Inhibitors of Inorganic Polyphosphate and Nucleic Acids Attenuate in vitro Thrombin Generation in Plasma from Trauma Patients
Author:
MacArthur Taleen A.1, Goswami Julie, Navarro Sergio M.1, Vappala Sreeparna2, La Chanel C.3, Yudin Nikoli1, Zietlow John1, Smith Stephanie A.4, Morrissey James H.4, Spears Grant M.5, Bailey Kent R.5, Dong Jing-Fei6, Kozar Rosemary A.7, Kizhakkedathu Jayachandran N.2, Park Myung S.1
Affiliation:
1. Division of Trauma, Critical Care, and General Surgery, Department of Surgery, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905 2. Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia, Vancouver, BC, V6T 2B5 3. Department of Chemistry, University of British Columbia, Vancouver, BC, V6T 2B5 4. Department of Biological Chemistry, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109 5. Clinical Statistics and Biostatistics, Department of Health Sciences Research, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905 6. Division of Hematology, University of Washington School of Medicine, Bloodworks Research Institute, 1551 Eastlake Avenue E, Seattle, WA 98102 7. Shock Trauma Center, University of Maryland School of Medicine, 22 S Greene St., Baltimore, MD 21201
Abstract
ABSTRACT
Background
Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8) and universal heparin reversal agent 8 (UHRA-8).
Methods
Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/- MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, p < 0.05 significant.
Results
Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], p < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], p = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], p = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], p < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], p < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all p < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, p < 0.001).
Conclusion
PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.
Publisher
Ovid Technologies (Wolters Kluwer Health)
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