Morey A. Blinder
Washington University in St. Louis
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Journal of Clinical Oncology | 1989
Joanne Mortimer; Morey A. Blinder; Susan Schulman; Appelbaum Fr; Buckner Cd; Clift Ra; Jean E. Sanders; Storb R; Thomas Ed
Of 455 acute nonlymphocytic leukemia (ANL) patients who underwent marrow transplantation, 95 (21%) relapsed a median of 6.5 months posttransplantation and 62 received further treatment. Twenty achieved remission. Success of therapy was related to the length of time from marrow transplant to relapse and to the use of cytarabine (Ara-C) and daunomycin. Aggressive chemotherapy for patients relapsing within 100 days of marrow transplant was associated with a high incidence of early death (six of 14 patients) and a low probability of remission (one of 14). Of 23 patients who relapsed in excess of 1 year from marrow transplant, 15 achieved a complete remission. The median disease-free survival is 6 months (range, 0.4 to 53+ months). Acute lymphocytic leukemia (ALL) recurred in 130 of 366 patients (36%), and 94 received further therapy. Fifty-two achieved a remission. Remissions were more common in late relapse patients (greater than 1 year from transplantation): 65% v 7% for those relapsing within 100 days from transplant (P less than .05). Testicular relapse occurred in 11 patients and was the sole site of relapse in seven. Three are alive and free of disease 58 to 109+ months after relapse. The median survival for the treated patients is 10.5 months (range, 5 to 109+ months). We propose that reinduction be attempted in all patients relapsing greater than 1 year from marrow transplantation. Ara-C and daunomycin should be employed in the treatment of ANL. The decision for treatment of patients relapsing earlier than 1 year should be made on an individual basis.
Annals of Internal Medicine | 2003
Xinglong Zheng; Arnel M. Pallera; Lawrence T. Goodnough; J. Evan Sadler; Morey A. Blinder
Context Many adults with thrombotic thrombocytopenic purpura (TTP) have autoantibodies that promote clotting by inhibiting a von Willebrand factorcleaving protease (ADAMTS13) in plasma. Contribution This 42-year-old woman had chronic relapsing TTP despite plasma exchange; splenectomy; and treatment with vincristine, prednisone, and cyclosporine. She had low to absent ADAMTS13 activity and an IgG inhibitor. After immunosuppressive therapy with rituximab and cyclophosphamide, the TTP remitted, ADAMTS13 levels normalized, and the inhibitor was undetectable. Cautions Intensive immunosuppressive therapy aimed at the autoimmune aspect of TTP should be tested in prospective trials before being used widely. The Editors Most adults with idiopathic thrombotic thrombocytopenic purpura (TTP) have autoantibodies that inhibit a von Willebrand factorcleaving protease in plasma (1-3). This protease recently was cloned and identified as a new member of the ADAMTS metalloproteases, ADAMTS13 (4-8). Plasma exchange therapy has increased survival in patients with TTP from less than 10% to approximately 75% (9). However, plasma exchange does not directly address the underlying autoimmune process, and up to one third of patients have relapse after initially successful treatment (10). Anecdotal data suggest that immunosuppressive therapy can sometimes be beneficial, but this approach has not been tested systematically in patients known to have ADAMTS13 deficiency. We report the case of a woman with chronic relapsing TTP who had undetectable ADAMTS13 activity and elevated ADAMTS13 inhibitor titers. Treatment with rituximab and cyclophosphamide resulted in prompt disappearance of ADAMTS13 antibodies, normalization of ADAMTS13 activity, and remission of thrombotic microangiopathy. Case Report A 42-year-old woman was hospitalized in May 1999 with gait disturbance, disorientation, and lethargy. She had been healthy, with three uncomplicated pregnancies and deliveries and no previous symptoms of autoimmune disease. Computed tomography showed many cerebral infarcts. The platelet count was 60 109 cells/L, the hemoglobin level was 96 g/L, and the fibrinogen level was normal. The serum lactate dehydrogenase level was 1157 U/L. The patient received intravenous immunoglobulin but did not respond. She was transferred to our institution in June 1999 (Figure, day 1). Figure. Platelet count ( top ) and ADAMTS13 activity ( bottom ) in a patient with thrombotic thrombocytopenic purpura during 2.5 years of observation. On admission, hematocrit was 0.231, platelet count was 24 109 cells/L, haptoglobin level was 0.09 g/L (normal range, 0.27 to 2.2 g/L), and serum creatinine concentration was 141 mol/L (1.6 mg/dL) (normal range, 50 to 125 mol/L [0.6 to 1.4 mg/dL]). Prothrombin time and partial thromboplastin time were normal. Results of direct and indirect antiglobulin tests were negative. The peripheral smear contained more than 10 schistocytes per high-power field. Thrombotic thrombocytopenic purpura was diagnosed, and plasma exchange (1.5 volumes daily) was begun (Figure, top). The platelet count normalized but decreased to 34 109 cells/L by day 22. Prednisone (1 mg/kg of body weight per day) and aspirin (325 mg/d) were added without sustained benefit. The platelet count improved transiently after laparoscopic splenectomy on day 36 but decreased to less than 100 109 cells/L by day 43. Two intravenous doses of vincristine, 2 mg each, resulted in gradual improvement. Frequency of plasma exchanges was decreased to every other day, and the patient was discharged on day 85 with a normal platelet count. Plasmapheresis was discontinued on day 97. On day 105, the platelet count was 43 109 cells/L. Plasma exchange was resumed, and cyclosporine, 75 mg twice per day, was started. The platelet count increased, and plasma exchange was tapered over 3 weeks. During the next 4 months, blood counts were relatively stable. The daily prednisone dose was decreased to 40 mg. On day 248, the patient was admitted with cortical blindness and a platelet count of 58 109 cells/L. Plasma exchange was followed by an increase in platelet count but no improvement in vision. The patient was discharged after 12 days, and plasma exchange was tapered over 2 weeks. During the next 11 months, the patient was hospitalized four times for relapsed TTP and each time was treated with plasma exchange. The prednisone dose was tapered to 5 mg/d. On day 572, the patient was hospitalized with deafness and thrombocytopenia. The platelet count increased rapidly with plasma exchange. The serum creatinine concentration increased to 221 mol/L (2.5 mg/dL), and cyclosporine therapy was discontinued. The patient received two doses of intravenous rituximab (375 mg/m2 weekly). The creatinine concentration decreased to 159 mol/L (1.8 mg/dL), the platelet count remained above 100 109 cells/L, and symptoms were stable for 5 months. On day 740, the platelet count was 69 109 cells/L. The patient received daily plasma exchange for 16 days, responded well, and was discharged. She was admitted twice during the next 4 months to receive plasma exchange for relapsing TTP. Beginning on day 849, the patient received one dose of intravenous cyclophosphamide, 1 g/m2, and four doses of intravenous rituximab, 375 mg/m2, every 7 to 14 days. No side effects of rituximab were noted. During 10 months of follow-up, the patient has had a normal platelet count, stable hematocrit, normal lactate dehydrogenase level and creatinine concentration, and rare schistocytes. No other signs or symptoms of TTP have been noted. Her neurologic defects (blindness and deafness) persist unchanged. Methods Informed consent was obtained from the patient and her family. ADAMTS13 was assayed as described elsewhere (11); however, the substrate was 10 g of von Willebrand factor per mL in 5 mmol of TrisHCl per L (pH, 8.0), 1.5 mol of urea per L, and 1 mmol of phenylmethanesulfonyl fluoride per L (Sigma, St. Louis, Missouri). Plasma samples were heat-treated at 56 C for 30 minutes and were serially diluted in phosphate-buffered saline. Diluted plasma (5 L) was added to normal human plasma (5 L) and incubated at 37 C for 30 minutes. Residual ADAMTS13 activity was measured as described earlier. One unit of inhibitor reduces the ADAMTS13 activity of an equal volume of normal plasma by 50%. Recombinant ADAMTS13 (7) truncated after the metalloprotease (residues 1 to 289) was cloned in pcDNA3.1/V5-His TOPO (Invitrogen, Carlsbad, California), expressed in transiently transfected Chinese hamster ovary cells (CHO-S), and purified from conditioned medium on TALON metal affinity resin (BD Biosciences Clontech, Palo Alto, California). ADAMTS13 was immunoprecipitated with IgG adsorbed from plasma samples onto protein A agarose. Proteins were analyzed by using sodium dodecyl sulfatepolyacrylamide gel electrophoresis and Western blot with monoclonal anti-V5 antibody (Invitrogen). Results Early in her disease, the patient had complete deficiency of plasma ADAMTS13 activity and an inhibitor was detected (Figure, bottom). Plasma therapy over the next 19 months resulted in several short periods of remission, even though ADAMTS13 inhibitor titers decreased minimally and plasma ADAMTS13 activity remained low. The inhibitory activity was recovered in IgG purified from the patients plasma and immunoprecipitated the metalloprotease domain of recombinant ADAMTS13 (data not shown). For continuing autoimmune TTP, immunosuppressive therapy with rituximab was initiated. Rituximab is usually given at a dose of 375 mg/m2, repeated weekly for four doses (12, 13). The patient received an abbreviated course of two doses, which was followed by prompt disappearance of ADAMTS13 inhibitor, normalization of ADAMTS13 activity, and a normal platelet count. The patient had the first of three additional clinical relapses 5 months after receiving rituximab. Before the second course of rituximab plus cyclophosphamide, ADAMTS13 activity was 33% of normal and no ADAMTS13 inhibitor was detected. These values were obtained after 9 days of daily plasmapheresis, which may have partially corrected the ADAMTS13 deficiency. Subsequently, symptoms of TTP resolved, platelet count and plasma ADAMTS13 activity increased, and the ADAMTS13 inhibitor remained undetectable. The most recent ADAMTS13 level was 17%, with no inhibitor detected. Discussion Although idiopathic TTP is usually an autoimmune disease (1-3), standard therapy does not address this underlying mechanism. Plasma exchange may increase patient survival because it removes deleterious antibodies and replenishes ADAMTS13 protein. Most patients have self-limited disease that remits after 1 to several weeks of plasma exchange. However, approximately one third of patients have a chronic relapsing course (10). Thus, TTP often behaves as an aggressive autoimmune disease, and some patients might benefit from additional therapy directed at B cells and antibody production. Many immunosuppressive regimens have been tried in TTP, with encouraging but inconclusive results. Corticosteroids are often administered at the time of plasma exchange (14), but their efficacy has not been systematically evaluated (9, 10). Case reports and small series have described sustained responses to splenectomy (15), and responses to cyclosporine (16), vincristine, cyclophosphamide, and azathioprine (17, 18) have also been described. This anecdotal experience provides a rationale for testing additional immunosuppressive strategies in patients with relapsing or refractory TTP. Rituximab is a chimeric anti-CD20 monoclonal antibody developed for treatment of non-Hodgkin lymphoma; CD20 is expressed on B cells. Rituximab has emerged as a promising treatment for autoimmune disorders, including autoimmune hemolytic anemia (12) and idiopathic thrombocytopenic purpura (13). Common side effects observed during the treatment of lymphoma include transient hypotension and fever during the first
Biochimica et Biophysica Acta | 1983
Richard Lottenberg; Julie A. Hall; Morey A. Blinder; Ellen P. Binder; Craig M. Jackson
Kinetic parameters for the action of bovine alpha-thrombin on 24 commercially available peptide p-nitroanilides have been determined. The selectivity constant, kcat/Km, ranges from 3.3 X 10(1) to 1.1 X 10(8) M-1 X S-1 for the poorest and the best substrates, respectively. The best substrates for thrombin were identified as those with arginine in the P1 position, proline or a proline homolog in the P2 position, and an apolar amino acid in the P3 position. Quantitative distinction between lysine and arginine in the P1 position and other amino acids in the P2-P4 positions of the substrate is reported from the changes in the kinetic parameters for substrates differing in only a single amino acid in these positions. Effects of NaCl, CaCl2 and poly(ethylene glycol) concentrations, pH and temperature on the action of thrombin on selected substrates have been assessed. A source of large systematic error in thrombin concentration estimates was identified as resulting from adsorption losses. These losses were eliminated by inclusion of poly(ethylene glycol) in dilution and reaction buffers.
American Journal of Hematology | 2009
Huichung T. Ling; Joshua J. Field; Morey A. Blinder
Idiopathic thrombotic thrombocytopenic purpura (TTP) is a life‐threatening disease mediated by autoantibodies directed against ADAMTS‐13. A number of small series and case reports have shown promising results with rituximab in refractory or relapsed TTP. In this report, we present 13 patients with TTP treated with rituximab. Twelve of the 13 patients (92%) achieved complete response; no subsequent relapses occurred with median follow‐up of 24 months (range, 13–84 months). The addition of rituximab to standard therapy appears to be effective in sustaining long‐term remission in TTP. However, the optimal dosing and timing of rituximab warrant further investigation. Am. J. Hematol., 2009.
The New England Journal of Medicine | 2017
Suresh Vedantham; Samuel Z. Goldhaber; Jim A. Julian; Susan R. Kahn; Michael R. Jaff; David J. Cohen; Elizabeth A. Magnuson; Mahmood K. Razavi; Anthony J. Comerota; Heather L. Gornik; Timothy P. Murphy; Lawrence M. Lewis; James R. Duncan; Patricia Nieters; Mary Clare Derfler; Marc Filion; Chu Shu Gu; Stephen T. Kee; Joseph R. Schneider; Nael Saad; Morey A. Blinder; Stephan Moll; David B. Sacks; Judith C. Lin; John H. Rundback; Mark J. Garcia; Rahul Razdan; Eric VanderWoude; Vasco Marques; Clive Kearon
Background The post‐thrombotic syndrome frequently develops in patients with proximal deep‐vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter‐directed thrombolysis (hereafter “pharmacomechanical thrombolysis”) rapidly removes thrombus and is hypothesized to reduce the risk of the post‐thrombotic syndrome. Methods We randomly assigned 692 patients with acute proximal deep‐vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter‐mediated or device‐mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post‐thrombotic syndrome between 6 and 24 months of follow‐up. Results Between 6 and 24 months, there was no significant between‐group difference in the percentage of patients with the post‐thrombotic syndrome (47% in the pharmacomechanical‐thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24‐month follow‐up period (12% in the pharmacomechanical‐thrombolysis group and 8% in the control group, P=0.09). Moderate‐to‐severe post‐thrombotic syndrome occurred in 18% of patients in the pharmacomechanical‐thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post‐thrombotic syndrome were lower in the pharmacomechanical‐thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow‐up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups. Conclusions Among patients with acute proximal deep‐vein thrombosis, the addition of pharmacomechanical catheter‐directed thrombolysis to anticoagulation did not result in a lower risk of the post‐thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT ClinicalTrials.gov number, NCT00790335.)
British Journal of Haematology | 1997
Niall S. Colwell; Douglas M. Tollefsen; Morey A. Blinder
We investigated a patient with a long‐standing IgGκ monoclonal gammopathy who developed severe haemorrhagic complications. At IgG concentrations of ∼50 g/l the patient had severe bleeding associated with prolongation of the thrombin time, activated partial thromboplastin time, and reptilase time. Plasmapheresis resulted in improvement in the thrombin time and resolution of bleeding. Depletion of the IgG by absorption of plasma with protein G–Sepharose in vitro resulted in normalization of the thrombin time and reptilase time. The purified IgG bound to immobilized thrombin and immunoprecipitated human α‐, β‐ and γ‐thrombin but not prothrombin, other vitamin K‐dependent coagulation factors, or fibrinogen. Purified IgG at concentrations >1×10−2 g/l decreased (∼50%) the rate of hydrolysis of a chromogenic substrate by thrombin. Addition of purified IgG to normal pooled plasma at concentrations >1×10−2 g/l prolonged the thrombin time and activated partial thromboplastin time, but the reptilase time was prolonged only at IgG concentrations >1 g/l. This finding suggests that at low concentrations the IgG produces a specific antithrombin effect, but at higher concentrations it also affects fibrin polymerization; the combination of these effects probably produced clinical bleeding. This is the first report of a monoclonal antithrombin antibody associated with bleeding in a patient with multiple myeloma.
Haemophilia | 2007
Joshua J. Field; Timothy S. Fenske; Morey A. Blinder
Summary. Acquired factor VIII (FVIII) inhibitors are a rare cause of coagulopathy which are associated with a high mortality rate. Treatment of bleeding episodes is often difficult and may vary with the degree of titre elevation. Individuals with very high‐titre antibodies [>100 Bethesda units mL−1 (BU)] may have difficulty achieving a complete sustained remission and, consequently, various treatments including immunosuppression, cytotoxic chemotherapy and plasmapheresis have been reported. Rituximab is an anti‐CD20 monoclonal antibody which has demonstrated efficacy in the treatment of individuals with acquired FVIII inhibitors, however there is limited data in the subgroup of patients with inhibitor titres >100 BU. In this study, we present four patients with acquired FVIII inhibitor titres >100 BU who were resistant to initial therapy with cyclophosphamide, vincristine and prednisone. The patients’ inhibitor titres ranged from 249 BU mL−1 to 725 BU mL−1 and all received 4 weekly infusions of rituximab at 375 mg m−2. Each patient partially responded to rituximab therapy with an improvement in inhibitor titres and FVIII activity, however, three of the four patients relapsed thereafter. The individual who did not relapse achieved a partial response for 13 months and then died of causes unrelated to her coagulopathy. We conclude that in patients with acquired FVIII inhibitors and titres >100 BU, treatment with rituximab alone is effective but not sufficient to achieve a sustained response. Rituximab in combination with other therapies may provide a better result in this high‐risk population.
American Journal of Hematology | 2011
Robyn T. Cohen; Anusha R. Madadi; Morey A. Blinder; Michael R. DeBaun; Robert C. Strunk; Joshua J. Field
Prior studies of asthma in children with sickle cell disease (SCD) were based on reports of a doctor‐diagnosis of asthma with limited description of asthma features. Doctor‐diagnoses of asthma may represent asthma or wheezing unrelated to asthma. Objectives of this study were to determine if asthma characteristics are present in adults with a doctor‐diagnosis of asthma and/or wheezing, and to examine the relationship between doctor‐diagnosis of asthma, wheezing and SCD morbidity. This was an observational cohort study of 114 adults with SCD who completed respiratory symptom questionnaires and had serum IgE measurements. A subset of 79 participants completed pulmonary function testing. Survival analysis was based on a mean prospective follow‐up of 28 months and data were censored at the time of death or loss to follow‐up. Adults reporting a doctor‐diagnosis of asthma (N = 34) were more likely to have features of asthma including wheeze, eczema, family history of asthma, and an elevated IgE level (all P < 0.05). However, there was no difference in pain or ACS rate, lung function, or risk of death between adults with and without a doctor‐diagnosis of asthma. In contrast, adults who reported recurrent, severe episodes of wheezing (N = 34), regardless of asthma, had twice the rates of pain and ACS, decreased lung function and increased risk of death compared with adults without recurrent, severe wheezing. Asthma features were not associated with recurrent, severe wheezing. Our data suggest that wheezing in SCD may occur independently of asthma and is a marker of disease severity. Am. J. Hematol. 2011.
Pediatric Blood & Cancer | 2013
Morey A. Blinder; Francis Vekeman; Medha Sasane; Alex Trahey; Carole Paley; Mei Sheng Duh
This study explored the blood transfusion patterns, SCD complications, utilization of iron chelation therapies (ICT), healthcare resource use, and costs in pediatric, transitioning (18 years old) and adult patients with SCD.
American Journal of Hematology | 1996
Yang-Xin Fu; Richard M. Kaufman; Amy E. Rudolph; Steven E. Collum; Morey A. Blinder
Acquired inhibitors of factor V are rare causes of clinical bleeding, whose severity ranges from mild to life‐threatening. Optimal treatment of patients with factor V inhibitors is uncertain. We report on our successful treatment approach in a patient with spontaneous, life‐threatening intracranial bleeding caused by a factor V inhibitor. The patient deteriorated after initial treatment with fresh‐frozen plasma and platelet transfusions. He was subsequently treated with a combination of plasma exchange and chemotherapy, which led to complete recovery. Our experience suggests that plasma exchange may be life‐saving in cases of severe bleeding caused by factor V inhibitors. The use of plasmapheresis in conjunction with chemotherapy is an efficacious and well‐tolerated treatment and should be considered in patients with factor V inhibitors.