title: Hemostasis and endothelial damage during sepsis.
abstract: The sepsis syndrome represents a disease continuum, including severe sepsis and septic shock associated with high mortality. One of the main problems in severe sepsis and septic shock, resulting in organ failure and death, are disturbances in the hemostasis due to sepsis-related coagulopathy. Sepsis-related coagulopathy affects not only traditional coagulation factors, but also the platelets and endothelium. Functional testing of the hemostatic system has found application in critical illness. Thrombelastography (TEG) provides an overview of the hemostatic system allowing for an evaluation of interactions between coagulation factors and platelets. Additionally, the role of the endothelium during sepsis can be explored through testing of biomarkers of endothelial damage. The three studies comprising this PhD thesis all investigate important aspects of the disturbed hemostasis during sepsis, including endothelial damage. Together, the specific findings from the three studies improve the existing understanding of sepsis-related coagulopathy, and the possible influences of some of the treatments offered these patients. The first study investigates the occurrence of antimicrobial-induced thrombocytopenia among critically ill patients. In sepsis, thrombocytopenia is a predictor of poor outcome, and reports, of mainly casuistic nature, have previously hypothesized that specific antimicrobial agents could induce in sepsis-related thrombocytopenia. This hypothesis was tested using a randomized designed set-up, encompassing 1147 critically ill patients, and no significant difference in risk of thrombocytopenia was observed among patients receiving large amounts of antimicrobials vs. patients receiving standard-of-care. As a consequence, the risk of antimicrobial-induced thrombocytopenia in the general population of critically ill patients seemingly does not represent a substantial problem and thrombocytopenia during critical illness is most likely due to other factors such as infection severity. In the second study of the thesis, the role of endothelial damage during sepsis was explored. Levels of biomarkers of superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin (sTM), respectively) were determined in a cohort of 1103 critically ill patients. The results showed that only high levels of sTM were associated with a markedly increased risk of 90-day mortality, as well as multi-organ failure. The finding suggests that profound damage to the endothelium is centrally involved in the pathogenesis of death in sepsis. Thus, the endothelium may be a target for new interventions against sepsis. In the third study, we investigated, using a randomized controlled trial, how mild induced hypothermia (cooling to 32-34°C for 24 hours, MIH) influenced sepsis-related coagulopathy using TEG; functional coagulopathy improved in patients exposed to the intervention compared with the control group. This improvement of coagulopathy parameters during MIH persisted after rewarming. These results not only add to the understanding of the effect of hypothermia on the hemostatic system, but indicate that MIH reduces sepsis-related coagulopathy assessed by TEG. Overall, this thesis emphasizes that the role of the hemostatic system during sepsis is not only complex, but centrally involved in disease severity and prognosis. The endothelium seems to play a central role in the morbidity and mortality of sepsis, which cannot be explained simply by the presences of organ failure. Thus, restoring the broken endothelium and reducing coagulopathy appears to be essential in order to significantly improve sepsis out-comes. MIH could be a promising intervention in sepsis, in part due to the improvement of the coagulopathy. Despite the increased focus on the hemostatic system during sepsis, it seems that continued research on restoring disrupted hemostasis - including endothelial damage - is needed.
authors.affiliation: Centre for Health and Infectious Disease Research (CHIP), Rigshospitalet, University of Copenhagen, Department of Infectious Diseases and Rheumatology, Section 2100, Finsencentret, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. maegjo@gmail.com.
authors.forename: Maria Egede
authors.initials: ME
authors.lastname: Johansen
mesh_terms: D004212:Academic Dissertations as Topic; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000502:physiology*; D016638:Critical Illness; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018805:Sepsis / Q000097:blood* / Q000150:complications / Q000473:pathology; D013916:Thrombelastography / Q000379:methods; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D018180:Thrombomodulin / Q000097:blood
chemical_list: D015415:Biomarkers; C546931:THBD protein, human; D018180:Thrombomodulin