Complement activation during intravascular hemolysis: Implication for sickle cell disease and hemolytic transfusion reactions

Merle, Nicolas S.; Boudhabhay, Idris; Léon, Juliette; Frémeaux‐Bacchi, Véronique; Roumenina, Lubka T.

doi:10.1016/j.tracli.2019.02.008

Cited by 30 publications

(26 citation statements)

References 131 publications

(171 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the current study, the clinically most affected SCD patient had elevated C4d plasma levels, in addition to C3bc and C3bBbP, indicating an additional activation of the classical and/or the lectin pathway. Heme did not elevate C4d in our experimental model, which is in line with previous results (37), so this may imply alternative mechanisms of complement activation in SCD, such as chronic continuous activation, or part of a delayed hemolytic transfusion reaction involving alloantibodies and classical pathway activation (38,39). Thereby, the classical and lectin pathway may recognize damaged selfmolecules released in vivo, which are not generated in whole blood ex vivo.…”

Section: Discussionsupporting

confidence: 91%

Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood

Thomas

Gerogianni

McAdam

et al. 2019

The Journal of Immunology

View full text Add to dashboard Cite

Heme is a critical danger molecule liberated from hemeproteins in various conditions, including from hemoglobin in hemolytic diseases. Heme may cause thromboinflammatory damage by activating inflammatory and hemostatic pathways, such as complement, the TLRs, coagulation, and platelets. In this study, we explored the effect of single and dual inhibition of complement component C5 and TLR coreceptor CD14 on heme-induced thromboinflammation in an ex vivo human whole blood model. Heme induced a dose-dependent activation of complement via the alternative pathway. Single inhibition of C5 by eculizumab attenuated the release of IL-6, IL-8, TNF, MCP-1, MIP-1a, IFN-g, LTB-4, MMP-8 and-9, and IL-1Ra with more than 60% (p < 0.05 for all) reduced the upregulation of CD11b on granulocytes and monocytes by 59 and 40%, respectively (p < 0.05), and attenuated monocytic tissue factor expression by 33% (p < 0.001). Blocking CD14 attenuated IL-6 and TNF by more than 50% (p < 0.05). In contrast to single inhibition, combined C5 and CD14 was required for a significantly attenuated prothrombin cleavage (72%, p < 0.05). Markers of thromboinflammation were also quantified in two patients admitted to the hospital with sickle cell disease (SCD) crisis. Both SCD patients had pronounced hemolysis and depleted plasma hemopexin and haptoglobin. Plasma heme and complement activation was markedly increased in one patient, a coinciding observation as demonstrated ex vivo. In conclusion, heme-induced thromboinflammation was largely attenuated by C5 inhibition alone, with a beneficial effect of adding a CD14 inhibitor to attenuate prothrombin activation. Targeting C5 has the potential to reduce thromboinflammation in SCD crisis patients.

show abstract

Section: Discussionsupporting

confidence: 91%

Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood

Thomas

Gerogianni

McAdam

et al. 2019

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Taken together, recent mouse models and data from patients suggest that complement plays a key role in the SCD disease process and is a potential therapeutic target . The HU treatment resulted in prevention of complement activation on blood cells.…”

Section: Discussionmentioning

confidence: 91%

Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy

et al. 2020

View full text Add to dashboard Cite

The complement system is an innate immune defense cascade that can cause tissue damage when inappropriately activated. Evidence for complement over activation has been reported in small cohorts of patients with sickle cell disease (SCD). However, the mechanism governing complement activation in SCD has not been elucidated. Here, we observe that the plasma concentration of sC5b-9, a reliable marker for terminal complement activation, is increased at steady state in 61% of untreated

show abstract

“…Hemolysis leads to pronounced tubular injury (2,(32)(33)(34)(35). Complement AP activation is an important pathogenic mechanism in the development of AKI, especially in the tubulointerstitium, where it has been shown to drive severe injury (19,20,36).…”

Section: Discussionmentioning

confidence: 99%

Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis

et al. 2020

View full text Add to dashboard Cite

Worsening of acute tubular necrosis in the hepatoFH −/− mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI.

show abstract

Complement activation during intravascular hemolysis: Implication for sickle cell disease and hemolytic transfusion reactions

Cited by 30 publications

References 131 publications

Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood

Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood

Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy

Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis

Contact Info

Product

Resources

About