Sridharan, Meera

Abstract Complement-mediated thrombotic microangiopathy can be difficult to recognize when it presents in the setting of an apparent clinical trigger, such as pregnancy, severe hypertension, or kidney transplantation. These conditions can each cause endothelial injury directly but may also unmask complement dysregulation in susceptible individuals. In these situations, the critical question is not whether a trigger exists but whether it fully explains the syndrome and whether urgent complement blockade is warranted to prevent irreversible kidney injury. In this How I Treat article, we use 3 real-world cases to illustrate how we approach this decision in practice. We emphasize the bedside features that most influence our threshold to treat, including the pattern and severity of kidney injury, tempo of disease progression, and lack of improvement with supportive or trigger-directed care. We also address the interpretation of complement genetic findings, pregnancy- and transplant-specific risk stratification, and the individualization of treatment duration. Functional assays can support mechanistic assessment in selected cases but remain an adjunct to diagnosis and should not drive management decisions.

Complement-mediated hemolytic uremic syndrome (CM-HUS), commonly referred to as atypical HUS, is a rare thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway, typically triggered by a “two-hit” mechanism. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage, most commonly affecting the kidneys. While our understanding of the complement system has advanced significantly, CM-HUS remains a complex, heterogeneous disorder influenced by a spectrum of genetic variants, risk haplotypes, and acquired factors such as anti-factor H autoantibodies. This review highlights the current knowledge of CM-HUS pathogenesis, focusing on genetic variants in regulatory and activating proteins of the complement system. We also discuss the diagnostic complexity posed by incomplete penetrance, overlapping phenotypes, and limitations of genetic and functional assays. Emerging ex-vivo assays and complement biomarkers are explored as tools for refining diagnosis and risk stratification. The use of complement inhibitors such as eculizumab and ravulizumab has significantly improved renal outcomes and survival. This review provides a comprehensive, clinically grounded update on the genetics, pathophysiology, diagnostics, and therapeutic considerations in CM-HUS, aiming to provide clinicians and researchers with a deeper understanding of this complex, complement-driven disease.

Abstract Background Despite advances in the diagnosis and treatment of immune thrombotic thrombocytopenic purpura (iTTP), recent mortality estimates remain around 5–10%. Predicting iTTP mortality risk has been of interest, as it may help individualize treatment or potentially guide the use of more intensive or novel therapies based on disease severity. However, prior attempts at mortality prediction have yielded inconsistent results, and no individual variable has demonstrated independent or reliable predictive ability. In a previous analysis utilizing the USTMA iTTP registry, which included 419 patients from 15 TTP referral centers, we reported that mortality due to immune TTP was unpredictable (Blood. 2021;138[Suppl 1]:1047). Neither the French Thrombotic Microangiopathy (TMA) Reference Score (previously validated in the French TMA Registry), nor a previous logistic regression model attempt (developed by USTMA investigators in 2021) demonstrated sufficient accuracy in predicting iTTP mortality in the USTMA dataset (AUC = 0.63 and 0.69, respectively). We subsequently utilized gradient boosted machine, a machine learning approach capable of handling multiple continuous variables and the complex interactions between them in large datasets, and developed a novel prediction tool: the USTMA Mortality Index (Res Pract Thromb Haemost. 2024; 8(3):102388). It demonstrated good performance in predicting iTTP mortality (AUC = 0.77) in repeated 10-fold cross-validation. However, it has not yet undergone external validation. Objectives To externally validate the USTMA Mortality Index to predict mortality due to acute iTTP in a multicenter cohort. Methods We performed an external validation using an independent cohort of iTTP patients from 5 institutions: University of Utah, Case Western Reserve University, Rochester Regional Health, University of Illinois, and Mayo Clinic. Patients in the validation cohort were not part of the development cohort (the USTMA registry). We included patients with confirmed iTTP and defined acute iTTP mortality as death within 30 days of admission. USTMA Mortality Index variables were collected at initial presentation, which included (in order of highest to lowest relative influence): lactate dehydrogenase, serum creatinine, age, hemoglobin, platelet count, presence of stupor/coma, fever. The model's prediction accuracy was assessed using area under the receiver operating characteristic curve (AUC). We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) based on the previously defined cut-offs of 4.27% and 9.08% mortality risk in the original model, which categorized patients into standard risk, high risk, and very high risk of predicted mortality. Results The external validation cohort included 103 patients with confirmed iTTP and 11 deaths (10.7% mortality rate). The USTMA Mortality Index demonstrated poor performance with AUC of 0.69 (95% CI, 0.55–0.83) in the validation cohort. The wide confidence interval reflects substantial uncertainty in model performance, ranging from poor to excellent, and is likely due to the small number of deaths. At a risk threshold ≥4.27%:Sensitivity = 64%Specificity = 70%PPV = 20%NPV = 94% At a risk threshold ≥9.08%:Sensitivity = 18%Specificity = 87%PPV = 14%NPV = 90% Conclusion The USTMA Mortality Index demonstrated poor performance in the external validation cohort (AUC = 0.69, 95% CI, 0.55–0.83), contrasting with its previously favorable performance in repeated 10-fold cross-validation. This discrepancy likely reflects model overfitting, a known challenge in AI-based clinical modeling. Our study is limited by the small number of deaths, resulting in a wide confidence interval ranging from poor to excellent performance. Given that neither the French TMA Reference Score, nor our group's prior logistic regression model (2021), nor the USTMA Mortality Index (2024) could reliably predict mortality upon external validation in our cohorts, these findings collectively suggest that mortality in acute iTTP remains difficult to predict at this time, regardless of statistical methodology or current machine learning capabilities. Clinical decision-making, including the use of therapies such as caplacizumab, should not be guided solely by mortality risk predictions. Instead, efforts to reduce mortality and improve outcomes should prioritize individualized clinical assessment over model-based stratification at this time.

Abstract Introduction: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy due to a severely deficient ADAMTS13 activity caused by ADAMTS13 autoantibodies. Pregnancy is a recognized risk for precipitating acute episodes of iTTP. iTTP is immediately life-threatening to both mother and fetus. This scoping review explores the neonatal outcomes of pregnant mothers with iTTP. Methods: We performed a comprehensive literature search (1990 to 2023) in major scientific databases using the Ovid MEDLINE, Embase, EBM Reviews (Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), and Scopus to identify studies related to iTTP and pregnancy outcomes. Eligible studies included those published in English that reported women with a diagnosis of iTTP that later become pregnant, or women that were initially diagnosed with iTTP during pregnancy or postpartum. Cases were included if there was documentation of confirmed ADAMTS13 deficiency and ADAMTS13 inhibitor was positive or if the author indicated cases were acquired or iTTP. Results were displayed descriptively. Two authors reviewed titles and abstracts, and a third author resolved conflicts. Relevant studies were extracted and analyzed descriptively. Results: 125 publications underwent full review; 52 publications (38 manuscripts, 13 abstracts) consisting of case series (n=18) and case reports (n=33) were included in final analysis. 1 review article with a case series was also included. Data regarding 206 pregnancies (antepartum iTTP: n=91, postpartum iTTP: n=24, and pregnancies in patients with a history (hx) of iTTP but no iTTP during current pregnancy: n=91) from 158 patients was included. Antepartum iTTP presented in the first, second and third trimesters in 21%, 38.7%, and 40 % respectively. When reported (n=67), plasma exchange (TPE) was used in 92.5% cases of iTTP. In 3 pregnancies, FFP was used instead of TPE, Rituximab was used in 19 (7 antepartum) and caplacizumab was used in 6 (2 antepartum) cases of ITTP. Of pregnancies with antepartum iTTP or with a hx of iTTP (n=182), fetal outcomes were available in 161 pregnancies. Of these, there were 46 fetal deaths (28.6%) and 31/46 (67.4%) occurred in those with antepartum iTTP. Fetal outcomes were available in 84/91 pregnancies with a hx of iTTP with no acute iTTP at current pregnancy and 82% (69/84) resulted in a live birth. ADAMTS13 activity was available in 58/91 pregnancies with a hx of iTTP with no acute iTTP and 88 % of these pregnancies had ADAMTS13> 20%. Of pregnancies with a hx of iTTP and available ADAMTS13, there were 7 fetal deaths; one was unrelated to iTTP. The remainder occurred in the first trimester (n=4) and second trimester (n=2); ADAMTS13 was < 20% in 3 patients, and > 20% in 3 patients. Of those with pregnancy losses with ADAMTS13> 20%, one patient had two other miscarriages (one before diagnosis of iTTP and one after diagnosis but no ADAMTS13 available). Another had a pregnancy with a live birth 2 years later (no ADAMTS13 available) and the third patient had ADAMTS13> 20% with a positive inhibitor. In pregnancies with both fetal outcomes and ADAMTS13 activity (n=53), live-births trended towards higher ADAMTS13 activities compared to fetal demise (p, 0.066). There were 5 maternal deaths associated with pregnancy (antepartum iTTP:4, postpartum iTTP: 1). Of those not receiving TPE (n=5), one pregnancy was associated with maternal and fetal death due to late iTTP recognition, one patient was lost to follow-up post-delivery to a live infant. The other three patients received FFP, and steroids; one of these patients suffered a fetal loss. Fetal outcomes were available in 5/7 pregnancies using antepartum rituximab and 4/5 were associated with fetal demise. In pregnancies using antepartum caplacizumab, there was one fetal death and one live birth. Conclusions: Pregnancy in patients with a diagnosis of iTTP carries significant associated morbidity and mortality. To our knowledge, this is the most comprehensive report on fetal mortality. With 28.6% of fetal demise, it is significantly higher than the fetal mortality in the general population (5.5 fetal deaths per 1000 live births). In the current cohort, 82% of pregnancies occurring in women with a hx of iTTP but without acute iTTP resulted in a live birth. This supports benefit of optimizing ADAMTS13 activity in women with a hx of iTTP interested in pregnancy.