Use of Whole Blood and Cell-rich Coagulation Assays for the Detection of Non-Overt DIC in Sepsis

Activation of the coagulation system occurs early in patients with sepsis, although clinically overt disseminated intravascular coagulation (DIC) is identified in only a minority of patients with severe sepsis. Uncontrolled activation of the coagulation system may contribute to the pathophysiology of multiple organ failure and the subsequent morbidity and mortality of sepsis. Identification of risk factors predicting progression to severe sepsis and DIC has been elusive. We propose that whole blood and cell-rich coagulation assays will offer improved sensitivity to both the procoagulant and anti-coagulant changes which occur early in sepsis and will improve recognition of non-overt DIC. Future studies will address whether these assays have sufficiently high predictive value to identify subgroups of patients who could benefit from early intervention.

Specific Aims:

1. We hypothesize that increased thrombin generation will precede development of overt DIC by a clinically significant time period. Our primary objective is to determine if endogenous thrombin potential measured at first diagnosis of sepsis prior to the onset of DIC and organ failure is predictive of overt DIC.
2. There is significant individual variation among the healthy population in endogenous thrombin generation due to known and unknown polymorphisms within coagulation proteins. We predict that host variables in thrombin generation will contribute to susceptibility to DIC and poor outcome during sepsis. A secondary objective of this study is to determine if host coagulation variables predispose to the morbidity and mortality associated with sepsis.

Experimental Design and Methods

The study design will be a prospective observational study of patients presenting to the Memorial Hermann Hospital Emergency Department with sepsis. Criteria for sepsis include evidence of systemic inflammatory response syndrome as defined by the ACCP/SCCM Consensus Conference, and a known or suspected infection. Exclusion criteria include signs of severe sepsis or septic shock, as defined by the ACCP/SCCM Consensus Conference, at presentation, including: organ dysfunction, hypoperfusion and perfusion abnormalities. Chronic medical conditions associated with immune suppression or coagulopathies, such as neutropenia and sickle cell disease, and use of medications leading to immune dysfunction or coagulopathies, such as chronic steroid use or anti-coagulation will also be reasons for exclusion. In addition, because of the volume of blood required from each patient for laboratory studies, only patients 25 kg body weight or more will be enrolled. Withdrawal from the study will be at the discretion of the treating physician or subject. All efforts will be made to collect clinical information from patients who have withdrawn.