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Integr Med Res. 2017 Dec; 6(4): 337–343.

Published online 2017 Aug 10. doi: 10.1016/j.imr.2017.08.001
PMCID: PMC5741396
PMID: 29296560

Medicinal leech therapy—an overall perspective

Ali K. Sig,a,⁎ Mustafa Guney,b Aylin Uskudar Guclu,b and Erkan Ozmenc

Author information Article notes Copyright and License information Disclaimer

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Abstract

Complementary medicine methods have a long history, but modern

medicine has just recently focused on their possible modes of action.
Medicinal leech therapy (MLT) or hirudotherapy, an old technique, has
been studied by many researchers for possible effects on various
diseases such as inflammatory diseases, osteoarthritis, and after
different surgeries. Hirudo medicinalis has widest therapeutic usage
among the leeches, but worldwide, many different species were tested
and studied. Leeches secrete more than 20 identified bioactive
substances such as antistasin, eglins, guamerin, hirudin, saratin, bdellins,
complement, and carboxypeptidase inhibitors. They have analgesic, anti-
inflammatory, platelet inhibitory, anticoagulant, and thrombin
regulatory functions, as well as extracellular matrix degradative and
antimicrobial effects, but with further studies, the spectrum of effects
may widen. The technique is cheap, effective, easy to apply, and its
modes of action have been elucidated for certain diseases. In conclusion,
for treatment of some diseases, MLT is not an alternative, but is a
complementary and/or integrative choice. MLT is a part of
multidisciplinary treatments, and secretes various bioactive substances.
These substances vary among species and different species should be
evaluated for both treatment capability and their particular secreted
molecules. There is huge potential for novel substances and these could
be future therapeutics.

Keywords: Hirudo medicinalis, hirudotherapy, leech

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1. Introduction

Medicinal leech therapy (MLT) or hirudotherapy is a kind of

complementary and integrative treatment method applied with blood-
sucking leeches. One or more leeches are attached to the skin of
problematic area and the purpose is to gain potential utilities of leech
saliva that is secreted while the leeches are feeding. MLT has been used
for centuries and the term leech was provided from the word “laece”
(physician). The first recorded applications were observed in ancient
Eygpt.1, 2 In addition, Chinese, Arabic, Anglo-Saxon, Ancient Greek, and
Roman medical records have many references to MLT. In 17th century
Europe, MLT reached its widest area of application.1, 3 Since the 1900s,
attention of medical professionals has decreased, but in the last 30 years,
MLT has become an important part of much scientific research.1, 4

Leeches live in fresh water and are segmented, hermaphrodite,

carnivorous worms. They are sensitive to vibrations on the water, touch,
light, heat, sound, and various chemicals. They are multisegmented,
including “brain parts”, and each segment has different organs such as
ganglions and testicles. Two sucker parts work for creeping and
adherence; the anterior one has three jaws including many teeth. They
generally bite warm parts of the host and suck its blood with rhythmic
contractions.3, 5 Feeding usually takes almost 40 minutes and a leech
digests 10–15 mL of blood per feeding. Digestion is achieved by many
enzymes and mutual microorganisms such as Aeromonas
hydrophila and Pseudomonas hirudinia.6, 7

MLT was previously tested and is widely used after plastic,

reconstructive, and microsurgical applications, in cardiovascular
diseases, deep vein thrombosis, postphlebitic syndrome, complications
of diabetes mellitus, tinnitus, acute and chronic otitis, and in reducing the
pain of osteoarthritis.4, 8 There are more than 600 leech species,
but Hirudo medicinalis, Hirudo troctina, Hirudo nipponia, Hirudo
quinquestriata, Poecilobdella granulosa, Hirudinaria javanica, Hirudinaria
manillensis, Haementeria officinalis, and Macrobdella decora are the most
frequently applied worldwide.3

Many studies have found that leeches have various bioactive molecules
in their secretions. More than 20 molecules and their modes of action
have been identified, but there are many more awaiting exploration.
These molecules have analgesic, anti-inflammatory, platelet inhibitory,
anticoagulant, and thrombin regulatory functions, as well as extracellular
matrix degradative and antimicrobial effects.6, 9, 10, 11, 12, 13, 14, 15 It
is believed that with further studies, more indications may emerge due
to recently elucidated effect mechanisms. In this article, we aim to gather
information about MLT, provide an overall vision, and to take a broad
look at modes of action.

1.1. Leeches work with secreted proteins

To date, many scientific studies have shed light on the effect mechanisms
of leeches. Although more than 100 particular proteins with different
molecular masses are observed in leech secretions, only a few have been
identified that have a major active role.16 The effect mechanisms are
divided into six types to make them more understandable, but these
mechanisms are closely related to each other and should be evaluated as
a whole (Table 1). Following a leech bite, it has to establish a sucking
pathway (extracellular matrix degradation); inhibit adhesion,
aggregation, and coagulation (inhibition of platelet functions, and
anticoagulant effect); increase blood flow; protect itself (antimicrobial
activity); and avoid detection (analgesic and anti-inflammatory effects).

Table 1
Potential bioactive substances in leech secretions.

Modes of
Substance
action
Analgesic and Antistasin,10, 14, 17 hirustasin,10, 14 ghilantens,18, 19 eglin
anti- C,14 LDTI,20 complement C1 inhibitor,21 guamerin and
inflammatory piguamerin,10, 14 carboxypeptidase inhibitor,14 bdellins and
effect bdellastasin,14, 18
Extracellular
matrix Hyaluronidase and collagenase9, 10, 14
degradation
Increasing
Acetylcholine,10, 14 histamine-like molecules7, 10, 14
blood flow
Inhibition of
Saratin,9, 10, 14, 22 calin,9, 10, 14, 23 apyrase,9, 10, 14 decorsin9, 10, 14, 24, 
platelet
25
function
Hirudin,7, 9, 14, 15 gelin,9, 14 factor Xa
Anticoagulant
inhibitor,9, 10, 14 destabilase,9, 14, 26, 27, 28 new leech protein-1, whitide,
effect
and whitmanin29
Antimicrobia Destabilase,9, 14, 26, 27, 28chloromycetyn,9, 10, 14theromacin,
l effect theromyzin, and peptide B30, 31
Open in a separate window

LDTI, leech-derived tryptase inhibitor.

1.2. Extracellular matrix degradation

Following the bite, leeches immediately release hyaluronidase

(27.5 kDa) and collagenase (100 kDa) enzymes to facilitate tissue
penetration and spread of their bioactive molecules. These enzymes also
support antimicrobial activity.9, 10, 14

1.3. Analgesic and anti-inflammatory effects

It is believed that leeches exert analgesic and anti-inflammatory effects

so as to avoid detection by the host while feeding.15 Despite this, it has
not been possible to isolate any analgesic molecule acting in this way
from leech secretions until now. So, studies have focused on indirect
mechanisms to achieve this goal. For example, some studies have
indicated that some kininases and antistasin may inhibit the kinin–
kallikrein mechanism, which is a major nociceptive route.17 There is more
information about the anti-inflammatory effects.

Antistasin was identified from H. officinalis (Mexican medicinal leech)

and it serves as a potent factor Xa inhibitor and has an inhibitory effect
on the kinin–kallikrein system.17 Factor Xa is a prothrombin activator,
and plays a critical role in the common pathway of the coagulation
cascade.32 The Kinin–kallikrein system is also connected to the
coagulation cascade and has a major role in the inflammatory
response.33 Researchers claim that antistasin has both anticoagulant and
anti-inflammatory effects, but current studies have often focused on the
anticoagulant activity, which seems to be the predominant mechanism of
action.34 The Ghilantens were also found in secretions of Haementeria
ghilianii (Amazonian Leech) and they show high structural homology
with antistasin. There are only few data about their anticoagulant effects,
and other possible functions are controversial due to lack of additional
studies.18, 19

Leech-derived tryptase inhibitor (LDTI) has three isoforms (a, b, and c)

and acts by inhibiting proteolytic enzymes of mast cells. LDTI, a Kazal-
type serine protease inhibitor, especially inhibits mast cell tryptase, but
also trypsin and chymotrypsin.20 Mast cell tryptases are serine proteases
in cell granules and their release causes inflammatory reactions. These
effects are strongly related to the kinin–kallikrein system, chemotaxis,
leukocyte activation, vasoactive actions, and accordingly, pain-
generating interactions. Their levels are correlated with allergic and
inflammatory diseases such as anaphylaxis, asthma, and
arthritis.35, 36 LDTI is an inhibitor of mast cell tryptase, trypsin,
chymotrypsin, thrombin, and plasmin, but inhibitory effects on factor Xa,
plasma kallikrein, and neutrophil elastase are controversial.37 Even with
inhibition of mast cell tryptase, potential benefits of anti-inflammatory
effects can be foreseen. However, recombinant LDTI has shown
inconsistent actions in different studies, so it is hard to comment on
actual clinical effects of LDTI.37, 38

Eglin C is an inhibitor of human neutrophil elastase and cathepsin

G.14 These two enzymes are immune serine proteases in the
chymotrypsin family that are stocked in azurophil granules of
polymorphonuclear neutrophils and released as a part of the
inflammatory response.39, 40 Inhibition by eglin C causes decreasing
levels of free oxygen radicals in neutrophils and prevents tissue
inflammation and destruction. In test models, eglin C was shown to be a
potential therapeutic agent for shock and emphysema.14 Further studies
are needed to show other potential effects, but the molecule itself is
promising. Other isolated eglins act in similar ways, resulting in anti-
inflammatory effects. Another leukocyte elastase inhibitor is cysteine-
rich guamerin, which was isolated from H. nipponia (Korean medicinal
leech). From the same leech, piguamerin was also isolated and has an
inhibitory effect on kallikrein and trypsin. As previously stated,
hirustasin (Hirudo antistasin) is a serine protease inhibitor and acts as
an inhibitor of kallikrein, trypsin, chymotrypsin, and cathepsin G. It was
isolated from H. medicinalis (European medicinal leech) and H.
officinalis (Mexican medicinal leech).10, 14 Separately, bdellins and
bdellastasin were detected as trypsin, plasmin, and sperm acrozine
inhibitors.14, 18 Human neutrophil elastase and cathepsin G have
activating effects on factor X (prothrombin activator) and enhancing
activity on factor XII and tissue factor, so, as a result, their inhibition by
these substances may cause additional anticoagulant outcomes, but this
area needs further study.40, 41

Complement component C1 has a critical role in the classic pathway of

the complement system.42 In leech secretions, complement C1 inhibitor is
a 60- to 70-kDa protein, but the effect mechanism is only partially
known.21 This protein might be just one part of the protein pool that
inhibits the complement system in many ways. In addition, the original
C1 inhibitor in humans suppresses factor XIIa, factor XIa, plasma
kallikrein, and thrombin. This substance inhibits both the coagulation
cascade and kinin–kallikrein system.43 Currently, there are no data of
similar effects of leech C1 inhibitor, but it is possible and needs further
study.

The mechanism causing the inhibitory effect on carboxypeptidases

(kininase 1) is contentious. The enzymes carboxypeptidase N and M
participate in kinin degradation, resulting in agonism of B receptors,
which causes a bradykinin-related inflammatory response.33 Inhibition of
carboxypeptidases by leech secretions should not affect bradykinin
action via B2 (constitutive) receptors, but may prevent B1 (inducible)
receptors. Although these two receptors basically work with similar
mechanisms, it has been stated that B1 receptors are related to chronic
inflammation, whereas B2 receptors are related to acute inflammation.
Strong correlations have been found between B1 and inflammatory
diseases such as multiple sclerosis, asthma, and rheumatoid arthritis.
However, studies have indicated that action of bradykinin is not limited
to these receptors, so possible anti-inflammatory effects of
carboxypeptidase inhibition are controversial and should be tested
separately.44

1.4. Increasing blood flow

Leech feeding and therapeutic effects require increased blood flow.

These are achieved mainly by histamine-like molecules that cause
vasodilatation and arise via local vascular
permeability.7, 10, 14 Acetylcholine is also a component in leech
secretions, causing endothelial muscle relaxation and
vasodilatation.10, 14, 45

1.5. Inhibition of platelet functions

Destruction of the blood vessel wall for sucking blood causes activation
of platelets and the coagulation cascade, which are fatal for the leech. For
this reason, leech secretions contain many bioactive molecules to locally
inhibit these actions.

In a normal host, wall destruction causes spread and release of collagen

particles and they are targets of free vonWillebrand factor (vWF). This
complex strongly binds to glycoprotein (GP) Ib on platelets as vWF
works like a bridge. With this binding, upregulatory mechanisms occur,
especially with the critical role of adenosine diphosphate (ADP), and via
GpIIb–IIIa and fibrinogen, platelets bind to each other to make a plug and
stop any bleeding. This reaction also starts another chain of releasing
substances such as thromboxane A2, platelet activation, and coagulation
cascade.42 In leech secretions, various molecules (saratin, calin, decorsin,
and apyrase) react against different parts of this chain.9, 10, 14

Saratin, a 12-kDa protein, affects only the initial stage of platelet

adhesion, and inhibits collagen–vWF reaction competitively. Some
animal studies have indicated promising results with recombinant
saratin molecule as a potential local therapeutic agent for antithrombotic
therapies and atherosclerosis.22 Other leech-secreted proteins, calin and
leech antiplatelet protein, show the same action on platelet adhesion. 24 In
contrast, decorsin, which is isolated from Macrobdella decora (American
medicinal leech), is structurally similar to anticoagulant leech proteins
hirudin and antistasin, but functionally it is an efficient GPIIb–IIIa
inhibitor and acts potentially against platelet aggregation.24, 25
As previously stated, ADP has a critical role in platelet aggregation by
especially activating GPIIb–IIIa receptors and increasing affinity of
platelets to vWF.42 The enzyme apyrase converts ADP to adenosine
monophosphate and blocks aggregation by indirectly inhibiting these
receptor mechanisms. ADP also has strong relations with arachidonic
acid, platelet-activating factor, and epinephrine activity, so additionally
apyrase indirectly acts in an opposing way to these substances. 14 An
additional molecule is also described that acts as an inhibitor of platelet-
activating factor and thrombin-induced platelet aggregation by
suppressing thromboxane production in platelets.46, 47, 48

The enzyme collagenase also destroys collagen particles, which initiates

all these adhesion and aggregation reactions, and provides additional
supportive action to the inhibitory effects.46

1.6. Anticoagulant effect

Coagulation during feeding is fatal for leeches, so anticoagulant effects

are necessary.15 The coagulation cascade is a chain reaction and bioactive
molecules in leech secretions have effects at various points. Hirudin and
gelin mainly work as thrombin inhibitors, factor Xa inhibitor breaks the
chain reaction, and destabilase has a fibrinolytic effect.9, 14 Thrombin
has a strong effect on platelet activation and ADP release and so these
inhibitors may indirectly have a negative impact on platelet functions. 42

Hirudin is a 7.1-kDa protein and irreversibly binds to thrombin, which

causes consumption of active thrombin and results in antithrombin
activity.7, 15 This substance is the most interesting one and was the
subject of many studies. There is a strong consensus about it being a
therapeutic alternative to heparin, since it has higher anticoagulant
activity and fewer adverse effects.15 Gelin is an eglin analog and a potent
thrombin inhibitor. Gelin also shows inhibitory effects on chymotrypsin,
cathepsin G, and neutrophil elastase.14

Factor Xa inhibitor breaks the coagulation cascade and has a direct

anticoagulant effect. It has a critical role in MLT of osteoarthritis and
rheumatoid arthritis.9, 10 In addition, as previously stated, antistasin
directly inhibits factor Xa,17 and ghilantens, LDTI, C1 inhibitor, and eglins
have possible anticoagulant effects, potentially via direct and/or indirect
inhibition of coagulation factors.18, 19, 20, 35, 36, 40, 41, 43

Destabilase is an enzyme with glycosidase activity and shows both

antibacterial and fibrinolytic actions.26, 27 This enzyme has various
isoforms with different capabilities, and is extracted from different leech
species.28 Destabilase has a major degradative action on stabilized fibrin
and it should also be evaluated as an anticoagulant agent.26

Recently, novel anticoagulant peptides from different leech species have

been identified (new leech protein-1, whitide, and whitmanin). Many
other peptides have also been isolated, but their function is unknown at
present.29

1.7. Antimicrobial effect

To date, only two main molecules, destabilase and chloromycetin, have

been shown to have antimicrobial activity.9, 10, 14 As previously stated,
destabilase has β-glycosidase activity, which directly disrupts β1–4
bonds that are important in the peptidoglycan layer in bacterial cell
walls.14, 49 It is clear that this action is similar to that of lysozyme
(muramidase) that is commonly found in human saliva and lachrymal
fluid.50 Other studies have shown that antimicrobial activity does not only
depend on glycosidase enzymatic activity, but it also has nonenzymatic
components.27 Even the denaturated form destabilase shows a dose-
dependent bacteriostatic effect on Staphylococcus aureus, Pseudomonas
aeruginosa, and Escherichia coli.51 Chloromycetin is a potent antibiotic
found in leech secretions, but unfortunately the data are limited about
this molecule. 9 Additionally, theromacin, theromyzin, and peptide B have
been isolated as antimicrobial peptides.30, 31

1.8. Other possible actions

Many in vitro studies have indicated the anticancer effects of leech saliva

extracts. Since coagulation is related to metastasis and tumor
progression, blocking the cascade can have an antitumor effect. 52 Hirudin
has been studied in this regard, with promising results for metastasis,
especially from mesothelioma. In addition, other anticoagulant derivates
are claimed to have similar effects, as well as reducing cell growth and
tumor angiogenesis.15, 29 The extracts have been found to induce
apoptosis and cell differentiation and cause cell cycle arrest. The main
mechanisms of action seem to depend on suppressing oncogenic gene
expression and upregulating apoptotic chains.29 Effects against cell
degeneration have also been reported. Eglin C, bdellastasin, destabilase,
bdellins, and hirudin are cytoprotective and exert positive stimulatory
actions, especially on neurons, but these studies are only at the
preliminary stage.15

Leech saliva extracts have also been studied for possible effects on
cerebral ischemia–reperfusion injury. Although, as previously stated,
leech saliva extracts induce apoptosis, these studies have indicated that
saliva extracts have opposing actions by protecting cerebral cells from
ischemia–reperfusion injury. Significant changes in superoxide
dismutase, nitric oxide, and malondialdehyde levels, and expression of
adhesion molecules have been detected on cerebral cells treated with
with leech saliva extracts. Pteridines have been isolated as potential
antianoxic substances, but it is clear that this activity cannot be related to
only one substance.29
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2. Conclusion

MLT has a long history but it is only recently that its effect mechanisms
have started to be clarified. When a leech bites, hyaluronidase and
collagenase allow access to the tissues and blood vessels; vasodilatation
occurs by the action of histamine-like molecules; platelet functions, kinin
activity, and the coagulation cascade are inhibited; and inflammatory
reactions are suppressed. In addition, analgesic and antimicrobial effects
are observed. Experiments on mice have shown a positive effect on
wound/tissue repair.6, 9, 10, 11, 12, 13, 14

There is no consensus on the duration of application and number of

simultaneously applied leeches. Medical professionals usually suggest a
maximum of four or five leeches at the same time and a maximum
duration of 6–8 hours, but these may vary due to physician’s clinical
evaluation. The total duration of MLT is another unclarified issue.
Physicians should consider the bleeding period after application, which
may cause excess blood loss. Clinical monitoring and laboratory tests
(blood count) are strongly recommended.7 The necessity for blood
transfusion is related to the number of leeches applied, the duration of
their application, patient conditions, and comorbidity.7, 53

Joint diseases such as osteoarthritis and epicondylitis, extremity vein

diseases, and flap surgery (skin grafting) are major indications for MLT.
MLT is also useful for soft-tissue and periorbital hematoma, purpura
fulminans, macroglossia, penile replantation, postphlebitic syndrome,
and ecchymosis. In addition, anticoagulants obtained from leeches are
used for peripheral arterial occlusion and infectious
myocarditis.9, 10, 11, 12, 13, 54, 55 Their use in dentistry has also been
tested.56 MLT is not recommended when there is hemorrhagic diathesis,
anticoagulant therapy, leukemia, bone narrow suppression, dialysis,
cirrhosis, chemotherapy, radiotherapy, and cachexis.7

There are some potential complications with MLT. Allergies to leeches

and their secretions should be considered.57 Infection is a serious
condition that shows wide variability from local infections to bacteremia.
Antibiotic prophylaxis significantly reduces the risk of leech-borne
infections. Infectious agents vary depending on etiology, leech species,
application area, and patient condition, but by far, Aeromonas spp. is the
most common.7, 53, 58, 59, 60, 61, 62, 63 Furthermore, leeches can be
vectors for some viruses, fungi and parasites in animals,64, 65, 66, 67 but
it seems that application of leeches to humans also has infection
potential.68, 69 However, these complications are rare and the most
common adverse effects are itching and bleeding on the application area.
These adverse effects can be eliminated by small interventions.
Orthostatic hypotension and vasovagal symptoms may occur especially
in elderly patients. Regional lymphadenopathy has also been reported.
MLT usually leaves a scar, therefore, patients should be informed about
this, especially before application to particular body
parts.6, 7, 54, 70 Since this therapy has a potential risk of blood-
transmitted diseases, reuse of leeches is strictly forbidden.71

In conclusion, MLT is a valuable traditional technique with strong

biochemical actions. Although modes of action and bioactive substances
still await further exploration, their utility in certain medical conditions
is obvious. Indications and potential complications should be evaluated,
including antibiotic prophylaxis and application frequency, and dosage
and delivery timing depend on the patient and physician’s opinion. It
must be noted that MLT is not a treatment method by itself, but it can be
an important part of a multidisciplinary approach.
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Conflicts of interest

All authors have no conflicts of interest to declare.

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 Articles from Integrative Medicine Research are provided here courtesy of Korea Institute of
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