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.

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.

Plasma ADAMTS13 activity and von Willebrand factor antigen and activity in patients with subarachnoid haemorrhage.

Increased von Willebrand factor (VWF) and reduced ADAMTS13 activity are associated with arterial thrombosis. This may also be the culprit mechanism implicated in delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage (SAH). It was our objective to determine plasma VWF and ADAMTS13 in patients with SAH and healthy subjects; and to explore the levels of those markers and outcome after SAH. Forty consecutive patients were enrolled between September 2007 and April 2014 in a pilot study. Plasma samples were collected from SAH patients on post-bleed day (PBD) 0, 1, 3, 5, 7 and 10 and healthy controls. VWF antigen (VWFAg) and VWF activity (VWFAc) were determined by enzyme-linked immunoassay and collagen binding assay, respectively. ADAMTS13 activity was determined by the cleavage of a fluorescent substrate. Univariate descriptive statistics and cluster analyses were performed based on outcomes in the group with SAH only. Mean age of SAH patients was 52.4 years (26-84 years) and 30 (75 %) were women. 12/40 (30 %) had a high Hunt and Hess grade (IV-V) and 25 (62.5 %) were treated with coil embolisation. Plasma VWFAg and VWFAc were significantly higher in SAH patients than those in healthy subjects on each PBD (p<0.0001). Concurrently, plasma ADAMTS13 activity in SAH patients was significantly lower than that in healthy subjects (p<0.0001). Among those with SAH, cluster analysis demonstrated that patients with higher VWFAg and VWFAc and/or lower ADAMTS13 activity might be at risk of increased mortality. In conclusion, the relative deficiency of plasma ADAMTS13 activity in SAH patients may associate with worse outcome.

Elevated Red Cell Distribution Width is Associated with Cerebral Infarction in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Elevated red blood cell distribution width (RDW) has been associated with thrombotic disorders including myocardial infarction, venous thromboembolism, and ischemic stroke, independent of other inflammatory and coagulation biomarkers. The purpose of this study was to determine whether elevated RDW is associated with cerebral infarction and poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In this retrospective single-center cohort of aSAH patients (October 2009-September 2014), elevated RDW was defined as a mean RDW >14.5 % during the first 14 days after aSAH. Outcomes included cerebral infarction (CI) by any mechanism and poor functional outcome, defined as discharge modified Rankin Scale (mRS) >4, indicating severe disability or death. RESULTS: Of 179 patients, 27 % had a high Hunt-Hess grade (IV-V), and 76 % were women. Twenty-four patients (13.4 %) underwent red blood cell (RBC) transfusion and compared to patients with normal RDW, patients with an elevated RDW were at greater odds of RBC transfusion (OR 2.56 [95 % CI, 1.07-6.11], p = 0.035). In univariate analysis, more patients with elevated RDW experienced CI (30.8 vs. 13.7 %, p = 0.017). In the multivariable model, elevated RDW was significantly associated with CI (OR 3.08 [95 % CI, 1.30-7.32], p = 0.011), independent of known confounders including but not limited to age, sex, race, high Hunt-Hess grade, and RBC transfusion. In multivariable analysis, RDW elevation was also associated with poor functional outcome (mRS > 4) at discharge (OR 2.59 [95 % CI, 1.04-629], p = 0.040). CONCLUSIONS: RDW elevation is associated with cerebral infarction and poor outcome after aSAH. Further evaluation of this association is warranted as it may shed light on mechanistic relations between anemia, inflammation, and thrombosis after aSAH.

Thromboelastography Parameter Predicts Outcome After Subarachnoid Hemorrhage: An Exploratory Analysis.

OBJECTIVE: Hypercoagulability after subarachnoid hemorrhage (SAH) is well described and may be platelet mediated. Thromboelastography (TEG) provides a global assessment of coagulation. We sought to determine whether the maximum amplitude (MA) parameter of TEG, a measure of platelet strength and function, is associated with outcome after SAH. METHODS: One hundred ten TEG analyses were performed for patients with moderate-to-severe SAH and compared with 6 healthy age- and sex-matched controls. TEG indices included MA, G value (G), alpha angle, and thrombus generation and were correlated to functional outcomes and laboratory tests including complete blood count, erythrocyte sedimentation rate, high sensitivity C-reactive protein, fibrinogen, and d-dimer, obtained on post-bleed days (PBDs) 1, 3, 5, 7, and 10. RESULTS: MA was significantly elevated compared with controls on PBD 3 (70.0 mm ± 4.5 mm vs. 64.1 mm ± 6.5 mm; P = 0.02), PBD 5 (72.6 mm ± 5.3 mm vs. 64.1 mm ± 6.5 mm; P = 0.003), PBD 7 (73.0 mm ± 5.4 mm vs. 64.1 mm ± 6.5 mm; P = 0.003), and PBD 10 (73.4 mm ± 6.0 mm vs. 64.1 mm ± 6.5 mm; P = 0.005). G was significantly elevated compared with controls on PBD 3 (P = 0.03), PBD 5 (P = 0.01), PBD 7 (P = 0.01), and PBD 10 (P = 0.02). The only biomarker associated with poor outcome was CRP. Multivariate logistic regression demonstrated an association between elevated MA and outcome (odds ratio 39.1, P = 0.006) independent of CRP, age, Hunt Hess grade, and transfusion. CONCLUSIONS: TEG indices are associated with poor outcome after SAH and may identify a platelet-mediated hypercoagulable state. The association between MA and outcome was stronger than that between traditional biomarkers and was independent of age and Hunt Hess grade.

Thromboelastography defines late hypercoagulability after TBI: a pilot study.

INTRODUCTION: Traumatic brain injury (TBI) is associated with a hypercoagulable state, the mechanism and duration of which remain unclear. We sought to determine whether thromboelastography (TEG) analysis could identify the hypercoagulable state after TBI, as defined by elevations in maximal amplitude (MA), thrombus generation (TG), G value (G), and alpha angle (αA). METHODS: Patients with moderate-severe TBI, defined primarily as a GCS <12, admitted between 1/2012 and 8/2013 were eligible for enrolment in this prospective cohort study. TEG profiles were obtained between 0-24 h (T1), 24-48 h (T2), 48-72 h (T3), 72-96 h (T4), and 96-120 h (T5) after admission. Early TEG was defined as 0-48 h, and late TEG was defined as >48 h. RESULTS: Twenty five patients (80 % men) and 7 age- and sex-matched control subjects were studied. Median age was 38 years (range 18-85). Early MA was [63.6 mm (60.5, 67.4)] versus late MA [69.9 mm (65.2,73.9); p = 0.02], early TG was [763.3 mm/min (712.8, 816.2)] versus late TG [835.9 mm/min (791.2,888.3); p = 0.02], and early G was [8.8 d/cm(2) (7.7,10.4)] versus late G [11.6 d/cm(2) (9.4,14.1); p = 0.02]. Study patients had higher MA (p = 0.02), TG (p = 0.03), and G (p = 0.02) values at T5 compared to controls. There was a linear increase per day of MA by 2.6 mm (p = 0.001), TG 31.9 mm/min (p ≤ 0.001), and G value by 1.3 d/cm(2) (p ≤ 0.001) when clustered by pairs in regression analysis. Lower MA values trended toward home discharge (p = 0.08). CONCLUSION: The data suggest a progressive and delayed hypercoagulable state observed days after initial TBI. The hypercoagulable state may reflect excess platelet activity.