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Hematology Thrombocytopenia Table 2: Proportion of Patients Across Spectrum of TTP and HUS with Severe ADAMTS-13 Deficiency (<10 % Enzyme Activity) as Reported in Worldwide Registry Data Oklahoma/US UK 1995–2008 (n=261) 2002–2006 (n=178) Korea 2005–2008 (n=66) France + Japan * 2000–2007 (n=361) 1998–2008 (n=919) Primary idiopathic TTP-HUS 46/98 (47 %) 67 % 14/39 (36 %) 160/214 (75 %) 195/284 (69 %) Primary congenital TTP-HUS NR NR NR NR 40/41 (98 %) Secondary TTP-HUS 12/141 (9 %) 50 % 6/27 (22 %) ?/118 (NR) 89/497 (18 %) dHUS NR NR NR NR 0/132 (0 %) aHUS NR NR NR NR 0/24 (0 %) Mortality if severely deficient 13/60 (22 %) NR 3/16 (19 %) 18/160 (11 %) 29/180 (16 %) Relapse if severely deficient 16/47 (34 %) 26/178 (15 %) 2/13 (15 %) 28/142 (20 %) NR Overall mortality 78/261 (30 %) 21/178 (12 %) 15/66 (23 %) 25/214 (12 %) NR In this registry, the deficient group included 155 patients with <5 % activity and an additional 5 patients with 13–18 % activity and presence of an inhibitor. *In this registry, severe deficiency was defined as <3 % ADAMTS-13 activity; patients with documented Escherichia coli 0157:H7 infection and thrombotic microangiopathy were included as typical diarrheal hemolytic uremic syndrome (dHUS) cases for purposes of this table. aHUS = atypical HUS; NR = not reported; TTP = thrombocytopenic purpura. + HMWVWF release, and antibody formation against shiga-toxin all seem to play major roles. 33–35 Recent advancements in the understanding of aHUS have elucidated the role of abnormal complement activation due to a variety of gain or loss of function mutations of complement regulating genes. 36 In 20 % of cases, this is due to a familial form of aHUS, which presents early in childhood and carries a 50 to 80 % rate of end-stage renal disease (ESRD) or death. 37 In 80 % of cases, aHUS occurs sporadically in adults or children without a family history of aHUS. Complement dysregulation has also been observed in shiga-toxin-mediated diarrheal HUS and raises important therapeutic considerations that will be discussed below. 38,39 Diagnosis The almost certain fatality of TTP-HUS has been dramatically mitigated by two major changes in the approach to this disease: rapid diagnosis and immediate treatment with plasma exchange in appropriate patients. All adult patients who present with the dyad of unexplained thrombocytopenia and hemolytic anemia without normal INR, PTT, and D-dimer are classified as having TTP-HUS, but must be investigated for dHUS or aHUS. Diagnostic tests should be sent off but not delay immediate therapy with plasma exchange in all patients, except those in whom stem cell transplantation, malignancy, mitomycin C exposure, or malignant hypertension can be identified as the underlying disorder. Diagnostic testing should include ADAMTS-13 activity (if available) (see Table 2), complement activity (C3, C4, and CH50 if available), and stool and serum tests for shiga toxin. Subsequent positive microbiologic results for shiga toxin suggest an alternate diagnosis of dHUS, while abnormalities in complement suggest aHUS but these tests of complement lack both sensitivity and specificity. In both these conditions, there may be a role for plasma exchange in adults, as will be discussed later. Children who present with unexplained thrombocytopenia and microangiopathic anemia, often with severe renal failure, are assumed to have dHUS if there is a preceding history of bloody diarrhea, and the diagnosis is confirmed when microbiology is positive for shiga toxin. Supportive treatment with judicious volume repletion is indicated while plasma exchange is usually not. In the absence of a bloody diarrhea prodrome, the child may have either TTP or aHUS and plasma exchange is indicated. More detailed testing of complement dysregulation may be indicated in this setting if the ADAMTS13 testing is normal since detailed complement testing is both time-consuming and expensive. The role of plasma exchange in select circumstances in dHUS is discussed later. 84 Management Whereas mortality was almost certain in early reports of TTP-HUS, rates have been reduced to 10–20  % in the last 2 decades, largely with the use of plasma exchange. Plasma exchange was first described in 1977 by Bukowski, after several prior reports of TTP patients responding to exchange blood transfusions. 40–43 In the same year, Byrnes described a young woman with pregnancy-associated TTP whom he treated sequentially with selective blood product replacement. He showed the plasma fraction of blood was the main blood component in achieving a response. 44 Following several reports of successful treatment with simple plasma infusion, the superiority of plasma exchange in the treatment of TTP was established in 1991 by two randomized controlled trials (RCTs). 45,46 This success of plasma exchange has been attributed to its ability to both remove an unwanted substance (inhibitory ADAMTS-13 antibody), replace a deficient substance (ADAMTS-13 enzyme), and allow for larger volume of plasma to be infused. Further elucidation of the pathophysiology across the spectrum of TTP/ HUS and observations about when plasma exchange and other therapies have been of benefit have advanced our understanding of the role of various therapies in specific clinical circumstances. Primary TTP-HUS Emergent plasma therapy is indicated in all patients with TTP-HUS and has transformed worldwide disease-related death into the exception rather than the rule in this condition. 41,42,44,47–51 Plasma infusion should only serve as a temporizing measure until plasma exchange therapy can be delivered. The superiority of plasma exchange in treatment of primary TTP-HUS was established in a landmark RCT that demonstrated a higher disease response rate (47 % versus 25 %; p=0.025) and a lower mortality rate (22 % versus 37  %; p=0.035) at 6 months. 45 In the same study, patients in the plasma exchange group received three times more plasma volume than those in the infusion group. A retrospective study of 110 TTP-HUS patients reported that patients with greater disease severity received on average an additional 10–15  ml/kg/day of plasma volume compared with those with fewer risk factors and that this approach trended toward higher survival rates. 52 A subsequent case report by Clark et al. described a patient with severe TTP (and a dismal prognosis due to advanced age, fever, coma, severe anemia, thrombocytopenia, and renal failure) who dramatically responded to a 48-hour continuous 78 liter plasma exchange session. 53 On c ol og y & H ematolog y Re vie w