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review

Wien Med Wochenschr


DOI 10.1007/s10354-015-0382-5

Medical leech therapy in plastic reconstructive


surgery
Khosrow S. Houschyar · Arash Momeni · Zeshaan N. Maan · Malcolm N. Pyles · Olivia S. Jew ·
Marion Strathe · Andreas Michalsen

Received: 30 April 2015 / Accepted: 4 August 2015


© Springer-Verlag Wien 2015

Summary  The use of Hirudo medicinalis in clinical prac- men und erläutern die Rolle, die die medizinischen Blut-
tice has increased in recent years. The primary indication egel auf dem Gebiet der plastischen Chirurgie spielen.
in plastic surgery has traditionally been venous conges-
tion. However, other reported clinical applications were Schlüsselwörter  Blutegel  · Venöse Stauung  · Rekonst-
in varicose veins, thrombophlebitis, and osteoarthritis. ruktion
In this review, we summarize recent data elucidating
the role that medicinal leeches play in the field of plastic
surgery. Introduction

Keywords  Leech · Venous congestion · Reconstruction Medicinal leeches (Hirudo medicinalis, Hirudi verbana)
have been used in medicine for thousands of years to treat
a variety of ailments. The popularity of leech therapy has
Blutegeltherapie in der plastischen varied throughout history, reaching a peak in early nine-
rekonstruktiven Chirurgie teenth century Europe, during that time leech supplies
were regularly exhausted. During the latter half of the
Zusammenfassung  Die Verwendung von Hirudo medi- nineteenth century, their use fell out of favor, as a new
cinalis in der klinischen Praxis hat in den letzten Jahren paradigm of medical practice began to emerge [1]. In the
zugenommen. Die primäre Indikation in der plastischen 1970s and 1980s, leech therapy was revived as an adjunct
Chirurgie ist traditionell die venöse Stauung. Darüber to plastic, reconstructive, and trauma surgery. In the 1980s,
hinaus sind weitere klinische Anwendungen bei Krampf- French microsurgeons began using leeches to assist with
adern, Thrombophlebitis, und Osteoarthritis bekannt. In distal digital replantation involving arterial repairs [2].
dieser Übersicht fassen wir die jüngsten Daten zusam- Currently, medicinal leeches are used successfully for only
a few medical conditions, most notably venous conges-
tion and arthritic pain. This former condition is a serious
K. S. Houschyar, MD () · A. Momeni, MD · Z. N. Maan, MBBS, complication following microsurgical procedures such as
MRCS · M. N. Pyles · O. S. Jew · M. Strathe
free flap transfer or replantation [3]. If surgical correction
Division of Plastic and Reconstructive Surgery, Department of
Surgery, Stanford School of Medicine,
of venous congestion is not feasible or fails, then medici-
Stanford, USA nal leeches are used to provide drainage of the affected tis-
e-mail: Khosrow.Houschyar@Bergmannstrost.com sues until new vessels develop to prevent sequelae such as
necrosis [4]. In the following sections, we present a sum-
K. S. Houschyar, MD
Clinic for Plastic and Reconstructive Surgery,
mation of data describing the utility of medicinal leeches,
Bergmannstrost Halle, particularly in plastic and reconstructive surgery.
Merseburger Str. 165,
06112 Halle, Germany
Basic biology of leeches and agents
A. Michalsen, MD
Department of Internal and Complementary Medicine,
Immanuel Hospital Berlin, Leeches belong to the phylum Annelida, class Hirudinea.
Berlin, Germany H. medicinalis/H. verbena is the species that inflicts the

13 Medical leech therapy in plastic reconstructive surgery   1


review

Fig. 1  Medicinal leech mor-


phology. a Hirudo medicinalis
attached to the skin. b After
attaching its head sucker to
the skin, the leech uses its
three jaws with razor-sharp
teeth to make a neat Y-
shaped cut. Salivary ductules
between the teeth secrete
several pharmacologically
active substances, including
a local anesthetic and the
potent anticoagulant hirudin

deepest bite and the most prolonged post-bite extrava- Table 1  Components and effects of medicinal leech saliva
sation in its class [2]. H. medicinalis, while applied, can
Components of Effect on host
grow to approximately 10  cm in length, with its resting
leech saliva
length being approximately one third of its maximal
length. The leech crawls using a large posterior sucker. Hirudin Inhibits blood coagulation by binding to thrombin
On its posterior end, the leech has three jaws arranged Calin Inhibits blood coagulation and collagen-mediated
in a tri-radiate configuration that can attach to and bite platelet aggregation by blocking the binding of von
Willebrand factor to collagen
through human skin, while the smaller anterior sucker is
utilized for feeding (Fig. 1). Medicinal leeches have two Hirustasin Inhibits kallikrein, neutrophilic cathepsin G, trypsin,
chymotrypsin
different mechanisms of bloodletting. The first mecha-
Hyaluronidase Increases interstitial viscosity, antibiotic effects
nism is through passive bleeding after each bite: this
accounts for the majority of the average blood meal vol- Eglins Anti-inflammatory, inhibits the activity of chymotryp-
sin, subtilisin, cathepsin G, chymase, elastase
ume for a leech [5]. This temporarily increases tissue per-
fusion by actively drawing off blood within the congested Destabilize Dissolves fibrin
tissue, as demonstrated by Laser Doppler analysis [6]. Bdellins Anti-inflammatory, inhibits plasmin, acrosin, trypsin
Moreover, as the leech bite continues, it reduces conges- Factor Xa inhibitor Inhibits the activity of coagulation factor Xa by form-
tion due to the anticoagulant effect of leech saliva, which ing complexes
contains the potent thrombin inhibitor hirudin, apyrase, Complement Replace natural complement inhibitors in case of
collagenase, hyaluronidase, factor Xa inhibitor, and fibri- inhibitors deficiency
nase I and II (Table 1). Leech saliva contains several sub- Histamine-like Vasodilator, increases the inflow of blood at the bite
stances that make their alimentary behavior possible: (1) substances site
an anesthetic compound that makes the leech bite pain- Tryptase inhibitor Inhibits proteolytic enzymes of host mast cells
less, (2) a histamine-like vasodilator that increases blood Carboxypeptidase A Increases the inflow of blood at the bite site
flow to the area of feeding, and (3) the most important inhibitor
component of leech saliva, hirudin (a selective throm- Acetylcholine Vasodilator
bin inhibitor). Hirudin is stabilized by three disulfide Anesthetic sub- Anesthetic
bridges. Its three-dimensional structure reveals three stance
distinct regions: a central core, a “finger”, and a loop. Collagenase Faciliates tissue penetration
Recombinant biotechnology has been used to produce Apyrase Inhibitor of platelet aggregation by inhibition of
recombinant hirudin (r-hirudin), which, unlike natural adenosine triphosphate
hirudin, lacks the sulfate group at Tyr-63 [7].

for 1–2 days prior to therapy. The leech can be directed to


Practical considerations a precise target tissue using a small plastic tube, which is
of particular benefit when used intra-orally [8]. To pre-
Patients should be informed about the possible risks and vent aberrant leech biting of medical providers, medi-
benefits of medicinal leech therapy and written consent cal gloves should be worn at all times during treatment
should be obtained before therapy is initiated. Patient or handling of the leeches. Interestingly, leeches do not
education is critical for effective use of medicinal leech attach to and feed from devitalized tissue. Therefore,
therapy. In particular, the patient should keep the pro- when presented with tissue of questionable viability, the
posed site of application free of fragrances and chemicals

2   Medical leech therapy in plastic reconstructive surgery 13


review

absence of leech feeding behavior may serve as an indi- extended period of time without clotting the blood source
cation for debridement. [14]. Thrombin activity is neutralized by hirudin in stoi-
Leeches should be obtained from reputable medical chiometric amounts at extremely low concentrations
leech producing companies where they are maintained of both reactants. This makes hirudin the most known
appropriately in farms and kept alive through artificial potent and specific inhibitor of thrombin. Effective inhi-
animal blood feedings. Leeches obtained from the natu- bition of thrombin by antithrombin and heparin cofactor
ral environment should not be used for hirudotherapy. II requires the catalytic actions of heparin (Fig. 2). In con-
Prior to use in therapy, leeches should be starved suffi- trast, hirudin effectively inhibits thrombin independently
ciently to ensure adequate blood draw. of any cofactor, forming noncovalent but irreversible 1:1
The actual volume of blood drawn by a single leech complexes with thrombin. Hirudin binds to at least two
is minimal, approximately 2–20  mL per feeding. The sites on thrombin, and therefore is classified as a bivalent
amount of active and passive blood loss during a single direct thrombin inhibitor (DTI). Additionally, hirudin
leech bite varies and is related to the length of leech star- inhibits both free and clot-bound thrombin, as well as
vation, leech size, and concentration of secretions. The thrombin bound to fibrin split products [7]. In contrast,
secretions from a single leech have been found to pre- heparin-antithrombin complexes are relatively poor at
vent in vitro coagulation of 50–100 mL of human blood. accessing and inactivating clot-bound thrombin. This
The presence of hirudin in the leech saliva ensures sus- could explain why hirudin is more effective than heparin
tained oozing from the leeching site even after the leech in promoting dissolution of mural thrombi in experimen-
has detached, allowing therapy sessions to be spaced tal models [15]. Another important difference is that hiru-
up to 6–8 h apart [9]. Because the leech bite site on the din shows virtually no interaction with plasma proteins,
host may continue to ooze blood for as long as 24–48 h, whereas binding characteristics of heparin to plasma
the benefit from leech phlebotomy is thought to far proteins is the major explanation for its many limitations,
exceed the individual meal volume [10]. Indeed, when including its unpredictable dose–response relationship,
leech therapy is utilized for retained hematomas, there the potential for heparin “resistance”, and the induction
is continued drainage of dark nonclotted blood from of neo-antigens after binding to PF4 (resulting in hepa-
leech attachment sites for some time after leech detach- rin-induced thrombocytopenia [HIT]) [16]. Lepirudin,
ment [2]. Leeches will detach spontaneously after they a recombinant hirudin, is a direct irreversible thrombin
are maximally engorged. At this point, they should be inhibitor, binding to both free and clot-bound thrombin.
removed and disposed of as biohazardous waste follow- Lepirudin has been investigated extensively in controlled
ing sacrifice in 70 % alcohol or by freezing. clinical trials for acute coronary syndrome (ACS), includ-
ing myocardial infarction (MI) and unstable angina pec-
toris; and in pilot studies for prophylaxis and treatment
Coagulation cascade of deep-vein thrombosis (DVT) [17]. Lepirudin has also
been studied for anticoagulation in other clinical settings
The hemostatic system maintains blood in a fluid state such as hemodialysis and cardiac surgery utilizing the
under normal conditions and responds to vessel injury cardiopulmonary bypass (CPB). Hirudins are approved
by the rapid formation of a clot. Once a platelet plug has for only two indications: HIT complicated by thrombo-
formed (primary hemostasis), the products of the coagu- sis (lepirudin) as well as thrombosis prophylaxis after
lation pathway (secondary hemostasis) strengthen the major orthopedic surgery, a clinical situation in which
plug [11]. Coagulation can be initiated from within the desirudin has been studied systematically [18]. However,
circulation (intrinsic) or outside the circulation (extrin- despite this approval, the use of desirudin for postopera-
sic). It involves a cascade of protein activation leading to tive thromboprophylaxis is negligible (primarily due to
the conversion of fibrinogen to fibrin via generation of high cost) [7] and will not be discussed further. Recently,
thrombin. The factors required for coagulation are nor- additional antithrombotic compounds have been identi-
mally found in the circulation as proenzymes or cofactors. fied in leech oral secretions. A prostanoid fraction of leech
The secondary hemostatic response is initiated by tissue saliva and the enzyme destabilase have both been shown
factor (TF), a glycoprotein expressed on the subendothe- to inhibit adenosine diphosphate-induced platelet aggre-
lium of damaged vessels and the surface of nonvascular gation. Calin, another protein isolated from leech saliva,
cells, such as monocytes, after tissue injury or inflamma- has been shown to prevent wound closure after leech bite.
tion [12]. Activation of the coagulation cascade by TF is Calin inhibits collagen-mediated platelet adhesion and
known as the “extrinsic” pathway because the circula- activation through its interference with both direct plate-
tion is not normally exposed to TF. TF activates and then let-collagen aggregation and as well as inhibition of von
forms a complex with FVIIa to produce a complex that Willebrand factor-dependent platelet adhesion to colla-
activates both FX and FIX. In the presence of the cofactor gen in vessel walls [19]. Together this is the biochemical
FVa and calcium ions, FXa forms the “prothrombinase” basis of prolonged bleeding from the leech bite, which
complex, which activates prothrombin (FII), converting normally persists for 12 h. This prolonged bleeding is the-
it to thrombin (FIIa) [13]. By stopping thrombus forma- orized to preserve the host by allowing for an outflow of
tion, hirudin is essential to the process of venous decon- blood that cleanses the wound bed, thereby preventing a
gestion by permitting the leech to feed on blood for an potentially lethal sepsis.

13 Medical leech therapy in plastic reconstructive surgery   3


review

Fig. 2  The hirudin-thrombin complex. a Thrombin is a coagu- tive side effects of possible hemorrhaging that warfarin has.
lation protein that has many effects in the coagulation cas- Other studies on hirudin have also pointed to the possibility of
cade. It is a serine protease that alters soluble fibrinogen into its therapeutic applications toward osteoarthritis, specifically
insoluble strands of fibrin, as well as catalyzes many other on the knee joint, as well as its ability to greatly reduce the
coagulation-related reactions. Hirudin acts as a direct inhibi- unsightly appearance of varicose veins. b Hirudin chemical
tor of thrombin to stop coagulation at its source, unlike other structure: Full length hirudin consists of 65 amino acids. These
well-known drugs such as Coumadin (warfarin) and hepa- amino acids are organized into a compact N-terminal domain
rin. Hirudin is an anticoagulant peptide that directly inhibits containing three disulfide bonds and a C-terminal domain that
thrombin and can possibly replace the current drug warfarin is completely disordered when the protein is denatured in so-
to help prevent strokes and heart attacks due to clotting. War- lution. The C-terminal domain forms numerous electrostatic
farin affects the blood coagulation mechanisms by inhibiting interactions with an anion-binding exosite of thrombin, while
the vitamin K functions, which plays an essential role in the the last five residues form a helical loop that constructs many
synthesis of several blood coagulation factors. Since hirudin hydrophobic contacts
directly inhibits thrombin, as a drug, it will not have the nega-

Treatment options with leeches mation and pain. Michalsen et al. [23], recently published
several randomized controlled trials that demonstrated
Medicinal leeches have been used throughout the ages to significantly better pain relief among patients with osteo-
treat a myriad of diseases and conditions with and with- arthritis of the knee, rhizarthrosis, and chronic lateral epi-
out objective proof of their benefit or understanding of condylitis [24] treated with leech therapy compared with
their mechanism of action. The use of leeches has been topical diclofenac therapy. Meanwhile, the use of leeches
expanded to treat disease entities other than those char- in this area is supported by a further randomized con-
acterized by venous congestion [20]. Leeches have been trolled trial (RCT) and a meta-analysis [25]. A well-known
used successfully to treat purpura fulminans, sublingual entity in urologic trauma, penile amputation poses a dif-
hematoma, and infectious ear pathologies (otitis media ficult surgical problem. The current approach to penile
and otitis externa) [21]. In cases of macroglossia second- replantation involves reapproximation of the urethra
ary to traumatic giant lingual hematoma, leeches have and corporal bodies with microsurgical anastomosis of
been proved effective in decreasing the time to extuba- the dorsal artery and vein. Adequacy of postoperative
tion by bringing about a rapid resolution of lingual swell- venous outflow is critical to the success of replantation.
ing. The mechanism of action for leech therapy in these Prior to the common use of microvascular techniques,
clinical scenarios is not well understood [22]. nonmicrosurgical penile replantations were plagued by
The application of medicinal leeches increases blood skin loss, urethral strictures and fistulae, loss of the glans
flow within congested tissue. Due to the presence of anti- penis, and sensory deficits. Anecdotal evidence suggests
inflammatory substances in their saliva, leech therapy has that the success of nonmicrosurgical replantation may be
also been used in recent times to treat localized inflam- augmented with the adjunctive use of leech therapy.

4   Medical leech therapy in plastic reconstructive surgery 13


review

Leeches in plastic surgery

The successful use of leeches, specifically of H. medici-


nalis, for treating poor circulation in skin flaps in plastic
surgery has long been recognized [26]. The focus of leech
therapy is still on the postoperative treatment of the local,
pedicled or microsurgical flap to treat a hemodynamic
imbalance or venous insufficiency [27]. The venous con-
gestion of a skin flap with consecutive thrombosis and
decreased perfusion dreaded complication [28]. In addi-
tion, there is necrosis of the corresponding skin or tissue
area with subsequent infection and risk of sepsis, resulting
in the loss or partial loss of the flap and undesirable con- Fig. 3  The relative number of publications reporting the use of
sequences by released necrotoxins [29]. Most commonly, leeches in plastic and reconstructive surgery over time
the initial approach to venous congestion is surgical explo-
ration and examination of the venous pedicle to alleviate
venous insufficiency [2]. Only when venous compromise
is determined to be surgically irreparable or if surgery is
contraindicated leech therapy should be considered [30].
Therapy with leeches initially aggravates the venous insuf-
ficiency before later producing a visible improvement in
graft perfusion, with success rates of > 80 % reported in the
literature [31]. The number of leeches and frequency of
treatment are quite variable and are determined by a mul-
titude of factors. In 1960, Derganc and Zdravic reported a
series of 20 pedicled flaps compromised by notable venous
engorgement [32]. Using 3–6 leeches at a time on the most
congested portion of the flap, and repeating this 2–3 times
over an unspecified period, they were able to completely
salvage 70 % of their flaps [32]. In a case series and meta-
analysis, de Chalain reviewed 108 cases in which leeches
were applied to replants, free-tissue transfers, and pedicle
flaps for an average of 4.2 days for venous congestion. The
survival rate was 83 % in 89 uninfected cases [33].
Vascular congestion poses a significant challenge in
reconstructive surgery. Traumatic injury with extensive Fig. 4  Use of medicinal leeches in different types of tissue
soft tissue loss and/or the need for replantation constitute
an important indication for medicinal leeching. Clinical
signs that should prompt consideration of leech ther- case series, 51 case reports, and 7 randomized controlled
apy in these settings include the development of tissue trials (Fig.  3). Interestingly, the greatest increase in the
edema, purple discoloration, and warmth of the recon- number of studies was seen from the short period of 2011–
structed/replanted tissue, which all suggest ongoing 2013. Free flaps (22.11 %) were the most common indica-
venous congestion in the presence of preserved arterial tion for leech therapy in this series, followed by pedicled
inflow. Leech use has also been described in distal digital flaps (16.84 %), ear replantations (11.58 %), digital replan-
replantation when venous repair was technically impossi- tations (10.53 %), lip replantations (9.47 %), penile recon-
ble. Foucher and Norris reported on their series of digital structions (8.42 %), nipple congestions (5.26 %), scalp
replantations distal to flexor digitorum superficialis inser- replantations (4.21 %), degloving injuries (2.11 %), and
tion and found a 68.1 % survival rate in digits performed ring avulsions (2.11 %) (Fig. 4).
without vein repair [33]. In 2004, Tuncali et al. reported
on two cases of class IIC ring avulsion injury (arterial sup-
ply intact, venous drainage disrupted) in which they were Complications and contraindications
unable to perform a venous repair. Both patients received
4–6 leeches per day for 7–10 days and both recovered Besides the positive effects of leech therapy, there are a
“excellent” function of the replanted fingers [33]. variety of complications involved, with the most common
A hand search was conducted including all issues of being anemia, localized infection, and sepsis. The inci-
PubMed for the years between 1970 and 2013. Parameters dence of anemia increases with prolonged duration of
of interest included the use of medicinal leeches in differ- leech therapy and with high quantities of leeches used [6].
ent fields of plastic surgery worldwide. Of the 95 included Aside from these more serious complications, patients are
papers published between 1970 and 2013, there were 37

13 Medical leech therapy in plastic reconstructive surgery   5


review

also at risk for local pain and itching during the treatment and the utilization of effective antibiotic prophylaxis,
as well as episodic hypotension from bleeding. leech therapy represents an attractive treatment option
The reported incidence of infection ranges from 2 for flap salvage.
to 20 % [34]. Local infections range from cellulitis and
abscess formation to myonecrosis. Aeromonas species Acknowledgments
(e.g., Aeromonas hydrophila), Pseudomonas fluorescens, The study was supported by a grant from the Karl and
and other glucose-nonfermenting gram-negative rods Veronica Carstens Foundation, Essen, Germany.
have been isolated from H. medicinales. Aeromonas spe-
cies are the prominent bacterial flora in the leech gut and Ethical approval 
are essential for digestion of blood. This species also has Ethical approval was not required for this study.
a high affinity for muscle tissue, which makes deep tis-
sue infections associated with gas production more likely Conflict of interest 
[35]. Sepsis due to systemic infection with A. hydrophila No potential conflicts of interest were disclosed.
has been repeatedly observed after leech application in
reconstructive surgery indications, but not in any of the
other relevant fields of use. This supports the conclusion References
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