Useful properties and harm of hirudotherapy

Hirudotherapy, or leech therapy, is an ancient treatment method that has been used in medicine since ancient times. Modern research confirms some of the healing properties of hirudotherapy due to the unique bioactive substances in the saliva of leeches. Here are the main beneficial properties of hirudotherapy:

Medical leeches have three saw-like jaws (tripartite) with about 100 sharp teeth on each. After piercing the skin, anticoagulants (hirudin) are injected and blood is sucked out. Large adult leeches can eat ten times their weight in one meal. [1] Leech therapy involves an initial bite, during which the leech sucks 5 to 15 ml of blood over a period of 20 to 45 minutes. The effect of the treatment lies in the amount of blood the leech ingests and the anticoagulant enzymes that allow blood to flow from the site when the leech is disconnected.

There are over 600 species of leeches, but the most commonly used worldwide are Hirudo Medicinalis, Hirudo troctina, Hirudo nipponia, Hirudo quinquestriata, Poecilobdella granulosa, Hirudinaria javanica, Hirudinaria manillensis, Haementeria officinalis and Macrobdella decora. [2], [3]

Degradation of extracellular matrix

After being bitten, leeches immediately secrete the enzymes hyaluronidase (27.5 kDa) and collagenase (100 kDa), which facilitate the penetration into tissues and distribution of their biologically active molecules. These enzymes also support antimicrobial activity. [4]

Improved blood circulation

The mechanism of action of hirudotherapy (treatment with leeches) in improving blood circulation is mainly due to the unique composition of leech saliva, containing a variety of biologically active substances. The main components of leech saliva that help improve blood circulation include:

1. Hirudin is a natural thrombin inhibitor that prevents blood clotting. Hirudin blocks thrombin, preventing it from converting fibrinogen into fibrin, which is the basis for the formation of blood clots. This helps to thin the blood and improve its circulation.
2. Kalin is another substance that slows blood clotting by acting through inhibition of platelet aggregation. This helps to reduce the formation of blood clots and improve microcirculation.
3. Hyaluronidase - an enzyme that promotes the penetration of other components of leech saliva deeper into the tissue by breaking down the intercellular substance. This improves local blood circulation and promotes the resorption of congestion.
4. Egliins are proteins with anti-inflammatory properties that also help reduce swelling and improve blood flow.
5. BDNF (brain-derived neurotrophic factor) - promotes nerve cell repair and regeneration, and improves neuronal function, which may indirectly affect blood flow regulation.
6. Anesthetics and analgesic components - provide a localanesthetic effect at the site of leech attachment, making the procedure less painful for the patient.
7. Destabilase: This protein helps dissolve blood clots and has anti-inflammatory properties.
8. Bdellins: These are proteins that have anticoagulant and antibacterial properties.
9. Saratins: Glycoproteins that inhibit platelet adhesion and aggregation, thereby preventing blood clots.

Exposure to these components leads to improved blood microcirculation in the area where leeches are applied, reduces edema, resolves venous congestion and promotes better oxygenation and tissue nutrition. Hirudotherapy is used in various medical fields, including plastic surgery, traumatology, cardiology and phlebology, due to its anticoagulant, anti-inflammatory and regenerative properties.

Suppression of platelet function

Destruction of the blood vessel wall for blood absorption causes activation of platelets and the coagulation cascade, which is detrimental to the leech. For this reason, leech secretions contain many biologically active molecules that locally inhibit these actions.

In the normal host, wall disruption causes the proliferation and release of collagen particles that target free von Willebrand factor (vWF). This complex binds firmly to glycoprotein (GP) Ib on platelets as Willebrand factor acts as a bridge. This binding triggers mechanisms of up-regulation, especially with the crucial role of adenosine diphosphate (ADP), and through GpIIb-IIIa and fibrinogen, platelets bind to each other, forming a plug and stopping any bleeding. This reaction also triggers another chain of releasing substances such as thromboxane A 2, platelet activation and the coagulation cascade. In leech secretions, different molecules (saratin, kalin, decorin and apyrase) react against different parts of this chain. [5]

Saratin, a 12 kDa protein, affects only the initial stage of platelet adhesion and competitively inhibits the reaction of collagen with Willebrand factor. Some animal studies have shown promising results using recombinant saratin molecule as a potential topical therapeutic agent for antithrombotic therapy and atherosclerosis. [6] Other leech-secreted proteins, kalin and leech antiaggregant protein, show similar effects on platelet adhesion. [7] In contrast, decorsin, isolated from Macrobdella decora (American medicinal leech), is structurally similar to the anticoagulant leech proteins hirudin and antistasin, but functionally it is an effective inhibitor of GPIIb-IIIa and potentially acts against platelet aggregation. [8]

As indicated earlier, ADP plays a crucial role in platelet aggregation, especially by activating GPIIb-IIIa receptors and increasing the affinity of platelets for Willebrand factor. The enzyme apyrase converts ADP to adenosine monophosphate and blocks aggregation by indirectly inhibiting these receptor mechanisms. ADP also has strong bonds with arachidonic acid, platelet activating factor, and adrenaline activity, so apyrase, in addition, indirectly acts in opposition to these substances. [9] An additional molecule that acts as an inhibitor of platelet activation factor and thrombin-induced platelet aggregation by suppressing thromboxane production in platelets has also been described. [10], [11]

The enzyme collagenase also breaks down collagen particles, which initiates all these adhesion and aggregation reactions and has an additional supportive effect on the inhibitory effects. [12]

Anticoagulant effect

Blood clotting during feeding is detrimental to leeches, so anticoagulant action is necessary. The blood clotting cascade is a chain reaction, and the bioactive molecules of leech secretion affect different points. Hirudin and gel act mainly as thrombin inhibitors, factor Xa inhibitor breaks the chain reaction, and destabilase has a fibrinolytic effect. Thrombin has a strong effect on platelet activation and ADP release, so these inhibitors may have an indirect negative effect on platelet function.

Hirudin is a 7.1 kDa protein that binds irreversibly to thrombin, which causes consumption of active thrombin and results in antithrombin activity. [13] This substance is the most interesting and has been the subject of many studies. There is a strong opinion that it is a therapeutic alternative to heparin because it has higher anticoagulant activity and fewer side effects. Gelin is an analog of eglin and is a potent thrombin inhibitor. Gelin also has an inhibitory effect on chymotrypsin, cathepsin G and neutrophil elastase. [14]

Factor Xa inhibitor disrupts the clotting cascade and exerts a direct anticoagulant effect. It plays a crucial role in MLT in osteoarthritis and rheumatoid arthritis. In addition, as previously stated, antistasin directly inhibits factor Xa, [15], and hilanthenes, LDTIs, inhibitor C1, and eglins have possible anticoagulant effects, potentially through direct and/or indirect inhibition of clotting factors. [16], [17], [18]

Destabilase is an enzyme with glycosidase activity that exhibits both antibacterial and fibrinolytic activities. [19] This enzyme has different isoforms with different capacities and is extracted from different species of leeches. [20] Destabilase has a strong destabilizing effect on stabilized fibrin and should also be considered as an anticoagulant. [21]

Recently, novel anticoagulant peptides from different leech species (novel leech protein-1, wytid and witmanin) have been identified. Many other peptides have also been isolated, but their function is currently unknown. [22]

Anti-inflammatory action

Anti-inflammatory effect of hirudotherapy is largely due to the unique composition of leech saliva. Leech saliva contains many biologically active substances that have a healing effect on the human body. Here are the basic mechanisms of anti-inflammatory action of hirudotherapy:

1. Hirudin is a powerful natural anticoagulant found in the saliva of medical leeches. It prevents blood clotting, improving microcirculation in the area of suction and reducing inflammation by improving the delivery of oxygen and nutrients to the tissues and facilitating the removal of metabolic waste.
2. Eglinins are proteins that have potent anti-inflammatory effects. They inhibit the action of certain enzymes, such as elastase and cathepsin, which play an important role in the development of inflammatory processes.
3. Direct anti-inflammatory action. Leech saliva contains components that directly affect the inflammatory process, reducing the severity of inflammation and swelling in the area of application.
4. Improved blood flow and lymphatic drainage. Improved microcirculation and stimulation of lymphatic drainage help to reduce local inflammation and accelerate recovery processes, thereby reducing swelling and improving the functional state of tissues.
5. Reduction of immune cell activity. Some components of leech saliva can modulate the activity of immune cells, reducing the production of inflammatory mediators and cytokines, which also helps to reduce the intensity of the inflammatory process.

It is important to note that the mechanisms of anti-inflammatory action of hirudotherapy are not fully understood, and the potential effects may vary depending on the individual patient and specific disease.

Analgesic effect

The analgesic effect of hirudotherapy (leech therapy) is one of the key aspects that make this method popular in the treatment of various conditions. This effect is achieved through several mechanisms due to the bioactive substances contained in the saliva of leeches:

1. Direct analgesic action: The saliva of leeches contains natural analgesics and anesthetics that can directly affect the nerve endings at the site of attachment, reducing the sensation of pain.
2. Anticoagulants and anti-inflammatory components: Hirudin and other anticoagulant substances in leech saliva help improve blood flow and reduce inflammation in the area of application. This may indirectly reduce pain associated with inflammation and swelling.
3. Improved microcirculation: Hyaluronidase and other enzymes that improve the penetration of bioactive ingredients into the tissues help to improve microcirculation and lymphatic drainage, which can also reduce pain caused by congestion and insufficient blood supply.
4. Reducing the local inflammatoryresponse: Eglinas, which have anti-inflammatory effects, help to reduce the severity of the local inflammatory response, which also helps to reduce pain.
5. Stimulation of endorphin release: The process of the leech bite and subsequent absorption of blood can stimulate the release of endogenous opioids in the body - endorphins, which are natural painkillers and help reduce pain on a general level.

The analgesic effect of hirudotherapy makes it a useful treatment for patients with chronic pain, including osteoarthritis, myositis, and in the post-operative period to reduce pain and speed recovery.

Lymphatic drainage effect

Lymphatic drainage effect of hirudotherapy is one of the important advantages of this method of treatment, which helps to improve lymphatic circulation and reduce swelling. This effect is achieved through several mechanisms of action based on the properties of bioactive substances in the saliva of leeches. Here are the main mechanisms underlying the lymphatic drainage action of hirudotherapy:

• Improvement of microcirculation. Leech saliva contains anticoagulants such as hirudin, which prevent blood clotting and improve microcirculation in the treatment area. Improved microcirculation promotes efficient lymphatic outflow, thereby reducing swelling and improving tissue metabolism.
• Stimulation of lymph flow. Exposure to leeches can stimulate the lymphatic system, accelerating the processes of lymphatic drainage. This is due to the physical irritation of the skin and subcutaneous tissues during the suctioning process, which can improve lymphatic flow.
• Anti-inflammatory action. Anti-inflammatory components in leech saliva, such as eglins, can reduce inflammation in tissues, thereby reducing obstacles to normal lymphatic flow and improving lymphatic drainage.
• Reduction of blood viscosity. In addition to anticoagulant action, components of leech saliva can reduce blood viscosity, which also favorably affects the circulation of lymph and helps to reduce swelling.
• Dissolution of fibrin clots. Leech saliva contains enzymes that can dissolve fibrin clots that may form in lymph nodes and vessels, thereby improving lymphatic circulation and helping to reduce swelling.
• Stimulation of tissue regeneration. Biologically active substances in the saliva of leeches can stimulate repair and regeneration processes in tissues, which also has a positive effect on the functioning of the lymphatic system and helps to improve lymphatic drainage.

Lymphatic drainage effect of hirudotherapy makes this method of treatment useful for reducing swelling, accelerating the recovery process after injury and surgery, as well as for the treatment of diseases associated with disorders of lymphatic circulation.

Stimulation of the immune system

Stimulation of the immune system with hirudotherapy (leech therapy) occurs due to the complex effect of biologically active substances contained in the saliva of leeches. These substances not only improve blood circulation and have anticoagulant properties, but can also affect the human immune system. Mechanisms of immune system stimulation include:

1. Leukocyte activation: Certain components of leech saliva can stimulate leukocyte activity, which increases the overall responsiveness of the immune system to infection and inflammation.
2. Cytokine production: Exposure to leech saliva can stimulate the production of various cytokines, molecules that play a key role in regulating immune responses. Cytokines help coordinate interactions between cells of the immune system, enhancing the inflammatory response to threats to the body.
3. Increased phagocytosis: Leech saliva can help to increase the phagocytic activity of macrophages and neutrophils, which increases the efficiency of killing pathogens and cleaning tissues from damaged cells and microbial debris.
4. Regulation of inflammation: Although inflammation is an important part of the immune response, its over-activation can lead to tissue damage. Components of leech saliva can help regulate inflammation, maintaining a balance between the necessary defense response and preventing harm to the body.
5. Improvement of microcirculation and lymphatic drainage: Improved blood flow and lymphatic drainage in the area of leech application contributes to more effective removal of toxins and pathogens from tissues, which indirectly supports the immune system.

It is important to note that the mechanisms of the effects of hirudotherapy on the immune system are not fully understood, and most conclusions are based on assumptions about the possible effects of components of leech saliva. E

Antimicrobial effect

To date, only two major molecules, destabilase and chloromycetin, have antimicrobial activity. [23] Destabilase has β-glycosidase activity, which directly disrupts β1-4 bonds that are important in the peptidoglycan layer in bacterial cell walls. This action is apparently similar to that of lysozyme (muramidase), which is commonly found in human saliva and tear fluid. [24] Other studies have shown that the antimicrobial activity depends not only on the enzymatic activity of glycosidase, but also has non-enzymatic components. [25] Even the denatured form of destabilase exerts a dose-dependent bacteriostatic effect on Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. [26] Chloromycetin is a potent antibiotic found in leech secretions, but unfortunately data on this molecule are limited. In addition, theromacin, theromyzin and peptide B have been identified as antimicrobial peptides. [27]

Other possible actions

Many in vitro studies have shown the anticancer effect of leech saliva extracts. Since coagulation is associated with tumor metastasis and progression, blocking the cascade may have an antitumor effect. [28] In this regard, hirudin has been studied with promising results in metastasis, especially mesothelioma. In addition, other anticoagulant derivatives have been claimed to have similar effects and also to reduce cell growth and tumor angiogenesis. [29] The extracts have been found to induce apoptosis and cell differentiation, and to cause cell cycle arrest. The main mechanisms of action appear to depend on suppression of oncogenic gene expression and activation of apoptotic circuits. Effects against cell degeneration have also been reported. Eglin C, bdellastasin, destabilase, bdellins and hirudin have cytoprotective effects and have positive stimulatory effects, especially on neurons, but these studies are only at a preliminary stage.

Leech saliva extracts have also been studied for possible effects on ischemia-reperfusion injury in the brain. Although leech saliva extracts induce apoptosis as previously indicated, these studies showed that saliva extracts have the opposite effect, protecting brain cells from ischemia-reperfusion injury. Brain cells treated with leech saliva extracts showed significant changes in the levels of superoxide dismutase, nitric oxide and malonic dialdehyde, and the expression of adhesion molecules. Pteridines have been identified as potential anti-anoxic substances, but it is clear that this activity cannot be attributed to only one substance.

However, despite the potential benefits, hirudotherapy should only be performed by qualified professionals in an appropriate setting. It is important to remember that the effectiveness and safety of the method may depend on the specific disease and individual characteristics of the body. Before starting treatment, it is recommended to consult a doctor to avoid possible side effects and contraindications.

Indications for the procedure

Indications for leech therapy

• For varicose veins.
• Chronic skin diseases such as scabies, psoriasis, eczematous dermatitis, chronic ulcers, ringworm, reddish freckles and favus.
• Phlebitis and thrombotic conditions.
• To reduce blood viscosity, it is useful in coronary artery thrombosis and coronary heart disease.
• To prevent postoperative blood clotting. [30]
• To relieve pain and reduce inflammation in conditions such as osteoarthritis. [31]
• In the treatment of asthma, acute rhinopharyngitis and rhinitis. [32]
• Treatment of hyoid hematoma and massive lingual hematoma.
• Use of leeches for gum disease. For example, direct application of 3-4 leeches can be a successful treatment for abscess and inflammation. [33]
• Treatment of hypertension, migraines, phlebitis, varicose veins, arthritis, hemorrhoids and ovarian cysts. [34]

Contraindications to the procedure

Contraindications to leech therapy: [35], [36]

• Hemophilia.
• Kids.
• Pregnancy.
• Leukemia.
• Anemia.
• Arterial insufficiency.
• Previous exposure to leeches (due to risk of anaphylaxis or allergic reaction)
• Patient refusal of blood transfusion.
• Patient refusal of leech treatment.
• Unstable medical condition.

Complications after the procedure

Although hirudotherapy has many potential benefits, it can also carry certain health risks or harms. It is important to consider these aspects before starting treatment:

Risk of infections

One of the main risks of hirudotherapy is the possibility of infection at the site of the leech bite. Although medical leeches are grown under sterile conditions, the risk of infection cannot be completely ruled out. Six case reports (Schnabl et al., 2010; Wang et al., 2011, Bibbo et al., 2013; Giltner et al., 2013; Gonen et al., 2013; Wilmer et al., 2013) and 2 retrospective cohort studies (Kruer et al., 2015; Verriere et al., 2016) have been published in this field. Their results showed that Aeromonas spp. Were most frequently observed in the field of infections (Table). Leeches were most often used for venous stasis and patients were on prophylactic antibiotics.

Another retrospective cohort study conducted by Kruer at Johns Hopkins Hospital included all adult patients receiving medical leech therapy during the 38-month analysis period. According to their report, 91.5% of them received antimicrobial prophylaxis such as ciprofloxacin, trimethoprim-sulfamethoxazole, piperacillin-tazobactam, and ceftriaxone. In addition, 11.9% of all patients had surgical site infection, and microbiologic analysis showed that the isolated microorganisms were Aeromonas species., Enterococcus spp., Proteus Vulgaris, Morganella morganii, Corynebacterium spp. And Candida parapsilosis. Researchers suggested that sulfamethoxazole/trimethoprim (SXT) and ciprofloxacin may be effective antibiotics to prevent leech infections (Kruer et al., 2015).

Allergic reactions

Eight case reports (Kukova et al., 2010; Karadag et al., 2011; Pietšak et al., 2012; Khelifa et al., 2013; Altamura et al., 2014; Rasi et al, 2014; Brzezinski et al., 2015; Gülyesil et al., 2017) have been published in this field and only in one case leeches were reused. The most common reaction was erythema, edema and swelling with black scab in the center of the bite site, and some reactions such as cutaneous pseudolymphoma and type IV hypersensitivity reaction were also observed in patients. Most cases were treated with oral antihistamines and topical corticosteroids. The hypothesis discussed by the authors was that the reactions and allergies were caused by a substance contained in leech saliva, but no evidence or prevention methods were found.

Bleeding

Four case reports (Ikizceli et al., 2005; Zengin et al., 2012; Dogan et al., 2016; Güven, 2016) have been published in the field of leech bleeding and anticoagulant effects. Prolonged bleeding is defined in these articles as continuous bleeding for more than 2 hours despite compression of the sting site, which can cause severe anemia and hemorrhagic shock. To stop this, some have chosen to place primary sutures on the leech bite sites (Ikizceli et al., 2005; Dogan et al., 2016) and some have used tranexamic acid instead of fresh frozen plasma (Güven, 2016).

Hypotension

Some patients may develop low blood pressure after a hirudotherapy session, which is especially dangerous for people with pre-existing blood pressure problems.

Personality mismatch

Some people may experience extreme discomfort or stress from the procedure, which can negatively affect their overall health and even lead to psychological effects.

Misapplication

Failure to maintain sterility or improper application of leeches can increase the risk of side effects and reduce the effectiveness of treatment.

Before starting hirudotherapy treatment, it is necessary to consult a qualified specialist to assess all potential risks and contraindications. It is important to choose an experienced specialist and a reputable clinic to minimize possible risks and achieve the best treatment results.