Endothelial Microparticles as a Biomarker for Diagnosis and Prognosis in Early Sepsis
| Status: | Recruiting |
|---|---|
| Conditions: | Infectious Disease |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 5/5/2018 |
| Start Date: | May 2014 |
| End Date: | October 2020 |
| Contact: | Grace Mammen, BA, CCRP |
| Email: | gwm2004@med.cornell.edu |
| Phone: | 646-962-2672 |
Sepsis is a major global health problem, leading to substantial morbidity and mortality
despite medical care. The initial diagnosis of sepsis is a clinical challenge, as it is based
on nonspecific systemic criteria. Excessive endothelial activation is a cardinal feature of
sepsis and contributes to microvascular leak, edema, circulatory shock and organ failure.
Activated endothelial cells shed endothelial microparticles (EMPs) which can be measured in
plasma and are found at low levels in healthy subjects. Elevated EMPs have been reported in
sepsis, but whether their effect is beneficial or deleterious is unclear. In this context, we
hypothesize that circulating EMP levels can be assessed as a biomarker differentiating sepsis
from non-sepsis critical illness. This may also suggest that EMP levels correlate with 30-day
mortality. We propose to measure circulating EMPs at ICU admission in subjects with suspected
sepsis. Final diagnoses will be adjudicated using standard criteria and 30-day mortality
ascertained. Subjects determined not to have sepsis will serve as the control group. EMP
levels will be correlated with diagnosis to ascertain the utility of EMP levels as a
diagnostic biomarker for sepsis. For those subjects with proven sepsis, EMP levels will be
correlated to 30-day mortality to assess EMP level as a prognostic marker in sepsis.
despite medical care. The initial diagnosis of sepsis is a clinical challenge, as it is based
on nonspecific systemic criteria. Excessive endothelial activation is a cardinal feature of
sepsis and contributes to microvascular leak, edema, circulatory shock and organ failure.
Activated endothelial cells shed endothelial microparticles (EMPs) which can be measured in
plasma and are found at low levels in healthy subjects. Elevated EMPs have been reported in
sepsis, but whether their effect is beneficial or deleterious is unclear. In this context, we
hypothesize that circulating EMP levels can be assessed as a biomarker differentiating sepsis
from non-sepsis critical illness. This may also suggest that EMP levels correlate with 30-day
mortality. We propose to measure circulating EMPs at ICU admission in subjects with suspected
sepsis. Final diagnoses will be adjudicated using standard criteria and 30-day mortality
ascertained. Subjects determined not to have sepsis will serve as the control group. EMP
levels will be correlated with diagnosis to ascertain the utility of EMP levels as a
diagnostic biomarker for sepsis. For those subjects with proven sepsis, EMP levels will be
correlated to 30-day mortality to assess EMP level as a prognostic marker in sepsis.
In the presence of infection, normal immune and physiologic responses act in concert to
eradicate pathogens. When these responses are inappropriately regulated, sepsis develops.
Sepsis is characterized by systemic manifestations of infection. The diagnosis is made by
identifying at least 2 of the components of the systemic inflammatory response syndrome
(SIRS), based on four clinical and laboratory criteria: respiratory rate, tachycardia,
temperature, and leukocyte level in the presence of a documented infection. The presence of
acute organ dysfunction in this setting defines severe sepsis, and hypotension that is not
reversed with fluid administration defines the entity of septic shock. Severe sepsis as well
as its most severe form, septic shock, are significant global health concerns, afflicting
millions of patients worldwide, increasing in incidence, and having an associated mortality
rate of >25%. In the United States alone, an estimated 750,000 people develop sepsis or
severe sepsis each year, and sepsis/septic shock is the 11th leading illness leading to
mortality in the US. The annual cost burden of sepsis is estimated to be more than $17
billion. For these reasons, clinical investigators interested in sepsis have directed efforts
toward identifying a biomarker that would be useful in making an early diagnosis of sepsis.
In addition to early diagnosis, biomarkers for prognosis have been sought to guide severity
assessment and to guide more personalized treatment of individual patients.
Endothelial Activation in Sepsis Endothelial activation occurs early in systemic infections
and is an adaptive response, allowing leukocyte migration to sites of microbial invasion. In
sepsis, however, endothelial activation is excessive and poses the following risks: harm via
tissue damage due to excessive leukocyte recruitment, disseminated intravascular coagulation
(DIC) relating to loss of endothelial anticoagulant properties, apoptotic death of
endothelial cells, and loss of microvascular barrier function. The dysfunctional endothelial
barrier leads to vascular leak and tissue edema, hallmarks of sepsis. This loss of
endothelial barrier function is linked to increased morbidity and mortality in animal models
of sepsis.
Endothelial Microparticles Microparticles are intact vesicles of a size 0.2-2.0 μm which are
released from plasma membranes of multiple cell types in the setting of cell injury,
activation, and/or apoptosis. In healthy individuals, microparticles found in the plasma are
derived from platelets, erythrocytes, leukocytes, and endothelial cells. EMPS generally
circulate at a relatively low level and reflect normal endothelial cell turnover. Elevated
circulating levels of EMPs can be identified in a number of illnesses including sickle cell
disease, immune-mediated thrombotic syndromes such as antiphospholipid syndrome and
heparin-induced thrombocytopenia, diabetes, chronic renal failure, acute coronary syndrome,
stroke, venous thromboembolic disease, metabolic syndrome, severe hypertension, paroxysmal
nocturnal hemoglobinuria, and multiple sclerosis. The functional roles that may be played by
endothelial microparticles are diverse and include neutrophil activation, chemotactic
attraction of leukocytes, platelet aggregation, generation of thrombin (in vitro) and
superoxide anions, stimulation of endothelial proliferation, induction of angiogenesis, MMP-2
and MMP-9 expression enabling vascular invasion of the basement membrane, and carrying of
endothelial proteins and protein C.
Given the importance of the endothelium in the pathogenesis of sepsis, we propose to examine
the role of endothelial-derived microparticles (EMPs) as a biomarker in sepsis.
eradicate pathogens. When these responses are inappropriately regulated, sepsis develops.
Sepsis is characterized by systemic manifestations of infection. The diagnosis is made by
identifying at least 2 of the components of the systemic inflammatory response syndrome
(SIRS), based on four clinical and laboratory criteria: respiratory rate, tachycardia,
temperature, and leukocyte level in the presence of a documented infection. The presence of
acute organ dysfunction in this setting defines severe sepsis, and hypotension that is not
reversed with fluid administration defines the entity of septic shock. Severe sepsis as well
as its most severe form, septic shock, are significant global health concerns, afflicting
millions of patients worldwide, increasing in incidence, and having an associated mortality
rate of >25%. In the United States alone, an estimated 750,000 people develop sepsis or
severe sepsis each year, and sepsis/septic shock is the 11th leading illness leading to
mortality in the US. The annual cost burden of sepsis is estimated to be more than $17
billion. For these reasons, clinical investigators interested in sepsis have directed efforts
toward identifying a biomarker that would be useful in making an early diagnosis of sepsis.
In addition to early diagnosis, biomarkers for prognosis have been sought to guide severity
assessment and to guide more personalized treatment of individual patients.
Endothelial Activation in Sepsis Endothelial activation occurs early in systemic infections
and is an adaptive response, allowing leukocyte migration to sites of microbial invasion. In
sepsis, however, endothelial activation is excessive and poses the following risks: harm via
tissue damage due to excessive leukocyte recruitment, disseminated intravascular coagulation
(DIC) relating to loss of endothelial anticoagulant properties, apoptotic death of
endothelial cells, and loss of microvascular barrier function. The dysfunctional endothelial
barrier leads to vascular leak and tissue edema, hallmarks of sepsis. This loss of
endothelial barrier function is linked to increased morbidity and mortality in animal models
of sepsis.
Endothelial Microparticles Microparticles are intact vesicles of a size 0.2-2.0 μm which are
released from plasma membranes of multiple cell types in the setting of cell injury,
activation, and/or apoptosis. In healthy individuals, microparticles found in the plasma are
derived from platelets, erythrocytes, leukocytes, and endothelial cells. EMPS generally
circulate at a relatively low level and reflect normal endothelial cell turnover. Elevated
circulating levels of EMPs can be identified in a number of illnesses including sickle cell
disease, immune-mediated thrombotic syndromes such as antiphospholipid syndrome and
heparin-induced thrombocytopenia, diabetes, chronic renal failure, acute coronary syndrome,
stroke, venous thromboembolic disease, metabolic syndrome, severe hypertension, paroxysmal
nocturnal hemoglobinuria, and multiple sclerosis. The functional roles that may be played by
endothelial microparticles are diverse and include neutrophil activation, chemotactic
attraction of leukocytes, platelet aggregation, generation of thrombin (in vitro) and
superoxide anions, stimulation of endothelial proliferation, induction of angiogenesis, MMP-2
and MMP-9 expression enabling vascular invasion of the basement membrane, and carrying of
endothelial proteins and protein C.
Given the importance of the endothelium in the pathogenesis of sepsis, we propose to examine
the role of endothelial-derived microparticles (EMPs) as a biomarker in sepsis.
Inclusion Criteria:
- Adults age 18 and older
- Clinician-suspected diagnosis of sepsis
- Willingness of subject or Legally Authorized Representative (LAR) to participate in
the study
Exclusion Criteria:
- Desire to forego life-sustaining therapy
- Trauma or surgical subjects
- Pregnancy
- Subjects who, in the opinion of the treating physician and/or investigator, would be
at increased risk by the additional blood draw, for instance, subjects with severe
anemia, or subjects with anemia who are unwilling or unable to receive blood
transfusions
We found this trial at
2
sites
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New York, New York 10021
Principal Investigator: Ronald G Crystal, MD
Phone: 646-962-2672
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