Plasma fibrinolysis is related to the degree of organ dysfunction but not to the concentration of von Willebrand Factor in critically ill patients

Boudjeltia, Karim Zouaoui; Ollieuz, Sandra; Piagnerelli, Michaël; Biston, Patrick; Cauchie, Philippe; Vincent, Jean‐Louis; Brohée, Dany; Vanhaeverbeek, Michel

doi:10.1186/1477-9560-7-10

Cited by 5 publications

(3 citation statements)

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“…Several reports address fibrinolysis in sepsis as well as the potential mechanisms involved [ 16 ]. Boudjeltia et al [ 17 ] demonstrated a decrease in plasma fibrinolysis in sepsis, which was associated with organ dysfunction. As a mechanism, an increase in plasminogen activator inhibitor 1 (PAI-1), which is produced by endothelium and liver, has been demonstrated [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of thromboelastometry with procalcitonin, interleukin 6, and C-reactive protein as diagnostic tests for severe sepsis in critically ill adults

et al. 2010

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IntroductionEstablished biomarkers for the diagnosis of sepsis are procalcitonin, interleukin 6, and C-reactive protein. Although sepsis evokes changes of coagulation and fibrinolysis, it is unknown whether thromboelastometry can detect these alterations. We investigated whether thromboelastometry variables are suitable as biomarkers for severe sepsis in critically ill adults.MethodsIn the observational cohort study, blood samples were obtained from patients on the day of diagnosis of severe sepsis (n = 56) and from postoperative patients (n = 52), and clotting time, clot formation time, maximum clot firmness, alpha angle, and lysis index were measured with thromboelastometry. In addition, procalcitonin, interleukin 6, and C-reactive protein levels were determined. For comparison of biomarkers, receiver operating characteristic (ROC) curves were used, and the optimal cut-offs and odds ratios were calculated.ResultsIn comparison with postoperative controls, patients with sepsis showed an increase in lysis index (97% ± 0.3 versus 92 ± 0.5; P < 0.001; mean and SEM) and procalcitonin (2.5 ng/ml ± 0.5 versus 30.6 ± 8.7; P < 0.001). Clot-formation time, alpha angle, maximum clot firmness, as well as interleukin 6 and C-reactive protein concentrations were not different between groups; clotting time was slightly prolonged. ROC analysis demonstrated an area under the curve (AUC) of 0.901 (CI 0.838 - 0.964) for the lysis index, and 0.756 (CI 0.666 - 0.846) for procalcitonin. The calculated cut-off for the lysis index was > 96.5%, resulting in a sensitivity of 84.2%, and a specificity of 94.2%, with an odds ratio of 85.3 (CI 21.7 - 334.5).ConclusionsThe thromboelastometry lysis index proved to be a more reliable biomarker of severe sepsis in critically ill adults than were procalcitonin, interleukin 6, and C-reactive protein. The results also demonstrate that early involvement of the hemostatic system is a common event in severe sepsis.

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Section: Discussionmentioning

confidence: 99%

Comparison of thromboelastometry with procalcitonin, interleukin 6, and C-reactive protein as diagnostic tests for severe sepsis in critically ill adults

et al. 2010

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“…VWF is often described as "a marker of endothelial activation." [32][33][34] In many cases, this is undoubtedly true, but is only part of the story, especially given the effect of oxidation on preventing the cleavage and enhancing the function of this important adhesive molecule. In sickle cell disease, for example, we recently demonstrated that patients not only have elevated concentrations of VWF antigen in their plasma, 35 but also elevated concentrations of ULVWF, with enhanced activity as detected by increased binding of the llama nanobody AU/VWFa-11, which detects a gain-offunction conformation of the platelet-binding A1 domain.…”

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confidence: 99%

Shear stress–induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region

Chen

Gallagher

et al. 2011

Blood

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VWF is required for platelet adhesion to sites of vessel injury, a process vital for both hemostasis and thrombosis. Enhanced VWF secretion and oxidative stress are both hallmarks of inflammation. We recently showed that the neutrophil oxidant hypochlorous acid (HOCl) inhibits VWF proteolysis by ADAMTS13 by oxidizing VWF methionine 1606 (M1606) in the A2 domain. M1606 was readily oxidized in a substrate peptide, but required urea in multimeric plasma VWF. In the present study, we examined whether shear stress enhances VWF oxidation. With an HOCl-generating system containing myeloperoxidase (MPO) and H 2 O 2 , we found that shear stress accelerated M1606 oxidation, with 56% becoming oxidized within 1 hour. Seven other methionine residues in the VWF A1A2A3 region (containing the sites for platelet and collagen binding and ADAMTS13 cleavage) were variably oxidized, one completely. Oxidized methionines accumulated preferentially in the largest VWF multimers. HOCl-oxidized VWF was hyperfunctional, agglutinating platelets at ristocetin concentrations that induced minimal agglutination using unoxidized VWF and binding more of the nanobody AU/VWFa-11, which detects a gain-offunction conformation of the A1 domain. These findings suggest that neutrophil oxidants will both render newly secreted VWF uncleavable and alter the largest plasma VWF forms such that they become hyperfunctional and resistant to proteolysis by ADAMTS13. (Blood. 2011; 118(19):5283-5291) IntroductionVWF is an enormous plasma glycoprotein synthesized in endothelial cells and megakaryocytes, the primary function of which is to attach platelets to sites of blood vessel injury. 1 VWF also chaperones coagulation factor VIII in plasma, protecting it from degradation and delivering it to the platelet surface, where it participates in blood coagulation. 2 VWF comprises homopolymers of a 2050-amino acid polypeptide synthesized through N-terminal disulfide bonding of C-terminal disulfide-bonded dimers. 3 Each monomer has many domains, including 3 tandem A domains (A1A2A3) containing, respectively, the platelet glycoprotein (GP) Ib-binding site, the cleavage site for ADAMTS13, and a collagen-binding site. 3 The polymers can reach a mass of Ͼ 20 million Da 4 and are either constitutively secreted or stored in granules, the Weibel-Palade bodies of endothelial cells, or the ␣-granules of platelets, from which they are released upon stimulation. 5 Newly released VWF multimers (termed ultra-large VWF or ULVWF) are hyperadhesive for platelets compared with the VWF normally found in plasma, 6 but are rapidly converted to smaller, less reactive plasma forms by cleavage by the metalloprotease ADAMTS13. 1 In addition to its hemostatic roles, VWF is also involved in thrombosis. The most obvious example is when ADAMTS13 fails to process ULVWF, resulting in the sometimes fatal microvascular clotting syndrome, thrombotic thrombocytopenic purpura. 7 VWF has also been implicated in thrombosis associated with disorders such as HELLP syndrome (hemolysis, elevated liver enzymes, a...

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“…99 Euglobulin clot lysis time was prolonged in sepsis patients 75 and correlated positively but weakly with C-reactive protein and SOFA score. 100 The euglobulin clot lysis time is especially time-and work-consuming as it contains an extra precipitation step; furthermore, as the analysis is performed in a specific fraction of plasma, the interactions of other plasma components with clot formation are not taken into account. Thus, this assay is only infrequently used today.…”

Section: Plasma-based Fibrin Formation and Lysis Assaysmentioning

confidence: 99%

Fibrinolytic Alterations in Sepsis: Biomarkers and Future Treatment Targets

Larsen

Hvas

2021

Semin Thromb Hemost

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Sepsis is a life-threatening condition which develops as a dysregulated immune response in the face of infection and which is associated with profound hemostatic disturbances and in the most extreme cases disseminated intravascular coagulation (DIC). In addition, the fibrinolytic system is subject to alterations during infection and sepsis, and impaired fibrinolysis is currently considered a key player in sepsis-related microthrombus formation and DIC. However, we still lack reliable biomarkers to assess fibrinolysis in the clinical setting. Furthermore, drugs targeting the fibrinolytic system have potential value in sepsis patients with severe fibrinolytic disturbances, but these are still being tested in the preclinical stage. The present review provides an overview of key fibrinolytic changes in sepsis, reviews the current literature on potential laboratory markers of altered fibrinolysis in adult sepsis patients, and discusses future perspectives for diagnosis and treatment of fibrinolytic disturbances in sepsis patients.

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Plasma fibrinolysis is related to the degree of organ dysfunction but not to the concentration of von Willebrand Factor in critically ill patients

Cited by 5 publications

References 33 publications

Comparison of thromboelastometry with procalcitonin, interleukin 6, and C-reactive protein as diagnostic tests for severe sepsis in critically ill adults

Comparison of thromboelastometry with procalcitonin, interleukin 6, and C-reactive protein as diagnostic tests for severe sepsis in critically ill adults

Shear stress–induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region

Fibrinolytic Alterations in Sepsis: Biomarkers and Future Treatment Targets

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