scholarly journals Recent advances in disseminated intravascular coagulation: endothelial cells and fibrinolysis in sepsis-induced DIC

2015 ◽  
Vol 3 (1) ◽  
pp. 8 ◽  
Author(s):  
Seiji Madoiwa
Keyword(s):  
Endothelial Cells ◽  
Disseminated Intravascular Coagulation ◽  
Intravascular Coagulation ◽  
Recent Advances

Abstract 659: Inhibition of vWF Secretion with Novel G alpha12 N-terminal alpha-SNAP Binding Domain Peptide Increases Survival in Septic Rodents

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Luiza Rusu ◽  
Martin Schlapfer ◽  
Stephan Offermanns ◽  
Xiaoping Du ◽  
Richard D Minshall
Keyword(s):  
Endothelial Cells ◽  
Disseminated Intravascular Coagulation ◽  
Critical Role ◽  
Cecal Ligation ◽  
Binding Domain ◽  
Critical Determinant ◽  
Intravascular Coagulation ◽  
Microvascular Thrombosis ◽  
G Alpha 12 ◽  
G Protein Alpha Subunit

Severe sepsis is associated with disseminated intravascular coagulation (DIC) as a result of interdependent mechanisms of systemic intravascular inflammation, microvascular thrombosis, and thrombocytopenia. Currently, no drug is available to concomitantly treat these events in sepsis. A poorly understood mechanism and yet critical determinant of sepsis-induced microvascular thrombosis is von Willebrand Factor (vWF) secretion by activated endothelial cells. We recently discovered that heterotrimeric G protein alpha subunit G alpha 12 plays a critical role in basal and evoked vWF secretion by endothelial cells by promoting Weibel-Palade body (WPB) exocytosis. Based on the observed interaction of G alpha 12 with alpaSNAP, a critical member of the exocyst complex required for plasma membrane fusion and exocytosis of WPB contents, we generated a myristoylated Galpha12 N-terminal alphaSNAP Binding Domain (Myr-SBD) blocking peptide and tested the hypothesis that this would selectively and potently inhibit Galpha12 interaction with alphaSNAP and thereby block vWF secretion, limit platelet adhesion and prevent microvascular thrombosis associated with cecal ligation and puncture (CLP) induced sepsis. CLP-induced fulminant sepsis in rats and mice was associated with a 2-3-fold increase in plasma vWF within first 24 hrs. Importantly, we observed reduced plasma vWF levels 24 hrs after CLP surgery in mice given a one-time i.v. bolus (2 μmol/kg) of micellar Myr-SBD at the time of surgery as compared to Myr-scrambled peptide or vehicle only group. Strikingly, this was associated with increased survival without adversely inducing hemorrhage and vascular leakage. Furthermore, and consistent with the hypothesis that Gα12-dependent increase in vWF secretion during sepsis leads to poor outcome, control WT mice succumbed to sepsis in less than 96 hrs whereas 80% of Gα12-/- mice shown previously to have significantly reduced plasma vWF levels survived. Inhibition of Galpha12/alphaSNAP dependent vWF secretion may therefore be an effective strategy for blocking microvascular thrombosis, disseminated intravascular coagulation, and death due to sepsis.

scholarly journals Role of Vascular Endothelial Cells in Disseminated Intravascular Coagulation Induced by Seawater Immersion in a Rat Trauma Model

2017 ◽  
Vol 2017 ◽  
pp. 1-10
Author(s):  
Dajin Zhang ◽  
Jia Qu ◽  
Ming Xiong ◽  
Yuanyuan Qiao ◽  
Dapeng Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Disseminated Intravascular Coagulation ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Intravascular Coagulation ◽  
Pathway Activation ◽  
Lethal Time ◽  
Qpcr Array ◽  
Trauma Model

Trauma complicated by seawater immersion is a complex pathophysiological process with higher mortality than trauma occurring on land. This study investigated the role of vascular endothelial cells (VECs) in trauma development in a seawater environment. An open abdominal injury rat model was used. The rat core temperatures in the seawater (SW, 22°C) group and normal sodium (NS, 22°C) group declined equivalently. No rats died within 12 hours in the control and NS groups. However, the median lethal time of the rats in the SW group was only 260 minutes. Among the 84 genes involved in rat VEC biology, the genes exhibiting the high expression changes (84.62%, 11/13) on a qPCR array were associated with thrombin activity. The plasma activated partial thromboplastin time and fibrinogen and vWF levels decreased, whereas the prothrombin time and TFPI levels increased, indicating intrinsic and extrinsic coagulation pathway activation and inhibition, respectively. The plasma plasminogen, FDP, and D-dimer levels were elevated after 2 hours, and those of uPA, tPA, and PAI-1 exhibited marked changes, indicating disseminated intravascular coagulation (DIC). Additionally, multiorgan haemorrhagia was observed. It indicated that seawater immersion during trauma may increase DIC, elevating mortality. VECs injury might play an essential role in this process.

Disseminated intravascular coagulation in paediatrics

2016 ◽  
Vol 102 (2) ◽  
pp. 187-193 ◽  
Author(s):  
Revathi Rajagopal ◽  
Jecko Thachil ◽  
Paul Monagle
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Diagnostic Tests ◽  
Early Life ◽  
Clinical Manifestations ◽  
Review Article ◽  
Morbidity And Mortality ◽  
Significant Morbidity ◽  
Intravascular Coagulation ◽  
Management Algorithm ◽  
Recent Advances

Disseminated intravascular coagulation (DIC) in paediatrics is associated with significant morbidity and mortality. Although there have been several recent advances in the pathophysiology of DIC, most of these studies were done in adults. Since the haemostatic system is very different in early life and changes dramatically with age, creating a variety of challenges for the clinician, delay in the diagnosis of DIC can happen until overt DIC is evident. In this review article, we report the aetiology, pathophysiology, clinical manifestations, diagnostic tests and a management algorithm to guide paediatricians when treating patients with DIC.

Recombinant Thrombomodulin and Activated Protein C in the Treatment of Disseminated Intravascular Coagulation

1999 ◽  
Vol 82 (08) ◽  
pp. 718-721 ◽  
Author(s):  
Ikuro Maruyama
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Activated Protein C ◽  
Coagulation Cascade ◽  
Regulation System ◽  
Luminal Surface ◽  
Intravascular Coagulation

IntroductionThe blood coagulation cascade is regulated by the luminal surface of the endothelial cell lining.1 Endothelial cells synthesize tissue factor pathway inhibitor (TFPI), which, in part, binds to the cell surface glycosaminoglycans and inhibits factors Xa, VIIa, and tissue factor.2 Endothelial cells also produce and exhibit thrombomodulin (TM) on their luminal surface.3 TM is a kind of thrombin receptor that forms a 1:1 complex with thrombin. In this complex, thrombin activates protein C (PC) more than 1,000-fold more than thrombin alone. TM then loses its procoagulant activities, which include fibrinogen clotting, activation of factors V and VIII, and platelet activation. Thus, TM converts thrombin from a procoagulant protease to an anticoagulant. Pathologic states, such as an endothelial injury or perturbation or continuous rapid coagulation cascade activation, overcomes the endothelial regulating activity, resulting in the development of intravascular coagulation and the induction of disseminated intravascular coagulation (DIC). Theoretically, then, supplementing soluble TM or activated PC (APC) to reconstitute the endothelial coagulation regulation system in the circulation and regulate pathologically-activated blood coagulation could be beneficial. In this chapter, application of soluble TM and APC in the treatment of DIC is reviewed.

scholarly journals Recent advances in pathophysiology of disseminated intravascular coagulation: the role of circulating histones and neutrophil extracellular traps

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2143 ◽  
Author(s):  
Yasir Alhamdi ◽  
Cheng-Hock Toh
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Cell Injury ◽  
Neutrophil Extracellular Traps ◽  
Intravascular Coagulation ◽  
Extracellular Traps ◽  
Complex Interactions ◽  
Recent Advances ◽  
Novel Biomarkers

Disseminated intravascular coagulation (DIC) is an acquired condition that develops as a complication of systemic and sustained cell injury in conditions such as sepsis and trauma. It represents major dysregulation and increased thrombin generationin vivo. A poor understanding and recognition of the complex interactions in the coagulation, fibrinolytic, inflammatory, and innate immune pathways have resulted in continued poor management and high mortality rates in DIC. This review focuses attention on significant recent advances in our understanding of DIC pathophysiology. In particular, circulating histones and neutrophil extracellular traps fulfil established criteria in DIC pathogenesis. Both are damaging to the vasculature and highly relevant to the cross talk between coagulation and inflammation processes, which can culminate in adverse clinical outcomes. These molecules have a strong potential to be novel biomarkers and therapeutic targets in DIC, which is still considered synonymous with ‘death is coming’.

INHIBITOR OF THE FACTOR VIIA-TISSUE FACTOR COMPLEX IS REDUCED IN PATIENTS WITH DISSEMINATED INTRAVASCULAR COAGULATION BUT NOT IN PATIENTS WITH SEVERE HEPATOCELLULAR DISEASE

1987 ◽  
Author(s):  
M S Bajaj ◽  
S V Rana ◽  
R B Wysolmerski ◽  
S P Bajaj
Keyword(s):  
Endothelial Cells ◽  
Cell Line ◽  
Tissue Factor ◽  
Disseminated Intravascular Coagulation ◽  
Factor Viia ◽  
Hepatoma Cell ◽  
Sodium Dodecyl ◽  
Hepatoma Cell Line ◽  
Intravascular Coagulation ◽  
Hepatocellular Disease

Recently, inhibition of factor VIIa-tissue factor activity by a plasma component(s) which requires factor Xa has been described. In this communication, we have developed a specific radiometric assay (which utilizes 3H-factor IX and is sensitive to <1% of plasma level) for this inhibitor and have measured its activity in various disease states. Strikingly, the levels of this inhibitor were found to be normal in patients with advanced chronic hepatocellular disease but low in patients with disseminated intravascular coagulation (DIC). When endotoxin was used to induce DIC in rabbits, the levels of this inhibitor fell by 30 to 90%. Human umbilical vein endothelial cells (HUVE), bovine pulmonary artery endothelial cells, and a human hepatoma cell line (HepG2) all synthesized and secreted this inhibitor whereas a promyelocytic cell line (HL-60) did not and a monocytic cell line (U937) appears to synthesize only small amounts. When ammonium sulfate fractionated human plasma, and serum-free conditioned media from both HUVE and HepG2 cells were electrophoresed on sodium dodecyl sulfate acrylamide gels, two activity peaks corresponding to Mr ≃45,000 and Mr =33,000 were eluted in each case. These observations suggest that (a) the inhibitor is consumed in DIC and that (b) endothelial cells (or other cells) synthesize sufficient amounts of this inhibitor in vivo to compensate for any decreased production by liver cells. Furthermore, the inhibitor levels were found to be normal in patients on chronic warfarin therapy suggesting that the inhibitor is not a vitamin K-dependent protein.

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