93 results match your criteria: "Bloodworks Research Institute[Affiliation]"
In this issue of , Kohli et al report a noncoagulation role of thrombomodulin (TM) expressed on trophoblast cells in maintaining placental growth and healthy embryogenesis. They show that (1) the inflammatory cytokine interleukin-1β (IL-1β) suppressed TM synthesis from trophoblast stem cells in culture and induced the ectodomain shedding of TM from these cells; (2) the TM shedding was also induced in pregnant C57BL/6J mice infused with endothelial cell-derived extracellular vesicles (eEVs), which cause placental inflammation; (3) the IL-1β receptor antagonist anakinra prevented TM shedding in these eEV-infused pregnant mice and reduced placental abnormalities in these mice; (4) the soluble TM that resists proteolysis and oxidation (solulin) reduced TM shedding in the pregnant C57BL/6J mice infused with eEVs and prevented fetal death, intrauterine growth restriction, placental inflammation, and growth suppression; and (5) the protection offered by solulin was reproduced in transgenic mice with enhanced expression of TM in embryonic tissue, including trophoblasts. The key findings from the pregnant mice were reproduced in well-controlled in vitro experiments using trophoblastic stem cells in culture and further validated by studying placentas collected from patients with preeclampsia.
View Article and Find Full Text PDFShock
September 2021
Division of Trauma, Critical Care, and General Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota.
Background: Damage-associated molecular patterns (DAMPs) stimulate endothelial syndecan-1 shedding and neutrophil extracellular traps (NET) formation. The role of NETs in trauma and trauma-induced hypercoagulability is unknown. We hypothesized that trauma patients with accelerated thrombin generation would have increased NETosis and syndecan-1 levels.
View Article and Find Full Text PDFTraumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy.
View Article and Find Full Text PDFThromb Res
February 2021
Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX, United States of America; Baylor College of Medicine, Houston, TX, United States of America.
Traumatic brain injury (TBI) continues to be a major healthcare problem and there is much to be explored regarding the secondary pathobiology to identify early predictive markers and new therapeutic targets. While documented changes in thrombosis and inflammation in major trauma have been well described, growing evidence suggests that isolated TBI also results in systemic alterations in these mechanisms. Here, we review recent experimental and clinical findings that demonstrate how blood-brain barrier dysfunction, systemic immune response, inflammation, platelet activation, and thrombosis contribute significantly to the pathogenesis of TBI.
View Article and Find Full Text PDFJ Am Soc Echocardiogr
April 2021
Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon. Electronic address:
Background: Echocardiographic molecular imaging techniques are beginning to be applied to evaluate preclinical efficacy of new drugs. In a large clinical trial, anti-interleukin-1β (IL-1β) immunotherapy reduced atherosclerotic events, yet treatment effects were modest, and the mechanisms of action were not fully elucidated. We tested the hypothesis that echocardiographic molecular imaging can assess changes in vascular thromboinflammatory status in response to anti-IL-1β therapy.
View Article and Find Full Text PDFAntioxidants (Basel)
November 2020
Bloodworks Research Institute, Seattle, WA 98102, USA.
Preeclampsia (PE) is a common obstetric disease characterized by hypertension, proteinuria, and multi-system dysfunction. It endangers both maternal and fetal health. Although hemostasis is critical for preventing bleeding complications during pregnancy, delivery, and post-partum, PE patients often develop a severe prothrombotic state, potentially resulting in life-threatening thrombosis and thromboembolism.
View Article and Find Full Text PDFAcute traumatic coagulopathy is a complex phenomenon following injury and a main contributor to hemorrhage. It remains a leading cause of preventable death in trauma patients. This phenomenon is initiated by systemic injury to the vascular endothelium that is exacerbated by hypoperfusion, acidosis, and hypothermia and leads to systemic activation of the coagulation cascades and resultant coagulopathy.
View Article and Find Full Text PDFJACC Basic Transl Sci
October 2020
Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon.
This study used in vivo molecular imaging to characterize endotheliall activation attributable to von Willebrand factor (vWF)-mediated platelet adhesion in atherosclerosis. In atherosclerotic mice lacking the low-density lipoprotein receptor on Western diet, the additional genetic deletion of the ADAMTS13, which cleaves endothelial-associated vWF, produced greater aortic molecular imaging signal for not only vWF and platelets, but also for endothelial adhesion molecules VCAM1 and P-selectin, larger plaque size, and lower aortic distensibility. Sustained ADAMTS13 therapy reduced signal for all 4 molecular targets and plaque size.
View Article and Find Full Text PDFBJOG
May 2021
Department of Obstetrics and Gynaecology, Tianjin Medical University General Hospital and Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, China.
Objective: Pre-eclampsia (PE) is a pregnancy-associated condition initiated by placental factors. We have demonstrated that placental extracellular vesicles (pcEVs) cause hypertension and proteinuria in pregnant and non-pregnant mice.
Study Design: An observational study with both case-control and longitudinal designs.
J Thromb Haemost
December 2020
Bloodworks Research Institute, Seattle, WA, USA.
Traumatic brain injury (TBI) is a leading cause of death and disability. Patients with isolated TBI lose a limited amount of blood to primary injury, but they often develop secondary coagulopathy, resulting in delayed or recurrent intracranial and intracerebral hematoma. TBI-induced coagulopathy is closely associated with poor outcomes for these patients, including death.
View Article and Find Full Text PDFJ Clin Invest
August 2020
Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA-PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress.
View Article and Find Full Text PDFHaematologica
June 2020
Department of Neurosurgery, Tianjin Medical University General Hospital and Tianjin Neurological Institute, Tianjin, China
Preeclampsia is a pregnancy-induced condition that impairs the mother's health and results in pregnancy termination or premature delivery. Elevated levels of placenta-derived extracellular vesicles (pcEV) in the circulation have been consistently associated with preeclampsia, but whether these vesicles induce preeclampsia or are the product of preeclampsia is not known. Guided by a small cohort study of preeclamptic patients, we examined the impact of pcEV on the pathogenesis of preeclampsia in mouse models.
View Article and Find Full Text PDFJ Thromb Haemost
September 2019
Bloodworks Research Institute, Seattle, Washington.
Objective: Clinical and laboratory studies have demonstrated that platelets become hyperactive and prothrombotic in conditions of inflammation. We have previously shown that the proinflammatory cytokine interleukin (IL)-6 forms a complex with soluble IL-6 receptor α (sIL-6Rα) to prime platelets for activation by subthreshold concentrations of collagen. Upon being stimulated with collagen, the transcription factor signal transducer and activator of transcription (STAT) 3 in platelets is phosphorylated and dimerized to act as a protein scaffold to facilitate the catalytic action between the kinase Syk and the substrate phospholipase Cγ2 (PLCγ2) in collagen-induced signaling.
View Article and Find Full Text PDFIn this issue of , Muia et al and Zhu et al, using complementary approaches, provide important insights into the structure and function of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin-1 repeats, member 13), identifying critical structural features and interactions that allosterically regulate its proteolytic activity on von Willebrand factor (VWF).
View Article and Find Full Text PDFTransfusion
April 2019
Bloodworks Research Institute, Seattle, Washington.
Traumatic brain injury (TBI)-induced coagulopathy has long been recognized as a significant risk for poor outcomes in patients with TBI, but its pathogenesis remains poorly understood. As a result, current treatment options for the condition are limited and ineffective. The lack of information is most significant for the impact of blood transfusions on patients with isolated TBI and in the absence of confounding influences from trauma to the body and limbs and the resultant hemorrhagic shock.
View Article and Find Full Text PDFHaematologica
January 2020
BloodWorks Research Institute, Seattle, WA, USA
Coagulopathy often develops soon after acute traumatic brain injury and its cause remains poorly understood. We have shown that injured brains release cellular microvesicles that disrupt the endothelial barrier and induce consumptive coagulopathy. Morphologically intact extracellular mitochondria accounted for 55.
View Article and Find Full Text PDFIn this issue of , Dunne et al report that platelets from type O subjects bound poorly to von Willebrand factor (VWF) of mixed ABOs under arterial shear stress, as compared with those from non-O subjects. The binding difference between O and non-O platelets was defined by several key biophysical measurements that govern the platelet reactivity toward VWF under physical forces. Platelets contain 2 receptors that bind VWF: the glycoprotein Ib (GPIb)-IX-V complex and the integrin αIIbβ3, but this ABO effect is likely on the GPIb-VWF interaction, which is regulated by fluid shear stress and exhibits “catch bond” characteristics.
View Article and Find Full Text PDFInt J Med Sci
June 2019
Department of Medicine, University of Washington, Seattle, WA USA.
Endothelial activation caused by HIV-1 infection leads to release of von Willebrand factor (VWF), which enters the circulation or attaches to vessel walls and self-assembles into strings and fibers, enabling platelet adhesion; this adhesive activity is regulated by the VWF-cleaving protease ADAMTS13. Our objective was to assess VWF adhesive activity and ADAMTS13 protease activity in HIV-1 infection. We measured levels of VWF antigen, VWF activation factor (a measure of adhesive activity), ADAMTS13 antigen, ADAMTS13 activity, and apolipoprotein A1 (which interferes with VWF self-association) in serum samples from HIV-1-infected men whose infections were acute (n=10), chronic untreated (n=10), or chronic treated (n=10), compared to uninfected controls (n=10).
View Article and Find Full Text PDFDNA Cell Biol
April 2019
1 Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Collagen is a major component of the subendothelial matrix and participates in bleeding arrest by activating and aggregating platelets at the site of vascular injury. The most common type I collagen exists in both soluble and fibrillar forms, but structural exchangeability between the two forms is currently unknown. Using atomic force microscopy, we show that type I collagen switches between soluble and fibrillar forms in a pH-dependent and ion-independent manner.
View Article and Find Full Text PDFSci Rep
January 2019
Bloodworks Research Institute, Seattle, Washington, USA.
We developed a high-throughput mass spectrometry-based method to simultaneously quantify numerous small-molecule thiols and disulfides in blood plasma. Application of this assay to analyze plasma from patients with known oxidative stress (sickle cell disease and sepsis) and from a patient with sickle cell disease treated with the antioxidant N-acetylcysteine suggests that cysteine disulfides, in particular protein-bound cysteine, serve as sensitive plasma biomarkers for the extent of oxidative stress and effectiveness of antioxidant treatment.
View Article and Find Full Text PDFBlood Res
December 2018
Department of Hematology, Istanbul School of Medicine, Istanbul, Turkey.
Background: Bone marrow involvement (BMI) affects the lymphoma stage, survival, and treatment. Bone marrow biopsy (BMB) and fluorodeoxyglucose (FDG) positron emission tomography- computed tomography (PET/CT) are useful techniques to detect BMI. Both have advantages and disadvantages.
View Article and Find Full Text PDFBlood Res
September 2018
Department of Hematology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.
JAMA Neurol
November 2018
Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education in China and Tianjin, Tianjin Neurological Institute, Tianjin, China.
Importance: Chronic subdural hematoma (CSDH) is a trauma-associated condition commonly found in elderly patients. Surgery is currently the treatment of choice, but it carries a significant risk of recurrence and death. Nonsurgical treatments remain limited and ineffective.
View Article and Find Full Text PDFBackground: Antiphospholipid syndrome (APS) is characterized by recurrent thromboembolic events in the setting of pathologic autoantibodies, some of which are directed to β2-Glycoprotein 1 (β2GPI). The mechanisms of thrombosis in APS appear to be multifactorial and likely include a component of endothelial activation. Among other things, activated endothelium secretes von Willebrand factor, a hemostatic protein that in excess can increase the risk of thrombosis.
View Article and Find Full Text PDFBlood
September 2018
Department of Neurosurgery, Tianjin Institute of Neurology, Tianjin, China.
von Willebrand factor (VWF) is an adhesive ligand, and its activity is proteolytically regulated by the metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat 13). An elevated level of plasma VWF has been widely considered a marker for endothelial cell activation in trauma and inflammation, but its causal role in these pathological conditions remains poorly defined. Using a fluid percussion injury mouse model, we demonstrated that VWF released during acute traumatic brain injury (TBI) was activated and became microvesicle-bound.
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