Experimental Evaluation of a New Tissue Factor-Based Topical Hemostat (TT-173) for Treatment of Hepatic Bleeding.

Background: Excessive blood loss is a relevant complication of partial liver resection. Topical hemostatic agents have proven useful to improve the control of the bleeding in this among other surgical indications. Until now all of these products have been based on the action of thrombin. In contrast TT-173 is a new topical hemostatic agent based on recombinant tissue factor naturally incorporated into membrane vesicles. This work sought to assess the efficacy and toxicity of TT-173 in an animal model of liver resection.Materials and Methods: Procoagulant activity of 0.15, 0.41, and 1 mg of TT-173 was evaluated in pigs subjected the resection of hepatic lobe margins. The most effective of these doses was also compared against thrombin. In addition, the toxicity, local tolerance, systemic absorption, and immunogenicity of the product were investigated in rats subjected to liver biopsy lesion.Results: The three doses of TT-173 evaluated significantly reduced the bleeding time in liver lesions. The highest dose of product was significantly more effective than the others and thrombin. Application of high doses of TT-173 in rats did not cause any local or systemic alterations. Absorption into blood stream was negligible and no immunogenic reaction against the product was detected.Conclusions: TT-173 shows favorable pharmacodynamic properties for improving hemostasis in partial liver resection which support further investigation of the product in this surgical indication.

A new topical hemostatic agent TT-173 reduces blood loss in a sheep model of total knee arthroplasty.

BACKGROUND: Total knee arthroplasty is associated with blood loss during the intervention and may require allogenic blood transfusion. Treatments such as tranexamic acid and fibrin sealants improved the bleeding control in several clinical trials, but the hemorrhage associated with the intervention is still significant. Thus far, very few studies have evaluated hemostatic treatments in animal models of total knee arthroplasty. This work describes a sheep model of bleeding associated with total knee arthroplasty and investigates a new class of hemostatic treatment based on recombinant tissue factor. METHODS: Sheep were treated with the anticoagulant heparin, and the joint was accessed by a paramedial incision. Ligaments and menisci were eliminated and femoral condyles and tibia plateau were sectioned exposing the trabecular bone. An intra-articular drain was used to recover and quantify the blood loss during the 90-min period after treatment. The efficacy of one milligram and three milligrams of TT-173 was evaluated and compared with tranexamic acid. The occurrence of analytical alterations and systemic absorption was also investigated. RESULTS: Treatment with TT-173 reduced the blood loss in comparison with control or tranexamic acid. No significant differences were observed between the two doses evaluated. Moreover, a dose of six milligrams of TT-173 did not induce any clinical or analytical alteration, and significant systemic absorption was not observed. CONCLUSION: Data obtained strongly suggest that TT-173 could be useful in reducing the blood loss associated with total knee arthroplasty and without safety concerns derived from the systemic absorption of the product.

HESTAT: Study protocol for a phase II/III, randomized, placebo-controlled, single blind study to evaluate the new hemostatic agent TT-173 in total knee arthroplasty.

BACKGROUND: Several hemostatic treatments intended to reduce the bleeding associated to total knee arthroplasty have been investigated with varying degrees of success. TT-173 is a new topical agent based on recombinant tissue factor that activates the extrinsic pathway of coagulation. This trial aim is to evaluate the efficacy and safety of TT-173 in total knee arthroplasty. METHODS/DESIGN: This is a phase II/III, sequential, simple blind, randomized, multicenter, placebo controlled and parallel clinical trial that will recruit 189 evaluable patients. Those randomized to treatment group will receive 2mg of TT-173 over the surgical surfaces of the knee. Control patients will receive physiologic saline. The follow up will consist in 6 visits during a period of 35 (±7) days. Primary endpoints will be the total blood loss and the incidence and severity of adverse events. Secondary and exploratory endpoints will include drainage production, decrease in hemoglobin level, transfusion ratio, analytical alterations, pain intensity, motion range, immunogenicity of TT-173 and the occurrence of systemic absorption. At the end of phase II, results will be evaluated by an independent committee that will recommend the continuation or the discontinuation of the trial. DISCUSSION: The design proposed maximizes the safety of the participants, avoids the risk of bias derived from the limitations of masking and enable the eventual discontinuation of the trial if this is recommended by the Interim Analysis Committee. If TT-173 proves its efficacy and safety in this indication, it would become a useful tool to improve the bleeding control in total knee arthroplasty. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02687399. Registered the 9th of February 2016.

Analytical parameters and vital signs in patients subjected to dental extraction.

BACKGROUND: Dental consultation may provoke stress to the patient, especially when a dental surgery is going to be performed, stressful situations can cause a reaction in the sympathetic nervous system that could lead to cardiovascular alterations. Blood pressure and cardiac frequency are used often as an indirect measurement and this parameters combined can serve as good indicators of stress. Objective: Analyze the changes in vital signs and analytical parameters induced by a dental extraction. MATERIAL AND METHODS: 24 healthy patients who required a simple dental extraction underwent to a blood test and motorization of their pre- and post-extraction vital signs before, at 2 and 48 hours after the procedure. Data analysis was performed by means of repeated measures one way ANOVA followed by multiple comparisons Bonferroni's Post-hoc test. RESULTS: The evaluated patients were 13 women and 11 men with an average age of 35.1. Thirteen patients (54.17% of the sample) were smokers and five were regular drinkers (20.8%). No significant differences were observed in the vital signs with the exception of diastolic blood pressure and cardiac rate that were slightly lower after extraction. Only two analytical parameters showed statistical significant changes. Total bilirubin was significantly higher at 48 hours after extraction and leukocyte count was significantly lower at this time. In any case, the magnitude of the changes observed was very low. The analytical parameters and the vital signs did not show any relevant change. CONCLUSIONS: Eventual alterations found after simple tooth extraction should not be attributed to the procedure. Key words:Blood pressure, heart rate, monitoring physiologic, oxygen saturation, tooth extraction.

Nonclinical Evaluation of the New Topical Hemostatic Agent TT-173 for Skin Grafting Procedures.

Blood loss during grafting surgery represents a major concern of this procedure and the development of hemostatic agents for this indication is highly desirable. TT-173 is the first biologically active treatment based on tissue factor instead of thrombin. This study sought to investigate the efficacy, systemic absorption, and toxicology of TT-173 in animal models to support clinical evaluation of the product in donor sites of patients subjected to skin grafting. Procoagulant efficacy of 148 µg of TT-173 was evaluated in pigs in presence and absence of anticoagulant treatment with unfractioned heparin. Systemic absorption was quantified and characterized in rats subjected to severe skin lesions with affectation of muscular plane using TT-173 radiolabeled with I. The same animal model was used to test the toxicology of a dose of 80 µg of the product. Application of TT-173 significantly reduced the bleeding time of donor sites, even under anticoagulant treatment. Systemic absorption was low; it was excreted through urine and did not concentrate in organs such as liver, lung, or spleen suggesting that the absorbed dose could correspond to degradation fragments without procoagulant activity. Finally, a dose of 80 µg of TT-173 did not cause analytical disturbances suggestive of intravascular coagulation or any other adverse reaction. Nonclinical data obtained suggest that TT-173 could be useful to reduce the blood loss associated to burns treatment and support the clinical evaluation of the product in donor sites of patients subjected to skin grafting.

EHTIC study: Evaluation of a new hemostatic agent based on tissue factor in skin grafting procedures.

BACKGROUND: Excessive bleeding is a major concern in scar debridement and grafting procedures. TT-173 is a new topical hemostatic agent based on recombinant human tissue factor that has shown promising results in patients who underwent tooth extraction. EHTIC study sought to evaluate the efficacy and safety of TT-173 to reduce the bleeding in donor sites of skin grafting procedures. METHODS: EHTIC study was a phase II, randomized, parallel, double blind, placebo controlled trial. Patients received TT-173 (n=38) or placebo (n=33) sprayed over donor site after graft harvest. Time to hemostasis and incidence of adverse events were recorded. Systemic absorption of the product and its immunogenicity were also measured during the follow up of the subjects. RESULTS: Treatment with TT-173 significantly reduced the bleeding time from 7 to 3min (Log-Rank p<0.0001). Moreover, bleeding stopped within the 10min of evaluation period in all the patients that received TT-173. In contrast, 24.24% of patients from placebo group required additional measures to arrest hemorrhage (Fisher p=0.0013). Product related adverse events, systemic absorption into blood stream, interferences with the healing of the donor site or immunogenic reaction against TT-173 were not observed. CONCLUSION: The new hemostatic agent TT-173 has proven efficacious and safe to reduce the bleeding from donor site. This study paves the way for further investigation of the product as topical hemostatic treatment in plastic surgery and other surgical indications.

Characterization of the Biodistribution and Systemic Absorption of TT-173, a New Hemostatic Agent of Recombinant Human Tissue Factor, Using Radiolabeling with 18F.

BACKGROUND AND OBJECTIVES: TT-173 is the first topical hemostatic agent based on tissue factor. To prevent thromboembolic events and intravascular coagulation it is necessary to rule out the systemic absorption of new bioactive hemostats. Here, we radiolabeled TT-173 with [18F]SBF to characterize its systemic absorption and biodistribution. METHODS: A group of rats were administered intravenously with [18F]TT-173 and were subjected to a positron emission tomography study. A second group of animals received the [18F]TT-173 topically over a skin lesion in the flank. Topical absorption was quantified and the biodistribution patterns observed were compared. RESULTS: After topical application, low amounts of [18F]TT-173 were absorbed and distributed without relevant accumulation in any organ. On the other hand, after intravenous injection, [18F]TT-173 accumulated in lungs, liver and spleen, consistent with intravascular clot formation and the posterior capillary trapping and phagocytosis by the reticuloendothelial system. In both cases, a substantial concentration of radioactive product was found in urine consistent with renal excretion of degradation products of [18F]TT-173. CONCLUSIONS: After topical application, [18F]TT-173 did not show a significant systemic accumulation in animal organs. Minor radioactive concentration found in lungs, liver and spleen likely corresponds with fragments of the product without procoagulant activity. Radiolabeling with [18F]SFB enables the characterization of systemic absorption and biodistribution of new topical hemostats like TT-173.

TETIS study: evaluation of new topical hemostatic agent TT-173 in tooth extraction.

OBJECTIVES: TT-173 is a new hemostatic agent consisting of yeast-derived microvesicles containing a modified version of recombinant human tissue factor. In the present work, the procoagulant activity of TT-173 has been evaluated for the first time in humans. METHODS: This is a phase I, randomized, placebo-controlled study to evaluate the efficacy, safety, systemic absorption, and immunogenicity of TT-173 in healthy volunteers undergoing tooth extraction. Subjects received TT-173 or placebo into the alveolar cavity, just after tooth extraction. Time to clot formation, bleeding time, and adverse events were recorded. RESULTS: Treatment with TT-173 reduced the bleeding time and the time to clot formation. No adverse events related with product administration were reported. In the same way, neither systemic absorption nor immunogenic reaction against the product was detected. Our findings pave the way to evaluate the usefulness of this new topical hemostatic agent in more complex oral surgeries and in those patients affected with coagulation disorders that may compromise the realization of dental procedures. CONCLUSION: The new hemostatic agent TT-173 has proven efficacious and safe in healthy subjects undergoing tooth extraction supporting its further evaluation in more complex surgeries. CLINICAL RELEVANCE: The development of this new topical hemostatic agent could contribute to bleeding control in oral and maxillofacial surgery.