Cause Of Thrombotic Microangiopathy Research Articles

Vitamin B12 Deficiency in Thrombotic Thrombocytopenic Purpura-Like Cases.

Thrombotic microangiopathies (TMA) are characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage which occur in the setting of endothelial damage and platelet activation. Vitamin B12 (cobalamin) deficiency could lead to a picture that resembles TMA, termed metabolic mediated TMA (MM-TMA). A 60-year-old female was brought to the hospital after she was found unresponsive. On presentation, she was pale, lethargic, tachycardic, and febrile. Laboratory investigations revealed normocytic anemia, thrombocytopenia, and elevated bilirubin. Blood smear revealed schistocytes and tear drop cells. Given the presence of hemolytic anemia, thrombocytopenia, acute renal failure, and altered mental status, a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) was made with a PLASMIC score of 7 indicating high risk. She received plasma exchange, caplacizumab, and intravenous methylprednisolone. Given the patient's low level of vitamin B12, she was initiated on intramuscular cyanocobalamin 1000 μg daily. The encephalopathy resolved and renal function improved. On day 6, ADAMTS13 activity was normal ruling out the diagnosis of TTP. Accordingly, plasmapheresis, steroids, and caplacizumab were discontinued. With continued aggressive B12 replacement, hemolysis resolved indicating severe vitamin B12 deficiency was the likely culprit of this patient's microangiopathic hemolytic anemia. This case serves to highlight the variable presentation of vitamin B12 deficiency. Severe vitamin B12 deficiency can even mimic TTP. If patients have markers of hemolysis, a low vitamin B12 level, and low reticulocyte count we should consider vitamin B12 deficiency as a likely cause of microangiopathic hemolytic anemia as early detection allows for early initiation of appropriate management. Vitamin B12 deficiency can be a cause of thrombotic microangiopathy.

Malignant hypertension as a rare cause of thrombotic microangiopathy associated with end-stage renal disease

Malignant hypertension (MH) can precipitate and worsen renal thrombotic microangiopathy. Also, renal thrombotic microangiopathies (TMA) can cause malignant hypertension. Case reports regarding this clinical presentation are limited. A 36-year-old man presented with low urine output and bilateral leg swelling for five days with two episodes of haemoptysis. He was identified as a patient with hypertensive emergency with hypertension mediated organ damage (HMOD) in cardiac and renal functions with thrombotic microangiopathy. Renal biopsy revealed focal acute tubular injury with moderate tubulointerstitial nephritis and hypertensive vascular changes. Multiple anti-hypertensive medications were used for adequate blood pressure control. Despite that, the patient had worsening renal function, and eventually became dependent on haemodialysis. Malignant hypertension has to be considered as one of the aetiologies of TMA as it can lead to end-stage renal disease (ESRD) and poor outcomes. Diagnosis is difficult when both entities are presenting together.

#198 Different patterns of renal thrombotic microangiopathy

Abstract Background and Aims Thrombotic microangiopathy (TMA) is a renal lesion often associated with microangiopathic hemolysis. However, there are cases of TMA that present without hemolysis, hematuria or even proteinuria, sometimes being an incidental histopathological finding. In these situations, little is known about the long-term effects on renal function. The aim of our study is to describe the clinical and histopathological presentation of patients with renal TMA biopsied in our center, focusing on those without hemolysis and with low clinical suspicion of TMA. Method We conducted a retrospective observational unicentric study. Clinical and histological parameters were collected from patients biopsied between 2015 and 2023, whose renal biopsy (RB) showed TMA, with a minimum follow-up of 6 months. We excluded renal transplant recipients. Results Data were collected from 41 patients (17 men, 24 women), with a mean age at the time of RB of 54 ± 16 years and a mean eGFR of 80 ± 23 ml/min/1.72 m2. 12 of them (29%) had chronic kidney disease (CKD). Twenty-seven patients (66%) did not have hemolysis at diagnosis. Compared to patients with hemolysis, they were of older age (58 vs 47 years, p = 0.030) and had higher prevalence of CKD (41% vs 7%, p = 0.028). They had a milder clinical presentation, with lower creatinine (168 vs 419 μmol/L, p = 0.029), lower need for renal replacement therapy (RRT) (4% vs 50%, p = 0.001), less hematuria (33% vs 79%, p = 0.008) and proteinuria (67% vs 100%, p = 0.035). Histologically, patients without hemolysis had less fibrosis (56% vs 86%, p = 0.084) and fewer chronic TMA lesions (double contours, wrinkling of the basement membrane) (52% vs 93%, p = 0.009), despite delayed renal biopsy compared to patients with hemolysis (99 ± 118 vs 28 ± 30 days since clinical presentation, p = 0.036). The causes of TMA that were most commonly associated with the absence of hemolysis were drugs (89% without hemolysis) and glomerulopathies such as IgA nephropathy, minimal change disease and fibrillary glomerulonephritis (100% without hemolysis). Within this group of patients without hemolysis, 13 (32%) had a low clinical suspicion of TMA, defined as the absence of hemolysis, hypertension and predisposing factors, in some cases being an incidental finding in the RB. As expected, they also had a mild presentation and did not require RRT. In some cases, they even presented without proteinuria (7 patients, 64%). When comparing the severity of the lesions in renal tissue with patients with high clinical suspicion of TMA, patients with low clinical suspicion presented a similar prevalence of mesangiolysis, vascular damage and a similar proportion of affected glomeruli. Chronic TMA lesions were present in both groups (Table 1). When analysing the evolution of renal function, there are several confounding factors to consider (higher prevalence of CKD in patients without hemolysis, targeted treatment in patients with hemolysis, different time of follow-up between groups...). In our results, there were no statistically significant differences in the evolution of creatinine and proteinuria between groups, even when TMA was an incidental finding. In our sample, these findings were not attributable to a larger number of other histopathological lesions in patients with low suspicion of TMA, as there were no differences between groups (see Table 1). Conclusion Renal TMA should be suspected even in the absence of hemolysis, hypertension or proteinuria, as in our sample one third of diagnoses were incidental and their mild presentation may have delayed renal biopsy. The severity of histological lesions and the evolution of renal function in these cases are comparable to those of patients with a high clinical suspicion. Therefore, its prompt identification, etiological study and treatment are equally important. Currently, we have insufficient data to provide the different clinical scenarios in which TMA should be suspected. However, based on our findings, in the presence of drugs TMA should be considered in the differential diagnosis along with Acute Interstitial Nephritis, even in the absence of urinary abnormalities.

Thrombotic Microangiopathy in Solid Organ Transplantation

Thrombotic Microangiopathy (TMA) is a syndrome characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. The presence of schistocytes on peripheral smear, a negative Coombs test, elevated lactate dehydrogenase, increased reticulocyte count and low haptoglobin are often the clues for MAHA. The microvascular process often targets vasculature in kidneys, brain, gastrointestinal system, heart, and skin. A timely diagnosis and treatment are often crucial to prevent severe end organ damage and death. TMA is classified into primary and secondary forms. Primary TMA includes TTP and complement mediated or atypical hemolytic uremic syndrome (aHUS), often related to a mutation or deficiency and clinically expressed in the setting of a precipitant condition. Secondary TMA is a manifestation of underlying disorder and can occur in clinical scenarios associated with autoimmune disease, malignancy, infections, SOT (Solid Organ Transplant), pregnancy, HSCT (Hematopoietic Stem Cell Transplantation), medications, or methylmalonic acidemia. Transplant associated TMA (TA-TMA) can be complement mediated or aHUS and could be related to the ischemic reperfusion injury, induction regimen, calcineurin inhibitor (CNI) use, mammalian target of rapamycin (MTOR) inhibitor use, or could be infection related. Cost, access, and turnaround time are often the limitations for certain TTP and complement specific testing. Treatment should not be delayed while waiting for such tests. Treatment must be individualized based on the underlying cause of TMA. Terminal complement blockade utilizing monoclonal antibodies directed against C5 complement is the treatment for complement mediated TMA. C5 inhibitors have also been used successfully in treatment of secondary HUS cases where, unlike aHUS, defects in complement cannot be demonstrated. Such treatment has demonstrated improvement in renal function, MAHA and platelet counts.

Thrombotic Microangiopathy in Renal Transplant Recipients

Background and Aim: Thrombotic microangiopathy (TMA) is a disease of microvasculature, triggered by numerous immunological and nonimmunological factors. The aim of this study is to identify the incidence, etiology, and clinical characteristics of posttransplant TMA in renal allografts and its impact on graft outcome. Patients and Methods: In this retrospective study, the records of patients who underwent renal transplantation between January 2013 and December 2017 were reviewed, and those recipients who had allograft biopsy-proven TMA were analyzed. Based on the clinical characteristics and investigations, the recipients were divided into two groups: those with systemic features of TMA and those with allograft-limited TMA. The clinical course and graft outcome of both the groups were compared and analyzed. Results: The number of patients who underwent renal transplantation during the study period was 212. Out of them, 16 patients had biopsy-proven TMA. Five patients had TMA with systemic features and the remaining 11 patients had allograft-limited TMA. In this study, the incidence of TMA among postrenal transplant recipients was 7.5%. The most common cause for TMA was acute antibody-mediated rejection (ABMR), followed by TMA due to tacrolimus toxicity. In one patient, TMA was secondary to disseminated tuberculosis (TB). TB as a cause of TMA is rarely reported. One-year graft survival in patients with allograft-limited TMA was 72.7% when compared to 50% in patients with systemic TMA, but this difference was statistically insignificant (P = 0.2). The graft loss was high in patients with TMA secondary to ABMR in both the groups. Conclusion: One-year graft survival is better in patients with allograft-limited TMA. Diligent search for an etiology for TMA should be made in all patients with TMA, as the treatment differs between each category.

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.

A Moderate Decrease in ADAMTS13 Activity Correlates with the Severity of STEC-HUS.

Atypical hemolytic uremic syndrome (HUS) develops as a result of damage to the endothelium of microvasculature vessels by Shiga toxin produced by enterohemorrhagic Escherichia coli (STEC-HUS). STEC-HUS remains the leading cause of acute kidney injury (AKI) in children aged 6 months to 5 years. The pathomorphological essence of the disease is the development of thrombotic microangiopathy (TMA). One of the key causes of TMA is an imbalance in the ADAMTS13-von Willebrand factor (vWF)-platelet system. The goal of the work was to clarify the role of a moderate decrease in ADAMTS13 activity in the pathogenesis of STEC-HUS. The activity of ADAMTS13 was determined in 138 children (4 months-14.7 years) in the acute period of STEC-HUS and the features of the course of the disease in these patients were analyzed. The study revealed a decrease in the activity and concentration of ADAMTS13 in 79.8% and 90.6% of patients, respectively. Measurements of von Willebrand factor antigen content and the activity of von Willebrand factor in the blood plasma of part of these patients were carried out. In 48.6% and 34.4% of cases, there was an increase in the antigen concentration and the activity of the Willebrand factor, respectively. Thrombocytopenia was diagnosed in 97.8% of children. We have demonstrated that moderately reduced ADAMTS13 activity correlates with the risk of severe manifestations of STEC-HUS in children; the rate of developing multiple organ failure, cerebral disorders, pulmonary edema, and acute kidney injury with the need for dialysis increases. It is assumed that reduction in ADAMTS13 activity may serve as a predictor of disease severity.

Clinical features of women with thrombotic microangiopathy in pregnancy: A case series from a single Japanese tertiary perinatal care center.

Although perinatal thrombotic microangiopathy has become increasingly understood, the racial characteristics of patients with this condition remain unclear. Herein, we report the characteristics of patients with perinatal thrombotic microangiopathy at a single institution in Japan. We conducted a retrospective study over a 5-year period from January 1, 2017, to December 31, 2021, using the electronic medical records of pregnant women who delivered at the perinatal center of our hospital. We extracted the data of those who developed perinatal thrombotic microangiopathy and evaluated their characteristics at the time of disease onset, final diagnosis, and maternal and fetal outcomes. Of the 10 224 deliveries that occurred during the 5-year period, only seven patients (0.06%) had perinatal thrombotic microangiopathy. The median pre-pregnant body mass index was 18.65 kg/m2 (minimum 17.3 kg/m2 , maximum 20.7 kg/m2 ). More than half of the patients were conceived by in-vitro fertilization, and 42% these had twin deliveries. Four patients had a history of rheumatic disease. The other three patients without underlying diseases developed thrombotic microangiopathy with HELLP syndrome, and one patient transitioned to atypical hemolytic uremic syndrome. Based on low body mass index and in-vitro fertilization, which are characteristic of Japanese women, medical complications and twin pregnancies may be a risk for thrombotic microangiopathy. Additionally, depending on the cause of thrombotic microangiopathy, its timing and onset differed.

#5990 COMPLEMENT GENES PROFILE OF PATIENTS WITH SEVERE HYPERTENSION AND RENAL THROMBOTIC MICROANGIOPATHY

Abstract Background and Aims Hereditary or acquired complement system dysregulation found to be driving cause of endothelial damage in atypical haemolytic uremic syndrome (aHUS) – ultrarare life-threatening disease, that always manifests with renal thrombotic microangiopathy (TMA), resulting in poor outcome in absence of appropriate treatment. Nevertheless, several studies show high incidence of rare genetic variants of complement system in other TMA’s, including hypertension-induced TMA. Here we report results of complement genes screening in patients (pts) with histologically identified renal TMA and severe hypertension in Russia, at first diagnosed as hypertension-induced TMA. Method A total of 28 Caucasian pts diagnosed with renal TMA (confirmed by kidney biopsy in all cases) and severe hypertension enrolled in the study. The main characteristic of the clinical picture was the absence of microangiopathic hemolysis and thrombocytopenia in prevailing of the pts, thus most of the primary and secondary causes of TMA clinically excluded. Examination of DNA samples was performed in all pts using next generation sequencing (NGS) technology. For statistical analysis continuous variables were presented as Mean (±Standart deviation) or Median (interquartile range) as appropriate. Results Baseline demographic and clinical characteristics of group are listed in Table 1. 13 pts (46%) had malignant form of hypertension (MHT) confirmed by eye examination. Mean systolic arterial pressure (SAP) observed at the time of presentation was 210±29 mmHg, mean diastolic arterial pressure (DAP) was 122±19 mmHg. Kidney morphology revealed chronic TMA lesions in 12 pts (43%), acute and chronic alterations simultaneously detected in 13 pts (46%). Predominantly acute lesions with glomerular and extraglomerular thrombi found in 3 (11%) pts only. Complement genes abnormalities revealed in 7 (25%) out of 28 pts. Complement factor I (CFI) rare variants were found in 2 pts (CFI c. 772<A, CFI c.1217G>A), one of this pts also had additional variant in complement factor H related protein 4 (CFHR4 c.766G>A). Complement factor C3 rare variant was observed in 1 pt (C3 c.2203C>T), membrane cofactor protein (MCP or CD46) rare variant in 1 pt (CD46 c. 198A>T), complement factor H related protein 5 (CFHR5) variant detected in 1 pt (CFHR5 c.136C>T), homozygous deletion of CFHR1 and CFHR3 detected in 1 pt and heterozygous deletion of the same complement factor H related protein genes found in another pt. Conclusion A quarter of pts with TMA and severe hypertension may have genetic defects in the complement system. These results confirmed that complement-mediated HUS may be misdiagnosed as hypertension-induced TMA. Lack of convincing hematological signs of TMA is common in this group, making aHUS diagnosis more sophisticated.

#3740 AFTER ALL A TYPICAL HUS

Abstract Background and Aims Typical Hemolytic Uremic Syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by the triad of acute renal failure, hemolytic anemia and thrombocytopenia. TMAs are classified into: Inherited or primary acquired (atypical HUS), secondary or infection associated. Infection with Shiga-toxin–producing Escherichia coli (E. coli), mainly of serotype O157:H7, is the most common cause of typical HUS, but other serotypes have been rarely associated such as Enteroagregative Escherichia coli (EAEC) serotype O104:H4. Method Case Report Results We report a case of a 51-years-old male with past medical history of arterial hypertension (treated with Perindopril) and IgGk Multiple Myeloma (MM) diagnosed 10 years prior submitted to two bone marrow autotransplants (9 and 4 years prior) and multiple chemotherapy agents including Carfilzomib-Pomalidomide-Dexamethasone (last cycle 4 days before the onset of symptoms). One week after returning from a trip to Brazil, he was admitted to the emergency department with a two-day history of non-bloody diarrhea (4-5 liquid stools per day) and asthenia, with similar positive familiar epidemiology. He denied abdominal pain, fever, nausea or vomiting. At physical examination, he was hypertensive (177/90 mmHg), anuric (12,5 ml/h), dehydrated and apyretic. Abdominal palpation was painless and there were no signs of peritoneal irritation. Laboratory tests showed hemoglobin 10.5 g/dl, new onset thrombocytopenia (261 000/uL » 21 000/uL), kidney disfunction (serum creatinine (sCr) 0.74 mg/dL to 9 mg/dL and serum urea (sU) 41 mg/dL to 260 mg/dL), hyperkaliemia (6 mEq/L) and metabolic acidosis (pH 7,39 and bicarbonate 18.4 mEq/L). LDH was 1949 U/L, C-reactive protein 30.6 mg/L, procalcitonin 3.77 ng/mL, haptoglobin <0.07 g/L and with normal complement levels (C3 and C4). Schistocytes were present in peripheral blood smear. The diagnosis of Acute Kidney Injury related with TMA was established and the patient was transferred to the Nephrology ward and urgent hemodialysis was started. Exhaustive study was performed showing normal renal ultrasound, non-nephrotic proteinuria (1.6 g/g), urinalysis showed leukocyturia and erythrocyturia. Autoimmune study including PR3-ANCA, MPO-ANCA, anti-GBM antibody, Anti-dsDNA antibody, anti-beta 2-glycoprotein I antibodies, anticardiolipin antibodies, anti-ADAMTS13 antibodies and ADAMTS13 activity, as well as study of complement C5, C'3, C'4, factor B, H and I, anti-factor H ac, AH 50 and CH50b were unremarkable. Blood and urine culture and antistreptolysin O titers were negative. Specific stool cultures for E. coli O157, Shigella, Salmonella, Yersinia and Campylobacter were negative. Stool evaluation for parasites were also negative. Viral serology for HIV, HBV, HCV and Plasmodium tests were negative. PCR stool was required due to high suspicion of E.coli infection. The suspicion of a Carfilzomib induced TMA was also raised, while molecular techniques results were awaited. MM was stable and treatment was held until recovery of kidney function. During hospitalization the patient recovered diuresis and creatinine decreased. On the 11th day of hospitalization, he was discharged but still depended on hemodialysis. Finally, stool PCR techniques identified aatA and aggR genes associated with EAEC O104:H4 allowing the diagnosis of acquired infectious HUS rather than drug-related TMA. One week after discharge, the dialysis was stopped due to sCr 3 mg/dL. Four months later, he resumed Carfilzomib and kidney function remained stable with sCr 0.9 mg/dL, despite sustained proteinuria of 1.2 g. Conclusion The authors emphasize the importance of considering other causes of TMA when E.coli O157 infection is excluded, namely drug-related causes (as Carfilzomib) or less frequent infectious agents such as EAEC O104:H4. This case reveals the importance of requesting PCR in the stool even when the E.coli test is negative. This is of particular relevance in immunosuppressed patients. This diagnosis allowed continuing MM treatment.

Isolated arterial mucoid intimal thickening lesion in early post-transplant kidney allograft biopsies.

Thrombotic microangiopathy (TMA) on kidney biopsy shows a variable combination of features: arterial mucoid intimal thickening, acellular closure of glomerular capillary loops, fragmented red blood cells, fibrin thrombi, and arterial fibrinoid necrosis. However, some early post-transplant kidney biopsies show only arterial mucoid intimal thickening. We aimed to elucidate the importance of this finding. We identified 19 biopsies showing isolated arterial mucoid intimal thickening and compared them with 22 bona fide TMA biopsies identified based on the pathological findings (excluding rejection) (2011-2020). Additionally, delayed graft function (DGF) (n=237), and no DGF (control, n=1314) groups were included for survival analysis. Seven of 19 cases with isolated arterial mucoid intimal thickening showed peripheral blood schistocytes but no other systemic features of TMA. Eight patients underwent adjustments in maintenance immunosuppression (mainly calcineurin inhibitors). None of the cases progressed to full-blown TMA on consecutive biopsies. The overall and death-censored graft survival rates in this group were comparable to the DGF group, but significantly better than the TMA group (P=.005 and .04, respectively). Isolated arterial mucoid intimal thickening in early post-transplant biopsies may be an early/mild form of TMA, probably requiring adjustment in immunosuppressive regimen. Careful exclusion of known causes of TMA, and donor-derived arterial injury are important.

Eculizumab in the management of drug-induced thrombotic microangiopathy: A scoping review of the literature

Drug-induced TMA (DI-TMA) is a thrombotic microangiopathy (TMA) caused by certain drugs, usually managed by drug discontinuation and supportive measures. Data on the use of complement-inhibition with eculizumab in DI-TMA is scarce, and its benefit in cases of severe or refractory DI-TMA is unclear. We conducted a comprehensive search in PubMed, Embase and MEDLINE databases (2007–2021). We included articles that reported on DI-TMA patients treated with eculizumab and its clinical outcomes. All other causes of TMA were excluded. We evaluated the outcomes of hematologic recovery, renal recovery, and a composite of both (complete TMA recovery). 35 studies fulfilled our search criteria, which included 69 individual cases of DI-TMA treated with eculizumab. Most cases were secondary to chemotherapeutic agents, and the most implicated drugs were gemcitabine (42/69), carfilzomib (11/69), and bevacizumab (5/69). The median number of eculizumab doses given was 6 (range 1–16). 55/69 (80 %) patients achieved renal recovery, after 28–35 days (5–6 doses). 13/22 (59 %) patients were able to discontinue hemodialysis. 50/68 (74 %) patients achieved complete hematologic recovery after 7–14 days (1–2 doses). 41/68 (60 %) patients met criteria for complete TMA recovery. Eculizumab was safely tolerated in all cases, and appeared to be effective in achieving both hematologic and renal recovery in DI-TMA refractory to drug discontinuation and supportive measures, or with severe manifestations associated with significant morbidity or mortality. Our findings suggest that eculizumab may be considered as a potential treatment for severe or refractory DI-TMA that does not improve after initial management, although larger studies are needed.

Drug-induced de novo thrombotic microangiopathy diagnosed 2 years after renal transplantation: a case report and literature review

BackgroundPost-transplant de novo thrombotic microangiopathy (TMA) is a rare yet serious complication that generally can develop in renal transplant recipients immediately after reperfusion or several months after transplantation. Here, we report a case of systemic tacrolimus-associated TMA in a patient diagnosed 2 years after renal transplantation.Case presentationA 49-year-old woman presented with severe anemia 18 months after undergoing renal transplantation. Anemia was refractory to recombinant human erythropoietin and was suspected to be due to excessive menstruation. Anemia persisted even after hysterectomy, and thereafter, pancytopenia developed. A bone marrow biopsy was performed and showed no evidence of myeloproliferative neoplasms. Furthermore, an increase in serum lactate dehydrogenase level and the appearance of schistocytes on peripheral blood smear was noted 24 months post-transplant. Other possible causes of de novo TMA were excluded, and an allograft biopsy was performed. Pathological findings of the allograft biopsy showed that some afferent arterioles had formed thrombi. Suspecting tacrolimus to be the cause of TMA, 25 months after the transplant, we switched treatment to cyclosporine. Pancytopenia and renal function improved after switching to this calcineurin inhibitor. Subsequently, her allograft renal function stabilized for three years after renal transplantation.ConclusionWe encountered a case of secondary drug-induced TMA in the late stages of renal transplantation. Therefore, TMA should be suspected when anemia with hemolysis is observed in recipients of kidney transplant.

Pregnancy associated atypical hemolytic uremic syndrome presenting with preeclampsia with HELLP syndrome and following treatment with Eculizumab

Abstract Objectives Pregnancy associated atypical hemolytic uremic syndrome (p-aHUS) is a rare condition of thrombotic microangiopathy (TMA) which causes an increase of fetal and maternal morbidity and mortality. It presents typically with a triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia and acute progressive renal failure. Differential diagnoses of HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome, preeclampsia, thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC) syndrome must be considered. In the following case report, presented is a 32-year-old, 38 weeks pregnant Caucasian woman admitted to Eberswalde Hospital with signs of preeclampsia and HELLP Syndrome. Caesarean Section was performed due to HELLP syndrome and fetal distress. Acute renal failure occurs shortly after a successful delivery. After a diagnosis of p-aHUS is established, the patient was given Eculizumab, which yielded significant improvements. Case presentation A 32-year-old, 38 week pregnant Caucasian woman was admitted to Eberswalde Hospital with upper right abdominal pain. After a laboratory examination, a diagnosis of HELLP syndrome was established and a Caesarean Section was performed. The follow-up examination revealed deterioration of clinical signs with the patient experiencing dyspnea, oliguria, and oedema, as well as aggravation of laboratory values, ranging from severe thrombocytopenia, hemolytic anemia, liver injury, and acute kidney injury. After excluding other possible causes of TMA, a diagnosis of p-aHUS was established and a treatment with Eculizumab was administered. Clinical and laboratory signs of hemolysis and kidney functions were found to improve gradually after two administrations of Eculizumab. The patient was discharged after 20 days of hospitalization with significantly improved condition and hematological values. Conclusions A successful treatment of p-aHUS requires a comprehensive assessment and a prompt diagnosis, which can be confounded by multiple similar differential diagnoses. Treatment with Eculizumab was found to significantly improve the outcome of the patient, but more studies are required to decide on a standardized regiment for p-aHUS.

Drug Induced Thrombotic Microangiopathy Secondary to Quetiapine; The Second Reportable Case in Medical Literature

INTRODUCTION Thrombotic microangiopathy (TMA) describes a group of disorders that are often related to microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. A common etiology is from exposure to certain drugs. Hereby, we present the second reportable case in medical literature of TMA secondary to quetiapine exposure. CASE PRESENTATION A 27 years old male patient with past medical history of schizoaffective disorder and depression, was admitted for altered mental status. Patient was completely disoriented with noncoherent speech. Home medications included quetiapine 775mg and valproate 750mg. Labs on admission were significant for Hb 7.6, Platelets 16, Wbc 8.1, Na 139, K 4.7, Hco3 23, Cr 14.5. Patient received 1 PRBC unit on admission. Hb was 7.9 on day 2, and his home medication quetiapine was resumed on that evening. Within 24hrs of receiving quetiapine, Hb and platelets reached a low point of 6.6 and 11 respectively. And within 48hrs, 3 PRBCs and 1 platelet units were transfused, resulting in Hb 6.7 and platelets 45 at the end of that 48hrs period. Clinically, patient was restless and agitated. His speech became slurred. Patient also had severe AKI with oliguria requiring hemodialysis. Further workup showed undetectable haptoglobin, elevated LDH, total bilirubin 3.22 and direct bilirubin 0.72, reticulocytes 12%, schistocytes on peripheral smear, INR 1.1, normal B12 level, valproic acid level of 52.7 (within normal reference range), negative HIV and syphilis, negative Coombs test, negative ANA/ANCA panel, negative platelet antibody, AdamTS13 level 99.1% (prior to plasma exchange), negative CFH antibody. Progression of laboratory findings and treatments received are shown in the accompanying figures (Figure 1, 2). In total, patient received 7 PRBC units, 1 single donor platelets unit, methylprednisolone followed by prednisone course, 5 plasma exchange sessions, 2 Rituximab infusions. During his hospital stay, patient gradually recovered, lab values demonstrated stability, and was discharged on day 15. DISCUSSION Drug induced thrombotic microangiopathy (DITMA) is part of a larger entity called thrombotic microangiopathies (TMA), which is often observed with MAHA and thrombocytopenia. DITMA is subdivided into an immune mechanism with prior or ongoing exposure to a drug thereby generating antibodies, and a nonimmune mechanism usually occurring after chronic exposure to a drug resulting in accumulation or can occur with acute exposure. The clinical presentation in immune mediated DITMA usually has a severe and sudden onset, with lab findings of MAHA, thrombocytopenia, severe acute kidney injury, along with normal or mildly decreased AdamTS13 activity (above 10%). However, DITMA is a diagnosis of exclusion, therefore other differentials have to be ruled out including thrombotic thrombocytopenic purpura (TTP) that is associated with an AdamTS13 level less than 10%, complement mediated TMA that can be evaluated with CFH antibody, hemolytic uremic syndrome (HUS) that typically presents in children with diarrhea, metabolism mediated TMA that is often related to vitamin B12 deficiency. Once the diagnosis is made, management involves discontinuation of the inciting drug. However, when the diagnosis is uncertain, therapies utilized in other forms of TMA may be used. Patients with DITMA should avoid re-exposure to the implicated drug in the future. The Oklahoma registry and the blood center of Wisconsin developed a criteria to evaluate patients with evidence of TMA and a suspected drug etiology. In our case, it meets the criteria for definite immune-mediated association with quetiapine, where other causes of TMA were excluded, quetiapine was the only drug taken during hospitalization, patient was taking this drug prior to hospitalization and subsequent exposure lead to manifestations of TMA within 24 hours. Literature review for similar reports revealed as few as 3 cases of quetiapine associated TMA, but AdamTS13 was noted to be either <10% or not documented. However, a case report published in 2021 shows quetiapine associated TMA with normal AdamTS13 level. Therefore, our case report would be the second reportable case in medical literature of quetiapine associated DITMA with normal ADAMTS13 levels. CONCLUSION It is of vital importance to raise awareness on how a commonly prescribed psychiatric medication such as quetiapine can cause an immune mediated TMA that is life-threatening. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The favorable outcome of subsequent pregnancy in a patient with a history of obstetric atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a severe life-threatening disease associated with uncontrolled activation of alternative complement pathway. Obstetric aHUS, which develops in pregnant women and puerperas, is characterized by a particularly severe course with multiple organ failure, high death risk and end-stage renal disease. The prognosis of patients with obstetric aHUS has changed dramatically after the introduction of eculizumab, a monoclonal antibody to C5 complement component, into clinical practice. With timely initiation of the complement blocking therapy, the patients would not only survive, but also completely restore the function of the affected organs. Naturally, the question arises on the possibility of repeated pregnancies in women with previous obstetric aHUS and on the strategy of pregnancy management.&#x0D; The paper describes a clinical case of successful treatment with eculizumab for obstetric aHUS in the third trimester of the first pregnancy in a young and previously healthy woman, and the management of her second pregnancy. A 23-year old woman at 35-36 weeks of her first pregnancy developed the clinical picture of obstetric thrombotic microangiopathy, which was interpreted as a manifestation of severe preeclampsia and HELLP syndrome. However, after an emergency surgical delivery, the patient's condition continued to deteriorate despite the plasma exchange procedure. After exclusion of the other causes of thrombotic microangiopathy, aHUS was diagnosed and treatment with eculizumab was started, which resulted in complete recovery. No aHUS-associated mutations were identified. The complement inhibitor treatment was discontinued after 12 months. Four years after the first birth, the patient had a second pregnancy after preconception planning. During pregnancy, the patient was closely monitored for a timely identification of potential complications and had prevention of placental complications with acetylsalicylic acid and low molecular weight heparin. No aHUS recurrence and/or other complications were observed, and the patient did not require treatment with eculizumab during pregnancy. Elective caesarean section was performed at 39 week of gestation. A healthy boy was born with a bodyweight of 3370 g, a height of 50 cm, and Apgar score 8-9.&#x0D; In women with obstetric aHUS history, a favorable outcome of repeated pregnancies is possible, in some cases even without any prophylactic use of complement-blocking therapy, provided that with complete remission of aHUS has been achieved, with close monitoring during gestation and prevention of placenta-associated complications.

Monoclonal gammopathy of renal significance presenting with cryoglobulinaemia type I associated severe thrombotic microangiopathy

ABSTRACTWe report a 53-year-old man who presented with acute renal failure. His medical history revealed a spondyloarthropathy, for which secukinumab was started recently, and a monoclonal gammopathy of unknown significance. Kidney function deteriorated despite the withdrawal of secukinumab and dialysis was started. In the serum, type 1 cryoglobulins were present and a kidney biopsy showed ischaemic glomeruli, with thrombosis of the larger interlobular arteries. Other causes of thrombotic microangiopathy were excluded. Bone marrow immunophenotyping showed 1% monoclonal plasma cells. A diagnosis of monoclonal gammopathy of renal significance was made. Haematological treatment resulted in haematological and renal response.

Complement Activation and Thrombotic Microangiopathy Associated With Monoclonal Gammopathy: A National French Case Series

Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy (TMA) with kidney involvement, is a rare condition in patients with monoclonal gammopathy. In the absence of known causes of TMA, the role of complement activation in endothelial injury in patients with monoclonal gammopathy remains unknown and was the focus of this investigation. Case series. We studied the 24 patients in the French national registry of HUS between 2000 and 2020 who had monoclonal gammopathy without other causes of secondary TMA. We provide the clinical histories and complement studies of these patients. Monoclonal gammopathy-associated TMA with kidney involvement is estimated to be 10 times less frequent than adult atypical HUS (aHUS) in the French national registry. It is characterized by severe clinical features, with 17 of 24 patients requiring dialysis at disease onset, and with median renal survival of only 20 months. TMA-mediated extrarenal manifestations, particularly cutaneous and neurological involvement, were common and associated with poor overall prognosis. Complement studies identified low C3, normal C4, and high soluble C5b-9 levels in 33%, 100%, and 77% of tested patients, respectively, indicating a contribution of the alternative and terminal complement pathways in the pathophysiology of the disease. Genetic abnormalities in complement genes known to be associated with aHUS were found in only 3 of 17 (17%) who were tested. Retrospective study without comparison group; limited number of patients, limited available blood samples. Within the spectrum of TMA, TMA associated with monoclonal gammopathy represents a distinct subset. Our findings suggest that HUS associated with monoclonal immunoglobulin is a complement-mediated disease akin to aHUS.

Thrombotic microangiopathy with transiently positive direct Coombs test in an adult with poststreptococcal acute glomerulonephritis: a case report

BackgroundTo date, a few case reports have described the association between poststreptococcal acute glomerulonephritis (PSAGN) and hemolytic anemia/thrombocytopenia, both with or without a pathology similar to that of thrombotic microangiopathy (TMA). However, the detailed mechanism leading to the complication of TMA in PSAGN patients remains to be clarified. In contrast, infection with neuraminidase-producing Streptococcus pneumoniae is a well-known cause of TMA, and it has been reported that transient positivity of the direct Coombs test is observed in up to 90% of such patients.Case presentationA 44-year-old man was hospitalized for acute nephritic syndrome 3 weeks after developing pharyngitis. PSAGN was suspected owing to a low complement C3, increased antistreptolysin-O and serum creatinine (5.46 mg/dL), and hematuria/proteinuria. The throat antigen test for group A Streptococcus was positive. He developed hemolytic anemia with thrombocytopenia from hospital day 9. TMA was suspected owing to minimal coagulation abnormalities. ADAMTS-13 activity was normal, whereas the direct Coombs test was transiently positive. Renal biopsy demonstrated glomerular endocapillary proliferation without crescents, but with severe tubulitis and peritubular capillaritis on light microscopy. Immunofluorescence demonstrated C3 deposition along the glomerular capillary walls, and many subepithelial humps were observed on electron microscopy. The deposition of nephritis-associated plasmin receptor (NAPlr), a nephritogenic protein of Streptococcus pyogenes, was observed only in glomeruli. Thus, the histological diagnosis was typical PSAGN, but with atypical severe tubulointerstitial lesions. A positive direct Coombs test is often observed in pneumococcal TMA patients, which is attributed to the exposure of Thomsen–Friedenreich (T) antigen by neuraminidase. As Streptococcus pyogenes is one of the neuraminidase-producing bacteria other than Streptococcus pneumoniae, T-antigen exposure was analyzed in the renal tissue of this patient using labelled peanut lectin as a probe, which has strong and specific binding affinity for T-antigen. Exposure of T-antigen was found on tubular epithelial cells and small vessels in the tubulointerstitial area, but not in the glomeruli of this patient.ConclusionThese findings suggest that 2 pathogenic proteins of Streptococcus pyogenes, i.e., NAPlr and neuraminidase, induced glomerular lesions of PSAGN and tubulointerstitial inflammation with TMA, respectively, resulting in severe acute kidney injury in this patient.

Thrombotic microangiopathy in children.

The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like Streptococcus pneumoniae-HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.