Different Kinetics of Serum ADAMTS13, GDF-15, and Neutrophil Gelatinase-Associated Lipocalin in the Early Phase of Aneurysmal Subarachnoid Hemorrhage

Growth differentiation factor 15 (GDF-15), neutrophil gelatinase-associated lipocalin (NGAL), and ADAMTS13 have previously been implicated in the pathophysiological processes of SAH. In the present study, we aim to examine their role in the early period of SAH and their relationship to primary and secondary outcomes. Serum samples were collected at five time periods after SAH (at 24 h (D1), at 72 h (D3), at 120 h (D5), at 168 h (D7) and at 216 h (D9), post-admission) and) were measured by using MILLIPLEX Map Human Cardiovascular Disease (CVD) Magnetic Bead Panel 2. We included 150 patients with SAH and 30 healthy controls. GDF-15 levels at D1 to D9 were significantly associated with a 3-month unfavorable outcome. Based on the ROC analysis, in patients with a good clinical grade at admission (WFNS I-III), the GDF-15 value measured at time point D3 predicted a 3-month unfavorable outcome (cut-off value: 3.97 ng/mL, AUC:0.833, 95%CI: 0.728–0.938, sensitivity:73.7%, specificity:82.6%, p < 0.001). Univariate binary logistic regression analysis showed that serum NGAL levels at D1-D5 and ADAMTS13 levels at D7-D9 were associated with MVS following SAH. GDF-15 is an early indicator of a poor 3-month functional outcome even in patients with mild clinical conditions at admission.

[1]  G. Zipfel,et al.  Early Brain Injury After Subarachnoid Hemorrhage: Incidence and Mechanisms , 2023, Stroke.

[2]  G. Yap,et al.  Emerging Roles of Growth Differentiation Factor 15 in Immunoregulation and Pathogenesis. , 2023, Journal of immunology.

[3]  K. Kario,et al.  Growth Differentiation Factor‐15 Predicts Death and Stroke Event in Outpatients With Cardiovascular Risk Factors: The J‐HOP Study , 2021, Journal of the American Heart Association.

[4]  B. Hoh,et al.  Interleukin-6: Important Mediator of Vasospasm following Subarachnoid Hemorrhage. , 2021, Current neurovascular research.

[5]  B. Hoh,et al.  Pathophysiology of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: A Review , 2021, Journal of the American Heart Association.

[6]  G. Engström,et al.  Circulating Growth Differentiation Factor 15 Levels Are Associated With Risk of Both Intracerebral and Subarachnoid Hemorrhage , 2021, Frontiers in Neurology.

[7]  P. Kochanek,et al.  CSF lipocalin-2 increases early in subarachnoid hemorrhage are associated with neuroinflammation and unfavorable outcome , 2021, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  M. Aibiki,et al.  ADAMTS13 activity decreases in the early phase of trauma associated with coagulopathy and systemic inflammation: a prospective observational study , 2021, Thrombosis Journal.

[9]  D. Levy,et al.  Growth Differentiation Factor 15 and NT‐proBNP as Blood‐Based Markers of Vascular Brain Injury and Dementia , 2020, Journal of the American Heart Association.

[10]  Jwa-Jin Kim,et al.  Association of plasma level of growth differentiation factor-15 and clinical outcome after intraarterial thrombectomy. , 2020, Journal of Stroke & Cerebrovascular Diseases.

[11]  W. Fridman,et al.  Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint , 2020, Frontiers in Immunology.

[12]  Xiaoyu Dong,et al.  Association of serum growth differentiation factor 15 level with acute ischemic stroke in a Chinese population , 2019, The International journal of neuroscience.

[13]  M. Pisani,et al.  GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance , 2019, Cell.

[14]  M. Evans,et al.  CRP Stimulates GDF15 Expression in Endothelial Cells through p53 , 2018, Mediators of inflammation.

[15]  Søren B. Padkjær,et al.  GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand , 2017, Nature Medicine.

[16]  Uzay Erdogan,et al.  Measuring serum matrix metalloproteinase-9 levels in peripheral blood after subarachnoid hemorrhage to predict cerebral vasospasm , 2016, SpringerPlus.

[17]  R. Keep,et al.  Role of lipocalin 2 in intraventricular haemoglobin-induced brain injury , 2016, Stroke and Vascular Neurology.

[18]  R. Keep,et al.  White Matter Injury After Subarachnoid Hemorrhage: Role of Blood–Brain Barrier Disruption and Matrix Metalloproteinase-9 , 2015, Stroke.

[19]  C. DeCarli,et al.  Associations of Circulating Growth Differentiation Factor-15 and ST2 Concentrations With Subclinical Vascular Brain Injury and Incident Stroke , 2015, Stroke.

[20]  S. Mayer,et al.  Subarachnoid hemorrhage: who dies, and why? , 2015, Critical Care.

[21]  S. Banerjee,et al.  GDF-15 as a Target and Biomarker for Diabetes and Cardiovascular Diseases: A Translational Prospective , 2015, Journal of diabetes research.

[22]  R. Keep,et al.  Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  G. Murray,et al.  Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial , 2014, The Lancet Neurology.

[24]  C. Bai,et al.  Increased serum levels of lipocalin-1 and -2 in patients with stable chronic obstructive pulmonary disease , 2014, International journal of chronic obstructive pulmonary disease.

[25]  Myungwon Jin,et al.  Lipocalin-2 Deficiency Attenuates Neuroinflammation and Brain Injury after Transient Middle Cerebral Artery Occlusion in Mice , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  E. Keller,et al.  Effect of ADAMTS‐13 on cerebrovascular microthrombosis and neuronal injury after experimental subarachnoid hemorrhage , 2014, Journal of thrombosis and haemostasis : JTH.

[27]  P. Bourin,et al.  Concise Review: Growth Differentiation Factor 15 in Pathology: A Clinical Role? , 2013, Stem cells translational medicine.

[28]  Daniel R Kramer,et al.  Cerebral Vasospasm in Traumatic Brain Injury , 2013, Neurology research international.

[29]  M. Bottai,et al.  Association of plasma neutrophil gelatinase-associated lipocalin (NGAL) with sepsis and acute kidney dysfunction , 2013, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[30]  R. Keep,et al.  Role of iron in brain lipocalin 2 upregulation after intracerebral hemorrhage in rats , 2013, Brain Research.

[31]  W. Mack,et al.  Matrix Metalloproteinases in Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage , 2013, Neurology research international.

[32]  Gang Chen,et al.  Potential contribution of matrix metalloproteinase-9 (mmp-9) to cerebral vasospasm after experimental subarachnoid hemorrhage in rats. , 2012, Annals of clinical and laboratory science.

[33]  C. Feistritzer,et al.  Lipocalin‐2 ameliorates granulocyte functionality , 2012, European journal of immunology.

[34]  D. Geschwind,et al.  Lipocalin 2 is present in the EAE brain and is modulated by natalizumab , 2012, Front. Cell. Neurosci..

[35]  A. Algra,et al.  Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial , 2012, The Lancet.

[36]  R. Wachter,et al.  Growth-differentiation factor-15 and functional outcome after acute ischemic stroke , 2012, Journal of Neurology.

[37]  R. Lichtinghagen,et al.  Growth Differentiation Factor 15 Plasma Levels and Outcome after Ischemic Stroke , 2011, Cerebrovascular Diseases.

[38]  A. Gaggar,et al.  A Self-Propagating Matrix Metalloprotease-9 (MMP-9) Dependent Cycle of Chronic Neutrophilic Inflammation , 2011, PloS one.

[39]  John H. Zhang,et al.  Metamorphosis of Subarachnoid Hemorrhage Research: from Delayed Vasospasm to Early Brain Injury , 2010, Molecular Neurobiology.

[40]  V. Friedrich,et al.  Luminal platelet aggregates in functional deficits in parenchymal vessels after subarachnoid hemorrhage , 2010, Brain Research.

[41]  Joseph P Broderick,et al.  Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies: Proposal of a Multidisciplinary Research Group , 2010, Stroke.

[42]  J. Mandrekar Receiver operating characteristic curve in diagnostic test assessment. , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[43]  M. Vermeulen,et al.  Reduced ADAMTS13 Activity in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[44]  Ale Algra,et al.  Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis , 2009, The Lancet Neurology.

[45]  G. Cantore,et al.  Tumor Necrosis Factor-&agr; Mediates Hemolysis-Induced Vasoconstriction and the Cerebral Vasospasm Evoked by Subarachnoid Hemorrhage , 2009, Hypertension.

[46]  A. Chauhan,et al.  Abbreviations used: AD- , 2022 .

[47]  J. Sadler Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. , 2008, Blood.

[48]  Tetsuro Ago,et al.  GDF15, a Cardioprotective TGF-β Superfamily Protein , 2006 .