Thrombotic thrombocytopenic purpura
2005; Elsevier BV; Volume: 3; Issue: 8 Linguagem: Inglês
10.1111/j.1538-7836.2005.01425.x
ISSN1538-7933
AutoresBernhard Lämmle, Johanna A. Kremer Hovinga, Lorenzo Alberio,
Tópico(s)Platelet Disorders and Treatments
ResumoSummaryThis overview summarizes the history of thrombotic thrombocytopenic purpura (TTP) from its initial recognition in 1924 as a most often fatal disease to the discovery in 1997 of ADAMTS‐13 deficiency as a major risk factor for acute disease manifestation. The cloning of the metalloprotease, ADAMTS‐13, an essential regulator of the extremely adhesive unusually large von Willebrand factor (VWF) multimers secreted by endothelial cells, as well as ADAMTS‐13 structure and function are reviewed. The complex, initially devised assays for ADAMTS‐13 activity and the possible limitations of static in vitro assays are described. A new, simple assay using a recombinant 73‐amino acid VWF peptide as substrate will hopefully be useful. Hereditary TTP caused by homozygous or double heterozygous ADAMTS‐13 mutations and the nature of the mutations so far identified are discussed. Recognition of this condition by clinicians is of utmost importance, because it can be easily treated and – if untreated – frequently results in death. Acquired TTP is often but not always associated with severe, autoantibody‐mediated ADAMTS‐13 deficiency. The pathogenesis of cases without severe deficiency of the VWF‐cleaving protease remains unknown, affected patients cannot be distinguished clinically from those with severely decreased ADAMTS‐13 activity. Survivors of acute TTP, especially those with autoantibody‐induced ADAMTS‐13 deficiency, are at a high risk for relapse, as are patients with hereditary TTP. Patients with thrombotic microangiopathies (TMA) associated with hematopoietic stem cell transplantation, neo‐plasia and several drugs, usually have normal or only moderately reduced ADAMTS‐13 activity, with the exception of ticlopidine‐induced TMA. Diarrhea‐positive‐hemolytic uremic syndrome (D+ HUS), mainly occurring in children is due to enterohemorrhagic Escherichia coli infection, and cases with atypical, D− HUS may be associated with factor H abnormalities. Treatment of acquired idiopathic TTP involves plasma exchange with fresh frozen plasma (FFP), and probably immunosuppression with corticosteroids is indicated. We believe that, at present, patients without severe acquired ADAMTS‐13 deficiency should be treated with plasma exchange as well, until better strategies become available. Constitutional TTP can be treated by simple FFP infusion that rapidly reverses acute disease and – given prophylactically every 2–3 weeks – prevents relapses. There remains a large research agenda to improve diagnosis of TMA, gain further insight into the pathophysiology of the various TMA and to improve and possibly tailor the management of affected patients. This overview summarizes the history of thrombotic thrombocytopenic purpura (TTP) from its initial recognition in 1924 as a most often fatal disease to the discovery in 1997 of ADAMTS‐13 deficiency as a major risk factor for acute disease manifestation. The cloning of the metalloprotease, ADAMTS‐13, an essential regulator of the extremely adhesive unusually large von Willebrand factor (VWF) multimers secreted by endothelial cells, as well as ADAMTS‐13 structure and function are reviewed. The complex, initially devised assays for ADAMTS‐13 activity and the possible limitations of static in vitro assays are described. A new, simple assay using a recombinant 73‐amino acid VWF peptide as substrate will hopefully be useful. Hereditary TTP caused by homozygous or double heterozygous ADAMTS‐13 mutations and the nature of the mutations so far identified are discussed. Recognition of this condition by clinicians is of utmost importance, because it can be easily treated and – if untreated – frequently results in death. Acquired TTP is often but not always associated with severe, autoantibody‐mediated ADAMTS‐13 deficiency. The pathogenesis of cases without severe deficiency of the VWF‐cleaving protease remains unknown, affected patients cannot be distinguished clinically from those with severely decreased ADAMTS‐13 activity. Survivors of acute TTP, especially those with autoantibody‐induced ADAMTS‐13 deficiency, are at a high risk for relapse, as are patients with hereditary TTP. Patients with thrombotic microangiopathies (TMA) associated with hematopoietic stem cell transplantation, neo‐plasia and several drugs, usually have normal or only moderately reduced ADAMTS‐13 activity, with the exception of ticlopidine‐induced TMA. Diarrhea‐positive‐hemolytic uremic syndrome (D+ HUS), mainly occurring in children is due to enterohemorrhagic Escherichia coli infection, and cases with atypical, D− HUS may be associated with factor H abnormalities. Treatment of acquired idiopathic TTP involves plasma exchange with fresh frozen plasma (FFP), and probably immunosuppression with corticosteroids is indicated. We believe that, at present, patients without severe acquired ADAMTS‐13 deficiency should be treated with plasma exchange as well, until better strategies become available. Constitutional TTP can be treated by simple FFP infusion that rapidly reverses acute disease and – given prophylactically every 2–3 weeks – prevents relapses. There remains a large research agenda to improve diagnosis of TMA, gain further insight into the pathophysiology of the various TMA and to improve and possibly tailor the management of affected patients. In 1924, Dr Eli Moschcowitz described a 16‐year‐old girl who died within 2 weeks after the abrupt onset and progression of petechial bleeding, pallor, fever, paralysis, hematuria and coma [1Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease.Proc N Y Pathol Soc. 1924; 24: 21-4Google Scholar]. Disseminated microvascular 'hyaline' thrombi were detected at autopsy, and these widespread thrombi in arterioles and capillaries, later found to be largely composed of platelets, remain the pathologic hallmark of Moschcowitz' disease or thrombotic thrombocytopenic purpura (TTP) today [2Asada Y. Sumiyoshi A. Hayashi T. Suzumiya J. Kaketani K. Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen.Thromb Res. 1985; 38: 469-79Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 3Hosler G.A. Cusumano A.M. Hutchins G.M. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases.Arch Pathol Lab Med. 2003; 127: 834-9Crossref PubMed Google Scholar]. Moschcowitz suspected that a powerful agglutinative and hemolytic poison was responsible for this disease [4Moschcowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries.Arch Intern Med. 1925; 36: 89-93Crossref Scopus (0) Google Scholar]. In a landmark paper of 1966, Amorosi and Ultmann [5Amorosi E.L. Ultmann J.E. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature.Medicine (Baltimore). 1966; 45: 139-59Crossref Google Scholar] reviewed some 250 reported patients with TTP, added 16 new cases and established a pentad of clinical and laboratory features still considered to be the key diagnostic criteria: microangiopathic hemolytic anemia with fragmented erythrocytes (schistocytes) in the peripheral blood smear (Fig. 1), thrombocytopenia, (often fluctuating) neurologic signs and symptoms, renal dysfunction and fever. Nowadays, it is generally believed that intravascular platelet clumping under high shear stress in the microcirculation results in thrombocytopenia, ischemic neurologic, renal and other organ dysfunction and intravascular fragmentation of red blood cells in the partially occluded arterioles and capillaries. Hemolytic uremic syndrome (HUS), reported in 1955 by Gasser et al. [6Gasser C. Gautier E. Steck A. Siebenmann R.E. Oechslin R. Hämolytisch‐urämische Syndrome: bilaterale Nierenrindennekrosen bei akuten erworbenen hämolytischen Anämien.Schweiz Med Wochenschr. 1955; 85: 905-9PubMed Google Scholar] in five children, is a disease clinically very similar to TTP. In routine clinical practice, TTP was often diagnosed in adult patients with predominant neurologic symptoms whereas a diagnosis of HUS was often made in children with predominant renal failure. Nevertheless, this distinction was not universally accepted and some authors adopted the term 'TTP/HUS' presuming a similar pathomechanism with variable organ tropism. Whereas many cases of TTP occur in previously healthy persons, childhood HUS is often associated with preceding hemorrhagic colitis caused by verocytotoxin‐producing Escherichia coli O157:H7 infection, and this illness is nowadays labelled typical (diarrhea‐positive or D+) HUS [7Griffin P.M. Tauxe R.V. The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome.Epidemiol Rev. 1991; 13: 60-98Crossref PubMed Google Scholar]. In addition, thrombotic microangiopathies (TMA) associated with pregnancy, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), disseminated cancer, anticancer agents such as mitomycin C, hematopoietic stem cell transplantation, various drugs such as cyclosporine A, ticlopidine, clopidogrel, quinine and others, and human immunodeficiency virus infection have been observed and variably referred to as TTP, HUS, TTP‐HUS, TTP‐like disease or secondary TTP (for review see Refs [8Ruggenenti P. Remuzzi G. The pathophysiology and management of thrombotic thrombocytopenic purpura.Eur J Haematol. 1996; 56: 191-207Crossref PubMed Google Scholar, 9George J.N. How I treat patients with thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome.Blood. 2000; 96: 1223-9Crossref PubMed Google Scholar]). Numerous hypotheses on the etiology and pathogenesis of idiopathic TTP have been put forward over the years (for reviews, see Refs [8Ruggenenti P. Remuzzi G. The pathophysiology and management of thrombotic thrombocytopenic purpura.Eur J Haematol. 1996; 56: 191-207Crossref PubMed Google Scholar, 10Moake J.L. Chow T.W. Thrombotic thrombocytopenic purpura: understanding a disease no longer rare.Am J Med Sci. 1998; 316: 105-119Crossref PubMed Scopus (0) Google Scholar, 11Furlan M. Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor‐cleaving protease.Best Pract Res Clin Haematol. 2001; 14: 437-54Crossref PubMed Scopus (0) Google Scholar, 12Moake J.L. Thrombotic microangiopathies.N Engl J Med. 2002; 347: 589-600Crossref PubMed Scopus (1129) Google Scholar]). Among others, endothelial injury, e.g. by oxidative stress, decreased prostacyclin production, reduced fibrinolytic capacity of the vessel wall, anti‐endothelial cell autoantibodies and specifically antibodies toward glycoprotein IV (CD36) [13Tandon N.N. Rock G. Jamieson G.A. Anti‐CD36 antibodies in thrombotic thrombocytopenic purpura.Br J Haematol. 1994; 88: 816-25Crossref PubMed Google Scholar, 14Schultz D.R. Arnold P.I. Jy W. Valant P.A. Gruber J. Ahn Y.S. Mao F.W. Mao W.W. Horstman L.L. Anti‐CD36 autoantibodies in thrombotic thrombocytopenic purpura and other thrombotic disorders: identification of an 85 kD form of CD36 as a target antigen.Br J Haematol. 1998; 103: 849-57Crossref PubMed Scopus (0) Google Scholar] that is located on microvascular endothelial cells and platelets, and the capacity of TTP plasma to induce apoptosis of microvascular endothelial cells [15Laurence J. Mitra D. Steiner M. Staiano‐Coico L. Jaffe E. Plasma from patients with idiopathic and human immunodeficiency virus‐associated thrombotic thrombocytopenic purpura induces apoptosis in microvascular endothelial cells.Blood. 1996; 87: 3245-54Crossref PubMed Google Scholar] have been proposed as pathogenetic factors. Moreover, a 37‐kDa protein [16Siddiqui F.A. Lian E.C. Novel platelet‐agglutinating protein from a thrombotic thrombocytopenic purpura plasma.J Clin Invest. 1985; 76: 1330-7Crossref PubMed Google Scholar], and a 59‐kDa protein or a calcium‐dependent cysteine protease (calpain) [17Murphy W.G. Moore J.C. Kelton J.G. Calcium‐dependent cysteine protease activity in the sera of patients with thrombotic thrombocytopenic purpura.Blood. 1987; 70: 1683-7Crossref PubMed Google Scholar, 18Kelton J.G. Moore J.C. Warkentin T.E. Hayward C.P. Isolation and characterization of cysteine proteinase in thrombotic thrombocytopenic purpura.Br J Haematol. 1996; 93: 421-6Crossref PubMed Google Scholar] were identified in serum or plasma from patients with acute TTP and suggested to be responsible for in vivo platelet aggregation. In 1982, Moake et al. [19Moake J.L. Rudy C.K. Troll J.H. Weinstein M.J. Colannino N.M. Azocar J. Seder R.H. Hong S.L. Deykin D. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura.N Engl J Med. 1982; 307: 1432-5Crossref PubMed Google Scholar] reported the presence of unusually large von Willebrand factor (ULVWF) multimers in plasma of four patients with a chronic relapsing course of TTP during remission. They suspected that these highly polymeric VWF multimers, similar in size to those found in endothelial cell‐culture supernatant, were responsible for in vivo platelet clumping in the microvasculature. Moake et al. [19Moake J.L. Rudy C.K. Troll J.H. Weinstein M.J. Colannino N.M. Azocar J. Seder R.H. Hong S.L. Deykin D. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura.N Engl J Med. 1982; 307: 1432-5Crossref PubMed Google Scholar] hypothesized that the lack of a 'depolymerase' was responsible for the persistence of these ULVWF multimers in their patients. In 1996, Furlan et al. [20Furlan 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: 4223-34Crossref PubMed Google Scholar] and Tsai [21Tsai H.M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion.Blood. 1996; 87: 4235-44Crossref PubMed Google Scholar] simultaneously isolated a hitherto unknown plasma protease that specifically cleaved VWF multimers at the peptide bond Tyr842–Met843 of the mature VWF subunit (Tyr1605–Met1606 in amino acid numbering including the VWF propeptide), the peptide bond previously shown to be cleaved during physiologic processing of VWF in vivo [22Dent J.A. Berkowitz S.D. Ware J. Kasper C.K. Ruggeri Z.M. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor.Proc Natl Acad Sci USA. 1990; 87: 6306-10Crossref PubMed Scopus (310) Google Scholar]. One year later, four patients, including two brothers, with a chronic relapsing TTP and showing ULVWF multimers in their plasma during remission, were found to completely lack any VWF‐cleaving protease (VWF‐cp) activity [23Furlan M. Robles R. Solenthaler M. Wassmer M. Sandoz P. Lämmle B. Deficient activity of von Willebrand factor‐cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura.Blood. 1997; 89: 3097-103Crossref PubMed Google Scholar]. In 1998, we observed another patient with a severe course of TTP lacking any VWF‐cp activity whose plasma contained an IgG autoantibody inhibiting VWF‐cp activity in normal plasma [24Furlan M. Robles R. Solenthaler M. Lämmle B. Acquired deficiency of von Willebrand factor‐cleaving protease in a patient with thrombotic thrombocytopenic purpura.Blood. 1998; 91: 2839-46Crossref PubMed Google Scholar]. The inhibitor disappeared transiently after plasma exchange and replacement of fresh frozen plasma (FFP), corticosteroid and vincristine treatment and this was paralleled by normalization of VWF‐cp and clinical remission. Reappearance of the IgG inhibitor with disappearance of protease activity preceded the first clinical relapse and only splenectomy performed 1 year after disease onset led to persistent clinical remission, absence of inhibitor and normal VWF‐cp activity [24Furlan M. Robles R. Solenthaler M. Lämmle B. Acquired deficiency of von Willebrand factor‐cleaving protease in a patient with thrombotic thrombocytopenic purpura.Blood. 1998; 91: 2839-46Crossref PubMed Google Scholar]. Two separate retrospective studies on large cohorts of patients with TTP and HUS appearing in the same issue of the New England Journal of Medicine [25Furlan M. Robles R. Galbusera M. Remuzzi G. Kyrle P.A. Brenner B. Krause M. Scharrer I. Aumann V. Mittler U. Solenthaler M. Lämmle B. Von Willebrand factor‐cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic‐uremic syndrome.N Engl J Med. 1998; 339: 1578-84Crossref PubMed Scopus (0) Google Scholar, 26Tsai H.M. Lian E.C. Antibodies to von Willebrand factor‐cleaving protease in acute thrombotic thrombocytopenic purpura.N Engl J Med. 1998; 339: 1585-94Crossref PubMed Scopus (0) Google Scholar] demonstrated that the majority of patients with acute sporadic TTP had a severe deficiency of VWF‐cp, most of them with inhibiting autoantibodies that disappeared in all [26Tsai H.M. Lian E.C. Antibodies to von Willebrand factor‐cleaving protease in acute thrombotic thrombocytopenic purpura.N Engl J Med. 1998; 339: 1585-94Crossref PubMed Scopus (0) Google Scholar] or some [25Furlan M. Robles R. Galbusera M. Remuzzi G. Kyrle P.A. Brenner B. Krause M. Scharrer I. Aumann V. Mittler U. Solenthaler M. Lämmle B. Von Willebrand factor‐cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic‐uremic syndrome.N Engl J Med. 1998; 339: 1578-84Crossref PubMed Scopus (0) Google Scholar] patients in remission. Six familial cases (three pairs of siblings) had a complete protease deficiency without inhibitors [25Furlan M. Robles R. Galbusera M. Remuzzi G. Kyrle P.A. Brenner B. Krause M. Scharrer I. Aumann V. Mittler U. Solenthaler M. Lämmle B. Von Willebrand factor‐cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic‐uremic syndrome.N Engl J Med. 1998; 339: 1578-84Crossref PubMed Scopus (0) Google Scholar] and 23 patients with a diagnosis of HUS had normal or subnormal VWF‐cleaving protease activity [25Furlan M. Robles R. Galbusera M. Remuzzi G. Kyrle P.A. Brenner B. Krause M. Scharrer I. Aumann V. Mittler U. Solenthaler M. Lämmle B. Von Willebrand factor‐cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic‐uremic syndrome.N Engl J Med. 1998; 339: 1578-84Crossref PubMed Scopus (0) Google Scholar]. Acute TTP was mostly fatal until the empirical introduction of plasma therapy in the 1970s [27Byrnes J.J. Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma.N Engl J Med. 1977; 297: 1386-9Crossref PubMed Scopus (275) Google Scholar]. In a prospective randomized study, the Canadian Apheresis Study Group [28Rock G.A. Shumak K.H. Buskard N.A. Blanchette V.S. Kelton J.G. Nair R.C. Spasoff R.A. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.N Engl J Med. 1991; 325: 393-7Crossref PubMed Google Scholar] showed the superiority of plasma exchange and FFP replacement over FFP infusion. Using plasmapheresis and FFP replacement, some 80% of the patients survive the acute TTP episode [9George J.N. How I treat patients with thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome.Blood. 2000; 96: 1223-9Crossref PubMed Google Scholar]. The number of plasma exchange procedures and hence the treatment duration varies greatly and many patients relapse during follow‐up [29Shumak K.H. Rock G.A. Nair R.C. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group.Ann Intern Med. 1995; 122: 569-72Crossref PubMed Google Scholar, 30Vesely S.K. George J.N. Lämmle B. Studt J.D. Alberio L. El‐Harake M.A. Raskob G.E. ADAMTS‐13 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: 60-8Crossref PubMed Scopus (0) Google Scholar, 31Sadler J.E. Moake J.L. Miyata T. George J.N. Recent advances in thrombotic thrombocytopenic purpura.Hematology (Am Soc Hematol Educ Program). 2004; : 407-23Crossref PubMed Scopus (281) Google Scholar]. Often, additional treatment, such as corticosteroids [32Bell W.R. Braine H.G. Ness P.M. Kickler T.S. Improved survival in thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome. Clinical experience in 108 patients.N Engl J Med. 1991; 325: 398-403Crossref PubMed Google Scholar], vincristine, other immunosuppressive medication and/or splenectomy is given, especially in refractory or relapsing cases (for reviews, see Refs [8Ruggenenti P. Remuzzi G. The pathophysiology and management of thrombotic thrombocytopenic purpura.Eur J Haematol. 1996; 56: 191-207Crossref PubMed Google Scholar, 9George J.N. How I treat patients with thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome.Blood. 2000; 96: 1223-9Crossref PubMed Google Scholar, 10Moake J.L. Chow T.W. Thrombotic thrombocytopenic purpura: understanding a disease no longer rare.Am J Med Sci. 1998; 316: 105-119Crossref PubMed Scopus (0) Google Scholar, 33Rock G.A. Management of thrombotic thrombocytopenic purpura.Br J Haematol. 2000; 109: 496-507Crossref PubMed Scopus (139) Google Scholar]). These largely empirical treatments seemed to be pathophysiologically supported by the discovery that many patients with acute TTP had an autoantibody‐mediated deficiency of the specific VWF‐cp: plasma exchange and corticosteroids would probably remove circulating autoantibodies and suppress formation of VWF‐cp inhibitors, respectively, and FFP replacement would supply the lacking protease. The very careful clinical observation during long‐term follow‐up of a patient with frequently recurring severe thrombocytopenia and microangiopathic hemolytic anemia since childhood, repeatedly showing a prompt response within a few hours to simple plasma infusion, led Upshaw [34Upshaw J.D. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia.N Engl J Med. 1978; 298: 1350-2Crossref PubMed Google Scholar] to conclude that his and Schulman's similar patient [35Schulman I. Pierce M. Lukens A. Currimbhoy Z. Studies on thrombopoiesis. I: a factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency.Blood. 1960; 16: 943-57Crossref PubMed Google Scholar] were congenitally deficient in a plasma factor protecting from hemolysis and thrombocytopenia. For reviews giving personal accounts of the discovery of ULVWF in TTP, VWF‐cleaving protease and its deficiency in TTP the reader is referred to three interesting recent historical sketches by Furlan [36Furlan M. Proteolytic cleavage of von Willebrand factor by ADAMTS‐13 prevents uninvited clumping of blood platelets.J Thromb Haemost. 2004; 2: 1505-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], Tsai [37Tsai H.M. A journey from sickle cell anemia to ADAMTS‐13.J Thromb Haemost. 2004; 2: 1510-4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and Moake [38Moake J.L. Defective processing of unusually large von Willebrand factor multimers and thrombotic thrombocytopenic purpura.J Thromb Haemost. 2004; 2: 1515-21Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. von Willebrand factor‐cleaving protease was purified to homogeneity and subjected to N‐terminal amino acid sequence analysis [39Gerritsen H.E. Robles R. Lämmle B. Furlan M. Partial amino acid sequence of purified von Willebrand factor‐cleaving protease.Blood. 2001; 98: 1654-61Crossref PubMed Scopus (0) Google Scholar, 40Fujikawa K. Suzuki H. McMullen B. Chung D. Purification of human von Willebrand factor‐cleaving protease and its identification as a new member of the metalloproteinase family.Blood. 2001; 98: 1662-6Crossref PubMed Scopus (0) Google Scholar, 41Soejima K. Mimura N. Hirashima M. Maeda H. Hamamoto T. Nakagaki T. Nozaki C. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor‐cleaving protease.J Biochem (Tokyo). 2001; 130: 475-80Crossref PubMed Google Scholar]. This allowed to identify VWF‐cp as a new member of the ADAMTS (a disintegrin and metalloprotease with thrombospondin type 1 motifs) family of metalloproteases, denoted as ADAMTS‐13 [42Zheng X. Chung D. Takayama T.K. Majerus E.M. Sadler J.E. Fujikawa K. Structure of von Willebrand factor‐cleaving protease (ADAMTS‐13), a metalloprotease involved in thrombotic thrombocytopenic purpura.J Biol Chem. 2001; 276: 41059-63Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and to locate the gene to chromosome 9q34. Simultaneously, Levy et al. [43Levy G.G. Nichols W.C. Lian E.C. Foroud T. McClintick J.N. McGee B.M. Yang A.Y. Siemieniak D.R. Stark K.R. Gruppo R. Sarode R. Shurin S.B. Chandrasekaran V. Stabler S.P. Sabio H. Bouhassira E.E. Upshaw Jr, J.D. Ginsburg D. Tsai H.M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.Nature. 2001; 413: 488-94Crossref PubMed Scopus (1430) Google Scholar], performing a genome‐wide linkage analysis in patients with hereditary TTP displaying severe VWF‐cp deficiency and their family members detected the same gene, ADAMTS‐13. They identified several different mutations as being presumably responsible for the severely deficient protease activity and hereditary TTP in homozygous or double heterozygous carriers of mutated alleles, whereas family members with a heterozygous mutation had about 50% of protease activity and were clinically asymptomatic [43Levy G.G. Nichols W.C. Lian E.C. Foroud T. McClintick J.N. McGee B.M. Yang A.Y. Siemieniak D.R. Stark K.R. Gruppo R. Sarode R. Shurin S.B. Chandrasekaran V. Stabler S.P. Sabio H. Bouhassira E.E. Upshaw Jr, J.D. Ginsburg D. Tsai H.M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.Nature. 2001; 413: 488-94Crossref PubMed Scopus (1430) Google Scholar]. The ADAMTS‐13 gene spans approximately 37 kb, contains 29 exons and encodes a precursor polypeptide composed of 1427 amino acid residues [42Zheng X. Chung D. Takayama T.K. Majerus E.M. Sadler J.E. Fujikawa K. Structure of von Willebrand factor‐cleaving protease (ADAMTS‐13), a metalloprotease involved in thrombotic thrombocytopenic purpura.J Biol Chem. 2001; 276: 41059-63Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43Levy G.G. Nichols W.C. Lian E.C. Foroud T. McClintick J.N. McGee B.M. Yang A.Y. Siemieniak D.R. Stark K.R. Gruppo R. Sarode R. Shurin S.B. Chandrasekaran V. Stabler S.P. Sabio H. Bouhassira E.E. Upshaw Jr, J.D. Ginsburg D. Tsai H.M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.Nature. 2001; 413: 488-94Crossref PubMed Scopus (1430) Google Scholar] (Fig. 2). The polypeptide consists of a signal peptide, a short propeptide with a C‐terminal furin cleavage site, a catalytic domain with a typical reprolysin‐type active site sequence (HEXGHXXGXXHD) coordinating a Zn2+ ion and a Ca2+ binding site motif (E83, D173, C281, D284), a disintegrin domain, a thrombospondin type 1 domain, a cysteine‐rich domain, a spacer domain, seven additional thrombosponding type 1 motifs and two CUB domains (Fig. 2). The calculated molecular mass is 145 kDa, the protein isolated from human plasma has an apparent mass of 180 kDa [39Gerritsen H.E. Robles R. Lämmle B. Furlan M. Partial amino acid sequence of purified von Willebrand factor‐cleaving protease.Blood. 2001; 98: 1654-61Crossref PubMed Scopus (0) Google Scholar] and is heavily glycosylated [44Plaimauer B. Scheiflinger F. Expression and characterization of recombinant human ADAMTS‐13.Semin Hematol. 2004; 41: 24-33Crossref PubMed Scopus (0) Google Scholar]. Northern blotting of various tissues revealed a 4.7‐kb mRNA transcript in liver tissue [41Soejima K. Mimura N. Hirashima M. Maeda H. Hamamoto T. Nakagaki T. Nozaki C. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor‐cleaving protease.J Biochem (Tokyo). 2001; 130: 475-80Crossref PubMed Google Scholar, 42Zheng X. Chung D. Takayama T.K. Majerus E.M. Sadler J.E. Fujikawa K. Structure of von Willebrand factor‐cleaving protease (ADAMTS‐13), a metalloprotease involved in thrombotic thrombocytopenic purpura.J Biol Chem. 2001; 276: 41059-63Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and in situ hybridization showed that ADAMTS‐13 was mainly expressed in the perisinusoidal cells of the liver [45Lee T.P. Bouhassira E.E. Lyubsky S. Tsai H.M. ADAMTS‐13, the von Willebrand factor cleaving metalloprotease, is expressed in the perisinusoidal cells of the liver.Blood. 2002; 100Google Scholar]. Low expression of ADAMTS‐13 mRNA was found in several other organs [46Plaimauer B. Zimmermann K. Volkel D. Antoine G. Kerschbaumer R. Jenab P. Furlan M. Gerritsen H. Lämmle B. Schwarz H.P. Scheiflinger F. Cloning, expression, and functional characterization of the von Willebrand factor‐cleaving protease (ADAMTS‐13).Blood. 2002; 100: 3626-32Crossref PubMed Scopus (0) Google Scholar] and mRNA was recently detected in platelets [47Suzuki M. Murata M. Matsubara Y. Uchida T. Ishihara H. Shibano T. Ashida S. Soejima K. Okada Y. Ikeda Y. Detection of von Willebrand factor‐cleaving protease (ADAMTS‐13) in human platelets.Biochem Biophys Res Commun. 2004; 313: 212-6Crossref PubMed Scopus (0) Google Scholar]. In addition, a shorter 2.4‐kb mRNA transcript was isolated from placenta, skeletal muscle and tumor cell lines [42Zheng X. Chung D. Takayama T.K. Majerus E.M. Sadler J.E. Fujikawa K. Structure of von Willebrand factor‐c
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