sympathicotonia) at the start of or during leech therapy, have been reported. According to Michalsen et al. [41, 42] vasovagal attacks can occur in 0.1% of patients undergoing hirudotherapy, mainly in those with a history of developing such attacks or syncope during invasive procedures such as venopunction. It is highly recommended that patients drink plenty of fluids during hirudotherapy. In order to prevent those systemic side effects, hirudotherapy should be performed in a calm atmosphere, under constant blood pressure monitoring, and with the patient lying down. Hirudotherapy can cause some negative psychological or emotional reactions in patients, especially when detached leeches fall inside the dressing or other parts of the patient’s body. Less than 10% of patients undergoing leech therapy for osteoarthritis had initial qualms before treatment, which usually disappeared after the first treatment course. In fact many patients treated with leeches and who had successful treatment changed their attitude towards hirudotherapy in a positive way. Nevertheless, it might be necessary to prepare the patients psychologically before the application of leeches [41, 42]. Contraindications related to hirudotherapy include arterial insufficiency, hemophilia, hemorrhagic diathesis, hematological malignancies, expressed and firm anemia, expressed and firm hypotension, sepsis, HIV-infection, decompensated forms of hepatobiliary diseases, any form of cachexia, and individual intolerance to leeches. Leech therapy is also not recommended in pregnancy and lactation, in patients with an unstable medical status, history of allergy to leeches or severe allergic diathesis, disposition to keloid scar formation, arterial insufficiency, and in those using anticoagulants, immunosuppressants, and some vasoactive drugs such as Ginkgo biloba products [33]. 8. Mechanisms Involved Hirudotherapy depends on the following main properties of medicinal leeches: the blood-letting action during active suction of blood, passive oozing of the wound, and injection of biologically active substances with the saliva into the host. The saliva of H. medicinalis contains more than 100 bioactive substances, including coagulation inhibitors, platelet aggregation inhibitors, vasodilators, and anaesthetizing, antimicrobial and anti-inflammatory agents [43, 44]. One of the most important ingredients is hirudin, which is the principal anticoagulant responsible for enhanced bleeding and prevention of coagulation. In addition to hirudin, leeches secrete two inhibitors of Factor Xa responsible for the conversion of prothrombin to thrombin [45]. Furthermore, leech saliva is an effective platelet aggregation inhibitor due to the presence of active ingredients such as calin, apyrase, platelet activating factor (PAF-) antagonist, collagenase, and prostaglandin. Their main function is preventing the ingested blood from congealing within the leech’s gut. The medical benefit to the patient is a sustained local bleeding that can last several hours after the end of each leech session. The saliva of the medicinal leech also contains proteinase inhibitors, such as bdellins [46], eglin, inhibitors of α-chymotrypsin, subtilisin, and the granulocytic neutral proteases-elastase and cathepsin G [47, 48], responsible for the anti-inflammatory effect of leeching. Medicinal leeches also secrete hirustasin, which selectively inhibits tissue kallikreins that are largely responsible for the maintenance of a normal level of blood pressure. Hirustasin can also