Prevention and treatment of surgical, post traumatic, obstetric and gynecological hemorrhages are a challenge in human and veterinary medicine. Administration of procoagulant and antifibrinolytic drugs are used in veterinary patients in trying to control surgical, traumatic and non-traumatic hemorrhages. Different drugs are commonly involved in people for hemorrhage control like e-aminocaproic acid, tranexamic acid, aprotinin and etamsylate (ETM). These different drugs have different mechanisms of action and have different indications. This abstract will deal with the why, when and how to administer ETM in dogs and cats.

Pharmacology (Why)

ETM is a hemostatic agent used in human and veterinary medicine to control spontaneous and iatrogenic (e.g., postoperative) hemorrhages. The hemostatic action of ETM involve the first step of hemostasis by improving platelet adhesiveness and restoring capillary resistance reinforcing capillary membranes by polymerizing hyaluronic acid. Promotes angioprotective action, thrombopoiesis, PLT release from bone marrow, and has proaggregant action mediated by a thromboxane A2 or prostaglandin F2a dependent mechanism. The precise mechanism of action is not completely known. Its activity is the consequence of the activation of thromboplastin formation on damaged sites of small blood vessels, decreases the PgI2 (Prostacyclin I2) synthesis, promotes P-selectin-dependent platelet adhesive mechanisms. ETM can antagonize the anticoagulant effect and the hemorrhagic properties of heparin. Promoting platelet aggregation and adhesion, resulting in a decrease or stop of the capillary bleeding. ETM reduces the prostacyclin (metabolite 6-oxo-prostaglandin F1a) concentration, which is potent vasodilator and a platelets disruptor. In the brain, it reduces the reperfusion hemorrhage of the ischemic areas controlling the secondary damage and closing the ductus increasing the cerebral blood flow. When administered in non-hemorrhagic patient it does not affect the normal coagulation mechanism and does not alter the prothrombin time, fibrinolysis, platelet count and function; instead, it reduces the bleeding time also if there is platelet dysfunction. In humans, it has been administered for 30 years as vascular protector in surgical hemorrhage. ETM reduces the hemorrhage in pigs with standard wound and prevents the intraventricular hemorrhage in neonatal dogs. Various experimental studies were run in animals: in 1970 Carton et al. investigated the effect of ETM on coagulation, producing a 7 mm incision after 1 hour of the intravenous ETM administration of 20 mg/kg. The study was run on 10 dogs of different ages and breeds, it was found a statistically significant difference comparing the bleeding time (40% of reduction) before and after the ETM administration. The authors used ETM in different clinical situations proposing its use to treat capillary hemorrhagic syndromes (e.g., epistaxis) as a vascular protection and for presurgical hemostasis. Another study run in 1984 by Ment et al., demonstrated that ETM is efficacious in preventing intraventricular hemorrhage (IVH) and stabilizes capillary blood vessel in premature puppies. They included in a double blinded study puppies beagles measuring prostaglandin levels before and after the ETM administration and the cerebral blood flow using autoradiography. In the treated group, it was observed a reduction in the incidence (statistically significant [p<0.05]) of intraventricular hemorrhage, significant decreases in levels of TXB2 and 6-keto PGF1, products derived from TXA2 and PGI2, reduced the basal CBF level in all brain. In another double blinded study run by Molina et al. in 2013, they evaluated the antihemorrhagic effect of ETM on hemorrhagic gastroenteritis in 19 dogs. ETM was compared with saline solution and administered every 8 hours for 7 days. The gastrointestinal hemorrhages were successfully treated, the control group had hemorrhages for 5.5 days instead in the treated group hematochezia was controlled in 3.3 days, the recovery was shorter and better in the treated group: 6.44 days and 10.7 in the placebo group. In another double blinded study run in 20 beagles, ETM was evaluated for preventing the gingival bleeding after a dental plaque removal. After 1 week the same patients received the same oral treatment but on the other half part of the mouth. The 65% of treated group had a reduction of the gingival bleeding instead the placebo group had a 35% of reduction. The amount of the gingival hemorrhage was determined as ml of blood measured in the water delivered during the procedure. The patient treated had a reduction of 27% of the blood lost during the procedure. Another interesting study (2017 Laborda) run on 6 healthy beagles, serial hepatic biopsies were done during general inhalation anesthesia, all the dogs were tested for coagulation profile, blood count and biochemistry. A standardized simple automatic incision of the liver surface was obtained using the “Surgicutt^®” device (Surgicutt, ITC, USA), the incision was repeated four times in different lobules, the bleeding time and the quantity of blood collected were reported. After that, the ETM was administered by IV and after 30 minutes the incisions, parallels to the prior incisions, were repeated. The bleeding time was reduced in the treatment group (2.50±1.47 vs 3.75±1.22 min; p<0.001). In the author experience, ETM was administered IV at least 30 minutes before liver surgery and spill over the site where the liver surgery was done, at the moment of this publication the data are still collecting, the clinical impression is that the bleeding time is reduced, and the coagulation strength is improved.

The European Agency for the Evaluation of Medical Products (EMEA) reported that the acute intravenous LD₅₀ values of etamsylate is 800 mg/kg in mouse and 1350 mg/kg in rat. Moreover, in an experimental study to verify the toxicity and side effect of ETM was done in a group of Wistar rats in which were given daily subcutaneous doses of 0, 10 or 100 mg/kg bw/day, 6 days per week, for 32 weeks, no overt signs of toxicity and treated rats gained weight in a similar manner to the controls, also hematology parameters during all the weeks. After the study, no organ weight or gross pathological changes were observed, however, a histopathological investigation was not done. The same agency affirmed that the pharmacovigilance records reveal the absence of evidence of adverse effects. No adverse reproductive effect in humans has been reported, it is secreted in the breast milk, no effect is reported in neonates. In a multicenter trial, run in humans, ETM was administered at 12.5 mg/kg given every 6 hours for the treatment and prevention of periventricular hemorrhage, and demonstrated a reduction in patent ductus arteriosus.

Indications and Use (When and How)

ETM is labeled for the use in dogs, cats, bovines, horses, sheep, goats and pigs. ETM can be useful in the treatment of following hemorrhages:

• Traumatic
• Spontaneous
• Surgical
• Obstetric
• Gynecological

The onset of action is 10 min when administered IV, 30 min if administered by IM injection, the maximum effect is achieved between 30 min to 4 hours. For prevention of surgical hemorrhage, it is better to administer ETM IV, 30 min before the procedure. The suggested dosage ranges from 5.0–12.5 mg/kg IV, IM. The author administers ETM at 12.5 mg/kg IV every 6 hours until the hemorrhage is under control.

References

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