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OBJECTIVE: To report a pediatric case of drug-induced thrombotic microangiopathy caused by cocaine. CASE DESCRIPTION: We report a nine-month-old patient who developed thrombotic microangiopathies after extreme cocaine intoxication, multiple organ dysfunction syndrome with hemodynamic dysfunction, anuric renal failure, liver failure, encephalopathy, and myocardial injury, corresponding phenotypically to thrombocytopenia-associated multiple organ failure. The patient received continuous venous hemofiltration and therapeutic plasma exchange, recovering satisfactorily. She was discharged after 30 days of hospitalization under the guidance of the childcare service, and was healthy after one year of follow-up. Toxicological samples confirmed high levels of cocaine and derivatives in blood, urine and hair. COMMENTS: To our knowledge, this is the first reported pediatric case. There are particularities of cocaine intoxication pathophysiology that can trigger thrombotic microangiopathies because of vasoconstriction, direct endothelial injury, platelet activation, and increasing von Willebrand factor and fibrinogen levels. All of which results in a prothrombotic state, inflammatory dysregulation, and microvascular thrombi. The increasing use of cocaine, especially among young adults, puts children at high risk of toxicity, either by passive unintentional exposure, or abuse due to the increased availability in homes.

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BACKGROUND Bevacizumab is an approved targeted therapy for metastatic cancer treatment. It can have adverse effects on multiple organs. Despite its low incidence, thrombotic microangiopathy (TMA) is the most severe complication. TMA has been associated with complement dysregulation, and treatment with eculizumab can be effective, despite the paucity of literature on eculizumab therapy for bevacizumab-associated TMA. To date, 10 cases have been reported, with less than half of them including a kidney biopsy. We present a new case of bevacizumab-associated TMA successfully treated with eculizumab, along with kidney biopsy records and an overview of mechanisms underlying TMA development in bevacizumab-treated patients. CASE REPORT A female patient diagnosed with metastatic breast cancer who was treated with bevacizumab in conjunction with chemotherapy was admitted to the hospital for acute kidney injury requiring hemodialysis, microangiopathic hemolytic anemia, and thrombocytopenia. TMA was diagnosed and was later confirmed by a kidney biopsy. Primary causes for TMA, such as ADAMTS13 deficiency and shiga toxin associated hemolytic-uremic syndrome, were ruled out, and the patient's condition was ultimately found to be triggered by exposure to bevacizumab. After discontinuing bevacizumab and receiving 4 weekly doses of eculizumab, kidney function and hematological parameters improved. CONCLUSIONS Bevacizumab-associated TMA can be reversed or attenuated in some patients with the use of eculizumab (inhibiting complement system overactivation), possibly reducing time to recovery, with fewer long-term sequelae. This additional case encourages future clinical trials to evaluate the safety and efficacy of eculizumab in cases of TMA associated with bevacizumab.

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BACKGROUND: Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease that potentially leads to kidney graft failure due to ongoing Thrombotic Microangiopathy (TMA). The aim was evaluating the frequency of TMA after kidney transplantation in patients with aHUS in a Brazilian cohort stratified by the use of the specific complement-inhibitor eculizumab. METHODS: This was a multicenter retrospective cohort study including kidney transplant patients diagnosed with aHUS. We collected data from 118 transplant centers in Brazil concerning aHUS transplanted patients between 01/01/2007 and 12/31/2019. Patients were stratified into three groups: no use of eculizumab (No Eculizumab Group), use of eculizumab for treatment of after transplantation TMA (Therapeutic Group), and use of eculizumab for prophylaxis of aHUS recurrence (Prophylactic Group). RESULTS: Thirty-eight patients with aHUS who received kidney transplantation were enrolled in the study. Patients' mean age was 30 years (24-40), and the majority of participants was women (63% of cases). In the No Eculizumab Group (n = 11), there was a 91% graft loss due to the TMA. The hazard ratio of TMA graft loss was 0.07 [0.01-0.55], p = 0.012 in the eculizumab Prophylactic Group and 0.04 [0.00-0.28], p = 0.002 in the eculizumab Therapeutic Group. CONCLUSION: The TMA graft loss in the absence of a specific complement-inhibitor was higher among the Brazilian cohort of kidney transplant patients. This finding reinforces the need of eculizumab use for treatment of aHUS kidney transplant patients. Cost optimization analysis and the early access to C5 inhibitors are suggested, especially in low-medium income countries.

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Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity.

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ABSTRACT This paper described the pathophysiology of suicide deaths from paraquat poisoning which occurred in patients who died in fewer than 24 hours after ingesting paraquat. These deaths were referred to as hyperacute paraquat poisoning deaths. Thrombotic microangiopathy was the predominant pathological finding in all these cases and was evident in the brain, lung, heart, kidneys and in all organs and tissues examined. Of note, diffuse alveolar capillary thrombosis occurred, causing damage to alveolar walls, including those in subpleural locations, resulting in focal visceral pleural rupture leading to pneumothorax and pneumomediastinum in these cases, thus giving rise to yet another mechanism of pneumothorax and pneumomediastinum in paraquat toxicity. Thrombotic microangiopathy is the major pathological mechanism that underlies paraquat poisoning and has not hitherto been reported.

RESUMEN El presente trabajo describe la fisiopatología de las muertes por suicidio por intoxicación con paraquat en pacientes que murieron en menos de 24 horas después de ingerirlo. Estas muertes fueron referidas como muertes por envenenamiento hiperagudo con paraquat. La microangiopatía trombótica fue el hallazgo patológico predominante en todos estos casos, y se hizo evidente en el cerebro, el pulmón, el corazón, los riñones y en todos los órganos y los tejidos examinados. Es de notar que se produjo una trombosis capilar alveolar difusa, que causó daño a las paredes alveolares, incluyendo aquellas en localizaciones subpleurales. Esto trajo como resultado la ruptura pleural visceral focal que condujo al neumotórax y al neumomediastino en estos casos, dando así lugar a otro mecanismo de neumotórax y neumomediastino en la toxicidad del paraquat. La microangiopatía trombótica es el mecanismo patológico principal que subyace en el envenenamiento por paraquat, y no ha sido reportada hasta el momento.

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