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Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in 2014—Current Knowledge and Outcomes with Plasma Exchange

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Published Online: Nov 20th 2014 Oncology & Hematology Review, 2014;10(2):82–9 DOI:
Authors: Myriam Farah, Ainslie M Hildebrand, Susan Huang, Hassnah Dammas, William F Clark
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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.


Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical, diarrhea, idiopathic, secondary, ADAMTS-13, plasma exchange, plasma infusion, epidemic, rituximab, eculizumab


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. 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 resentation.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.

The underlying pathologic finding in both TTP and HUS is systemic occlusive microthrombi formation typically affecting the brain and kidneys, although any organ may be involved. In their seminal reports, Moschcowitz1 and Baehr10 described the presence of hyaline microthrombi rich with platelet aggregates, highlighting the major role of platelet involvement in the pathogenesis of this disease. Early kinetic analyses demonstrated that both disorders share a similar pattern of severe platelet consumption with little fibrinogen or plasminogen consumption, thereby differentiating them from the entity of DIC11. For decades, the pathophysiology remained a mystery until Moake demonstrated the pathogenic role of unusually large multimers of von Willebrand factor (vWF) mediating platelet-rich microthrombi formation in patients with TTP.12–14

vWF is normally synthesized by endothelial cells and megakaryocytes and exists in the circulation as a series of multimers containing anywhere between 2 to 40 subunits, varying in molecular weight from 540 to 20,000 kDa.15 The variable multimeric structures each have distinct functional abilities, with high molecular weight vWF (HMWVWF) having the greatest ability to induce platelet aggregation.16 Moake’s speculation about impaired degradation of vWF multimers leading to pathogenic accumulation of HMWVWF was confirmed years later when two independent groups identified a vWF cleaving protease responsible for physiologic control of vWF multimer length, and later demonstrated a circulating inhibitory autoantibody to this protease in patients with TTP.17–20 This protease was subsequently identified as ADAMTS-13, and a link between ADAMTS-13 deficiency and TTP pathogenesis has now been established.

Early enthusiasts suggested use of ADAMTS-13 levels as a diagnostic and prognostic criterion to distinguish primary TTP from its secondary forms and from HUS and thereby predict which patients would benefit from plasma exchange therapy.18, 20–25 The potentially deleterious consequences of this approach have since been demonstrated by several important observations. First, patients with severe ADAMTS-13 deficiency do not always present with clinical TTP-HUS, thereby highlighting the role of other pathophysiologic variables in this syndrome. Second, registry data have demonstrated that up to two-thirds of patients with clinically diagnosed idiopathic TTP and the majority of patients with secondary TTP lack severe ADAMTS-13 deficiency and still respond to plasma exchange.9,26–30

Based on available data, several conclusions can be made about ADAMTS-13 at the present time (see Table 2). Severe ADAMTS-13 deficiency appears to be most strongly associated with primary TTP, in both its idiopathic (functional deficiency with inhibitory antibody present) and the congenital form (quantitative ADAMTS-13 deficiency). Enzyme activity is reduced but variable in secondary TTP and usually preserved in both diarrheal and aHUS. Severe ADAMTS-13 deficiency is associated with more severe thrombocytopenia and higher rates of relapse, and inversely associated with severity of renal disease. It has not been shown to predict severity of clinical disease, response to plasma exchange, or death. Therefore, the presence or absence of severe ADAMTS-13 deficiency should not be used to guide initial diagnosis or management.

Early reports about the pathogenesis of TTP and HUS questioned whether they were separate and distinct forms of thrombotic microangiopathies or in fact variants of the same disorder.31 Although the histopathology is similar in both entities, microthrombi in TTP but not HUS are rich in vWF, and endothelial cell swelling predominates in HUS but not TTP.32

The exact mechanism underlying microthrombi formation in diarrheal HUS is not known. Endothelial injury induced by shiga-toxin possibly involving molecular mimicry of platelet CD36 receptors, stimulation of endothelial 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

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.

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.53Controlled studies are necessary to establish the role of large volume and twice-daily plasma exchange therapy in a subset of TTP patients.

Despite differences in currently available plasma product composition, theoretical benefits of one plasma product over another has not been substantiated in controlled studies.54 There is no robust evidence for use of corticosteroid in conjunction with plasma exchange and its use is largely dictated by center-specific practices; however, a recent small RCT of highdose therapy does suggest benefit.55–57 At the present time most centers provide steroids either at outset or if patient is not responding early to plasma exchange. Centers that do use corticosteroids may routinely encounter lower allergic reaction rates to plasma. Solvent detergent treated (S/D) fresh frozen plasma (Octaplas; Octapharma) is now available in North America and is expected to further lower reaction rates.

Ten percent of TTP-HUS patients respond to initial therapy but relapse within 1 to 30 days (refractory TTP) and require further plasma exchange. In these patients, diagnostic investigations to rule out alternate diagnoses should be undertaken. This includes a renewed search for underlying secondary causes (including sepsis and occult malignancy) and complement testing to exclude aHUS. Large volume and twice daily exchanges have been used in these patients but require further study. A further 30 % of patients relapse within 1 month to 14 years and require further plasma exchange therapy. Registry data show that the number of plasma exchange treatments to achieve remission is lower in relapsed cases then in first episodes of acquired idiopathic TTP.26,27

The role of rituximab in treatment of refractory primary TTP is currently under investigation. While several patients with relapsed and refractory TTP have been successfully treated with rituximab, there is great variability in dosage and administration across reported observational studies.27,58–102 Rituximab is a chimeric mouse/human monoclonal anti-CD20 that binds to the CD20 antigen on B-lymphocytes and mediates B-cell lysis by both complement and antibody-dependent cytotoxic pathways. It has been shown to normalize ADAMTS-13 activity in 7–24 weeks.93,96 One study reported normalization in platelet counts within 2 weeks of treatment in 21 of 24 patients and sustained remission in 18 of these patients at 30 months.103 There is limited evidence for rituximab use as a first-line treatment in incident patients, and preliminary results indicate potentially lower relapse rates.104–106

Splenectomy is an option for patients with TTP who are classified as frequent relapsers or refractory to plasma exchange or rituximab therapy.107–109 Antiplatelet agents, vincristine, cyclophosphamide, cyclosporine, and intravenous immunoglobulin have all been used in uncontrolled studies, but RCTs demonstrating their efficacy remains lacking.110–119 Platelet transfusions should be avoided due to theoretical harm of worsening disease severity, but may be necessary in cases of life-threatening thrombocytopenia or prior to expected surgery.120

Secondary TTP-HUS
While idiopathic TTP-HUS has been reported to have a response rate of approximately 80 % to plasma exchange, some patients with secondary thrombotic microangiopathies do not respond at all.9 Evidence to support plasma exchange in secondary thrombotic microangiopathies comes largely from case series. There are no RCTs to assess the efficacy of plasma exchange in any one subgroup of secondary TTP-HUS. There are currently no consensus recommendations regarding indication, patient selection, method, timing, and duration of plasma exchange therapy for secondary TTP-HUS in general. However, expert opinion suggesting the initiation of therapeutic plasma exchange for all adults who fulfill the diagnostic criteria for TTP-HUS and investigation of secondary causes guided by the clinical presentation is widely accepted.121

Prompt initiation of plasma exchange remains the cornerstone of treatment in cases of TTP-HUS associated with autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and mixed connective tissues disease. Additional immunosuppressive drugs are often required and while recent case reports suggest a role for rituximab in refractory cases, routine use cannot be recommended at present.68,77,122,123

Many cases of TTP-HUS are reported during pregnancy and postpartum, and a distinction between severe preeclampsia and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome must be made. Pregnancy-associated TTP-HUS is associated with high maternal mortality and long-term morbidity, including preterm delivery and intrauterine fetal death. Improved survival in this setting has been attributed to aggressive treatment with plasma exchange.124 Plasma exchange has also been shown to be effective in episodes of TTP-HUS precipitated by acute pancreatitis.125,126

TTP-HUS has been reported in association with several infections, including HIV, although the exact mechanism of this relationship remains unclear. In some cases the thrombotic microangiopathy has been thought secondary to opportunistic infections, and in some cases HIV has been considered an inflammatory trigger. If the diagnosis of TTP is suggested in a patient with HIV infection after the exclusion of opportunistic infections, prompt initiation of highly active antiviral therapy (HAART) and plasma exchange appear to be effective in reducing viral loads and inducing remission.127,128

Response to plasma exchange in drug-induced TTP-HUS is variable, as reported in the setting of chemotherapy and antiplatelet agents.129,130 In all cases, the offending drug should be identified and withheld. Plasma exchange has not been shown to be effective for TTP-HUS associated with mitomycin C administration.

Syndromes resembling TTP-HUS may be also diagnosed in the setting of untreated disseminated malignancy or following allogeneic hematopoietic cell transplant. Given the frequency of diagnostic uncertainty, unclear benefit, and high risk for side effects, plasma exchange is not recommended in these cases.131–135 Further, despite recent case reports documenting the effectiveness of rituximab in post-transplant thrombotic microangiopathy, insufficient evidence exists to support routine use.136 Malignant hypertension, disseminated malignancy, and sepsis are often misdiagnosed as TTP-HUS given the shared clinical features. However, there is no proven role for plasma exchange in these cases.135,137

Atypical Hemolytic Uremic Syndrome
Major progress has been made during the last decade in understanding the role of complement dysregulation in the pathophysiology of aHUS.36 Plasma therapy is considered first-line treatment in aHUS cases despite an absence of randomized controlled studies.138–140 Plasma infusion is thought to replace defective complement components and regulators with functional proteins141 while plasma exchange offers the additional advantage of removal of mutant CFH, CFI, CFB, C3, and CFH autoantibodies while restoring functional complement regulators. One exception to this may be in patients with abnormal CD46, a noncirculating membrane-bound complement protein (MCP), which do not seem to respond to plasma exchange but may exhibit higher spontaneous remission rates.142,143

The second touted therapy in aHUS is eculizumab, given its capacity to inhibit the final pathway of complement activation.144 To date, use of eculizumab in several patients with aHUS has been described including aHUS in native kidneys, aHUS recurrence treated post-transplantation, and prevention of aHUS with pretransplant treatment.144–162

Preliminary results from two international multicenter phase II trials conducted in 2009–2010 in adults and adolescents with native kidney or post-transplant aHUS who were either resistant to plasma therapy (17 patients) or dependent on chronic plasma therapy (20 patients) have been resented.163,164 In these patients, a switch to eculizumab induced a rapid increase in platelet counts, cessation of hemolysis, and improvement or stabilization of renal function. No patients needed to return to plasma therapy or initiate dialysis. Further controlled studies are necessary to establish the role of eculizumab in aHUS, which remains an investigational and costly therapy at present.

While a number of other therapies including other immunosuppressant medications and intravenous immunoglobulin have been tried in aHUS, data supporting their use remains sparse and widespread use cannot be recommended.110,165

Typical/Diarrheal Hemolytic Uremic Syndrome
Approximately 15 % of children with shiga-toxin-mediated diarrhea will develop dHUS, a majority of whom will have severe renal impairment.166 Treatment is supportive with judicious volume repletion and/or renal replacement therapy. Anti-motility agents, narcotic opiates, and nonsteroidal anti-inflammatory agents should be avoided. Corticosteroids, anti-platelet agents, and anti-thrombotic agents are not effective. Antibiotic therapy should generally not be administered as it nearly triples the risk for dHUS development, possibly through bacterial lysis and liberation of shiga toxin, but should be rapidly instituted in patients with bowel perforation.167

Plasma exchange is routinely not indicated in dHUS due to a lack of proven efficacy in controlled studies.168 In a subset of patients with severe neurologic symptoms, consideration for plasma exchange should be given, as severe neurologic symptoms are associated with higher rates of both death and progression to ESRD. In the same review that established this association, it was also shown that studies that used plasma exchange reported lower mortality rates than those who did not, a noteworthy detail even in the face of possible selection bias in those studies.169

Presence of severe neurologic symptoms should also prompt consideration of eculizumab based on the following observations. Complement dysregulation can play a pathogenic role in patients with clinically severe dHUS and alteration of complement activation could ameliorate the disease course.38,39 Eculizumab has been used with success in patients with aHUS as well as other glomerular disorders driven by complement dysregulation.144,170 Lapeyraque et al. recently reported three children with rapidly progressive dHUS with severe renal and neurologic involvement who responded dramatically to eculizumab therapy, providing a rationale for further controlled study into this therapy.171

Limited data regarding adult dHUS are largely derived from epidemic outbreak reports as shown in Table 3, and demonstrate considerably higher mortality rates than seen in children.172,173 The role for plasma exchange in adult dHUS was suggested by a report from the Lanarkshire outbreak where 16 of 22 adult dHUS patients were treated with plasma exchange and only five died (31 % mortality) compared with five deaths in six patients who did not receive plasma exchange. This observational study has been criticized for lack of a comparable control group and treatment allocation bias and controlled studies in this area are most definitely needed.

Many questions have recently arisen since the 2011 German E.coli 0104:H4 epidemic, the largest outbreak to date with 3,816 cases of enterohemorrhagic enterocolitis, and 845 cases of dHUS. Nearly all dHUS cases occurred in adults (88 %) and predominantly in females (68 %), probably reflective of the disease transmission vector.174 Preliminary communications indicate that many patients received plasma exchange, a number of patients with severe neurologic involvement also received eculizumab rescue therapy, and a limited number of patients received immunoadsorption therapy.175,176 Adult mortality rate was astoundingly low at 4 %, and neurologic outcomes were surprisingly good despite severity of presenting symptoms.174,177

These outcomes have spurred a heated debate regarding the role of plasma exchange and eculizumab in adult patients with dHUS.178 While RCTs are needed to settle these matters, it is unlikely that a sufficiently powered trial could be designed outside of an epidemic. We eagerly await further detailed publications stemming from the German outbreak to outline whether favorable outcomes were driven by differences in host, organism, or therapy. In the absence of randomized studies, history may have to be our greatest teacher for now.

Long-term Outcomes
Up to 80–90 % of incident adult TTP-HUS respond to plasma exchange therapy, of whom 30 % relapse within 10 years. Given the widespread occlusive microthrombosis that occurs in TTP-HUS, a number of shortand long-term sequelae are likely mediated by impairment in several organs. Renal involvement has been shown to be not uncommon in TTPHUS patients at presentation and at last follow-up (see Table 4).

Central nervous system (CNS) involvement is common in TTP and HUS and when severe contributes to disease-related mortality. Recent studies have also demonstrated the long-term impact of residual CNS microthrombosis in patients with seemingly complete neurologic recovery. These include abnormalities affecting attention, alertness, memory, motor function, and endurance, in addition to clinically undetected brain abnormalities diagnosed on magnetic resonance imaging (MRI) studies.179,180 In addition, survivors followed up to 5 years after initial presentation report persistently reduced health-related physical and mental quality of life, regardless of cause of TTP-HUS, ADAMTS-13 activity, duration of plasma exchange therapy, or severity of neurologic symptoms at presentation.181

Critical cardiac involvement is most likely more common than it has been reported. A recent review identified a total of 111 patients reported in the literature with documented cardiac involvement, of whom 47 had a total of 67 cardiac events, 31 died, and only 24 had preceding cardiac symptoms.182 The majority of ‘asymptomatic’ patients had abnormalities in cardiac blood flow suggestive of small vessel disease. Little is known about long-term cardiac outcomes in survivors of cardiac events and whether early cardiac therapy would alter these outcomes.183,184

Adult and Childhood Diarrheal Hemolytic Uremic Syndrome
While most incident children with dHUS survive without plasma exchange and recover renal function, pooled data from a systemic review of nearly 3,400 patients indicate a 9 % long-term mortality rate over an average of 4 years.169 In addition, 25 % of children face persistent renal impairment as evidenced by a glomerular filtration rate (GFR) <80 ml/minute, hypertension, or proteinuria, and 3 % progress to ESRD. Severity of neurologic and renal involvement are important predictors of both death and ESRD.

In adults, longitudinal data from the Walkerton epidemic have highlighted associations between severe enterocolitis and proteinuria, reduced renal function, cardiovascular disease, and hypertension.185,186 However, little is known about the long-term outcomes of adult dHUS patients. The recent German outbreak will provide opportunity to fill this gap in knowledge.

Future Treatments
As our understanding of TTP and HUS progresses, a number of future treatment strategies are on the horizon and under study. These include anti-CD36 antibodies and recombinant ADAMTS-13 in idiopathic TTP-HUS and recombinant human factor H in aHUS.187,188 Furthermore, experimental strategies aimed at early reduction in intestinal shiga-toxin absorption and prevention of downstream effects of shiga-toxin mediated endothelial injury are under investigation.189

Article Information:

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.


William F Clark, MD, FRCPC, London Health Sciences Centre, A2-343, 800 Commissioners Road East, London, ON N6A 5W9, Canada. E:




  1. Moschcowitz E, An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries; an undescribed disease, Arch Intern Med, 1925;36:89–93.
  2. Gasser C, Gautier E, Steck A, et al., [Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia], Schweiz Med Wochenschr, 1955;85:905–9.
  3. Amorosi EL, Ultman JE. Thrombotic thrombocytopenic purpura: Report of 16 cases and review of the literature, Medicine (Baltimore), 1994;45: 139–59.
  4. George JN, Terrell DR, Swisher KK, Vesely SK, Lessons learned from the Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome registry, J Clin Apher, 2008;23:129–37.
  5. Rock G, Kelton JG, Shumak KH, et al., Laboratory abnormalities in thrombotic thrombocytopenic purpura. Canadian Apheresis Group, Br J Haematol, 1998;103:1031–6.
  6. George JN, Vesely SK, Terrell DR, The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS, Semin Hematol, 2004;41:60–7.
  7. Baron JM, Baron BW, Thrombotic thrombocytopenic purpura and its look-alikes, Clin Adv Hematol Oncol, 2005;3:868–74.
  8. Nathanson S, Kwon T, Elmaleh M, et al., Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome, Clin J Am Soc Nephrol, 2010;5:1218–28.
  9. Vesely SK, George JN, Lämmle B, et al., ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients, Blood, 2003;102:60–8.
  10. Baehr G, Kelmerer P, Schifrin A, Acute febrile anemia and thrombocytopenic purport with diffuse platelet thrombosis of capillaries and arterioles, Tr A Am Physicians; 1936;51:43.
  11. Harker LA, Slichter SJ, Platelet and fibrinogen consumption in man, N Engl J Med, 1972;287:999–1005.
  12. Moake JL, Rudy CK, Troll JH, et al., Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura, N Engl J Med, 1982;307:1432–5.
  13. Moake JL, Byrnes JJ, Troll JH, et al., Abnormal VIII: von Willebrand factor patterns in the plasma of patients with the hemolyticuremic syndrome, Blood, 1984;64:592–8.
  14. Moake JL, Turner NA, Stathopoulos NA, et al., Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation, J Clin Invest, 1986;78:1456–61.
  15. Sadler JE, Biochemistry and genetics of von Willebrand factor, Annu Rev Biochem, 1998;67:395–424.
  16. Arya M, Anvari B, Romo GM, et al., Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers, Blood, 2002;99:3971–7.
  17. Tsai HM, Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion, Blood, 1996;87:4235–44.
  18. Tsai HM, Lian EC, Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura, N Engl J Med, 1998;339:1585–94.
  19. Furlan M, Robles R, Lämmle B, Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis, Blood, 1996;87:4223–34.
  20. Furlan M, Robles R, Galbusera M, et al., von Willebrand factorcleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome, N Engl J Med, 1998;339:1578–84.
  21. Mori Y, Wada H, Gabazza EC, et al., Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity, Transfusion, 2002;42:572–80.
  22. Moore JC, Hayward CP, Warkentin TE, Kelton JG, Decreased von Willebrand factor protease activity associated with thrombocytopenic disorders, Blood, 2001;98:1842–6.
  23. Veyradier A, Obert B, Houllier A, et al., Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases, Blood, 2001;98:1765–72.
  24. Rick ME, Moll S, Taylor MA, et al., Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura, Thromb Haemost, 2002;88:598–604.
  25. Bianchi V, Robles R, Alberio L, et al., Von Willebrand factorcleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura, Blood, 2002;100:710–3.
  26. Hovinga JA, Vesely SK, Terrell DR, et al., Survival and relapse in patients with thrombotic thrombocytopenic purpura, Blood, 2010;115:1500–11; quiz 662.
  27. Scully M, Yarranton H, Liesner R, et al., Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features, Br J Haematol, 2008;142:819–26.
  28. Coppo P, Schwarzinger M, Buffet M, et al., Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience, PLoS One, 2010;5:e10208.
  29. Jang MJ, Chong SY, Kim IH, et al., Clinical features of severe acquired ADAMTS13 deficiency in thrombotic thrombocytopenic purpura: the Korean TTP registry experience, Int J Hematol, 2011;93:163–9.
  30. Fujimura Y, Matsumoto M, Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during 1998–2008, Intern Med, 2010;49:7–15.
  31. Desch K, Motto D, Is there a shared pathophysiology for thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome?, J Am Soc Nephrol, 2007;18:2457–60.
  32. Tarr PI, Shiga toxin-associated hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: distinct mechanisms of pathogenesis. Kidney Int Suppl, 2009;S29–32.
  33. Rock GA, Clark WF, Mechanism of microthrombosis in HUS, Kidney Int Suppl, 2009;S15–6.
  34. Nolasco LH, Turner NA, Bernardo A, et al., Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers, Blood, 2005;106:4199–209.
  35. Davis AK, Makar RS, Stowell CP, et al., ADAMTS13 binds to CD36: a potential mechanism for platelet and endothelial localization of ADAMTS13, Transfusion, 2009;49:206–13.
  36. Waters AM, Licht C, aHUS caused by complement dysregulation: new therapies on the horizon, Pediatr Nephrol, 2011;26:41–57.
  37. Noris M, Remuzzi G, Atypical hemolytic-uremic syndrome, N Engl J Med, 2009;361:1676–87.
  38. Orth D, Khan AB, Naim A, et al., Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome, J Immunol, 2009;182:6394–400.
  39. Orth D, Würzner R, Complement in typical hemolytic uremic syndrome, Semin Thromb Hemost, 2010;36:620–4.
  40. Bukowski RM, Hewlett JS, Harris JW, et al., Exchange transfusions in the treatment of thrombotic thrombocytopenic purpura, Semin Hematol, 1976;13:219–32.
  41. Bukowski RM, King JW, Hewlett JS, Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura, Blood, 1977;50:413–7.
  42. Rubinstein MA, Kagan BM, Macgillviray MH, et al., Unusual remission in a case of thrombotic thrombocytopenic purpura syndrome following fresh blood exchange transfusions, Ann Intern Med, 1959;51:1409–19.
  43. Pisciotta AV, Garthwaite T, Darin J, Aster RH, Treatment of thrombotic thrombocytopenic purpura by exchange transfusion, Am J Hematol, 1977;3:73–82.
  44. Byrnes JJ, Khurana M, Treatment of thrombotic thrombocytopenic purpura with plasma, N Engl J Med, 1977;297:1386–9.
  45. Rock GA, Shumak KH, Buskard NA, et al., Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group, N Engl J Med, 1991;325:393–7.
  46. Henon P, [Treatment of thrombotic thrombopenic purpura. Results of a multicenter randomized clinical study], Presse Med, 1991;20:1761–7.
  47. Bell WR, Braine HG, Ness PM, Kickler TS, Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients, N Engl J Med, 1991;325:398–403.
  48. Gurkan E, Baslamisli F, Guvenc B, et al., Thrombotic thrombocytopenic purpura in southern Turkey: a single-center experience of 29 cases, Clin Lab Haematol, 2005;27:121–5.
  49. Shamseddine A, Saliba T, Aoun E, et al., Thrombotic thrombocytopenic purpura: 24 years of experience at the American University of Beirut Medical Center, J Clin Apher, 2004;19:119–24.
  50. Bandarenko N, Brecher ME, United States Thrombotic Thrombocytopenic Purpura Apheresis Study Group (US TTP ASG): multicenter survey and retrospective analysis of current efficacy of therapeutic plasma exchange, J Clin Apher, 1998;13:133–41.
  51. Dervenoulas J, Tsirigotis P, Bollas G, et al., Economopoulos T, et al., Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): treatment outcome, relapses, prognostic factors. A single-center experience of 48 cases, Ann Hematol, 2000;79:66–72.
  52. Forzley BR, Sontrop JM, Macnab JJ, et al., Treating TTP/HUS with plasma exchange: a single centre’s 25-year experience, Br J Haematol, 2008;143:100–6.
  53. Clark WF, Forzley BR, Sontrop JM, et al., TTP/HUS: observational studies generate hypotheses that lead to randomized controlled trials, Kidney Int Suppl, 2009;S50–1.
  54. Brunskill SJ, Tusold A, Benjamin S, et al., A systematic review of randomized controlled trials for plasma exchange in the treatment of thrombotic thrombocytopenic purpura, Transfus Med, 2007;17:17–35.
  55. Balduini CL, Gugliotta L, Luppi M, et al., High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study, Ann Hematol, 2010;89:591–6.
  56. Altuntas F, Aydogdu I, Kabukcu S, et al., Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: a retrospective multicenter study, Transfus Apher Sci, 2007;36:57–67.
  57. Toyoshige M, Zaitsu Y, Okafuji K, et al., Successful treatment of thrombotic thrombocytopenic purpura with high-dose corticosteroid, Am J Hematol, 1992;41:69.
  58. Sui T, Yang RC, [Treatment of thrombotic thrombocytopenic purpura with rituximab], Zhonghua Xue Ye Xue Za Zhi, 2011;32:487–8.
  59. Stein GY, Blickstein D, Orlin J, et al., Long-term response to rituximab in patients with relapsing thrombotic thrombocytopenic purpura, Isr Med Assoc J, 2011;13:398–401.
  60. Scully M, Cohen H, Cavenagh J, et al., Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13, Br J Haematol, 2007;136:451–61.
  61. Scott SM, Szczepiorkowski ZM, Rituximab for TTP, Am J Hematol, 2005;80:87–8.
  62. Schleinitz N, Ebbo M, Mazodier K, et al., Rituximab as preventive therapy of a clinical relapse in TTP with ADAMTS13 inhibitor, Am J Hematol, 2007;82:417–8.
  63. Scaramucci L, Niscola P, Palumbo R, et al., Rapid response and sustained remission by rituximab in four cases of plasmaexchange- failed acute thrombotic thrombocytopenic purpura, Int J Hematol, 2009;89:398–9.
  64. Sallah S, Husain A, Wan JY, Nguyen NP, Rituximab in patients with refractory thrombotic thrombocytopenic purpura, J Thromb Haemost, 2004;2:834–6.
  65. Rüfer A, Brodmann D, Gregor M, et al., Rituximab for acute plasma-refractory thrombotic thrombocytopenic purpura. A case report and concise review of the literature, Swiss Med Wkly, 2007;137:518–24.
  66. Reddy PS, Deauna-Limayo D, Cook JD, et al., Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura, Ann Hematol, 2005;84:232–5.
  67. Ozdogu H, Boga C, Kizilkilic E, et al., A dramatic response to rituximab in a patient with resistant thrombotic thrombocytopenic purpura (TTP) who developed acute stroke, J Thromb Thrombolysis, 2007;23:147–50.
  68. Niewold TB, Alpert D, Scanzello CR, Paget SA, Rituximab treatment of thrombotic thrombocytopenic purpura in the setting of connective tissue disease, J Rheumatol, 2006;33:1194–6.
  69. Niaz FA, Aleem A, Response to rituximab in a refractory case of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus, Saudi J Kidney Dis Transpl, 2010;21:109–12.
  70. Narayanan P, Jayaraman A, Rustagi RS, et al., Rituximab in a child with autoimmune thrombotic thrombocytopenic purpura refractory to plasma exchange, Int J Hematol, 2012;96:122–4.
  71. Montoya RC, Poiesz BJ, Rituximab as prophylaxis in chronic relapsing thrombotic thrombocytopenic purpura: a case report and review of the literature, Blood Coagul Fibrinolysis, 2012;23:338–41.
  72. Lombardi AM, de Marinis GB, Scandellari R, et al., Clinical biological remission induced by rituximab in acute refractory chronic relapsing TTP, Thromb Res, 2010;126:e154–6.
  73. Ling HT, Field JJ, Blinder MA, Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature, Am J Hematol, 2009;84:418–21.
  74. Kuppachi S, Chander P, Yoo J, Membranous nephropathy and thrombotic thrombocytopenic purpura treated with rituximab, J Nephrol, 2009;22:561–4.
  75. Koshino M, Kudou D, Okoshi Y, et al., [Successful treatment with rituximab in a patient with refractory thrombotic thrombocytopenic purpura refractory to plasma exchange], Rinsho Ketsueki, 2010;51:127–31.
  76. Kivity S, Agmon-Levin N, Rituximab for thrombotic thrombocytopenic purpura, Isr Med Assoc J, 2011;13:436–7.
  77. Kameda T, Dobashi H, Kittaka K, et al., Two cases of refractory thrombotic thrombocytopenic purpura associated with collagen vascular disease were significantly improved by rituximab treatment, Clin Rheumatol, 2007;26:2159–62.
  78. Jasti S, Coyle T, Gentile T, et al., Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature, J Clin Apher, 2008;23:151–6.
  79. Illner N, Wolf G, [Rituximab as effective therapy in very severe thrombotic thrombocytopenic purpura (TTP)], Dtsch Med Wochenschr, 2010;135:71–4.
  80. Hull MJ, Eichbaum QG, Efficacy of rituximab and concurrent plasma exchange in the treatment of thrombotic thrombocytopenic purpura, Clin Adv Hematol Oncol, 2006;4:210–4; discussion 7–8.
  81. Hong H, Aoyama Y, Yamamura R, et al., [Rituximab provided long-term remission in a patient with severe thrombotic thrombocytopenic purpura refractory to plasma exchange], Rinsho Ketsueki, 2006;47:1528–32.
  82. Herbei L, Venugopal P, Recurrent thrombotic thrombocytopenic purpura treated repeatedly and successfully with the monoclonal antibody rituximab, Clin Adv Hematol Oncol, 2006;4:215–7; discussion 7–8.
  83. Heidel F, Lipka DB, von Auer C, et al., Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia, Thromb Haemost, 2007;97:228–33.
  84. Harambat J, Lamireau D, Delmas Y, et al., Successful treatment with rituximab for acute refractory thrombotic thrombocytopenic purpura related to acquired ADAMTS13 deficiency: a pediatric report and literature review, Pediatr Crit Care Med, 2011;12:e90–3.
  85. Hamasaki Y, Matsuoka A, Waki M, Kawakami K, [Effective treatment with rituximab for primary thrombotic thrombocytopenic purpura complicated with multiple cerebral infarctions], Rinsho Ketsueki, 2012;53:342–6.
  86. Hagel S, Jantsch J, Budde U, et al., Treatment of acquired thrombotic thrombocytopenic purpura (TTP) with plasma infusion plus rituximab, Thromb Haemost, 2008;100:151–3.
  87. Gutterman LA, Kloster B, Tsai HM, Rituximab therapy for refractory thrombotic thrombocytopenic purpura, Blood Cells Mol Dis, 2002;28:385–91.
  88. Gupta D, Roppelt H, Bowers B, et al., Successful remission of thrombotic thrombocytopenic purpura with rituximab in a patient with undifferentiated connective tissue disorder, J Clin Rheumatol, 2008;14:94–6.
  89. George JN, Woodson RD, Kiss JE, et al., Rituximab therapy for thrombotic thrombocytopenic purpura: a proposed study of the Transfusion Medicine/Hemostasis Clinical Trials Network with a systematic review of rituximab therapy for immune-mediated disorders, J Clin Apher, 2006;21:49–56.
  90. Galbusera M, Bresin E, Noris M, et al., Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report, Blood, 2005;106:925–8.
  91. Foley SR, Webert K, Arnold DM, et al., A Canadian phase II study evaluating the efficacy of rituximab in the management of patients with relapsed/refractory thrombotic thrombocytopenic purpura, Kidney Int Suppl, 2009;S55–8.
  92. Ferrer E, Moral MA, Spotlight on rituximab as a new therapeutic option for dermatomyositis and thrombotic thrombocytopenic purpura, Drug News Perspect, 2006;19:482–4.
  93. Fakhouri F, Vernant JP, Veyradier A, et al., Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13- deficient thrombotic thrombocytopenic purpura: a study of 11 cases, Blood, 2005;106:1932–7.
  94. Elliott MA, Heit JA, Pruthi RK, et al., Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13-deficiency: a report of four cases and a systematic review of the literature, Eur J Haematol, 2009;83:365–72.
  95. Chow KV, Carroll R, Branley P, et al., Anti-CD20 antibody in thrombotic thrombocytopenic purpura refractory to plasma exchange, Intern Med J, 2007;37:329–32.
  96. Chemnitz J, Draube A, Scheid C, et al., Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab, Am J Hematol, 2002;71:105–8.
  97. Carella AM, D’Arena G, Greco MM, et al., Rituximab for allo-SCTassociated thrombotic thrombocytopenic purpura, Bone Marrow Transplant, 2008;41:1063-5.
  98. Boctor FN, Smith JA, Timing of plasma exchange and rituximab for the treatment of thrombotic thrombocytopenic purpura, Am J Clin Pathol, 2006;126:965; author reply 6.
  99. Bhagirath VC, Kelton JG, Moore J, Arnold DM, Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura. Transfusion, 2012;52:2517–23.
  100. Benetatos L, Vassou A, Bourantas KL, Effectiveness of rituximab as prophylaxis in thrombotic thrombocytopenic purpura, Clin Lab Haematol, 2006;28:288–9.
  101. Basquiera AL, Damonte JC, Abichaín P, et al., Longterm remission in a patient with refractory thrombotic thrombocytopenic purpura treated with rituximab and plasma exchange, Ann Hematol, 2008;87:321–3.
  102. Ahmad A, Aggarwal A, Sharma D, et al., Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP), Am J Hematol, 2004;77:171–6.
  103. de la Rubia J, Moscardó F, Gómez MJ, et al., Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study, Transfus Apher Sci, 2010;43:299–303.
  104. Froissart A, Buffet M, Veyradier A, et al., Efficacy and safety of firstline rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center, Crit Care Med, 2012;40:104–11.
  105. Bresin E, Gastoldi S, Daina E, et al., Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies, Thromb Haemost, 2009;101:233–8.
  106. Scully M, McDonald V, Cavenagh J, et al., A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura, Blood, 2011;118:1746–53.
  107. Schneider PA, Rayner AA, Linker CA, et al., The role of splenectomy in multimodality treatment of thrombotic thrombocytopenic purpura, Ann Surg, 1985;202:318–22.
  108. Rowe JM, Francis CW, Cyran EM, Marder VJ, Thrombotic thrombocytopenic purpura: recovery after splenectomy associated with persistence of abnormally large von Willebrand factor multimers, Am J Hematol, 1985;20:161–8.
  109. Höffkes HG, Weber F, Uppenkamp M, et al., Recovery by splenectomy in patients with relapsed thrombotic thrombocytopenic purpura and treatment failure to plasma exchange, Semin Thromb Hemost, 1995;21:161–5.
  110. Watt T, Warshaw B, Katzenstein HM, Atypical hemolytic uremic syndrome responsive to steroids and intravenous immune globulin, Pediatr Blood Cancer, 2009;53:90–1.
  111. Allan DS, Kovacs MJ, Clark WF, Frequently relapsing thrombotic thrombocytopenic purpura treated with cytotoxic immunosuppressive therapy, Haematologica, 2001;86:844–50.
  112. Gutterman LA, Stevenson TD, Treatment of thrombotic thrombocytopenic purpura with vincristine, JAMA, 1982;247:1433–6.
  113. Mazzei C, Pepkowitz S, Klapper E, Goldfinger D, Treatment of thrombotic thrombocytopenic purpura: a role for early vincristine administration, J Clin Apher, 1998;13:20–2.
  114. Akaogi J, Akasaka N, Yamada H, et al., Intravenous cyclophosphamide therapy in a case with refractory thrombotic microangiopathic hemolytic anemia and SLE, Clin Rheumatol, 2004;23:541–3.
  115. Böhm M, Betz C, Miesbach W, et al., The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine, Br J Haematol, 2005;129:644–52.
  116. Stein GY, Zeidman A, Fradin Z, et al., Treatment of resistant thrombotic thrombocytopenic purpura with rituximab and cyclophosphamide, Int J Hematol, 2004;80:94–6.
  117. Pasquale D, Vidhya R, DaSilva K, et al., Chronic relapsing thrombotic thrombocytopenic purpura: role of therapy with cyclosporine, Am J Hematol, 1998;57:57–61.
  118. Amorosi EL, Karpatkin S, Antiplatelet treatment of thrombotic thrombocytopenic purpura, Ann Intern Med, 1977;86:102–6.
  119. Rosove MH, Ho WG, Goldfinger D, Ineffectiveness of aspirin and dipyridamole in the treatment of thrombotic thrombocytopenic purpura. Ann Intern Med, 1982;96:27–33.
  120. Coppo P, Lassoued K, Mariette X, et al., Effectiveness of platelet transfusions after plasma exchange in adult thrombotic thrombocytopenic purpura: a report of two cases, Am J Hematol, 2001;68:198–201.
  121. George JN, How I treat patients with thrombotic thrombocytopenic purpura: 2010, Blood, 2010;116:4060–9.
  122. Musio F, Bohen EM, Yuan CM, Welch PG, Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus, Semin Arthritis Rheum, 1998;28:1–19.
  123. Kfoury Baz EM, Mahfouz RA, Masri AF, Thrombotic thrombocytopenic purpura in a patient with rheumatoid arthritis treated by plasmapheresis, Ther Apher, 1999;3:314–6.
  124. Egerman RS, Witlin AG, Friedman SA, Sibai BM, Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy: review of 11 cases, Am J Obstet Gynecol, 1996;175(4 Pt 1):950–6.
  125. Swisher KK, Doan JT, Vesely SK, et al., Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpurahemolytic uremic syndrome: report of five patients with a systematic review of published reports, Haematologica, 2007;92:936–43.
  126. McDonald V, Laffan M, Benjamin S, et al., Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry, Br J Haematol, 2009;144:430–3.
  127. Hart D, Sayer R, Miller R, et al., Human immunodeficiency virus associated thrombotic thrombocytopenic purpura – favourable outcome with plasma exchange and prompt initiation of highly active antiretroviral therapy, Br J Haematol, 2011;153:515–9.
  128. Benjamin M, Terrell DR, Vesely SK, et al., Frequency and significance of HIV infection among patients diagnosed with thrombotic thrombocytopenic purpura, Clin Infect Dis, 2009;48:1129–37.
  129. Gore EM, Jones BS, Marques MB, Is therapeutic plasma exchange indicated for patients with gemcitabine-induced hemolytic uremic syndrome?, J Clin Apher, 2009;24:209–14.
  130. Zakarija A, Kwaan HC, Moake JL, et al., Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008), Kidney Int Suppl, 2009;S20–4.
  131. Lesesne JB, Rothschild N, Erickson B, et al., Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry, J Clin Oncol, 1989;7:781–9.
  132. Cantrell JE, Phillips TM, Schein PS, Carcinoma-associated hemolytic-uremic syndrome: a complication of mitomycin C chemotherapy, J Clin Oncol, 1985;3:723–34.
  133. Ho VT, Cutler C, Carter S, et al., Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation, Biol Blood Marrow Transplant, 2005;11:571–5.
  134. Ruutu T, Barosi G, Benjamin RJ, et al., Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group, Haematologica, 2007;92:95–100.
  135. Francis KK, Kalyanam N, Terrell DR, et al., Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: A report of 10 patients and a systematic review of published cases., Oncologist, 2007;12:11–9.
  136. Au WY, Ma ES, Lee TL, et al., Successful treatment of thrombotic microangiopathy after haematopoietic stem cell transplantation with rituximab, Br J Haematol, 2007;137:475–8.
  137. George JN, Evaluation and management of patients with thrombotic thrombocytopenic purpura, J Intensive Care Med, 2007;22:82–91.
  138. Loirat C, Noris M, Fremeaux-Bacchi V, Complement and the atypical hemolytic uremic syndrome in children, Pediatr Nephrol, 2008;23:1957–72.
  139. Ariceta G, Besbas N, Johnson S, et al., Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol, 2009;24:687–96.
  140. Taylor CM, Machin S, Wigmore SJ, Goodship TH, Working party from the Renal Association tBCfSiHatBTS. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom, Br J Haematol, 2010;148:37–47.
  141. Licht C, Weyersberg A, Heinen S, et al., Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis, 2005;45:415–21.
  142. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al., Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome, J Am Soc Nephrol, 2007;18:2392–400.
  143. Caprioli J, Noris M, Brioschi S, et al., Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome, Blood, 2006;108:1267–79.
  144. Köse O, Zimmerhackl LB, Jungraithmayr T, et al., New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab, Semin Thromb Hemost, 2010;36:669–72.
  145. Al-Akash SI, Almond PS, Savell VH, et al., Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation, Pediatr Nephrol, 2011;26:613–9.
  146. Ariceta G, Arrizabalaga B, Aguirre M, et al., Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants, Am J Kidney Dis, 2012;59:707–10.
  147. Chandran S, Baxter-Lowe L, Olson JL, et al., Eculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation – a case report, Transplant Proc, 2011;43:2097–101.
  148. Châtelet V, Lobbedez T, Frémeaux-Bacchi V, et al., Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report, Transplant Proc, 2010;42:4353–5.
  149. Davin JC, Gracchi V, Bouts A, et al., Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation, Am J Kidney Dis, 2010;55:708–11.
  150. Dorresteijn EM, van de Kar NC, Cransberg K, Eculizumab as rescue therapy for atypical hemolytic uremic syndrome with normal platelet count, Pediatr Nephrol, 2012;27:1193–5.
  151. Gruppo RA, Rother RP, Eculizumab for congenital atypical hemolytic-uremic syndrome, N Engl J Med, 2009;360:544–6.
  152. Hadaya K, Ferrari-Lacraz S, Fumeaux D, et al., Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation, Am J Transplant, 2011;11:2523–7.
  153. Krid S, Roumenina L, Beury D, et al., Renal Transplantation Under Prophylactic Eculizumab in Atypical Hemolytic Uremic Syndrome with CFH/CFHR1 Hybrid Protein, Am J Transplant, 2012;12:1938–44.
  154. Lapeyraque AL, Frémeaux-Bacchi V, Robitaille P, Efficacy of eculizumab in a patient with factor-H-associated atypical hemolytic uremic syndrome, Pediatr Nephrol, 2011;26:621–4.
  155. Larrea CF, Cofan F, Oppenheimer F, et al., Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation, 2010;89:903–4.
  156. Mache CJ, Acham-Roschitz B, Frémeaux-Bacchi V, et al., Complement inhibitor eculizumab in atypical hemolytic uremic syndrome, Clin J Am Soc Nephrol, 2009;4:1312–6.
  157. Nester C, Stewart Z, Myers D, et al., Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome, Clin J Am Soc Nephrol, 2011;6:1488–94.
  158. Nürnberger J, Philipp T, Witzke O, et al., Eculizumab for atypical hemolytic-uremic syndrome, N Engl J Med, 2009;360:542–4.
  159. Ohanian M, Cable C, Halka K, Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome, Clin Pharmacol, 2011;3:5–12.
  160. Prescott HC, Wu HM, Cataland SR, Baiocchi RA, Eculizumab therapy in an adult with plasma exchange-refractory atypical hemolytic uremic syndrome, Am J Hematol, 2010;85:976–7.
  161. Shin JI, Lee JS, More on eculizumab for congenital atypical hemolytic-uremic syndrome, N Engl J Med, 2009;360:2142–3; author reply 3.
  162. Tschumi S, Gugger M, Bucher BS, et al., Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings, Pediatr Nephrol, 2011;26:2085–8.
  163. Legendre C, Babu S, Furman R, (editors), Safety and efficacy of eculizumab in aHUS resistant to plasma therapy: interim analysis from a phase II trial. American Society of Nephrology; 2010; Denver, CO, USA.
  164. Muus P, Legendre C, Douglas H, (editors), Safety and efficacy of eculizumab in aHUS patients on chronic plasma therapy: interim analysis of a phase II trial. American Society of Nephrology; 2010; Denver, CO, USA.
  165. Boyer O, Balzamo E, Charbit M, et al., Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies, Am J Kidney Dis, 2010;55:923–7.
  166. Tarr PI, Gordon CA, Chandler WL, Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome, Lancet, 2005;365:1073–86.
  167. Wong CS, Mooney JC, Brandt JR, et al., Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis, Clin Infect Dis, 2012;55:33–41.
  168. Michael M, Elliott EJ, Craig JC, et al., Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials, Am J Kidney Dis, 2009;53:259–72.
  169. Garg AX, Suri RS, Barrowman N, et al., Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression, JAMA, 2003;290:1360–70.
  170. Radhakrishnan S, Lunn A, Kirschfink M, et al., Eculizumab and refractory membranoproliferative glomerulonephritis, N Engl J Med, 2012;366:1165–6.
  171. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, et al., Eculizumab in severe Shiga-toxin-associated HUS, N Engl J Med, 2011;364:2561–3.
  172. Dundas S, Murphy J, Soutar RL, et al., Effectiveness of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli O157:H7 outbreak, Lancet, 1999;354:1327–30.
  173. Carter AO, Borczyk AA, Carlson JA, et al., A severe outbreak of Escherichia coli O157:H7 – associated hemorrhagic colitis in a nursing home, N Engl J Med, 1987;317:1496–500.
  174. Frank C, Werber D, Cramer JP, et al., Epidemic profile of Shigatoxin- producing Escherichia coli O104:H4 outbreak in Germany, N Engl J Med, 2011;365:1771–80.
  175. Colic E, Dieperink H, Titlestad K, Tepel M, Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study, Lancet, 2011;378:1089–93.
  176. Greinacher A, Friesecke S, Abel P, et al., Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4- associated haemolytic uraemic syndrome: a prospective trial, Lancet, 2011;378:1166–73.
  177. Magnus T, Röther J, Simova O, et al., The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak, Brain, 2012;135(Pt 6):1850–9.
  178. Birn H, Ivarsen P, Svensson M, et al., Should all adult patients with diarrhoea-associated HUS receive plasma exchange?, Lancet, 2012;379:515–6; author reply 6–7.
  179. recovery from thrombotic thrombocytopenic purpura, Transfusion, 2009;49:1092–101.
  180. Cataland SR, Scully MA, Paskavitz J, et al., Evidence of persistent neurologic injury following thrombotic thrombocytopenic purpura, Am J Hematol, 2011;86:87–9.
  181. Lewis QF, Lanneau MS, Mathias SD, et al., Long-term deficits in health-related quality of life after recovery from thrombotic thrombocytopenic purpura, Transfusion, 2009;49:118–24.
  182. Hawkins BM, Abu-Fadel M, Vesely SK, George JN, Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review, Transfusion, 2008;48:382–92.
  183. Gami AS, Hayman SR, Grande JP, Garovic VD, Incidence and prognosis of acute heart failure in the thrombotic microangiopathies, Am J Med, 2005;118:544–7.
  184. Patschan D, Witzke O, Dührsen U, et al., Acute myocardial infarction in thrombotic microangiopathies – clinical characteristics, risk factors and outcome, Nephrol Dial Transplant, 2006;21:1549–54.
  185. Clark WF, Sontrop JM, Macnab JJ, et al., Long term risk for hypertension, renal impairment, and cardiovascular disease after gastroenteritis from drinking water contaminated with Escherichia coli O157:H7: a prospective cohort study, BMJ, 2010;341:c6020.
  186. Clark WF, Kortas C, Suri RS, et al., Excessive fluid intake as a novel cause of proteinuria, CMAJ, 2008;178:173–5.
  187. Schiviz A, Wuersch K, Piskernik C, et al., A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13, Blood, 2012;119:6128–35.
  188. Schmidt CQ, Slingsby FC, Richards A, Barlow PN, Production of biologically active complement factor H in therapeutically useful quantities, Protein Expr Purif, 2011;76:254–63.
  189. Bitzan M, Schaefer F, Reymond D, Treatment of typical (enteropathic) hemolytic uremic syndrome, Semin Thromb Hemost, 2010;36:594–610.

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