Increased fragmentation of von Willebrand factor, due to abnormal cleavage of the subunit, parallels disease activity in recurrent hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and discloses predisposition in families. The Italian Registry of Familial and Recurrent HUS/TTP.
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We investigated here the changes in von Willebrand factor (vWF) multimers in recurrent, sporadic and familial forms of hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP) to see whether they are actually proteolyzed in vivo in these patients. Molecular determinants of fragments in vWF were also characterized to identify possible sites of cleavage of the subunit. Unusually large vWF multimers were found in blood of 8 of 10 patients with recurrent HUS/TTP, both in the acute phase and in remission, but never in familial and sporadic cases. Instead, all of the groups showed evidence of enhanced fragmentation of vWF multimers during the acute phase. Increased fragmentation was also shown by decrease in native 225-kD vWF subunit. In recurrent and sporadic HUS/TTP, enhanced fragmentation normalized at remission, but the abnormality persisted in familial HUS/TTP patients. The latter findings suggest that patients with familial HUS/TTP may have a congenital abnormality in vWF processing. Analysis with specific monoclonal antibodies showed the presence of the normal vWF fragments with apparent molecular mass of 189, 176, and 140 kD in all patients; however, in 6 recurrent and in 5 familial cases, novel fragments that differed in size from normal ones were found. The size of these abnormal fragments differed from one patient to another and none of them was ever found in normal plasma. These results documented, for the first time in HUS/TTP, an abnormal cleavage of the vWF subunit that might account for the increased fragmentation observed in these patients. (+info)
Successful treatment of resistant thrombotic thrombocytopenic purpura/hemolytic uremic syndrome with autologous peripheral blood stem and progenitor (CD34+) cell transplantation.
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The first-line treatment of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS syndrome) induces a response and survival rate of approximately 85%, even if a considerable number of patients relapse; nevertheless, a number of these patients are resistant to conventional management. Immunoablation followed by stem cell transplantation has been shown to be capable of inducing remissions in a large spectrum of experimental autoimmune disorders. We report here the case of a 20-year-old male patient with the TTP-HUS syndrome who was resistant to conventional treatment and was transplanted with autologous immunoselected CD34+ PBPC after conditioning with cyclosphosphamide, anti-T lymphocyte globulin and prednisone. Seven months after transplant the patient is alive and well, without any further treatment being given. (+info)
Calpain activity in bone marrow transplant-associated thrombotic thrombocytopenic purpura.
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The pathophysiology of thrombotic thrombocytopenic purpura (TTP) is not well understood. Recent studies have described a platelet aggregating factor which has been characterized as a calcium-dependent cysteine protease (calpain) in patients with TTP. A type of TTP, sometimes called secondary TTP, has been associated with bone marrow transplantation (BMT). However, unlike primary adult TTP, BMT-TTP has important differences and often does not respond well to plasma exchange. We describe the measurement of calpain activity in a group of BMT patients (with and without the clinical syndrome of transplant-associated TTP). Calpain was measured using a functional assay (14C-serotonin platelet release with inhibition by the cysteine protease inhibitor, leupeptin) in the sera of patients following autologous (auto) or allogeneic (allo) BMT. We also independently diagnosed and graded the BMT-TTP on the day of blood sampling using a scale that related to the percentage schistocytes and lactic dehydrogenase level. Calpain activity was detected in 1/8 (13%) grade 0-1 (6 auto, 2 allo); 6/16 (38%) grade 2 (3 auto, 13 allo) 9/16 (56%) grade 3 (2 auto, 14 allo) and 8/8 (100%) grade 4 BMT-TTP. Pre-BMT samples were tested in 10 allo-BMT patients who had positive calpain results post-BMT. One patient gave positive results before the transplant. This patient developed grade 4 BMT-TTP (day 24 post-BMT) and died despite apheresis. Positive calpain results were highly associated with neurologic symptoms, P < 0.001. Nineteen of 24 (79%) patients with positive results had neurologic symptoms compared to three of 21 (14%) patients with negative results. In conclusion, calpain was detected in half of the BMT patients with mild to moderate BMT-TTP (grades 2-3) and was uniformly found in those with severe (grade 4) BMT-TTP. Typically the calpain activity develops as TTP complicates the transplant process. It is unknown whether calpain contributes to the pathogenesis of this disorder, or is a secondary event. (+info)
Thrombotic thrombocytopenic purpura associated with ticlopidine therapy.
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A patient who developed thrombotic microangiopathy while on ticlopidine therapy is reported. Thrombotic microangiopathy resolved with discontinuation of the drug and treatment with plasma exchange and has not recurred during 10 months of follow-up. The emerging data on the risk of developing thrombotic microangiopathy while on Ticlopidine and the possible mechanisms underlying this association are reviewed. The need for careful monitoring of the platelet count and hematocrit in addition to the white cell count during the first 3 months of therapy with this drug is emphasized. It is important that nephrologists, who are frequently called upon to diagnose thrombotic microangiopathy, be aware of its association with ticlopidine. Other drug-induced syndromes of thrombotic microangiography are also considered and compared, with respect to possible mechanisms of disease in each case. (+info)
Outbreak of Escherichia coli O157:H7 and Campylobacter among attendees of the Washington County Fair-New York, 1999.
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September 3, 1999, the New York State Department of Health (NYSDOH) received reports of at least 10 children hospitalized with bloody diarrhea or Escherichia coli O157:H7 infection in counties near Albany, New York. All of the children had attended the Washington County Fair, which was held August 23-29, 1999; approximately 108,000 persons attended the fair during that week. Subsequently, fair attendees infected with Campylobacter jejuni also were identified. An ongoing investigation includes heightened case-finding efforts, epidemiologic and laboratory studies, and an environmental investigation of the Washington County fairgrounds. This report presents the preliminary findings implicating contaminated well water. (+info)
Close relationship between systemic lupus erythematosus and thrombotic thrombocytopenic purpura in childhood.
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OBJECTIVE: To determine the association between childhood-onset thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE). METHODS: The charts of all 5 patients diagnosed with idiopathic TTP at the Hospital for Sick Children (HSC) in Toronto from 1975 to 1998, and all cases of childhood-onset TTP (ages 6-20 years) reported in the literature over the same period were reviewed. Fourteen of the 44 patients identified in the literature were excluded from the analysis for lack of clinical and laboratory information. The remaining 35 patients were grouped into either an SLE/TTP group or a TTP only group, according to the presence or absence of the American College of Rheumatology (ACR) classification criteria for SLE. The groups were compared for differences in clinical or laboratory features. RESULTS: The clinical presentation and initial disease course of pediatric patients with TTP were similar to those observed in adults. Of the 35 patients with childhood-onset TTP included in this review, 9 (26%) fulfilled > or = 4 ACR criteria for SLE and 8 (23%) were found to have incipient SLE. Of the 5 patients initially diagnosed with idiopathic TTP at the HSC, 3 were diagnosed with SLE within 3 years, and the other 2 patients fulfilled 3 ACR classification criteria for SLE within 4 years of disease onset. The clinical syndrome of pediatric TTP presenting with proteinuria, especially with high-grade proteinuria, was significantly associated with the development or coexistence of childhood-onset SLE. CONCLUSION: TTP in childhood is a rare, but life-threatening, disease. Unlike in adults, TTP in childhood is commonly associated with SLE. High-grade proteinuria at diagnosis of TTP is the best predictor for the presence or subsequent development of SLE. (+info)
Induction of microthrombotic thrombocytopenia in normal mice by transferring a platelet-reactive, monoclonal anti-gp70 autoantibody established from MRL/lpr mice: an autoimmune model of thrombotic thrombocytopenic purpura.
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MRL/MpJ-lpr/lpr (MRL/lpr) mice spontaneously develop immune complex-mediated glomerulonephritis and thrombocytopenia. Although the presence of cross-reactive anti-phospholipid antibodies in sera of MRL/lpr mice has been demonstrated, possible relationships between detected autoantibodies and the development of thrombocytopenia have not been elucidated. Recent genetic analyses in a few different strains of lupus-prone mice have pointed out a close correlation between autoantibodies reactive with endogenous retroviral env gene product, gp70, and the development and severity of glomerulonephritis. In the process of establishing possibly nephritogenic anti-gp70 autoantibody-producing hybridoma cells from MRL/lpr mice, we identified an IgG2a-producing anti-gp70 hybridoma clone that induced microvascular intraluminal platelet aggregation, thrombocytopenia, and amenia upon transplantation into syngeneic non-autoimmune mice. This and two other anti-gp70 antibodies bound onto the surface of mouse platelets, and purified IgG2a of the anti-gp70 autoantibody induced glomerular lesions with characteristics of thrombotic thrombocytopenic purpura when injected into non-autoimmune mice. The pathogenic anti-gp70 autoantibody specifically precipitated a platelet protein with an approximate relative molecular mass of 40 000. (+info)
Plasma exchange as successful treatment of thrombotic thrombocytopenic purpura post autologous bone marrow transplant in a child.
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We describe the case of a small child with stage IV neuroblastoma who developed thrombotic thromobocytopenic purpura (TTP) post autologous bone marrow transplant. Pneumococcal sepsis may have been the cause, a previously unreported association in transplant-associated TTP. Despite the child's size (10 kg) and the severity of the disease early intensive treatment with whole blood exchange and subsequently plasma exchange with cryosupernatant proved to be rapidly effective, in contrast to previous reports on its ineffectiveness in this setting. (+info)