www.ncbi.nlm.nih.gov, https://doi.org/10.2147/IBPC.S99553.
Koupenova, Milka, et al. “SARS-CoV-2 Initiates Programmed Cell Death in Platelets.” Circulation Research, vol. 129, no. 6, Sept. 2021, pp. 631–46. PubMed Central, https://doi.org/10.1161/CIRCRESAHA.121.319117.
Kurosawa, Yuko, et al. “A Single-Dose of Oral Nattokinase Potentiates Thrombolysis and Anti-Coagulation Profiles.” Scientific Reports, vol. 5, 2015. www.ncbi.nlm.nih.gov, https://doi.org/10.1038/srep11601.
Lai, Chao-Hung, et al. “Lumbrokinase from Earthworm Extract Ameliorates Second-Hand Smoke-Induced Cardiac Fibrosis.” Environmental Toxicology, vol. 30, no. 10, Sept. 2015, pp. 1216–25. PubMed, https://doi.org/10.1002/tox.21993.
Pinzon, Rizaldy Taslim, et al. “Effect of DLBS1033 on Functional Outcomes for Patients with Acute Ischemic Stroke: A Randomized Controlled Trial.” Stroke Research and Treatment, vol. 2021, Apr. 2021, p. 5541616. PubMed Central, https://doi.org/10.1155/2021/5541616.
Ramachandran, Lintu, et al. “Nattokinase-Associated Hemoperitoneum in an Elderly Woman.” Cureus, vol. 13, no. 12, p. e20074. PubMed Central, https://doi.org/10.7759/cureus.20074. Accessed 23 Feb. 2022.
Ren, N. N., et al. “[A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia].” Zhonghua Yi Xue Za Zhi, vol. 97, no. 26, July 2017, pp. 2038–42. PubMed, https://doi.org/10.3760/cma.j.issn.0376-2491.2017.26.005.
Suzuki, Yasuhiro, et al. “Dietary Supplementation with Fermented Soybeans Suppresses Intimal Thickening.” Nutrition, vol. 19, no. 3, Mar. 2003, pp. 261–64. ScienceDirect, https://doi.org/10.1016/S0899-9007(02)00853-5.
Tjandrawinata, R. R., et al. “The Safety and Tolerability of Lumbrokinase DLBS1033 in Healthy Adult Subjects.” Drug Research, vol. 66, no. 6, June 2016, pp. 293–99. PubMed, https://doi.org/10.1055/s-0035-1569406.
Tjandrawinata, Raymond R, et al. “Bioactive Protein Fraction DLBS1033 Containing Lumbrokinase Isolated from Lumbricus Rubellus: Ex Vivo, in Vivo, and Pharmaceutic Studies.” Drug Design, Development and Therapy, vol. 8, Sept. 2014, pp. 1585–93. PubMed Central, https://doi.org/10.2147/DDDT.S66007.
Wang, Yi-Hsin, Ke-Min Chen, et al. “Lumbrokinase Attenuates Myocardial Ischemia-Reperfusion Injury by Inhibiting TLR4 Signaling.” Journal of Molecular and Cellular Cardiology, vol. 99, Oct. 2016, pp. 113–22. PubMed, https://doi.org/10.1016/j.yjmcc.2016.08.004.
Wang, Yi-Hsin, Shun-An Li, et al. “Sirt1 Activation by Post-Ischemic Treatment With Lumbrokinase Protects Against Myocardial Ischemia-Reperfusion Injury.” Frontiers in Pharmacology, vol. 9, 2018, p. 636. PubMed, https://doi.org/10.3389/fphar.2018.00636.
Weng, Yunqi, et al. “Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease.” International Journal of Molecular Sciences, vol. 18, no. 3, Feb. 2017, p. 523. PubMed Central, https://doi.org/10.3390/ijms18030523.
Zhang, Fuming, et al. “Interactions between Nattokinase and Heparin/GAGs.” Glycoconjugate Journal, vol. 32, no. 9, Dec. 2015, p. 695. www.ncbi.nlm.nih.gov, https://doi.org/10.1007/s10719-015-9620-8.
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.