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Abstract The assessment of hemostasis is necessary to make suitable decisions on the management of patients with thrombotic disorders. In some clinical situations, for example, during thrombophilia screening, the presence of anticoagulants in sample makes diagnosis impossible. Various elimination methods may overcome anticoagulant interference. DOAC-Stop, DOAC-Remove and DOAC Filter are available methods to remove direct oral anticoagulants in diagnostic tests, although there are still reports on their incomplete efficacy in several assays. The new antidotes for direct oral anticoagulants – idarucizumab and andexanet alfa – could be potentially useful, but have their drawbacks. The necessity to remove heparins is also arising as heparin contamination from central venous catheter or therapy with heparin disturbs the appropriate hemostasis assessment. Heparinase and polybrene are already present in commercial reagents but a fully-effective neutralizer is still a challenge for researchers, thus promising candidates remain in the research phase.

The methods used in preclinical studies should minimize the suffering and the number of animals but still provide precise and consistent results enabling the introduction of drug candidates into the phase of clinical trials. Thus, we aimed to develop a method allowing us to perform preliminary safety and toxicity studies of candidates for human medicines, while reducing the number of animals. We have devised a method based on a combination of two devices: Plugsys (Transonics System Inc., Ithaca, NY, USA) and PhysioSuite (Kent Scientific Corporation, Torrington, CT, USA), which allow simultaneous registration of nine circulatory and respiratory parameters, and body temperature. Vehicle and adrenaline, or nitroglycerin, as reference substances were administered into the right femoral vein of Wistar rats. Physiological conditions were registered over 60 min after drug administration by measuring systolic, diastolic and mean blood pressure, heart rate (HR), blood perfusion of paw vessels, blood oxygen saturation, respiratory rate, average and peak exhaled CO2, and body temperature. Blood pressure was measured by cannula placed in the left common carotid artery and connected to the pressure transducer (Plugsys). The other parameters were measured by the PhysioSuite. Adrenaline-induced immediate dose-related hypertension and nitroglycerin hypotension were correlated with the change in blood perfusion. They both increased HR. Adrenaline decreased blood oxygen saturation and slightly affected respiratory parameters, while nitroglycerin caused a progressive increase in respiratory rate and a decrease in the peak of exhaled CO2. Our method may become an inseparable part of the preliminary safety and toxicity studies of tested drugs, while being an important step towards improving animal welfare.

Protamine sulfate (PS) is the only available option to reverse the anticoagulant activity of unfractionated heparin (UFH), however it can cause cardiovascular and respiratory complications. We explored the toxicity of PS and its complexes with UFH in zebrafish, rats, and mice. The involvement of nitric oxide (NO) in the above effects was investigated. Concentration–dependent lethality, morphological defects, and decrease in heart rate (HR) were observed in zebrafish larvae. PS affected HR, blood pressure, respiratory rate, peak exhaled CO2, and blood oxygen saturation in rats. We observed hypotension, increase of HR, perfusion of paw vessels, and enhanced respiratory disturbances with increases doses of PS. We found no effects of PS on human hERG channels or signs of heart damage in mice. The hypotension in rats and bradycardia in zebrafish were partially attenuated by the inhibitor of endothelial NO synthase. The disturbances in cardiovascular and respiratory parameters were reduced or delayed when PS was administered together with UFH. The cardiorespiratory toxicity of PS seems to be charge–dependent and involves enhanced release of NO. PS administered at appropriate doses and ratios with UFH should not cause permanent damage of heart tissue, although careful monitoring of cardiorespiratory parameters is necessary.

The aim of this paper is to present a new perspective on the religious function of the Latin adjectives cretatus (whitened with chalk) and calidus (having a white spot on the forehead). The researchers of Roman religion have attributed to the former a specific role. Whitening chalk was used to cover any imperfections in the appearance of the sacrificial animal. According to them, cretatus could also have a pejorative meaning. The author of the article, however, disagrees with this view and suggests to examine more closely the context in which the adjective was used and references to the white colour of the victims. He argues for a different, positive interpretation, namely that the adjective cretatus was used to indicate the effect of a ceremonial act intended to emphasise Roman piety. In the case of the other adjective, calidus, the examination of the context in which the word appeared proves that it most likely did not serve as a technical religious term and animals with a white spot on their foreheads were not considered pars pro toto as white victims in Rome. [ABSTRACT FROM AUTHOR]

Celem badań było określenie rzeczywistego wpływu stopnia chropowatości powierzchni pojemnika na plastyczne płynięcie metalu w procesie współbieżnego mikrowyciskania pręta metalowego. Do badań użyto zestawu narzędziowego autorskiego projektu oraz wyżarzonego, aluminiowego drutu o średnicy 1.7 mm, dla którego wyznaczono charakterystykę materiałową. Zestaw składa się z dwóch modeli pojemników na wsad i prostokątnych matryc o tych samych wymiarach, różniących się stopniem chropowatości. W celu wyznaczenia stopnia chropowatości warstw wierzchnich pojemników na wsady dla każdego z nich wyznaczono profile z użyciem mikroskopu laserowego. W trakcie przeprowadzania prób współbieżnego wyciskania wyznaczono przebiegi ciśnień na stemplu dla poszczególnych próbek a następnie zarejestrowano deformacje linii równoległych naniesionych na przekrojach wzdłużnych wyciśniętych elementów. Otrzymane próbki poddano testom mikrotwardości. Następnie wykonano numeryczną analizę analogicznych procesów mikrowyciskania. Chropowatość pojemników zamodelowano w formie sztywnej trójkątnej fali z zerowym współczynnikiem tarcia na kontakcie m = 0. Wyznaczono kształty siatek de- formacyjnych wyciśniętego materiału oraz ciśnienia na stemplach. Przeprowadzone badania ujawniły możliwość wytwarzania wyrobów o różnych właściwościach mechanicznych, uzyskiwanych poprzez dobór określonej chropowatości narzędzia.

Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, β-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents.