How I treat thrombotic microangiopathy in the era of rapid genomics.

Thrombotic microangiopathy (TMA) encompasses various genetically-driven diseases. The emergence of ultrafast genomic sequencing has recently opened up new avenues of research for genetic investigations in the setting of intensive care units. TMA is likely to be a suitable focus for fast-track genomic sequencing. By establishing an expeditious molecular diagnosis of patients with the complement-dependent hemolytic uremic syndrome, fast-track genomic sequencing allows for the timely implementation or withdrawal of anti-C5 treatment while averting unnecessary, costly, and potentially harmful therapy in patients testing negative for the syndrome. Furthermore, genomics has the potential to reshape the taxonomic classification of TMA owing to comprehensive genomic analysis. The most significant results from such analysis can be categorized as (1) new descriptions of genetic diseases previously not recognized as associated with TMA and (2) an enrichment of the phenotypic spectrum of diseases traditionally related to TMA. The latter draws on the concept of retrophenotyping, wherein genomic investigation precedes full clinical description. By taking precedence over a phenotypic approach, an unbiased genomic-focused analysis maximizes the chances of discovering new descriptions of a given variant. Presented here are 4 cases of TMA which highlight these issues and substantiate the promise of fast-track genomic sequencing.

A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Alemtuzumab-induced immune-mediated thrombotic thrombocytopenic purpura: A newly described drug-related autoimmune disease.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease that may result from drug exposure. We report a case of iTTP occurring in a 39-year-old patient, 45 months following introduction of the anti-CD52 lymphoid cell depleting monoclonal antibody alemtuzumab, to treat a relapsing-remitting multiple sclerosis. Treatment consisted in plasma exchange, corticosteroids and caplacizumab, allowing clinical remission 3 months after the diagnosis, attested by the absence of thrombocytopenia and recovery of ADAMTS-13 activity. As other autoimmune disorders, iTTP may occur following alemtuzumab. This diagnosis should be suspected in patients with features of thrombotic microangiopathy following this treatment.

Thrombotic microangiopathy - the importance of a multidisciplinary approach.

PURPOSE OF REVIEW: The purpose of this review is to highlight the importance of a multidisciplinary thrombotic microangiopathies (TMA) Team. This goal will be accomplished through review of the complement system, discuss various causes of thrombotic microangiopathies (TMA), and aspects of their diagnosis and management. In so doing, readers will gain an appreciation for the complexity of this family of disorders and realize the benefit of a dedicated multidisciplinary TMA Team. RECENT FINDINGS: TMA causes derive from multiple specialty areas, are difficult to timely recognize, pose complex challenges, and require multidisciplinary management. Hematopoietic stem cell transplant-associated TMA (TA-TMA) and TA-TMA related multiorgan dysfunction syndrome (TA-TMA MODS) are areas of burgeoning research; use of complement testing and eculizumab precision-dosing has been found to better suppress complement activity in TA-TMA than standard eculizumab dosing. Newer tests are available to risk-stratify obstetric patients at risk for severe pre-eclampsia, whose features resemble those of TA-TMA MODS. Numerous disorders may produce TMA-like findings, and a systematic approach aids in their identification. TMA Teams elevate institutional awareness of increasingly recognized TMAs, will help expedite diagnostic and therapeutic interventions, and create pathways to future TMA-related research and facilitate access to clinical trials. SUMMARY: Establishment of a TMA-Team is valuable in developing the necessary institutional expertise needed to promptly recognize and appropriately manage patients with TMA.

Neurological involvement in hematopoietic stem cell transplantation-associated thrombotic microangiopathy.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT). The understanding of TA-TMA pathophysiology has expanded in recent years. Dysregulation of the complement system is thought to cause endothelial injury and, consequently, microvascular thrombosis and tissue damage. TA-TMA can affect multiple organs, and each organ exhibits specific features of injury. Central nervous system (CNS) manifestations of TA-TMA include posterior reversible encephalopathy syndrome, seizures, and encephalopathy. The development of neurological dysfunction is associated with a significantly lower overall survival in patients with TA-TMA. However, there are currently no established histopathological or radiological criteria for the diagnosis of CNS TMA. Patients who receive total body irradiation (TBI), calcineurin inhibitors (CNI), and severe acute and chronic graft-versus-host disease (GVHD) are at a high risk of experiencing neurological complications related to TA-TMA and should be considered for directed TA-TMA therapy. However, the incidence and clinical manifestations of TA-TMA neurotoxicity remain unclear. Studies specifically examining the involvement of CNS in TMA syndromes are limited. In this review, we discuss clinical manifestations and imaging abnormalities in patients with nervous system involvement in TA-TMA. We summarize the mechanisms underlying TA-TMA and its neurological complications, including endothelial injury, evidence of complement activation, and treatment options for TA-TMA.

Risk factors of death or chronic renal replacement therapy requirements in patients with thrombotic microangiopathies without ADAMTS-13 deficiency.

Thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multisystem organ dysfunction, is a life-threatening disease. Patients with TMA who do not exhibit a severe ADAMTS-13 deficiency (defined as a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 activity ≥10%: TMA-13n) continue to experience elevated mortality rates. This study explores the prognostic indicators for augmented mortality risk or necessitating chronic renal replacement therapy (composite outcome: CO) in TMA-13n patients. We included 42 TMA-13n patients from January 2008 to May 2018. Median age of 41 years and 60% were female. At presentation, 62% required dialysis, and 57% warranted intensive care unit admission. CO was observed in 45% of patients, including a 9-patient mortality subset. Multivariate logistic regression revealed three independent prognostic factors for CO: early administration of eculizumab (median time from hospitalization to eculizumab initiation: 5 days, range 0-19 days; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.94), presence of neuroradiological lesions (OR, 6.67; 95% CI, 1.12-39.80), and a PLASMIC score ≤4 (OR, 7.39; 95% CI, 1.18-46.11). In conclusion, TMA-13n patients exhibit a heightened risk of CO in the presence of low PLASMIC scores and neuroradiological lesions, while early eculizumab therapy was the only protective factor.

Late transplant-associated thrombotic microangiopathy verified in bone marrow biopsy specimens is associated with chronic GVHD and viral infections.

OBJECTIVES: To describe late transplant-associated thrombotic microangiopathy (TA-TMA) as chronic endothelial complication in bone marrow (BM) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: BM specimens along with conventional diagnostic parameters were assessed in 14 single-institutional patients with late TA-TMA (more than 100 days after HCST), including 11 late with history of early TA-TMA, 10 with early TA-TMA (within 100 days), and 12 non TA-TMA patients. Three non-HSCT patients served as control. The time points of BM biopsy were +1086, +798, +396, and +363 days after HSCT, respectively. RESULTS: Late TA-TMA patients showed an increase of CD34+ and von Willebrand Factor (VWF)+ microvascular endothelial cells with atypical VWF+ conglomerates forming thickened VWF+ plaque sinus in the BM compared to patients without late TA-TMA and non-HSCT. Severe chronic (p = .002), steroid-refractory GVHD (p = .007) and reactivation of HHV6 (p = .002), EBV (p = .003), and adenovirus (p = .005) were pronounced in late TA-TMA. Overall and relapse-free survival were shorter in late TA-TMA than in patients without late TA-TMA (5-year OS and RFS: 78.6% vs. 90.2%, 71.4% vs. 86.4%, respectively). CONCLUSION: Chronic allo-immune microangiopathy in BM associated with chronic, steroid-refractory GVHD and/or viral infections are key findings of late, high-risk TA-TMA, which deserves clinical attention.

D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards models were used to identify sub-distribution hazard ratios (sHR)  for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.

Thrombotic Microangiopathy After Hematopoietic Stem Cell and Solid Organ Transplantation: A Review for Intensive Care Physicians.

Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies.

Post-COVID-19 complement-mediated TMA: A case report.

Systemic COVID-19 disease is associated with a variety of organ involvement in infected patients. A rarely reported complication is the induction of complement-mediated thrombotic microangiopathy (TMA). TMA is an extremely rare pathological condition that results in thrombosis in capillaries and small arterioles, due to an endothelial injury. It is often combined with thrombocytopenia, Coombs-negative hemolytic anemia, and end-organ damage. This case involves a patient who was admitted to our hospital for the purpose of diagnosis and treatment of acute kidney injury (AKIN 3) with severe proteinuria after a preceding SARS-CoV-2 infection. A 77-year-old male patient had COVID-19 pneumonia in January 2021 with the need of high-flow oxygen therapy in the intensive care unit. In March 2021, he was hospitalized again due to elevated serum creatinine levels and proteinuria. The patient exhibited normal vital parameters. A renal biopsy showed severe TMA. A diagnosis of COVID-19-associated TMA was made, and treatment with high-dose glucocorticoid therapy and plasma exchange was initiated. Additionally, therapy with eculizumab was established. Unfortunately, the kidney failure was initially progressive, so that hemodialysis (HD) was temporarily necessary. In May 2021, kidney function recovered to an estimated glomerular filtration rate of ~ 30 mL/min/1.73m2 corresponding to chronic kidney disease stage 3bA3 - 4A3. COVID-19-associated TMA is an extremely rare disease. TMA may be a possible long-term complication with the risk of end-stage renal disease if not properly diagnosed and treated.

To bite the hand that feeds you: A case of thrombotic microangiopathy due to Tiger snake bite.

This report details the case of a 51-year-old man with a Tiger snake bite who developed systemic envenomation, coagulopathy and thrombotic microangiopathy (TMA) requiring renal replacement therapy. He received plasma exchange as additional therapy while awaiting confirmation of the cause of the TMA. We discuss clinical decision making in detection of systemic envenomation and management of the rare complication of TMA, as well as current Australian guidelines around antivenom administration. This is the fourth known documented case of TMA from a Tiger snake bite in Australia.

The Phenomenon of Thrombotic Microangiopathy in Cancer Patients.

Thrombotic microangiopathy (TMA) encompasses a range of disorders characterized by blood clotting in small blood vessels, leading to organ damage. It can manifest as various syndromes, including thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and others, each with distinct causes and pathophysiology. Thrombo-inflammation plays a significant role in TMA pathogenesis: inflammatory mediators induce endothelial injury and activation of platelet and coagulation cascade, contributing to microvascular thrombosis. Primary TMA, such as TTP, is primarily caused by deficient ADAMTS13 metalloproteinase activity, either due to antibody-mediated inhibition or intrinsic enzyme synthesis defects. In cancer patients, a significant reduction in ADAMTS13 levels and a corresponding increase in VWF levels is observed. Chemotherapy further decreased ADAMTS13 levels and increased VWF levels, leading to an elevated VWF/ADAMTS13 ratio and increased thrombotic risk. Drug-induced TMA (DITMA) can result from immune-mediated or non-immune-mediated mechanisms. Severe cases of COVID-19 may lead to a convergence of syndromes, including disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and TMA. Treatment of TMA involves identifying the underlying cause, implementing therapies to inhibit complement activation, and providing supportive care to manage complications. Plasmapheresis may be beneficial in conditions like TTP. Prompt diagnosis and treatment are crucial to prevent serious complications and improve outcomes.

[Lupus nephritis and thrombotic microangiopathy: A review].

Lupus nephritis (LN) is one of the most common organ-specific manifestations of systemic lupus erythematosus (SLE). Various clinical signs of LN develop in at least 50% of patients with SLE. In addition to LN, the spectrum of renal lesions associated with SLE also includes vascular pathology. One of the variants of renal microvascular injury is thrombotic microangiopathy (TMA), the mechanisms of which are diverse. The review focuses on the main forms of TMA, including antiphospholipid syndrome and nephropathy associated with antiphospholipid syndrome, TMA caused by complement system regulation disorders and deficiency of ADAMTS13. In most cases, these forms of TMA are combined with LN. However, they may also exist as a single form of kidney damage. This article discusses the TMA pathogenesis, the impact on kidney prognosis, and treatment options.

A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies.

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.

Haemolytic uraemic syndrome.

Haemolytic uraemic syndrome (HUS) is a heterogeneous group of diseases that result in a common pathology, thrombotic microangiopathy, which is classically characterised by the triad of non-immune microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In this Seminar, different causes of HUS are discussed, the most common being Shiga toxin-producing Escherichia coli HUS. Identifying the underlying thrombotic microangiopathy trigger can be challenging but is imperative if patients are to receive personalised disease-specific treatment. The quintessential example is complement-mediated HUS, which once carried an extremely high mortality but is now treated with anti-complement therapies with excellent long-term outcomes. Unfortunately, the high cost of anti-complement therapies all but precludes their use in low-income countries. For many other forms of HUS, targeted therapies are yet to be identified.

Renal Thrombotic Microangiopathy: A Review.

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.

C3 Glomerulopathy With Concurrent Thrombotic Microangiopathy: Clinical and Immunological Features.

RATIONALE & OBJECTIVE: C3 glomerulopathy (C3GN) and atypical hemolytic uremic syndrome (aHUS) are 2 distinct rare kidney diseases caused by dysregulation of the alternative complement pathway. Patients with C3GN and concurrent kidney lesions of thrombotic microangiopathy (TMA) have been rarely reported. We characterized the clinical features and underlying immunological abnormalities in these patients. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients with C3GN and concomitant TMA lesions on biopsy registered from 2009 to 2019 in the French National Registry of C3GN. FINDINGS: Among 278 registered patients with C3GN, 16 (6%) had biopsy-proven glomerular and/or vascular TMA lesions. Their median age at diagnosis was 39 years (range, 7-76), and 59% were female. Fourteen of the 16 patients (88%) had an estimated glomerular filtration rate of<30mL/min/1.73m2 and 3 of 16 (19%) required dialysis. Twelve of the 14 evaluated patients (86%) showed evidence of mechanical hemolysis. Fifty percent of the patients had low C3 levels. Six of the 14 evaluated patients had a rare variant in complement genes, and 4 of the 16 patients (25%) had monoclonal gammopathy. Among the 16 patients, 10 (63%) received eculizumab, 5 (31%) received immunosuppressive therapy, and 4 (25%) received clone-targeted chemotherapy. Median kidney survival was 49 months. LIMITATIONS: Small retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Concomitant C3GN and TMA is extremely rare and is associated with poor kidney outcomes. Genetic or acquired abnormalities of the alternative complement pathway are common as is the presence of monoclonal gammopathy, which may inform the selection of treatment approaches.

How I treat microangiopathic hemolytic anemia in patients with cancer.

Microangiopathic hemolytic anemia (MAHA) with thrombocytopenia, suggests a thrombotic microangiopathy (TMA), linked with thrombus formation affecting small or larger vessels. In cancer patients, it may be directly related to the underlying malignancy (initial presentation or progressive disease), to its treatment, or a separate incidental diagnosis. It is vital to differentiate incidental thrombotic thrombocytopenia purpura or atypical hemolytic uremic syndrome in cancer patients presenting with a TMA, as they have different treatment strategies, and prompt initiation of treatment impacts outcome. In the oncology patient, widespread microvascular metastases or extensive bone marrow involvement can cause MAHA and thrombocytopenia. A disseminated intravascular coagulation (DIC) picture may be precipitated by sepsis or driven by the cancer itself. Cancer therapies may cause a TMA, either dose-dependent toxicity, or an idiosyncratic immune-mediated reaction due to drug-dependent antibodies. Many causes of TMA seen in the oncology patient do not respond to plasma exchange and, where feasible, treatment of the underlying malignancy is important in controlling both cancer-TMA or DIC driven disease. Drug-induced TMA should be considered and any putative causal agent stopped. We will discuss the differential diagnosis and treatment of MAHA in patients with cancer using clinical cases to highlight management principles.

Comparison of multiple treatments in the management of transplant-related thrombotic microangiopathy: a network meta-analysis.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA) is a fatal post-transplant complication. It has a high mortality rate and worse prognosis, but treatment strategies remain controversial. We screened 6 out of 3453 studies on the treatment of TA-TMA. These investigations compared 5 treatment strategies with a network meta-analysis approach. The final outcome was the proportion of patients who responded to these therapies. There were significant differences in response rates for each treatment. Achieving analysis through direct and indirect evidence in the rank probabilities shows that rTM (recombinant human soluble thrombomodulin) is most likely to be rank 1 (64.98%), Eculizumab intervention rank 2 (48.66%), ISM (immunosuppression manipulation) rank 3 (32.24%), TPE (therapeutic plasma exchange) intervention rank 4 (69.56%), and supportive care intervention rank 5 (70.20%). Eculizumab and ISM have significantly higher efficacy than supportive care (odds ratio (OR): 18.04, 18.21 respectively); and TPE having lower efficacy than all other TA-TMA therapies exception to supportive care. In our study, rTM and Eculizumab may be the best choice when treating TA-TMA.