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PubMed2006

Recurrent idiopathic thrombotic thrombocytopenic purpura: a role for vaccination in disease relapse?

The presence of antibodies against a disintegrin-like metalloproteinase with thrombospondin type 1 motif, isoform 13 (ADAMTS 13 protease) is the main cause (70% to 80%) of idiopathic and recurrent thrombotic thrombocytopenic purpura (TTP). However, etiologic factors that trigger the onset and potential relapses of TTP remain unclear. Immunologic deregulation and infectious agents are suspected. We report the case of a 51-year-old white man presenting with idiopathic TTP caused by autoantibodies against ADAMTS 13 protease. The first acute TTP episode needed long-term plasma exchanges because of early relapses. Consequently, vincristine therapy and splenectomy were performed. Those treatments induced TTP remission for 18 months. Relapses occurred twice between 1 and 3 months after vaccination. However, those relapses were not as severe as the first acute episode and responded to short-course plasma exchanges. ADAMTS 13 antibodies and decreased ADAMTS 13 protease activity were searched for and detected first during the second relapse. This case challenges the role of vaccination as an etiologic factor in the recurrence of idiopathic TTP.

ADAM Proteins↗
PubMed2004

The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS.

The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry enrolls all consecutive patients for whom plasma exchange treatment is requested for clinically diagnosed TTP-HUS within a defined geographic region. During 14.5 years, from January 1, 1989 until June 30, 2003, 301 patients have been enrolled; follow-up is complete on 300 patients. Clinical categories have been designated based on associated conditions and potential etiologies; presenting features and clinical outcomes have been defined to allow comparisons between groups. ADAMTS-13 activity was measured on 142 (88%) of 161 consecutive patients enrolled from 1995 to 2001. Only 13% of all patients, and 33% of patients with idiopathic TTP-HUS, had severe ADAMTS-13 deficiency (<5% activity). The presenting features and clinical outcomes of patients with severe ADAMTS-13 deficiency were heterogeneous and not distinct from patients without severe ADAMTS-13 deficiency. These data suggest that severe ADAMTS-13 deficiency does not detect all patients who may be appropriately diagnosed with TTP-HUS and who may respond to plasma exchange treatment. Prospective data from consecutive patients are essential to translate new observations on pathogenesis into improved patient care.

ADAM Proteins↗
PubMed2004

Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells.

When histamine-stimulated endothelial cells are perfused with platelets in buffer, the platelets form long beads-on-a-string structures on the surface of the cells. The strands connecting the platelets are composed of ultralarge multimers of von Willebrand factor (ULVWF) and can be rapidly cleaved when perfused with normal plasma or purified ADAMTS-13 metalloprotease, but not with plasma from patients with either congenital or acquired thrombotic thrombocytopenic purpura (TTP). These ULVWF strings anchor to the surface of the endothelial cell at least partly through P-selectin, as their formation is prevented by either soluble P-selectin or P-selectin antibodies. They are also able to support the attachment of beads coated with ADAMTS-13. The metalloprotease binds to both the A1 and A3 domains of VWF, the latter with higher affinity. This attachment docks the enzyme close to its substrate site within the A2 domain. We propose that attachment of newly released ULVWF to the endothelial cell surface facilitates its cleavage by ADAMTS-13 by allowing tensile force to be applied to the A2 domain, thereby exposing the ADAMTS-13 cleavage site.

ADAM Proteins↗
PubMed2004

Assays of ADAMTS-13 activity.

Various assays for determination of ADAMTS-13 activity in plasma have been developed, all comprising two steps. The first step consists of proteolyzing a substrate by ADAMTS-13. Substrates were either exogenous von Willebrand factor (VWF) (purified from human plasma concentrates or recombinant VWF [rVWF]), purified VWF fragments, or endogenous VWF (from the tested plasma sample). All assays required a step in which substrate unfolding is performed using either urea or guanidine. Test plasmas were used at various dilutions and ADAMTS-13 was activated in most cases by divalent cations. The second step consists of quantifying the digestion products or the residual VWF remaining after proteolysis. Cleavage of VWF was thus estimated using electrophoresis (generation of proteolytic fragments or decrease of the size of multimers), functional methods (decrease of the collagen binding activity or of ristocetin cofactor activity), or immunological methods (enzyme-linked immunosorbent assay [ELISA] or immunoradiometric assay (IRMA) using selected monoclonal antibodies to VWF). Since 1998, all of these assays have been used to demonstrate the relevance of a deficient ADAMTS-13 activity in thrombotic thrombocytopenic purpura (TTP). However, improvements are required, as these methods remain cumbersome, time-consuming, and too remote from physiology to be routinely helpful for rapid laboratory diagnosis.

ADAM Proteins↗
PubMed2004

Severe ADAMTS-13 deficiency in childhood.

Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathic disorder with high morbidity and significant mortality. The primary form of TTP is caused by severe deficiency, acquired or hereditary, of the von Willebrand factor cleaving protease (VWF-CP), ADAMTS-13. Because TTP occurs less frequently in children, general pediatricians are not well informed about the spectrum of clinical symptoms and altered laboratory values, increasing the risk of nondiagnosis and possible fatal outcome. If renal involvement is present, the condition can easily be misdiagnosed as hemolytic-uremic syndrome (HUS). We present a case series of children with severe VWF-CP deficiency with emphasis on the clinical heterogeneity responsible for misdiagnosis and inappropriate treatment. The inherited form may involve onset of symptoms ranging from isolated thrombocytopenia to the full clinical picture characteristic of classical TTP. The most common assumed diagnoses of oligosymptomatic forms are immune thrombocytopenia (ITP) and Evans syndrome, respectively. Accordingly, this article is directed towards pediatricians on neonatal and intensive care units, as well as their colleagues specializing in nephrology, hematology, and neurology.

ADAM Proteins↗
PubMed2004

von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience.

Severe deficiency of von Willebrand factor (VWF)-cleaving protease (ADAMTS-13) activity (<5% of normal) is a specific finding for acute idiopathic thrombotic thrombocytopenic purpura (TTP), a disorder that presents as thrombocytopenia, microangiopathic hemolytic anemia, and often organ dysfunction such as neurological disturbances or renal failure, and fever. Between January 2001 and July 2003, ADAMTS-13 activity was determined in plasma samples of 396 consecutive patients referred to our laboratory for diagnostic purposes. Plasma samples with ADAMTS-13 activity less than 5% were in addition tested for the presence of inhibitory antibodies. Patients were assigned to 10 predefined clinical categories according to information provided by the referring clinician: thrombotic microangiopathy (TMA) not further specified; neoplasia- or chemotherapy-associated TMA; TMA following hematopoietic stem cell transplantation; TMA with additional/alternative disorder; idiopathic TTP; hemolytic-uremic syndrome (HUS) not specified; HUS with diarrhea prodrome (D+HUS); atypical HUS; other hematological disorder; and no clinical information available. Severe ADAMTS-13 deficiency was found in 69 (17%) patients, including 42 with acquired idiopathic TTP, either at initial presentation or at relapse, 14 with confirmed or suspected hereditary TTP, 10 with TMA not further specified, two with neoplasia- or chemotherapy-associated TMA, and one in continued clinical remission 3.4 years after splenectomy for plasma-refractory TTP. Forty-three (62%) patients with ADAMTS-13 activity less than 5% displayed inhibitory antibodies. Severe ADAMTS-13 deficiency was found in 60% of patients diagnosed with acute idiopathic TTP, but in none of 130 patients diagnosed with HUS or in any of the 14 patients with hematopoietic stem cell transplantation-associated TMA. Thus, plasma ADAMTS-13 activity less than 5% does not identify all patients clinically diagnosed with TTP, and severe ADAMTS-13 deficiency is not invariably associated with clinical manifestations of microvascular platelet clumping.

ADAM Proteins↗
PubMed2004

The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

A total of 290 Japanese patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) were analyzed with respect to ADAMTS-13 activity and its inhibitor. Twenty-one patients (17 families) had Upshaw-Schulman syndrome, and 12 patients (six families) had familial HUS of undetermined etiology. The number of patients with acquired HUS and TTP was 44 and 213, respectively. In acquired TTP, patients with severe deficiency of ADAMTS-13 activity secondary to the presence of an inhibitor were high responders to plasma exchange, but others were low responders to plasma exchange. The former patients were associated with "idiopathic" TTP, drugs, and pregnancy, and the latter patients with malignancy and stem cell transplantation. Patients with autoimmune disease-associated TTP fit into both groups.

ADAM Proteins↗
PubMed2004

Plasma therapy in thrombotic thrombocytopenic purpura: review of the literature and the Bern experience in a subgroup of patients with severe acquired ADAMTS-13 deficiency.

Based on clinical studies daily plasma exchange (PE) has become the first-choice therapy for thrombotic thrombocytopenic purpura (TTP) since 1991. Recent findings may explain its effectiveness, which particularly may include supply of ADAMTS-13 and removal of anti-ADAMTS-13 autoantibodies and unusually large von Willebrand factor (VWF) multimers. The most preferable PE regimens as well as replacement fluids are discussed and treatment-related adverse reactions are summarized. Proposals for a potential reduction of their frequency and for improvement of treatment efficiency are given. These suggestions are partially based on the experience of our institution in adult patients with severe ADAMTS-13 deficiency (<5% activity), and include (1) continuous calcium-gluconate infusion during PE in order to reduce citrate-related adverse reactions; (2) the evaluation of solvent/detergent-treated (S/D) plasma as replacement fluid in order to reduce adverse events due to fresh frozen plasma (FFP); (3) the evaluation of immunoadsorption in order to increase procedural efficiency in autoantibody removal; and (4) the substitution of ADAMTS-13 by means of recombinant drug instead of plasma.

ADAM Proteins↗
PubMed2002

Assays of von Willebrand factor-cleaving protease: a test for diagnosis of familial and acquired thrombotic thrombocytopenic purpura.

Endothelial cells secrete von Willebrand factor (vWF) multimers that are larger than those found in the circulating plasma. These very large multimeric forms of vWF, capable of spontaneously binding to and agglutinating the blood platelets under conditions of high fluid shear rate, are degraded by a specific metalloprotease cleaving the peptide bond 842Tyr-843Met of the vWF subunit. The vWF-cleaving protease was found to be deficient in patients with familial thrombotic thrombocytopenic purpura (TTP). The acute events in these patients can be successfully treated and prophylactically prevented by repletion of the missing protease using fresh frozen plasma (FFP). In another, apparently more common, form of TTP, the protease deficiency is due to inhibiting circulating antibodies directed against the vWF-cleaving protease. Therapy of these patients should include immunosuppressive treatment in addition to plasma exchange and replacement with FFP. Normal activity of vWF-cleaving protease was established in patients with a clinically similar disorder: hemolytic-uremic syndrome (HUS). The level of vWF-cleaving protease activity is thus a laboratory parameter that provides important information for the differential diagnosis and treatment of patients with TTP/HUS. Several assays of vWF-cleaving protease have been described and are summarized here.

ADAM Proteins↗
PubMed2002

[Thrombotic thrombocytopenic purpura - a rare cause of thrombocytopenia in systemic lupus erythematosus].

HISTORY AND ADMISSION FINDINGS: An 18-year old woman with a systemic lupus erythematosus was referred to our hospital with anaemia, thrombocytopenia and neurological symptoms. Skin haemorrhages had occurred some weeks before. The patient also noticed cardiac palpitations. After the primary care doctor had increased the dosage of prednisolone from 7.5 mg per day to 20 mg per day the symptoms didn't substantially change and that the patient was referred to hospital. An acute lupus flare was assumed. INVESTIGATIONS: Laboratory examinations showed a Coombs-negative haemolytic anaemia with schistocytes. Von Willebrand factor(vWF)-cleaving protease was decreased. The presence of an inhibitor of the enzyme was proved. Further test results as anti-ds-DNA, anti-Sm, C 3, ESR, CRP were normal. C 4 was slightly decreased. Cerebral MRI, cerebral SPECT and Duplex sonography of the extracranial arteries didn't show any pathologic findings. The performed MRI of the heart revealed signs of myocardial damage. DIAGNOSIS, TREATMENT AND COURSE: As cause of the recent symptoms a thrombotic-thrombocytopenic purpura (TTP) was diagnosed. This obviously was due to an auto-antibody against the vWF-cleaving protease. After intensive immunosuppressive therapy with prednisolone and cyclosporin the clinical and laboratory findings normalised. An acute therapy with fresh frozen plasma and plasmapheresis was not necessary, as the symptoms were moderate. Because of the transient cerebral deficits for a short time we administered a low dose of aspirin. The MRI signs of myocardial affection didn't change after 3 months of immunosuppressive treatment so that we started an ACE inhibitor treatment. CONCLUSION: Thrombocytopenia in systemic lupus erythematosus demands an individual differential diagnosis. Rare causes as TTP have to be excluded. This disorder has to be diagnosed quickly and the adequate therapy has to be started early.

ADAM Proteins↗
PubMed2005

The changing paradigm of thrombotic thrombocytopenic purpura.

New discoveries have changed a 20-year-old concept about the mechanism of microvascular thrombosis in thrombotic thrombocytopenic purpura (TTP). The classic model of TTP pathogenesis in which ultra large von Willebrand factor (ULvWF) is proposed to mediate spontaneous platelet aggregation in high sheer stress has evolved into a model in which vWF-platelet aggregates form on stimulated endothelial cell surfaces. The classic model of TTP pathogenesis was based on the proposed pathogenicity of plasma ULvWF in TTP microvascular thrombosis. The current model suggests that platelet binding to endothelial-bound vWF and cleavage of endothelial-bound vWF-platelet aggregates may be most critical in TTP pathogenesis and treatment. A clearer understanding of the mechanism of microvascular thrombosis in TTP will allow better targeted treatment.

ADAM Proteins↗
PubMed1998

von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.

BACKGROUND: Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. METHODS: Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients. RESULTS: We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic-uremic syndrome, 11 had normal levels of activity of von Willebrand factor-cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. CONCLUSIONS: Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolyticuremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.

ADAM Proteins↗
PubMed1998

Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura is a potentially fatal disease characterized by widespread platelet thrombi in the microcirculation. In the normal circulation, von Willebrand factor is cleaved by a plasma protease. We explored the hypothesis that a deficiency of this protease predisposes patients with thrombotic thrombocytopenic purpura to platelet thrombosis. METHODS: We studied the activity of von Willebrand factor-cleaving protease and sought inhibitors of this protease in plasma from patients with acute thrombotic thrombocytopenic purpura, patients with other diseases, and normal control subjects. We also investigated the effect of shear stress on the ristocetin cofactor activity of purified von Willebrand factor in the cryosupernatant fraction of the plasma samples. RESULTS: Thirty-nine samples of plasma from 37 patients with acute thrombotic thrombocytopenic purpura had severe deficiency of von Willebrand factor-cleaving protease. No deficiency was detected in 16 samples of plasma from patients with thrombotic thrombocytopenic purpura in remission or in 74 plasma samples from normal subjects, randomly selected hospitalized patients or outpatients, or patients with hemolysis, thrombocytopenia, or thrombosis from other causes. Inhibitory activity against the protease was detected in 26 of the 39 plasma samples (67 percent) obtained during the acute phase of the disease. The inhibitors were IgG antibodies. Shear stress increased the ristocetin cofactor activity of von Willebrand factor in the cryosupernatant of plasma samples obtained during the acute phase, but decreased the activity in cryosupernatant of plasma from normal subjects. CONCLUSIONS: Inhibitory antibodies against von Willebrand factor-cleaving protease occur in patients with acute thrombotic thrombocytopenic purpura. A deficiency of this protease is likely to have a critical role in the pathogenesis of platelet thrombosis in this disease.

ADAM Proteins↗