Relative Deficiency of Plasma A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeats 13 Activity and Elevation of Human Neutrophil Peptides in Patients with Traumatic Brain Injury

Abstract

Traumatic microvascular injury (tMVI) is a universal endophenotype of traumatic brain injury (TBI) that is responsible for significant neurological morbidity and mortality. The mechanism underlying tMVI is not fully understood. The present study aims to determine plasma levels of von Willebrand factor (VWF), a disintegrin and metalloprotease with thrombospondin type 1 repeats (ADAMTS) 13 activity, and human neutrophil peptides (HNP) 1-3 and to correlate these biomarkers with functional outcomes after moderate-severe TBI. Thirty-one consecutive TBI patients (Glasgow Coma Scale [GCS] range, 3-12) were enrolled into the study between February 2010 and November 2014. Blood samples were collected on 0, 1, 2, 3, and 5 days after admission and analyzed for plasma levels of VWF antigen (VWFAg), collagen-binding activity (VWFAc), ADAMTS13 activity, and HNP1-3 proteins. Mean values of plasma VWFAg, VWFAc, and HNP1-3 were significantly increased in TBI patients compared to those in healthy controls (n = 30). Conversely, mean plasma values of ADAMTS13 activity in TBI patients were significantly decreased during the first 2 days after admission. This resulted in a dramatic reduction in the ratio of ADAMTS13 activity to VWFAg or ADAMTS13 to VWFAc in all 5 post-TBI days. Cluster analysis demonstrated that high median plasma levels of VWFAg and HNP1-3 were observed in the cluster with a high mortality rate. These results demonstrate that a relative deficiency of plasma ADAMTS13 activity, resulting from activation of neutrophils and endothelium, may contribute to the formation of microvascular thrombosis and mortality after moderate-severe TBI.

Keywords: ADAMTS13; coagulopathy; inflammation; traumatic brain injury; von Willebrand factor.

Conflict of interest statement

X.L.Z. is a speaker for Alexion and serves as a consultant for Ablynx and BioMedica.

Figures

FIG. 1.

Plasma VWF antigen, VWF collagen binding activity, and the ratios of VWF activity to antigen in healthy controls and TBI patients. (A and B) Plasma VWF antigen (VWFAg) and collagen-binding activity (VWFAc), respectively, in healthy control and in patients on admission (D0), day 1 (D1), 2 (D2), 3 (D3), and 5 (D5) post-TBI are shown as the medians ±95% confidential intervals. (C) Ratios of plasma VWFAc to VWFAg in patients and healthy controls are also shown as the medians ±95% confidential intervals. Kruskal–Wallis analysis determined the significance of the differences between the control and patient values at various days after TBI. Symbols (*, **, ***, and ****) indicate the p values <0.05, <0.01, <0.005, and <0.0001, respectively. n.s., not significant; TBI, traumatic brain injury; VWF, von Willebrand factor.

FIG. 2.

Plasma ADAMTS13 activity and the ratios of ADAMTS13 to VWF in healthy controls and TBI patients. (A) Plasma ADAMTS13 activities in healthy controls and patients on admission (D0), day 1 (D1), 2 (D2), 3 (D3), and 5 (D5) post-TBI are shown as the medians ±95% confidential intervals. (B and C) Ratios of plasma ADAMTS13 activity to (VWFAg) or (VWFAc), respectively, in healthy controls and TBI patients are shown as the medians ±95% confidential intervals. Symbols (n.s., *, **, ***, and ****) indicate the p values >0.05, <0.05, <0.01, <0.005, and <0.0001, respectively. ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 repeats 13; n.s., not significant; TBI, traumatic brain injury; VWF, von Willebrand factor.

FIG. 3.

Plasma levels of HNP1-3 in healthy controls and TBI patients. Plasma concentrations of HNP1-3 in healthy controls and patients on admission (D0), day 1 (D1), 2 (D2), 3 (D3), and 5 (D5) post-TBI are shown as the medians ±95% confidential intervals. Symbols (*, **, ***, and ****) indicate the p values <0.05, <0.01, <0.005, and <0.0001, respectively. HNP1-3, human neutrophil peptides 1–3; n.s., not significant; TBI, traumatic brain injury; VWF, von Willebrand factor.

FIG. 4.

The diagram depicts how TBI may perturb the ADAMTS13/VWF function, resulting in thrombus formation. When a patient suffers from TBI, acute inflammation results in activation of neutrophils and vascular endothelial cells and release of HNP1-3 and VWF, respectively. Locally released HNP1-3 may bind to VWF, which blocks its proteolysis by ADAMTS13; additionally, increased VWF results in consumption of VWF. Inflammatory cytokines released during the acute inflammation may suppress the synthesis of ADAMTS13 from hepatic stellate cells and endothelial cells while triggering the release of VWF from endothelial cells. The net results are the reduction of ADAMTS13 or decrease in the ratio of ADAMTS13 to VWF. The relative deficiency may cause platelet adhesion and aggregation, and thrombus formation in the brain or elsewhere. ADAMTS13 (or A13), a disintegrin and metalloprotease with thrombospondin type 1 repeats 13; HNP1-3, human neutrophil peptides 1–3; TBI, traumatic brain injury; VWF, von Willebrand factor.