Thrombotic Microangiopathy Syndrome Research Articles

Hematological features and alternate diagnoses in critically ill thrombotic antiphospholipid syndrome patients.

Severe thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome. This French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers' ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied. One hundred and thirty-four patients, female 72%, median [IQR] age 45 [34-56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3-8.8] g/dL and 38 [21-60] g/L, respectively. The lowest platelet count below 20g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27-74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients. Thrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients. Key Points • Thrombocytopenia is the hallmark laboratory finding in CAPS. • A complete thrombotic microangiopathy pattern is infrequent in CAPS patients. • Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated.

#1234 Thrombotic microangiopathy (TMA) response during index atypical haemolytic uremic syndrome (aHUS) hospitalisation

Abstract Background and Aims aHUS is associated with dysregulation of the alternative complement pathway. C5 inhibitors (C5i) improve TMA response and renal recovery, but significant morbidity may remain. Although C5i studies have reported on TMA response rates after treatment discontinuation, TMA response data during index hospitalisation are limited. This study described TMA response during index aHUS hospitalisation using real-world evidence from a large, diverse cohort of presumed incident aHUS in the United States (US). Methods This was a retrospective cohort study of hospitalised adult patients with presumed aHUS with electronic healthcare records in the US Premier Healthcare Database, which contains ∼25% of all US hospitalisations (January 1, 2011–June 30, 2021). aHUS was defined as the presence of an International Classification of Diseases (ICD)-9-CM/ICD-10-CM diagnostic code for TMA or haemolytic uremic syndrome (HUS) and a treatment code for a C5i, without a diagnostic code for secondary causes of TMA/HUS or other C5i indications. Complete TMA response was defined by &amp;gt;25% decline of serum creatinine (SCr) and normalisation of platelets and lactate dehydrogenase (LDH) from index presentation, without renal replacement therapy (RRT) at discharge. Included patients had longitudinal laboratory data; patients with in-hospital death were excluded. Patient demographics, clinical characteristics, treatment patterns, and clinical outcomes were assessed as risk factors. Variables were analysed by Wilcoxon signed-rank test, Kruskal–Wallis test, Fisher's exact test, or Chi-square test, as appropriate. Results Of 634 adult patients hospitalised with presumed aHUS, 556 survived to discharge. SCr, platelet, LDH, and all three TMA response criteria data were available for 21.0% (117/556), 18.9% (105/556), 18.2% (101/556), and 16.5% (92/556) of patients, respectively. Median duration between the first and last laboratory measurement before discharge was 21 days (interquartile range [IQR]: 12–33) for SCr, 21 days (IQR: 14–32) for platelets, and 17.5 days (IQR: 11–27) for LDH. Only 6.5% (6/92) of patients achieved a complete TMA response at discharge, preventing statistical analysis with other parameters. Platelet normalisation occurred in 53.3% (56/105) of patients and was associated with younger median age (39 vs 54 years; P = 0.0167) and median time from admission to C5i (8 vs 10 days; P = 0.0459). LDH normalisation occurred in 29.7% (30/101) and was associated with male sex (60.0% vs 22.5%; P = 0.0005), Hispanic ethnicity (20.0% vs 7.0%; P = 0.0330), and median duration of intensive care unit stay (3.5 vs 8 days; P = 0.0185). A drop of &amp;gt;25% in SCr from admission to discharge occurred in 20.5% (24/117) and was associated with Hispanic ethnicity (16.7% vs 8.6%; P = 0.0089) and no RRT (45.8% vs 14.0%; P = 0.0014). Among patients with mortality data, the association between platelet normalisation and 60-day post-discharge mortality was significant (P = 0.0499). LDH normalisation and a &amp;gt;25% decline in SCr were not associated with 60-day (P = 0.6368 and P = 1.000, respectively) or 365-day (P = 0.4288 and P = 0.7023, respectively) post-discharge mortality. Conclusions In this US population of hospitalised adults with presumed incident aHUS, few patients achieved a complete TMA response at discharge, despite C5i. Small sample size limited assessment of clinical characteristics associated with complete TMA response; however, achievement of each TMA response criterion was associated with unique clinical and patient characteristics. Future efforts should focus on characterising patients with aHUS at high risk at discharge and on developing novel precision therapies to improve outcomes.

Thrombotic microangiopathy associated with anticancer and immune system targeting drugs: New insights from real-world data using the WHO pharmacovigilance database.

The worldwide development of immune system targeting/anticancer drugs has revolutionized immuno-oncology, but their implication in thrombotic microangiopathy syndromes (TMA) is increasingly suspected. Using real-world data, the aim of this study was to identify drugs associated with TMA reporting and to describe the evolution of TMA reporting over time with a focus on these drugs. A global disproportionality study was performed using the individual case safety reports (ICSRs) extracted from the World Health Organization (WHO) pharmacovigilance database (VigiBase) from its inception (1968) to April 30, 2022. Of the 31,251,040 ICSRs, 6946 cases of suspected drug-induced TMA were included from 55 countries. The outcome was fatal in 18.2% of cases. A total of 72 immune system targeting/anticancer drugs were associated with significant overreporting, including 17 drugs with a potential new safety concern for TMA. Although the rate of TMA reporting per million of ICSRs has remained fairly stable, an absolute increase in reported cases of suspected drug-induced TMA has been observed over the last decade. The pattern of drugs reported in TMA has evolved with a substantial increase in the proportion of cases involving immune system-targeting drugs/anticancer drugs from 47.3% (205/433) in the period 1992-2001 to 80.7% (3819/4730) in the period 2012-2021. Several recently marketed immune system targeting/anticancer drugs have been identified as potential new drugs associated with TMA, which will require confirmatory studies. The number of drugs associated with TMA reporting markedly increased within the past 10 years, primarily due to innovative anticancer drugs.

Surufatinib-induced renal thrombotic microangiopathy: first case report and review of literature

Angiogenesis inhibitors such as tyrosine kinase inhibitors (TKIs) are common therapeutics currently used to treat oncologic disease. Surufatinib is a novel, small-molecule multiple receptor TKI approved by the National Medical Products Administration (NMPA) for the treatment of progressive, advanced, and well-differentiated pancreatic and extrapancreatic neuroendocrine tumours (NETs). Thrombotic microangiopathy (TMA) is a well-documented complication of TKIs targeting the VEGF-A/VEGFR2 signalling pathway. Here, we describe a 43-year-old female patient with biopsy-proven TMA and nephrotic syndrome due to surufatinib treatment for adenoid cystic carcinoma. Histological lesions included glomerular endothelial swelling, widening of subendothelial spaces, mesangiolysis, and double contour, which caused nephrotic proteinuria. Effective management was achieved by drug withdrawal and oral anti-hypertensive regents. The management of surufatinib-related nephrotoxicity without compromising its anticancer effects is challenging. Hypertension and proteinuria must be closely monitored during drug use to reduce or stop the dose in a timely manner before severe nephrotoxicity occurs.

Bilateral Proliferative Retinopathy as the Initial Presentation of Atypical Hemolytic Uremic Syndrome: A Case Report.

In this case report, we describe a 34-year-old male patient who presented with vision loss and was found to have profound occlusive retinal vasculopathy. His initial laboratory studies were unremarkable, but five weeks after his ocular symptoms began, he developed acute multi-organ failure and was ultimately diagnosed with atypical hemolytic uremic syndrome (aHUS). His course was complicated by a stroke, respiratory distress requiring intubation, long-term hemodialysis, and eventually death. Occlusive retinal vasculopathy may be the presenting finding in aHUS, although thrombotic microangiopathy syndromes typically present with acute kidney injury and or failure, hemolytic anemia, and thrombocytopenia. [Ophthalmic Surg Lasers Imaging Retina 2023;54:297-300.].

Six-Month Outcomes in Patients with Complement Mediated Thrombotic Microangiopathy Treated with Complement Inhibitors in the Real World

Background Complement-mediated (CM) thrombotic microangiopathy (TMA), also known as atypical hemolytic uremic syndrome, is a serious and potentially life-threatening disorder. Anti-C5 monoclonal antibodies (aC5-mab) reduce the morbidity and mortality. Experience outside clinical trials has been limited due to the rarity of the condition. Aims To examine the outcomes of patients diagnosed with CM-TMA treated outside clinical trials. Methods Retrospective, single-institution study. The inclusion criteria required a diagnosis of CM-TMA (laboratory values consistent with TMA syndrome or TMA on a biopsy, with normal ADAMTS13 and absent shiga toxin) and available 6 month follow up data. Day 1 refers to the first day of therapy with aC5-mab. Results Twenty subjects met our inclusion criteria for this report. All were hospitalized during their initial diagnosis. Four (20%) passed away during the hospitalization, while another 2 (10%) died after hospitalization but before 6 months. Fourteen individuals made it to the 6 month follow up. Initiation of aC5-mab occurred at a median of 11 (3 to 48) days after the initial TMA Event. All patients received aC5-mab while hospitalized. Median laboratory values prior to aC5-mab demonstrated: platelets 81.5/uL, LDH 758 U/L, Cr 3.8 g/dL, and hemoglobin 8.6 g/dL. Median values for those who died during hospitalization and before 6 months were: platelets 79/uL, LDH 1044 U/L, Cr 2.1 g/dL, and hemoglobin 9.1 g/dL. Median values at discharge for surviving patients during hospitalization were: platelets 212/uL, LDH 332 U/L, Cr 3.2 g/dL, and hemoglobin 8.0 g/dL. Median values at 6 months were: platelets 201/uL, LDH 231.5 U/L, Cr 1.8 g/dL, and hemoglobin 11.4 g/dL. Renal replacement therapy (RRT) was administered to 17 subjects while receiving aC5-mab, with 7 patients receiving RRT prior to admission. At hospital discharge, 8 patients were on RRT, and at 6 months, 5 individuals remained on RRT. Five (25%) patients had kidney transplants prior to the diagnosis of CM-TMA. Six subjects died, 4 during the hospitalization that led to the diagnosis of CM-TMA and 2 after discharge. The causes of death during hospitalization were severe pneumonia (Day 4), multi-organ failure from lupus flare (Day 6), acute hypoxic respiratory failure from pulmonary hypertension (Day 24) and aspiration pneumonia (Day 47). After hospital discharge, 1 individual who had completed 4 weekly doses of aC5-mab passed away due to CMV pneumonia and sepsis 1 month later. Another patient expired 5 weeks after discharge due to sepsis from an intra-abdominal infection four weeks after the last dose of aC5-mab. Fourteen subjects remained alive at 6 months; 12 continued aC5-mab and 2 had stopped it after 4 and 5 months of therapy with no complications at 6 months. Conclusion This is a real-world study of patients with newly diagnosed CM-TMA treated with aC5-mab that provides 6-months follow-up data. Our findings confirm the efficacy of aC5-mab at treating CM-TMA. One of the most important findings from this study includes the description of 6 patients that died after initiation of therapy with aC5-mab. This might be due to our aggressive use of aC5-mab in critically ill patients (selection bias). In these patients the laboratory criteria recommended to diagnose CM-TMA can overlap with other conditions leading to significant variability in the management. Limitations to this study include the retrospective nature and sample size. Further studies to assess the use of aC5-mab in critically ill patients and criteria to define the subjects unlikely to benefit from aC5-mab are urgently needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diapers and Dialysis: A Case Report on Postpartum Atypical Hemolytic Uremic Syndrome

While thrombotic microangiopathy (TMA) syndromes such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and atypical hemolytic uremic syndrome (aHUS) present similarly with hemolytic anemia, thrombocytopenia, and renal injury, their etiology and treatment differs.

Combining imaging flow cytometry and machine learning for high-throughput schistocyte quantification: A SVM classifier development and external validation cohort.

SummaryBackgroundSchistocyte counts are a cornerstone of the diagnosis of thrombotic microangiopathy syndrome (TMA). Their manual quantification is complex and alternative automated methods suffer from pitfalls that limit their use. We report a method combining imaging flow cytometry (IFC) and artificial intelligence for the direct label-free and operator-independent quantification of schistocytes in whole blood.MethodsWe used 135,045 IFC images from blood acquisition among 14 patients to extract 188 features with IDEAS® software and 128 features from a convolutional neural network (CNN) with Keras framework in order to train a support vector machine (SVM) blood elements’ classifier used for schistocytes quantification.FindingKeras features showed better accuracy (94.03%, CI: 93.75-94.31%) than ideas features (91.54%, CI: 91.21-91.87%) in recognising whole-blood elements, and together they showed the best accuracy (95.64%, CI: 95.39-95.88%). We obtained an excellent correlation (0.93, CI: 0.90-0.96) between three haematologists and our method on a cohort of 102 patient samples. All patients with schistocytosis (>1% schistocytes) were detected with excellent specificity (91.3%, CI: 82.0-96.7%) and sensitivity (100%, CI: 89.4-100.0%). We confirmed these results with a similar specificity (91.1%, CI: 78.8-97.5%) and sensitivity (100%, CI: 88.1-100.0%) on a validation cohort (n=74) analysed in an independent healthcare centre. Simultaneous analysis of 16 samples in both study centres showed a very good correlation between the 2 imaging flow cytometers (Y=1.001x).InterpretationWe demonstrate that IFC can represent a reliable tool for operator-independent schistocyte quantification with no pre-analytical processing which is of most importance in emergency situations such as TMA.FundingNone.

The clinical significance of low complement levels in patients with catastrophic antiphospholipid syndrome: A descriptive analysis of 73 patients from the "Catastrophic antiphospholipid syndrome registry".

To explore the prevalence and clinical significance of low complement levels in patients with catastrophic antiphospholipid syndrome (CAPS). We reviewed data from the "CAPS Registry" on C3 and/or C4 complement plasma protein levels during acute CAPS episodes. Patients were classified into those with low and normal complement levels. Data on clinical presentation, with special focus on thrombotic microangiopathy (TMA) features, diagnosis of systemic lupus erythematosus (SLE), and antiphospholipid antibody (aPL) profile were reviewed. The chi-square exact test was performed to evaluate differences between categorical data. The "CAPS Registry" includes 566 patients with a total of 578 episodes of CAPS. Data on complement plasma protein levels was available in 73 episodes from the same number of patients. Low levels of C3 and/or C4 complement plasma proteins were detected in 42 (58%) CAPS episodes. Low complement levels were more common in SLE patients (55% SLE vs. 19% No SLE; p<0.001). The frequencies of clinical TMA (72% vs. 80%; p=0.4) or TMA syndrome (86% vs. 84%, p=0.9), frequency of triple aPL triple positivity (67% vs 33%; p=0.3), or the mortality (35% vs. 31%; p=0.7) were similar between low and normal complement groups. In our study, low levels of C3 and C4 plasma proteins are detected in 58% episodes of CAPS, which were not associated with clinical presentation including TMA features, aPL triple positivity, or mortality.

Evaluation of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies: Lessons learned from a 14-year retrospective study.

Thrombotic thrombocytopenic purpura (TTP) is a clinical thrombotic microangiopathy (TMA) syndrome defined by the pentad of symptoms. Therapeutic plasma exchange with plasma replacement is an ASFA Category I modality that can reduce morbidity and mortality if initiated early. We describe a 14-year review of patients referred for plasma exchange with a suspected diagnosis of TTP. For 70 patients referred for urgent plasma exchange, clinical, therapeutic, and laboratory data were retrospectively analyzed, and the diagnosis was determined. Fifteen of the patients were diagnosed with TTP based upon ADAMTS-13 activity with the other 51 patients having other non-TTP TMA diagnoses. The mortality rate was significant for both TTP and non-TTP TMAs. PLASMIC scores were also calculated retrospectively and were noted to have limited value. TMA is a diagnostic challenge and encompasses different syndromes with similar presentations. Determining an accurate diagnosis, including prompt ADAMTS-13 testing, makes it possible to initiate appropriate therapy for the multiple different TMAs that can be seen in clinical practice.

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.

Proteinuria Increases the PLASMIC and French Scores Performance to Predict Thrombotic Thrombocytopenic Purpura in Patients With Thrombotic Microangiopathy Syndrome

IntroductionPLASMIC and French scores have been developed to help clinicians in the early identification of patients with thrombotic thrombocytopenic purpura (TTP). Nevertheless, the validity of these scores in thrombotic microangiopathy (TMA) cohorts with low TTP prevalence remains uncertain. We aimed to evaluate their diagnostic value in routine clinical practice using an unselected cohort of patients with TMA. We also analyzed the value of adding proteinuria level to the scores. MethodsWe retrospectively included all patients presenting with a biological TMA syndrome between January 1, 2008, and December 31, 2019, in a tertiary hospital. TMA etiology was ascertained, and scores were evaluated. Modified scores, built by adding 1 point for low proteinuria (<1.2 g/g), were compared with original scores for TTP prediction. ResultsAmong 273 patients presenting with a full biological TMA syndrome, 238 were classified with a TMA diagnosis. Complete scores and proteinuria level were available in 134 patients with a TTP prevalence of 7.5%. Area under the receiver operating characteristic curve (AUC) of PLASMIC and French scores for TTP diagnosis was 0.65 (0.46–0.84) and 0.72 (0.51–0.93), respectively. AUC of modified PLASMIC and French scores was 0.76 (0.59–0.92) (P = 0.003 vs. standard score) and 0.81 (0.67–0.95) (P = 0.069 vs. standard score), respectively. Specificity, positive predictive value (PPV), and positive likelihood ratio of high-risk scores were significantly improved by adding proteinuria level. ConclusionPLASMIC and French scores have low predictive values when applied to an unselected TMA cohort. Including proteinuria level in the original scores improves their performance for TTP prediction.

COVID-19-ASSOCIATED THROMBOTIC THROMBOCYTOPENIC PURPURA: A FATAL NIGHTMARE

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: COVID-19 virus has been reported to be associated with many unusual conditions and coagulopathies including thrombotic microangiopathies, DVTs, and PEs. However, cases of COVID 19 associated TTP are very rare. We discuss a patient with confirmed COVID-19 pneumonia who then developed acquired autoimmune TTP. CASE PRESENTATION: A 68-year-old female with no significant past medical history presented to the hospital with generalized weakness, shortness of breath, and cough. The onset of symptoms was about 7 days. Initial labs were significant for positive COVID-19 on PCR, WBC 10.4 k/ul, Lactic 1.3, D-dimer 3109 ng/ml. Chest x-ray revealed diffuse bilateral pulmonary infiltrates. She was placed on high flow oxygen with saturation between 80 - 89%. Remdesivir, Dexamethasone & one unit of COVID Convalescent Plasma were started for COVID-19 pneumonia. On day 2, she was switched to BIPAP due to worsening respiratory distress. On day 3, she was intubated due to rapidly progressive ARDS. Blood cultures were negative. She developed neutrophil predominant leukocytosis and anemia. On day 5, she developed thrombocytopenia. On day 8, her platelet counts declined to 17,000. Peripheral smears showed minor areas of clumping while platelet still significantly decreased. Redraw with citrate tube showed no major difference in platelet count. Testing showed evidence of hemolysis with undetectable haptoglobin, rising bilirubin level, and markedly elevated LDH with worsening renal functions. Directs Coombs test was IgG positive with abundant schistocytes on smear. PLASMIC SCORE 7 indicating a high risk for ADAMTS 13 deficiency. The patient was started on high dose IV steroids and needed a total of 2 units of packed red blood cell, 7 units of platelets, and 27 units of fresh frozen plasma. Her condition continued to deteriorate, and she was transferred to a tertiary care center that has plasmapheresis capability. Unfortunately, the patient died a few days later despite treatment. DISCUSSION: There have been only few cases in the literature discussing TTP involvement with COVID-19 infection. A case series and a four patient mini-review of this association were published in January 2021. COVID-19 seems to be the primary trigger. Autoimmunity and endothelial damage could be important factors in these manifestations. Plasmapheresis seem to improve this condition. However, due to the low population of patients, more cases are needed to draw a conclusion and better understand the presentation of COVID-associated coagulopathy. CONCLUSIONS: This case highlights the importance of evaluating and recognizing the hematological complication associated with COVID-19. Therapeutic plasma exchange and IV steroids should be started early. Rapid progression if not treated promptly. Further studies are needed to understand pathogenesis, clinical course, and proper management. REFERENCE #1: George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014 Nov 6;371(19):1847-8. doi: 10.1056/NEJMc1410951. PMID: 25372103. REFERENCE #2: I ba, T., Levy, J.H., Connors, J.M. et al. The unique characteristics of COVID-19 coagulopathy. Crit Care 24, 360 (2020). https://doi.org/10.1186/s13054-020-03077-0 REFERENCE #3: Tehrani HA, Darnahal M, Vaezi M, Haghighi S. COVID-19 associated thrombotic thrombocytopenic purpura (TTP) ; A case series and mini-review. Int Immunopharmacol. 2021 Apr;93:107397. doi: 10.1016/j.intimp.2021.107397. Epub 2021 Jan 22. PMID: 33524803; PMCID: PMC7825972. DISCLOSURES: No relevant relationships by Musa Abu-Jubara, source=Web Response No relevant relationships by Dania Abu-Jubara, source=Web Response No relevant relationships by Adebayo Fasanya, source=Web Response

De Novo and Recurrent Thrombotic Microangiopathy After Renal Transplantation: Current Concepts in Management.

Thrombotic microangiopathy is a well-recognized complication of kidney transplantation that leads frequently to allograft failure. This serious outcome can greatly depend on the underlying etiology and on the timing of therapeutic interventions. Thrombotic microangiopathy syndrome may occur with no previous history of thrombotic microangiopathy (that is, de novo thrombotic microangiopathy), mostly due to medica tions or infections. More frequently, it may recur after kidney transplant in patients with endstage renal failure due to atypical hemolytic uremic syndrome. However, for patients with Shiga-toxininduced hemolytic uremic syndrome, particularly pediatric patients, there is a favorable prognosis. A fundamental tool for management of this disease is genetic screening for abnormal mutations; this can recognize the suggested approach of therapy and may determine the outcome of the disease to a large extent. Although patients with complement factor H and I mutations have worse prognosis, other patients with membrane cofactor protein mutations, for example, have a more favorable prognosis. Accordingly, the plan of therapy can be tailored with a better chance of cure. Unfortunately, the successful use of the biological agent eculizumab, an anti-C5 agent, in some of these syndromes is largely impeded by its high cost, which is linked to its use as a life-long therapy. However, newly suggested therapeutic options may ameliorate this drawback.

Quantitative Alterations in Complement Alternative Pathway and Related Genetic Analysis in Severe Phenotype Preeclampsia.

Preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome share many clinical and biologic features with thrombotic microangiopathy syndromes caused by complement abnormalities. Our hypothesis was that similar functional and genetic alterations in the complement alternative pathway (CAP) are present in these disorders of pregnancy. We conducted quantitative analysis of proteins involved in CAP using ELISA and nephelometry on prospectively collected blood samples from patients with severe phenotype preeclampsia (defined as delivery ≤34 weeks due to preeclampsia), HELLP syndrome, or eclampsia, and matched normotensive controls (n=25 in each arm) between 2011 and 2016. Sequencing was performed to interrogate 14 genes encoding CAP components. Both groups were similar in age, gravidity, parity, marital status, and race. The study group had a higher BMI (mean±SD, 32±8 versus 25±4 kg/m2; P=0.002) and earlier gestational age at delivery (32.5±3.6 versus 40.3±1 weeks; P<0.001). Serologic studies demonstrated elevated Bb subunit (median [range], 1.2 [0.5-4.3] versus 0.6 [0.5-1] μg/ml; P<0.001), complement C5 concentration (28 [18-33] versus 24 [15-34] mg/dl; P=0.03), and sMAC (371 [167-761] versus 184 [112-249] ng/ml; P<0.001) concentrations in patients with preeclampsia. Two thirds of patients with preeclampsia had at least one nonsynonymous sequence variant in CAP genes. Patients with severe phenotype preeclampsia manifest functional alterations in CAP activation. Genetic variants in the CAP genes were detected in several patients, but a larger population study is necessary to fully evaluate genetic risk. Genetic screening and complement-targeted treatment may be useful in risk stratification and novel therapeutic approaches.

Clinical characteristics, triggering etiologies, and response of plasmapheresis in thrombotic microangiopathy in Taiwan.

Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006–2010) and 1352 patients with TMA in the 2011 cohort (2011–2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.

Potential Benefit of Soluble Thrombomodulin in Coping with COVID-19/SARS-CoV-2-Induced Coagulopathy

Researchers should investigate the coagulopathy that accompanies Coronavirus Disease 2019 (COVID-19), as the incidence, as well as the mortality associated with coagulopathy, is higher than expected in COVID-19 patients. We read with interest the article published by Tang N et al. suggesting that elevated plasma levels of the fibrin degradation product D-dimer might be a predictive marker for mortality of patients with COVID-19 [1]. The same authors also reported that the use of heparin improved the prognosis of COVID-19 patients with severe coagulopathy and D-dimer levels &gt;6-fold of the normal upper limit [2]. The high plasma levels of D-dimer suggest that the fibrinolytic system is not inhibited; nonetheless, thrombotic events are frequently noted in COVID-19 patients transferred to intensive care units [3]. Curiously, severe cases of COVID-19 are complicated by cytokine release syndrome in conjunction with Hemophagocytic Lymphohistiocytosis (HLH) [4], suggesting that extremely exaggerated hypercoagulability is induced in COVID-19. The pathophysiology of COVID-19-induced coagulopathy has not been fully elucidated. However, recently, postmortem examination of patients with COVID-19 who died of respiratory failure found thrombi in parallel with the deposition of the C5b-9 complex in the microvasculature, indicating terminal complement activation [5]. These pathological findings are reminiscent of the pathogenesis of Transplant-Associated Thrombotic Microangiopathy (TA-TMA) and atypical Hemolytic Uremic Syndrome (aHUS), in which activation of the complement system plays a role. Other possible factors involved in the pathogenesis of COVID-19-induced coagulopathy may be related to the tropism of Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes COVID-19, to vascular endothelial cells [6]. SARS-CoV-2 infects vascular endothelial cells via the Angiotensin-Converting Enzyme 2 (ACE2) receptor, leading to vascular derangement, so-called endotheliitis, which may result in coagulopathy and TMA. Thrombomodulin (TM) is a cell-surface expressed glycoprotein comprising six distinct domains, including an NH2-terminal lectinlike region, six tandem Epidermal Growth Factor (EGF)-like structures, an O-glycosylation site-rich domain, a transmembrane domain, and a cytoplasmic tail domain [7]. TM binds to thrombin via its EGF-like region and Converts Protein C (PC) to Activated PC (APC), which inhibits coagulant factors FVIIIa and FVa in the presence of protein S, thereby inhibiting further thrombin generation. Interestingly, TM has an anti-inflammatory effect; the lectin-like domain of TM binds and degrades High Mobility Group Box-1 (HMGB1) and attenuates inflammation. Additionally, after interacting with thrombin, TM converts carboxypeptidase Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) to activated TAFI (TAFIa), which inactivates C3 and C5. Furthermore, the fifth domain of EGF-like region of TM (TME5) interacts with the cell-surface chemokine receptor G protein-coupled receptor protein 15 (GPR15) and then exerts cytoprotective effects on vascular endothelial cells in association with upregulation of antiapoptotic MCl-1 proteins, which is mediated by the activation of extracellular signal-regulated kinase [7]. Recombinant human soluble TM (rhTM) comprises extracellular domains of TM. A clinical trial comparing the efficacy and safety of rhTM with Unfractionated Heparin (UFH) in patients with Intravascular Coagulation (DIC) caused by hematological malignancies or infection found that a greater number of patients treated with rhTM recovered from DIC with acceptable toxicity profiles than those who received UFH. Based on these results, the use of rhTM has been approved for the treatment of DIC in Japan since 2008. The use of rhTM effectively treated many patients with DIC with various types of underlying diseases, including transplant-associated complications such as TA-TMA, hepatic sinusoidal obstruction syndrome/veno-occlusive disease and engraftment syndrome [8]. Importantly, endothliitis plays a role in the development of all of these conditions, suggesting the possible cytoprotective roles of rhTM in vascular endothelial cells. Moreover, prompt improvement of DIC caused by HLH developed in association with immune reconstitution syndrome after initiation of highly active antiretroviral therapy for acquired immunodeficiency syndrome was noted in the individual who received rhTM [9]. Thus, the use of anticoagulant rhTM with additional activities for immune systems and vascular endothelial cells could counteract severe COVID-19 with coagulopathy, although a systematic review and meta-analysis of rhTM therapy for sepsis-induced coagulopathy failed to prove the significant improvement of clinical outcomes of patients with sepsis-induced coagulopathy [10].

New in the differential diagnosis of different variants of thrombotic microangiopathies in obstetrics

All variants of thrombotic microangiopathy (TMA) in obstetric practice develop in an avalanche-like manner and require a rapid decision on the choice of treatment tactics. Although all these diseases have similar features, typical of the TMA syndrome as a whole, they are separate diseases with differing etiology and pathogenesis. Because the manifestations of TMA are almost identical in the different diseases, they may all imitate pre-eclampsia and the therapeutic approaches differ, a differential diagnosis is essential and often determines the prognosis.The differential diagnostic search between the different TMA variants that can develop in pregnancy is described, as the prognosis of life often depends on the correct diagnosis. The main differences between pre-eclampsia/HELLP syndrome and life-threatening conditions such as atypical hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura and catastrophic antiphospholipid syndrome are considered. Algorithms of diagnostic search are proposed. Attention is drawn to the fact that existing algorithms for the diagnosis of severe TMA prior to ADAMTS 13 results, based on the severity of thrombocytopenia and azotemia as well as scoring during pregnancy can serve as a guide, but not as a defining feature of the diagnosis.The key to the differential diagnosis is the effect of delivery on the regression of TMA: if hemolysis and thrombocytopenia decrease after delivery, one can speak of ‘pure’ pre-eclampsia (PE) or HELLP-syndrome. If persistent or increasing, thrombotic thrombocytopenic purpura (TTP) and aHUS should be considered. With an ADAMTS 13 level of less than 10%, a diagnosis of TTP is made. With ADAMTS 13 over 10-20%, the patient falls into the «grey zone» and a repeat enzyme test is required. If there are signs of fulminant multiple organ failure, especially in a patient with initial suspicion of APS, CAPS can be suspected. To confirm it, high titres of APA are required. In addition, TMA may cause: sepsis and various urgent obstetric conditions complicated by the development of DIC.

Neurological manifestations of thrombotic microangiopathy syndromes in adult patients.

The objective of this study was to compare the frequency and severity of neurologic manifestations in adult patients diagnosed with thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and atypical HUS (aHUS). This is a retrospective cohort study of adult patients diagnosed with TTP, HUS and atypical HUS hospitalized at a tertiary center between January 2004 and October 2016. A total of 42 TTP, 16 HUS and 20 aHUS episodes were reviewed to collect clinical, laboratory and radiographic data, as well as information regarding long-term functional outcome. Neurologic symptoms are more common in patients with TTP and HUS as compared to aHUS (p < 0.001 and p = 0.002, respectively). Encephalopathy occurred in 29 TTP (69%) and 11 HUS (68%) episodes. Focal deficits were only observed in patients with TTP (n = 8 [19%]). Seizures were most commonly seen in HUS patients (n = 8 [50%]). Posterior reversible encephalopathy syndrome (PRES) was the most common neuroimaging finding in these syndromes; ischemic infarcts and hemorrhages occurred uncommonly. There was no correlation between presence of neurologic symptoms or neuroimaging abnormalities and poor outcome. Patients with TTP and HUS appear to have a similar spectrum of neurologic manifestations, whereas neurologic involvement is less common in aHUS. PRES is the most common imaging abnormality, and may present atypically. Despite presence of neurologic symptoms or neuroimaging abnormalities, patients with thrombotic microangiopathy (TMA) tend to have favorable long-term outcomes.

De Novo and recurrent thrombotic microangiopathy (TMA) after renal transplantation: current concepts in management

Thrombotic microangiopathy (TMA) is a well-recognized complication of kidney transplantation that leads frequently to allograft failure. This serious outcome depends greatly on the underlying etiology as well as the timing of therapeutic interventions. TMA syndromes may occur with no previous history of TMA, i.e., de novo TMA, mostly due to medications or infection, or more frequently recurs after kidney transplantation i.e., recurrent TMA in patients with ESRF due to the atypical hemolytic uremic syndrome (aHUS). On the other hand, patients with shiga-toxin induced HUS (classic HUS), particularly in childhood has a favorable prognosis. One of the fundamental tools of management of this disease is the genetic screening for abnormal mutations, determination of which will recognize the tools of therapy and consequently outcome of the disease to a large extent. While patients with CFH and CFI mutations have a worse prognosis, other patients with MCP mutations-for example- have a more favorable prognosis. Accordingly, plan of therapy can be thoroughly drawn with a better chance of cure. Unfortunately, the successful use of the biological agent “eculizumab”, an anti-C5 agent, in some of these syndromes is largely impeded by its high cost linked to its use as a life-long therapy. However, a new therapeutic option has been recently admitted ameliorating this drawback and improve the cost-effectiveness balance.