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PubMed2006

Successful management of pregnancy in women with a history of thrombotic thrombocytopaenic purpura.

Pregnancy is an initiating event for acute thrombotic thrombocytopaenic purpura (TTP). There is a high risk of relapse during pregnancy and of foetal morbidity. We describe five cases with successful maternal and foetal outcomes in patients with a history of TTP. Cases 1 and 2 presented with TTP in their first pregnancy and had second-trimester foetal losses. Case 3 had four TTP relapses and soon after achievement of clinical remission became pregnant. Case 4 presented with TTP and left-sided stroke in pregnancy. ADAMTS-13 activity was less than 5% at presentation in four patients and prior to therapy during pregnancy in cases 1-4. Case 5, who had a single acute episode of TTP and became pregnant 6 years later, had normal ADAMTS-13 activity throughout pregnancy. Only case 3 had evidence of an inhibitor on mixing studies. All five patients underwent close haematological and obstetric monitoring and continued low-dose aspirin throughout pregnancy. Patients 1-4 had regular plasma exchange and received low molecular weight heparin during pregnancy. Patient 4 also received rituximab during the third trimester with no observed maternal or neonatal toxicity. Live healthy infants were delivered in all five cases in the third trimester. These findings suggest that successful pregnancy outcome is achievable in patients with a history of TTP and that patients with severely reduced ADAMTS-13 activity at the onset of pregnancy, necessitates regular plasma exchange during pregnancy.

ADAM Proteins↗
PubMed2006

Identification of plasma antifibrin/fibrinogen antibodies in a patient with hemolytic uremic syndrome.

We investigated a patient with atypical hemolytic uremic syndrome without diarrhea to determine the presence of antibodies and the specificity of the related antigens. The patient experienced repeated episodes of hemolytic uremic syndrome. She is dialysis dependent. von Willebrand factor (vWF), vWF multimers, platelet aggregation, ADAMTS-13 activity and platelet immunoblots were determined. During acute episodes vWF increased threefold, with unusually large vWF multimers on two occasions. Platelet aggregation was normal but the plasma caused spontaneous aggregation of normal platelets. Reactivity was removed after absorption with protein A. Protein blotting against platelet and microvascular endothelial cells showed strong and persistent reactivity against antigens of 200 and 55 kDa. Two-dimensional immunoblots of the whole platelet proteome and incubation with plasma identified strong immunoreactivity with two target spots in the 55-kDa area. Mass spectroscopy confirmed the target as beta-fibrin, molecular weight 50.73 kDa, isoelectric point 7.95, with MASCOT scores of 859 and 750, Two years after presentation another band was detected at 66 kDa and identified as the alpha subunit of fibrin. This patient's plasma contained a platelet-aggregating factor that was removed by immunoglobulin absorption. She developed antibodies against the alpha and beta subunits of fibrin/fibrinogen.

ADAM Proteins↗
PubMed2005

Immunotherapy for thrombotic thrombocytopenic purpura.

PURPOSE OF REVIEW: This review focuses on recent advances in the use of immune-based therapy to treat patients with refractory and relapsing acquired thrombotic thrombocytopenic purpura. RECENT FINDINGS: Advances in understanding of the pathophysiology of idiopathic thrombotic thrombocytopenic purpura have provided the rationale for immune-based treatment approaches to refractory and relapsing cases of thrombotic thrombocytopenic purpura. The demonstration that a severe deficiency of von Willebrand factor-cleaving protease activity in acquired thrombotic thrombocytopenic purpura is due to an autoantibody inhibitor of the von Willebrand factor-cleaving protease argues for targeting the antibody inhibitor of the von Willebrand factor-cleaving protease with immunosuppressive therapy as a means of increasing protease activity and inducing a sustained remission of the disease. Recent publications, largely case reports and small series of patients, have suggested a role for rituximab and cyclosporine in cases refractory to plasma exchange or resistant to the tapering of plasma exchange therapy. SUMMARY: In the future, a better understanding of the relation between the von Willebrand factor-cleaving protease activity, the nature and titer of von Willebrand factor-cleaving protease inhibitors, and the risk of relapse of thrombotic thrombocytopenic purpura will be important to further validate the strategy of targeting the von Willebrand factor-cleaving protease inhibitory antibody as an effective means of treating acquired thrombotic thrombocytopenic purpura. Prospective data from carefully designed clinical trials are needed to define the effectiveness of specific immunosuppressive therapies at suppressing antibody inhibitors of von Willebrand factor-cleaving protease, improving von Willebrand factor-cleaving protease activity, and inducing a sustained remission of the disease.

ADAM Proteins↗
PubMed2006

Thrombotic microangiopathy with acquired deficiency in ADAMTS 13 activity in lung transplant recipients.

BACKGROUND: Thrombotic microangiopathy may develop after solid organ transplantation, but it is usually not associated with severe deficiency in von Willebrand factor-cleaving metalloprotease (ADAMTS 13) activity. METHODS: We present the cases of two lung transplant recipients who experienced a thrombotic microangiopathy associated with an acquired severe (<5%) deficiency in ADAMTS 13 activity. RESULTS: A major feature of both cases was the occurrence of a diffuse alveolar hemorrhage. CONCLUSION: Our two cases of lung transplant patients, with thrombotic microangiopathy related to an acquired ADAMTS 13 deficiency recipients, confirm that this mechanism may also be involved in the pathogenesis of thrombotic microangiopathy developing after solid organ transplantation. Therefore, we consider that ADAMTS 13 activity should be assessed on a systematic basis in this setting.

ADAM Proteins↗
PubMed2004

Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease.

ADAMTS-13, the metalloprotease that disposes physiologically of the most thrombogenic multimers of von Willebrand factor (VWF), tends to be low in plasma when VWF is high. We evaluated the behaviour of these two proteins in naturally occurring, experimental and clinical situations associated with VWF levels spanning from undetectable to supranormal. ADAMTS-13 was approximately 10% higher (and VWF 35% lower) in 65 healthy individuals of blood group O than in 65 individuals of groups A, B and AB. Thirty-three patients with type 3 von Willebrand disease (VWD) with undetectable plasma VWF had approximately 35% higher levels of ADAMTS-13 than a comparable group of healthy individuals with normal VWF. When VWF was raised to supranormal levels by desmopressin (DDAVP) in 10 healthy volunteers, ADAMTS-13 decreased by approximately 20%, with no change of the protease in three patients with severe VWD who had no post-DDAVP VWF rise. When VWF was raised from very low to normal levels by the infusion of VWF-containing plasma concentrates in four patients with type 3 VWD and one with type 1 VWD plasma, ADAMTS-13 decreased in parallel. These data show that throughout a large spectrum of plasma VWF levels there is a negative association between this protein and the activity of its major cleaving protease.

ADAM Proteins↗
PubMed2005

Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet.

A randomized prospective trial compared cryosupernatant plasma (CSP) to fresh frozen plasma (FFP) for treatment of thrombotic thrombocytopenic purpura (TTP). A total of 236 patients were required: 28 patients were treated with CSP and 24 with FFP within 30 months. There were no differences in survival at 1 month. By day 9, 17 of 26 patients with CSP and 18 of 24 with FFP had a platelet count >100 x 10(9)/l. At entry, von Willebrand factor (VWF) multimers were normal in all patients (range 1.1-3.95 IU/ml). ADAMTS-13 levels showed large variations ranging from 10% to 100% activity. At entry, no individual had <5% VWF cleaving protease. By day 9 (end of cycle), 89% (FFP) and 67% (CSP) had levels >50% of the controls. At 6 months some patients showed inhibitors to the enzyme in spite of adequate or normal platelet counts. The data from this study do not show an apparent advantage to the use of CSP in TTP. A large number of patients will be required to determine appropriate replacement therapy. We were not able to find a statistically significant relationship between the low level of protease activity at presentation of TTP and response.

ADAM Proteins↗
PubMed2005

The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine.

The therapeutic efficacy of plasma exchange (PE) in thrombotic thrombocytopenic purpura (TTP) is attributed to the restoration in ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity by substitution of the enzyme and removal of ADAMTS-13-neutralizing autoantibodies. We explored this rationale by analysing ADAMTS-13 activity and corresponding inhibitor levels during PE-treatment in 27 episodes from 23 adults with TTP. All patients with an initial episode of TTP (n = 14) and nine of 11 patients with a relapse showed severe ADAMTS-13 deficiency. ADAMTS-13 inhibitors were detected in 81% of these patients. Twenty-one patients responded to PE-therapy and two patients died. For patients with severe ADAMTS-13 deficiency, 15 patients (71%) showed a PE-induced recovery in ADAMTS-13 activity and six patients (29%) had persistent severe ADAMTS-13 deficiency despite clinical response. Three patients with recurrent TTP demonstrated a permanent increase in inhibitor titre during therapy. Six patients (43%) with an initial episode of TTP displayed a transient increase in inhibitor titre during PE-therapy, which was associated with deterioration in clinical and haematological symptoms of TTP. Treatment with vincristine induced an immediate increase in platelet count and ADAMTS-13 activity in seven of eight patients. We conclude that ADAMTS-13 activity and inhibitor levels, as measured using current methodology, do not solely determine the clinical course of TTP.

ADAM Proteins↗
PubMed2005

Haemolytic uraemic syndrome is an immune-mediated disease: role of anti-CD36 antibodies.

Haemolytic uraemic syndrome (HUS) is a disorder in which platelet microthrombi are formed that have a particular propensity to deposit in the kidney microvasculature, resulting in impaired renal function and thrombocytopenia. The mechanism of formation of these microthrombi is not known. In this study, we showed that plasma from five adult and six paediatric cases of HUS caused aggregation and release of adenosine triphosphate from normal platelets. The plasma reacted against platelet lysate in a protein blot and all samples showed reactivity against a band at 88 kDa, corresponding to the membrane antigen CD36. This was confirmed by probing with Mo91, a monoclonal antibody to CD36. CD36 was also identified in the immune complex formed by incubation of patient plasmas with normal platelet lysate. In other studies, bands of 32 and 7.7 kDa were obtained when purified verotoxin was protein blotted and probed with either patient plasma or with anti-CD36 antibody Mo91 suggesting structural homologies between CD36 and verotoxin. While a direct cause-effect relationship is not yet established, the data support the concept of an immunological pathogenesis for HUS and suggest that molecular mimicry involving one or both of the homologous domains in membrane-bound CD36 and verotoxin lead to the development of antibodies capable of inducing the pathophysiological events characteristic of HUS.

ADAM Proteins↗
PubMed2006

An evaluation of cyclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura.

We present the results of two consecutively performed cohort studies that evaluated the clinical effects of corticosteroids or cyclosporin as an adjunct to plasma exchange (PE) for the treatment of an acute episode of thrombotic thrombocytopenic purpura (TTP). In comparing 12 corticosteroid-treated patients with eight cyclosporin-treated patients, none of the cyclosporin-treated patients suffered an exacerbation or recurrence of TTP in the first 30 d after discontinuing PE compared with 6/10 (60%) of the corticosteroid-treated patients (P = 0.042). These data suggest that cyclosporin may have advantages over corticosteroids as an adjunct to PE therapy in the initial treatment of idiopathic TTP.

ADAM Proteins↗
PubMed2005

Combination vincristine and plasma exchange as initial therapy in patients with thrombotic thrombocytopenic purpura: one institution's experience and review of the literature.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) was once a highly fatal disease with mortality reaching nearly 95 percent; however, application of therapeutic plasma exchange (TPE) has dramatically increased survival. Nevertheless, mortality remains substantial (10%-30% in many published reports), requiring the search for more efficacious treatments. Vincristine (VCR) has been generally reserved for refractory TTP. Despite its effectiveness in a salvage mode, VCR has not been widely advocated as first-line therapy in conjunction with TPE. We previously reported improved survival when VCR and TPE were administered at presentation in patients treated from 1979 to 1994. Utilizing this standardized approach, outcomes of an additional group of patients and the results of a literature review of VCR therapy for TTP are reported. STUDY DESIGN AND METHODS: Medical records of all patients with a diagnosis of TTP treated between 1995 and 2002 at Cedars-Sinai Medical Center were reviewed. TPE was performed daily, exchanging 1.25 plasma volumes, until the platelet count normalized. Patients received VCR 1.4 mg/m2, (up to 2.0 mg total dose) after the first TPE. A literature review of all publications utilizing VCR in the management of TTP was performed with MEDLINE. RESULTS: Twelve consecutive patients meeting the diagnostic criteria received treatment with VCR and TPE. All patients achieved durable remission. Patients tolerated VCR without significant complications. CONCLUSION: Our 100 percent survival rate, as well as evidence garnered from the literature review, suggests that combination therapy with VCR and TPE at presentation might be more effective than TPE alone and therefore warrants consideration as first-line therapy for TTP patients.

ADAM Proteins↗
PubMed2004

ADAMTS-13 activity in plasma is rapidly measured by a new ELISA method that uses recombinant VWF-A2 domain as substrate.

The metalloprotease ADAMTS-13 cleaves von Willebrand factor (VWF) at the Y842/M843 peptide bond located in the A2 domain. Measurement of ADAMTS-13 activity is a clinical utility for thrombotic diseases, but the current assays used for diagnostic and clinical research are non-physiological and time consuming. We have expressed in bacteria a recombinant VWF-A2 peptide (aa 718-905) that contains both a 6xHis tag at the N-terminal end and a Tag-100 epitope at the C-terminal end. Diluted plasma was mixed with the VWF-A2 peptide and digestion was allowed to proceed in a Ni2+-coated microtiter well plate for 2 h. The immobilized Ni2+ captures the VWF-A2 peptide by its 6xHis tag and cleavage of the A2 peptide is measured by the removal of the C-terminus fragment of the A2 peptide that contains the Tag-100. The cleavage activity for this assay was defined by the low detection of A2 peptide containing the Tag-100 epitope by the antiTag-100 monoclonal antibody. The assay was completed in <5 h. We then used the assay to analyze ADAMTS-13 activity in plasma from 39 healthy donors and 16 samples from patients diagnosed as thrombotic thrombocytopenic purpura. The average of enzyme activity +/- SEM for normal plasmas diluted 1 : 50 was 40 +/- 4.2% while the value obtained for the patients was 2.4 +/- 0.7%. These results were validated by a traditional long incubation assay (24 h). Our assay provides significant advantages over currently used assays because it is quicker, reproducible, cost effective and measures ADAMTS-13 activity under physiological and non-denaturing conditions. This assay is clinically useful and significant in measuring ADAMTS-13 activity in plasma.

ADAM Proteins↗
PubMed2004

Variations among normal individuals in the cleavage of endothelial-derived ultra-large von Willebrand factor under flow.

von Willebrand factor (VWF) freshly released from endothelial cells is normally cleaved by the ADAMTS-13 metalloprotease to prevent the direct release of these ultra-large (UL) and hyper-reactive multimers into plasma. The balance of ULVWF proteolysis may be regulated by the amount of ULVWF released and the processing capacity of ADAMTS-13. The former associates with the size of ULVWF storage pool, sensitivity of vascular endothelial cells to stimulation, and the type of agonists, whereas the latter associates with the activity of ADAMTS-13. These parameters may vary significantly among individuals. We have determined the variations of ADAMTS-13 activity in 68 normal individuals by a flow-based assay and a static assay using ULVWF strings and recombinant VWF A2 domain as substrates, respectively. We found that the levels of ADAMTS-13 activity required to cleave the platelet-decorated ULVWF strings under flow is significantly higher than that of static assays. Normal plasma diluted to 25% significantly reduced its ability to cleave ULVWF strings under flow, whereas 2% plasma retained 48% enzyme activity in static assay. ADAMTS-13 activity varied from 33 to 100% among individuals and the variations were greater at shorter incubations of plasma with the substrate. Furthermore, the production of ULVWF from endothelial cells also varied among individuals. These results suggest that the commonly used static assays may underestimate the ADAMTS-13 activity required to cleave newly released ULVWF. They also demonstrated that the proteolysis of ULVWF may vary significantly among individuals, potentially contributing to the individual's vulnerability to thrombosis so that measurement of ADAMTS-13 may serve as a marker for TTP and other thrombotic diseases.

ADAM Proteins↗
PubMed2004

Measurement of von Willebrand factor cleaving protease (ADAMTS-13): results of an international collaborative study involving 11 methods testing the same set of coded plasmas.

BACKGROUND: ADAMTS-13 is a von Willebrand factor (VFW)-cleaving protease. Its congenital or acquired deficiency is associated with thrombotic thrombocytopenic purpura (TTP) and more rarely with the hemolytic uremic syndrome. We report on a survey evaluating 11 methods for ADAMTS-13 measurement performed in different labs. DESIGN: Two plasmas, one normal and one from a patient with familial TTP, were mixed at the co-ordinating center to prepare 6 plasmas with 0%, 10%, 20%, 40%, 80% and 100% ADAMTS-13 levels. Each plasma was aliquoted and assembled into sets of 60 (coded from 1 to 60), each containing 10 copies of the original 6 plasmas. Plasmas were frozen and shipped in dry ice to 10 labs with a common frozen reference plasma. Laboratories were asked to measure ADAMTS-13 with their methods. Results were sent to the coordinating center for statistical analysis. RESULTS: Of the 10 methods performed under static conditions 9 were quantitative and one was semiquantitative. One method performed under flow conditions evaluated the extent of cleavage of endothelial cell-derived ultralarge VWF string-like structures and expressed results as deficient, normal, or borderline. Linearity (expected-vs-observed levels), assessed as the squared correlation coefficient, ranged from 0.98 to 0.39. Reproducibility, expressed as the coefficient of variation for repeated measurements, ranged from < 10% to 83%. The majority of methods were able to discriminate between different ADAMTS-13 levels. The majority were able to detect the plasma with 0% level and some of them to discriminate between 0% and 10%. Overall the best performance was observed for three methods measuring cleaved VWF by ristocetin cofactor, collagen binding, and immunoblotting of degraded multimers of VWF substrate, respectively. The poor interlaboratory agreement of results was hardly affected by the use of the common standard. The method performed under flow conditions identified the plasmas with 0%, 10%, 20% and 40% activity as deficient in 7, 5, 1 and 3 of the 10 replicate measurements. The plasmas with 80% and 100% were identified as normal in all of the 10 replicate measurements. CONCLUSIONS: The survey shows varied performance, but supports an optimistic view about the reliability of current methods for ADAMTS-13.

ADAM Proteins↗