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1 1 Physiological properties of thrombocytes at newborn calves 2 3 Oshurkova Julija Leonidovna*, PhD in Biology, associate professor of internal noncontagious 4 diseases, surgery and obstetrics of Federal State Budgetary Educational Institution of Higher 5 Education "Vologda State Dairy Farming Academy by N.V. Vereshchagin", 6 160555, Russia, Vologda-Dairy, Schmidt's street, 2, e-mail: [email protected], +7 (812) 7 701-07-57 8 9 Zavalishina Svetlana Yurievna, PhD in Biology, associate professor, associate professor of 10 adaptive physical culture and medicobiological sciences of Kursk Institute of Social Education 11 (branch) of Russian State Social University. Researched ID 36505389100 12 13 Fomina Lyubov Leonidovna, PhD in Biology, associate professor of internal noncontagious 14 diseases, surgery and obstetrics of Federal State Budgetary Educational Institution of Higher 15 Education "Vologda State Dairy Farming Academy by N.V. Vereshchagin". 16 17 Soboleva Elena Nikolaevna, PhD in Veterinary, senior teacher of department of internal 18 noncontagious diseases, surgery and obstetrics of Federal State Budgetary Educational Institution of 19 Higher Education "Vologda State Dairy Farming Academy by N.V. Vereshchagin". 20 Baruzdina Elena Sergeyevna, senior teacher of department of internal noncontagious diseases, 21 surgery and obstetrics of Federal State Budgetary Educational Institution of Higher Education 22 "Vologda State Dairy Farming Academy by N.V. Vereshchagin". 2 23 Tkachyova Elena Nikolaevna, senior teacher of department of internal noncontagious diseases, 24 surgery and obstetrics of Federal State Budgetary Educational Institution of Higher Education 25 "Vologda State Dairy Farming Academy by N.V. Vereshchagin". 26 27 Glagoleva Tatyana Ivanovna, PhD in Biology, doctoral candidate of All-Russian Research 28 Institute of Physiology, Biochemistry and Nutrition of Animals. 29 30 31 32 Summary The aim of the work: having generalized the available information on physiology of thrombocytes, to elucidate its features in newborn calves. 33 Material and Methods. The study was performed on the basis of 50 modern literary sources. 34 The method of the study included analysis and synthesis, generalization, induction and deduction 35 based on systematic approach. 36 Results. The analysis of the available literature suggests that stability of cholesterol and total 37 phospholipid level as a part of thrombocyte membranes, and also constant level of peroxide 38 oxidation of lipids in them which in many respects provide low level of thrombocyte activity, is 39 characteristic of newborn calves. Stability of thrombocyte aggregation in newborn calves in 40 response to weak aggregation agonists should be considered as a result of constancy of receptors 41 mechanisms expression on their surface, level phospholipase A2 activity regulating arachidonic acid 42 excretion from phospholipids. Stability of thrombocyte aggregation in response to strong inductors 43 in newborn calves is due to the stability of receptor mechanisms, phospholipase C low activity, 44 weak generation of phosphatidic acid and slowed rate of Ca2+ release into the cytoplasm. 45 Conclusion. Low platelet activity in calves in a phase of neonatality is a basis of optimum level of 46 microcirculation in their tissues, adequate, on the one hand, to their genetic program, and, on the 3 47 other, to influences of the external environment. Species features of thrombocyte activity under the 48 influence of certain environmental factors on the organism and mother state during pregnancy remain 49 unclear. Further studies would not only enrich physiological science, but also show additional ways to 50 influence viability and livestock efficiency index. 51 Keywords: hemostasis; thrombocytes; calves; neonatality phase; physiology. 52 Introduction 53 Development of modern biological science is accompanied by further accumulation of 54 knowledge [7], their practical use [33] and tracking their social consequences [45]. One of the most 55 actively developing branches of agriculture on the planet is livestock production, which for several 56 decades follows the way of intensification based on the competent use of knowledge of cattle 57 biology [34]. Of special interest is a neonatality phase – the earliest stage of post-natal ontogenesis 58 [46]. It is at this age that functioning of all organs and systems develops based on adequate 59 activation of the genetic program of the living being under the influence of environmental factors [1, 60 26]. It was found that the nature of all physiological processes in animals at more advanced age 61 depends in many aspects on its successful progress [47]. Great attention is given to a neonatality 62 phase in newborn cattle because of its high vulnerability to harmful effects of the environment, 63 which can easily disturb many vital processes in animal organism [48]. 64 One of the systems making an organism of a newborn animal as a whole is blood [48]. At the 65 same time the system of hemostasis [28] and its primary link – thrombocytes, which both provide its 66 liquid properties and timely bleeding control [6, 12] is very important for its successful functioning. 67 In human studies it was shown that rheological properties of blood, proper microcirculation and rate 68 of exchange processes in tissues [2, 4, 36] is highly dependent on thrombocyte activity level. 69 Processes of platelet hemostasis activity development in young cattle significantly influence the 70 intensity of growth and at the same time can be easily disturbed by any environmental factors [10]. 4 71 Adequate age dynamics of many physiological indicators is determined by readiness of 72 thrombocytes to react by adhesion, aggregation and secretion to the stimulus, thus providing in 73 capillaries optimum hemocirculation level necessary for further ontogenesis [8, 13]. It is of great 74 biological value since it provides optimum level of delivery of oxygen and nutrients, making 75 necessary conditions for complete realization of genetically stipulated animal efficiency [37, 50]. 76 Introduction into practice of approaches for the restoration of the disturbed processes at their 77 deviations from physiological state in animals was the important step forward in biology and 78 veterinary [35, 49]. It becomes clear that the prognosis of state, and success or failure of correction 79 is in many respects connected with dynamics of hematologic factors in animals, including activity of 80 platelet hemostasis significantly influencing tissue microcirculation. 81 The aim of the work: having generalized the available information on physiology of 82 thrombocytes, to elucidate its features in newborn calves. The hypothesis of the study was: 83 generalization of the known aspects of platelet function activity in newborn calves would help to 84 determine accurately their still unclear aspects and allow planning the ways for further studies of 85 thrombocytes physiology in newborn calves. 86 Material and Methods 87 The study was performed on the basis of 50 modern literary sources. Analysis and synthesis, 88 generalization, induction and deduction based on systematic approach were used in the study. 89 Results 90 Generalizing data on mammal thrombocyte physiology, many of which were revealed in man, 91 it is necessary to specify that thrombocytes are nuclear-free blood cells, which have the form of 92 smooth biconvex disks with a diameter of 2-5 microns. Thrombocyte plasma membrane consists of 93 polar phospholipids and proteins and has the thickness of 7-8 nanometers [37, 40]. Thrombocytes 94 have a set of specific organelles, including three types of granules: α-granules, dense granules and 5 95 lysosomes, and mitochondria, vacuoles, peroxisomas, Golgi apparatus. All organelles have their own 96 membrane, and mitochondria - a double membrane. Dense granules contain ADP, ATP, serotonin, 97 pyrophosphate, Сa2+ ions; α-granules - a growth factor, ß-thromboglobulin, factor V III, Willebrand 98 factor (WF) antigen, factor V, fibrinogen, thrombospondin, fibronectin, lysosomal granules - 99 phosphatases, arylsulphatases, acidic hydrolases [9]. Membrane-free structures – microtubules 100 microfilaments and glycogen granules are found in thrombocyte cytosols [17]. 101 Thrombocytes circulate in the blood, practically without interacting with each other, other 102 blood cells and vascular endothelium [22]. In case of blood vessel damage, thrombocytes are affected 103 by various substances, initiating the processes of their aggregation and adhesion [11]. 104 influence of aggregate stimulators on thrombocytes, they quickly change their disc form to spherical, 105 form pseudopodia, often of irregular shape [33]. Under the 106 Activation and subsequent aggregation of thrombocytes (AT) are caused by substances, various 107 by their chemical nature: thrombin, collagen, adenosine diphosphate (ADF), adrenaline, serotonin, 108 A23187 ionophor, prostaglandins G2 and H2, arachidonic acid (AA), thromboxane A2, factor of 109 thrombocyte activation. ADF, serotonin, adrenaline, and vasopressin are weak aggregating agents. 110 Thrombin, collagen, A23187 ionophor are strong inductors of thrombocyte aggregation [21, 31]. 111 The rate of thrombocyte aggregation and release reaction (excretion of granular contents in the 112 environment) depends on the nature of the aggregating agent and its dose. When strong inductors 113 influence thrombocytes, high rate of cell aggregation is observed and, as a rule, it is of irreversible 114 character [14]. Under the influence of high concentration of weak agonists and low concentrations of 115 strong agents, thrombocytes release substances contained in the dense granules (reaction of release o f 116 I ) . High collagen and thrombin concentrations initiate release of substances from α-granules and 117 lysosomes (reaction of release of II) . Release reaction is necessary for the formation of a platelet 118 stopper, vasospasm and acceleration of blood coagulation processes [25]. 6 119 There are several ways of thrombocyte activation by substances causing their aggregation and 120 release reaction. The first way includes arachidonic acid metabolism and thromboxane A2formation, 121 which is a calcium ionophor. The second way is connected with phosphatidylinositol metabolism and 122 phosphatidic acid formation, which is also a calcium ionophor [20]. The third way is due to the release 123 of phospholipid lysolecithin component of thrombocyte plasma membrane, called thrombocyte 124 activation factor. This factor is supposed to activate thrombocytes irrespective of Сa2+ release [15, 125 38]. 126 Process of thrombocytes activation under the influence of aggregation inductors can be divided 127 into three stages. The first stage includes interaction of the aggregate with plasma membrane 128 receptors and signal transmission into a cell [18]. The second - transformation of a signal with 129 participation of secondary messengers, which causes Ca2+ ions release into the cytoplasm [43]. The 130 third stage is external manifestation of the cell response, and includes pseudopodia formation, 131 thrombocyte shape changes, their interaction with each other - aggregation and reaction of chemicals 132 release from them [41]. The important role in perception of an external signal, its translation and 133 response is played by thrombocyte plasma membrane - glycoproteins, and to thrombocyte contractile 134 proteins which activity is regulated by Ca2+ ions [16, 19]. 135 In the analysis of the available literature on the platelet hemostasis physiology and mechanisms 136 of its regulation in newborn calves, the sources describing its stability were found. Authors 137 associated it with constancy of optimum quantity and ratio of cholesterol and phospholipids and 138 constant level of lipid peroxide oxidation in thrombocytes [3, 5]. 139 One more mechanism providing AT stability in calves in the neonatal period is the lack of 140 thromboxane formation activity dynamics in thrombocytes. This was provided in newborn calves by 141 the lack of reliable dynamics of activity of two enzymes of its synthesis in thrombocytes - 142 cyclooxygenase and thromboxane synthetase. There are data that ATP and ADF content in 7 143 thrombocytes of calves during a neonatal period is stable. There are no significant fluctuations in 144 their secretory process activity from thrombocytes in calves during the neonatal period [10]. 145 Researchers revealed low actin and myosin contents in intact thrombocytes of physiologically 146 mature newborn calves, which remain unchanged within the first 10 days of life. Intensity of 147 additional actin and myosin formation in them on the background of thrombocyte activation by 148 strong and weak inductor and their subsequent aggregation is also insignificant and stable [47]. 149 AT studied under the influence of a number of inductors and their combinations revealed 150 lack of dynamics of thrombocyte sensitivity level in calves to external stimuli during a neonatal 151 period. Collagen causes the highest AT actively in them. AT is slightly less active in response to 152 ADF and Ristomycin. Thrombin and adrenalin AT develop still later, also without any reliable 153 dynamics during a neonatal phase. The established AT stability in newborn calves concerning 154 isolated inductors was coordinated with constant time of AT development in them on the 155 background of all combinations of inductors [4]. This information was confirmed by the results of 156 the study of thrombocyte intravascular activity in them. During neonatality, the high level of 157 discocytes and low total quantity of active forms of thrombocytes in the blood of calves remain 158 stable. It is supplemented by constant low blood content of freely circulating platelet aggregates of 159 any sizes [3, 10], that is extremely important for providing optimum conditions of microcirculation 160 during their adaptation to the extrauterine life. 161 Discussion 162 The analysis of the available literature suggests that stability of cholesterol and general 163 phospholipid level in thrombocyte membranes, and constant level of lipid peroxide oxidation, which 164 mainly provide low thrombocyte activity [10], is characteristic of newborn calves. 165 In healthy newborn calves, thrombocyte adhesive ability shows no dynamics due to 166 constancy of receptors to FW and collagen on their surfaces, and because of constant FW 8 167 concentration in their blood [3]. FW molecule is known to bind with one of its ends to collagen, and 168 by the other – to thrombocyte through a receptor - GPIb, forming "an adhesion axis": collagen - FW 169 - GPIb [23, 24]. 170 The important mechanism of stability of thrombocyte aggregation in calves during neonatality 171 is constancy of low level of arachidonic acid exchange [4, 10]. Due to the lack of dynamics of 172 cyclooxygenase and thromboxane synthetase activity during neonatality, thromboxane formation 173 level remains low in calves. It is followed by constant actin- and myosin formation at permanently 174 low adenosine phosphates secretion from platelets, still further slowing the involvement of intact 175 thrombocytes in aggregate formation [10]. 176 Stability of thrombocyte aggregation in newborn calves in response to weak aggregation agonists 177 - ADF and adrenaline interacting with the corresponding receptors of their membrane, should be 178 considered as a result of constancy of fibrinogen receptors (GPIIb-IIIA) expression on their surface, 179 phospholipase A2activity level, regulating arachidonic acid release from phospholipids [27,39]. AT 180 constancy in response to strong inductors has in its basis stability of phospholipase C low activity, 181 small level of phosphatidic acid generation and slowed Ca2+ release into the cytoplasm in newborn 182 calves [42, 44]. 183 The analysis of the available information on the combined action of two aggregation inductors 184 on the process of thrombocyte aggregation in newborn calves allowed to state the existence of their 185 unexpressed synergetic influence in physiological conditions. The established regularities of 186 thrombocyte aggregation dynamics in a neonatal phase in calves in vitro were confirmed by 187 intravascular thrombocyte activity. In view of a high level of discocytes, characteristic of newborn 188 calves, it is possible to claim weak activation of thrombocytes in vivo. It can be explained by the 189 fact that in blood of newborn calves only a small number of thrombocytes have a rounded shape and 190 form processes with transition from a discocyte to the disco-echinocyte, then to spherocyte and a 9 191 sphero-echinocyte. Besides the above listed mechanisms, it is promoted by a low level of expression 192 of fibrinogenic receptors (GPIIb-IIIA) on their membrane and low degree of availability of 193 subendothelium tissues to thrombocytes [29, 30]. 194 Conclusion 195 Low platelet activity in calves in a phase of neonatality is a basis of optimum level of 196 microcirculation in their tissues, adequate, on the one hand, to their genetic program, and, on the 197 other, to influences of the external environment. Despite the large volume of the available information 198 on thrombocytes, their functional features in calves during neonatal period cannot be considered to be 199 studied completely. Species features of thrombocyte activity under the influence of different 200 environmental factors of the organism, including weather and climatic conditions and mother state during 201 pregnancy are still not determined. The level of activity of many mechanisms of platelet activity is not 202 established in mixed bred cattle, especially in case of crossing animals of highly productive breeds. Many 203 aspects of thrombocyte response mechanisms to aggregation inductors also remain unclear in newborn 204 calves. Undoubtedly, further studies of the above problems will not only enrich physiological science, but 205 also reveal new ways of influencing viability and productivity of cattle stock. 206 207 208 209 210 211 10 212 213 214 215 216 217 218 219 220 221 222 REFERENCES 223 224 1. Amelina I.V., Medvedev I.N. Transcriptional activity of chromosome nucleolar organizing 225 regions in population of Kursk region. 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