Blood Clot Formation under Flow: The Importance of Factor XI Depends Strongly on Platelet Count

AbstractA previously validated mathematical model of intravascular platelet deposition and tissue factor (TF)-initiated coagulation under flow is extended and used to assess the influence on thrombin production of the activation of factor XI (fXI) by thrombin and of the activation of factor IX (fIX) by fXIa. It is found that the importance of the thrombin-fXIa-fIXa feedback loop to robust thrombin production depends on the concentration of platelets in the blood near the injury. At a near-wall platelet concentration of ∼250,000/μL, typical in vessels in which the shear rate is <200 s−1, thrombin activation of fXI makes a significant difference only at low densities of exposed TF. If the near-wall platelet concentration is significantly higher than this, either because of a higher systemic platelet count or because of the redistribution of platelets toward the vessel walls at high shear rates, then thrombin activation of fXI makes a major difference even for relatively high densities of exposed TF. The model predicts that the effect of a severe fXI deficiency depends on the platelet count, and that fXI becomes more important at high platelet counts

Late debut undifferentiated forms of spinal amyotrophy (clinical observation)

The clinical observation of a patient with undifferentiated form of spinal amiotrofii awards as monomelic form of spinal degeneration.В клиническом наблюдении представлен пациент с недифференцированной формой спинальной амиотрофии, дебютировавшей как мономелическая форма спинальной дегенераци

Расстройства липидного обмена при тяжелом сепсисе: клиническое значение и новые методы коррекции

Objective: to reveal the basic regularities in the development of lipid metabolic disturbances in severe sepsis and to evaluate the efficiency of parenteral use of new balanced lipid emulsions in this cohort of patients. Subjects and methods. A prospective study was conducted in 88 patients with severe sepsis of different etiologies in the intensive care unit (ICI), Sverdlovsk Regional Clinical Hospital One. Among the lipid metabolic parameters, serum cholesterol, triglycerides (TG), high-density lipoproteins, low-density lipoproteins, and atherogenicity index were measured. Out of the systemic inflammatory markers and the additional criteria for sepsis severity, the serum levels of C-reactive protein, nitric oxide, lactate, D-dimers, the anti-inflammatory cytokine IL-4 and the proinflammatory cytokine IL-8 were determined. Serum was taken on days 1, 3, 5, and 7 after admission to the ICI. The quantitative attributes were comparatively analyzed by the statistical program «Statistica 6.0». Results. The severity assessed by the APACHE II scale, the degree of multiple organ failures (MOF) evaluated by the SOFA scale, and lung lesion according to the MURREY scale were found to be closely related to the baseline serum TG levels in patients with severe sepsis. The findings suggest that patients with high TG levels have much higher resuscitative mortality rates. The clinical evaluation of the efficiency of the new method for correction of lipid metabolic disturbances in severe sepsis has indicated that the patients receiving balanced (omega-3 fatty acids-enriched) fat emulsions as 20% Lipoplus solution had lower APACHE II scores within the first 7 days of intensive therapy and significantly more positive SOFA MOF changes. Specific changes were revealed in the presence of systemic inflammatory markers, such as C-reactive protein, IL-8, and IL-4, which confirms that balanced lipid emulsions are able to affect the system of pro- and anti-inflammatory mediators. Conclusion. The baseline increased serum TG level may be regarded as an additional criterion for the severity of sepsis. The new-generation balanced fat emulsions used in the parenteral feeding program for patients with severe sepsis can reduce the severity of their condition and the manifestations of MOF and affect the system of pro- and anti-inflammatory mediators. Key words: severe sepsis, lipid metabolic disturbances, balanced lipid emulsions.Цель исследования — выявить основные закономерности развития расстройств липидного обмена при тяжелом сепсисе и оценить эффективность парентерального применения новых сбалансированных липидных эмульсий у данной категории больных. Материал и методы. Проведено проспективное исследование у 88 больных с тяжелым сепсисом различной этиологии в ОРИТ Свердловской областной клинической больницы №1. Из показателей липидного обмена оценивались холестерин и триглицериды (ТГ) в сыворотке крови, а также липопротеиды высокой плотности, низкой плотности и индекс атерогенности. Из маркеров системного воспаления и дополнительных критериев тяжести сепсиса определяли сывороточные уровни С-реактивного белка, оксида азота, лак-тата, Д-димеров, антивоспалительного цитокина IL-4 и провоспалительного цитокина IL-8. Забор сыворотки проводили на 1-е, 3-и, 5-е и 7-е сутки от момента поступления в ОРИТ. Сравнительный анализ количественных признаков проводили с помощью статистической программы «Statistica 6.0». Результаты. Выявлена тесная взаимосвязь между тяжестью состояния пациентов по шкале APACHE II, степенью выраженности ПОН по шкале SOFA и степенью легочного повреждения по шкале MURREY c исходным уровнем триглицеридов сыворотки крови у больных с тяжелым сепсисом. Полученные данные свидетельствуют о высокой реанимационной летальности у пациентов с высоким уровнем ТГ. Клиническая оценка эффективности нового метода коррекции расстройств липидного обмена при тяжелом сепсисе показала, что у больных, получавших сбалансированные (обогащенные омега-3 жирными кислотами), жировые эмульсии в виде 20% раствора Липоплюса выявлены низкие показатели тяжести состояния по APACHE II в течение первых 7 суток интенсивной терапии и достоверно позитивная динамика ПОН по шкале SOFA. Выявлена специфическая динамика маркеров системного воспаления: С-реактивного протеина, IL-8 и IL-4 — подтверждающая возможность воздействия на систему про- и антивоспалительных медиаторов с помощью сбалансированных липидных эмульсий. Заключение. Исходно повышенный уровень ТГ сыворотки крови можно рассматривать как дополнительный критерий тяжести сепсиса. Применение сбалансированных жировых эмульсий нового поколения в программе парентерального питания больных с тяжелым сепсисом позволяет уменьшить тяжесть состояния и выраженность ПОН, а также оказывает воздействие на систему про- и антивоспалительных медиаторов. Ключевые слова: тяжелый сепсис, расстройства липидного обмена, сбалансированные жировые эмульсии

Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation