Jing Fei Dong

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..MgSO(4) is critical for maintaining endothelial integrity and regulates ULVWF proteolysis and aggregation under flow conditions. These results provide a new insight into additional mechanisms involved with magnesium therapy...

..To characterize effects of the GP Ib alpha mutation (A156V) on its interaction with von Willebrand factor (vWf) under high fluid shear stress...

..Thrombotic thrombocytopenic purpura exemplifies how von Willebrand factor can be responsible for life-threatening thrombosis. This review summarizes recent progress on ADAMTS13, which prevents this deadly event...

..Once released, these cleaved VWF fragments become inaccessible for the metalloprotease to prevent further cleavage...

..Dissecting the process of ULVWF proteolysis is important for not only understanding the pathophysiology of thrombotic microangiopathies, but also developing more effective means to treat these deadly diseases...

..These results suggest that cleavage of EC-derived ULVWF multimers by ADAMTS-13 is a rapid physiologic process that occurs on endothelial cell surfaces...

..Studies measuring the GP Ibalpha-VWF bond strength of three of the mutants using laser tweezers showed that progressive deletion of the cytoplasmic domain led to progressive weakening of the strength of individual GP Ibalpha-VWF bonds...

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..Finally, the strength of the minimal ULVWF-P-selectin bond was measured to be 7.2 pN. We, therefore, conclude that P-selectin may anchor ULVWF strings to endothelial cells and facilitate their cleavage by ADAMTS13...

..04). In conclusion, platelets in AR subjects demonstrate increased basal sensitivity to submaximal stimulation, which could predict responses to antiplatelet therapy...

..These results suggest that the CUB-1 domain may serve as the docking site for ADAMTS13 to bind ULVWF under flow, a critical step to initiate ULVWF proteolysis...

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..These data demonstrate that intronic SNPs could directly or indirectly influence intersubject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity...

..The wild type and the mutant without the spacer were more active in the presence of plasma, raising the possibility of ADAMTS-13 cofactors in plasma...

..Because His86 is 2 nm away from the region of GP Ibalpha with the largest surface of contact with VWF, the data suggest that the LRRs regulate GP Ibalpha affinity for VWF allosterically...

..In conclusion, large platelets are more active than small platelets and aspirin fails to eliminate these differential activation properties...

..They further suggest that the HPA phenotype may be redox-regulated...

..It also blocked shear-induced platelet aggregation and thrombus formation on immobilised VWF under arterial shear stress. These results demonstrate that T30923 may have therapeutic potentials to regulate the GP Ibalpha-VWF interaction...

..Post-integrin occupancy signaling through MAPK and MLCK after alpha(IIb)beta(3) cross-linking may explain in part the increased adhesive properties of the Pro(33) variant of integrin beta(3)...

..These results suggest that the thiol-disulfide state may serve as an important structural determinant of VWF adhesion activity and can be modified by fluid shear stress...

..This novel recombinant VWF-A2 protein has potential utility as matrix for a rapid clinical measurement of plasma ADAMTS-13 activity...

..We propose that attachment of newly released ULVWF to the endothelial cell surface facilitates its cleavage by ADAMTS-13 by allowing tensile force to be applied to the A2 domain, thereby exposing the ADAMTS-13 cleavage site...

..These findings support the notion that endotoxemia promotes platelet thrombus formation independent of neutrophils and without enhancement of platelet aggregation, via a TLR4-dependent mechanism...

..Therefore, the Hb-VWF interaction may be considered as a therapeutic target for treating thrombotic and vaso-occlusive complications in patients with severe intravascular haemolysis such as those with SCD...

..The deficiency may contribute to the development of thrombocytopenia and ischemic organ failure associated with sepsis...

..These differences indicate an increase in measures of platelet reactivity among Asian Indians and may help elucidate the reported disparity in cardiovascular disease rates between the two ethnic groups...

..These studies have important implications in bleeding and thrombotic disorders, including von Willebrand disease and TTP...

..They also identify an ADAMTS-13 mutant that is resistant to proteolytic degradation, while maintaining a normal VWF-cleaving activity...

..These include clinical studies to improve risk assessment for arterial thrombosis, as well as genetic studies to establish determinants of the hyperreactive platelet phenotype...

..These results illustrate the need to standardize assay protocols in order to obtain consistent measurements. Our studies further optimize sample preparation for microparticle detection...

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..This review also discusses the potential for ADAMTS-13 as a therapeutic drug for thrombotic conditions other than TTP...

..ADAMTS-13 fits in the consensus of the ADAMTS family metalloproteases, but also contains two unique C- terminal CUB domains. Studying mutations in CUB domains could provide insights into the functional role of these domains...

..Although the mechanism for these observed differences are not clear, we hypothesize that in vivo platelet activation in PAD patients may contribute to the differences and will need to be further investigated...

..The aim of this study was to evaluate the relationship between reticulated platelets (RPs), platelet size, and platelet function in patients with stable coronary artery disease (CAD) taking aspirin and clopidogrel...

..Thus, shear stress enhances the adhesive phenotype of the Pro33 cells to multiple physiologic substrates...

..Because von Willebrand factor (vWF) and P-selectin are suggested to mediate LPS-induced platelet-microvessel interactions, we determined whether vWF and P-selectin contribute to microvascular thrombosis in endotoxemia...

..However, outcomes associated with platelet transfusions are poorly characterized. We hypothesized that increased platelet:red blood cells (RBC) ratios would decrease hemorrhagic death and improve survival after massive transfusion (MT)...

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..In summary, we identified a cluster of intronic VWF SNPs that associate with plasma levels of VWF, individually or additively, in a large cohort of healthy subjects...

..ULVWF is also significantly more potent than P-VWF in mediating both shear-induced platelet aggregation and ristocetin-mediated platelet agglutination...

..Therefore, we suggest that the conformational state of ULVWF multimers is more critical than their size for interaction with platelets...

..This process may function as a protective mechanism to prevent in vivo irreversible platelet activation and aggregation under temporary high shear...

..The second mutation involves changing the lysine residues at 253, 258, and 262 to alanine. This also led to distinct changes in VWF binding and abolition of sulfation...

..These findings are in contrast to the functionally similar selectin bonds where some of the mutations have been reported to affect only the dissociation rate...

..The enhanced platelet aggregation parallels with increased whole blood viscosity at these temperatures, suggesting that enhanced mechanical cross-linking may be responsible for the enhanced platelet aggregation...

..We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIbalpha on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding...

..The second leucine-rich repeat was found to be critical for GP Ibalpha to bind vWf and could potentially be used in the development of a novel recombinant anti-thrombotic drugs...

..GrB also cleaves the matrix form of fibrinogen at several sites. These studies suggest extracellular GrB may help control localized coagulation during inflammation...

..These processes may contribute to the evolution of glomerular occlusion by platelet and fibrin thrombi in diarrhea-associated HUS...

..This interaction may be a central mechanism for homing of EPCs to vascular injury sites...

..The findings describe a potential linkage between inflammation and thrombosis that may be of therapeutic importance...

..These results suggest that EPC mobilization following traumatic brain injury may take a different course compared to that associated with body or vascular injuries...

..Autoantibodies recognizing GPV were not seen in the 28 nonthrombocytopenic control RA patients. Thus, GPV seems to be targeted in gold-induced autoimmune thrombocytopenia...

..In a pathologically relevant timeframe, high shear alone is likely to be insufficient in inducing platelet activation and aggregation, but acts synergistically with other stimuli...

..Thus, localization of the GP Ib-IX-V complex within rafts is crucial for both platelet adhesion and postadhesion signaling...

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..Results of the study will help us to understand how defective ULVWF proteolysis contributes to the development of atherothrombosis associated with the syndrome. ..

..Results will help us to dissect this novel mechanism of shear-induced VWF activation. New information will be critical for development new strategies to regulate the role of VWF in hemostasis and thrombosis. ..

..Finally, they allow us to develop a clinical assay to test the activity of the VWF-cleaving protease. Thus, giving the ability to diagnose TTP. This assay will be fast and more physiologically relevant. ..

..Finally, they allow us to develop a clinical assay to test the activity of the VWF-cleaving protease thus giving the ability to diagnose TTP. This assay will be fast and more physiologically relevant. ..

..Finally, they allow us to develop a clinical assay to test the activity of the VWF-cleaving protease thus giving the ability to diagnose TTP. This assay will be fast and more physiologically relevant. ..

..Results will help us to dissect this novel mechanism of shear-induced VWF activation. New information will be critical for development new strategies to regulate the role of VWF in hemostasis and thrombosis. ..