Hematology

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Atypical hemolytic uremic syndrome (aHUS) Atypical hemolytic uremic syndrome (aHUS) is a severe genetic disease that presents as a systemic thrombotic microangiopathy (TMA); patients typically exhibit non-immune hemolytic anemia, thrombocytopenia and organ dysfunction, most often renal disease.

Overview of aHUS
 

Atypical hemolytic uremic syndrome (aHUS) is a systemic disease with poor prognosis characterized by non-immune hemolytic anemia, thrombocytopenia, and renal impairment. It affects 2 persons per million annually and is only slightly more common in children under 18 years of age than in adults1. aHUS can be familial or sporadic in form; in the latter case it can be idiopathic or induced by such events as pregnancy, HELLP syndrome, drug use, organ transplant, or HIV or other infection. In over 50% of cases, aHUS is known to be caused by uncontrolled activation of the complement system, and both familial and sporadic forms of aHUS can be caused by complement-related genetic defects. Loss of function mutations in inhibitors of the complement system, including complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP/CD46), complement factor H-related proteins (CFHR1, CFHR3, CFHR4), thrombomodulin (THBD), and C4b binding protein (C4BP), as well as gain of function mutations in complement factor B (CFB) and complement component 3 (C3), which promote alternative pathway activation, are commonly associated with aHUS. Occasionally, patients have mutations in more than one gene2,3. Sequence analysis of the genes associated with aHUS is useful to confirm diagnosis, assess family members at risk, and possibly direct therapeutic decisions.

Dense deposit disease (DDD), also known as membranoproliferative glomerulonephritis type II, is another rare disease which can result in renal failure and is associated with complement abnormalities. It is characterized by proteinuria, hematuria, acute nephritic, and/or nephrotic disease. The molecular underpinning of aHUS and DDD are similar; mutations in CFH and CFHR5 are responsible for the majority of DDD, and mutations in lamin A/C (LMNA) and C3 have also been implicated in DDD4. Since the majority of the genes responsible for aHUS and DDD overlap, Next Generation Sequencing technology is useful for diagnosis of both DDD and aHUS.

aHUS Approach
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By adding thorough analysis of complement and regulatory genes relevant in aHUS and DDD to our current panel of genetic and plasma-based assays of ADAMTS13, we are able to offer a comprehensive laboratory panel for the evaluation of patients with TMA. This panel provides a comprehensive genetic analysis of patients with TMA with a turnaround time of 28 days. Rapid definitive diagnosis of these patients would enable physicians to accelerate the start of definitive treatment and enable improvement in patient care.

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aHUS References
download-icon-red Chantal Loirat, Véronique Frémeaux-Bacchi. Atypical hemolytic uremic syndrome. Orphanet Journal of Rare Diseases. 2011;6:60

download-icon-redBellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S, Myburgh J, Norton R, Scheinkestel C, Su S. Intensity of continuous renal-replacement therapy in critically ill patients. New England Journal of Medicine. 2009;361:17

download-icon-red Iain Moore, Lisa Strain, Isabel Pappworth, David Kavanagh, Paul N. Barlow, Andrew P. Herbert, Christoph Q. Schmidt, Scott J. Staniforth, Lucy V. Holmes, Roy Ward, Lynn Morgan, Timothy H. J. Goodship, and Kevin J. Marchbank. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood. 2010; 115:379-387

download-icon-redBrackman D, Sartz L, Leh S, Kristoffersson AC, Bjerre A, Tati R, Frémeaux-Bacchi V, Karpman D. Thrombotic Microangiopathy Mimicking Membranoproliferative Glomerulonephritis. Nephrol Dial Transplant. 2011 Oct; 26(10):3399-403.

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