Gemcitabine-Associated Thrombotic Microangiopathy: Response to Complement Inhibition and Reinitiation of Gemcitabine

2017 ◽  
Vol 16 (2) ◽  
pp. e119-e122 ◽  
Author(s):  
Jeffrey L. Turner ◽  
Joshua Reardon ◽  
Tanios Bekaii-Saab ◽  
Spero R. Cataland ◽  
Matthew J. Arango
Keyword(s):  
Thrombotic Microangiopathy ◽  
Complement Inhibition

scholarly journals Adult post COVID-19 multisystem inflammatory syndrome and thrombotic microangiopathy

2020 ◽  
Author(s):  
Idris Boudhabhay ◽  
Marion Rabant ◽  
Louis-Marie Coupry ◽  
Armance Marchal ◽  
Lubka T Roumenina ◽  
...  
Keyword(s):  
Renal Function ◽  
Thrombotic Microangiopathy ◽  
Dramatic Improvement ◽  
Case Presentation ◽  
Complement Inhibition ◽  
Clinical Series ◽  
Long Term Consequences ◽  
Inflammatory Syndrome

Abstract Background: The coronavirus disease 2019 pandemic has affected millions of people worldwide but medium and long-term consequences are unknown. Clinical series of Kawasaki-like multisystem inflammatory syndrome in children (MIS-C), occurring after SARS-Cov-2 spreading, have been recently described. Case presentation: We describe a case of post COVID-19 MIS in a 46-year-old man, with biopsy-proven renal thrombotic microangiopathy (TMA). Specific complement inhibition with Eculizumab was initiated promptly and lead to a dramatic improvement of renal function. Conclusion: Our case suggests that post COVID-19 MIS is not restricted to children and that TMA could play a central role in the pathophysiology of this syndrome

scholarly journals Case Report: Adult Post-COVID-19 Multisystem Inflammatory Syndrome and Thrombotic Microangiopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Idris Boudhabhay ◽  
Marion Rabant ◽  
Lubka T. Roumenina ◽  
Louis-Marie Coupry ◽  
Victoria Poillerat ◽  
...  
Keyword(s):  
Renal Function ◽  
Case Report ◽  
Thrombotic Microangiopathy ◽  
Therapeutic Option ◽  
Dramatic Improvement ◽  
Case Presentation ◽  
Complement Inhibition ◽  
Clinical Series ◽  
Inflammatory Syndrome

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide. A clinical series of Kawasaki-like multisystem inflammatory syndrome (MIS), occurring after SARS-CoV-2 infection, have been described in children (MIS-C) and adults (MIS-A), but the pathophysiology remains unknown.Case PresentationWe describe a case of post-COVID-19 MIS-A in a 46-year-old man with biopsy-proven renal thrombotic microangiopathy (TMA). Specific complement inhibition with eculizumab was initiated promptly and led to a dramatic improvement of renal function.ConclusionOur case suggests that that TMA could play a central role in the pathophysiology of post-COVID-19 MIS-A, making complement blockers an interesting therapeutic option.

scholarly journals The use of eculizumab in Capnocytophaga canimorsus associated thrombotic microangiopathy: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Magnus Holter Bjørkto ◽  
Andreas Barratt-Due ◽  
Ingvild Nordøy ◽  
Christina Dörje ◽  
Eivind Galteland ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Severe Infection ◽  
Complement Factor ◽  
Disease Entity ◽  
Thrombotic Microangiopathies ◽  
Capnocytophaga Canimorsus ◽  
Factor B ◽  
Case Presentation ◽  
Complement Inhibition ◽  
Diagnostic Difficulties

Abstract Background The use of complement inhibition is well established for complement mediated thrombotic microangiopathy, but its role in secondary forms of thrombotic microangiopathy is debated. We here present a case of thrombotic microangiopathy triggered by Capnocytophaga canimorsus, illustrating the diagnostic difficulties in discriminating between different thrombotic microangiopathies, and the dilemmas regarding how to treat this disease entity. Case presentation A previously healthy 56-year-old woman presented with fever and confusion. She was diagnosed with sepsis from Capnocytophaga canimorsus and thrombotic microangiopathy. Marked activation of both T-cells, endothelium and complement were documented. She was successfully treated with antimicrobial therapy, the complement inhibitor eculizumab and splenectomy. After several weeks, a heterozygote variant in complement factor B was localized, potentially implying the diagnosis of a complement mediated TMA over an isolated infection related TMA. Conclusions We discuss the possible interactions between complement activation and other findings in severe infection and argue that complement inhibition proved beneficial to this patient’s rapid recovery.

scholarly journals Complement Inhibition with Eculizumab in Adult Transplant-Associated Thrombotic Microangiopathy: Opening the Pandora’s Box

2021 ◽  
Vol 27 (3) ◽  
pp. S270-S271
Author(s):  
Eleni Gavriilaki ◽  
Ioanna Sakellari ◽  
Zoi Bousiou ◽  
Ioannis Batsis ◽  
Despina Mallouri ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Complement Inhibition

scholarly journals COMPLEMENT INHIBITION FOR THE TREATMENT OF COVID-19 TRIGGERED THROMBOTIC MICROANGIOPATHY WITH CARDIAC FAILURE—a case report

2021 ◽  
Author(s):  
Didar Utebay ◽  
Harald Seeger ◽  
Antonia M S Müller ◽  
Sascha David
Keyword(s):  
Cardiogenic Shock ◽  
Thrombotic Microangiopathy ◽  
Viral Myocarditis ◽  
Clinical Signs ◽  
Signs And Symptoms ◽  
High Dose ◽  
Severe Thrombocytopenia ◽  
Multisystem Disease ◽  
Complement Inhibition ◽  
Clinical Signs And Symptoms

Abstract Background Severe coronavirus disease 2019 (COVID-19) has been increasingly recognized as a multisystem disease. SARS–CoV-2 can infect literally any cell type that expresses its target receptor angiotensin-converting enzyme 2. However, COVID-19 associated organ dysfunction is not only mediated by direct viral effects but also by the interaction between the host`s immune response, endotheliopathy and microvascular coagulopathy. It has been proposed that the activation of the complement system plays a central role in the pathophysiology of severe COVID-19 and the associated endotheliopathy. Case summary A 76 year-old male patient with indeterminate cardiogenic shock in the setting of confirmed SARS-CoV-2 infection was admitted to our ICU. Coronary angiography did not reveal a plausible explanation for his symptoms. The patient developed renal failure, neurological symptoms, severe thrombocytopenia, and a Coombs-negative hemolytic anaemia with schistocytes. All together the clinical picture was highly suggestive of a thrombotic microangiopathy (TMA) with microvascular cardiac involvement. Conventional therapeutic strategies including high-dose steroids and seven sessions of therapeutic plasma exchange were all unsuccessful. Interestingly, complement inhibition with Eculizumab as rescue approach led to a rapid clinical and laboratory improvement and the patients was discharged with normalized organ functions at day 36. Conclusion The etiology of cardiogenic shock observed in this patient cannot simply be explained by his focal and chronic coronary findings. Although viral myocarditis was not formally excluded, both the clinical features of TMA and the rapid resolution of all clinical signs and symptoms after pharmacological complement inhibition suggest a SARS-CoV-2-driven microangiopathic origin of heart failure.

scholarly journals Complement-mediated thrombotic microangiopathy associated with lupus nephritis

2018 ◽  
Vol 2 (16) ◽  
pp. 2090-2094 ◽  
Author(s):  
Mi Hee Park ◽  
Nicholas Caselman ◽  
Scott Ulmer ◽  
Ilene Ceil Weitz
Keyword(s):  
Lupus Nephritis ◽  
Thrombotic Microangiopathy ◽  
Complement Inhibition ◽  
Key Points

Key Points CM-TMA is a unique subset of patient with LN. CM-TMA in LN is responsive to complement inhibition with eculizumab.

scholarly journals Thrombotic Microangiopathy Variants Are Independently Associated with Critical Disease in COVID-19 Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Eleni Gavriilaki ◽  
Styliani Kokoris ◽  
Tasoula Touloumenidou ◽  
Evdoxia Koravou ◽  
Maria Koutra ◽  
...  
Keyword(s):  
Intensive Care ◽  
Genetic Susceptibility ◽  
Thrombotic Microangiopathy ◽  
Case Series ◽  
Missense Variant ◽  
Factor H ◽  
Pathogenic Variant ◽  
World Health ◽  
Complement Factor ◽  
Complement Inhibition

Background: Several recent studies support the notion of excessive complement activation in patients with severe coronavirus disease-19 (COVID-19), with beneficial results of complement inhibition in case series. In this context, severe COVID-19 shares common characteristics with complement-mediated thrombotic microangiopathy (TMA). TMA is commonly characterized by genetic susceptibility, and presents with thrombocytopenia, anemia, increased lactate dehydrogenase (LDH), and organ damage (renal, neurological, cardiac). Aims: We hypothesized that genetic susceptibility would be also evident in patients with severe COVID-19 and would be associated with disease severity. Methods: We prospectively studied consecutive adult patients hospitalized with COVID-19 in our referral centers (April-May 2020). Diagnosis was confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). COVID-19 severity was assessed based on World Health Organization's (WHO) criteria into moderate/severe, and critical disease. Additional data on patients' history and course were recorded by treating physicians that followed patients up to discharge or death. Patients' DNA was obtained from peripheral blood samples. Probes were designed using the Design studio (Illumina). Amplicons cover exonic regions of TMA-associated genes (Complement factor H/CFH, CFH-related, CFI, CFB, CFD, C3, CD55, C5, MCP, thombomodulin/THBD, ADAMTS13) spanning 15 bases into the intronic regions. We used 10ng of initial DNA material. Libraries were quantified using Qubit and sequenced on a MiniSeq System in a 2x150 bp run. Analysis was performed using the TruSeq Amplicon application (BaseSpace). Alignment was based on the banded Smith-Waterman algorithm in the targeted regions (specified in a manifest file). We performed variant calling with the Illumina-developed Somatic Variant Caller in germline mode and variant allele frequency higher than 20%. Both Ensembl and Refseq were used for annotation of the output files. Variants clinical significance was based on ClinVar and the current version of the Complement Database, as we have previously described. Results: We studied 60 patients, 40 with moderate/severe disease hospitalized in COVID-19 general ward (GW) and 20 with critical disease hospitalized in intensive care units (ICU). Among them, 11 patients succumbed due to COVID-19 disease. Patients laboratory characteristics are shown in Figure. In genetic analysis, patients presented heterogeneous variant profiles including pathogenic, benign, likely benign, and variants of unknown significance (median number of variants: 62, range: 51-89). Search in the Complement Database revealed seven patients, each carrying one pathogenic or likely pathogenic variant in C3, CD46, DGKE, and CFH. Based on ClinVar, we found a pathogenic variant of ADAMTS13 (rs2301612, missense) in 28 patients. We also detected two missense risk factor variants, previously detected in complement-related diseases: rs2230199 in C3 (13 patients); and rs800292 in CFH (26 patients). Among them, 22 patients had a combination of these characterized variants. This combination was significantly associated with critical disease that required intensive care (p=0.037), as well as low lymphocyte counts (p=0.021) and high neutrophil-to-lymphocyte ratio (p=0.050). In the multivariate model, critical disease was an independent predictor of double heterozygocity in these variants. Furthermore, one patient had a rare germline missense variant in CFI (rs112534524), previously detected in complement-related diseases. This patient suffered from critical disease but survived after long-term ICU hospitalization. Interestingly, five patients showed a likely protective missense variant in CFB (rs641153). Conclusion: We have detected for the first time rare and pathogenic TMA-associated variants in patients with severe COVID-19. Our findings of variants in complement-regulatory genes and ADAMTS13 suggest genetic susceptibility and define proof-of-concept for proper selection of patients that would benefit from complement inhibition. Table Disclosures Gavriilaki: Omeros Pharmaceuticals: Consultancy.

scholarly journals Prevalence and Characteristics of Venous Thromboembolism in Patients with Complement Mediated Thrombotic Microangiopathy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2091-2091
Author(s):  
Aria Wei ◽  
Gloria Frances Gerber ◽  
Kathryn Dane ◽  
Evan M. Braunstein ◽  
Robert Brodsky ◽  
...  
Keyword(s):  
Risk Factors ◽  
Platelet Count ◽  
Venous Thromboembolism ◽  
Thrombotic Microangiopathy ◽  
Board Member ◽  
Advisory Board ◽  
Complement Inhibition ◽  
Splenic Infarct ◽  
Therapeutic Anticoagulation ◽  
Significant Difference

Abstract BACKGROUND: Microvascular and arterial thromboses are well described in patients with thrombotic microangiopathy (TMA) including complement mediated TMA (CM-TMA)/atypical hemolytic uremic syndrome. Hemolytic disorders are associated with increased risk of venous thromboembolism (VTE), and patients with CM-TMA may have additional risk factors of hospitalization and central lines and may not consistently receive thromboprophylaxis due to thrombocytopenia. However, little is known about the prevalence and clinical correlates of VTE in CM-TMA. METHODS: We performed this single center retrospective cohort study of consecutive patients with CM-TMA enrolled in the Johns Hopkins Complement Associated Disease Registry between January 2014 and December 2020. Data regarding clinical presentation, laboratory studies including clinical complement gene sequencing, terminal complement inhibition and anticoagulation therapy, VTE events including characteristics and risk factors for VTE were collected. A diagnosis of CM-TMA was based on: (1) platelet count <150 × 10 9/L, (2) schistocytes on peripheral blood smear or TMA on renal biopsy, if performed, (3) ADAMTS13 activity >10%, (4) Shiga toxin negative, and (5) serum creatinine >2.25 mg/dL at presentation, which was considered supportive but not required for diagnosis. We only included VTE events post-CM-TMA diagnosis. VTE characteristics, treatment and outcomes were summarized using descriptive statistics. The Chi-squared test and Mann Whitney test were used to compare categorical and continuous variables across groups with and without VTE, respectively. RESULTS: Of 44 patients diagnosed with CM-TMA and followed for a median of 3.1 years (IQR 0.8-5.5), 8 (18.2%) experienced at total of 10 VTE events (5.6 VTE events/100 patient-years). There was no significant difference between patients with and without VTE in age at diagnosis, sex, race, BMI, need for dialysis, treatment with eculizumab, and presence of mutations in complement genes (Table 1). VTE events included 5 deep vein thromboses, 4 pulmonary emboli and 1 splenic infarct (Table 2). The majority (70%) of VTE events were provoked with 5 (50%) associated with a catheter or vascular access for dialysis and 2 (20%) events following major surgeries. The median time from CM-TMA diagnosis to the first VTE event was 4.9 months (IQR 0.76-26) with 3 events occurring during the index hospitalization for CM-TMA. Of 10 VTE events, 5 occurred while on complement inhibition and 2 on anticoagulation (1 on therapeutic and 1 on prophylactic anticoagulation). Of note, only 1 of 3 patients diagnosed with VTE during their index CM-TMA hospitalization received thromboprophylaxis. At the time of VTE diagnosis, the median platelet count was 182.5 x 10 9/L (IQR 143.75-332.75); 80% had a platelet count >150 x 10 9/L , and 10% each had a platelet count <50 x 10 9/L or 50-150 x 10 9/L. VTE was treated with therapeutic anticoagulation with enoxaparin, warfarin or a direct oral anticoagulant in 7 of 8 patients for a median duration of 7 months (IQR 4-14). One patient experienced recurrent PEs; the first PE occurred 2 months following the index CM-TMA hospitalization and the second event was 4 years later while off of anticoagulation and complement inhibition. A second patient experienced a splenic infarct 7 months after initial CM-TMA diagnosis while non-compliant with ravulizumab, followed by a catheter-associated upper extremity DVT 2 months later while on therapeutic anticoagulation and ravulizumab. No VTEs were fatal. CONCLUSION: VTE is common in patients with CM-TMA (18.2%), with a prevalence comparable to thrombotic thrombocytopenic purpura (18%, Tse et al. 2020) but greater than that reported in dialysis patients (Moinar et al. 2017). In CM-TMA patients, VTE is commonly provoked by hospitalization or dialysis catheters and tends to occur after platelet count recovery and in the absence of thromboprophylaxis. Factors such as renal impairment, prolonged hospitalization, complement dysregulation, and free hemoglobin release may also increase VTE risk. Our results highlight the high prevalence of VTE in CM-TMA and the importance of thromboprophylaxis once the platelet count is greater than 50 x 10 9/L. Figure 1 Figure 1. Disclosures Dane: Alexion: Honoraria; Sanofi Genzyme: Honoraria; Janssen: Honoraria. Chaturvedi: Sanofi Genzyme: Other: Advisory board member; Alexion: Other: Advisory board member; Dova: Other: Advisory board member; Argenx: Other: Advisory board member; UCB: Other: Advisory board participation.

scholarly journals Complement inhibition does not impair the clinical antiviral capabilities of virus-specific T-cell therapy

2020 ◽  
Vol 4 (14) ◽  
pp. 3252-3257
Author(s):  
Jeremy D. Rubinstein ◽  
Xiang Zhu ◽  
Carolyn Lutzko ◽  
Tom Leemhuis ◽  
Jose A. Cancelas ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Thrombotic Microangiopathy ◽  
Viral Infections ◽  
Clinical Effectiveness ◽  
Blocking Agent ◽  
T Cell Therapy ◽  
Complement Inhibition ◽  
Key Points ◽  
Terminal Complement

Key Points The use of terminal complement blockade is compatible with virus-specific T-cell (VST) expansion and clinical effectiveness. VST and complement-blocking agent concurrent therapy may be safely used in patients with thrombotic microangiopathy and viral infections.

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