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Mechanisms of microvascular thrombosis in thrombotic thrombocytopenic purpura

2009; Elsevier BV; Volume: 75; Linguagem: Inglês

10.1038/ki.2008.610

1523-1755

Han‐Mou Tsai,

Renal Diseases and Glomerulopathies

Recent studies have demonstrated that thrombotic thrombocytopenic purpura (TTP), a serious thrombotic disorder affecting the arterioles and capillaries of multiple organs, is caused by a profound deficiency in the von Willebrand factor cleaving metalloprotease, ADAMTS13. ADAMTS13, a 190-kD plasma protease originating primarily in hepatic stellate cells, prevents microvascular thrombosis by cleaving von Willebrand factor when the substrate is conformationally unfolded by high levels of shear stress in the circulation. Deficiency of ADAMTS13, due to genetic mutations or inhibitory autoantibodies, leads to accumulation of superactive forms of vWF, resulting in vWF-platelet aggregation and microvascular thrombosis. Analysis of ADAMTS13 has led to the recognition of subclinical TTP and atypical TTP presenting with thrombocytopenia or acute focal neurological deficits without concurrent microangiopathic hemolysis. Infusion of plasma replenishes the missing ADAMTS13 and ameliorates the complications of hereditary TTP. The patients are at risk of both acute and chronic renal failure if they receive inadequate plasma therapy. The more frequent, autoimmune type of TTP requires plasma exchange therapy and perhaps immunomodulatory measures. Current studies focus on the factors affecting the phenotypic severity of TTP and newer approaches to improving the therapies for the patients. Recent studies have demonstrated that thrombotic thrombocytopenic purpura (TTP), a serious thrombotic disorder affecting the arterioles and capillaries of multiple organs, is caused by a profound deficiency in the von Willebrand factor cleaving metalloprotease, ADAMTS13. ADAMTS13, a 190-kD plasma protease originating primarily in hepatic stellate cells, prevents microvascular thrombosis by cleaving von Willebrand factor when the substrate is conformationally unfolded by high levels of shear stress in the circulation. Deficiency of ADAMTS13, due to genetic mutations or inhibitory autoantibodies, leads to accumulation of superactive forms of vWF, resulting in vWF-platelet aggregation and microvascular thrombosis. Analysis of ADAMTS13 has led to the recognition of subclinical TTP and atypical TTP presenting with thrombocytopenia or acute focal neurological deficits without concurrent microangiopathic hemolysis. Infusion of plasma replenishes the missing ADAMTS13 and ameliorates the complications of hereditary TTP. The patients are at risk of both acute and chronic renal failure if they receive inadequate plasma therapy. The more frequent, autoimmune type of TTP requires plasma exchange therapy and perhaps immunomodulatory measures. Current studies focus on the factors affecting the phenotypic severity of TTP and newer approaches to improving the therapies for the patients. Thrombotic thrombocytopenic purpura (TTP) typically presents with thrombocytopenia and hemolytic anemia with fragmentation of the red cells. Other manifestations include mental changes, focal neurological deficits, seizures, hematuria, proteinuria, fever, abdominal pain with or without pancreatitis, and electrocardiographic abnormalities.1Bukowski R.M. Thrombotic thrombocytopenic purpura. A review.Prog Hemost Thromb. 1982; 6: 287-337PubMed Google Scholar The conventional classification of microangiopathic disorders, based primarily on the clinical features of the patients, is notable for ambiguity and uncertainty. Recent discoveries of deficient ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat, member 13) in TTP2Tsai H.M. Thrombotic thrombocytopenic purpura: a thrombotic disorder caused by ADAMTS13 deficiency.Hematol Oncol Clin North Am. 2007; 21: 609-632Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and defective complement regulation in non-shiga toxin-associated hemolytic uremic syndrome3Saunders R.E. barrategui-Garrido C. Fremeaux-Bacchi V. et al.The interactive factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and factor I mutations with structural models.Hum Mutat. 2007; 28: 222-234Crossref PubMed Scopus (145) Google Scholar have provided a new framework to classify thrombocytopenia and microangiopathic hemolysis on the basis of molecular defects and associated disease conditions (Table 1).Table 1A molecular and etiologic classification of thrombotic microangiopathyRenal failure: uncommonRenal failure: commonDefective vWF proteolysisDysregulation of complement activation Mutations of ADAMTS13 Mutations of CFH, IF, MCP, BF Inhibitory antibodies of ADAMTS13 Autoantibodies of CFHTumor cell embolismShiga toxins (e.g. E. coli O157:H7)Paroxysmal nocturnal hemoglobinuriaNeuraminidase (e.g. S. pneumoniae)Infectious vasculitis (e.g. C. difficile, R. rickettsii, B. anthracis)Drugs (e.g. calcineurin inhibitors, mitomycin, gemcitabine, quinine)IdiopathicAutoimmune disorders (e.g. SLE, scleroderma)BM/stem cell transplantationMiscellany (e.g. HELLP syndrome, surgery, pancreatitis)IdiopathicBF, complement factor B; BM, bone marrow; CFH, complement factor H; HELLP, hemolysis with elevated liver enzymes and low platelet counts; IF, complement factor I; MCP, membrane cofactor protein (CD46); SLE, systemic lupus erythematosus; vWF, von Willebrand factor. Open table in a new tab BF, complement factor B; BM, bone marrow; CFH, complement factor H; HELLP, hemolysis with elevated liver enzymes and low platelet counts; IF, complement factor I; MCP, membrane cofactor protein (CD46); SLE, systemic lupus erythematosus; vWF, von Willebrand factor. In this review, TTP refers to the thrombotic disorder resulting from severe deficiency of ADAMTS13, due to genetic mutations or inhibitory autoantibodies. Very low levels of ADAMTS13 activity may occasionally be observed in patients with various pathological states, such as disseminated intravascular coagulopathy, liver disease, or sepsis. Nevertheless, it is unclear how accurately a low ADAMTS13 value measured in in vitro assays reflects decreased activity in patients with any of these conditions. ADAMTS13, a metalloprotease of the M12B subfamily, cleaves vWF at the Tyr1605–Met1606 bond in the central A2 domain of the vWF polypeptide whenever this normally cryptic bond is rendered accessible by circulatory shear stress or chaotropic agents. This cleavage progressively converts the endothelial vWF polymer to smaller multimers that are conformationally less flexible and less adhesive. When ADAMTS13 is deficient, vWF multimers are conformationally unfolded by shear stress but are not cleaved, resulting in accumulation of hyperactive forms of vWF that cause platelet aggregation and microvascular thrombosis characteristic of TTP.1Bukowski R.M. Thrombotic thrombocytopenic purpura. A review.Prog Hemost Thromb. 1982; 6: 287-337PubMed Google Scholar The evidence in support of this model of TTP is as follows: (1) exposure to arteriolar levels of shear stress in capillary tubes renders vWF susceptible to cleavage by ADAMTS13;4Tsai H.M. Lian E.C. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.N Engl J Med. 1998; 339: 1585-1594Crossref PubMed Scopus (1479) Google Scholar (2) exposure of vWF to shear stress in various devices causes conformational unfolding that is detectable by either atomic force or fluorescent microscopy, increases its platelet-aggregating capacity, and causes direct vWF–platelet aggregation that is abolished by ADAMTS13.5Siedlecki C.A. Lestini B.J. Kottke-Marchant K.K. et al.Shear-dependent changes in the three-dimensional structure of human von Willebrand factor.Blood. 1996; 88: 2939-2950Crossref PubMed Google Scholar, 6Konstantopoulos K. Chow T.W. Turner N.A. et al.Shear stress-induced binding of von Willebrand factor to platelets.Biorheology. 1997; 34: 57-71Crossref PubMed Scopus (52) Google Scholar, 7Tsai H.M. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.J Mol Med. 2002; 80: 639-647Crossref PubMed Scopus (43) Google Scholar, 8Donadelli R. Orje J.N. Capoferri C. et al.Size regulation of von Willebrand factor-mediated platelet thrombi by ADAMTS13 in flowing blood.Blood. 2006; 107: 1943-1950Crossref PubMed Scopus (63) Google Scholar, 9Schneider S.W. Nuschele S. Wixforth A. et al.Shear-induced unfolding triggers adhesion of von Willebrand factor fibers.Proc Natl Acad Sci USA. 2007; 104: 7899-7903Crossref PubMed Scopus (550) Google Scholar The current model of ADAMTS13 as a regulator of vWF–platelet aggregation explains why the thrombi of TTP characteristically contain abundant vWF and platelets but little fibrin, and are limited to the high shear environments of arterioles and capillaries.10Asada Y. Sumiyoshi A. Hayashi T. et al.Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic pupura, with special reference to factor VIII related antigen.Thromb Res. 1985; 38: 467-479Abstract Full Text PDF Scopus (232) Google Scholar, 11Tsai H.M. Chandler W.L. Sarode R. et al.von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome.Pediatr Res. 2001; 49: 653-659Crossref PubMed Scopus (150) Google Scholar It also explains why the size of vWF increases early in the course of TTP, before the large multimers become progressively depleted along with worsening thrombocytopenia.12Tsai H.M. The kidney in thrombotic thrombocytopenic purpura.Minerva Med. 2007; 98: 731-747PubMed Google Scholar In animal models of ADAMTS13 deficiency, no thrombosis occurs if vWF is absent.13Chauhan A.K. Walsh M.T. Zhu G. et al.The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis.Blood. 2008; 111: 3452-3457Crossref PubMed Scopus (57) Google Scholar In cell cultures or in ex vivo vascular perfusion studies, endothelial cells, when profoundly perturbed by agonists such as histamine, may become decorated with elongated strands of adherent vWF, providing the matrix for platelet adhesion.14Dong J.F. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions.J Thromb Haemost. 2005; 3: 1710-1716Crossref PubMed Scopus (140) Google Scholar, 15Motto D.G. Chauhan A.K. Zhu G. et al.Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.J Clin Invest. 2005; 115: 2752-2761Crossref PubMed Scopus (264) Google Scholar This process, occurring under very low levels of shear stress, similar to those encountered in the venules, may not account for the thrombosis of TTP, which affects arterioles and capillaries but not venules. Furthermore, serial investigation of patients with relapsing TTP has shown that endothelial perturbation follows rather than precedes the onset of thrombocytopenia.16Romani D.W. Fijnheer R. Brinkman H.J. et al.Endothelial cell activation in thrombotic thrombocytopenic purpura (TTP): a prospective analysis.Br J Haematol. 2003; 123: 522-527Crossref PubMed Scopus (14) Google Scholar Recent studies have suggested that binding of vWF to platelets or factor VIII may promote its cleavage by ADAMTS13 under shear stress.17Shim K. Anderson P.J. Tuley E.A. et al.Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress.Blood. 2008; 111: 651-657Crossref PubMed Scopus (142) Google Scholar, 18Cao W. Krishnaswamy S. Camire R.M. et al.Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13.Proc Natl Acad Sci USA. 2008; 105: 7416-7421Crossref PubMed Scopus (88) Google Scholar Nevertheless, there is no evidence that vWF proteolysis by ADAMTS13 is impaired in patients with thrombocytopenia or factor VIII deficiency. Clinical experience indicates that platelet thrombosis does not occur when ADAMTS13 is greater than 10% of the normal. However, there is no fixed threshold level of ADAMTS13 below which microvascular thrombosis invariably occurs, as the level is likely to be affected by multiple factors such as circulatory shear stress profile, platelet receptor and reactivity levels, vWF, and perhaps other as yet unknown factors. In animal studies, inactivation of the ADAMTS13 gene causes microvascular thrombosis in some but not in other strains of mice.15Motto D.G. Chauhan A.K. Zhu G. et al.Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.J Clin Invest. 2005; 115: 2752-2761Crossref PubMed Scopus (264) Google Scholar It is intriguing to speculate that the epistatic genes affecting the response to ADAMTS13 deficiency in mice might also contribute to the heterogeneity of phenotypic severity observed in patients with severe ADAMTS13 deficiency. In hereditary TTP, severe deficiency of ADAMTS13 results from homozygous or double heterozygous mutations of the ADAMTS13 gene. The mutations, mostly non-recurrent, cause severe deficiency of plasma ADAMTS13 activity levels by decreasing its biosynthesis, intracellular trafficking and secretion, and/or proteolytic activity. A 'two-hit' hypothesis has been postulated by some researchers to explain the variable phenotypic severity associated with ADAMTS13 deficiency. Nevertheless, a review of hereditary TTP cases described in the literature and in our own series shows that ADAMTS13 was severely deficient in 19 of 59 siblings of the index cases. Of these 19 siblings, 17 had clinical disease; the other 2 cases had older sisters that were symptomatic only during pregnancy. Thus, current evidence indicates that, with few exceptions, severe ADAMTS13 deficiency is sufficient to confer TTP. In autoimmune TTP, autoantibodies inhibit the proteolytic activity of ADAMTS13. Structural-functional analysis shows that the central spacer domain of ADAMTS13 is an essential component for the ADAMTS13 epitope recognized by TTP autoantibodies.19Zhou W. Dong L. Ginsburg D. et al.Enzymatically active ADAMTS13 variants are not inhibited by anti-ADAMTS13 autoantibodies: a novel therapeutic strategy?.J Biol Chem. 2005; 280: 39934-39941Crossref PubMed Scopus (48) Google Scholar, 20Luken B.M. Turenhout E.A. Kaijen P.H. et al.Amino acid regions 572–579 and 657–666 of the spacer domain of ADAMTS13 provide a common antigenic core required for binding of antibodies in patients with acquired TTP.Thromb Haemost. 2006; 96: 295-301Crossref PubMed Scopus (57) Google Scholar ADAMTS13 variants truncated upstream of the spacer domain are proteolytically active but are not suppressible by the autoantibodies of TTP. Such variants might have therapeutic advantages for autoimmune TTP.19Zhou W. Dong L. Ginsburg D. et al.Enzymatically active ADAMTS13 variants are not inhibited by anti-ADAMTS13 autoantibodies: a novel therapeutic strategy?.J Biol Chem. 2005; 280: 39934-39941Crossref PubMed Scopus (48) Google Scholar The incidence of TTP, estimated to be 1.74 cases per 106 person-years in the Oklahoma registry,21Terrell D.R. Williams L.A. Vesely S.K. et al.The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency.J Thromb Haemost. 2005; 3: 1432-1436Crossref PubMed Scopus (269) Google Scholar is likely to vary in different communities. The risk factors of autoimmune TTP include female gender, middle age (30–50 years), HIV infection, and perhaps African/Hispanic ethnicity. With the exception of ticlopidine,22Tsai H.M. Rice L. Sarode R. et al.Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura.Ann Intern Med. 2002; 132: 794-799Crossref Scopus (198) Google Scholar no etiological agents have been definitively associated with autoimmune TTP. The levels of ADAMTS13 inhibitors tend to fluctuate, often causing one or more episodes of relapse before remitting to low or undetectable levels. Occasionally, the antibodies may increase not only in molar concentration but also in inhibitory potency, suggesting activation of the immune system and somatic hypermutation of the B cells.23Dong L. Chandrasekaran V. Zhou W. et al.Evolution of ADAMTS13 antibodies in a patient with fatal thrombotic thrombocytopenic purpura.Am J Hematol. 2008; 83: 815-817Crossref PubMed Scopus (13) Google Scholar Pregnancy is not a risk factor for autoimmune TTP. Nevertheless, pregnancy decreases the level of ADAMTS13 by ∼30%, and more if it is complicated by pre-eclampsia/eclampsia or HELLP (hemolysis with elevated liver enzymes and low platelet counts) syndrome.24Lattuada A. Rossi E. Calzarossa C. et al.Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome.Haematologica. 2003; 88: 1029-1034PubMed Google Scholar, 25Sanchez-Luceros A. Farias C.E. Amaral M.M. et al.von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women.Thromb Haemost. 2004; 92: 1320-1326PubMed Google Scholar Thus, pregnancy may precipitate acute exacerbation of TTP in a woman with low baseline ADAMTS13 levels owing to genetic mutations or autoantibodies of ADAMTS13. The molecular mechanism of TTP provides a basis to assess the efficacy of plasmapheresis and other therapeutic modalities. For hereditary TTP, a small amount of plasma, for example, ≤15 ml per kg body weight every 2–3 weeks, is sufficient to prevent acute exacerbation. Nevertheless, the regimen of plasma replacement should be tailored not only to prevent acute exacerbation but also to minimize chronic injury to vital organs. Some factor VIII concentrates contain ADAMTS13 activity and may be a potential alternative to fresh frozen plasma for patients with allergy to whole plasma.26Allford S.L. Harrison P. Lawrie A.S. et al.Von Willebrand factor-cleaving protease activity in congenital thrombotic thrombocytopenic purpura.Br J Haematol. 2000; 111: 1215-1222Crossref PubMed Scopus (83) Google Scholar For autoimmune TTP, plasma exchange is necessary to overcome the inhibitors. Plasma-exchange therapy is effective for TTP because most patients have low inhibitor levels.27Tsai H.M. Li A. Rock G. Inhibitors of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura.Clin Lab. 2001; 47: 387-392PubMed Google Scholar The efficacy of corticosteroids remains controversial. Cryoprecipitate-depleted plasma and fresh frozen plasma contain similar levels of ADAMTS13 activity,26Allford S.L. Harrison P. Lawrie A.S. et al.Von Willebrand factor-cleaving protease activity in congenital thrombotic thrombocytopenic purpura.Br J Haematol. 2000; 111: 1215-1222Crossref PubMed Scopus (83) Google Scholar and are similarly effective for TTP.28Zeigler Z.R. Shadduck R.K. Gryn J.F. et al.Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic purpura (TTP).J Clin Apheresis. 2001; 16: 19-22Crossref PubMed Scopus (119) Google Scholar, 29Rock G. Anderson D. Clark W. et al.Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet.Br J Haematol. 2005; 129: 79-86Crossref PubMed Scopus (70) Google Scholar Immunotherapy with rituximab may benefit patients with persistent autoimmune TTP,30Yomtovian R. Niklinski W. Silver B. et al.Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature.Br J Haematol. 2004; 124: 787-795Crossref PubMed Scopus (113) Google Scholar, 31George J.N. Woodson R.D. Kiss J.E. 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 Apheresis. 2006; 21: 49-56Crossref PubMed Scopus (92) Google Scholar but its role for patients with acute TTP is not clear. Future investigation should define the role of immunomodulation in the management of autoimmune TTP, and develop non-suppressible variants of ADAMTS13 or antibody blockers that may be used to bypass or suppress the autoimmune inhibitors. Conflicting data exist for the frequency and severity of renal failure in TTP. An earlier review of TTP suggested that renal dysfunction was common, with creatinine >176.8 μmol/l in 45% of the cases, and that dialysis therapy was necessary in 12% of the patients.32Ridolfi R.L. Bell W.R. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature.Medicine (Baltimore). 1981; 60: 413-428Crossref PubMed Scopus (386) Google Scholar Nevertheless, the definition of TTP varied, and it is likely that not all of the patients in the reviewed series had TTP as defined currently. In a recent series of TTP with demonstrated ADAMTS13 deficiency, serious renal failure is infrequent (Table 2). Current evidence suggests that advanced renal failure, hypertension, fluid overload, and need of dialysis therapy are uncommon in autoimmune TTP.Table 2Renal failure in autoimmune and hereditary TTPAutoimmune TTPNo. of casesCases with Cr>265.2 mmol/lCases requiring dialysisLiterature33Vesely S.K. George J.N. Lammle 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: 60-68Crossref PubMed Scopus (572) Google Scholar, 34Coppo P. Bengoufa D. Veyradier A. et al.Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement.Medicine (Baltimore). 2004; 83: 233-244Crossref PubMed Scopus (148) Google Scholar, 35Zheng X.L. Kaufman R.M. Goodnough L.T. et al.Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.Blood. 2004; 103: 4043-4049Crossref PubMed Scopus (382) Google Scholar, 36Raife T. Atkinson B. Montgomery R. et al.Severe deficiency of VWF-cleaving protease (ADAMTS13) activity defines a distinct population of thrombotic microangiopathy patients.Transfusion. 2004; 44: 146-150Crossref PubMed Scopus (72) Google Scholar1153 (2.6%, range 0–11%)4 (3.5%, range 0–10%)Author's series Non-referral380 (0%)0 (0%) Referral3002 (0.75%)aOne case developed graft dysfunction and TTP immediately after renal allograft transplantation;44 the other case was found to have crescenteric nephropathy because of anti-glomerular basement membrane antibody 11 months after his TTP, which was complicated with acute renal failure.450 (0%)Total4535 (1.1%)4 (0.9%)Hereditary TTPNo. of casesAcute renal failurebRequiring dialysis therapy.Chronic renal failureLiterature37Noris M. Bucchioni S. Galbusera M. et al.Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement.J Am Soc Nephrol. 2005; 16: 1177-1183Crossref PubMed Scopus (118) Google Scholar, 38Assink K. Schiphorst R. Allford S. et al.Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency.Kidney Int. 2003; 63: 1995-1999Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 39Schneppenheim R. Budde U. Oyen F. et al.von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP.Blood. 2003; 101: 1845-1850Crossref PubMed Scopus (194) Google Scholar, 40Matsumoto M. Yagi H. Ishizashi H. et al.The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.Semin Hematol. 2004; 41: 68-74Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 41Veyradier A. Lavergne J.M. Ribba A.S. et al.Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome).J Thromb Haemost. 2004; 2: 424-429Crossref PubMed Scopus (106) Google Scholar, 42Donadelli R. Banterla F. Galbusera M. et al.In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura.Thromb Haemost. 2006; 96: 454-464PubMed Google Scholar6878 (dialysis: 6)Author's series43Levy G.G. Nichols W.C. Lian E.C. et al.Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.Nature. 2001; 413: 488-494Crossref PubMed Scopus (1435) Google Scholar2551 (dialysis: 0)Total9312 (13%)9 (9.7%)TTP, thrombotic thrombocytopenic purpura.a One case developed graft dysfunction and TTP immediately after renal allograft transplantation;44Pham P.T. Danovitch G.M. Wilkinson A.H. et al.Inhibitors of ADAMTS13: a potential factor in the cause of thrombotic microangiopathy in a renal allograft recipient.Transplantation. 2002; 74: 1077-1080Crossref PubMed Scopus (49) Google Scholar the other case was found to have crescenteric nephropathy because of anti-glomerular basement membrane antibody 11 months after his TTP, which was complicated with acute renal failure.45Ahmed S. Siddiqui A.K. Chandrasekaran V. Correlation of thrombotic thrombocytopenic purpura disease activity with von Willibrand factor-cleaving protease level in ulcerative colitis.Am J Med. 2004; 116: 786-787Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholarb Requiring dialysis therapy. Open table in a new tab TTP, thrombotic thrombocytopenic purpura. In contrast, acute or chronic renal failure is not infrequent with hereditary TTP (Table 2). ADAMTS13 is synthesized primarily in the hepatic stellate cells46Zhou W. Inada M. Lee T.P. et al.ADAMTS13 is expressed in hepatic stellate cells.Lab Invest. 2005; 85: 780-788Crossref PubMed Scopus (158) Google Scholar, 47Uemura M. Tatsumi K. Matsumoto M. et al.Localization of ADAMTS13 to the stellate cells of human liver.Blood. 2005; 106: 922-924Crossref PubMed Scopus (236) Google Scholar but also in glomerular podocytes and endothelial cells.48Shang D. Zheng X.W. Niiya M. et al.Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts.Blood. 2006; 108: 2207-2215Crossref PubMed Scopus (86) Google Scholar, 49Turner N. Nolasco L. Tao Z. et al.Human endothelial cells synthesize and release ADAMTS-13.J Thromb Haemost. 2006; 4: 1396-1404Crossref PubMed Scopus (146) Google Scholar, 50Manea M. Kristoffersson A. Schneppenheim R. et al.Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura.Br J Haematol. 2007; 138: 651-662Crossref PubMed Scopus (72) Google Scholar Thus, patients with hereditary TTP may have higher risk of renal failure because they lack the protection provided by locally secreted ADAMTS13. Mutation in complement factor H has been described in a patient with ADAMTS13 mutations and renal failure.37Noris M. Bucchioni S. Galbusera M. et al.Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement.J Am Soc Nephrol. 2005; 16: 1177-1183Crossref PubMed Scopus (118) Google Scholar Plasma therapy reverses acute renal failure caused by genetic ADAMTS13 deficiency, and is also effective for preventing the development of chronic renal failure. The high prevalence rate of renal dysfunction among the hereditary TTP patients reflects the current practice, favoring no or minimal maintenance therapy. A strategy of periodic monitoring of blood counts, urinalysis, and renal function, with maintenance plasma therapy individually tailored to ameliorate thrombocytopenia, hematuria, proteinuria, or deteriorating renal function, may provide the best strategy of preventing acute and chronic renal failures for patients with hereditary TTP. H-M Tsai has received consulting fees from Navigant BioTechnologies. The payment was made to Montefiore Medical Center. This work is supported in part by a grant (R01 HL62136) from the National Heart, Lung and Blood Institute of the National Institutes of Health, USA.