Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_35_библиотеки_им_акад_М_И_Перельмана

The list of regulation factors that dictate hematopoietic stem cell differentiation, called hematopoiesis, is both intrin­sic and extrinsic and incorporates a vast spectrum of molecu­lar signaling networks. Hematopoiesis is central to both normal and pathological clinical medicine, which explains why theelderly have decreased immune system protection and an increased likelihoodofprevalent hematologic cancers such as leukemias and lymphomas [16]. Intrinsic regulation of hematopoiesis includes genetic and epigenetic elements. Epigenetic methylation candrive the expressional activation of genes responsible for differentiation [17]. Genetic expres­sivity is robustly regulated via transcription factors and can select for the tissue fate of the HSC. For example, the plu­ripotent HSC differentiates to a multipotent form via IL6 and stem cell factor, whereas the second step of HSC differentia­tion to a particular blood organ is molecularly programmed by GM-CSF, M-CSF, IL-1 to IL-5, INF, TNF, and a myriad of endocrine growth factors [18]. Additionally, homeostatic extrinsic regulation factors in the bone marrow microenvi­ronment provide extracellular signaling that supply direct and indirect control of hematopoietic component differentia­tion. Bone marrow stroma in the long bone of adult bone marrow is the major regulatory entity, but other regulatory contributions are made by endothelial cells, non-myelinating Schwann cells, megakaryocytes, macrophages, and osteo­blasts [19]. Signaling from sympathetic nerves, oxygen con­ditions, and numerous circulating factors all supply direct and indirect control of HSC.

Exposure of blood to the cardiopulmonary bypass circuit results in a profound inammatory response mediated by complement, neutrophils, endothelium, monocytes, and platelet-activating response with release of PF4 by alpha granules [8, 9]. The inammatory response is, therefore, sys­temic and multifactorial. As a consequence of localized isch­emia with associated ischemia-reperfusion injury, microemboli, exogenous heparin, and even hypothermia, cardiopulmonary bypass can result in marked coagulopathy [10]. The surface activation mechanisms of hemostasis are related to endothelial injury which leads to extrinsic pathway tissue factor production and activation. This mechanism of coagulation ignition is the accepted primary mechanism of cardiac surgery-induced coagulopathy. The coagulation cas­cade is traditionally presented in a simplistic but organized manner that allows for an overview of the components of the biochemical reactions that occur with hemostasis while fail­ing to demonstrate the complex interconnected nature of the pathway that allows for the appropriate balance between hemostasis and clot lysis that prevents intravascular throm­bosis from a runaway reaction or uncontrolled bleeding from inadequate activation. The culmination of the reactions of the intrinsic pathway, extrinsic pathway, and common path­ways results in the terminal reaction where thrombin cleaves brinogen to produce soluble brin, which subsequently forms insoluble clot when factor XIII crosslinks strands of brin. Thrombin accelerates the hemostatic pathway reac­tions by amplication of hemostatic reactions, it promotes inammatory mediators’ activation and chemotactic mecha­nisms, and it also serves to activate protein C, which serves to temper the hemostatic reactions through negative feed­back mechanisms. As a most important component of the hemostatic system, it is believed that cardiopulmonary bypass may affect the thrombin burst, resulting in coagulop­athy by thrombocytopenia (platelet consumption), dimin­ished platelet interactions, and the concentration of protein substrates present [10].