Effect of Renin-Angiotensin System on Platelet in Patient With Sepsis

Overview

As a common and serious medical condition , sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection , which is a major and familiar cause of death in intensive care units(ICU). As a frequent laboratory abnormality in patients with sepsis , thrombocytopenia on intensive care unit admission is independently associated with increased mortality in patients. Furthermore, a low platelet count is a marker with further significance , which is always used for evaluating the prognosis of patients. Herein, this study aimed to investigate the effect of renin-angiotensin system on thrombocytopenia in patient with sepsis and explore the possible underlying molecular mechanisms.

Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. According to the Centers for Disease Control and Prevention, sepsis occurs in 1.5 million Americans annually and it causes more than 250,000 deaths annually in the United States alone. Thrombocytopenia is a frequent laboratory abnormality in patients with sepsis. Sequential \[Sepsis-related\] Organ Failure Assessment (SOFA) score of 2 points or more represents organ dysfunction . As the index of coagulation , platelet count is involved in SOFA . The changes of quality and quantity in platelet is closely associated with the morbidity and mortality of infectious diseases . Furthermore , thrombocytopenia is independently related with increased mortality in severe sepsis patients . Therefore , rectify of thrombocytopenia is of significant role to prevent potentially life-threatening complications in patients with sepsis. Currently , donor-derived platelet transfusion is the only treatment of severe thrombocytopenia seen in sepsis . However , platelets used in the clinic is associated with lots of concerns , for example , sufficient availability , quality , and complications due to immunologic and/or infectious issues . So , it is necessary and urgent to focus our efforts on the development of therapeutic agents to overcome our dependence on donor-derived platelets for transfusion . Deriving from megakaryocytes , platelets are anucleate , having only cytoplasmic components imparted by megakaryocytes residing in the bone marrow,circulating in the bloodstream and having an important role in the body because of their functions in hemostasis , thrombosis , inflammation , and vascular biology . There are numerous reasons why thrombocytopenia often accompany patients with sepsis , such as platelet-vessel wall interaction , excessive consumption of platelet in DIC and platelet activation . Furthermore, research indicates that the intrinsic machinery for programmed cell death (apoptosis) regulates the life span of the anucleate platelet. Besides, several mechanisms have been proposed to explain the platelet apoptosis ,among which reactive oxygen sepsis(ROS) appears to play critical role. More studies have shown that the renin-angiotensin-aldosterone system(RAAS) is activated in sepsis,providing an important physiologic mechanism to preserve volume status and vascular tone. As the main effect factor of the RAAS, angiotensin II plays a key role in several biological processes, including apoptosis,coagulation ,cell growth, and inflammatory response in addition to its classical hemodynamic function of regulating arterial blood pressure.Numerous researches claimed , angiotensin II (Ang II) has been associated with organ failures and mortality by promoting the generation of a large amount of intracellular ROS. However, no studies have shown the relation between Ang II-related ROS and thrombocytopenia during sepsis. Therefore, the investigators hypothesized that Ang II , by promoting the generation of a large amount of intracellular ROS , plays a critical role in the development of thrombocytopenia during sepsis.In the present study, the investigators will analyze the mechanism of platelet apoptosis during sepsis, and explore whether angiotensin II receptor blockers could protect ROS induced platelet apoptosis, which is helpful for prevention and treatment of thrombocytopenia.