Ramucirumab, anti-VEGF receptor 2 monoclonal antibody, and cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), are also implicated in causing renal-limited TMA (51, 52). Drug-induced TMA has been reported in children with acute lymphoblastic leukemia (34, 35) and adults with solid tumors (36, 37), receiving multiagent chemotherapy. Jodele et al. described 13 patients developing TMA after high-dose chemotherapy and autologous stem cell transplantation for neuroblastoma (12 patients receiving carboplatin/etoposide/melphalan and one cyclophosphamide/thiotepa) (38). Finally, a high incidence of TMA was observed in melanoma patients receiving a lymphodepleting preparative chemotherapy regimen with total body irradiation (TBI) prior to autologous T cell therapy (39). In all cases, the co-administration of multiple drugs hinders the identification of the causative agent. These combined reviews identified 403 articles that reported data on 688 individual patients with TMA attributed to 84 drugs.
Table 1 Classification Of Thrombotic Microangiopathies (based On Brocklebank V, Et Al )
The first ones were presented by the Bone Marrow Transplant Clinical Trials Network (BMT-CTN) 123 in 2005, followed by International Working Group (IWG) 124 in 2007. More recently, Jodele et al. 126 presented wider criteria that included kidney and/or neurological dysfunction. They define kidney manifestations as HTN, proteinuria ≥30 mg/dL or terminal complement activation. The clinical spectrum of kidney adverse effects of VEGF inhibitors (VEGFi) is composed by a new-onset or exacerbation of HTN, proteinuria (sometimes in nephrotic range) and TMA with severe AKI.
The other three isomers TMA-3, TMA-4 and TMA-5 are not known to have been used as recreational drugs to any great extent, and remain obscure scientific curiosities. Trimethoxyamphetamine-2, a psychedelic amphetamine and stimulant first synthesised by Alexander Shulgin. An uncommon compound of similar activity to other psychedelic amphetamines.
Recent Activity
Therefore, a biopsy should be considered when the clinical picture is ambiguous, there is no response to definitive therapy, the degree of reversibility of kidney injury is unclear, or a second pathology is suspected. For this study we included all patients enrolled through 2014 with their first episode of clinically suspected acquired TTP (475 patients) and also all patients in whom TMA was first identified by a kidney biopsy (12 patients). Not included in this study were the 12 patients who were enrolled at the time of a recurrent episode of TTP.
Thrombotic Microangiopathy In Oncology – A Review
These diseases are referred to as secondary thrombotic microangiopathies or secondary HUS. The common consequences are endothelial cell damage with consecutive thrombus formation and complement activation (16). Triggers are tumors, stem cell transplantation, use of medications, pregnancy, autoimmune diseases, kidney disease, or malignant hypertension (etable 2). Historical case reports of patients with TTP receiving either no treatment or non-specific treatment reveal a mortality of 72–94%.
Typical Hemolytic Uremic Syndrome
To score a point, the “offense” (two proteases, Factors B and D, and a stabilizing protein, Properdin P) will engage with C3 basketball to create the powerful alternative pathway C3 convertase. Once C3 convertase is formed, a series of slam dunks via an efficient amplification loop generates large amounts of C3b on the surface of the pathogen. This will opsonize the hapless pathogen and activate the terminal pathway with its lethal weapon, membrane attack complex (MAC) C5b-9. Viralkumar Amrutiya is a second-year nephrology fellow at Virginia Commonwealth University, Richmond, VA. He is a graduate of Hebei Medical University, Shijiazhuang, Hebei, China, and completed his residency and chief year at Hackensack Meridian Health – Palisades Medical Center in North Bergen, NJ.
HSCT-TMA could also be minimized by protecting kidneys from TBI, e.g. fractionating irradiation over several days 128. Diagnosing HSCT-TMA is difficult and requires integration of clinical and pathologic data. These patients frequently develop MAHA, thrombocytopenia and kidney dysfunction in a post-transplantation period, due to innumerable reasons 89,91. An autopsy-based study showed that patients with acute GVHD had a higher probability of developing TMA, independently of CNI and mTORI use 97.
- The other three isomers TMA-3, TMA-4 and TMA-5 are not known to have been used as recreational drugs to any great extent, and remain obscure scientific curiosities.
- New-onset or exacerbation of HTN could occur several months before the diagnosis 30,31.
- The prognosis is poor, with a mortality rate of almost 75% at 4 months, mainly in the cases with pulmonary involvement 23,25,26.
- Several observational studies and case series reported other treatment options, all of which require further study.
- This results in the clinical picture of an immune-mediated, acquired thrombotic thrombocytopenic purpura (aTTP) (figure 2).
- 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.
Table IV
Alternative pathway inhibitors in development (see illustration) are pegcetacoplan (anti-C3), iptacopan (anti-factor B) and danicopan (anti-factor D). DITMA Review Methods – Methods of assessment of reports of DITMA and determination of scores designating the level of evident for a causal association of the drug with TMA. Different methods were used for individual patient reports and group data.
Anti-C5 Monoclonal Antibody
Subsequently, intravenously administrated high molecular PEO was determined as the causative factor (15). Tyrosine kinase inhibitors (TKIs) are effective in the treatment of hematologic malignancies and solid tumors. Imatinib and ponatinib are small-molecule BCR-ABL TKIs, used mainly in the treatment of chronic myeloid leukemia.
The exact mechanisms are not completely understood, although there is evidence of direct toxicity to endothelial cells, with subsequent complement activation 41,44. Patients present systemic features of TMA, in association with AKI 42,45,46. At least one case reported successful use of eculizumab, but the patient also presented a complement protein mutation 41. Immune-mediated reactions – Just like DITP, drugs can cause TMA by the formation of drug-dependent antibodies.
Key Diagnostic Findings In Acute 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. 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.
Team 1: Primary TMA Versus Team 2: Secondary TMA
All patients except two pediatric patients with sickle cell disease underwent HSCT for hematologic malignancies. When antibody-mediated TMA is suspected, a trial with plasmapheresis could be useful. However, some cases only respond with complete malignancy remission 141. 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.
With treatment, up to 90 percent of people can achieve remission, though nearly one-third may relapse. However, it should be noted that TMA cases triggered by cancer and other malignancies are more likely to have a poorer outlook than those diagnosed during pregnancy, for example. Malignant hypertension, which is sudden, abnormally high blood pressure, is also a known contributor to TMA.
In the normal kidney (as in the rest of the body), there are small blood vessels called capillaries. They are lined with a slippery coating of cells known as endothelial cells (see Figure 1). The diagnostic and prognostic criteria for TA-TMA remains an open issue.
