Role of procoagulant microparticles in mediating... : Hepatology (original) (raw)

Liver Failure/Cirrhosis/Portal Hypertension

Role of procoagulant microparticles in mediating complications and outcome of acute liver injury/acute liver failure

Stravitz, Todd R.1; Bowling, Regina2; Bradford, Robert L.3; Key, Nigel S.3; Glover, Sam2; Thacker, Leroy R.4; Gabriel, Don A.2,3

1_Section of Hepatology and Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA_

2_Invitrox, Inc., Research Triangle Park, NC_

3_Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC_

4_Department of Biostatistics, Virginia Commonwealth University, Richmond, VA_

Received September 10, 2012; accepted January 30, 2013.

This work was partially supported by UL1TR00058 from the National Center for Advancing Translational Sciences.

Address reprint requests to: R. Todd Stravitz, M.D., F.A.C.P., F.A.C.G., Section of Hepatology and Hume-Lee Transplant Center, Virginia Commonwealth University, P.O. Box 980341, Richmond, VA 23298-0341. Email:[email protected]; fax: 804-828-4945.

Potential conflict of interest: D.A.G. acknowledges his role as Chief Medical Officer of Invitrox, Inc. The focus of Invitrox is to develop new technology to detect and phenotype microparticles and to explore potential clinical applications of this technology.

Abstract

Microparticles (MPs), membrane fragments of 0.1-1.0 μm, are derived from many cell types in response to systemic inflammation. Acute liver failure (ALF) is a prototypical syndrome of systemic inflammatory response syndrome (SIRS) associated with a procoagulant state. We hypothesized that patients with ALF develop increased procoagulant MPs in proportion to the severity of systemic complications and adverse outcome. Fifty patients with acute liver injury (ALI), 78% of whom also had hepatic encephalopathy (HE; ALF), were followed until day 21 after admission. MPs were characterized by Invitrox Sizing, Antigen Detection and Enumeration, a light-scattering technology that can enumerate MPs as small as 0.15 μm, and by flow cytometry. Procoagulant activity was assessed by a functional MP-tissue factor (MP-TF) assay. Sixteen patients (32%) died and 27 (54%) recovered without liver transplantation (LT). Total MPs (0.15-1.0 μm) were present in nearly 19-fold higher concentrations in ALI/ALF patients, compared to healthy controls (P < 0.0001). MP-TF assays revealed high procoagulant activity (9.05 ± 8.82 versus 0.24 ± 0.14 pg/mL in controls; P = 0.0008). MP concentrations (0.28-0.64 μm) were higher in patients with the SIRS and high-grade HE, and MPs in the 0.36-0.64-μm size range increased in direct proportion to SIRS severity (P < 0.001) and grade of HE (P < 0.002). Day 1 MPs (0.28-0.64 μm) correlated with laboratory predictors of death/LT (higher phosphate and creatinine; lower bicarbonate), and day 1 and 3 MPs were higher in patients who died or underwent LT, compared to spontaneous survivors (P ≤ 0.01). By flow cytometry, 87% of patients had circulating CD41+ MPs, indicating platelet origin. Conclusion: Highly procoagulant MPs of specific size ranges are associated with the SIRS, systemic complications, and adverse outcome of ALI/ALF. MPs may contribute to the multiorgan system failure and high mortality of ALF. (HEPATOLOGY 2013;)