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.
Competing Interests: 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.
(© The Author(s) 2021.)