Abstract TP120: Complement Activation Contributes to Malignant Transformation of Stroke and Limits Cognitive Recovery After Reperfusion Therapy

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ali M Alawieh ◽  
Wuwei Feng ◽  
Alejandro M Spiotta ◽  
Stephen Tomlinson
Keyword(s):  
Malignant Transformation ◽  
Complement Activation ◽  
Reperfusion Therapy ◽  
Functional Independence ◽  
Cognitive Outcomes ◽  
Cognitive Recovery ◽  
Complement Inhibition ◽  
Rehabilitation Therapy ◽  
Risk Of Hemorrhage ◽  
Treatment Window

Introduction: Ischemic stroke involves an ischemic event followed by post-ischemic neuroinflammation, leading to acute mortality, neuronal loss, and impaired recovery. Standard of care reperfusion therapy (thrombolysis or thrombectomy) has a limited treatment window due to risk of hemorrhage, and leads to functional independence in only a subset of patients. We studied the role of complement and neuroinflammation in the pathophysiology behind the major clinical challenges of reperfusion therapy; the risk of hemorrhage and limited cognitive recovery. Methods: We used 3 stroke models, namely transient middle cerebral artery occlusion (MCAO), permanent MCAO and microembolic models, to investigate the effects of t-PA, mechanical reperfusion, rehabilitation therapy, and complement inhibition in mice. We used B4-Crry, a site-targeted inhibitor of C3 activation that specifically localizes to neoepitopes expressed in the post-ischemic brain following its intravenous administration. A retrospective analysis was also performed for cognitive and motor recovery in human patients following reperfusion therapy. Results: Complement inhibition with B4-Crry improved the safety, efficacy and treatment window of reperfusion therapy, decreased hemorrhagic transformation, and improved cognitive recovery. Despite reperfusion with t-PA, there was ongoing complement-dependent microglial activation and phagocytosis of hippocampal synapses for at least 30 days leading to pronounced long-term cognitive deficits. Administration of B4Crry, alone or in combination with thrombolytic therapy, limited complement deposition in the perilesional brain, and reduced microgliosis and synaptic uptake. Reperfusion therapy alone did not improve cognitive outcomes, even when combined with rehabilitation therapy. Reperfusion therapy did not improve cognitive outcomes in stroke patients. Conclusions: Although post-stroke reperfusion therapy limits the size of injury and improves motor deficits, post-reperfusion complement activation and neuroinflammation contribute to the malignant transformation of stroke acutely and seeds a chronic neurodegenerative inflammatory response. Complement modulation may be a promising adjuvant to reperfusion therapy.

scholarly journals Disruptive and protective outcomes to memory and attention when treating diffuse glioma

2019 ◽  
Author(s):  
R Romero-Garcia ◽  
J Suckling ◽  
M Owen ◽  
M Assem ◽  
R Sinha ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Cognitive Deficits ◽  
Brain Networks ◽  
Cognitive Outcomes ◽  
Attention Deficits ◽  
Diffuse Glioma ◽  
Cognitive Recovery ◽  
Memory And Attention ◽  
Neurite Density ◽  
With Memory

ABSTRACTSurgical resection with adjuvant chemotherapy and radiotherapy are effective treatments to delay glioma progression and improve survival. Nevertheless, a large proportion of patients have treatment-induced cognitive deficits that dramatically reduce their life quality. Predicting the treatment-induced functional impairments is difficult due to the complex interlocking and diffusely spread networks that underpin different aspects of cognition. Here we investigated glioma interactions with brain networks in relation to cognitive recovery after surgical resection and during chemo-radiotherapy treatment. Seventeen patients with diffuse non-enhancing glioma (aged 22-56 years) were longitudinally MRI-scanned and cognitively assessed using a tablet-based screening tool before and after surgery, and during a 12-months recovery period. Using structural MRI and Neurite Orientation Dispersion and Density Imaging (NODDI) derived from diffusion-weighted images, we respectively estimated tumour overlap and Neurite Density (as an in-vivo proxy measure of axon and dendrite concentration) with brain networks and functional maps derived from normative data in healthy participants. We found that neither total lesion volume nor tumour location based on traditional lobular divisions were associated with memory or attention deficits. However, tumour and lesion overlap with the Default Mode Network (DMN), Attention Network and attention-related regions located in frontal and parietal cortex was associated with memory and attention deficits. This association was above and beyond the contributions of preoperative cognitive status and tumour volume (Linear Mixed Model, Pfdr<0.05). On the other hand, Neurite Density was reduced not only within the tumour, but also beyond the tumour boundary, revealing a distal effect with global consequences to brain networks. High preoperative Neurite Density outside the tumour, but within the Frontoparietal Network was associated with better memory and attention recovery. Moreover, postoperative and follow-up Neurite Density within the DMN, Frontoparietal and Attention Networks were associated with memory and attention improvements (Pfdr<0.05). We conclude that gliomas located on brain networks that are fundamental for cognitive processing mediate cognitive deficits and they exert a distal effect on Neurite Density in these networks that is also associated with cognitive recovery. Our work provides insights into the brain reorganisation that occurs due to the presence of a tumour and its subsequent removal, which has potential capability to predict cognitive outcomes. Understanding the pathophysiology underlying tumour related cognitive outcomes will be vital to the development of novel prognostic biomarkers, subgroup stratification in clinical trials, and individualised rehabilitation programmes.

Advancing therapeutic complement inhibition in hematologic diseases: PNH and beyond

Blood ◽  
2021 ◽  
Author(s):  
Eleni Gavriilaki ◽  
Régis Peffault de Latour ◽  
Antonio Maria Risitano
Keyword(s):  
Complement Activation ◽  
Lectin Pathway ◽  
Prototype Model ◽  
Complement Inhibition ◽  
Hematologic Diseases ◽  
Classical Complement Pathway ◽  
Complement Inhibitors ◽  
Hemolytic Transfusion Reaction ◽  
Personalized Approach ◽  
Long Acting

Complement is an elaborate system of the innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototype model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan have been also now approved with PNH. Novel agents, such as factor B and factor D inhibitors, are under study with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug needs to be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease (CAD), primarily with the C1s inhibitor of the classical complement pathway, sutimlimab, but also with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, are investigated in transplant-associated thrombotic microangiopathy (TA-TMA). With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction (DHTR) or immune thrombocytopenia (ITP), might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases focusing on: a) complement biology for the clinician, b) complement activation and therapeutic inhibition in prototypical complement-mediated hematologic diseases, c) hematologic entities under investigation for complement inhibition, and d) other complement-related disorders of potential interest to hematologists.

Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention

2006 ◽  
Vol 291 (5) ◽  
pp. G844-G850 ◽  
Author(s):  
Werner Hartwig ◽  
Martina Klafs ◽  
Michael Kirschfink ◽  
Thilo Hackert ◽  
Lutz Schneider ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Complement Activation ◽  
Necrotizing Pancreatitis ◽  
Weight Ratio ◽  
Dry Weight ◽  
Organ Injury ◽  
Sham Operation ◽  
Midline Laparotomy ◽  
Complement Inhibition ◽  
Edematous Pancreatitis

In acute pancreatitis, local as well as systemic organ complications are mediated by the activation of various inflammatory cascades. The role of complement in this setting is unclear. The aim of the present study was to determine the level of complement activation in experimental pancreatitis, to evaluate the interaction of complement and leukocyte-endothelium activation, and to assess the effects of complement inhibition by soluble complement receptor 1 (sCR1) in this setting. Necrotizing pancreatitis was induced in Wistar rats by the combination of intravenous cerulein and retrograde infusion of glycodeoxycholic acid into the biliopancreatic duct; edematous pancreatitis was induced by intravenous cerulein only. In control animals, a sham operation (midline laparotomy) was performed. Complement activation, leukocyte sequestration, and pancreatic as well as pulmonary injury were assessed in the presence/absence of sCR1. Increased levels of C3a were found in necrotizing but not in edematous pancreatitis. When complement activation in necrotizing pancreatitis was blocked by sCR1, levels of C3a and total hemolytic activity (CH50) were decreased. Leukocyte-endothelial interaction, as assessed by intravital microscopy, and pancreatic as well as pulmonary organ injury (wet-to-dry weight ratio, MPO activity, and histology) were ameliorated by sCR1. As a result of the present study, necrotizing but not edematous pancreatitis is characterized by significant and early complement activation. Based on the interaction of complement and leukocytes, complement inhibition by sCR1 may be a valuable option in the treatment of leukocyte-associated organ injury in severe pancreatitis.

scholarly journals Acute Stroke Reperfusion Therapy Trends in the Expanded Treatment Window Era

2014 ◽  
Vol 23 (9) ◽  
pp. 2316-2321 ◽  
Author(s):  
Ganesh Asaithambi ◽  
Xin Tong ◽  
Mary G. George ◽  
Albert W. Tsai ◽  
James M. Peacock ◽  
...  
Keyword(s):  
Acute Stroke ◽  
Reperfusion Therapy ◽  
Treatment Window

Abstract TP239: Cross-Training In-Hospital Operating Staff Significantly Improves Door-to-Puncture Time in Thrombectomy Patients

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Angela M Callahan ◽  
Axel Rosengart ◽  
Karissa Graham ◽  
Kellie Capone ◽  
Kathryn Wright ◽  
...  
Keyword(s):  
Operating Room ◽  
Patient Characteristics ◽  
Reperfusion Therapy ◽  
Functional Independence ◽  
Stroke Severity ◽  
Fisher Exact Test ◽  
Large Contribution ◽  
Chi Square ◽  
Exact Test ◽  
Significant Difference

Objective: Delay in endovascular reperfusion in patients with acute large-vessel cerebral occlusion decreases the likelihood of functional independence. Given the large contribution of the pre-puncture, in-hospital time period to the overall speed of reperfusion therapy we evaluated the benefits and impediments of utilizing an immediately available OR team to reduce door-to-puncture time compared to a traditional model of an on-call team. Methods: Prospectively collected data were retrospectively analyzed to compare the readiness strategies of 2 comprehensive stroke centers of the Geisinger Health System serving stroke patients in rural and suburban Pennsylvania with different hospital level characteristics: Center A with an in-hospital available operating room team cross-trained in both operating and neuroendovascular procedures and center B with a dedicated on-call neuroendovascular team. Data compared included patient demographics and presentation characteristics, stroke severity, door-to-puncture time, and successful reperfusion ( t test, Fisher exact test, Chi square test). Results: There was no significant difference in the baseline stroke patient characteristics at center A (n=31) and center B (n= 45): 61% vs. 62% females; mean age 72 (range 47 to 93) vs. 69 (range 28 to 96) (p=0.35); admission NIHSS 17 vs 17, respectively. Successful reperfusion (TICI 2b-3) was achieved in 98% and 97% of cases in center A and B, respectively (p=0.79) but door-to-puncture time differed significantly between 50 in center A compared to 121 minutes in center B (58% reduction, p<0.02). Conclusion: Crossed-training in-hospital operating room staff in neuroendovascular procedures significantly reduces door-to-puncture time in thrombectomy patients when compared to a traditional on-call neuroendovascular call team. Based on existing data, this achievement in earlier reperfusion is expected to translate directly to improve clinical outcome.

scholarly journals Effects of Rehabilitation Therapy on Parkinsonians' Disability and Functional Independence

1996 ◽  
Vol 10 (4) ◽  
pp. 223-231 ◽  
Author(s):  
F. Patti ◽  
A. Reggio ◽  
F. Nicoletti ◽  
T. Sellaroli ◽  
G. Deinite ◽  
...  
Keyword(s):  
Functional Independence ◽  
Rehabilitation Therapy

scholarly journals Kinetic parameters of complement activation in patients with paroxysmal nocturnal hemoglobinuria during eculizumab therapy

2020 ◽  
Vol 65 (2) ◽  
pp. 126-137
Author(s):  
Yu. V. Tarasova ◽  
O. U. Klimova ◽  
L. A. Andreeva ◽  
L. V. Vasina ◽  
L. V. Galebskaya ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Induction Period ◽  
Kinetic Parameters ◽  
Conflict Of Interest ◽  
Complement Activation ◽  
Blood Cells ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Complement Inhibition ◽  
Hemolysis Rate

Introduction. Eculizumab inhibits the terminal steps of complement activation and is the standard treatment for paroxysmal nocturnal hemoglobinuria (PNH). Unstable complement inhibition causes “breakthrough” intravascular hemolysis and a suboptimal response to eculizumab therapy in some patients with PNH.Aim: to evaluate the stability of complement inhibition in eculizumab treatment by testing the kinetic parameters of complement activation.Materials and methods. The study included 12 PNH patients receiving long-term eculizumab therapy (median 54 months, range 4–66 months). The median age was 35 years (from 22 to 68 years), 92 % of patients were female. The median PNH clone size was 96  % of the granulocytes. The control group consisted of 12 healthy donors (age 25–60 years, women 75 %). Complement activation was evaluated immediately prior to the next eculizumab infusion, and then again after 5 and 10 days. Kinetic parameters (induction period, hemolysis rate, T50-the time required to achieve 50  % hemolysis) were recorded separately for the total complement activity and an alternative activation pathway using rabbit red blood cells (rRBC).Results. The parameters of complement activation directly before the next eculizumab administration corresponded to a marked inhibition of the overall activity of the system. The induction period was extended by 7 times compared to the control (median 180 vs 25 seconds, p < 0.0001), and the hemolysis rate was 28 times less (median 1.6 vs 45.1 × 106 rRBC/min, p < 0.0001). The T50 value exceeded the control value by 20 times (median 690 vs 35 seconds, p < 0.0001). The parameters of the alternative complement activation pathway were reduced by 2–3 times compared to the control. In one case, repeated tests revealed insuffi cient complement inhibition, which was associated with pharmacokinetic “breakthrough” hemolysis. The degree of further complement inhibition and the tendency to restore activity varied signifi cantly during dynamic testing on days 5 and 10 after eculizumab infusion.Conclusion. The results of this study demonstrate individual differences in the residual activity of complement in PNH patients receiving long-term eculizumab therapy. Testing of complement activity is necessary with a suboptimal response to eculizumab therapy and when considering therapy correction. Kinetic registration of residual complement-dependent lysis of rabbit red blood cells demonstrates a higher sensitivity than the traditional CH50 study.Conflict of interest: the authors declare no conflict of interest.Financial disclosure: the study had no sponsorship.

scholarly journals Complement Activation: The role in Health and Disease and Strategies of Therapeutic Complement Inhibition

2014 ◽  
Vol 2 (6) ◽  
pp. 115-121
Author(s):  
Nayareen Akhtar ◽  
Rezwanur Rahman ◽  
Shahin Sultana ◽  
Nurun Nahar Mawla
Keyword(s):  
Complement Activation ◽  
Complement Inhibition ◽  
Health And Disease

Abstract WP70: Reperfusion Therapy in Posterior Circulation Large Vessel Occlusion With Perfusion Deficits May Be Safe and Improve Outcomes Beyond 4.5 Hours

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Sujan Teegala Reddy ◽  
Kaushik Parsha ◽  
Deep Pujara ◽  
Clark Sitton ◽  
Sean Savitz ◽  
...  
Keyword(s):  
Ct Perfusion ◽  
Reperfusion Therapy ◽  
Functional Independence ◽  
Posterior Circulation ◽  
Large Vessel ◽  
Vessel Occlusion ◽  
Comprehensive Stroke Center ◽  
Stroke Center ◽  
To Receive ◽  
Perfusion Deficits

Introduction: Whether reperfusion therapy is safe and efficacious in acute ischemic strokes (AIS) due to posterior circulation large vessel occlusions (PCLVO) beyond 4.5 hrs is unknown. Methods: A retrospective analysis of AIS due to PCLVO presenting to a comprehensive stroke center up to 24 hrs from last known well. Patients were stratified based on the treatment received into reperfusion therapy (IV-tPA and/or endovascular thrombectomy) and no reperfusion therapy. All patients received CT/CTA and CT perfusion with RAPID mismatch determination. Functional independence (90 day mRS 0-2) and sICH were primary and secondary outcomes. The two groups were compared in the overall cohort in an ordinal logistic regression and in a propensity matched analyses. Results: Between 8/2017 and 5/2019, 52 patients were included [reperfusion = 23(44%) vs no-reperfusion=29(56%)]. Reperfusion rate beyond 4.5 hours was 26% (6/23). The two groups were similar at baseline except for larger perfusion delays (Tmax>6s) volume [median (IQR), 16 (0, 46) vs. 0 (0, 25) cc, p=0.03], and higher presentation NIHSS [median (IQR), 10 (5, 21) vs. 4 (1, 8), p=0.004] in the reperfusion group. Reperfusion was associated with higher functional independence rates 10 (43%) vs. 8 (28%), p=0.23 (fig 1), and a trend for a shift towards better outcomes adj cOR 1.89, 95% CI=0.59-6.13, p=0.29. There was no difference in sICH rates 9% vs. 0%, P=0.19. In a propensity matched analysis on NIHSS and perfusion deficit of 14 pairs, reperfusion was associated with statistically significant higher mRS 0-2 rates 9 (64%) vs. 1 (7%), p=0.004 (fig 2). Functional independence rates did not differ in the reperfusion group in relation to time (47% <4.5 hrs vs. 33%≥4.5 hrs), p=0.36 for heterogeneity. Conclusion: PCLVOs with more severe strokes and large perfusion deficits were more likely to receive reperfusion which was associated with a shift towards better outcomes both earlier and beyond 4.5 hours without worsening safety outcomes.

Sign in / Sign up

Export Citation Format

Share Document