scholarly journals Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD

Blood ◽  
2017 ◽  
Vol 130 (10) ◽  
pp. 1259-1266 ◽  
Author(s):  
Nicholas J. Gloude ◽  
Pooja Khandelwal ◽  
Nathan Luebbering ◽  
Dana T. Lounder ◽  
Sonata Jodele ◽  
...  
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Endothelial Injury ◽  
Neutrophil Recovery ◽  
Key Points

Key Points dsDNA production peaks 14 days after HSCT, likely a result of IL-8–driven neutrophil recovery. dsDNA production may serve as a mechanistic link between endothelial injury, TA-TMA, and GVHD.

scholarly journals Endothelial Injury, Neutrophil Extracellular Traps, and Complement Activation in Thrombotic Microangiopathy and GVHD

2017 ◽  
Vol 23 (3) ◽  
pp. S232-S233
Author(s):  
Nicholas J. Gloude ◽  
Sonata Jodele ◽  
Nathan Luebbering ◽  
Kelly E. Lake ◽  
Adam Lane ◽  
...  
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Neutrophil Extracellular Traps ◽  
Endothelial Injury ◽  
Extracellular Traps

scholarly journals Thrombotic microvascular injury is not mediated by thrombotic microangiopathy despite systemic complement activation in Covid-19 patients

2020 ◽  
Author(s):  
Adrien De Voeght ◽  
Doriane Calmes ◽  
Floran Beck ◽  
Jean-Baptiste Sylvestre ◽  
Philippe Delvenne ◽  
...  
Keyword(s):  
Lung Injury ◽  
Hemolytic Anemia ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
List Type ◽  
Histological Evidence ◽  
Microvascular Injury ◽  
Key Points ◽  
Moderate Elevation ◽  
D Dimer

AbstractHypoxemia and coagulopathy are common in severe symptomatic patients of coronavirus disease 2019 (COVID-19). Histological evidence shows implication of complement activation and lung injury. We research sign of complement activation and presence of thrombotic microangiopathy in 8 severe patients. Six of them presented moderate elevation of final pathway of complement – sC5b-9 (median value : 350 ng/mL [IQR : 300,5 - 514,95 ng/mL]). Two patients have been autopsied and presence of thrombotic microvascular injury have been found. Interestingly, none the 8 patients had signs of mechanical hemolytic anemia (median value of hemoglobin : 10,5 gr/dL[IQR : 8,1 - 11,9], median value of haptoglobuline 4,49 [IQR 3,55-4,66], none of the patients has schistocyte) and thrombocytopenia (median value: 348000/mL [IQR : 266 000 - 401 000). Finally, all 8 patients had elevated d-dimer (median value : 2226 µgr/l [IQR : 1493 – 2362]) and soluble fibrin monomer complex (median value : 8.5 mg/mL, IQR[<6 – 10.6]). In summary, this study show moderate activation of complement and coagulation with presence of thrombotic microvascular injury in patients with severe COVID-19 without evidence of systemic thrombotic microangiopathy.Key pointsSevere covid-19 patients show moderate elevation of final activation of complementNo sign of Thrombotic microangiopathy is found in severe covid-19 patients

scholarly journals Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

Blood ◽  
2014 ◽  
Vol 124 (4) ◽  
pp. 645-653 ◽  
Author(s):  
Sonata Jodele ◽  
Stella M. Davies ◽  
Adam Lane ◽  
Jane Khoury ◽  
Christopher Dandoy ◽  
...  
Keyword(s):  
Young Adults ◽  
High Risk ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Clinical Interventions ◽  
Poor Outcome ◽  
Risk Criteria ◽  
Key Points ◽  
Children And Young Adults

Key Points Proteinuria and elevated markers of complement activation at TMA diagnosis are associated with poor outcome. Clinical interventions should be considered in HSCT patients with these high-risk features at the time TMA is diagnosed.

scholarly journals Interferon-complement loop in transplant-associated thrombotic microangiopathy

2020 ◽  
Vol 4 (6) ◽  
pp. 1166-1177 ◽  
Author(s):  
Sonata Jodele ◽  
Mario Medvedovic ◽  
Nathan Luebbering ◽  
Jenny Chen ◽  
Christopher E. Dandoy ◽  
...  
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Mononuclear Cells ◽  
Transcriptional Regulatory Network ◽  
Tissue Injury ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Endothelial Injury ◽  
Hematopoietic Stem ◽  
Complement Pathways

Abstract Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

scholarly journals In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy

2017 ◽  
Vol 1 (20) ◽  
pp. 1632-1634 ◽  
Author(s):  
Seth J. Rotz ◽  
Nathan Luebbering ◽  
Bradley P. Dixon ◽  
Eleni Gavriilaki ◽  
Robert A. Brodsky ◽  
...  
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Key Points

Key Points Transplantation-associated thrombotic microangiopathy is associated with complement activation in vitro. This data further supports the use of eculizumab for the treatment of patients with TA-TMA.

scholarly journals Complement activation in thrombotic microangiopathy

2013 ◽  
Vol 33 (02) ◽  
pp. 96-104 ◽  
Author(s):  
R. Tati ◽  
D. Karpman
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Vascular Wall ◽  
Endothelial Injury ◽  
Host Cells ◽  
Wall Thickening ◽  
Vascular Lumen ◽  
Vessel Lumen ◽  
Complement Dysregulation ◽  
Subendothelial Matrix

SummaryThe endothelium lining the vascular lumen is continuously exposed to complement from the circulation. When erroneously activated on host cells, complement may generate a deleterious effect on the vascular wall leading to endothelial injury, exposure of the subendothelial matrix and platelet activation.In this review the contribution of complement activation to formation and maintenance of the pathological lesion termed thrombotic microangiopathy (TMA) is discussed. TMA is defined by vessel wall thickening affecting mainly arterioles and capillaries, detachment of the endothelial cell from the basement membrane and intraluminal thrombosis resulting in occlusion of the vessel lumen. The TMA lesion occurs in haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS is further sub-classified as associated with Shiga toxin-producing Escherichia coli (STEC-HUS) or with complement dysregulation (atypical HUS) as well as other less common forms. The contribution of dysregulated complement activation to endothelial injury and platelet aggregation is reviewed as well as specific complement involvement in the development of HUS and TTP.

scholarly journals Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy

Blood ◽  
2013 ◽  
Vol 122 (5) ◽  
pp. 803-806 ◽  
Author(s):  
Benjamin C. Lee ◽  
Chad L. Mayer ◽  
Caitlin S. Leibowitz ◽  
D. J. Stearns-Kurosawa ◽  
Shinichiro Kurosawa
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Nonhuman Primates ◽  
Defense Mechanism ◽  
Shiga Toxins ◽  
E Coli ◽  
Key Points ◽  
Uremic Syndrome

Key Points Complement activation is not required for development of thrombotic microangiopathy and HUS induced by EHEC Shiga toxins in nonhuman primates. Complement is an important defense mechanism, and benefits or risks of therapeutic inhibition should be studied further for this infection.

scholarly journals HUS and the case for complement

Blood ◽  
2015 ◽  
Vol 126 (18) ◽  
pp. 2085-2090 ◽  
Author(s):  
Edward M. Conway
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Response To Treatment ◽  
Microangiopathic Hemolytic Anemia ◽  
New Knowledge ◽  
Uremic Syndrome

Abstract Hemolytic-uremic syndrome (HUS) is a thrombotic microangiopathy that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Excess complement activation underlies atypical HUS and is evident in Shiga toxin–induced HUS (STEC-HUS). This Spotlight focuses on new knowledge of the role of Escherichia coli–derived toxins and polyphosphate in modulating complement and coagulation, and how they affect disease progression and response to treatment. Such new insights may impact on current and future choices of therapies for STEC-HUS.

Sign in / Sign up

Export Citation Format

Share Document