Accepted Manuscript. No more thrombotic thrombocytopenic purpura/hemolytic uremic syndrome please. Yeong-Hau H. Lien MD, PhD S (18)

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1 Accepted Manuscript No more thrombotic thrombocytopenic purpura/hemolytic uremic syndrome please Yeong-Hau H. Lien MD, PhD PII: S (18) DOI: Reference: AJM To appear in: The American Journal of Medicine Please cite this article as: Yeong-Hau H. Lien MD, PhD, No more thrombotic thrombocytopenic purpura/hemolytic uremic syndrome please, The American Journal of Medicine (2018), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 No more thrombotic thrombocytopenic purpura/hemolytic uremic syndrome please Yeong-Hau H. Lien, MD, PhD 1,2 Correspondence: 1 Department of Medicine, College of Medicine, University of Arizona, Yeong-Hau H. Lien, M.D., Ph.D., 2 Arizona Kidney Disease and Hypertension Center Tucson, Arizona, USA Arizona Kidney Disease and Hypertension Center 4511 N. Campbell Ave, Suite 100. Tucson, AZ USA Tel: (520) FAX: (520) lienhoward@gmail.com Funding: None CofI: None I declare that I am sole author and responsible for all content.

3 Old habits die hard. It is so in the medical field too. For decades, we have used the term thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) for patients presented with acute renal failure, microangiopathic hemolysis and thrombocytopenia, without diarrhea prodrome. Although, thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome are now known as two distinct diseases, 1 TTP/HUS still can be seen in medical records and even in medical journals today. This year is the 20th anniversary of discovery of the anti-von Willebrand factor-cleaving protease (now known as a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 [ADAMTS 13]) as the cause of acute thrombotic thrombocytopenic purpura. 2 This landmark paper was published by Tsai and Lian in the New England Journal of Medicine in 1998, which explains why plasma exchange is effective for thrombotic thrombocytopenic purpura. 2 Three years later, Tsai and collaborators identified mutations of ADAMTS13 in families with hereditary thrombotic thrombocytopenic purpura. 3 Since then, thrombotic thrombocytopenic purpura has been defined as a disease with excessive microthrombosis mediated by von Willebrand factor due to severe ADAMTS 13 deficiency from either anti- ADAMTS 13 or mutations in the ADAMTS 13 gene. 1 On the other hand, atypical hemolytic uremic syndrome with similar triad is due to uncontrolled activation of alternative pathway of complement system from either mutations in complement regulating genes or antibodies against complement regulating protein (anti-factor H). 1 Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome has been called for, 1 but whether due to ignorance or old habits, the term TTP/HUS is still widely used. In this issue, Dr. Han-Mo Tsai updated atypical hemolytic uremic syndrome attempting to open our mind for a variety of its presentations. 4 As he pointed out, the most common site of

4 complement activation via the alternative pathway is in the kidney. The renal damage in the form of thrombotic microangiopathy accounts for hemolysis and thrombocytopenia, as well as activation of the renin-angiotensin-aldosterone system and uncontrolled hypertension. In addition, the release of histamine and other vasoactive mediators from complement activation, causes capillary leak in various organs accounting for extra-renal manifestations. 4 Since compliment activation can occur spontaneously or be triggered by certain events, and the severity of compliment activation can be variable, the diagnosis of atypical hemolytic uremic syndrome has been a challenge for physicians. It should be pointed out that atypical hemolytic uremic syndrome can present as malignant hypertension and preeclampsia. The alternative pathway complement activation accounts for a small fraction of these two diseases, and only responds to specific treatment with eculizumab, the C5 monoclonal antibodies. 4 Knowing the pathogenesis of atypical hemolytic uremic syndrome helps us to understand the broad spectrum of atypical hemolytic uremic syndrome, recognize this disease in disguise, and come up a proper treatment. The genetics of atypical hemolytic uremic syndrome is fascinating. The identified disease causing genes include regulators and activators of alternative pathway of complement activation, but genotype-phenotype correlation is still not apparent. 4 Interestingly, similar mutations have been reported in patients with C3 glomerulopathy which includes C3 glomerulonephritis and dense deposit disease, both show membranoproliferative glomerulonephritis on renal biopsies with strong C3 deposition, which is clearly different from thrombotic microangiopathy found in atypical hemolytic uremic syndrome patients. 5 C3 glomerulopathy in fact is similar to atypical hemolytic uremic syndrome clinically in many ways, both respond to eculizumab and frequently recur after kidney transplantation. 5 More interestingly, there are cases with complement H

5 mutations initially presented with C3 glomerulopathy, but subsequently developed full-blown atypical hemolytic uremic syndrome. 6 It is still unclear why the same mutations in complement regulating factors lead to different renal pathologies in different patients, or same patients at different times. In this era of precision medicine, getting a genetic testing for a patient suspected of atypical hemolytic uremic syndrome is critical not only for the index patient, but also for family members. Unfortunately, genetic mutations can be identified in less than one-half of atypical hemolytic uremic syndrome patients who do not have anti-factor H. 4 Recently, using next generation sequencing, the mutation identification rate for atypical hemolytic uremic syndrome remains less than 30% in two studies. 7,8 One potential problem is the accuracy of clinical diagnoses which were provided by clinicians without validation. In fact, TTP/HUS was still listed as a clinical diagnosis in one study. 7 Mutation of ADAMTS13 were found in patients with atypical hemolytic uremic syndrome, 7 while compliment mutations in thrombotic thrombocytopenic purpura patients. 7,8 Obviously, untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome would be the very first step for a cost-effective genetic testing. Twenty years after Dr. Tsai and Dr. Lian knocked open the door to then-mysterious thrombotic thrombocytopenic purpura, 2 the information on the pathogenesis, diagnosis and treatment in thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and atypical hemolytic uremic syndrome has grown tremendously. As Confucius said, Rectification of names is a must, we shall no longer use the term of TTP/HUS.

6 References: 1. Tsai HM. Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome. Am J Med Mar;126(3): Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339(22): Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature Oct 4;413(6855): Tsai HM, Atypical Hemolytic Uremic Syndrome: Beyond Hemolysis and Uremia. Am J Med. 5. Sethi S, Fervenza FC. Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (ahus). Semin Thromb Hemost Jun;40(4): Vaziri-Sani F, Holmberg L, Sjöholm AG, et al. Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome. Kidney Int Mar;69(6): Bu F, Borsa NG, Jones MB, et al. High-Throughput Genetic Testing for Thrombotic Microangiopathies and C3 Glomerulopathies. J Am Soc Nephrol Apr;27(4): Gaut JP, Jain S, Pfeifer JD, et al. Routine use of clinical exome-based next-generation sequencing for evaluation of patients with thrombotic microangiopathies. Mod Pathol Dec;30(12):