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5 ABSTRACT Background: Thromboembolic disease is one of the most common causes of pregnant women morbidity and mortality. The pregnancy period is often the first time, when the apparent congenital or acquired thrombophilia is identi- fied. Patients with thrombophilia have an increased risk of pregnancy compli- cations. The optimal anticoagulant prophylaxis helps to prevent these compli- cations. Methods: The presented work is focused on monitoring of coagulation param- eters, blood counts and acute phase proteins in pregnant women (N = 68) with thrombophilia treated with enoxaparin during pregnancy and it is also con- cerned with evaluation of effectiveness of anticoagulant therapy during preg- nancy using anti FXa activity determination based on inhibition of FXa weight, coagulation parameters and acute phase proteins. In the first and the second part of the study, there is no control group of pregnant patients with severe thrombophilia, but no anticoagulation - this is justified by ethical rea- sons. In the third part, we examined by questionnaire our patients for enoxap- arin adverse reactions at the injection site. Finally, the last part is focused on evaluation of enoxaparin effects on bone remodelling markers, compared with a group of pregnant women without anticoagulation. Results: During the...

5 ABSTRACT Background: Thromboembolic disease is one of the most common causes of pregnant women morbidity and mortality. The pregnancy period is often the first time, when the apparent congenital or acquired thrombophilia is identi- fied. Patients with thrombophilia have an increased risk of pregnancy compli- cations. The optimal anticoagulant prophylaxis helps to prevent these compli- cations. Methods: The presented work is focused on monitoring of coagulation param- eters, blood counts and acute phase proteins in pregnant women (N = 68) with thrombophilia treated with enoxaparin during pregnancy and it is also con- cerned with evaluation of effectiveness of anticoagulant therapy during preg- nancy using anti FXa activity determination based on inhibition of FXa weight, coagulation parameters and acute phase proteins. In the first and the second part of the study, there is no control group of pregnant patients with severe thrombophilia, but no anticoagulation - this is justified by ethical rea- sons. In the third part, we examined by questionnaire our patients for enoxap- arin adverse reactions at the injection site. Finally, the last part is focused on evaluation of enoxaparin effects on bone remodelling markers, compared with a group of pregnant women without anticoagulation. Results: During the...

Anticoagulants are used as the first line therapy for management and prevention of thrombotic disorders. Thrombin and factor Xa have been the prime targets for regulation of the coagulation cascade. In this work, a small library of 17 benzofuran derivatives were synthesized and screened against thrombin and factor Xa. The derivatives that displayed inhibitory potential were docked on the exosite-II of factor Xa using a docking protocol that was developed in our research group. These compounds were based on the β-5 structural unit found in the oligomer -'CDSO3‘, which was prepared in our lab and was found to inhibit both thrombin and factor Xa by an exosite-II mediated allosteric disruption of the catalytic triad.The results revealed that these β-5 like derivatives are inhibitory against thrombin and factor Xa, although their potency is weak. Thrombin and factor Xa appear to recognize different structural features suggesting a significant selectivity in recognition. Furthermore, a slight preference for the benzofuran scaffold was observed with factor Xa. Probing the mechanism of inhibition using Michaelis-Menten kinetics reveal that these compounds display uncompetitive inhibition of these proteases and the mechanism of inhibition is allosteric. Docking of these compounds on factor Xa were done using GOLD (Genetic algorithm for ligand docking) and the results, explain the observed inhibition profile. The computed docked poses also give an idea of the residues on the exosite-II of factor Xa critical for inhibition. The molecules studied here are radically different in terms of structure and mechanism of inhibition from any other ligand described in literature. This represents an opportunity to discover novel molecules with a possibly different pharmacological and toxicological profile.

Chez le chien, la daltéparine est un anticoagulant utilisé pour la prévention et le traitement de la thrombose. La surveillance thérapeutique de la daltéparine par l’activité anti-facteur Xa (FXa) n’est pas un test fonctionnel. Cette étude avait pour but d’étudier l’emploi de la génération de thrombine (GT) pour évaluer les effets in vitro de la daltéparine sur du plasma canin, ainsi que pour détecter les effets pharmacodynamiques de la daltéparine administrée chez des chiens sains. Premièrement, les paramètres normaux de la GT ont été établis à partir du plasma de 25 beagles et 11 chiens sains de clients. Ensuite, des pools de plasma canin fortifié avec de la daltéparine, à dose croissante, ont été analysés selon la GT, l’activité anti-FXa et selon le temps de thromboplastine partielle activée (aPTT). Finalement, 24 beagles sains répartis au hasard dans 4 groupes on reçu soit une dose sous-cutanée (SC) de 50U/kg, 100U/kg ou 150U/kg de daltéparine ou un placebo. Du plasma pauvre en plaquettes (PPP) a été récolté pendant 24 heures et analysé selon la GT, l’anti-FXa et l’aPPT. In vitro, la daltéparine a démontré un effet anticoagulant sur la GT qui était concentration-dépendant. Les tests de GT et anti-FXa étaient plus sensibles aux effets de la daltéparine que l’aPPT. L’étude pharmacodynamique a démontré que le temps, la dose ainsi qu’une interaction temps*dose avaient un effet significatif sur les paramètres de GT et anti-FXa. La GT peut mesurer les effets pharmacodynamiques de la daltéparine à des doses variées chez des chiens sains. / Dalteparin is an anticoagulant used to prevent and treat thrombotic disorders in dogs. Measurement of anti-factor Xa (FXa) activity is currently used for monitoring therapy, but remains a non-functional test. The aim of this study was to investigate if a thrombin generation (TG) assay could be used for the in vitro evaluation of the effects of dalteparin on canine plasma, as well as for monitoring the pharmacodynamic effects of dalteparin administration in healthy dogs. Normal TG parameters were assessed in plasma from 25 adult beagles and 11 client-owned healthy dogs. Pooled plasma was spiked with dalteparin to obtain 9 final increasing concentrations. TG, anti-FXa activity and activated partial thromboplastin time (aPTT) were measured for each concentration. 24 healthy beagles were randomized across four equal groups. À single SC dose of 50 U/kg, 100 U/kg or 150 U/kg of dalteparin was given and compared to a placebo group. Platelet poor plasma (PPP) was collected over 24 hours and assed by TG, anti-FXa activity and aPTT. In vitro results showed that dalteparin exerted a concentration-dependent anticoagulant effect on TG parameters and TG and anti-FXa activity were more sensitive than aPTT to detect these effects. The pharmacodynamics study showed a time, dose and time*dose interaction that significantly affected TG and anti-FXa parameters. TG can be employed to measure the pharmacodynamics effects of dalteparin at different doses in healthy dogs.