Withdrawal of the offending drug and blood pressure control are the cornerstone of treatment, showing good results 6. Docetaxel is a taxane derivative that stabilizes microtubules, used in several solid cancers. Nevertheless, the presence of an alternative potential TMA trigger, namely another drug 51,58 or a metastatic cancer 59, was frequent. Doxorubicin is an anthracycline that acts as a topoisomerase II inhibitor. Pegylated liposomal doxorubicin (PLD) is commonly used in recurrent ovarian cancer.
84 Disease Driven Versus Continuous Eculizumab Therapy
However, characteristic features of other TMA are uncommon in DIC, such as severe thrombocytopenia, normal coagulation studies and platelet-rich microthrombi (without significant fibrin) 142,146. DIC pathogenesis also suggests that a procoagulant exposure may initiate the disease 145, although it shares many potential triggers with TMA 146. Scoring systems were developed to improve diagnosis accuracy of DIC, such as the ISTH (International Society of Thrombosis and Hemostasis) score, with a sensitivity and specificity above 90% 7,146.
Whilst a functional ADAMTS13 deficiency is essential for a diagnosis of TTP it is not sufficient to cause disease. Multiple secondary triggers have been identified that initiate disease, these include pregnancy and infection. Hematopoietic stem cell transplantation (HSCT) is no stranger to TMA, with an occurrence rate of 3%-39%.
Immune-mediated, Acquired Thrombotic Thrombocytopenic Purpura
In this opinion article, we aimed to summarize recent data on DITMA, categorizing drugs based on mechanisms of actions and specialties. A 63-year-old woman with 2 years of stage IIIB serous ovarian carcinoma presented to nephrology clinic for evaluation of AKI. Cancer treatment included debulking surgery followed by adjuvant carboplatin/paclitaxel and then paclitaxel/bevacizumab. Six months before presentation, disease progression prompted treatment change to bevacizumab/gemcitabine, although one month ago, bevacizumab was discontinued due to new-onset difficult-to-control hypertension.
What Is The Treatment?
MMC is an antibiotic that works as a cell-cycle specific alkylating agent, still used in bladder cancer 17. MMC-induced TMA was first described in 1971, becoming the prototype of TMA caused by classical chemotherapy 18. Additionally, complications of acute infection have been described including macro thrombosis and AKI. Almost a third of patients can still develop thrombosis despite anticoagulation in this prothrombotic state.76 While C5 inhibition was proposed for to prevent these broader thrombotic events, a trial of ravulizumab in COVID‐19 was stopped due to lack of efficacy. Shiga toxin was first detected in Shigella dysenteriae and this remains an important cause of HUS in developing countries. The clinical features are similar to STEC‐HUS but the diarrhoea is initially more watery before becoming bloody or mucoid and fever is common.
Treatment is based on immediate and permanent drug cessation 30,34 and recurrence has been described with repeated exposure 32. 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.
TMA Associated With Glomerular Disease
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. 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. 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.
Plasma Exchange Is Usually Ineffective
- This will require deeper evaluation of the DITMA pathophysiological mechanism for future reclassifications and drug/disease-based treatment.
- Data sharing is not applicable to this article as no new data were created or analyzed in this study.
- Despite the arising number of available drugs in recent years, post-HSCT kidney dysfunction remains a significant complication 138.
- Recent research developments have revolutionized the understanding of the disease processes and lead to the development targeted therapeutics for TMAs.
- As laboratory data returns, the diagnosis and treatment may change (e.g., an initial empiric diagnosis of TTP may be changed to a diagnosis of probable C-HUS after a normal ADAMTS13 level is reported).
- For DITP, the target condition is defined simply by a platelet count less than 100,000/µL.
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. Different from DITP, in which the drug-dependent antibodies react only with platelets, in DITMA the drug-dependent antibodies react with multiple different cells to cause the systemic microvascular thrombosis that defines TMA. Quinine-induced TMA is typically a very sudden and severe illness with severe kidney injury. Patients often can recall the exact time, place, and circumstances of their initial symptoms, and these symptoms typically occur within several hours of quinine exposure.
Tyrosine Kinase Inhibitors
Teresa Chuva is a Nephrology Physician Assistant, working at Portuguese Oncology Institute of Porto since her early residency in Nephrology. She has a particular interest in kidney effect of the most recent targeted therapies, with several peer-reviewed publications in the Onco-Nephrology field. João Pedro Barreto is a 2nd year Clinical Pathology resident whose fields of interest include hematopathology, cancer treatment adverse effects, their laboratory work-up and monitoring. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Despite its rarity, TMA in Oncology is a potentially fatal condition whose varied pathophysiological features remain vastly unknown. A high grade of suspicion is therefore crucial for a prompt recognition and treatment.
Others (e.g., vincristine, adriamycin, and 5-fluorouracil 5-FU) have also been implicated in fewer case reports almost always in the setting of concomitant or recent exposure with the abovementioned agents or antiangiogenic therapy. Clinical features of drug-induced thrombotic microangiopathies (DITMA) are shown. Finally, the histological examination remains the gold standard for TA-TMA diagnosis and ideally it should be performed whenever possible, even though the compromised clinical conditions of many patients limit the feasibility of such a diagnostic approach 37. Data were presented as number with percentage for categorical variables and as mean or median with range for continuous ones. Overall survival (OS) and one-hundred-day survival were calculated from TA-TMA diagnosis or from transplant date to death for any cause or last follow-up.
Primary TMAs mainly include hereditary or acquired forms of TTP and primary atypical hemolytic uremic syndrome (aHUS). Their pathogeneses are well-understood, and their respective diagnosis and treatment are well-developed. Drugs (including chemotherapy), pregnancy, malignant hypertension, autoimmune rheumatic diseases, infection, transplant, and malignancy constitute the secondary TMAs (Figure 1). Example published cases of type I (chemotherapy) and type II (targeted therapy) antineoplastics are presented along with therapeutics explored and outcomes where available. The overactivation or deregulation of complement system is not proven in DITMA patients and, consequently, indications for eculizumab treatment are limited. 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.
Inappropriate intravenous use of oxymorphone (Opana ER) or oxycodone ER (OxyContin) can lead to drug induced-TMA due to postulated toxicity of polyethylene oxide, a high molecular weight filler intended to make the pills tamper-resistant. 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. The clinical picture was further complicated by an invasive fungal infection. 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.
Data Sources, Search Strategies, Article Selection, And Review
In SLE the CP is a key driver of disease with AP recruitment also seen, although to date there is no correlation with complement activity and the development of a TMA in SLE. Case reports describe the use of eculizumab in SLE‐TMA suggested a response65 however larger case series failed to replicate this. 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.
The syndrome was characterized by AKI, non-nephrotic proteinuria and HTN, without anemia or thrombocytopenia. However, one of them was simultaneously treated with bevacizumab and, several years before, the 3 patients were treated with platins 54,56. Eculizumab was licensed for long term treatment of aHUS however there is no evidence for this recommendation.
Moreover, thrombocytopenia and anemia can sometimes make the biopsy a risky game. In classic cases, successful empiric treatment itself would clinch the diagnosis. On the other hand, it’s been observed that arterial wall changes are more specific for malignant hypertension (HTN) or scleroderma renal crisis, whereas glomerular changes are more specific for CM-TMA. 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.
