Background Thrombotic thrombocytopenic purpura and the hemolytic–uremicsyndrome are severe microvascular disorders of platelet clumpingwith similar signs and symptoms. Unusually large multimers ofvon Willebrand factor, capable of agglutinating circulatingplatelets under high shear stress, occur in the two conditions.We investigated the prevalence of von Willebrand factor–cleavingprotease deficiency in patients with familial and nonfamilialforms of these disorders.
Methods Plasma samples were obtained from 53 patients with thromboticthrombocytopenic purpura or hemolytic–uremic syndrome.Von Willebrand factor–cleaving protease was assayed indiluted plasma samples with purified normal von Willebrand factoras the substrate. The extent of the degradation of von Willebrandfactor was assessed by electrophoresis in sodium dodecyl sulfate–agarosegels and immunoblotting. To determine whether an inhibitor ofvon Willebrand factor–cleaving protease was present, wemeasured the protease activity in normal plasma after incubationwith plasma from the patients.
Results We examined 30 patients with thrombotic thrombocytopenicpurpura and 23 patients with the hemolytic–uremic syndrome.Of 24 patients with nonfamilial thrombotic thrombocytopenicpurpura, 20 had severe and 4 had moderate protease deficiencyduring an acute event. An inhibitor found in 20 of these patientswas shown to be IgG in five of five tested plasma samples. Of13 patients with nonfamilial hemolytic–uremic syndrome,11 had normal levels of activity of von Willebrand factor–cleavingprotease during the acute episode, whereas in 2 patients, theactivity was slightly decreased. All 6 patients with familialthrombotic thrombocytopenic purpura lacked von Willebrand factor–cleavingprotease activity but had no inhibitor, whereas all 10 patientswith familial hemolytic–uremic syndrome had normal proteaseactivity. In vitro proteolytic degradation of von Willebrandfactor by the protease was studied in 5 patients with familialand 7 patients with nonfamilial hemolytic–uremic syndromeand was normal in all 12 patients.
Conclusions Nonfamilial thrombotic thrombocytopenic purpurais due to an inhibitor of von Willebrand factor–cleavingprotease, whereas the familial form seems to be caused by aconstitutional deficiency of the protease. Patients with thehemolytic–uremic syndrome do not have a deficiency ofvon Willebrand factor–cleaving protease or a defect invon Willebrand factor that leads to its resistance to protease.
Thrombotic thrombocytopenic purpura, a disseminated thromboticmicroangiopathy, was initially described by Moschcowitz in 1924.1Three decades later, Gasser et al.2 reported a similar disorderin children that they called the hemolytic–uremic syndrome.Today the two conditions are often regarded as variants of asingle syndrome called thrombotic thrombocytopenic purpura–hemolytic–uremicsyndrome. The syndrome is characterized by thrombocytopenia,hemolytic anemia, fever, renal abnormalities, and neurologicdisturbances.3,4 The term thrombotic thrombocytopenic purpurais usually preferred for cases in adults in which neurologicdysfunction predominates, whereas cases involving predominantlyglomerular damage, which occur mainly in children, are diagnosedas the hemolytic–uremic syndrome. Because some cases ofthrombotic thrombocytopenic purpura can involve severe renalabnormalities and extrarenal manifestations can occur in thehemolytic–uremic syndrome, the two disorders are oftendifficult to distinguish. The terms microangiopathic hemolyticanemia and thrombotic microangiopathy have been used for casesthat are associated with infection, bone marrow transplantation,drug therapy, cancer, chemotherapy, and pregnancy. Endothelialinjury is generally considered the primary event.
Unusually large forms of von Willebrand factor occur in plasmain patients with chronic relapsing forms of thrombotic thrombocytopenicpurpura5 and the hemolytic–uremic syndrome.6 These extremelylarge multimers may agglutinate circulating platelets at siteswith high levels of intravascular shear stress.7 Increased bindingof von Willebrand factor to platelets and increased numbersof circulating platelet aggregates have been observed in patientswith thrombotic thrombocytopenic purpura.8 A specific von Willebrandfactor–cleaving protease has recently been isolated fromnormal human plasma.9,10 Severe deficiency of this proteasewas found in four patients with chronic relapsing thromboticthrombocytopenic purpura, two of whom were brothers.11 In anotherpatient with recurrent episodes of thrombotic thrombocytopenicpurpura, both a deficiency of protease activity and an autoantibodyagainst von Willebrand factor–cleaving protease were foundin plasma.12 These results suggest that von Willebrand factor–inducedagglutination of circulating platelets may be caused by constitutionalas well as acquired deficiencies of von Willebrand factor–cleavingprotease. Since the prognosis and treatment of patients maybe influenced by the severity and nature of the von Willebrandfactor–cleaving protease deficiency, we conducted a multicenterretrospective study of the prevalence of this deficiency inpatients with acquired and familial thrombotic thrombocytopenicpurpura or hemolytic–uremic syndrome.
Methods
Study Design and Patients
The participating centers (in Bern, Switzerland; Bergamo, Italy;Vienna, Austria; and Frankfurt and Magdeburg, Germany) providedfrozen plasma samples from patients who had received a diagnosisof thrombotic thrombocytopenic purpura–hemolytic–uremicsyndrome according to clinical and laboratory criteria. Thedisease was classified as familial if more than one family memberwas affected and if at least one of the following criteria wasmet: each affected family member had had multiple acute episodes,the acute episodes had occurred at different times in the caseof siblings, and the affected family members were living indifferent households when the episodes occurred. For each patient,a questionnaire was filled out concerning history; signs ofand laboratory data on intravascular hemolysis; the presenceof fragmented erythrocytes, fever, neurologic symptoms, andrenal dysfunction; the number of acute events; and possibleassociated risk factors, such as pregnancy, cancer, chemotherapy,bone marrow transplantation, and infection. Furthermore, availableinformation on therapy and its efficacy was collected. The disorderswere characterized as relapsing if there were complete remissionsbetween acute bouts and as chronic if complete recovery didnot occur between bouts. The diagnosis of the disease as thromboticthrombocytopenic purpura or the hemolytic–uremic syndromewas made by the investigators at each participating center withoutknowledge of the results of the von Willebrand factor–cleavingprotease assay. The study was approved by the ethics committeeof the University of Bern.
Assays
Blood samples were collected from patients before a plasma-exchangesession was begun. However, some patients who were examinedduring an acute episode had received plasma therapy on the dayspreceding the examination. Blood samples were anticoagulatedwith either sodium citrate or heparin. Platelet-poor plasmawas stored at –20°C until tested. Platelet countsand measurements of hemoglobin, lactate dehydrogenase, totalbilirubin, and creatinine were performed according to conventionallaboratory methods at each center. Von Willebrand factor antigenwas measured by an enzyme-linked immunosorbent assay with acommercial rabbit antiserum against human von Willebrand factor(Nordic, Tilburg, the Netherlands).
The assay of von Willebrand factor–cleaving protease activitywas performed as previously described.11 Plasma samples werediluted 1:20 with a solution of 0.15 mol of sodium chlorideper liter and 10 mmol of TRIS per liter (pH 7.4) containing1 mmol of serine protease inhibitor per liter (Pefabloc SC,Boehringer, Mannheim, Germany). The protease was activated bya five-minute incubation at 37°C with 10 mmol of bariumchloride per liter. Immediately after activation, 100 µlof the incubation mixture was added to 50 µl of protease-freevon Willebrand factor (with the concentration adjusted to about3 U of von Willebrand factor antigen per milliliter) that hadbeen purified by gel filtration on Sepharose CL-2B columns (PharmaciaLKB, Uppsala, Sweden) from a cryoprecipitate of normal humanplasma. The reaction mixture was dialyzed on the surface ofa hydrophilic filter that was 25 mm in diameter (VSWP, Millipore,Bedford, Mass.) for 24 hours at 37°C against 1.5 mol ofurea per liter and 5 mmol of TRIS–hydrochloric acid perliter (pH 8.0). The reaction was stopped by the addition of10 µl of EDTA (0.2 mol per liter, pH 7.4), and the extentof the degradation of von Willebrand factor was assessed bymultimer analysis with sodium dodecyl sulfate electrophoresison 1.4 percent agarose gels. After electrophoresis, the proteinswere transferred to nitrocellulose membranes and stained withperoxidase-conjugated rabbit antibodies against human von Willebrandfactor (P0226, Dako, Glostrup, Denmark).9 A pooled sample ofcitrated normal human plasma, obtained from 42 healthy malesubjects and stored at –70°C, was used to calibratethe protease assay.
Each plasma sample was assessed at least three times for vonWillebrand factor–cleaving protease activity, and theresults are given as mean percentages of the activity of normalpooled human plasma. Samples with activity levels that weremore than 50 percent of the value for normal pooled human plasmawere defined as normal. We assayed samples for an inhibitorof von Willebrand factor–cleaving protease by measuringthe protease activity in mixtures of plasma from patients andnormal plasma at three dilutions (4:1, 1:1, and 1:5) after a10-minute incubation at 37°C.12 The amount of protease activityinhibited by 1 ml of the patients' plasma was then estimated;thus, 1 U of inhibitor neutralizes the protease activity in1 ml of normal human plasma.
Proteolytic digestion of von Willebrand factor from the patients'plasma samples was assayed by multimer analysis after proteaseactivation and dialysis as described above, but without theaddition of von Willebrand factor substrate isolated from normalhuman plasma.
The activity of von Willebrand factor–cleaving proteasewas also determined in commercially prepared samples of virus–inactivatedfresh-frozen plasma provided by the Blood Transfusion Service(Swiss Red Cross, Bern, Switzerland) and Octapharma (Vienna,Austria). In six different batches from the Swiss Red Cross,virus had been inactivated by exposure to light in the presenceof methylene blue followed by filtration under sterile conditionswith LeukoVir filters (HemaSure, Marlborough, Mass.), whereassix batches from Octapharma had been treated with the solvent–detergentprocedure.
Affinity chromatography of IgG was performed on a 5-ml columnof protein A–Sepharose (Pharmacia LKB) as described previously.12We applied samples of plasma to a column that had been equilibratedwith 0.15 mol of sodium chloride per liter and 10 mmol of TRISper liter (pH 7.4). Plasma proteins were eluted with 0.15 molof sodium chloride per liter and 10 mmol of TRIS per liter (pH7.4), followed by 0.1 mol of sodium citrate per liter (pH 4.0).The inhibitor of von Willebrand factor–cleaving proteasewas assayed in the unbound fraction of the plasma samples aswell as in the IgG fraction eluted at pH 4.0 after dialysisagainst 0.15 mol of sodium chloride per liter and 10 mmol ofTRIS per liter (pH 7.4).
Results
The 53 patients with thrombotic microangiopathy who were includedin the study were divided into two groups (Table 1): 37 patientswithout a familial history of the disorder were classified ashaving nonfamilial thrombotic thrombocytopenic purpura or hemolytic–uremicsyndrome, and 16 patients with at least one additional affectedfamily member were classified as having a familial form. Theclinical diagnosis was thrombotic thrombocytopenic purpura in30 patients and the hemolytic–uremic syndrome in 23 patients.In the group of 24 patients with nonfamilial thrombotic thrombocytopenicpurpura, blood samples were obtained from 15 patients duringboth an acute episode and remission (Patients 1 to 15) and from9 patients during the acute event only (Patients 16 to 24).Of the 13 patients who were given a diagnosis of nonfamilialhemolytic–uremic syndrome, 8 had plasma samples obtainedboth during the acute event and during remission (Patients 25to 32), and 5 had plasma samples obtained during the acute eventalone (Patients 33 to 37). Of the 16 patients with familialthrombotic thrombocytopenic purpura or hemolytic–uremicsyndrome, plasma was obtained from 5 patients during an acuteevent and from 11 during remission. Eight patients with nonfamilialconditions died during the acute episode (Table 1). Thirteensiblings of patients with familial hemolytic–uremic syndromehad died; plasma samples from these family members were notavailable for investigation. In two patients (Patients 37 and42), the initial clinical diagnosis was thrombotic thrombocytopenicpurpura–hemolytic–uremic syndrome: in Patient 37,the kidneys were predominantly involved, whereas the other patienthad a sibling (Patient 43) with recurring thrombotic thrombocytopenicpurpura. They were subsequently given diagnoses of nonfamilialhemolytic–uremic syndrome and familial thrombotic thrombocytopenicpurpura, respectively.
Table 1. Clinical Characteristics of the Patients.
Laboratory values are presented in Table 2. Among the patientswith nonfamilial conditions, most had markedly increased levelsof von Willebrand factor antigen during the acute episode, andthe levels often remained abnormally high during remission.Of the 24 patients with nonfamilial thrombotic thrombocytopenicpurpura, 18 had normal plasma creatinine values during an acuteepisode, whereas most patients with nonfamilial hemolytic–uremicsyndrome had strikingly increased creatinine levels during anacute episode. All 13 patients with nonfamilial hemolytic–uremicsyndrome had had only a single acute event, whereas 14 of the24 patients with nonfamilial thrombotic thrombocytopenic purpurahad had more than one acute episode. It must be emphasized thatsix patients with thrombotic thrombocytopenic purpura and twopatients with the hemolytic–uremic syndrome died duringthe first acute episode, thus precluding a relapse. Six patientsfrom three families had familial thrombotic thrombocytopenicpurpura, and 10 patients from six families had familial hemolytic–uremicsyndrome. Patients 44 and 45, who were siblings, had eight siblingswho had died of the hemolytic–uremic syndrome; Patients46 and 51 had three and two siblings, respectively, who haddied of the disease.
Of the 24 patients with nonfamilial thrombotic thrombocytopenicpurpura, 20 had a severe deficiency of von Willebrand factor–cleavingprotease during an acute episode and 4 had moderately decreasedenzyme activity (Figure 1 and Table 2). In only 5 of 15 patients(Patients 5, 9, 10, 13, and 15) was there complete recoveryof the von Willebrand factor–cleaving protease activitywith the return of the platelet count to normal. In five additionalpatients (Patients 1, 6, 8, 12, and 14), protease activity wasevident only after extended periods — weeks to months— of clinical remission (data not shown). Twenty of the24 patients with nonfamilial thrombotic thrombocytopenic purpurahad a circulating inhibitor of von Willebrand factor–cleavingprotease during an acute episode. The levels of inhibitor, expressedin arbitrary units, are shown beneath the multimeric patternsof von Willebrand factor in Figure 1.
Figure 1. Activity of von Willebrand Factor–Cleaving Protease and the Level of Its Inhibitor in 24 Patients with Nonfamilial Thrombotic Thrombocytopenic Purpura (Patients 1 to 24), 13 Patients with Nonfamilial Hemolytic–Uremic Syndrome (Patients 25 to 37), 6 Patients with Familial Thrombotic Thrombocytopenic Purpura (Patients 38 to 43), and 10 Patients with Familial Hemolytic–Uremic Syndrome (Patients 44 to 53).
The following pairs of patients are siblings: Patients 38 and 39, 40 and 41, 42 and 43, 44 and 45, 47 and 48, 49 and 50, and 52 and 53. The siblings of Patients 46 and 51 had died before the study began. Plasma samples were collected during an acute event (A) and remission (R). The multimeric patterns of purified normal von Willebrand factor substrate after incubation with diluted plasma samples from the patients are shown. The protease assay was calibrated against various dilutions of normal plasma (1:20 to 1:640), and the levels of the protease inhibitor are expressed as the number of inhibitor units per milliliter of plasma. One unit of inhibitor neutralizes the protease activity in 1 ml of normal human plasma. TTP denotes thrombotic thrombocytopenic purpura, HUS hemolytic–uremic syndrome, and TBS 0.15 mol of sodium chloride per liter and 10 mmol of TRIS per liter (pH 7.4).
The nature of the inhibitor was examined by affinity chromatographyof plasma samples from five patients. The inhibitor in plasmasamples obtained from Patients 1, 12, 14, 18, and 20 duringan acute episode and from Patient 1 during remission was completelydepleted on a protein A–Sepharose column and was elutedfrom the column at pH 4.0, indicating the presence of IgG.
Eleven of the 13 patients with acute nonfamilial hemolytic–uremicsyndrome had normal levels of activity of von Willebrand factor–cleavingprotease (defined as activity that was more than 50 percentof the level in normal subjects), and 2 had lower levels ofactivity (26 to 50 percent of the level in normal subjects).All eight plasma samples collected during remission from patientswith nonfamilial hemolytic–uremic syndrome had normallevels of activity of von Willebrand factor–cleaving protease(Figure 1 and Table 2).
Two patients with acute familial thrombotic thrombocytopenicpurpura and four patients with familial thrombotic thrombocytopenicpurpura in remission had no activity of von Willebrand factor–cleavingprotease. None of these six patients had a detectable proteaseinhibitor (Figure 1 and Table 2). Another sibling of Patients42 and 43 also had complete deficiency of von Willebrand factor–cleavingprotease but was not included in the study because he had neverhad symptoms of thrombotic thrombocytopenic purpura. All 10patients with familial hemolytic–uremic syndrome had normalprotease activity (Figure 1 and Table 2). No deficiency of vonWillebrand factor–cleaving protease was found in 120 normalsubjects (data not shown). In plasma samples from five patientswith familial hemolytic–uremic syndrome (Patients 45,46, 50, 51, and 52) and seven patients with nonfamilial hemolytic–uremicsyndrome (Patients 27, 28, 29, 30, 31, 32, and 35), von Willebrandfactor was completely degraded by von Willebrand factor–cleavingprotease (data not shown).
The activity of von Willebrand factor–cleaving proteasewas determined in 12 batches of commercially prepared samplesof fresh-frozen plasma that had been treated with two virus-inactivatingprocedures. All 12 batches had normal protease activity (datanot shown).
Discussion
Thrombotic thrombocytopenic purpura and the hemolytic–uremicsyndrome share several clinical features: thrombocytopenia,intravascular hemolysis caused by erythrocyte fragmentation,and injury of the kidneys and the central nervous system. Differenttriggering factors may be involved, such as bacterial or viralinfection, pregnancy, drug therapy, chemotherapy, and bone marrowtransplantation. The conditions can occur in several membersof the same family. The causes and pathogenesis are unknown.It is generally assumed that endothelial-cell injury is theinitial event. Bacterial endotoxins, antibodies and immune complexes,oxidative injury, and certain drugs are possible causes of endothelialdamage. Reduced production of prostacyclin, impaired fibrinolysis,and platelet-aggregating agents have been implicated in thedevelopment of thrombotic thrombocytopenic purpura–hemolytic–uremicsyndrome. Moake et al.5,6 and Charba et al.13 attributed theenhanced intravascular platelet clumping in these syndromesto the presence of unusually large polymers of von Willebrandfactor. Systemic endothelial-cell injury may lead to excessiverelease from endothelial cells of extremely large polymers ofvon Willebrand factor that cannot be processed to smaller formsby a specific "depolymerase."5,14,15 Normal human plasma orits cryosupernatant was proposed to contain a disulfide-bondreductase capable of degrading unusually large von Willebrandfactor multimers to smaller molecular forms.16,17 We have recentlyisolated a specific protease from human plasma that cleavesthe subunit of von Willebrand factor between tyrosine at position842 and methionine at position 843,9 the same peptide bond thathad been shown to be cleaved in vivo.18 This protease was deficientin four patients with chronic relapsing thrombotic thrombocytopenicpurpura and unusually large circulating multimers of von Willebrandfactor,11 and no protease inhibitor was detected. The lack ofvon Willebrand factor–cleaving protease activity in anotherpatient was the result of an autoantibody that inhibited theprotease activity.12 The inhibitor persisted for about one yearand disappeared after splenectomy, which was followed by normalizationof protease activity, the multimeric pattern of von Willebrandfactor, and the platelet count.
In the present retrospective study, we found a high prevalenceof von Willebrand factor–cleaving protease deficiencyin 24 patients with nonfamilial thrombotic thrombocytopenicpurpura: 20 patients had severe protease deficiency (<5 percentof normal activity) and 4 moderate protease deficiency (5 to25 percent of normal activity) during an acute event. Althoughblood samples were generally collected before a plasma-exchangesession was begun, some patients who were examined during theacute episode had received plasma therapy on preceding days.Since the biologic half-life of the protease is longer thanone day (unpublished data), the protease activity in the fourpatients with moderate protease deficiency may originate fromplasma exchange with fresh-frozen plasma or the inhibitor titermay be affected by this treatment. An inhibitor was found in20 of 24 patients with acute thrombotic thrombocytopenic purpuraand turned out to be IgG in all 5 patients who were tested.
Among the patients with familial thrombotic thrombocytopenicpurpura, all six patients (two during an acute episode and fourwhile in remission) were found to have a protease deficiency(<5 percent of normal activity), but none had an inhibitor.We conclude that the deficiency of von Willebrand factor–cleavingprotease is highly associated with thrombotic thrombocytopenicpurpura. This deficiency may be inherited or acquired as a resultof an autoimmune mechanism. A possible association with knowntriggering conditions has been established in only 4 of 24 patientswith nonfamilial thrombotic thrombocytopenic purpura: 3 patients(Patients 5, 6, and 14) had their first episode during pregnancy,and 1 had undergone an allogeneic bone marrow transplantationfor acute leukemia. Three patients with nonfamilial thromboticthrombocytopenic purpura (Patients 9, 12, and 13) entered remissionafter splenectomy. In all three patients, splenectomy was followedby the disappearance of the inhibitor and normalization of proteaseactivity. Early remission in another patient (Patient 1), despitethe persistence of the von Willebrand factor–cleavingprotease deficiency due to an autoantibody against the protease,was followed by recurrent episodes of thrombotic thrombocytopenicpurpura, and he recovered only after splenectomy and the subsequentdisappearance of the inhibitor.11
Plasma exchange or infusion is considered the therapy of choicein patients with thrombotic thrombocytopenic purpura. Sincevon Willebrand factor–cleaving protease presumably isa hydrophobic high-molecular-weight protein,9 the question ariseswhether the protease activity survives the treatments used toinactivate viruses. We have found normal levels of activityof von Willebrand factor–cleaving protease in commerciallyprepared samples of fresh-frozen plasma in which viruses hadbeen inactivated either by exposure to light in the presenceof methylene blue or by the solvent–detergent procedure.We conclude that the use of these virus-inactivated productsis appropriate for plasma exchange in patients with thromboticthrombocytopenic purpura.
Eleven of 13 patients with nonfamilial acute hemolytic–uremicsyndrome had normal levels of activity of von Willebrand factor–cleavingprotease, and 2 had levels of activity that were 26 to 50 percentof normal, whereas all 10 patients with familial hemolytic–uremicsyndrome had normal protease activity. Proteolytic degradationof von Willebrand factor by von Willebrand factor–cleavingprotease was not impaired in five patients with familial andseven patients with nonfamilial hemolytic–uremic syndrome,indicating that platelet agglutination in these patients isnot due to resistance of von Willebrand factor to proteolyticcleavage. Our results thus suggest that neither a structuralabnormality of von Willebrand factor leading to its resistanceto the specific von Willebrand factor–cleaving proteasenor a deficiency of the protease is involved in the pathogenesisof acquired or familial hemolytic–uremic syndrome.
Our results show that patients with nonfamilial thrombotic thrombocytopenicpurpura have an acquired deficiency of von Willebrand factor–cleavingprotease that is caused by an autoimmune mechanism. Patientswith familial thrombotic thrombocytopenic purpura had a completeprotease deficiency in the absence of an inhibitor. It is likelythat these patients would readily, though only temporarily,recover if they received the protease through plasma-exchangetherapy. On the other hand, patients with nonfamilial thromboticthrombocytopenic purpura and high titers of inhibitor may needlarge volumes of infused plasma. Treatment with immunosuppressiveagents,19,20 immunoadsorption with a protein A–Sepharosecolumn,21 and treatment with vincristine12,22 or splenectomy12,23should be considered as additional therapeutic regimens in thesepatients. The deficiency of von Willebrand factor–cleavingprotease in patients with thrombotic thrombocytopenic purpuraand the normal von Willebrand factor–cleaving proteaseactivity in patients with the hemolytic–uremic syndromeprovide a means of discriminating between these two syndromes,which are often difficult to distinguish clinically. We concludethat the assay of von Willebrand factor–cleaving proteaseand its inhibitor may be useful in the differential diagnosisand treatment of patients with thrombotic thrombocytopenic purpura–hemolytic–uremicsyndrome.
Supported by grants from the Swiss National Science Foundation(32-47033.96); the Malcolm Hewitt Wiener Foundation, New York;the Central Laboratory, Blood Transfusion Service, Swiss RedCross, Bern, Switzerland; and Immuno, Vienna, Austria.
We are indebted to Daniel Landau, M.D., Soroka Medical Center,Beer Sheva, Israel, for providing plasma samples from Patients44 and 45.
Source Information
From the Central Hematology Laboratory, University Hospital, Bern, Switzerland (M.F., R.R., M.S., B.L.); Mario Negri Institute for Pharmacological Research, Bergamo, Italy (M.G., G.R.); the Department of Internal Medicine I, General Hospital, Vienna, Austria (P.A.K., B.B.); University Hospital, Frankfurt, Germany (M.K., I.S.); and University Children's Hospital, Magdeburg, Germany (V.A., U.M.).
Address reprint requests to Dr. Furlan at the Central Hematology Laboratory, University Hospital, Inselspital, CH-3010 Bern, Switzerland.
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(2009). A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus. Rheumatology (Oxford)
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(2009). A chicken sandwich leading to intensive care. BMJ
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Garagiola, I., Valsecchi, C., Lavoretano, S., Oren, H., Bohm, M., Peyvandi, F.
(2008). Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion. haematol
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Gao, W., Anderson, P. J., Sadler, J. E.
(2008). Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity. Blood
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Sadler, J. E.
(2008). Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood
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(2008). The difficult distinction between haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. NDT Plus
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Chauhan, A. K., Walsh, M. T., Zhu, G., Ginsburg, D., Wagner, D. D., Motto, D. G.
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van den Born, B.-J. H., van der Hoeven, N. V., Groot, E., Lenting, P. J., Meijers, J. C.M., Levi, M., van Montfrans, G. A.
(2008). Association Between Thrombotic Microangiopathy and Reduced ADAMTS13 Activity in Malignant Hypertension. Hypertension
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Spiel, A. O., Gilbert, J. C., Jilma, B.
(2008). Von Willebrand Factor in Cardiovascular Disease: Focus on Acute Coronary Syndromes. Circulation
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Lammle, B., Kremer Hovinga, J. A., George, J. N.
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Peyvandi, F., Lavoretano, S., Palla, R., Feys, H. B., Vanhoorelbeke, K., Battaglioli, T., Valsecchi, C., Canciani, M. T., Fabris, F., Zver, S., Reti, M., Mikovic, D., Karimi, M., Giuffrida, G., Laurenti, L., Mannucci, P. M.
(2008). ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. haematol
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Shim, K., Anderson, P. J., Tuley, E. A., Wiswall, E., Evan Sadler, J.
(2008). Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood
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Song, J., Lee, K. A, Park, T. S., Park, R., Choi, J. R.
(2008). Linear Relationship between ADAMTS13 Activity and Platelet Dynamics Even Before Severe Thrombocytopenia. Annals of Clinical & Laboratory Science
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(2007). Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol
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Bennett, C. L., Kim, B., Zakarija, A., Bandarenko, N., Pandey, D. K., Buffie, C. G., McKoy, J. M., Tevar, A. D., Cursio, J. F., Yarnold, P. R., Kwaan, H. C., De Masi, D., Sarode, R., Raife, T. J., Kiss, J. E., Raisch, D. W., Davidson, C., Sadler, J. E., Ortel, T. L., Zheng, X. L., Kato, S., Matsumoto, M., Uemura, M., Fujimura, Y.
(2007). Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura: A Report From the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol
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Desch, K. C., Motto, D. G.
(2007). Thrombotic Thrombocytopenic Purpura in Humans and Mice. Arterioscler. Thromb. Vasc. Bio.
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(2007). Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome: much progress and many remaining issues. haematol
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Swisher, K. K., Doan, J. T., Vesely, S. K., Kwaan, H. C., Kim, B., Lammle, B., Kremer Hovinga, J. A., George, J. N.
(2007). Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports. haematol
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Hunt, B.J., Tueger, S., Pattison, J., Cavenagh, J., D'Cruz, D.P.
(2007). Microangiopathic haemolytic anaemia secondary to lupus nephritis: an important differential diagnosis of thrombotic thrombocytopenic purpura. Lupus
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Austin, S., Cohen, H., Losseff, N.
(2007). Haematology and neurology. J. Neurol. Neurosurg. Psychiatry
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Ferrari, S., Scheiflinger, F., Rieger, M., Mudde, G., Wolf, M., Coppo, P., Girma, J.-P., Azoulay, E., Brun-Buisson, C., Fakhouri, F., Mira, J.-P., Oksenhendler, E., Poullin, P., Rondeau, E., Schleinitz, N., Schlemmer, B., Teboul, J.-L., Vanhille, P., Vernant, J.-P., Meyer, D., Veyradier, A., for the French and Clinical Biological Network on,
(2007). Prognostic value of anti-ADAMTS13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS13 activity. Blood
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(2007). Evaluation and Management of Patients With Thrombotic Thrombocytopenic Purpura. J Intensive Care Med
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Morishita, T., Matsumoto, M., Honoki, K., Yoshida, A., Takakura, Y., Fujimura, Y.
(2007). Successful Treatment of Primitive Neuroectodermal Tumor-associated Microangiopathy with Multiple Bone Metastases. Jpn J Clin Oncol
37: 66-69
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Cappellini, M. D.
(2007). Coagulation in the Pathophysiology of Hemolytic Anemias. ASH Education Book
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Mannucci, P. M., Peyvandi, F.
(2007). TTP and ADAMTS13: When Is Testing Appropriate?. ASH Education Book
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Francis, K. K., Kalyanam, N., Terrell, D. R., Vesely, S. K., George, J. N.
(2007). Disseminated Malignancy Misdiagnosed as Thrombotic Thrombocytopenic Purpura: A Report of 10 Patients and a Systematic Review of Published Cases. The Oncologist
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Gao, W., Anderson, P. J., Majerus, E. M., Tuley, E. A., Sadler, J. E.
(2006). Exosite interactions contribute to tension-induced cleavage of von Willebrand factor by the antithrombotic ADAMTS13 metalloprotease. Proc. Natl. Acad. Sci. USA
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Wu, J.-J., Fujikawa, K., McMullen, B. A., Chung, D. W.
(2006). Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Proc. Natl. Acad. Sci. USA
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Izzedine, H., Isnard-Bagnis, C., Launay-Vacher, V., Mercadal, L., Tostivint, I., Rixe, O., Brocheriou, I., Bourry, E., Karie, S., Saeb, S., Casimir, N., Billemont, B., Deray, G.
(2006). Gemcitabine-induced thrombotic microangiopathy: a systematic review. Nephrol Dial Transplant
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Hirata, S., Okamoto, H., Ohta, S., Kobashigawa, T., Uesato, M., Kawaguchi, Y., Tateishi, M., Hara, M., Kamatani, N., Tsai, H.-M.
(2006). Deficient activity of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura in the setting of adult-onset Still's disease. Rheumatology (Oxford)
45: 1046-1047
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Nishi, H., Hanafusa, N., Kondo, Y., Nangaku, M., Sugawara, Y., Makuuchi, M., Noiri, E., Fujita, T.
(2006). Clinical Outcome of Thrombotic Microangiopathy after Living-Donor Liver Transplantation Treated with Plasma Exchange Therapy. CJASN
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George, J. N.
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Shibagaki, Y., Matsumoto, M., Kokame, K., Ohba, S., Miyata, T., Fujimura, Y., Fujita, T.
(2006). Novel compound heterozygote mutations (H234Q/R1206X) of the ADAMTS13 gene in an adult patient with Upshaw-Schulman syndrome showing predominant episodes of repeated acute renal failure. Nephrol Dial Transplant
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Chauhan, A. K., Motto, D. G., Lamb, C. B., Bergmeier, W., Dockal, M., Plaimauer, B., Scheiflinger, F., Ginsburg, D., Wagner, D. D.
(2006). Systemic antithrombotic effects of ADAMTS13. JEM
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Ono, T., Mimuro, J., Madoiwa, S., Soejima, K., Kashiwakura, Y., Ishiwata, A., Takano, K., Ohmori, T., Sakata, Y.
(2006). Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood
107: 528-534
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Sadler, J. E.
(2006). Thrombotic Thrombocytopenic Purpura: A Moving Target. ASH Education Book
2006: 415-420
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Plaimauer, B., Fuhrmann, J., Mohr, G., Wernhart, W., Bruno, K., Ferrari, S., Konetschny, C., Antoine, G., Rieger, M., Scheiflinger, F.
(2006). Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood
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Nolasco, L. H., Turner, N. A., Bernardo, A., Tao, Z., Cleary, T. G., Dong, J.-f., Moake, J. L.
(2005). Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood
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Zhou, W., Dong, L., Ginsburg, D., Bouhassira, E. E., Tsai, H.-M.
(2005). Enzymatically Active ADAMTS13 Variants Are Not Inhibited by Anti-ADAMTS13 Autoantibodies: A NOVEL THERAPEUTIC STRATEGY?. J. Biol. Chem.
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Rock, G., Anderson, D., Benny, B., Clark, W., Leblond, P., Sutton, D., Sternbach, M., Wells, G., Members of the Canadian Apheresis Group, , Canadian Association of Apheresis Nurses,
(2005). Treatment of Thrombotic Thrombocytopenic Purpura Using Solvent Detergent Treated Plasma.. ASH ANNUAL MEETING ABSTRACTS
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Rieger, M., Mannucci, P. M., Hovinga, J. A. K., Herzog, A., Gerstenbauer, G., Konetschny, C., Zimmermann, K., Scharrer, I., Peyvandi, F., Galbusera, M., Remuzzi, G., Bohm, M., Plaimauer, B., Lammle, B., Scheiflinger, F.
(2005). ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood
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Uemura, M., Tatsumi, K., Matsumoto, M., Fujimoto, M., Matsuyama, T., Ishikawa, M., Iwamoto, T.-a., Mori, T., Wanaka, A., Fukui, H., Fujimura, Y.
(2005). Localization of ADAMTS13 to the stellate cells of human liver. Blood
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Galbusera, M., Bresin, E., Noris, M., Gastoldi, S., Belotti, D., Capoferri, C., Daina, E., Perseghin, P., Scheiflinger, F., Fakhouri, F., Grunfeld, J.-P., Pogliani, E., Remuzzi, G.
(2005). Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report. Blood
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Levy, G. G., Motto, D. G., Ginsburg, D.
(2005). ADAMTS13 turns 3. Blood
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De Cristofaro, R., Peyvandi, F., Palla, R., Lavoretano, S., Lombardi, R., Merati, G., Romitelli, F., Di Stasio, E., Mannucci, P. M.
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Noris, M., Bucchioni, S., Galbusera, M., Donadelli, R., Bresin, E., Castelletti, F., Caprioli, J., Brioschi, S., Scheiflinger, F., Remuzzi, G., for the International Registry of Recurrent and Fa,
(2005). Complement Factor H Mutation in Familial Thrombotic Thrombocytopenic Purpura with ADAMTS13 Deficiency and Renal Involvement. J. Am. Soc. Nephrol.
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Motto, D.
(2005). Hemoglobin versus ADAMTS13. Blood
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Studt, J.-D., Hovinga, J. A. K., Antoine, G., Hermann, M., Rieger, M., Scheiflinger, F., Lammle, B.
(2005). Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood
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Uchida, T., Wada, H., Mizutani, M., Iwashita, M., Ishihara, H., Shibano, T., Suzuki, M., Matsubara, Y., Soejima, K., Matsumoto, M., Fujimura, Y., Ikeda, Y., Murata, M.
(2004). Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood
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Lee, J.-L., Lee, J.-H., Kim, M.-K., Cho, H. S., Bae, Y. K., Cho, K. H., Bae, S. H., Ryoo, H. M., Lee, K. H., Hyun, M. S.
(2004). A Case of Bone Marrow Necrosis with Thrombotic Thrombocytopenic Purpura as a Manifestation of Occult Colon Cancer. Jpn J Clin Oncol
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Nishio, K., Anderson, P. J., Zheng, X. L., Sadler, J. E.
(2004). Binding of platelet glycoprotein Ib{alpha} to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Proc. Natl. Acad. Sci. USA
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Wolf, G.
(2004). Not known from ADAM(TS-13)--novel insights into the pathophysiology of thrombotic microangiopathies. Nephrol Dial Transplant
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Klaus, C., Plaimauer, B., Studt, J.-D., Dorner, F., Lammle, B., Mannucci, P. M., Scheiflinger, F.
(2004). Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. Blood
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Espinosa, G, Bucciarelli, S, Cervera, R, Lozano, M, Reverter, J-C, de la Red, G, Gil, V, Ingelmo, M, Font, J, Asherson, R A
(2004). Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies. Ann Rheum Dis
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Zheng, X. L., Kaufman, R. M., Goodnough, L. T., Sadler, J. E.
(2004). Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood
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Studt, J.-D., Hovinga, J. A. K., Radonic, R., Gasparovic, V., Ivanovic, D., Merkler, M., Wirthmueller, U., Dahinden, C., Furlan, M., Lammle, B.
(2004). Familial acquired thrombotic thrombocytopenic purpura: ADAMTS13 inhibitory autoantibodies in identical twins. Blood
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Pimanda, J. E., Ganderton, T., Maekawa, A., Yap, C. L., Lawler, J., Kershaw, G., Chesterman, C. N., Hogg, P. J.
(2004). Role of Thrombospondin-1 in Control of von Willebrand Factor Multimer Size in Mice. J. Biol. Chem.
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Matsumoto, M., Kokame, K., Soejima, K., Miura, M., Hayashi, S., Fujii, Y., Iwai, A., Ito, E., Tsuji, Y., Takeda-Shitaka, M., Iwadate, M., Umeyama, H., Yagi, H., Ishizashi, H., Banno, F., Nakagaki, T., Miyata, T., Fujimura, Y.
(2004). Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood
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Bowen, D. J., Collins, P. W.
(2004). An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Blood
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Kokame, K., Matsumoto, M., Fujimura, Y., Miyata, T.
(2004). VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood
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Sadler, J. E., Moake, J. L., Miyata, T., George, J. N.
(2004). Recent Advances in Thrombotic Thrombocytopenic Purpura. ASH Education Book
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Soejima, K., Matsumoto, M., Kokame, K., Yagi, H., Ishizashi, H., Maeda, H., Nozaki, C., Miyata, T., Fujimura, Y., Nakagaki, T.
(2003). ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood
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Scheiflinger, F., Knobl, P., Trattner, B., Plaimauer, B., Mohr, G., Dockal, M., Dorner, F., Rieger, M.
(2003). Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood
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Levi, M., Keller, T. T, van Gorp, E., ten Cate, H.
(2003). Infection and inflammation and the coagulation system. Cardiovasc Res
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Varadi, K., Schreiner, J., Plaimauer, B., Rieger, M., Scheiflinger, F., Knobl, P., Turecek, P. L., Schwarz, H. P.
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Zheng, X., Nishio, K., Majerus, E. M., Sadler, J. E.
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Chang, J. C., Naqvi, T.
(2003). Thrombotic Thrombocytopenic Purpura Associated with Bone Marrow Metastasis and Secondary Myelofibrosis in Cancer. The Oncologist
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(2003). Discrepant activity levels of von Willebrand factor-cleaving protease (ADAMTS-13) in congenital thrombotic thrombocytopenic purpura. Blood
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Caramuru, L. H., Soares, R. D. P. S., Maeda, N. Y., Lopes, A. A.
(2003). Hypoxia and Altered Platelet Behavior Influence von Willebrand Factor Multimeric Composition in Secondary Pulmonary Hypertension. CLIN APPL THROMB HEMOST
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(2003). ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood
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Savasan, S., Lee, S.-K., Ginsburg, D., Tsai, H.-M.
(2003). ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood
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Tsai, H.-M.
(2003). Advances in the Pathogenesis, Diagnosis, and Treatment of Thrombotic Thrombocytopenic Purpura. J. Am. Soc. Nephrol.
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Elliott, M. A., Nichols, W. L. Jr, Plumhoff, E. A., Ansell, S. M., Dispenzieri, A., Gastineau, D. A., Gertz, M. A., Inwards, D. J., Lacy, M. Q., Micallef, I. N. M., Tefferi, A., Litzow, M. R.
(2003). Posttransplantation Thrombotic Thrombocytopenic Purpura: A Single-Center Experience and a Contemporary Review. Mayo Clin Proc.
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Tsai, H.-M.
(2003). Platelet Activation and the Formation of the Platelet Plug: Deficiency of ADAMTS13 Causes Thrombotic Thrombocytopenic Purpura. Arterioscler. Thromb. Vasc. Bio.
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Schneppenheim, R., Budde, U., Oyen, F., Angerhaus, D., Aumann, V., Drewke, E., Hassenpflug, W., Haberle, J., Kentouche, K., Kohne, E., Kurnik, K., Mueller-Wiefel, D., Obser, T., Santer, R., Sykora, K.-W.
(2003). von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood
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Zheng, X., Pallera, A. M., Goodnough, L. T., Sadler, J. E., Blinder, M. A.
(2003). Remission of Chronic Thrombotic Thrombocytopenic Purpura after Treatment with Cyclophosphamide and Rituximab. ANN INTERN MED
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George, J. N., Vesely, S. K.
(2003). Thrombotic Thrombocytopenic Purpura: From the Bench to the Bedside, but Not Yet to the Community. ANN INTERN MED
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Dong, J.-f., Moake, J. L., Nolasco, L., Bernardo, A., Arceneaux, W., Shrimpton, C. N., Schade, A. J., McIntire, L. V., Fujikawa, K., Lopez, J. A.
(2002). ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood
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Tsai, H.-M., Lammle, B., Bianchi, V., Alberio, L., Furlan, M., Remuzzi, G., Galbusera, M., Mannucci, P. M.
(2002). Deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura. Blood
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Plaimauer, B., Zimmermann, K., Volkel, D., Antoine, G., Kerschbaumer, R., Jenab, P., Furlan, M., Gerritsen, H., Lammle, B., Schwarz, H. P., Scheiflinger, F.
(2002). Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood
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DeLoughery, T. G.
(2002). Thrombocytopenia in Critical Care Patients. J Intensive Care Med
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