Thrombotic microangiopathy in patients with sickle cell disease.

OBJECTIVE: To describe two cases of patients who had thrombotic microangiopathy (TMA) associated with sickle cell disease (SCD). CASE DESCRIPTION: Both patients started with a painful crisis and had acute chest syndrome during hospitalization. They showed significant worsening of hemolytic anemia, with very high levels of lactate dehydrogenase, thrombocytopenia, lowered level of consciousness, organ damage and the presence of schistocytes in peripheral blood. Due to the possibility of TMA, despite the very rare association with SCD, they were treated with fresh frozen plasma replacement and plasmapheresis, with good response. COMMENTS: TMA is a serious, life-threatening disease, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. The association of SCD and TMA is difficult to diagnose, since they can share a similar clinical presentation. Recognizing this association and promptly instituting treatment may impact the survival of these patients.

How We Interpret Thrombosis with Thrombocytopenia Syndrome?

Platelets play an important role in hemostasis, and a low platelet count usually increases the risk of bleeding. Conditions in which thrombosis occurs despite low platelet counts are referred to as thrombosis with thrombocytopenia syndrome, including heparin-induced thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, thrombotic microangiopathy (TMA), and disseminated intravascular coagulation. TMA includes thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (HUS), and atypical HUS. Patients with these pathologies present with thrombosis and consumptive thrombocytopenia associated with the activation of platelets and the coagulation system. Treatment varies from disease to disease, and many diseases have direct impacts on mortality and organ prognosis if therapeutic interventions are not promptly implemented. Underlying diseases and the results of physical examinations and general laboratory tests as part of a thorough workup for patients should promptly lead to therapeutic intervention before definitive diagnosis. For some diseases, the diagnosis and initial treatment must proceed in parallel. Utilization of not only laboratory tests but also various scoring systems is important for validating therapeutic interventions based on clinical information.

The kidney histopathological spectrum of patients with kidney injury following snakebite envenomation in India: scoping review of five decades.

INTRODUCTION: Snakebite is a public health problem leading to about 58,000 deaths every year in India. Kidney injury subsequent to snakebite envenomation is common with a reported prevalence of up to 32%. The current study aims to elucidate the spectrum of kidney histopathology in acute kidney injury (AKI) cases associated with snake bites. METHODS: We searched seven electronic database studies to identify studies describing the histopathological findings in the kidney with snakebite envenomation. Two reviewers independently conducted titles and abstract screening as well as full-text evaluation for the final inclusion decision. Data were extracted as per the standardized form. We conducted narrative synthesis. Studies done exclusively on autopsy findings, in vitro studies, and case reports were excluded. RESULTS: We retrieved 1464 studies and finally included 28 studies which met the eligibility criteria in the analysis. Most studies were single-centre and the majority were cross-sectional. Overall we included a total of 534 renal biopsies. Russell's viper bite was the most common cause related to AKI. Acute tubular necrosis was the most common finding followed by acute interstitial nephritis, acute cortical necrosis (ACN), and thrombotic microangiopathy (TMA). Vasculitis changes in vessels were rarely reported. Lesions such as ACN and TMA were associated with poor outcomes. CONCLUSION: This analysis supports the notion that renal biopsies are important to guide prognosis and increase our knowledge about post-snake bite AKI pathophysiology.

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.

An unusual complication of kidney biopsy: a case report.

BACKGROUND: The kidney biopsy is a routine procedure. Once an indication has been established, the benefit-risk balance may be considered. Sometimes, even with effective treatment, a severe complication may develop. CASE PRESENTATION: We present the case of a Caucasian 20-year-old young woman admitted to investigating and treating acute kidney injury. Renal involvement was characterized by kidney damage requiring hemodialysis treatment, positive immunologic testing, 0.5 g/day proteinuria, and microscopic hematuria. Contraindications were excluded, so an ultrasound-guided kidney biopsy was performed. To reduce the bleeding complication, Octostim (desmopressin) was administered. There were no direct complications following the kidney biopsy, so we continued the immunosuppressive treatment. Histologically founded thrombotic microangiopathy. However, 1 week later, severe bleeding developed with the need for urgent surgical left kidney removal. CONCLUSION: Kidney biopsy can be considered a routine procedure, and various bleeding episodes are most common in terms of complications, the detection of which is essential. Delayed bleeding complications are rare and can be caused by minor injuries. Our young patient had no injury during the hospitalization. We hypothesized that the developed serious and delayed bleeding complication resulted from effective immunosuppressive treatment. To the best of our knowledge, this is the first such case to date. However, renal biopsy in the case of thrombotic microangiopathy requires caution.

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.

Investigation of Clinical Features and Association between Vascular Endothelial Injury Markers and Cytomegalovirus Infection Associated with Thrombotic Microangiopathy in Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: Case-Based Research.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) can occasionally trigger thrombotic microangiopathy (TMA). Cytomegalovirus (CMV) may be reactivated during intensive immunosuppressive therapy for AAV and cause TMA. Therefore, we aimed to evaluate the clinical features of and the association between vascular endothelial injury markers and TMA due to CMV in patients with AAV. A 61-year-old female was diagnosed with AAV and severe kidney injury. Immunosuppressive therapy gradually improved her symptoms and laboratory findings. However, 2 weeks after induction therapy initiation, she exhibited altered consciousness, a significant decrease in platelet count, and hemolytic anemia, resulting in a TMA diagnosis. Plasma exchange did not improve TMA findings and routine screening test revealed CMV infection. Ganciclovir injection improved the infection and TMA findings. Consequently, we diagnosed her with CMV-induced TMA. Both AAV and CMV may induce severe vascular endothelial injury, potentially leading to TMA development. CMV-induced TMA should be considered when TMA develops during induction therapy against AAV. Moreover, of the three serum markers of vascular injury-serum sulfatides, soluble thrombomodulin, and pentraxin 3-serum sulfatides may be associated with the development of TMA, and a high level of soluble thrombomodulin may be associated with the development of CMV viremia during the clinical course of AAV.

Chronic thrombotic microangiopathy presenting as acute nephrotic syndrome in a patient with renal cancer receiving tyrosine kinase inhibitor therapy.

Thrombotic microangiopathy (TMA) is a rare but serious side effect of tyrosine kinase inhibitor (TKI) therapy. Previous case reports of renal TMA have usually occurred in the first few months of TKI initiation with only very few cases occurring within 2-3 years. We report a case of a patient who was referred to the Nephrology service for nephrotic syndrome and worsening renal function after 8 years of sunitinib therapy for metastatic clear cell carcinoma of the kidney. Renal biopsy showed chronic TMA without another secondary aetiology identified. With discontinuation of sunitinib and pharmacological optimisation of his hypertension, his renal function and proteinuria both significantly improved. No relapse or recurrence of disease activity was noted after a year of follow-up. This case highlights the importance of remaining vigilant for the development of renal TMA even after an extended duration of TKI therapy.

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.

Clinical Evaluation and Management of Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) refers to a diverse group of diseases that share clinical and histopathologic features. TMA is clinically characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and organ injury that stems from endothelial damage and vascular occlusion. There are several disease states with distinct pathophysiological mechanisms that manifest as TMA. These conditions are associated with significant morbidity and mortality and require urgent recognition and treatment. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are traditionally considered to be primary forms of TMA, but TMA more commonly occurs in association with a coexisting condition such as infection, pregnancy, autoimmune disease, or malignant hypertension, among others. Determining the cause of TMA is a diagnostic challenge because of limited availability of disease-specific testing. However, identifying the underlying etiology is imperative as treatment strategies differ. Our understanding of the conditions that cause TMA is evolving. Recent advances have led to improved comprehension of the varying pathogenic mechanisms that drive TMA. Development of targeted therapeutics has resulted in significant improvements in patient outcomes. In this article, we review the pathogenesis and clinical features of the different TMA-causing conditions. We outline a practical approach to diagnosis and management and discuss empiric and disease-specific treatment strategies.

Misdiagnosis of thrombotic microangiopathy in the emergency department: a multicenter retrospective study.

To estimate the rate of inappropriate diagnosis in patients who visited the ED with thrombotic microangiopathy (TMA) and to assess the factors and outcomes associated with emergency department (ED) misdiagnosis. Retrospective multicenter study of adult patients admitted to the intensive care unit (ICU) for TMA from 2012 to 2021 who had previously attended the ED for a reason related to TMA. Patient characteristics and outcomes were compared in a univariate analysis based on whether a TMA diagnosis was mentioned in the ED or not. Forty patients were included. The diagnosis of TMA was not mentioned in the ED in 16 patients (40%). Patients for whom the diagnosis was mentioned in the ED had more frequently a request for schistocytes research, and therefore had more often objectified schistocytes. They also had more frequently a troponin dosage in the ED (even if the difference was not significant), an ECG performed or interpreted, and were admitted more quickly in the ICU (0 [0-0] vs 2 [0-2] days; P = 0.002). Hemoglobin levels decreased significantly in both groups, and creatinine levels increased significantly in the misdiagnosis group between ED arrival and ICU admission. In patients with a final diagnosis of TTP, the time to platelets durable recovery was shorter for those in whom the diagnosis was mentioned in the ED without reaching statistical significance (7 [5-11] vs 14 [5-21] days; P = 0.3).

Thrombotic microangiopathy in a patient with anti-signal recognition particle antibody-positive immune-mediated necrotizing myopathy.

We describe the case of a 61-year-old woman with anti-signal recognition particle (SRP) antibody-positive immune-mediated necrotizing myopathy (IMNM) who exhibited biopsy-confirmed thrombotic microangiopathy (TMA). The patient developed proximal-dominant muscle weakness and was diagnosed with anti-SRP antibody-positive IMNM based on muscle biopsy results and serological examination. A high-dose corticosteroid prescription was initiated, followed by intravenous methylprednisolone and intravenous immunoglobulin therapy (IVIg). The patient showed IVIg-induced hemolytic anemia with preserved ADAMTS13 activity. Transient oral tacrolimus administration was initiated. Approximately 8 weeks after admission, the serum creatinine levels gradually increased. Renal histological examination revealed TMA, including ischemic changes in the renal tubules, stenosis, and occlusion of the interlobular arteries with fibrinoid necrosis of the afferent arteriolar walls. The arteriolar walls demonstrated an accumulation of C1q and C3c. Myofiber damage in patients with IMNM accounts for the activation of the classical pathway of the complement cascade in the sarcolemma due to antibody deposition. Additionally, a membrane attack complex is observed on capillaries in the muscle tissues of patients with anti-SRP antibody-positive IMNM. Although drug-induced pathomechanisms, such as IVIg and tacrolimus, can trigger the development of TMA, we suggest that the presence of serum anti-SRP antibodies would be implicated in complement-associated kidney vascular damage.