Microangiopathic Hemolytic Anemias
Pathophysiology
Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura.
Moake JL, Rudy CK, Troll JH, et al.
N Engl J Med. 1982;307:1432-1435.
Description: This was the first study to implicate unusually large vWF multimers in the pathogenesis of TTP and postulate that the above phenomenon was due to the deficiency of a plasma-derived protease.
PubMed citation number: 6813740
The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli.
Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, Lior H.
J Infect Dis. 1985;151:775-782.
Description: This study firmly established verotoxin-producing Escherichia coli as the inciting infectious agent in most children with diarrheal illness–related hemolytic uremic syndrome.
PubMed citation number: 3886804
von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
Furlan M, Robles R, Galbusera M, et al.
N Engl J Med. 1998;339:1578-1584.
Description: This study investigated the prevalence of von Willebrand factor–cleaving protease deficiency in patients with familial and nonfamilial forms of TTP and HUS. Samples were also tested for the presence of a protease inhibitor. The report concluded that “nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor–cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease.”
PubMed citation number: 9828245
Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
Tsai HM, Lian EC.
N Engl J Med. 1998;339:1585-1594.
Description : Similar to the above study, this group independently characterized the von Willebrand factor–cleaving protease, currently known as ADAMTS13, and identified inhibitory antibodies to ADAMTS13 in patients with acquired TTP. Both studies also suggested that antibodies to ADAMTS13 are specific for TTP and help distinguish it from hemolytic uremic syndrome (HUS); however, neither study described how patients with TTP were distinguished from those with HUS.
PubMed citation number: 9828246
Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.
Levy GG, Nichols WC, Lian EC, et al.
Nature. 2001;413:488-494.
Description : This study identified mutations in the ADAMTS13 gene in families with congenital TTP, thereby demonstrating a role for ADAMTS13 in normal vascular homeostasis and identifying the likely gene product to which inhibitory antibodies are directed in acquired TTP.
PubMed citation number: 11586351
Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.
Richards A, Kemp EJ, Liszewski MK, et al.
Proc Natl Acad Sci U S A. 2003;100:12966-12971.
PubMed citation number: 14566051
Genetic studies into inherited and sporadic hemolytic uremic syndrome.
Warwicker P, Goodship TH, Donne RL, et al.
Kidney Int. 1998;53:836-844.
Description: These 2 studies identified inactivating mutations in the membrane cofactor protein (MCP) and factor H genes, gene products that negatively regulate C3b deposition on target substrates, in patients with familial HUS. These studies provide a biologic rationale for the observation of low C3 levels in many patients with HUS and provide a framework for investigating complement deregulation in patients with the more common sporadic variant of the disease.
PubMed citation number: 9551389
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma.
George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB.
Transfusion. 2004;44:294-304.
Description: This is a systematic review of the literature that characterizes the clinical features of TTP-HUS in the allogeneic bone marrow/stem cell transplantation setting and suggests that, in most cases, these patients have other systemic diseases mimicking the entity of TTP-HUS.
PubMed citation number: 14962323
Epidemiology
Epidemiology of Escherichia coli O157:H7 outbreaks: United States, 1982-2002.
Rangel JM, Sparling PH, Crowe C, Griffin PM, Swerdlow DL.
Emerg Infect Dis. 2005;11:603-609.
Description: Route of transmission of 350 outbreaks of E. coli 0157:H7 occurring over a 20 year period is reported.
PubMed citation number: 15829201
Diagnosis
Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature.
Amorosi EL, Ultmann JE.
Medicine. 1966;45:139-159.
Description: This is a wonderful overview of the clinical manifestations of thrombotic thrombocytopenic purpura (TTP) at diagnosis in 271 previously reported cases and provides important information about the natural history of the disease in an era when effective therapy was lacking.
PubMed citation number: N/A
ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients.
Vesely SK, George JN, Lammle B, et al.
Blood. 2003;102:60-68.
Description: This study showed that while severely low (< 5%) von Willebrand factor–cleaving protease activity levels are specific for idiopathic TTP, they are not sensitive nor do they predict who will respond to plasma exchange, thus limiting the clinical utility of this test.
PubMed citation number: 12637323
Treatment
Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.
Rock GA, Shumak KH, Buskard NA, et al.
N Engl J Med. 1991;325:393-397.
Description: This study demonstrated that plasma exchange: (1) is an effective therapy for TTP; (2) is better than plasma infusion alone (although the difference in volume of plasma infused between the 2 arms remains a point of contention); and (3) established plasma exchange as the standard of care for patients with this disease.
PubMed citation number: 2062330
Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis.
Safdar N, Said A, Gangnon RE, Maki DG.
JAMA. 2002;288:996-1001.
Description: Meta-analysis of published randomized controlled trials of antibiotics for HUS. Concludes that there is insufficient evidence to determine whether antibiotic use contributes to the risk of HUS.
PubMed citation number: 12190370
Prognosis
Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry.
Lesesne JB, Rothschild N, Erickson B, et al.
J Clin Oncol. 1989;7:781-789.
Description: This registry study identified a severe, therapy-refractory TTP-HUS syndrome associated with the use of mitomycin-C for patients with a variety of solid tumors, most notably gastrointestinal adenocarcinomas. This study also demonstrates that while the pathologic and clinical features of TTP-HUS can occur in a variety of disorders, the underlying pathophysiology of mitomycin-C–associated TTP-HUS is likely different given the poor clinical responses to therapeutic plasma exchange.
PubMed citation number: 2497229
Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group.
Shumak KH, Rock GA, Nair RC.
Ann Intern Med. 1995;122:569-572.
Description: This study shows that while therapeutic plasma exchange is effective in the treatment of TTP, more than one-third (36%) of patients will have 1 or more relapses over a follow-up of 10 years.
PubMed citation number: 7887549
Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases.
Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D.
Ann Intern Med. 1998;128:541-544.
PubMed citation number: 9518398
Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression.
Garg AX, Suri RS, Barrowman N, et al.
JAMA. 2003;290:1360-1370.
Description : This meta-analysis of the clinical course of diarrhea-associated HUS better defines clinical features that portend worse long-term renal outcomes in patients with this disease.
PubMed citation number: 12966129
Select Review Articles
Thrombotic microangiopathy during pregnancy.
McCrae KR, Cines DB.
Semin Hematol. 1997;34:148-158.
PubMed citation number: 9109217
How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
George JN.
Blood. 2000;96:1223-1229.
PubMed citation number: 10942361
Thrombotic microangiopathies.
Moake JL.
N Engl J Med. 2002;347:589-600.
PubMed citation number: 12192020