TachoSil Mechanism of Action

Pharmacotherapeutic group: Local hemostatics. ATC code: B02BC30.
Pharmacology: Pharmacodynamics: TachoSil contains fibrinogen and thrombin as a dried coating on the surface of an equine collagen sponge matrix. Following contact with physiological fluids such as blood, lymph or physiological saline solution, the components of the coating dissolve and partly diffuse into the wound surface. This is followed by the fibrinogen-thrombin reaction which initiates the last phase of physiological blood coagulation. Fibrinogen is converted into fibrin monomers which spontaneously polymerise to form a fibrin clot that adheres the collagen sponge to the wound surface and achieves haemostasis. The fibrin is subsequently cross linked by endogenous factor XIII, creating a firm mechanically stable network with good adhesive properties and therefore provides sealing as well.
Clinical Trials: The haemostatic efficacy and safety of TachoSil was evaluated in four open-label, multicentre, randomised, controlled, parallel-group trials comparing TachoSil with standard surgical treatment in three surgical applications. TachoSil was applied once only topically during surgery. The patients were mostly Caucasian and aged between 18 and 86 years of age.
Liver resection: The data from two trials provide clinical evidence for TachoSil as an adjunct treatment of haemorrhage in patients undergoing at least segmental resection (anatomical or nonanatomical) of the liver. One hundred and twenty-one patients were randomly assigned to either TachoSil (n=59) or argon beam coagulator treatment (n=62) in one trial, and 119 patients were treated with either TachoSil (n=60) or argon beam coagulator (n=59) in the second trial. Randomisation was conducted intra-operatively if residual minor to moderate (oozing) bleeding was present after primary treatment of major venous or arterial (pulsating) bleeding had been controlled by standard surgical methods. Patient demographics and characteristics, physical condition, past and concomitant illness, concomitant medication, and laboratory tests (haematology, coagulation, liver enzymes) at baseline were similar for the two treatment groups, and the surgical procedures and primary haemostatic treatment were overall well balanced between treatment groups in the two trials.
Both trials demonstrated superiority of TachoSil as secondary haemostatic treatment. The primary efficacy endpoint, time to haemostasis, resulted in a mean (median, range) value of 3.9 (3.0, 3-20) minutes for TachoSil and 6.3 (4.0, 3-39) minutes for argon beamer treated patients, respectively in one trial (p=0.0007), and 3.6 (3.0, 3-8) minutes versus 5.0 (3.0, 3-23) minutes for the TachoSil and the argon beam coagulator treatment group, respectively, in the second liver trial (p=0.0018).
Kidney resection: A trial was conducted to investigate the haemostatic efficacy of TachoSil compared to standard surgery in patients scheduled for the resection of superficial tumours on the kidney.
Patient demographics and characteristics, physical condition, past and concomitant illness, concomitant medication, and laboratory tests (haematology and coagulation) at baseline, surgical procedures and primary haemostatic treatment were similar in the two treatment groups. A total of 185 subjects received trial treatment with 92 patients randomised to receive TachoSil and 93 patients to standard treatment. The primary efficacy endpoint was intra-operative time to haemostasis. The results demonstrated that TachoSil was significantly superior to standard surgery. Mean (median, range) time to haemostasis was 5.3 (3.0, 3-17) minutes for TachoSil and 9.5 (8.0, 3-27) minutes for comparator treatment, respectively (p<0.0001).
Cardiovascular surgery: In a cardiovascular trial comparing the efficacy and safety of TachoSil versus standard haemostatic treatment (haemostatic fleece without additional active coagulation stimulating compounds), patients with a planned elective surgery on the heart, the ascending aorta or aortic arch requiring a cardiopulmonary bypass procedure were eligible. Only patients with residual haemorrhage from the heart muscle, the pericardium, a major vessel or vascular bed requiring supportive haemostatic treatment were eligible for randomization. Patient demographics and baseline characteristics including physical condition, past and concomitant illness, concomitant medication, and laboratory tests were similar for the two treatment groups. In the Intention to Treat (ITT) population, 59 patients were randomised to TachoSil and 60 to standard treatment. The result of the primary efficacy endpoint, proportion of patients with haemostasis at 3 minutes, was 44/59 (75%) for TachoSil treated patients and 20/60 (33%) for standard haemostatic fleece treated patients (p<0.0001).
Pharmacokinetics: TachoSil is intended for epilesional use only.
Fibrin sealants/hemostatics are metabolized in the same way as endogenous fibrin by fibrinolysis and phagocytosis.
In animal studies, Tachosil biodegrades after administration to a wound surface with few remnants left after 13 weeks. Complete degradation of TachosSil was seen in some animals 12 months after its administration to a liver wound, whereas small remnants were still observed in others. The degradation was associated with infiltration of granulocytes and formation of resorptive granulation tissue encapsulating the degraded remnants of TachoSil. No evidence of local intolerability has been observed in animal studies.
From the experience in humans there have been isolated cases where remnants were observed as coincidental findings with no signs of functional impairment.