Pathways for Diagnosing and Treating CKD-Associated Pruritus: A Narrative Review.

Purpose of Review: Chronic kidney disease (CKD)-associated pruritus is a common, persistent, and distressing itch experienced by patients across the CKD spectrum. Although the disorder is associated with adverse outcomes and poor health-related quality of life, it remains underdiagnosed and undertreated. The purpose of this narrative review is to offer health care providers guidance on how to effectively identify, assess, and treat patients with CKD-associated pruritus, with the goal of reducing symptom burden and improving patient-important outcomes, such as quality of life (QoL). Sources of Information: A panel of nephrologists and researchers from across Canada and the United States was assembled to develop this narrative review based on the best available data, current treatment guidelines, and their clinical experiences. Methods: A panel of nephrologists who actively care for patients with pruritus receiving dialysis from across Canada was assembled. Two researchers from the United States were also included based on their expertise in the diagnosis and management of CKD-associated pruritus. Throughout Spring 2023, the panel met to discuss key topics in the identification, assessment, and management of CKD-associated pruritus. Panel members subsequently developed summaries of the pertinent information based on the best available data, current treatment guidelines, and added information on their own clinical experiences. In all cases, approval of the article was sought and achieved through discussion. Key Findings: This narrative review provides pragmatic guidance addressing: (1) methods for screening CKD-associated pruritus, (2) assessing severity, (3) management of CKD-associated pruritus, and (4) suggested areas for future research. The panel developed a 3-pillar framework for proactive assessment and severity scoring in CKD-aP: systematic screening for CKD-associated pruritus (pillar 1), assessment of pruritus intensity (pillar 2), and understanding the impact of CKD-associated pruritus on the patient's QoL (pillar 3). Management of CKD-associated pruritus can include ensuring optimization of dialysis adequacy, achieving mineral metabolism targets (ie, calcium, phosphate, and parathyroid hormone). However, treatment of CKD-associated pruritus usually requires additional interventions. Patients, regardless of CKD-associated pruritus severity, should be counseled on adequate skin hydration and other non-pharmacological strategies to reduce pruritus. Antihistamines should be avoided in favor of evidence-based treatments, such as difelikefalin and gabapentin. Limitations: A formal systematic review (SR) of the literature was not undertaken, although published SRs were reviewed. The possibility for bias based on the experts' own clinical experiences may have occurred. Key takeaways are based on the current available evidence, of which head-to-head clinical trials are lacking. Funding: This work was funded by an arm's length grant from Otsuka Canada Pharmaceutical Inc. (the importer and distributer of difelikefalin in Canada). LiV Medical Education Agency Inc. provided logistical and editorial support.

Motif de la revue: Le prurit associé à l'insuffisance rénale chronique (IRC) est une démangeaison cutanée fréquente, persistante et invalidante que les patients de tout le specter de l'IRC peuvent ressentir. Bien que le prurit soit associé à des effets indésirables et à une mauvaise qualité de vie liée à la santé, il demeure sous-diagnostiqué et sous-traité. L'objectif de cette revue narrative est d'offrir des conseils aux professionnels de la santé sur la façon d'identifier, d'évaluer et de traiter efficacement les patients atteints de prurit associé à l'IRC; ceci dans le but de réduire la charge des symptômes et d'améliorer les résultats importants pour les patients, notamment leur qualité de vie (QdV). Sources de l'information: Un comité de néphrologues et de chercheurs de partout au Canada et des États-Unis a été constitué pour élaborer la présente revue narrative à partir des meilleures données disponibles, des lignes directrices actuelles pour le traitement et de leurs expériences cliniques. Méthodologie: Un groupe de néphrologues canadiens qui s'occupent activement de patients dialysés souffrant de prurit a été constitué. Deux chercheurs des États-Unis ont été inclus au groupe en raison de leur expertise dans le diagnostic et la prise en charge du prurit associé à l'IRC. Le comité s'est réuni tout au long du printemps 2023 pour discuter de sujets clés en lien avec l'identification, l'évaluation et la prise en charge du prurit associé à l'IRC. Les membres du comité ont par la suite rédigé des résumés des informations pertinentes en se basant sur les meilleures données disponibles et les lignes directrices actuelles pour le traitement, auxquels ils ont ajouté des informations issues de leurs propres expériences cliniques. Dans tous les cas, l'approbation du manuscrit a été sollicitée et obtenue par discussion. Principaux résultats: Cette revue narrative offre des conseils pragmatiques sur les points suivants: (1) les méthodes de dépistage du prurit associé à l'IRC; (2) l'évaluation de sa gravité; (3) sa prise en charge; et (4) les domaines suggérés pour de futures recherches. Le comité a développé un cadre à trois piliers pour l'évaluation proactive du prurit associé à l'IRC et l'établissement d'un score de gravité: le dépistage systématique du prurit associé à l'IRC (pilier 1), l'évaluation de son intensité (pilier 2) et la compréhension de son impact sur la QdV du patient (pilier 3). La prise en charge du prurit associé à l'IRC peut inclure l'optimisation de l'adéquation de la dialyse et l'atteinte des cibles du métabolisme minéral (c.-à-d. calcium, phosphate et hormone parathyroïdienne). Cependant, son traitement nécessite habituellement des interventions supplémentaires. Les patients, quelle que soit la gravité du prurit associé à l'IRC, devraient être avisés d'hydrater adéquatement leur peau et informés des autres stratégies non pharmacologiques afin de réduire le prurit. On devrait éviter les antihistaminiques et les remplacer par des traitements fondés sur des données probantes comme la difélikéfaline et la gabapentine. Limites: Aucune revue systématique de la littérature n'a été formellement entreprise, bien que les revues systématiques publiées aient été examinées. La possibilité d'un biais fondé sur les expériences cliniques des experts est envisageable. Les principales conclusions de cette étude sont fondées sur les données probantes actuellement disponibles, pour lesquelles il n'existe pas d'essais cliniques comparatifs. Financement: Ces travaux ont été financés par une subvention indépendante d'Otsuka Canada Pharmaceutical Inc. (l'importateur et distributeur de la difélikéfaline au Canada). Un soutien logistique et éditorial a été fourni par liV Medical Education Agency Inc.

Prevalence of Adult Type 2 Diabetes Mellitus and Related Complications in Alberta, Canada: A Retrospective, Observational Study Using Administrative Data.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a prevalent chronic disease and a leading cause of morbidity/mortality in Canada. We evaluated the burden of T2DM in Alberta, Canada, by estimating the 5-year period prevalence of T2DM and rates of comorbidities and complications/conditions after T2DM. METHODS: We conducted a population-based, retrospective study linking administrative health databases. Individuals with T2DM (≥18 years of age) were identified between 2008-2009 and 2018-2019 using a published algorithm, with follow-up data to March 2020. The 5-year period prevalence was estimated for 2014-2015 to 2018-2019. Individuals with newly identified T2DM, ascertained between 2010-2011 and 2017-2018 with a lookback period between 2008-2009 and 2009-2010 and a minimum 1 year of follow-up data, were evaluated for subsequent cardiovascular, diabetic, renal, and other complication/condition frequencies (%) and rates (per 100 person-years). Complications/conditions were stratified by atherosclerotic cardiovascular disease (ASCVD) status at index and age. RESULTS: The 5-year period prevalence of T2DM was 11,051 per 100,000 persons, with the highest prevalence in men 65 to <75 years of age. There were 195,102 individuals included in the cohort (mean age 56.7±14.7 years). The most frequently reported complications/conditions (rates per 100 person-years) were acute infection (23.10, 95% confidence interval [CI] 23.00 to 23.30), hypertension (17.30, 95% CI 16.80 to 17.70), and dyslipidemia (12.20, 95% CI 11.90 to 12.40). Individuals who had an ASCVD event/procedure and those ≥75 years of age had higher rates of complications/conditions. CONCLUSIONS: We found that over half of the individuals had hypertension or infection after T2DM. Also, those with ASCVD had higher rates of complications/conditions. Strategies to mitigate complications/conditions after T2DM are required to reduce the burden of this disease on individuals and health-care systems.

Management of Type 2 Diabetic Kidney Disease in 2022: A Narrative Review for Specialists and Primary Care.

Purpose of review: Kidney disease is present in almost half of Canadian patients with type 2 diabetes (T2D), and it is also the most common first cardiorenal manifestation of T2D. Despite clear guidelines for testing, opportunities are being missed to identify kidney diseases, and many Canadians are therefore not receiving the best available treatments. This has become even more important given recent clinical trials demonstrating improvements in both kidney and cardiovascular (CV) endpoints with sodium-glucose cotransporter 2 (SGLT2) inhibitors and a nonsteroidal mineralocorticoid receptor antagonist, finerenone. The goal of this document is to provide a narrative review of the current evidence for the treatment of diabetic kidney disease (DKD) that supports this new standard of care and to provide practice points. Sources of information: An expert panel of Canadian clinicians was assembled, including 9 nephrologists, an endocrinologist, and a primary care practitioner. The information the authors used for this review consisted of published clinical trials and guidelines, selected by the authors based on their assessment of their relevance to the questions being answered. Methods: Panelists met virtually to discuss potential questions to be answered in the review and agreed on 10 key questions. Two panel members volunteered as co-leads to write the summaries and practice points for each of the identified questions. Summaries and practice points were distributed to the entire author list by email. Through 2 rounds of online voting, a second virtual meeting, and subsequent email correspondence, the authors reached consensus on the contents of the review, including all the practice points. Key findings: It is critical that DKD be identified as early as possible in the course of the disease to optimally prevent disease progression and associated complications. Patients with diabetes should be routinely screened for DKD with assessments of both urinary albumin and kidney function. Treatment decisions should be individualized based on the risks and benefits, patients' needs and preferences, medication access and cost, and the degree of glucose lowering needed. Patients with DKD should be treated to achieve targets for A1C and blood pressure. Renin-angiotensin-aldosterone system blockade and treatment with SGLT2 inhibitors are also key components of the standard of care to reduce the risk of kidney and CV events for these patients. Finerenone should also be considered to further reduce the risk of CV events and chronic kidney disease progression. Education of patients with diabetes prescribed SGLT2 inhibitors and/or finerenone is an important component of treatment. Limitations: No formal guideline process was used. The practice points are not graded and are not intended to be viewed as having the weight of a clinical practice guideline or formal consensus statement. However, most practice points are well aligned with current clinical practice guidelines.

Justification: L'insuffisance rénale est présente chez près de la moitié des patients canadiens atteints de diabète de type 2 (DT2). Il s'agit également de la première manifestation cardiorénale la plus fréquente du DT2. Bien qu'il existe des lignes directrices claires pour son dépistage, des occasions de diagnostiquer l'insuffisance rénale sont manquées, ce qui fait en sorte que de nombreux Canadiens ne reçoivent pas les meilleurs traitements disponibles. Cette préoccupation a pris de l'importance puisque de récents essais cliniques ont démontré des améliorations dans les paramètres rénaux et cardiovasculaires (CV) avec la prise de finérénone, un antagoniste non stéroïdien des récepteurs minéralocorticoïdes (nsMRA), et d'inhibiteurs du cotransporteur de glucose de sodium 2 (SGLT2). L'objectif de cet article est de fournir une revue narrative des données probantes actuelles appuyant cette nouvelle norme de soins pour le traitement de l'insuffisance rénale diabétique (IRD), ainsi que des points de pratique. Sources de l'information: Un groupe d'experts composé de cliniciens canadiens, dont neuf néphrologues, un endocrinologue et un prestataire de soins primaires, a été formé. Les auteurs de cette revue ont utilisé des lignes directrices et des essais cliniques publiés comme sources; ceux-ci ont été choisis sur la base d'une évaluation de leur pertinence pour les questions auxquelles ils avaient répondu. Méthodologie: Les panélistes se sont réunis virtuellement pour discuter de potentielles questions à répondre dans le cadre de cette revue, et se sont entendus sur dix questions clés. Deux membres du panel se sont portés volontaires pour être co-responsables et rédiger les résumés et les points de pratique pour chacune des questions identifiées. Ces derniers ont été distribués par courriel à l'ensemble des auteurs. Après deux tours de vote en ligne, une deuxième réunion virtuelle et la correspondance électronique qui a suivi, les auteurs sont parvenus à un consensus sur le contenu de la revue narrative, y compris sur tous les points de pratique. Principaux résultats: Il est essentiel que l'IRD soit diagnostiquée le plus tôt possible afin de prévenir de façon optimale la progression de la maladie et les complications qui y sont associées. On devrait procéder au dépistage systématique de l'IRD chez les patients diabétiques par l'évaluation de l'albumine urinaire ET de la fonction rénale. Les décisions relatives au traitement devraient être individualisées en fonction des risques et des avantages pour le patient, de ses besoins et préférences, de l'accès aux médicaments et des coûts, ainsi que du degré nécessaire de réduction de la glycémie. Les patients atteints d'IRD devraient être traités pour atteindre les cibles d'A1c et de pression artérielle. Le blocage du SRAA et le traitement avec des inhibiteurs du SGLT2 sont également des composantes clés de la norme de soins visant à réduire le risque d'événements rénaux et CV pour ces patients. La finérénone devrait également être envisagée pour réduire encore davantage les risques d'événements CV et de progression vers l'IRC. L'éducation des patients diabétiques auxquels on prescrit des inhibiteurs du SGLT2 et/ou de la finérénone est un élément important du traitement. Limites: Aucun processus officiel de directives n'a été utilisé. Les points de pratique ne sont pas notés et ne sont pas destinés à être considérés comme ayant le poids d'une directive de pratique clinique ou d'une déclaration de consensus officielle. Cependant, la plupart des points de pratique sont bien alignés avec les lignes directrices actuelles de pratique clinique.

CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum.

OBJECTIVE: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence. METHODS: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation. RESULTS: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering. CONCLUSION: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

Hypercoagulability and Inflammatory Markers in a Case of Congenital Thrombotic Thrombocytopenic Purpura Complicated by Fetal Demise.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disorder caused by an inherited genetic deficiency of ADAMTS13 and affects less than one per million individuals. Patients who are diagnosed with TTP during pregnancy are at increased risk of maternal and fetal complications including fetal demise. We present a case of a 32-year-old G3P0 (gravida 3, para 0) who presented at 20 weeks gestation with a new diagnosis of congenital TTP (cTTP) and fetal demise. METHODS: We describe the pathophysiology of pregnancy complications in a patient with cTTP using platelet procoagulant membrane dynamics analysis and quantitative proteomic studies, compared to four pregnant patients with gestational hypertension, four pregnant patients with preeclampsia, and four healthy pregnant controls. RESULTS: The cTTP patient had increased P-selectin, tissue factor expression, annexin-V binding on platelets and neutrophils, and localized thrombin generation, suggestive of hypercoagulability. Among 15 proteins that were upregulated, S100A8 and S100A9 were distinctly overexpressed. CONCLUSIONS: There is platelet-neutrophil activation and interaction, platelet hypercoagulability, and proinflammation in our case of cTTP with fetal demise.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a 'reduced' or 'standard' steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a 'standard'-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.

Immunoglobulin M Monoclonal Gammopathies of Clinical Significance.

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler's syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research.

Complement-Amplifying Conditions in Atypical Hemolytic Uremic Syndrome: A Canadian Case Series.

Rationale: Thrombotic microangiopathies (TMAs) are systemic disorders that often affect the kidneys and encompass a heterogeneous group of conditions, including atypical hemolytic uremic syndrome (aHUS). The complement pathway is thought to play a crucial role in the pathogenesis of aHUS, and a favorable response can be obtained through complement C5 inhibition. There is emerging evidence to suggest that the same is also true for several other forms of TMA. Objective: The purpose of this series is to report cases of aHUS in which both an innate defect of the alternative complement pathway and a complement-amplifying condition were suspected. Methods: This case series describes 8 patients who were managed in Canadian tertiary centers for aHUS and who presented initially with complement-amplifying conditions. Results: In all cases, aHUS was associated with organ dysfunction and in some, with an innate defect of the alternative complement pathway. The complement-amplifying conditions identified were diverse including immune disorders, pregnancy, and a Shiga toxin infection. Patients improved rapidly when treated with eculizumab or plasma exchange. Conclusions: These observations illustrate the seriousness of secondary aHUS. They also add to existing lines of evidence that the complement pathway is potentially involved in this condition and that it should be considered as a therapeutic target of interest under such circumstances.

Justification: Les microangiopathies thrombotiques (MAT) sont des troubles systémiques qui affectent souvent les reins et qui englobent un groupe hétérogène d'affections, notamment le syndrome hémolytique et urémique atypique (SHUa). On pense que la voie du complément joue un rôle crucial dans la pathogenèse du SHUa et qu'une réponse favorable pourrait être obtenue par inhibition du complément C5. De nouvelles preuves suggèrent qu'il en serait de même pour plusieurs autres formes de MAT. Objectif: Cette série vise à rapporter des cas de SHUa pour lesquels on soupçonnait à la fois une anomalie congénitale de la voie alterne du complément et une condition d'amplification du complément. Méthodologie: Cette série décrit les cas de huit patients qui présentaient initialement des conditions d'amplification du complément et qui ont été pris en charge pour un SHUa dans des centres tertiaires canadiens. Résultats: Dans tous les cas, le SHUa était associé à un dysfonctionnement d'organe et, dans certains cas, à une anomalie congénitale de la voie alterne du complément. Les conditions d'amplification du complément identifiées étaient diverses, notamment des troubles immunitaires, une grossesse et une infection à une shigatoxine. L'état des patients s'est rapidement amélioré après un traitement avec éculizumab ou des échanges plasmatiques. Conclusion: Ces observations illustrent la gravité du SHUa secondaire. Elles s'ajoutent aux preuves existantes qui suggèrent que la voie du complément est potentiellement impliquée dans cette pathologie et qu'elle devrait être considérée comme une cible thérapeutique d'intérêt dans de telles circonstances.

Measurement of erythrocyte membrane mannoses to assess splenic function.

Red blood cells (RBCs) lose plasma membrane in the spleen as they age, but the cells and molecules involved are yet to be identified. Sickle cell disease and infection by Plasmodium falciparum cause oxidative stress that induces aggregates of cross-linked proteins with N-linked high-mannose glycans (HMGs). These glycans can be recognised by mannose-binding lectins, including the mannose receptor (CD206), expressed on macrophages and specialised phagocytic endothelial cells in the spleen to mediate the extravascular haemolysis characteristic of these diseases. We postulated this system might also mediate removal of molecules and membrane in healthy individuals. Surface expression of HMGs on RBCs from patients who had previously undergone splenectomy was therefore assessed: high levels were indeed observable as large membrane aggregates. Glycomic analysis by mass spectrometry identified a mixture of Man5-9 GlcNAc2 structures. HMG levels correlated well with manual pit counts (r = 0.75-0.85). To assess further whether HMGs might act as a splenic reticuloendothelial function test, we measured levels on RBCs from patients with potential functional hyposplenism, some of whom exhibited high levels that may indicate risk of complications.

T and NK cell lymphoma cell lines do not rely on ZAP-70 for survival.

B-cell receptor (BCR) signalling is critical for the survival of B-cell lymphomas and is a therapeutic target of drugs such as Ibrutinib. However, the role of T-cell receptor (TCR) signalling in the survival of T/Natural Killer (NK) lymphomas is not clear. ZAP-70 (zeta associated protein-70) is a cytoplasmic tyrosine kinase with a critical role in T-cell receptor (TCR) signalling. It has also been shown to play a role in normal NK cell signalling and activation. High ZAP-70 expression has been detected by immunohistochemistry in peripheral T cell lymphoma (PTCL) and NK cell lymphomas (NKTCL). We therefore, studied the role of TCR pathways in mediating the proliferation and survival of these malignancies through ZAP-70 signalling. ZAP-70 protein was highly expressed in T cell lymphoma cell lines (JURKAT and KARPAS-299) and NKTCL cell lines (KHYG-1, HANK-1, NK-YS, SNK-1 and SNK-6), but not in multiple B-cell lymphoma cell lines. siRNA depletion of ZAP-70 suppressed the phosphorylation of ZAP-70 substrates, SLP76, LAT and p38MAPK, but did not affect cell viability or induce apoptosis in these cell lines. Similarly, while stable overexpression of ZAP-70 mediates increased phosphorylation of target substrates in the TCR pathway, it does not promote increased survival or growth of NKTCL cell lines. The epidermal growth factor receptor (EGFR) inhibitor Gefitinib, which has off-target activity against ZAP-70, also did not show any differential cell kill between ZAP-70 overexpressing (OE) or knockdown (KD) cell lines. Whole transcriptome RNA sequencing highlighted that there was very minimal differential gene expression in three different T/NK cell lines induced by ZAP-70 KD. Importantly, ZAP-70 KD did not significantly enrich for any downstream TCR related genes and pathways. Altogether, this suggests that high expression and constitutive signalling of ZAP-70 in T/NK lymphoma is not critical for cell survival or downstream TCR-mediated signalling and gene expression. ZAP-70 therefore may not be a suitable therapeutic target in T/NK cell malignancies.

Mainstreaming Genetic Testing for Adult Patients With Autosomal Dominant Polycystic Kidney Disease.

PURPOSE: Genetic testing results are currently obtained approximately 1 year after referral to a medical genetics team for autosomal dominant polycystic kidney disease (ADPKD). We evaluated a mainstream genetic testing (MGT) pathway whereby the nephrology team provided pre-test counseling and selection of patients with suspected ADPKD for genetic testing prior to direct patient interaction by a medical geneticist. SOURCES OF INFORMATION: A multidisciplinary team of nephrologists, genetic counselors, and medical geneticists developed an MGT pathway for ADPKD using current testing criteria for adult patient with suspected ADPKD and literature from MGT in oncology. METHODS: An MGT pathway was assessed using a prospective cohort and compared to a retrospective cohort of 56 patients with ADPKD who received genetic testing using the standard, traditional pathway prior to implementing the MGT for ADPKD. The mainstream pathway was evaluated using time to diagnosis, diagnostic yield, and a patient survey to assess patient perceptions of the MGT pathway. KEY FINDINGS: We assessed 26 patients with ADPKD using the MGT and 18 underwent genetic testing with return of results. Of them, 52 patients had data available for analysis in the traditional control cohort. The time for return of results using our MGT pathway was significantly shorter with a median time to results of 6 months compared to 12 months for the traditional pathway. We identified causative variants in 61% of patients, variants of uncertain significance in 28%, and 10% had negative testing which is in line with expectations from the literature. The patient surveys showed high satisfaction rates with the MGT pathway. LIMITATIONS: This report is an evaluation of a new genetic testing pathway restricted to a single, publicly funded health care center. The MGT pathway involved a prospective collection of a limited number of patients with ADPKD with comparison to a retrospective cohort of patients with ADPKD evaluated by standard testing. IMPLICATIONS: A MGT pathway using clearly defined criteria and commercially available gene panels for ADPKD can be successfully implemented in a publicly funded health care system to reduce the time required to obtain genetic results.

MOTIF: Actuellement, les résultats du dépistage génétique pour la maladie polykystique rénale autosomique dominante (ADPKD) sont obtenus environ un an après l'aiguillage en médecine génique. Nous avons évalué un parcours de dépistage génétique intégré (DGI) où l'équipe de néphrologie fournit des conseils pré-dépistage et sélectionne les patients soupçonnés d'ADPKD pour un test génétique avant l'interaction directe du patient avec un généticien médical. SOURCES: Une équipe multidisciplinaire constituée de néphrologues, de conseillers en génétique et de généticiens médicaux a développé un parcours de DGI à partir des critères existants pour les patients adultes soupçonnés d'ADPKD et de la littérature portant sur le DGI en oncologie. MÉTHODOLOGIE: Le parcours de DGI a été évalué dans une cohorte prospective puis comparé à une cohorte rétrospective de 56 patients atteints d'ADPKD ayant subi un dépistage génétique selon le parcours traditionnel, avant la mise en œuvre d'un parcours de DGI pour l'ADPKD. Le parcours intégré a été évalué en tenant compte du temps requis pour poser le diagnostic, du rendement diagnostique et d'un sondage auprès des patients évaluant leurs perceptions à l'égard du parcours lui-même. PRINCIPAUX RÉSULTATS: Le parcours de DGI a permis d'évaluer 26 patients atteints d'ADPKD, dont 18 ont subi des tests génétiques avec retour des résultats. Dans la cohorte témoin (dépistage traditionnel), 52 patients disposaient de données disponibles pour l'analyse. Le délai médian pour l'obtention des résultats était significativement plus court avec le parcours de DGI qu'avec le parcours traditionnel (6 mois c. 12 mois). Des variantes causales ont été relevées chez 61 % des patients, 28 % des patients présentaient des variantes de signification incertaine et 10 % ont obtenu des résultats négatifs, ce qui est conforme aux attentes posées par les résultats rapportés dans la littérature. Les sondages menés auprès des patients ont montré des taux de satisfaction élevés à l'égard du parcours de DGI. LIMITES: Ce rapport constitue l'évaluation d'un nouveau parcours de dépistage génétique limitée à un seul centre de soins de santé public. Ce parcours de DGI a été évalué dans une cohorte prospective formée d'un nombre limité de patients atteints d'ADPKD par rapport à une cohorte rétrospective de patients atteints d'ADPKD évalués par la méthode traditionnelle. IMPLICATIONS: Un parcours de DGI utilisant des critères clairement définis et des panels génétiques pour l'ADPKD disponible commercialement peut être mis en œuvre avec succès dans un système de santé public et accélérer l'obtention des résultats génétiques.

Making the Correct Diagnosis in Thrombotic Microangiopathy: A Narrative Review.

PURPOSE OF REVIEW: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli-induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment. SOURCES OF INFORMATION: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors. METHODS: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies. KEY FINDINGS: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA. LIMITATIONS: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.

JUSTIFICATION: La microangiopathie thrombotique (MAT) est suspectée chez les patients présentant une thrombocytopénie et la preuve d'une anémie hémolytique microangiopathique (AHMA). Les patients atteints de MAT peuvent être gravement malades, il est donc essentiel de déterminer rapidement et précisément l'étiologie sous-jacente. Grâce à une meilleure connaissance de la physiopathologie et des causes de la MAT, nous pouvons désormais classer les MAT par catégorie: purpura thrombocytopénique thrombotique (PTT), syndrome hémolytique urémique post-infectieux (SHU) principalement induit par STEC (Escherichia coli produisant la toxine Shiga), ou MAT associée à une affection coexistante ou à un SHU atypique (SHUa). Nous avons constaté un besoin dans la communauté médicale pour guider à la fois la détection rapide et précise de la MAT, la sélection des tests pour clarifier son étiologie et la séquence des étapes menant à l'initiation du traitement. SOURCES: Des recherches documentaires sur PubMed et les connaissances antérieures des auteurs ont permis de colliger les principales études publiées portant sur la détection, la classification et le traitement de la MAT chez les enfants ou les adultes. MÉTHODOLOGIE: Cet examen est le résultat d'un processus de consultation qui reflète le consensus des experts du Canada, des États-Unis et des Émirats arabes Unis. Les membres représentent des cliniciens, des chercheurs et des enseignants en médecine pédiatrique et adulte dans les domaines de l'hématologie, de la néphrologie et de la médecine de laboratoire. Les auteurs, par le biais d'un processus d'examen itératif, ont colligé et synthétisé l'information provenant des études publiées jugées pertinentes. PRINCIPAUX RÉSULTATS: Le PTT survient lors d'une activité insuffisante de la protéase du facteur Willebrand connue sous le nom d'ADAMTS13. Le SHU-STEC, aussi appelé SHU « typique ¼, est causé par des infections gastro-intestinales dues à des bactéries produisant la toxine Shiga (initialement appelée vérocytotoxine). Plusieurs états pathologiques ou expositions à des médicaments peuvent déclencher la MAT. Quant au SHU atypique (SHUa), il survient en présence d'anomalies héréditaires ou acquises de la voie du complément alternatif qui mènent à un dérèglement de l'activation du complément, souvent à la suite d'un événement déclencheur comme une infection. On peut diviser le processus de diagnostic étiologique de la MAT en deux étapes distinctes. La première couvre la présentation initiale et le diagnostic, y compris les processus de détection de la MAT, les tests initiaux et aiguillages appropriés, ainsi que les traitements empiriques si nécessaire. La deuxième étape consiste à confirmer le diagnostic étiologique et à procéder au traitement définitif. Pour de nombreuses formes de MAT, la réponse ultime aux traitements et le résultat du patient dépendent de la détection rapide et précise de la MAT et ensuite, d'une approche standardisée pour la recherche du diagnostic étiologique. Nous présentons une approche structurée pour détecter la présence de MAT ainsi qu'une démarche pour rechercher l'étiologie, y compris des tableaux de laboratoire normalisés. Nous soulignons l'importance d'une consultation précoce avec les spécialistes appropriés en hématologie et en néphrologie, et de la détermination d'un éventuel besoin d'échange de plasma (PLEX) pour le patient. Les cliniciens devraient envisager les traitements empiriques appropriés tout en suivant la démarche que nous recommandons pour le diagnostic étiologique définitif et la gestion de la MAT. LIMITES: La base factuelle de nos recommandations est constituée de petites études cliniques, de rapports de cas et de séries de cas. Ces études ne sont généralement pas contrôlées ou randomisées et ne se prêtent pas à une méthodologie plus stricte basée sur des lignes directrices ni à une approche fondée sur le GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Immunoglobulin-A Vasculitis With Renal Involvement in a Patient With COVID-19: A Case Report and Review of Acute Kidney Injury Related to SARS-CoV-2.

RATIONALE: Acute kidney injury is a common complication of COVID-19 and is associated with significantly increased mortality. The most frequent renal biopsy finding with SARS-CoV-2 infection is acute tubular injury; however, new onset glomerular diseases have been reported. The development of persistent urinary abnormalities in patients with COVID-19 should prompt consideration for renal biopsy to rule out glomerulonephritis. PRESENTING CONCERNS: A 30-year-old man with no prior medical history presented to the emergency department with symptoms of COVID-19 and new onset painful purpuric rash, arthralgia, and abdominal pain. SARS-CoV-2 infection was confirmed with nucleic acid testing and laboratory investigations revealed preserved renal function with dysmorphic hematuria and nephrotic range proteinuria. DIAGNOSIS: A skin biopsy of the purpuric rash was performed, which demonstrated leukocytoclastic vasculitis. Renal biopsy revealed focally crescentic and segmentally necrotizing IgA nephropathy. Overall, given the clinical syndrome of glomerulonephritis with purpuric rash, arthralgia, and abdominal pain, the presentation is most in keeping with a diagnosis of IgA vasculitis in the setting of COVID-19. INTERVENTIONS: The patient was treated conservatively for COVID-19 in the community. A 7-day course of prednisone was started for the vasculitic rash. IgA nephropathy was managed conservatively with blood pressure control and RAAS blockade with losartan. OUTCOMES: With conservative management, the patient's COVID-19 symptoms resolved completely and he did not require hospital admission. Following prednisone therapy, the patient's rash, arthralgia, and abdominal pain improved. However, despite resolution of COVID-19, hematuria and proteinuria persisted. With the initiation of RAAS blockade, renal function remained stable and proteinuria improved dramatically at 6 weeks. NOVEL FINDINGS: De novo glomerulonephritis is a renal manifestation of SARS-CoV-2 infection beyond acute tubular injury. IgA vasculitis appears to be a rare complication of COVID-19.

CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update.

OBJECTIVE: In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence. METHODS: A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation. RESULTS: Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations. CONCLUSION: The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.

BSH 2020 Student Essay Prize - 'How are you inspired by haematology and how will you inspire others to become haematologists?'

All medical personnel ponder their future career, and students perhaps more so than professionals. Indeed, there are many old and famous specialties in which we might envision ourselves forging a path, each competing for our attention. Far-off from the clamour and glamour of venerable medicine and surgery, however, there lies younger specialties that reward quiet curiosity and stolid perseverance. Chief amongst them, in my eyes, is the speciality of haematology. Often misunderstood or otherwise unheard of, the subject of haematology and those practice it have steadily plotted a course through the maelstrom of blood disease and unremittingly turned its tide back in favour of the patients, for whom they labour. As the British Society for Haematology celebrates its 60th anniversary, the question rightly posed this year to interested students is, based on our own personal reflections, how should we continue to nourish the buds of enthusiasm and interest for this still-blossoming specialty? In this essay, I put forth those intellectual and historical facets of haematology which have given me great inspiration, and I reflect on how we, as practitioners or as aspirants, can best cultivate the passion we feel for our subject in the hearts of others.

Immunoglobulin M Paraproteinaemias.

Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15-20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of "monoclonal gammopathy of clinical significance" entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Managing pregnancy-associated clinical emergencies in systemic lupus erythematosus: a case-based approach.

Introduction: Systemic lupus erythematosus (SLE)-related thrombocytopenia during pregnancy and the postpartum period have been associated with adverse pregnancy outcomes and perinatal complications. In this case report, we present two SLE patients with thrombocytopenia emergencies secondary to HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome and thrombotic thrombocytopenic purpura (TTP).Areas covered: The first case involved a 26-year-old woman, G1P0 at 26 weeks gestation (GA), with high-titer antiphospholipid antibodies (aPL) (positive lupus anticoagulant, anti-beta 2 glycoprotein-1 (aß2GP1), anti-cardiolipin) and non-criteria aPL to phosphatidylserine/prothrombin complex and anti-domain 1 ß2GP1. This case highlights the risks associated with aPL in pregnancy, considers management issues relating to anticoagulation during pregnancy and highlights the importance of maintaining a high index of suspicion for diagnosis of HELLP in SLE patients. The second case was a 36-year-old female, G3P2 at 32 weeks GA, with class III lupus nephritis (LN) who developed severe pre-eclampsia, which included mild thrombocytopenia. This case illustrates the challenges in identifying and differentiating between three pregnancy emergencies that can be seen in SLE patients (pre-eclampsia, LN, and TTP) and presents the management of TTP in peripartum SLE.Expert opinion: These two cases remind us of the importance of timely diagnosis and management of thrombocytopenia in this population.