scholarly journals Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis: comment

2016 ◽  
Vol 14 (11) ◽  
pp. 2315-2316
Author(s):  
H. Wada ◽  
T. Matsumoto ◽  
N. Fujimoto ◽  
H. Imai ◽  
K. Suzuki ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Intravascular Coagulation ◽  
Ischemic Limb ◽  
Shock Liver ◽  
Microvascular Thrombosis

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 SEPSIS-ASSOCIATED DISSEMINATED INTRAVASCULAR COAGULATION AND THROMBOEMBOLIC DISEASE

2010 ◽  
Vol 2 (3) ◽  
pp. e2010024 ◽  
Author(s):  
Nicola Semeraro ◽  
Concetta T. Ammollo ◽  
Fabrizio Semeraro ◽  
Mario Colucci
Keyword(s):  
Tissue Factor ◽  
Disseminated Intravascular Coagulation ◽  
Inflammatory Mediators ◽  
Infectious Agent ◽  
Plasminogen Activator Inhibitor ◽  
Multiple Organ ◽  
Plasminogen Activator Inhibitor 1 ◽  
Inflammatory Reactions ◽  
Intravascular Coagulation ◽  
Microvascular Thrombosis

Sepsis is almost invariably associated with haemostatic abnormalities ranging from subclinical activation of blood coagulation (hypercoagulability), which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), characterized by massive thrombin formation and widespread microvascular thrombosis, partly responsible of the multiple organ dysfunction syndrome (MODS), and subsequent consumption of platelets and coagulation proteins causing, in most severe cases, bleeding manifestations. There is general agreement that the key event underlying this life-threatening sepsis complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. Mechanistically, the latter, together with the micro-organism and its derivatives, causes DIC by 1) up-regulation of procoagulant molecules, primarily tissue factor (TF), which is produced mainly by stimulated monocytes-macrophages and by specific cells in target tissues; 2) impairment of physiological anticoagulant pathways (antithrombin, protein C pathway, tissue factor pathway inhibitor), which is orchestrated mainly by dysfunctional endothelial cells (ECs); and 3) suppression of fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1) by ECs and likely also to thrombin-mediated  activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Notably, clotting enzymes non only lead to microvascular thrombosis but can also elicit cellular responses that amplify the inflammatory reactions. Inflammatory mediators can also cause, directly or indirectly, cell apoptosis or necrosis and recent evidence indicates that products released from dead cells, such as nuclear proteins (particularly extracellular histones), are able to propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenetic mechanisms of DIC and MODS may have important implications for the development of new therapeutic agents that could be potentially useful particularly for the management of severe sepsis.

Disseminated intravascular coagulation in meningococcal sepsis

2003 ◽  
Vol 23 (03) ◽  
pp. 125-130 ◽  
Author(s):  
S. Zeerleder ◽  
R. Zürcher Zenklusen ◽  
C. E. Hack ◽  
W. A. Wuillemin
Keyword(s):  
Organ Dysfunction ◽  
Disseminated Intravascular Coagulation ◽  
Skin Necrosis ◽  
Multiple Organ ◽  
Meningococcal Sepsis ◽  
Multiple Organ Dysfunction ◽  
Intravascular Coagulation ◽  
Therapeutic Concepts ◽  
New Therapeutic Concepts ◽  
Coagulation And Fibrinolysis

SummaryWe report on a man (age: 49 years), who died from severe meningococcal sepsis with disseminated intravascular coagulation (DIC), multiple organ dysfunction syndrome and extended skin necrosis. We discuss in detail the pathophysiology of the activation of coagulation and fibrinolysis during sepsis. The article discusses new therapeutic concepts in the treatment of disseminated intravascular coagulation in meningococcal sepsis, too.

Plasma Thrombin Assay using a Chromogenic Substrate in Disseminated Intravascular Coagulation due to Snake Bite Envenomation

1979 ◽  
Vol 41 (03) ◽  
pp. 544-552 ◽  
Author(s):  
R P Herrmann ◽  
P E Bailey
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Degradation Products ◽  
Snake Bite ◽  
Chromogenic Substrate ◽  
Coagulation Parameters ◽  
Fibrinogen Degradation Products ◽  
Intravascular Coagulation

SummaryUsing the chromogenic substrate, Tos-Gly-Pro-Arg-pNA-HCL (Chromozym TH, Boehringer Mannheim) plasma thrombin was estimated in six cases of envenomation by Australian elapid snakes. All patients manifested findings chracteristic of defibrination due to envenomation by these snakes. Fibrin-fibrinogen degradation products were grossly elevated, as was plasma thrombin in all cases.Following treatment with antivenene, all abnormal coagulation parameters returned rapidly towards normal by 24 hours and plasma thrombin disappeared.

The Glycosaminoglycan of Recombinant Human Soluble Thrombomodulin Affects Antithrombotic Activity in a Rat Model of Tissue Factor-Induced Disseminated Intravascular Coagulation

1992 ◽  
Vol 67 (03) ◽  
pp. 366-370 ◽  
Author(s):  
Katsuhiko Nawa ◽  
Teru Itani ◽  
Mayumi Ono ◽  
Katsu-ichi Sakano ◽  
Yasumasa Marumoto ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Disseminated Intravascular Coagulation ◽  
Rat Model ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Soluble Thrombomodulin ◽  
Intravascular Coagulation ◽  
Platelet Counts ◽  
Recombinant Human Soluble Thrombomodulin

SummaryPrevious studies on recombinant human soluble thrombomodulin (rsTM) from Chinese hamster ovary cells revealed that rsTM was expressed as two proteins that differed functionally in vitro due to the presence (rsTMp) or absence (rsTMa) of chondroitin-4-sulfate. The current study evaluates the in vivo behavior of rsTM in rats and in a rat model of tissue factor-induced disseminated intravascular coagulation (DIC). rsTMp was more potent than rsTMa for prolongation of the activated partial thromboplastin time (APTT) and their in vivo half-lives determined by ELISA were 20 min for rsTMp and 5.0 h for rsTMa. Injection of a tissue factor suspension (5 mg/kg) resulted in DIC as judged by decreased platelet counts and fibrinogen concentrations, prolonged APTT, and increased fibrin and fibrinogen degradation products (FDP) levels. A bolus injection of either rsTM (0.2 mg/kg) 1 min before induction of DIC essentially neutralized effects on platelets, fibrinogen, and FDP levels, and had only a moderate effect on APTT prolongation. The dose of anticoagulant to inhibit the drop in platelet counts by 50% (ED50) was 0.2 mg/kg rsTMa, 0.07 mg/kg rsTMp, and 7 U/ kg heparin. The effect of increasing concentrations of rsTM and heparin on bleeding times were compared in experiments involving incision of the rat tail. Doubling of the bleeding times occurred at 5 mg/kg rsTMa, 3 mg/kg rsTMp or 90 U/kg heparin. These values represent a 25-fold increase over the ED50 for rsTMa, 43-fold for rsTMp and 13-fold for heparin. These results suggest that rsTMp is a potent anticoagulant to inhibit the platelet reduction when injected prior to the induction of DIC in rats.

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