In 475 (98%) of the 487 Oklahoma Registry patients included in this study, TMA was initially suspected from the clinical features of microangiopathic hemolytic anemia and thrombocytopenia; the etiology of TMA was attributed to a drug in 52 (11%) of these patients. In the other 12 patients included in this study, TMA was initially diagnosed by kidney biopsy; the etiology of TMA was attributed to a drug in six (50%) of these patients. Patients in whom TMA was diagnosed by kidney biopsy often did not have the clinical features of TMA. Only one of the six patients categorized as drug-induced was thrombocytopenic (her platelet count was 128,000/µL); only three had fragmented red blood cells reported on their peripheral blood smear.
Table IV
Most works about haemolytic anemia in the context of hematologic tumor report all kinds of causes, with only a few studies focusing on TMA. Besides, the majority includes both solid and hematologic tumours, with a broad incidence rate for the latter – 8% to 50% of TiTMA 34,139,141,142. The most common hematologic tumours behind TiTMA are Hodgkin lymphoma, aggressive Non-Hodgkin lymphomas, acute leukaemia and multiple myeloma 34,141,144. Pulmonary TMA is a rare condition, but more common in TiTMA patients, being characterized by intimal proliferation of the pulmonary arterioles with presence of tumor emboli 141,142.
DRUG-INDUCED THROMBOTIC MICROANGIOPATHY: EXPERIENCE OF THE OKLAHOMA REGISTRY AND THE BLOODCENTER OF WISCONSIN
Our goal was to assist clinicians in their evaluation of patients with suspected TMA by developing standardized criteria for assessing clinical evidence. This form of TMA can be seen with mucin-producing adenocarcinomas as well as disseminated malignancies. What occurs is microvascular obstruction with cancer cells, consumption of platelets in tumor microthrombi, and fragmentation of the passing red blood cells. As we learned in the drug-induced TMA section, chemotherapy agents like mitomycin-C, cisplatin, gemcitabine, or bevacizumab can cause TMA which will typically resolve with the withdrawal of the offending drug.
The Differential Diagnosis And Treatment Of Thrombotic Microangiopathies
The best clue to this pseudo-TMA is reticulocytopenia, while low B12 with high MMA and homocysteine levels are diagnostic. The best therapeutic approach is repletion of Vitamin B12, folate, CoQ-10, and carnitine. Pathogenesis is multifactorial, including fascinating Neutrophil Extracellular Traps, aptly called NETs, akin to basketball nets catching alternative pathway basketballs. This patient had also taken naproxen and therefore her serum was also tested for naproxen and naproxen glucuronide-dependent, platelet-reactive antibodies. This patient had also taken levaquin and therefore her serum was also tested for levaquin-dependent, platelet-reactive antibodies.
There are also solid particles in the blood, including red blood cells and platelets. Red blood cells carry oxygen from your lungs to the rest of your body, including the cells of your kidney. Platelets have the job of plugging up any damaged part of the blood vessel to keep it from leaking. In conclusion, our study provides real-world data on the use of narsoplimab in pediatric and adult patients with high-risk TA-TMA. Narsoplimab confirmed its effectiveness and safety across age groups, with no increased risk of infectious complications or other safety signals of concern noted.
Role Of Calcineurin Inhibitors
MCM, AG, AA, FL, MCF, BR, and GR contributed to screening potentially eligible adult patients, treating them with the drug, and monitoring them. FV, MV, SB, AB, AB are responsible for screening eligible pediatric patients for treatment, administering therapy, and monitoring. PT contributed to histological diagnosis, providing photographs of biopsies, and their description. CP is responsible for statistical analyses and contributed to data extraction. Throughout treatment with narsoplimab no safety signals of concern were observed. This safety profile is particularly significant for HSCT recipients, a population prone to severe infections, especially while undergoing immunosuppressive therapy such as CNIs.
Hypertension-associated TMA
Immune checkpoint inhibitors (CPIs) are part of this class of drugs, consisting of monoclonal antibodies that target inhibitory receptors expressed on T cells 85. Some authors reported favourable results using eculizumab in carfilzomib-induced TMA. In those cases, ADAMTS13 activity was normal, suggesting a pathophysiology similar to aHUS, with complement overactivation 83. One additional report refers to a patient with a complement mutation 84. As expected, plasmapheresis showed no clear benefit in this setting 75. Treatment is based on immediate and permanent drug cessation 30,34 and recurrence has been described with repeated exposure 32.
Chemotherapy-Associated Thrombotic Microangiopathy
However, it is not always feasible, mainly because of high bleeding risk 122. In rare cases, tubular reticular inclusions can be found, suggesting a high level of interferon activity, even in the absence of viral infection. Immunofluorescence is generally negative for immune complexes, although there may be unspecific fibrin deposition 8. Autopsy studies have showed a poor correlation between clinical and histological findings 91,97. Recently, there have been some reports of CPIs-induced TMA with ipilimumab and nivolimumab. Despite the temporal correlation, true causality is difficult to establish, since the reported cases presented confounding factors, namely metastatic malignancy and other drugs related with TMA 85.
Platelet Count
Thrombotic microangiopathy (TMA) is a rare but severe complication of tumors and their chemotherapeutic treatment. We report on two patients with chemotherapy-induced TMA who were successfully treated with a short course of the terminal complement inhibitor eculizumab. Both patients quickly achieved remission of microangiopathic hemolytic anemia and recovery of renal function. After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated.
7 Acquired Complement‐mediated AHUS
Some Authors (Cavero et al., 2017; Caravaca-Fontan and Praga, 2019) suggest to use the anti-complement therapy only in case of lack of improvement of hematological parameters and/or renal function recovery after causative drug discontinuation. This approach lacks supporting evidence, which is currently based on case reports and case series. Other Authors (Duineveld and Wetzels, 2019)do not suggest the use of eculizumab in secondary DITMA cases, relying on data indicating that renal outcome was not significantly altered by the use of the complement inhibitor. Moreover (Grall et al., 2021), reported a significantly better kidney response (83% vs. 64% of complete/partial recovery) and kidney outcome (eGFR 45 vs. 33 ml/min/1.73) in 13 patients with gemcitabine-induced TMA treated with anti-complement therapy. However, conflicting results were reported by previous articles gemcitabine-induced TMA treated with C5-inhibitor (Al Ustwani et al., 2014; Daviet et al., 2019).
- Notwithstanding the rarity of TMA, early recognition and treatment are essential to minimize its burden, including dialysis-dependent chronic kidney disease (CKD).
- Docetaxel and vincristine have also been reported to induce TMA (30, 31).
- In the second case, the diagnosis of TA-TMA was posed due to the onset of anemia, thrombocytopenia, elevated LDH, uncontrolled hypertension, and neurological symptoms such as confusion, tremors, and lethargy.
- Samples from patients in the Oklahoma Registry are not included in these data.
- Case reports describe the use of eculizumab in SLE‐TMA suggested a response65 however larger case series failed to replicate this.
As the patient began to experience melena, an esophagogastroduodenoscopy was performed. The patient was under treatment with CNI (tacrolimus) and steroids (methylprednisolone 1 mg/kg). The histologic examination revealed a deepithelialized mucosa with erosions, making it difficult to exclude either gastrointestinal acute GvHD (aGvHD) or ischemic damage from intestinal TA-TMA (iTAM) 26.
When the target is complement factor H, the paraprotein overactivates the alternative complement pathway, leading to C3 glomerulopathy or aHUS 147, 148, 149. VEGF inhibition is a potential pathological pathway in PIs-induced TMA, because they affect VEGF production through nuclear factor kappa B (NF-κB) inhibition 75, 76, 77. Immune-mediated and dose-dependent toxicity have also been proposed 75, 79.
