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. Proteinuria is described as an indirect sign of the anticancer effect of this drug. Kidney-limited TMA (type 2) is the main phenotype reported, with only mild anemia or thrombocytopenia 6,63,64.
2 Cobalamin C AHUS
Sixteen patients (80%) required the start of high-dose steroids as first-line treatment and a complete GvHD response was obtained in 6 of them (5 adult patients and 1 pediatric). The remaining 10 (50%) patients were deemed steroid-refractory and started a second-line therapy for acute GvHD, ruxolitinib in most cases. In a series of 9 cases of TMA related with monoclonal gammopathies 149, all the patients presented with a kidney-limited TMA, with no confounding factors on presentation. It has to be noted, however, that genetic mutations on complement factors and ADAMTS13 activity were not evaluated in all patients. By treating the underlying gammopathy, the TMA was reversed, which suggests a strong association between these entities. The secondary forms of TMA include an extensive range of causes, varying from infections to cancer, pregnancy, malignant hypertension, drugs, solid or hematopoietic transplantation, and autoimmune or metabolic diseases, etc.
Therapeutic Plasma Exchange
So TMA is a condition in which blood clots have formed in those blood vessels. Thrombotic microangiopathy (TMA) is a rare but potentially life threatening condition that affects the body’s small blood vessels. However, the presence of diarrhea is not sufficient to exclude other forms of TMA as ~ 30 – 40% of aHUS and TTP cases involve gastrointestinal symptoms, including bloody diarrhea 19, 20.
Complement Inhibition
Other patients with minimal kidney function abnormalities are often described as having thrombotic thrombocytopenic purpura (TTP). In this report, we use the term “DITMA” to describe all patients, including patients previously described as drug-induced HUS or TTP. In addition to these now well-defined entities, there are a number of diseases that are less clearly classified. 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).
Malignant Hypertension
The results are shown in Table 3 and the references are listed in Supplementary Material S54–S64. Defects in the blood vessel wall lining can produce rough patches that are like potholes on a road – they can slow traffic and cause a lot of damage. In the end, parts of your kidney can die from lack of blood flow, and your body can run low on red blood cells and platelets. Various therapeutic strategies have been explored for TA-TMA, however, their efficacy has been limited 12,13,14. The recent trend of rapid increase in the approval of new drugs brings challenges to the management of TMA.
Quinine-dependent antibodies reactive with platelets or other cells were reported for 24 of these 34 patients; drug-dependent antibodies were not reported for any other drug. For DITP, the target condition is defined simply by a platelet count less than 100,000/µL. In contrast, the clinical and pathologic features of TMA occur in multiple distinct complex disorders, making evaluation of a suspected drug etiology is more difficult.
It is important to exclude any other diagnosis before attributing TMA to a drug. The mechanisms of drug-induced endothelial damage are heterogenous and not completely understood. In terms of pathological mechanisms, genetic variants in complement genes are found very rarely in DITMA patients, while an acquired (both systemic or renal) complement hyperactivation was documented in more than a half of the DITMA patients.
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. Patients presenting with pneumococcal HUS (pHUS) are unwell and frequently require intensive care treatment.68 Three quarters of children who develop pHUS require dialysis and a third go on to develop ESRD. The CP is activated by molecules such as immune complexes and the LP is triggered when microbial carbohydrates are detected.
Table 2 Summary Case Report 1 And 2
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.
2 Complement System Overview
However, dose reduction or replacement of one of them by other agents may be beneficial. There are successful reports of other strategies in GVHD, such as mycophenolate mofetil, corticosteroids and basiliximab (IL2 receptor antagonist) 88,92,97,99. 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.
- Due to an intestinal perforation, this patient underwent an urgent colon resection.
- These patients frequently develop MAHA, thrombocytopenia and kidney dysfunction in a post-transplantation period, due to innumerable reasons 89,91.
- This case report described two patients who developed microangiopathic hemolysis and thrombocytopenia following levofloxacin treatment of respiratory tract infections.
- This type of TMA primarily affects the small blood vessels of the kidneys.
- Genetic mutations leading to dysregulation of the alternative complement pathway or autoantibodies against complement regulatory proteins are identified in ~ 50% of aHUS patients 4.
Thrombotic Microangiopathy (TMA) Region
Rituximab, a monoclonal antibody directed against the B‐lymphocyte CD20 antigen, is used in aTTP as an additional first line treatment, in refractory cases of TTP and/or to reduce the likelihood of relapse once in remission. Thrombotic thrombocytopenic purpura (TTP) is a rare systemic form of TMA due to a severe deficiency in ADAMTS13. ADAMTS13 is an enzyme (a disintegrin and metalloprotease with thrombospondin type 1 motif 13), which cleaves von Willebrand factor (VWF).2 Deficiency of ADAMTS13 in TTP results in the formation of ultra large VWF multimers on the endothelium.
Despite the pathological mechanism, response to plasmapheresis is poor 30,34,35. Few case reports document successful use of rituximab 11,36,37 and eculizumab 35,38,39. Given the wide spectrum of potential causes for TMA in cancer patients, the aim of this review is to gather the vast information available. For each entity, pathophysiological mechanisms, clinical features, therapeutic approaches and prognosis will be covered.
Table IV
D Endothelial cell swelling, characterized by the enlargement of endothelial cells in the capillaries of the lamina propria. Routine blood examinations were collected prior to each narsoplimab dose and then twice weekly. In what concerns HSCT-induced TMA, the high number of confounding factors have made it difficult to understand its underlying mechanisms. Tumor-induced TMA, in contrast, was recognized decades ago in the context of solid tumours; in the last few years, comprehension of TMA in onco-hematological patients was significantly improved. Despite the arising number of available drugs in recent years, post-HSCT kidney dysfunction remains a significant complication 138. A retrospective study showed that patients who recover from HSCT-TMA preserve only 40% of initial kidney function 99.
Compared to historical controls, rituximab (4 × 375 mg/m2) shortens the duration of treatment, reduces the risk of recurrence (10% versus 57%), and increases the duration of remission (with a median of 27 months versus 18 months) (14). Although rituximab is not approved for treatment of TTP (off-label use), it is currently the drug of choice for the long-term control of immune-mediated aTTP (recommendation grade I B) (5). 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.
The ADAMTS13 activity of the patient with evidence supporting a definite association of TMA with pentostatin was 50%. She was not tested for pentostatin-dependent, platelet-reactive antibodies. Twenty-two of the 37 patients who did not have definite evidence supporting a causal association with the suspected drug, including 10 patients in whom the mechanism was postulated to be immune-mediated, had drug-dependent antibody tests; all were negative. Twenty-four of these 37 patients had ADAMTS13 activity measured; none were severely deficient (mean, 63%; range, 25–100%).
