We acknowledge that in patients who do not have definite or probable evidence for a causal association, it remains possible that the suspected drug may have contributed to the etiology of TMA. DITMA Systematic Review Table of Drugs – This comprehensive table lists all 452 articles reporting data on 86 drugs, both case reports and group data. Both Immune-mediated and Toxicity-mediated mechanisms are included in this table. The scores represent out assessment of the strength of the causal association of the drug with TMA. (1-Definite Causal Association; 2-Probably Causal Association; 3-Possible Causal Association; 4-Unlikely Causual Association). The absence of genetic abnormalities in most patients does not exclude participation of complement in the pathogenesis of DITMA and other secondary TMAs.
Anti-C5 Monoclonal Antibody
Clearly, further studies are required to determine the mechanisms of TMA, given both the rarity of this situation and the common presence of confounding factors. Some authors defend that mucin production may exert a direct injury in the tumoral endothelial cells. Microvascular tumor emboli, procoagulants produced by tumor cells and impaired fibrinolysis have also been implicated 34,89,139,141,143. If patients present atypical clinical features of TMA or fail to respond to treatments for idiopathic TMA, some authors recommend searching for systemic malignancy, after excluding other secondary causes 14,141,143,144.
Close monitoring of renal function and hematological parameters after eculizumab withdrawal is mandatory; however, there are no evidence-based data about the reliability of a specific parameter and the optimal frequency of testing 33. These include the retrospective design, the limited number of patients treated, and their highly heterogeneous clinical presentation including the presence of both pediatric and adult cases. However, given the difficulties or the impossibility in promoting prospective control trials, real-world data are of paramount importance to understand the clinical potential of innovative treatment proposals in such a rare and often fatal disease.
Platelet Count
On the other hand, a series of 4 cases of biopsy-proven HSCT-TMA described a simultaneously acute and/or chronic GVHD in other organs 113. Monoclonal antibodies are used in a wide variety of diseases, with an increasing number of drugs targeted to Oncology. Cetuximab and trastuzumab have been implicated in DiTMA in case reports. Additional cases are essential to attribute TMA to these drugs 86, 87. Gemcitabine-induced TMA clinically presents as a predominantly kidney-limited disease, with AKI in almost every patient, frequently requiring haemodialysis. New-onset or exacerbation of HTN could occur several months before the diagnosis 30,31.
Table II presents the results of reassessing the status of the 58 patients in the Oklahoma Registry who had previously been assigned to the drug-induced category, 1989–2014. Using the evaluation criteria developed for our previous assessment of published reports, 21 patients (37%) had evidence supporting a definite association of the suspected drug with their episode of TMA. In 19 (90%) of these 21 patients, the etiology was attributed to quinine; 12 of the 19 patients with quinine-induced TMA has been reported previously;(8) the other seven patients with evidence supporting a definite association were diagnosed following this report.
The Classic Pentad Of TTP:
Two other pediatric patients initially treated with defibrotide at TA-TMA diagnosis did not respond to it. However, they subsequently started narsoplimab and responded after 8 and 12 doses, respectively. In the adult patients, nobody received other treatment for TA-TMA before narsoplimab. All responding patients were free from platelet and red-blood-cell transfusions at the end of the treatment. A Loss of glands in the colon mucosa, characterized by the disappearance and atrophy of glands.
What Are TTP And HUS?
Pregnancy related TTP typically presents in the second and third trimesters. In those with genetic mutations, this additional consumption of ADAMTS13 can lead to levels low enough for TTP to develop.77 There is a high mortality risk to the mother and the foetus and PE should be instituted urgently. Variants in Thrombomodulin (THBD), a transmembrane glycoprotein with anticoagulant properties and a negative regulator of the complement system on vascular endothelial cells, may lead to a TMA. If not identified and treated in a timely manner, prognosis is the worst in patients with Factor H mutations, with 60%-70% reaching kidney failure within a year of disease onset. Patients with CD46 mutations have a better prognosis, with approximately 80% remaining dialysis-independent. Anuja Java is a transplant nephrologist at Washington University in St. Louis, MO.
THROMBOTIC THROMBOCYTOPENIC PURPURA INCIDENCE AND PATHOGENESIS
Response rate was 62% (8/13) in adults and 71% (5/7) in pediatric patients. At the present moment, there is no solid evidence supporting any particular therapeutic approaches. Randomized controlled trials, an especially difficult achievement in a field like this, would be the only way to make it possible to recommend a specific therapy.
To date, several cases of the use of eculizumab in chemotherapy-induced TMA have been reported, most of them regarding gemcitabine (summarized in Table 1). Before the availability of eculizumab, a case series reported ~ 29 patients with suspected gemcitabine-related TMA. Despite discontinuation of gemcitabine, 7 (24%) patients progressed to end-stage renal disease (ESRD), and 3 (10%) patients developed chronic renal failure 30.
ETable 3 ADAMTS13 Activity
Trimethoxyamphetamine-2, a psychedelic amphetamine and stimulant first synthesised by Alexander Shulgin. An uncommon compound of similar activity to other psychedelic amphetamines. These three isomers are significantly more active as hallucinogenic drugs, and have consequently been placed onto the illegal drug schedules in some countries such as Japan. MA, TM, and FA contributed to data collection and performed the research. This action on serotonergic receptors likely underlies the psychedelic effects of these compounds.
TTP (thrombotic Thrombocytopenic Purpura)
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.
DITMA suspicion is ampilified by TMA resolution when the drug is withdrawn or recurrent endothelial injury during re-exposure to the drug. However, the possible side effects, especially the risk of meningococcal infection, the inconvenience of a bi-monthly application, and the significant costs have prompted interest in alternative dosing schedules and complete discontinuation. A recent review analyzed data from unpublished cases, published case reports, clinical trials, and the Global aHUS Registry regarding patient outcomes after eculizumab discontinuation 31. Of the case reports, a subsequent TMA manifestation was observed in 31% (16/52) of patients after eculizumab discontinuation. Data from five clinical trials documented a relapse in 20% (12/61) of patients after cessation of therapy with eculizumab with a median follow-up of 24 weeks. Of note, relapse risk was independent of an identified genetic mutation, high-risk polymorphism, or autoantibody status.
- Although the mechanisms of endothelial injury during DITMA still remain unknown; immune-mediated mechanisms or dose-dependent and cumulative toxicity are implied (11).
- Other nephrotoxins should be avoided any time close to the conditioning regimen 88, and platelet and RBC transfusion could be indicated 8.
- The mechanism is direct endothelial injury with release of von Willebrand factor multimers, which overwhelm ADAMTS13 capacity and activate coagulation-complement crosstalk.
- The moderate therapeutic success achieved with eculizumab has led to investigation of other targeted therapies that act on various stages of the complement system.
- The prognosis is poor, with a mortality rate of almost 75% at 4 months, mainly in the cases with pulmonary involvement 23,25,26.
Mechanisms that lead to complement activation or ADAMTS13 deficiency have also been suggested 6,14,15. Independently from the trigger, drug-induced endothelial injury is assumed as the initiating event in DiTMA, but the specific mechanism remains unclear for many drugs 1,6,15. TMA resulting from inhibitors of vascular endothelial growth factors8,9 has been established to involve injury to renal podocytes.
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. 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.
