Lumbrokinase – An Enzyme for More Than Just Circulatory Health! 

By Martin Kwok, BSc, MSAOM, ND

 

     Heart attack and stroke are the two most devastating and common circulatory issues we face in our time. Heart attacks are due to blockage of coronary arteries, and majority of stroke cases are due to thromboembolism. Currently there are three main categories of pharmaceutical agents used to treat or prevent ischemia issues: thrombolytics, antiplatelets, and anticoagulants. Thrombolytics can be a life-saver in acute situations when used appropriately but have a few drawbacks: short window of opportunity for its application, the risk of intra-cranial bleeding, and the fact that they have to be administered via intravenous infusion. Antiplatelets and anticoagulants may be used acutely or as a secondary prevention. They work by interfering with the coagulation system thus limiting the spread or worsening of the ischemia; they do not resolve the existing thrombus or embolus. It is still up to the body’s own fibrinolytic system to resolve the blockage, which may or may not happen. Like thrombolytics, antiplatelets and anticoagulants also carry the risks of causing unforeseen bleeding in spite of due care or testing. Is there not a safer and also effective natural option for helping patients besides the above categories of pharmaceuticals? The answer is “YES,” and the agent is called LUMBROKINASE!

 

What Is Lumbrokinase?

Diagram 1   Lumbrokinase Mechanism

Diagram 1 Lumbrokinase Mechanism

    Lumbrokinase is a complex enzyme preparation extracted from earthworms. Lumbrokinase can also be referred to as earthworm powder enzymes (EPE) or earthworm fibrinolytic enzymes (e-PPA). Earthworms have been used in traditional Eastern medicine for thousands of years in countries such as China, Japan, Korea, and others. According to the ancient Chinese medical publication Ben Cao Gang Mu (Compendium of Chinese Botanical and Animal Products), earthworms or “Earth Dragons” possess the properties to “invigorate blood, resolve stasis, and unblock the body’s meridians and channels.” As a result, earthworms are commonly included in traditional herbal formulae that treat ischemic or thromboembolic conditions.

 

    Inspired by the empirical wisdom of traditional Eastern medicine, modern Japanese researchers started searching for active ingredients that could account for the observed properties of earthworms. Finally, in 1983 Dr. Hisashi Mihara succeeded in extracting powerful fibrin-dissolving enzymes from earthworms, and he named this group of enzymes lumbrokinase.(1) Since then, Korean and Chinese researchers have compiled extensive in vitro, animal, and clinical data on the safety and potential applications of lumbrokinase over the past 30 years.

     As of February 18, 2018, a simple PubMed keyword search of “lumbrokinase” generated 65 results, with papers dating as far back as 1991 and as recent as February 2018. However, performing the same keyword search in one of the largest Chinese digital periodicals database (www.cnki.net) generated over 650 publications! This article is by no means an attempt to summarize all of the available clinical research on lumbrokinase, but merely to point out some of the clinically relevant highlights. Still, what is presented here is barely scratching the surface.

 

Mechanisms of Lumbrokinase

    Over the years various researchers have extracted lumbrokinase from different earthworm species by different methods and also studied its physiological properties in animal models. Most research indicated that lumbrokinase is primarily a fibrinolytic enzyme and it possesses both direct and indirect fibrinolytic effects.(2,3) It can activate the innate plasminogen system and also can achieve direct fibrinolysis independent of the plasminogen system (see Diagram 1). In 2004, Zhang el al discovered that lumbrokinase also inhibits PAI-1 activity and enhances t-PA activity.(4) In addition to being a strong fibrinolytic agent, lumbrokinase may indirectly achieve anticoagulation by inhibiting platelet functions. Jiang et al. were among the first researchers to report on such a property.(5) Interestingly, many people are not aware that lumbrokinase contains an enzyme that has opposing actions on the coagulation system. In a paper published in 2007, Zhao et al. demonstrated that lumbrokinase not only promotes fibrinolysis but also prothrombin activation (thus fibrinogenesis).(6) It appears that Nature has intended lumbrokinase to have a bi-directional rather than a uni-directional property. This built-in “balancing” mechanism may have contributed to the excellent safety record of lumbrokinase as explained later in the article.

 

Potential Clinical Applications

    As an oral enzyme supplement, lumbrokinase is not allowed or approved to make any therapeutic claims in North America. However, by looking into available animal and human research, it is not too hard for anyone to see the following potential applications:

           Ischemic Stroke. To further explore the traditional medical uses of earthworms in stroke, naturally one of the most intensely researched areas has been in the prevention and treatment of ischemic stroke patients. Lumbrokinase has been shown to be safe and effective for treating acute ischemic stroke by lowering blood viscosity, preventing re-perfusion damage, and reducing neural deficits.(7-9) It was also shown to improve the efficacy of aspirin as a secondary prevention of stroke.(10,11) In fact, for people who are resistant to aspirin (thus does not benefit from taking aspirin as a prevention), lumbrokinase appears to negate aspirin resistance and potentially help achieve the goal of cardiovascular disease prevention.(12)

           Coronary Artery Disease. Lumbrokinase is equally impressive in the treatment of coronary arterial diseases, including patients with unstable angina. Besides lowering whole blood viscosity, plasma viscosity, fibrinogen, and ESR, research data indicated that lumbrokinase was able to minimize angina attack frequency, minimize the need for nitroglycerine, and improve ST segment elevation on the EKG.(13-16) Other potential applications of lumbrokinase in circulatory conditions include deep venous thrombosis,(17) essential hypertension,(18) vascular dementia,(19) etc.

Kwok diagram 2.JPG

           Oncology. It is a well-known fact that most cancer patients (especially late stage) are hypercoagulable and prone to develop venous thromboembolism.(20-22) Thus, it is quite reasonable to use lumbrokinase in the prevention or treatment of cancer-associated thromboembolism. In recent years lumbrokinase has also been investigated as a potential anti-tumor and anti-metastatic agent. There is various in vitro and clinical evidence pointing towards the involvement of hypercoagulation in stimulating tumor growth and metastasis.(23,24) There are also evidence showing the potential use of anti-coagulants in limiting cancer growth and metastasis.(25-27) Thus, it is quite reasonable to investigate if lumbrokinase can be beneficial in the overall treatment of oncology patients. Though still early in the research stage, lumbrokinase has been shown to inhibit stomach cancer cell growth and liver cancer cell metastasis in vitro and in animal models.(28-30) Human studies are surely to follow in the near future.

           Chronic Biofilm-Associated Infections. Biofilm-associated chronic infection has become a popular topic in recent years. Thus, it is worth mentioning that lumbrokinase has been shown to break down biofilm and improve the effectiveness of antibiotics in vitro, though it still lacks human studies at this point. However, since chronic infection and chronic inflammation tend to create a hypercoagulable blood state,(31,32) some clinicians may feel that lumbrokinase’s true benefit is in reducing hypercoagulation-associated complications.

 

    Other note-worthy areas of lumbrokinase research: It may improve diabetic nephropathy(33) and diabetic neuropathy.(34) It may prevent the damage to heart cells from second-hand smoke.(35) It may also play a role in promoting bone repair and regeneration.(36,37)

 

Safety Record of Lumbrokinase

    The discovery of lumbrokinase in earthworms is not by accident but rather a targeted investigation into understanding traditional medical practices in Asian cultures. Earthworms have been used for many centuries (including present days) in traditional Asian medicine and are considered as a safe ingredient according to all ancient and modern medical writings and cumulative experiences.

 

    Even though earthworms appear to be very safe, what about enzymes extracted from earthworms? Past experiences with the development of pharmaceuticals have taught us to be vigilant about the risk of bleeding with any agent that affects the coagulation system. Thus, bleeding risk is one of the most watched for side-effect in the early research and trials involving lumbrokinase. To date, virtually all of the researchers who have ever studied or published on lumbrokinase concluded that it is a well-tolerated and very safe fibrinolytic enzyme preparation.

 

    The review paper by Wang et al estimated the overall adverse reaction rate to be about 3% with symptoms like mild headache, dizziness, constipation, and nausea; all the symptoms resolved spontaneously after stoppage of medicine and required no special treatment.(38) Another review paper by Tang et al reached an even lower rate of adverse reactions – 0.7% – though the authors believed this number to be an under-estimation.(39) The types of adverse reaction include nausea, vomiting, rash, skin itch, and dizziness; there are no bleeding issues nor damage to liver or kidney functions.

 

    Experiences in pharmaceutical drug development have taught researchers that clinical trials are simply simulations, no matter how perfect the study designs are. Adverse reaction profile of any drug can only be truly realized, in time, after it has been put on the market and used in real life conditions. Currently there are many lumbrokinase-containing products on the market, with most of them being sold in Asian countries. Some of these products are considered as nutritional supplements, some as Traditional Chinese Medicine, and some as pharmaceutical products. Over the past 30 years, lumbrokinase and earthworm-derived products have maintained an excellent safety record with little to none adverse reaction reported.

 

Differences Between Lumbrokinase Products and Other Enzymes

    Not all lumbrokinase products are made the same. Lumbrokinase is a mixture of enzymes from earthworms, thus products manufactured by different companies will have slightly different properties due to the differences in earthworm species used, extraction methods, and purification processes. As a result, some lumbrokinase products may affect lab tests like INR or aPTT and some may not. They may also differ in the type of capsules used, fillers, and the quality control processes. Despite the differences, good quality lumbrokinase products should provide similar clinical benefits when used properly. In addition to products with standardized enzymatic activities, there are also products that use ground-up earthworms or crudely extracted earthworm proteins, which may contain lumbrokinase but without having the enzymatic strength and total enzymatic activities assayed.

 

    Then how does lumbrokinase compare to other proteolytic enzymes? There are many oral proteolytic enzymes currently on the market, including bromelain, pancreatic enzymes, serrapeptase, nattokinase, etc. In terms of safety, by nature of being a protein, oral proteolytic enzymes are considered very safe. In terms of enzymatic activity, many proteolytic enzymes have broad-spectrum enzyme activities that are not specific towards fibrin. Presently only serrapeptase and nattokinase are being promoted as possessing fibrinolytic activities, thus more similar and comparable to lumbrokinase.

 

    Serrapeptase is an enzyme extracted from silkworms and has been shown to be an effective anti-inflammatory enzyme for pain and swelling reduction.(40) However, it still lacks clinical research supporting its use in thromboembolic conditions. On a milligram to milligram basis, the fibrinolytic strength of lumbrokinase is about 300-fold stronger than serrapeptase (see Table 1).

 

    Nattokinase is an enzyme extracted from traditional Japanese fermented soybeans and has been shown to an effective enzyme in improving various hypercoagulation-associated parameters; it looks very promising as an oral enzyme in the treatment and prevention of cardiovascular diseases. However, the use of nattokinase in human clinical trials involving thromboembolic conditions is still limited.(41) On a milligram to milligram basis, the fibrinolytic strength of lumbrokinase is about 30-fold stronger than nattokinase (see Table 1).

 

    Therefore, serrapeptase is not considered a strong fibrinolytic enzyme and should primarily be used for inflammation and pain association with oral/facial surgeries, sinus infection, arthritis, or chronic airway diseases. Respectively, nattokinase and lumbrokinase would be more suited for patients with mild and severe hypercoagulation or for patients with low and high cardiovascular risks.

 

Current and Future Challenges for Lumbrokinase

    The use of earthworms to achieve circulatory health in traditional medicine has come a long way. First there were dried earthworms used in traditional oriental herbal decoctions, and then there were ground-up earthworm powders. Later came crude extracts of earthworms, and now there is lumbrokinase -- a purified multiple-enzyme preparation extracted from earthworms. Just like omega-3 molecules from fish oil, polyphenols from green tea, and curcumin from turmeric root, in time lumbrokinase shall be known as the most valuable therapeutic ingredient from the humble earthworms.

 

    Even though lumbrokinase is a well-researched and clinically proven enzyme preparation, outside of Asia it is still relatively unknown to most practitioners and consumers. This is likely due to three main factors: first, most of the available clinical data on lumbrokinase is in Chinese and not readily accessible or understood by non-Chinese clinicians or researchers; second, pharmaceutical grade lumbrokinase is expensive and hard to come by (primarily from China), thus only a few companies are selling and promoting its clinical benefits; third, major pharmaceutical companies (with their massive influence on the media) have not found a way to profit from this enzyme yet. However, works have begun in further selecting and isolating one single enzyme from lumbrokinase for the eventual patenting and manufacturing of that specific enzyme via recombinant DNA technology.(42) Will a singular lumbrokinase, without the synergistic and balancing actions of other lumbrokinase sub-enzymes, still be as safe and effective as the whole lumbrokinase enzyme group? Only time can tell.

 

 References

 

    1.     Mihara H, et al. A novel fibrinolytic enzyme extracted from the earthworm, Lumbricus rubellus. Japanese Journal of Physiology. 1991;41(3):461–472.

    2.     Ma EL, et al. Effects of Rongshuan No 1 (F-1) on the antithrombotic and antiplatelet aggregation. Journal of Shenyang Pharmaceutical University. 2001;18(5):370-372.

    3.     He ZZ, et al. Separation and purification of earthworm fibrinolytic enzyme and the study of anti-thrombosis activity. Chinese Journal of Biochemical Pharmaceutics. 2001;22(6):284-286.

    4.     Zhang J, et al. Experimental study on the effect of lumbrokinase on fibrinolysis in rats. Chinese Journal of Pathophysiology. 2004;20(5):891-892.

    5.     Jiang DS, et al. Inhibition of platelet aggregation in hamsters by lumbrokinase extracted from Eisenia fetida. Journal of Capital Medical University. 1994;15(4):291-294.

    6.     Zhao J, et al. Eisenia fetida Protease-III-1 Functions in Both Fibrinolysis and Fibrogenesis. J Biomed Biotechnol. 2007;2007(5):97654.

    7.     Yang M, et al. Eisenia fetida lumbrokinase research VI – thrombolytic effect in rabbits and protective effects in experimental stroke model in hamsters. Biotechnology. 1995;5(3):9-11.

    8.     Li WY, et al. Observation of treating twenty-seven cases of ischemic stroke patients with lumbrokinase. New Chinese Medicine. 2003;34(4):63-64.

    9.     Zhang HY. Observation of treating acute ischemic stroke with lumbrokinase. Capital Medicine. 2000;7(3):45-46.

    10.   Zhang DJ, et al. Prevention of ischemic stroke recurrence using lumbrokinase. Capital Medicine. 2003;5(10):47-48.

    11.   Cao YJ, et al. Oral fibrinogen-depleting agent lumbrokinase for secondary ischemic stroke prevention: results from a multicenter, randomized, parallel-group and controlled clinical trial. Chin Med J (Engl). 2013 Nov;126(21):4060-5.

    12.   Sun MY, et al. Clinical Observations of Lumbrokinase Intervention in 60 Coronary Heart Disease Patients with Aspirin Resistance. Chinese Journal of Gerontology. 2009; 29: 760-761. 

    13.   Liu HS. Clinical observation of treating 60 angina patients with lumbrokinase. Tianjin Pharmacy. 2002;14(2):45-46. 

    14.   Yi XF, et al. Efficacy of treating unstable angina seniors with lumbrokinase. Capital Medicine. 2002;9(9):57-58.

    15.   Zhou HS, et al. Clinical observation of treating unstable angina seniors with lumbrokinase capsules. Central Plains Medical Journal. 2001;28(9):2-3.

    16.   Kasim M, et al. Improved myocardial perfusion in stable angina pectoris by oral lumbrokinase: a pilot study. J Altern Complement Med. 2009 May;15(5):539-44. 

    17.   Song JS, et al. Clinical analysis of treating 17 cases of deep venous thrombosis with lumbrokinase. Occupation and Health. 2001;17(4):111-115.

    18.   Ye SZ, et al. Observation of treating 51 cases of essential hypertension with lumbrokinase. Clinical Medicine. 2007;27(9):59.

    19.   Gao Y, et al. Efficacy of combining lumbrokinase with nimodipine in the treatment of vascular dementia. Journal of Liaoning University of Traditional Chinese Medicine. 2008;10(11):5-7.

    20.   De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol. 2004 Jun;50(3):187-96.

    21.   Molnar S, et al. Procoagulant factors in patients with cancer. Hematology. 2007 Dec;12(6):555-9.

    22.   Falanga A, et al. Hypercoagulability and tissue factor gene upregulation in hematologic malignancies. Semin Thromb Hemost. 2008 Mar;34(2):204-10.

    23.   Francis JL, et al. Effect of antihemostatic agents on experimental tumor dissemination. Thrombosis and Hemostasis. 2002; 28: 29-38. 

    24.   Caine GJ, et al. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia. 2002 Nov-Dec;4(6):465-73. 

    25.   Clerk CP, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005 Apr 1;23(10):2130-5.

    26.   Kakkar AK, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004 May 15;22(10):1944-8. 

    27.   DeFeo K, et al. Use of dabigatran etexilate to reduce breast cancer progression. Cancer Biol Ther. 2010 Nov 15;10(10):1001-8.

    28.   Li HY, et al. Antitumor activity of earthworm fibrinolytic enzyme. Chinese Pharmacological Bulletin. 2004;20(8):908-910.

    29.   Chen H, et al. Effect of earthworm fibrinolytic enzyme on the inhibition of invasion and metastasis in hepatocellular carcinoma cell. Jiangsu Medical Journal. 2008;34(4):383-385.

    30.   Chang CX, et al. Anti-metastatic activity of earthworm fibrinolytic enzyme on hepatoma cell in vivo. Traditional Chinese Drug Research & Clinical Pharmacology. 2009;20(6):520-524.

    31.   Levi M, et al. Infection and inflammation and the coagulation system. Cardiovasc Res. 2003 Oct 15;60(1):26-39.

    32.   Kitchens CS. Concept of hypercoagulability: a review of its development, clinical application, and recent progress. Semin Thromb Hemost. 1985 Jul;11(3):293-315.

    33.   Song WG, et al. Clinical observation of Boluoke with Lotensin, a new therapy for early stage diabetic nephropathy. Jiangxi Medical Journal. 2010 July; 45(7): 667-668.

    34.   Gu XL, et al. Observation of the effectiveness of treating diabetic peripheral neuropathy by lumbrokinase. Chinese Journal of Primary Medicine and Pharmacy. 2003 July; 10(7): 665.

    35.   Liao HE, et al. Cardio Protective Effects of Lumbrokinase and Dilong on Second-Hand Smoke-Induced Apoptotic Signaling in the Heart of a Rat Model. Chin J Physiol. 2015 Jun 30;58(3):188-96. 

    36.   Fu YT, et al. Porous gelatin/tricalcium phosphate/genipin composites containing lumbrokinase for bone repair. Bone. 2015 Sep;78:15-22. 

    37.   Fu YT, et al. Earthworm (Pheretima aspergillum) extract stimulates osteoblast activity and inhibits osteoclast differentiation. BMC Complement Altern Med. 2014 Nov 11;14:440. 

    38.   Wang CL, et al. Progress in lumbrokinase. Progress in Veterinary Med. 2009;30(11):86-90.

    39.   Tang YJ, et al. Lumbrokinase: A review of domestic research literatures. Capital Medicine. 2011;18(6):39-42.

    40.   Serrapeptase Monograph, Natural Health Products Ingredients Database, Health Canada. 2014 February 7. http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=serrapeptase&lang=eng

    41.   Weng YQ, et al. Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease. Int J Mol Sci. 2017 Mar; 18(3): 523. 

    42.   Wang KY, et al. Recombinant protein production of earthworm lumbrokinase for potential antithrombotic application. Evid Based Complement Alternat Med. 2013;2013:783971. 

 

Dr. Martin Kwok completed his Bachelor of Science degree from the University of British Columbia, BC, Canada. Then he went on to receive his Doctor of Naturopathic Medicine and Master of Science in Acupuncture & Oriental Medicine from Bastyr University in Washington State.

Dr. Kwok is dual-licensed as a naturopathic physician and a doctor of traditional Chinese medicine in BC, Canada, and has had an active practice at the Richmond Alternative Medical Clinic, Inc. (Richmond, BC, Canada) for over 20 years. Dr. Kwok has a general practice with focuses on cardiovascular conditions, cancer supportive care, and hyperthyroid issues.

Dr. Kwok currently holds positions as a board member at National Traditional Chinese Medicine Association of Canada, as the Editor-in-Chief at Dragon’s Medical Bulletin (an e-newsletter for health care professionals), as the Vice-President at Canada RNA Biochemical Inc., and as an advisor for Vita Aid Professional Products.

 

Dr. Kwok can be contacted by email at drmartinkwok@yahoo.ca or via his website at    www.DrMartinKwok.com.