scholarly journals Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling

2019 ◽  
Vol 3 (16) ◽  
pp. 2436-2447 ◽  
Author(s):  
Narcis Ioan Popescu ◽  
Alanson Girton ◽  
Tarea Burgett ◽  
Kessa Lovelady ◽  
K. Mark Coggeshall
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Bacterial Infections ◽  
Cytokine Signaling ◽  
Study Cohort ◽  
Immune Recognition ◽  
Autocrine Signaling ◽  
Primate Model ◽  
Intravascular Coagulation ◽  
Amplification Loop ◽  
Factor Α

Abstract Disseminated intravascular coagulation is a frequent manifestation during bacterial infections and is associated with negative clinical outcomes. Imbalanced expression and activity of intravascular tissue factor (TF) is central to the development of infection-associated coagulopathies. Recently, we showed that anthrax peptidoglycan (PGN) induces disseminated intravascular coagulation in a nonhuman primate model of anthrax sepsis. We hypothesized that immune recognition of PGN by monocytes is critical for procoagulant responses to PGN and investigated whether and how PGN induces TF expression in primary human monocytes. We found that PGN induced monocyte TF expression in a large cohort of healthy volunteers similar to lipopolysaccharide stimulation. Both immune and procoagulant responses to PGN involve intracellular recognition after PGN internalization, as well as surface signaling through immune Fcγ receptors (FcγRs). In line with our hypothesis, blocking immune receptor function, both signaling and FcγR-mediated phagocytosis, significantly reduced but did not abolish PGN-induced monocyte TF expression, indicating that FcγR-independent internalization contributes to intracellular recognition of PGN. Conversely, when intracellular PGN recognition is abolished, TF expression was sensitive to inhibitors of FcγR signaling, indicating that surface engagement of monocyte immune receptors can promote TF expression. The primary procoagulant responses to PGN were further amplified by proinflammatory cytokines through paracrine and autocrine signaling. Despite intersubject variability in the study cohort, dual neutralization of tumor necrosis factor-α and interleukin-1β provided the most robust inhibition of the procoagulant amplification loop and may prove useful for reducing coagulopathies in gram-positive sepsis.

Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C–deficient mice

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4823-4827 ◽  
Author(s):  
Marcel Levi ◽  
Janine Dörffler-Melly ◽  
Pieter Reitsma ◽  
Harry Büller ◽  
Sandrine Florquin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Activated Protein C ◽  
Intravascular Coagulation ◽  
Cytokine Activation ◽  
Tnf Α ◽  
Single Allele ◽  
Factor Α ◽  
Heterozygous Deficiency

Abstract In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/–) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/–mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/– mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/– mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.

scholarly journals Subacute Disseminated Intravascular Coagulation in a Patient with Liver Metastases of a Renal Cell Carcinoma

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
L. C. van der Wekken ◽  
R. J. L. F. Loffeld
Keyword(s):  
Renal Cell Carcinoma ◽  
Case Report ◽  
Cell Carcinoma ◽  
Disseminated Intravascular Coagulation ◽  
Renal Cell ◽  
Bacterial Infections ◽  
Hematological Malignancies ◽  
The Other ◽  
Intravascular Coagulation ◽  
Acute Form

Disseminated intravascular coagulation (DIC) is a syndrome characterised by simultaneous bleeding and thromboembolic formation. Its acute form is associated with severe bacterial infections and hematological malignancies. It has a fulminant presentation with prolonged bleeding times and diffuse thrombosis. On the other hand, chronic DIC can be asymptomatic for long periods of time and can be seen in patients with disseminated malignancies. This case report describes a patient who developed DIC within one week and bled profusely from venipuncture wounds. An underlying hepatogenic metastasised renal cell carcinoma appeared to be the cause. This is an uncommon and diagnostically challenging presentation.

scholarly journals Markers of Inflammation and Infection in Sepsis and Disseminated Intravascular Coagulation

2019 ◽  
Vol 25 ◽  
pp. 107602961984333 ◽  
Author(s):  
Priya Patel ◽  
Amanda Walborn ◽  
Matthew Rondina ◽  
Jawed Fareed ◽  
Debra Hoppensteadt
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Severity Of Illness ◽  
Diagnostic Algorithm ◽  
Fold Increase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intravascular Coagulation ◽  
Chromogenic Assay ◽  
Markers Of Inflammation ◽  
Positive Correlations ◽  
Factor Α

Sepsis is a severe systemic inflammatory response to infection that manifests with widespread inflammation as well as endothelial and coagulation dysfunction that may lead to hypotension, organ failure, shock, and death. Disseminated intravascular coagulation (DIC) is a complication of sepsis involving systemic activation of the fibrinolytic and coagulation pathways that can lead to multi-organ dysfunction, thrombosis, and bleeding, with a 2-fold increase in mortality. This study demonstrates the diagnostic and prognostic value of profiling various biomarkers of inflammation and infection in patients with sepsis-associated DIC to assess the severity of illness. Deidentified samples were obtained from adult patients with sepsis and suspected DIC. Platelet count, prothrombin time, D-dimer, and fibrinogen levels were used to assign International Society of Thrombosis and Hemostasis DIC scores to plasma samples from 103 patients with sepsis and suspected DIC. Using commercially available enzyme-linked immunosorbent assay, chromogenic assay, and RANDOX Biochip methods, levels of procalcitonin (PCT), extracellular nucleosomes, interleukin (IL) 6, IL-8, IL-10, and tumor necrosis factor α (TNFα) were measured in patients with sepsis and DIC and compared to levels in healthy individuals. Elevated levels of PCT, IL-6, IL-8, IL-10, and TNFα were observed in most patients with sepsis and DIC. Additionally, the levels of these markers show significant positive correlations with each other and with DIC score. Currently, no single biomarker can effectively diagnose DIC in patients with sepsis. This study lays the groundwork for the development of a diagnostic algorithm using several markers of inflammation and infection and DIC score as parameters in assessing severity of sepsis-associated coagulopathy in a clinical setting.

Thrombomodulin Alfa Treatment For Disseminated Intravascular Coagulation In Acute Promyelocytic Leukemia: A Retrospective Analysis Of The Open-Label, Multicenter Study Cohort

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2391-2391
Author(s):  
Tadashi Matsushita ◽  
Jyunichi Watanabe ◽  
Goichi Honda ◽  
Jun Mimuro ◽  
Hoyu Takahashi ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Disseminated Intravascular Coagulation ◽  
Promyelocytic Leukemia ◽  
Surveillance Study ◽  
Study Cohort ◽  
Newly Diagnosed ◽  
Open Label ◽  
Intravascular Coagulation ◽  
Post Marketing Surveillance ◽  
Post Marketing

Abstract Background Patients with acute promyelocytic leukemia (APL) patients present disseminated intravascular coagulation (DIC) that can result in life-threatening hemorrhagic complications. In 2008, the anticoagulant thrombomodulin alfa (TM-α, recombinant human soluble thrombomodulin) was approved for the treatment of DIC in Japan. After commercial launch, only small case series have been described in APL patients, and data from larger patients cohort are awaited. We accessed the clinical safety and beneficial effects of TM-α treatment in DIC patients with APL, by evaluating data on the open-label, multicenter, post-marketing surveillance study cohort. Patients and Methods A retrospective evaluation was carried out on a cohort of 172 patients with APL from the open-label, multicenter, post-marketing surveillance study of TM-α in Japan. Of all 172 patients, 31 were relapse/refractory APL patients and 141 were newly diagnosed. The newly diagnosed APL patients were generally received all-trans retinoic acid (ATRA) and anthracycline-containing induction therapy followed by consolidation therapy as previously reported by the Japan Adult Leukemia Study Group (Yanada et al, Eur. J. Haematol. 2007). The relapse/refractory APL patients were received arsenic trioxide, tamibarotene, and/or gemtuzumab ozogamicin. Early death (death within 30 days from the start of antileukemic treatment), severe hemorrhagic events, and the improvement of coagulopathy were analyzed. Results The study population consisted of 97 males and 75 females, with a median age of 58 (range 10 - 88). TM-α was administration by 380 ± 52.5 U/kg/day and the duration of dosing was 7.0 ± 6.3 days. In most patients (81 %), TM-α was started on or before the start of antileukemic treatment. Within the first 30 days, 12 patients (7 %) had severe hemorrhage and there were 24 (14 %) early deaths. Six of those (3.5% of 172 patients) were due to hemorrhage. TM-α treatment rapidly and significantly improved coagulopathy regardless of concomitant ATRA treatment (Table 1). Conclusions Although anticoagulation therapy during APL chemotherapy may induce severe hemorrhagic complication, our findings suggest that supportive care with TM-α ameliorates coagulopathy and reduces the risk of hemorrhagic early deaths in patients with APL. Disclosures: Watanabe: Asahi Kasei Pharma Corporation: Employment. Honda:Asahi Kasei Pharma Corporation: Employment.

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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