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The Role of Complement in the Pathogenesis of HUS and the TMA Spectrum Disorders

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Abstract

Purpose of Review

This review aims to examine the current definitions of primary and secondary hemolytic uremic syndromes. Specifically, it seeks to determine which external conditions can result in secondary Thrombotic microangiopathy (TMA), which can trigger cases of primary atypical uremic syndromes (aHUS), and the role of complement in the pathogenesis of TMA spectrum disorders.

Recent Findings

Building on the growing insight about the pathogenic role of dysregulation of the alternative complement pathway in primary aHUS, the successful use of complement-blocking treatment in cases of thrombotic microangiopathy with coexisting conditions (secondary TMA), along with the identification of complement mutations in some of these cases, indicates a so far possibly under-appreciated pathogenic role for complement in diagnoses within the TMA spectrum.

Summary

Uncontrolled complement activity and pro-thrombotic environments represent a unifying pathogenic mechanism in aHUS and the TMA spectrum disorders and point towards shared diagnostic and therapeutic pathways.

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Abbreviations

ADAMTS13:

A disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13

AP:

Alternative pathway (complement system)

aHUS:

Atypical hemolytic uremic syndrome

CMV:

Cytomegaloviruses

CP:

Classical pathway (complement system)

DEAP-HUS:

Deficiency of CFHR plasma proteins and autoantibody-positive form of _______hemolytic uremic syndrome

DGKE:

Diacylglycerol kinase epsilon

ESRD:

End-stage renal disease

FB:

Factor B

FH:

Factor H

FHR:

Factor H–related protein

FI:

Factor I

HELLP:

Hemolysis, elevated liver enzymes, and low platelet count

HSCT:

Hematopoietic stem cell transplantation

HUS:

Hemolytic uremic syndrome

INF2:

Inverted formin-2

LP:

Lectin pathway (complement system)

MAC:

Membrane attack complex

MAHA:

Microangiopathic hemolytic anemia

MBL:

Mannose-binding lectin

MCP:

Membrane cofactor protein (CD46)

SCR:

Short consensus repeat

STEC-HUS/eHUS:

Shiga toxin–producing E. coli mediated HUS

Stx:

Shiga toxin

THBD:

Thrombomodulin (CD141)

TMA:

Thrombotic microangiopathy

TTP:

Thrombotic thrombocytopenic purpura

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Authors and Affiliations

  1. Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

    Erin Jacobs, Carolina Ortiz & Christoph Licht

  2. Department of Pediatrics, University of Toronto, Toronto, ON, Canada

    Christoph Licht

  3. Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Christoph Licht

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  1. Erin Jacobs
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  2. Carolina Ortiz
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  3. Christoph Licht
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Correspondence to Christoph Licht.

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Jacobs, E., Ortiz, C. & Licht, C. The Role of Complement in the Pathogenesis of HUS and the TMA Spectrum Disorders. Curr Pediatr Rep 7, 1–11 (2019). https://doi.org/10.1007/s40124-019-00186-5

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