| Summary: | 碩士 === 國防醫學院 === 藥理學研究所 === 107 === Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Infection can cause excessive inflammation and abnormal blood coagulation, leading to disseminated intravascular coagulation (DIC), multiple organ failure and death. Septic patients with DIC have poor outcome. DIC is a serious disorder caused by excessive activation of platelets and coagulation factors, leading to blood clots formation, thrombocytopenia, and bleeding. Bleeding risk of DIC is due to low levels of platelets, and hence platelet transfusion is the supportive therapy for DIC. However, previous studies show that transfusion of platelets does not improve the severity of bleeding and mortality in DIC patients. Moreover, previous studies show that no difference in the incidence of bleeding risk between septic patients with thrombocytopenia and without thrombocytopenia. Thus, we evaluated the functional changes of platelets in septic rats and investigated the mechanisms of sepsis-induced platelet dysfunction. Adult male Wistar rats were divided into two groups: (1) Control and (2) lipopolysaccharide (LPS, 5 mg/kg for 10 min i.v. infusion). The changes of hemodynamic parameters, biochemical variables, platelet count, prothrombin time, and fibrinogen levels were recorded during the 6-h observation. At the end of experiment, whole blood (WB) was collected for the preparation of platelet-rich plasma (PRP), platelet-poor plasma (PPP), and washed platelet (WP). In addition, an aliquot of PRP was diluted with autologous PPP to acquire normalized PRP (nPRP) (platelet count = 300 × 103/μL). The reactivity of WB, PRP, nPRP, and WP to adenosine diphosphate (ADP), protease-activated receptor-4 agonist (P4), collagen, and arachidonic acid (AA) were determined. Our results showed that LPS caused hypotension, tachycardia, hyporesponsiveness to vasopressor, hypoperfusion, coagulopathy, and multiple organ dysfunction in rats. P4 and collagen-induced platelet aggregation were slightly attenuated in the WP of septic rats, while ADP, P4, collagen, and AA-induced platelet aggregation were significantly inhibited in the PRP, nPRP and WB of septic rats. In addition, plasma from LPS rats significantly inhibited ADP, P4, collagen, and AA-induced platelet aggregation in the WP of healthy controls. These results indicate the attenuation of platelet response to ADP, P4, collagen, and AA in septic rats could be attributed to the changes of plasma substances. After treatment with fibrinogen in the PRP of septic rats, ADP and P4-induced platelet aggregation were significantly enhanced. In addition, platelet hyporeactivity to ADP, P4 and AA in the PRP of septic rats were improved after treatment with sodium bicarbonate. Moreover, P4-induced platelet aggregation was significantly augmented in the PRP of septic rats after treatment with SQ-22,536, an adenylate cyclase inhibitor. Taken together, the attenuation of platelet response to different agonists in sepsis could be attributed to the changes of fibrinogen, lactate, and AC/PKA pathway. This study provides some targets involved in the platelet hyporeactivity caused by sepsis.
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