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Review
. 2021 Apr 22:8:20543581211008707.
doi: 10.1177/20543581211008707. eCollection 2021.

Making the Correct Diagnosis in Thrombotic Microangiopathy: A Narrative Review

Philip A McFarlane  1 , Martin Bitzan  2   3 , Catherine Broome  4 , Dana Baran  5 , Jocelyn Garland  6 , Louis-Philippe Girard  7 , Kuljit Grewal  8 , Anne-Laure Lapeyraque  9 , Christopher Jordan Patriquin  10 , Katerina Pavenski  11 , Christoph Licht  12
Affiliations
Review

Making the Correct Diagnosis in Thrombotic Microangiopathy: A Narrative Review

Philip A McFarlane et al. Can J Kidney Health Dis. .

Abstract
in English, French

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 », 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).

Keywords: STEC-induced hemolytic uremic syndrome; atypical hemolytic uremic syndrome; thrombotic microangiopathy; thrombotic thrombocytopenic purpura.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The membership of the group of authors was identified following a series of meetings and conferences related to thrombotic microangiopathy (TMA). The final membership was struck following an industry-sponsored TMA meeting; however, the sponsor was not involved in the genesis or content of the project or the selection of physician members. There was no support either financial or otherwise provided to this group from any industry or other sponsors. P.A.M and J.G. received honoraria from Alexion and Sanofi Genzyme. M.B., A.-L.L., K.G., and D.B. from Alexion. C.B. from Alexion, Sanofi, Argenx, and Appelis. L.-P.G. from Alexion and Genzyme and clinical trials from Chemocentryx and Alexion. C.J.P. from Alexion, Octapharma, Apellis, Biocryst, and Sanofi; received research support from Alexion, Octapharma, and Sanofi; and clinical trial participation—Site PI—Alexion, Ra Pharma, Apellis, and Sanofi. K.P. from Alexion, Sanofi, and Takeda and clinical trials from Sanofi and Takeda. C.L. received honoraria and unrestricted grants from Alexion, Apellis, Aurin, and Novartis.

Figures

Figure 1.
Figure 1.
Thrombotic microangiopathies by category. Source. Modified from Fakhouri et al. Note. TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura; STEC = Shiga toxin-producing Escherichia coli; HUS = hemolytic uremic syndrome; HSCT = hematopoietic stem cell transplantation; CFH = complement factor H; DGKE = diacylglycerol kinase epsilon; INF2 = inverted formin 2. *TMA forms predominantly affecting children.
Figure 2.
Figure 2.
Recommended tests during the workup of a suspected or confirmed thrombotic microangiopathy. Note. Test list: ALP = alkaline phosphatase; PCR = polymerase chain reaction; ELISA = enzyme-linked immunosorbent assay; ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ALT = alanine transaminase; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibodies; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CFB = complement factor B; CFH = complement factor H; CFHR = complement factor H related; CFI = complement factor I; CSF = cerebrospinal fluid; CXR = chest x-ray; C5b-9 = complement factor b-9; DGKE = diacylglycerol kinase epsilon; dsDNA = double stranded DNA; FDP = fibrin degradation product; gamma GT = gamma-glutamyl transferase; GBM = glomerular basement membrane; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; INF2 = inverted formin-2; LDH = lactate dehydrogenase; LPS = lipopolysaccharides; MCP = membrane cofactor protein; MMACHC = methylmalonic aciduria and homocystinuria type C protein; SCL-70 = antitopoisomerase antibody-type of antinuclear autoantibodies (seen in some cases of scleroderma); STEC = Shiga toxin-producing Escherichia coli; THBD = thrombomodulin; VTN = vitronectin; VWF = von Willebrand factor; TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura.
Figure 3.
Figure 3.
A diagnostic algorithm for suspected thrombotic microangiopathy. Note. Patients with previously confirmed diagnosis of aHUS (+TMA history and/or genetic mutation and/or kidney transplant) should be treated immediately with anti-C5 inhibitor. Complement genetic testing should be performed in all patients with aHUS, but treatment should not be delayed awaiting results. While waiting for ADAMTS13 results, a platelet count >30 × 109/L or serum creatinine >200 µmol/L almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP). TMA = thrombotic microangiopathy; TMA-CCD = thrombotic microangiopathy with coexisting disease or drug exposure; LDH = lactate dehydrogenase; PLEX = plasma exchange; TTP = thrombotic thrombocytopenic purpura; HUS = hemolytic uremic syndrome; aHUS = atypical hemolytic uremic syndrome; STEC = Shiga toxin-producing Escherichia coli; ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; INH = inhibitor antibody; C5 = complement component 5.
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