Dual Inhibition of Factor XIIa and Factor XIa Produces a Synergistic Anticoagulant Effect.

ABSTRACT: Clinical practice shows that a critical unmet need in the field of thrombosis prevention is the availability of anticoagulant therapy without bleeding risk. Inhibitors against FXIa or FXIIa have been extensively studied because of their low bleeding risk. However, whether these compounds produce synergistic effects has not yet been explored. In this study, analyses of activated partial thromboplastin time in combination with the FXIa inhibitor PN2KPI and the FXIIa inhibitor Infestin4 at different proportions were performed using the SynergyFinder tool identifying synergistic anticoagulation effects. Both an FeCl 3 -induced carotid artery thrombosis mouse model and a transient occlusion of the middle cerebral artery mouse model showed that the combination of PN2KPI and Infestin4, which are 28.57% and 6.25% of the effective dose, respectively, significantly prevents coagulation, and furthermore, dual inhibition does not cause bleeding risk.

Trombosis arteriales y venosas en la infancia (y II): profilaxis y tratamiento / Arterial and venous thrombosis in childhood (II): prophylaxis and treatment

El tratamiento antitrombótico en los pacientes pediátricos se realiza utilizando guías extrapoladas de adultos, a pesar de su diferente condición hemostática. En el tratamiento con heparinas,la heparina no fraccionada (HNF) se utiliza en perfusión continua en dosis adecuada a la edad y el peso corporal (en niños menores de un año 28 UI/kg/h, y en los mayores de dos años 20 UI/kg/h). En las heparinas de bajo peso molecular(HBPM), a veces alternativas a los anticoagulantes orales, la dosis varía en función de la edad, el peso corporal y el tipo de heparina, con el objetivo terapéutico de conseguir un nivel de anti-Xa entre 0,5 y 1 UI/mL a las 4 horas de administración. En cuanto al tratamiento anticoagulante oral, su aplicación es problemática debido a las diferentes condiciones hemostáticas de los niños; en un 2% de los casos las complicaciones son las hemorragias graves; la duración es variable según sea una tromboembolia por trombofilia (6 meses) o secundaria a una enfermedad(mínimo 3 meses). En las trombosis venosas agudas se debe iniciar el tratamiento con HNF seguido de tratamiento anticoagulante oral. En el tratamiento antiagregante, utilizado en los procesos tromboembólicos arteriales, el fármaco más utilizado es el ácido acetil salicílico (1-5 mg/kg/día), seguido del dipiridamol en dosis de 2-5 mg/kg/día. La utilización de trombolíticos requiere una evaluación escrupulosa de los riesgos potenciales debido a la disminución de la capacidad total del sistema fibrinolítico; los dos más utilizados son la urocinasa y el activador tisular del plasminógeno (AU)

The antithrombotic therapy in paediatric patients is carried out using guides extrapolated from adults, in spite of their different haemostatic condition. In the treatment with heparins, the unfractionated heparin (UH) is used in a continuous infusion in a dose suitable to the patient’s age and body weight (in children under the age of one 28 U/kg/h and in children over the age of two 20 U/kg/h). In low-molecular-weight heparins (LMWH), sometimes alternatives to oral anticoagulants, the dose varies according to the age, body weight and type of heparin with the therapeutic objective of achieving an anti-Xa level of between 0.5-1 U/mL 4 hours after administration. As regards the oral anticoagulant therapy, its application is problematic because of the different haemostatic conditions of children, with serious hemorrhagic complications accounting for 2% of the cases; the duration varies depending on whet herit is a thromboembolism because of thrombophilia (6 months)or whether it is secondary to a disease (minimum 3 months). In acute venous thrombosis a therapy with UH must be started followed by an OAT. In the antiplatelet therapy, used in the arterial thromboembolic processes, the most commonly used drug is aspirin (1-5 mg/kg/day), followed by dipiridamol in doses of 2-5 mg/kg/day. The use of thrombolytics requires a detailed evaluation of the potential risks due to the decrease of the total capacity of the fibrinolytic system. The two most commonly used thrombolytics are urokinase and the tissue plasminogen activator (AU)

An animal model for the study of arterial thrombosis

1. Thrombus formations induced by electrical stimulation of the carotid artery was investigated in anesthetized rabbits and rats. Occlusive Grade III thrombi were produced consistently in 34 normal Nwe Zealand rabbits and 58 untreated albino Wistar rats. Thrombus formation was monitored continously in sosme of the animals with a magnetic flowmwter or a thermistor probe applied on the carotid. 2. The usefulnes of the model for the screeening of drugs was tested by treating the animals with warfarin, heparin, prostacyclin (PGI2), dihydroprostacyclin (DiHPGI2), prostaglandin E1(PGE), and prostaglandin D2(PGD2). 3. All of the drugs except warfarin were infused continuously into the venous circulation during the entire experimental period at a rate of 0.2 ml/min. 4. Warfarin (10 mg/Kg), administered by gavage 24 h before the experimental, prevented thrombus formation, as did heparin iv (34 U/Kg). 5. Of the foru platelet antiaggregatory prostaglandins tested, PGI2 was the most potent inhibitor of thrombus formation and DiHPGI2 the least active, as evaluted by visual inspection of stimulated arterial segments whic were excised 30 min (rabbits) or 15 min (rats) after the stimulation was stopped. PGI2 wss less active inrats than in rabbits (Thershold Protective Dose ratio ca. 4:1). PGE1 and PGD2 showed intermediate activity in both animal models