First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of an Oral Formulation of DS-1040, an Inhibitor of the Activated Form of Thrombin-Activatable Fibrinolysis Inhibitor, in Healthy Subjects.

DS-1040, a low-molecular-weight imidazole derivative, inhibits the enzymatic activity of thrombin-activatable fibrinolysis inhibitor (TAFIa), enhancing endogenous tissue plasminogen activator-triggered fibrinolysis. This first-in-human, randomized, placebo-controlled, phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of an oral formulation of DS-1040. Healthy adults (aged 20-45 years; N = 56) were randomized 3:1 to receive DS-1040 orally administered as single ascending doses (50, 100, 200, or 400 mg) or placebo, or DS-1040 multiple ascending doses (100 mg once daily, 200 mg once daily, or 150 mg twice daily) or placebo for 14 days. Safety, PK, and PD parameters were assessed. All doses of DS-1040 were well tolerated; no serious/severe adverse events (AEs) or discontinuations due to AEs occurred. DS-1040 had no effect on coagulation parameters, and no treatment-related trends in the bleeding time were observed. DS-1040 exposure (peak concentration and area under the concentration-time curve) increased in a dose-proportional manner across the single-dose range. With multiple doses, steady state was achieved by day 7 with minimal accumulation (mean accumulation ratio 1.15-1.25), and the PK was time-independent. After 72 hours, approximately 10% of the DS-1040 400-mg single dose was recovered in urine as intact parent drug. The mean terminal half-life ranged from 17.2 to 24.9 hours, which was similar to previous intravenous administration data. Dose-dependent inhibition of total TAFIa activity was observed following single and multiple doses of oral DS-1040. The safety and PK/PD profiles of oral DS-1040 in healthy subjects support further clinical development.

Tissue-type plasminogen activator transgenic rats for evaluating inhibitors of the activated form of thrombin-activatable fibrinolysis inhibitor.

: No rodent models are currently available for evaluating inhibitors of the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa) without exogenous supplementation of tissue-type plasminogen activator (tPA). Characterization of tPA transgenic rats as a tool for the nonclinical evaluation of TAFIa inhibitors is the objective of the current study. tPA transgenic rats were subjected to rat models of tissue-factor-induced thromboembolism, FeCl3-induced deep vein thrombosis (DVT) and arterial thrombosis, and tail bleeding. Potato tuber carboxypeptidase inhibitor (PCI), a selective TAFIa inhibitor, was used as an experimental compound at doses of 0.1, 1, or 10 mg/kg, and its antithrombotic effects and bleeding prolongation effect were compared with nontransgenic rats. Intravenous PCI showed significant and dose-related increase in plasma D-dimer levels in the tissue-factor-induced thromboembolism model. Intravenous PCI also significantly and dose-dependently reduced thrombus weights in the two thrombosis models only in the tPA transgenic rats. These results suggest that sensitive in-vivo evaluation of TAFIa inhibitors can be achieved using tPA transgenic rats without exogenous supplementation of recombinant tPA. On the other hand, no statistically significant prolongation of bleeding times by PCI was observed in either strain, whereas increased bleeding times were observed with 10 mg/kg of intravenous recombinant tPA, suggesting that the low bleeding risk of TAFIa inhibitors is further confirmed in the tPA transgenic rats whose basal tPA levels are elevated. tPA transgenic rats may be beneficial for the pharmacological and toxicological evaluation of TAFIa inhibitors and further confirm that TAFIa is a promising target for various thrombotic disorders.

Inhibition of thrombin-activated fibrinolysis inhibitor decreases postoperative adhesion.

BACKGROUND: Postoperative adhesion is a problematic issue. The aim of this study is to identify the effect of a TAFI inhibitor (potato tuber carboxypeptidase inhibitor [PTCI]), novel agent, which reconciles formation and degradation of fibrosis, in the prevention of postoperative adhesions in rats. METHODS: A total of 48 rats were allocated in three groups; control group C, normal saline group N, and PTCI group P. After surgical adhesion formation under anesthesia, group N received 5 mL of normal saline, group P; 5 mg of PTCI in 5 mL normal saline was instilled in the peritoneum. Four weeks after surgery, rats were sacrificed and adhesions were assessed in gross macroscopic, microscopic, and immunohistologic aspects, and scoring was performed in each category. RESULTS: Besides two rats, one from each group N and C who died on the third postoperative day, no adverse events were found among the groups throughout the study. In gross adhesions, group P had significantly lower adhesion score than all other groups (P < 0.001). Group P had a significantly lower fibrosis and inflammation in microscopic assessments (P < 0.05) and immunohistochemistry (P < 0.001) compared with groups C and N. CONCLUSIONS: In conclusion, TAFI pathway inhibition resulted in reduction of postoperative adhesion number and severity. Clinical and microscopic findings show that TAFI inhibition plays a role in modulating adhesion formation.

Alterations in procoagulant, anticoagulant, and fibrinolytic systems before and after start of induction chemotherapy in children with acute lymphoblastic leukemia.

Induction chemotherapy is associated with increased thrombosis risk in children with acute lymphoblastic leukemia (ALL). In this prospective study, we explored the effects of ALL and induction chemotherapy on the procoagulant, anticoagulant, and fibrinolytic systems in 20 children with ALL. The levels of d-dimer, factor VIII, von Willebrand factor, protein C, antithrombin III, and thrombin-activated fibrinolysis inhibitor (TAFI) were elevated at diagnosis. These changes were not related with peripheral blast count. The levels of fibrinogen, d-dimer, coagulation inhibitors, and plasminogen decreased, whereas the levels of tissue factor pathway inhibitor and plasminogen activator inhibitor 1 increased progressively following prednisolone monotherapy, administration of vincristine plus daunorubicin, and l-asparaginase. The levels of factor VIII, d-dimer, and TAFI remained elevated during the study period. In conclusion, coagulation activation and impaired fibrinolysis already exist at diagnosis, whereas induction chemotherapy leads to reactivation of coagulation and progressive impairment in fibrinolytic and anticoagulant capacities in childhood ALL.

Nueva era en la terapia antiplaquetar basada en los resultados de ensayos clínicos recientes / New era in antiplatelet therapy based on results from recent clinical trials

La terapia antiplaquetar ha sido de gran beneficio en la reducción de episodios cardiovasculares, particularmente en pacientes con síndromes coronarios agudos (SCA). Avances recientes sobre el papel de las plaquetas en la aterotrombosis han facilitado el desarrollo de nuevos agentes potencialmente más beneficiosos que la terapia estándar con aspirina y/o clopidogrel. Se han completado amplios ensayos clínicos aleatorizados en pacientes con SCA empleando nuevos antagonistas del ADP, como prasugrel, ticagrelor y cangrelor, más potentes y eficaces que el clopidogrel, así como con inhibidores del receptor de la trombina. Estos agentes pueden suponer un avance para una medicina personalizada, eligiendo el agente antiplaquetar que más se adapte a las características individuales del paciente y al cuadro clínico (AU)

Plasminogen activation-based thrombolysis for ischaemic stroke: the diversity of targets may demand new approaches.

The plasminogen activating enzyme system has been exploited and harnessed for therapeutic, mainly thrombolytic benefit for many years. While plasminogen activator-based thrombolysis turned out to be a resounding success, it has become apparent that the "plasminogen activating system" per se is not only designed to simply remove fibrin and some other matrix proteins. Indeed, the plasminogen activators and the plasminogen activator inhibitors have important effects on cell signalling through both proteolytic and non-proteolytic means and can promote unwanted side effects, particularly in the brain. Tissue type plasminogen activator (t-PA) was heralded as a fibrin-selective plasminogen activator and subjected to clinical development in the early 1980's initially for the treatment of patients with myocardial infarction. t-PA was given FDA approval in the mid 1990's for use in ischaemic stroke patients, but it could only be administered within a short 3h window post- stroke as later use was associated with an increased risk of intracerebral haemorrhage. Hence only a small percentage of these patients were eligible for thrombolysis to restore blood flow to the brain. Since t-PA-mediated plasmin generation is not only impacting on the cerebral blood clot, extending the therapeutic time window for thrombolysis is not a simple task. The ultimate success will depend on how well the future generation of thrombolytic agents promote efficacious removal of a fibrin clot without promoting collateral damage particularly in the brain.

Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis.

The coagulation and fibrinolytic systems safeguard the patency of the vasculature and surrounding tissue. Cross regulation of coagulation and fibrinolysis plays an important role in preserving a balanced hemostatic process. Identification of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) as an inhibitor of fibrinolysis and one of the main intermediates between coagulation and fibrinolysis, greatly improved our understanding of cross regulation of coagulation and fibrinolysis. As TAFI is an enzyme that is activated by thrombin generated by the coagulation system, its activation is sensitive to the dynamics of the coagulation system. Defects in coagulation, such as in thrombosis or hemophilia, resonate in TAFI-mediated regulation of fibrinolysis and imply that clinical symptoms of coagulation defects are amplified by unbalanced fibrinolysis. Thrombomodulin promotes the generation of both antithrombotic activated protein C (APC) and prothrombotic (antifibrinolytic) activated TAFI, illustrating the paradoxical effects of thrombomodulin on the regulation of coagulation and fibrinolysis. This review will discuss the role of TAFI in the regulation of fibrinolysis and detail its regulation of activation and its potential therapeutic applications in thrombotic disease and bleeding disorders.