Reduction of mortality, cardiac damage, and cerebral damage by IL-1 inhibition in a murine model of TTP.

ABSTRACT: Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in von Willebrand factor cleavage resulting in capillary microthrombus formation and ischemic organ damage. Interleukin-1 (IL-1) has been shown to drive sterile inflammation after ischemia and could play an essential contribution to postischemic organ damage in TTP. Our objectives were to evaluate IL-1 involvement during TTP and to test the efficacy of the recombinant IL-1 receptor antagonist, anakinra, in a murine TTP model. We retrospectively measured plasma IL-1 concentrations in patients with TTP and controls. Patients with TTP exhibited elevated plasma IL-1α and -1ß concentrations, which correlated with disease course and survival. In a mouse model of TTP, we administered anakinra (IL-1 inhibitor) or placebo for 5 days and evaluated the efficacy of this treatment. Anakinra significantly reduced mortality of mice (P < .001). Anakinra significantly decreased TTP-induced cardiac damage as assessed by blood troponin concentrations, evaluation of left ventricular function by echocardiography, [18F]fluorodeoxyglucose positron emission tomography of myocardial glucose metabolism, and cardiac histology. Anakinra also significantly reduced brain TTP-induced damage evaluated through blood PS100b concentrations, nuclear imaging, and histology. We finally showed that IL-1α and -1ß trigger endothelial degranulation in vitro, leading to the release of von Willebrand factor. In conclusion, anakinra significantly reduced TTP mortality in a preclinical model of the disease by inhibiting both endothelial degranulation and postischemic inflammation, supporting further evaluations in humans.

Outcomes of patients with thrombotic thrombocytopenic purpura treated in an intensive care unit.

Background Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by widespread microthrombosis that can predispose to multiple organ failure. The literature is sparse on the outcomes of critically ill patients with TTP managed in intensive care units (ICUs). We aimed to determine the mortality of ICU patients admitted with TTP and evaluate the predictors of survival. We also compared the incidence of nosocomial infection among those who did or did not receive plasma exchange (PE). Methods We conducted a retrospective study in a tertiary ICU. Two authors screened patients for eligibility from the hospital information system based on peripheral smear reports. Adult critically ill TTP patients managed in ICU were included. Patients with a diagnosis of haemolytic uraemic syndrome, autoimmune causes of haemolysis and pregnancy-related conditions, etc. were excluded. Two authors extracted data from medical charts. No imputation of missing variables was done. Non-parametric statistics were used to report data. Statistical analyses were performed using Stata version 16. Results Of the 535 records that were screened, 33 patients were deemed eligible. Mortality among TTP patients was 14 (42%). The women to men ratio was 7:3. At admission, greater degree of anaemia, thrombocytopenia, and higher lactate dehydrogenase levels were observed in non-survivors compared to survivors (5.4 g/dl [4.8-7.1] v. 7.6 g/dl [6.1-8.9], p=0.05; 17x103 µl v. 21x103 µl, p=0.63; and 2987 (1904-3614) U/L v. 2126 U/L (1941-3319), p=0.71; respectively]. Nineteen (57%) patients had acute kidney injury (AKI), of which 11 survived: 6 recovered completely from renal failure and 5 progressed to end-stage renal disease. Nosocomial infection rates were not different among those receiving and not receiving PE therapy (7 [33%] v. 3 [25%], respectively). Conclusion TTP is more common in women and has a high mortality. Older age, low haemoglobin and higher platelet transfusions are predictors of poor survival. Nosocomial infection rates were similar irrespective of receiving PE therapy.

Uso de plasmaféresis en unidades de pacientes críticos / Indications, adverse effects and results of plasmapheresis in critical care patients

Background: Plasmapheresis is a therapeutic alternative for diseases in which a "humoral factor" has pathogenetic relevance. However it is not devoid of adverse effects. Aim: To review the indications, number of procedures, morbidity and clinical evolution of plasmapheresis in critical patients. Patients and Methods: A retrospective and descriptive study in four intensive care units of an University hospital. The severity of patients was evaluated with APACHE II and SOFA scores. Results: Twenty patients were studied. The most common indications of plasmapheresis were thrombotic thrombocytopenic purpura (TTP) in 50% of subjects and small vessel vasculitides in 30%. The number of procedures per patient oscillated between 2 and 14 (mean: 7.1±3.3). The registered adverse effects were hypocalcemia in 50% of patients, hypotension in 42.1%, coagulopathy in 35%, hypokalemia in 29%, rash in 20%, procedure related infections in 18% and fever in 10%. There was a significant decrease of 17±28% in prothrombin time, after the procedures. Seventy five percent of patients had a favorable evolution. Global mortality rate was 15%. All deaths occurred in patients with TTP and were attributed to the progression of the disease. No death was attributed to the procedure. The initial APACHE II and SOFA scores were 12.4±8.4 and 5.3±2.9, respectively. Both scores decreased after the procedure. Among other therapeutic measures, 15% of the patients received immunosuppressant treatment, 27% were dialyzed and 32% were mechanically ventilated. Conclusions: The most common indication of plasmapheresis was TTP. Adverse effects were frequent, however there was no procedure related mortality. The global mortality rate was 15% and all deaths occurred in patients with TTP.