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Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in
2014—Current Knowledge and Outcomes with Plasma Exchange
Myriam Farah, MD, FRCPC, 1 Ainslie M Hildebrand, MD, FRCPC, 2 Susan Huang, MD, FRCPC, 3 Hassnah Dammas, MD 4 and
William F Clark, MD, FRCPC 5
1. Assistant Professor of Medicine, Division of Nephrology, University of British Columbia, and Nephrology Consultant, St Paul’s Hospital, Vancouver, British Columbia,, Canada; 2. Senior Fellow, Kidney
Clinical Research Unit, Lawson Research Institute, London Health Science Centre, London, Ontario, Canada; 3. Assistant Professor of Medicine, Schulich School of Medicine, Western University and
Nephrology Consultant, London Health Science Centre, London, Ontario, Canada; 4. Renal Fellow, Schulich School of Medicine, Western University, Canada; 5 Professor of Medicine and Clinician
Scientist, Program of Experimental Medicine, Western University, Canada and Consultant Nephrologist and Director of Apheresis, London Health Science Centre, London, Ontario, Canada
Abstract Great progress has been made in our understanding of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome since Moschowitz
first described this entity in 1925. This review provides a contemporary insight into the pathophysiology, diagnosis, and classification of these
disorders in both adults and children. Lessons learned from major worldwide registry data and disease epidemics, including the 2011 German
outbreak, are discussed with recommendations for management of specific clinical conditions based on available evidence, including the role
of plasma exchange, rituximab, and eculizumab.
Keywords Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical, diarrhea, idiopathic, secondary, ADAMTS-13, plasma exchange,
plasma infusion, epidemic, rituximab, eculizumab
Disclosure: Myriam Farah, MD, FRCPC, Ainslie M Hildebrand, MD, FRCPC, Susan Huang, MD, FRCPC, Hassnah Dammas, MD, and William F Clark, MD, FRCPC, have no conflicts of
interest to declare. No funding was received in the publication of this article.
Received: May 3, 2014 Accepted: June 18, 2014 Citation: Oncology & Hematology Review, 2014;10(2):82–9
Correspondence: William F Clark, MD, FRCPC, London Health Sciences Centre, A2-343, 800 Commissioners Road East, London, ON N6A 5W9, Canada. E: email@example.com
Classification The two basic forms of thrombotic microangiopathies, excluding
disseminated intravascular coagulation (DIC), include thrombotic
thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS).
Early historic reports noted the presence of hemolytic anemia and
thrombocytopenia in both disorders and suggested differentiation of these
two entities based on the presence of clinical symptoms. Predominant
kidney failure, often seen in children with preceding diarrheal illness,
led to the clinical diagnosis of HUS, while fever, neurologic changes, and
kidney failure suggested TTP. 1–3
This classification scheme has been challenged by several main
observations. First, the classic triad of HUS (thrombocytopenia, hemolytic
anemia, and renal failure) or pentad of TTP (thrombocytopenia,
hemolytic anemia, neurologic signs, renal failure, and fever) is rarely
complete at presentation and often in the case of TTP only at or near
autopsy. 4 Second, a significant number of TTP patients are afflicted with
severe kidney failure and a preceding diarrheal illness, and neurologic
symptoms are commonly reported in both TTP and HUS. 5–8 Third, and most
importantly, treatment with plasma exchange has dramatically reduced
the mortality rate in TTP from nearly 90 % to approximately 20 %, thereby
making urgent diagnosis and treatment of TTP a life-saving priority.
82 Misclassification of a patient based on presenting clinical symptoms
could have fatal consequences.
Current nomenclature has evolved to classify all adult patients
who present with the dyad of unexplained thrombocytopenia and
microangiopathic anemia with normal international normalized ratio (INR),
partial thromboplastin time (PTT), and D-dimers as TTP-HUS. Within this
category, both a primary form (either idiopathic/acquired or hereditary)
and a secondary form (due to an identified underlying disorder) exist.
Secondary TTP-HUS comprises 50 % of TTP-HUS cases in adults and has
been described in eight major conditions as noted in Table 1. Registry
data indicate that even when applying the above classification criteria,
a small but significant number of patients with secondary TTP or DIC are
misclassified as idiopathic TTP at initial presentation. 9
The syndrome of HUS is more common in children but is also seen in
adults. It comprises a primary/atypical form characterized by abnormal
activation of the complement cascade, and a secondary/typical form
seen in shiga toxin mediated diarrheal illness (Escherichia coli 0157:H7,
E. coli 0104:H4, Shigella). The diagnosis of atypical HUS (aHUS) is usually,
but not exclusively, made in childhood in patients with repeated episodes
of clinical TTP-HUS and abnormalities in complement regulating genes.
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