Effect of Standard and Intensive Insulin Therapy on Membrane-Bound Tissue Factor and Plasma Coagulation Biomarkers in Patients with Hyperglycemia and Acute Stroke: Differential Effects of rtPA Administration
ISTH Academy. Rao A. Jul 9, 2019; 264443; PB1252
Dr. A Koneti Rao
Dr. A Koneti Rao
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Effect of Standard and Intensive Insulin Therapy on Membrane-Bound Tissue Factor and Plasma Coagulation Biomarkers in Patients with Hyperglycemia and Acute Stroke: Differential Effects of rtPA Administration

A.K. Rao1, N.T. Gentile1, F. Del Carpio-Cano1, H. Reimer1, V. Ramakrishnan2, Q. Pauls2, K. Patel2, W.G. Barsan3, A. Bruno4, iSPOT Investigators
1Lewis Katz School of Medicine at Temple University, Philadelphia, United States, 2Medical University of South Carolina, Charleston, United States, 3University of Michigan, Ann Arbor, United States, 4Medical College of Georgia at Augusta University, Augusta, United States

Main Topic: Diagnostics and OMICs
Category: Biomarkers of Thrombosis & Hemostasis

Background: Circulating tissue factor procoagulant activity (TF-PCA) and coagulation biomarkers are elevated in patients with hyperglycemia (HG) and acute ischemic stroke (AIS). The Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial (iSPOT) was an ancillary study to Stroke Hyperglycemia Insulin Network Effort (SHINE) trial, a multicenter, randomized, controlled trial comparing the efficacy and safety of standard (target blood glucose < 179 mg/dl) to intensive hyperglycemia control (target 80-130 mg/dl) on functional outcome. iSPOT studied changes over 48 hours in coagulation biomarkers and their relationships to neurological outcomes. In non-rtPA patients, there was a greater decline over 48 hours in FVIIa with standard compared with intensive control. Favorable outcome was associated with greater reductions in TF-PCA and FVIII, and increase in FVIIa with intensive treatment.These were not observed in rtPA patients.
Aims: To assess the differential effects of rtPA on coagulation biomarkers.
Methods: Samples were obtained at baseline (after rtPA, if administered) and at 48 hours. Membrane TF-PCA was measured in whole-blood cell lysates by clotting assay using rFVIIa and FX; factors VII, VIIa and VIII were by clotting assays; TAT, D-dimer, TF pathway inhibitor, and plasminogen activator inhibitor-1 were by ELISAs.
Results: 270 patients, (mean age, 65 years) were enrolled. 116 received intravenous rtPA prior to randomization. Baseline biomarker levels were different in rtPA patients compared to non-rtPA patients: TF-PCA (by ~ 30%, p< 0.0015) and plasma FVIII (~ 15%, p=0.037) were lower; FVIIa was higher (~40%, p< 0.0001) as were TFPI, PAI1, TAT, and DD (all p< 0.0001). Changes over 48 hours were also different for some biomarkers (e.g., FVIIa, TF-PCA).
Conclusions: rt-PA induces rapid changes in membrane TF-PCA, FVIII and FVIIa consistent with plasmin-induced cleavage. Effects of glucose control on coagulation biomarkers and their relationship to outcomes are different in rtPA vs non-rtPA patients.
Sponsor: NIH-NINDS U01NS079077, U01NS056975, U01NS059041

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