Last but not least, several antibiotics such as ciprofloxacin, penicillin, and metronidazole were reported with probable evidence to cause DITMA (2). A new case report implicates again ciprofloxacin in drug-induced TTP which resolved completely with plasma exchange (84). Another report, identified a highly effective and frequently prescribed fluoroquinolone, levofloxacin as a new potential suspect for DITMA (13). This case report described two patients who developed microangiopathic hemolysis and thrombocytopenia following levofloxacin treatment of respiratory tract infections. Both cases resolved after drug cessation; the first patient received also therapeutic plasma exchange.
Product Reviews
First synthesised in the 50s, this uncommon drug was reexamined by David Nichols in the 1990s. It is an analogue of mescaline which is roughly six times more potent, and is thus a powerful psychedelic phenethylamine. The remaining isomers were numbered by Shulgin in the order of their progressive position of substitution, as abbreviated above. The values for relative human potencies of TMA-4, -5, and -6 compared to that of mescaline were evaluated to be 4, 10, and 10, respectively. The isomers, except TMA-3, have both stimulant and psychedelic effects, and their qualitative effects on mood alteration and sensory enhancement are similar to those of mescaline.
Renal Involvement (~50%)
Fungal hyphae and necrotic areas were also identified in the biopsy, indicating potential outcomes of widespread endothelial damage (Fig. 1c/d). Despite iTAM presenting with clinical symptoms resembling those of intestinal GvHD and often coexisting with intestinal aGvHD—a notable trigger for TA-TMA 9, 27,28,29—our patient exhibited persistent gastric bleeding unresponsive to immunosuppressive therapy. This patient did not respond to narsoplimab and died 78 days after the diagnosis of TA-TMA. While eculizumab has emerged as one of the most promising treatments for other TMAs, such as aHUS, its efficacy in HSCT-TMA is arguably modest. Retrospective studies that showed superior results when compared to plasmapheresis were based on small samples 100, 101, 102, 103, 104. Worse outcomes were described in patients with higher sC5b-9, with a lower likelihood to respond to treatment 103.
TTP (thrombotic Thrombocytopenic Purpura)
However, less than 50% of the genetically identified variants have a known functional consequence. Computational prediction algorithms are used to predict the potential impact of these “variants of uncertain clinical significance” (VUS) on the mature protein. The presence of such variants is particularly vexing for clinical management.
Drugs Reported To Have A Definite Causal Association With TMA In 177 Individual Patient Reports
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.
Chemical Data
Moreover, several authors propose an aggressive treatment of GVHD in patients with HSCT-TMA 88, 94. The ubiquitin proteasome pathway is critical in the cell cycle, destroying targeted proteins. Bortezomib, carfilzomib and ixazomib act through proteasome inhibition, preventing the degradation of pro-apoptotic factors. Presently, they are used in several monoclonal gammopathies 56, including multiple myeloma 13,75, 76, 77.
Antinuclear Antibodies (ANA) & TMA
In most patients with TMA, a complement-activating trigger can be identified, and in 28% of patients with an activating trigger, a genetic risk mutation can be found 3. In agreement with others we found that TPE/plasma infusion was not effective in patients with chemotherapy-induced TMA 12, 13, 14, 15, 16, 17, 18. Thrombotic microangiopathy (TMA) encompasses a group of disorders presenting with microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and ischemic organ damage, most frequently of the kidneys and the central nervous system 1, 2. In many of the more atypical TTP/HUS disease patterns the optimal treatment has not yet been standardized.
More recently, Jodele et al. 103 showed a 50% rate of complete response to eculizumab, with severe disease being less responsive, which could suggest the existence of other targets of endothelial injury pathways. Besides, eculizumab comes with several challenges, namely the cost, timing of initiation, patient selection, dosing and duration of therapy 93,102. The moderate therapeutic success achieved with eculizumab has led to investigation of other targeted therapies that act on various stages of the complement system. Some studies, still on phase II/III, already show encouraging results 93.
Typical Hemolytic Uremic Syndrome
In the fifth non-responder, narsoplimab was discontinued due to inefficacy and a concomitant refractory poor graft function. None of the adult patients discontinued CNI at the diagnosis of TA-TMA, to avoid the risk of exacerbating the concomitant GvHD. Five pediatric patients tapered or discontinued CNIs at TA-TMA diagnosis. Between January 2018 and August 2023, 20 patients received narsoplimab for TA-TMA at the dose of 4 mg/kg. Thirteen patients were adults, with a median age of 40 (range, 32–71), and 7 patients were pediatric, with a median age of 13 (range, 5–19). All patients except two pediatric patients with sickle cell disease underwent HSCT for hematologic malignancies.
Further studies are needed to elucidate the role of genetic variants in complement-regulatory proteins in chemotherapy-induced TMA and to define parameters predictive of complement activation and likely TMA recurrence. Until then, the decision to withdraw eculizumab has to be made on an individual basis. Genetic mutations leading to dysregulation of the alternative complement pathway or autoantibodies against complement regulatory proteins are identified in ~ 50% of aHUS patients 4. However, genetic variants in complement regulatory proteins are also detected in patients with secondary, e.g., chemotherapy-induced, TMA 3. In such patients, the underlying dysregulation of the alternative complement system may be unmasked by the applied drug, acting as a complement-activating trigger.
- Treatment is based on immediate and permanent drug cessation 30,34 and recurrence has been described with repeated exposure 32.
- The difficulty of histologic diagnosis led to the development of non-invasive clinical criteria for HSCT-TMA diagnosis.
- It is an analogue of mescaline which is roughly six times more potent, and is thus a powerful psychedelic phenethylamine.
- For one patient, the dosage was increased to 3 times a week due to a poor initial response to the treatment.
This formulation markedly prolongs the half-life in the vascular compartment and limits its adverse effects 54,55. The first cancer drug recognized as a cause of TMA was Mitomycin C (MMC), but currently there is a fast-growing list of potential TMA triggers 1,5,6,14. Pregnancy and the postpartum are high‐risk periods for TTP and complement‐mediated aHUS. Most cases present with pneumonia (often with empyema) but it has also been reported with meningitis or sinus/ear infections.
Endothelial injury is also a feature of GVHD, with endothelial cells as the putative direct target of donor cytotoxic T lymphocytes 88,106,111. Patients with acute GVHD after HSCT present high levels of plasma markers of endothelial injury, indicating a probable link between endothelial lesion and the development of both GVHD and HSCT-TMA 8,106,112. HSCT-induced TMA (HSCT-TMA) has a wide range of reported incidence (up to 80%), that may be explained by the retrospective nature of the studies, the simultaneous analysis of pediatric and adult populations and a lack of uniform diagnostic criteria.
Bleomycin, an antibiotic that inhibits DNA synthesis, is frequently used in combination with platins in several cancers 42,46. Endothelial damage is a known effect of bleomycin, with case reports describing Raynaud’s phenomenon, digital infarcts and pulmonary toxicity. However, in all reports of bleomycin and TMA, there is a concurrent drug that could trigger TMA by itself 42,43,46. There is no evidence to define whether TMA is caused by a synergic mechanism.
