Yoshitaka Mori, Hideo Wada, Esteban C Gabazza, Nobuyuki Minami, Tsutomu Nobori, Hiroshi Shiku, Hideo Yagi, Hiromichi Ishizashi, Masanori Matsumoto, Yoshihiro Fujimura
Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity.
Transfusion. 2002 May;42(5):572-80.
Abstract/Text
BACKGROUND: Severe deficiency of vWF-cleaving protease (vWF-CPase) activity was recently found in patients with thrombotic thrombocytopenic purpura (TTP). Although the survival of patients with TTP has been dramatically improved with plasma exchange (PE), there are still many patients who are refractory to PE and immunosuppressive therapy.
STUDY DESIGN AND METHODS: The activities of vWF-CPase and its inhibitor were measured in 27 patients with nonfamilial TTP and hemolytic-uremic syndrome (HUS) to examine the relationship between the clinical variables and vWF-CPase activity.
RESULTS: Eight of nine patients with HUS had more than 40 percent of vWF-CPase activity, whereas one had 28 percent of the normal level at the acute phase. Ten of 12 TTP patients with a good outcome had a severe deficiency of vWF-CPase activity and its inhibitor, whereas four of six patients with a poor outcome had a moderate deficiency of vWF-CPase activity along with a lack of the inhibitor. PE produced normalization of the vWF-CPase activity and neutralization of the inhibitor in TTP patients with a good outcome; however, some TTP patients with vWF-CPase inhibitor had relapsed and required an immunosuppressive therapy. The response to the combination therapy with PE and immunosuppressive treatment was poor in TTP patients without a severe deficiency of vWF-CPase activity.
CONCLUSION: Assays of vWF-CPase activity and its inhibitor may be useful for predicting the response to therapy and the outcome of patients with TTP. In some patients, nonfamilial TTP with a poor prognosis may not be caused by a constitutional or acquired deficiency of vWF-CPase with its inhibitor. Although PE and immunosuppressive therapy are effective in patients with nonfamilial TTP and a vWF-CPase inhibitor, other therapeutic modalities may be needed for nonfamilial TTP with unknown etiology.
Sara K Vesely, James N George, Bernhard Lämmle, Jan-Dirk Studt, Lorenzo Alberio, Mayez A El-Harake, Gary E Raskob
ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients.
Blood. 2003 Jul 1;102(1):60-8. doi: 10.1182/blood-2003-01-0193. Epub 2003 Mar 13.
Abstract/Text
Initial management of patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. Although severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency may be specific for TTP, the role of ADAMTS13 activity measurements for initial management decisions is unknown. ADAMTS13 was measured before beginning plasma exchange treatment in 142 (88%) of 161 consecutive patients with clinically diagnosed TTP-HUS with assignment to 1 of 4 categories: less than 5% (severe deficiency), 5% to 9%, 10% to 25%, and more than 25%. Eighteen (13%) of 142 patients had severe ADAMTS13 deficiency. Among 6 predefined clinical categories (stem cell transplantation, pregnant/postpartum, drug association, bloody diarrhea, additional/alternative disorder, idiopathic), severe deficiency occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. The presenting features and clinical outcomes of the 16 patients with idiopathic TTP-HUS who had severe ADAMTS13 deficiency were variable and not distinct from the 32 patients with idiopathic TTPHUS who did not have severe ADAMTS13 deficiency. Many patients in all ADAMTS13 activity categories apparently responded to plasma exchange treatment. Therefore, severe ADAMTS13 deficiency does not detect all patients who may be appropriately diagnosed with TTP-HUS and who may respond to plasma exchange treatment.
Kazuya Sakai, Masanori Matsumoto
Clinical Manifestations, Current and Future Therapy, and Long-Term Outcomes in Congenital Thrombotic Thrombocytopenic Purpura.
J Clin Med. 2023 May 9;12(10). doi: 10.3390/jcm12103365. Epub 2023 May 9.
Abstract/Text
Congenital thrombotic thrombocytopenic purpura (cTTP) is an extremely rare disease characterized by the severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), caused by ADAMTS13 mutations. While ADAMTS13 supplementation by fresh frozen plasma (FFP) infusion immediately corrects platelet consumption and resolves thrombotic symptoms in acute episodes, FFP treatment can lead to intolerant allergic reactions and frequent hospital visits. Up to 70% of patients depend on regular FFP infusions to normalize their platelet counts and avoid systemic symptoms, including headache, fatigue, and weakness. The remaining patients do not receive regular FFP infusions, mainly because their platelet counts are maintained within the normal range or because they are symptom-free without FFP infusions. However, the target peak and trough levels of ADAMTS13 to prevent long-term comorbidity with prophylactic FFP and the necessity of treating FFP-independent patients in terms of long-term clinical outcomes are yet to be determined. Our recent study suggests that the current volumes of FFP infusions are insufficient to prevent frequent thrombotic events and long-term ischemic organ damage. This review focuses on the current management of cTTP and its associated issues, followed by the importance of upcoming recombinant ADAMTS13 therapy.
Hendrika A van Dorland, Magnus Mansouri Taleghani, Kazuya Sakai, Kenneth D Friedman, James N George, Ingrid Hrachovinova, Paul N Knöbl, Anne Sophie von Krogh, Reinhard Schneppenheim, Isabella Aebi-Huber, Lukas Bütikofer, Carlo R Largiadèr, Zuzana Cermakova, Koichi Kokame, Toshiyuki Miyata, Hideo Yagi, Deirdra R Terrell, Sara K Vesely, Masanori Matsumoto, Bernhard Lämmle, Yoshihiro Fujimura, Johanna A Kremer Hovinga, Hereditary TTP Registry
The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017.
Haematologica. 2019 Oct;104(10):2107-2115. doi: 10.3324/haematol.2019.216796. Epub 2019 Feb 21.
Abstract/Text
Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment for a study which aimed to improve the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 confirmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from around birth up to the age of 70 years. Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3 months of age (50% vs 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.
Copyright© 2019 Ferrata Storti Foundation.
Kazuya Sakai, Yoshihiro Fujimura, Toshiyuki Miyata, Ayami Isonishi, Koichi Kokame, Masanori Matsumoto
Current prophylactic plasma infusion protocols do not adequately prevent long-term cumulative organ damage in the Japanese congenital thrombotic thrombocytopenic purpura cohort.
Br J Haematol. 2021 Jul;194(2):444-452. doi: 10.1111/bjh.17560. Epub 2021 May 28.
Abstract/Text
Congenital thrombotic thrombocytopenic purpura (cTTP), known as Upshaw-Schulman syndrome, is an ultrarare thrombotic disorder caused by ADAMTS13 gene mutations; however, its long-term outcomes have not been widely studied. A questionnaire survey was administered to physicians of patients in the Japanese cTTP registry to characterise these outcomes. We analysed 55 patients in remission, with 41 cases receiving prophylactic fresh frozen plasma (FFP; median dosage: 13·2 ml/kg per month) and 14 receiving on-demand FFP. Patients receiving prophylactic FFP were considered as having a more severe form of the disease and had lower platelet counts and higher serum creatinine levels than those receiving on-demand FFP (median 138 × 109 /l vs. 243 × 109 /l, P = 0·003 and 0·71 mg/dl vs 0·58 mg/dl, P = 0·009, respectively). Patients who received prophylactic FFP more commonly developed organ damage, including renal impairment, cerebral infarctions, and cardiac hypofunction, than those who did not. Adverse FFP-related events were seen in 78% of the prophylactic FFP group, with allergic reactions being most common. Since current protocols for FFP administration to the prophylactic FFP group in Japan may be insufficient for preventing cumulative organ damage, a higher dosage of ADAMTS13 supply using recombinant ADAMTS13 agent is needed in these patients.
© 2021 British Society for Haematology and John Wiley & Sons Ltd.
G A Rock, K H Shumak, N A Buskard, V S Blanchette, J G Kelton, R C Nair, R A Spasoff
Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.
N Engl J Med. 1991 Aug 8;325(6):393-7. doi: 10.1056/NEJM199108083250604.
Abstract/Text
BACKGROUND: Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma exchange and plasma infusion have been useful treatments, it is not clear which is superior. In this report we describe a prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic thrombocytopenic purpura.
METHODS: One hundred two patients with thrombotic thrombocytopenic purpura were randomly assigned to receive either plasma exchange or plasma infusion with fresh-frozen plasma on seven of the first nine days after entry into the trial. The total volume of plasma received by patients undergoing plasma exchange was three times that received by patients undergoing plasma infusion. All the patients also received aspirin and dipyridamole. The outcomes in the two groups were compared at the end of the first treatment cycle (day 9) and after six months.
RESULTS: At the end of the first treatment cycle patients receiving plasma exchange had a higher rate of response as defined by an increase in the platelet count (24 of 51 patients) than those who received plasma infusion (13 of 51, P = 0.025). Of the 51 patients treated with plasma exchange, 2 died, whereas 8 of the 51 patients who received plasma infusion died (P = 0.035). After six months the outcome in the plasma-exchange group was still superior, with a response observed in 40 of 51 patients, whereas 25 of 51 patients in the plasma-infusion group responded (P = 0.002). Eleven patients in the plasma-exchange group died, as did 19 patients in the plasma-infusion group (P = 0.036). The overall mortality was 29 percent.
CONCLUSIONS: Plasma exchange is more effective than plasma infusion in the treatment of thrombotic thrombocytopenic purpura.
Masanori Matsumoto, Hideo Yagi, Hiromichi Ishizashi, Hideo Wada, Yoshihiro Fujimura
The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
Semin Hematol. 2004 Jan;41(1):68-74.
Abstract/Text
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.
A Pereira, R Mazzara, J Monteagudo, C Sanz, L Puig, A Martínez, A Ordinas, R Castillo
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a multivariate analysis of factors predicting the response to plasma exchange.
Ann Hematol. 1995 Jun;70(6):319-23.
Abstract/Text
The aim of this study was to investigate pretreatment prognostic factors that could be useful in predicting the response to plasma exchange in thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Thirty-two patients with TTP/HUS, treated with plasma exchange at our institution from 1980 to 1994, were studied. The main clinical and laboratory data at the beginning of plasma exchanges were analyzed by the Cox stepwise logistic regression, applied to either treatment failure or death. Seventeen (53%) patients attained a complete remission and 22 (69%) survived (five in advanced renal failure and long-term hemodialysis). Longer delay in initiating plasma exchanges, presence of stupor or coma, and higher creatinine levels at the beginning of plasma exchanges were independent predictors of treatment failure. Stupor or coma at the beginning of plasma exchanges was the only predictor of mortality from unremitted TTP/HUS. Hemoglobin levels, platelet count, and LDH activity, traditionally envisaged as markers of disease activity, neither correlated with previous duration of TTP/HUS nor had any prognostic value. Early diagnosis of TTP/HUS and prompt initiation of intensive plasma exchange emerged from this study as the most effective interventions for improving the prognosis of TTP/HUS patients.
Flora Peyvandi, Spero Cataland, Marie Scully, Paul Coppo, Paul Knoebl, Johanna A Kremer Hovinga, Ara Metjian, Javier de la Rubia, Katerina Pavenski, Jessica Minkue Mi Edou, Hilde De Winter, Filip Callewaert
Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis.
Blood Adv. 2021 Apr 27;5(8):2137-2141. doi: 10.1182/bloodadvances.2020001834.
Abstract/Text
The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317.
© 2021 by The American Society of Hematology.
W R Bell, H G Braine, P M Ness, T S Kickler
Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients.
N Engl J Med. 1991 Aug 8;325(6):398-403. doi: 10.1056/NEJM199108083250605.
Abstract/Text
BACKGROUND AND METHODS: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction. In early reports the mortality approached 100 percent. A treatment protocol was introduced in 1979 for patients admitted to Johns Hopkins Hospital with the diagnosis of TTP-HUS. Treatment regimens included 200 mg of prednisone a day, for patients with minimal symptoms and no central nervous system symptoms, and prednisone plus plasma exchange, for patients with rapid clinical deterioration who did not improve after 48 hours of prednisone alone and for patients presenting with central nervous system symptoms and rapidly declining hematocrit values and platelet counts.
RESULTS: A total of 108 patients were treated, and 91 percent survived. Prednisone alone was judged to be effective in 30 patients with mild TTP-HUS (two relapses and two deaths). Plasma exchange plus prednisone was given to 78 patients with complicated TTP-HUS, resulting in 67 relapses and 8 deaths. Relapses occurred in 22 of 36 patients given maintenance plasma infusions. Neither splenectomy nor treatment with aspirin and dipyridamole was effective in those with a poor response to plasma exchange. None of the 71 patients tested had positive cultures for O157:H7 Escherichia coli. Nine percent of the patients were pregnant, and none gave birth to infants with TTP-HUS.
CONCLUSIONS: Effective treatment with 91 percent survival is available for patients with TTP-HUS.
D R Harkness, J J Byrnes, E C Lian, W D Williams, G T Hensley
Hazard of platelet transfusion in thrombotic thrombocytopenic purpura.
JAMA. 1981 Oct 23-30;246(17):1931-3.
Abstract/Text
A patient with thrombotic thrombocytopenic purpura (TTP) showed for the first time catastrophic signs and symptoms of CNS involvement immediately after infusion of platelets. Postmortem examination revealed extensive deposits of platelet aggregates within the small blood vessels of the brain, whereas lesions elsewhere in the body consisted of platelets as well as fibrin and were associated with endothelial proliferation and microaneurysm formation. These findings are consistent with the view that the initial event in TTP may be platelet aggregation. The plasma of this patient contained platelet-aggregating activity. We conclude that platelet transfusions in patients with TTP may aggravate the disease process.
Sarah L Allford, Beverley J Hunt, Peter Rose, Samuel J Machin, Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology
Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias.
Br J Haematol. 2003 Feb;120(4):556-73.
Abstract/Text
Karen K Swisher, Deirdra R Terrell, Sara K Vesely, Johanna A Kremer Hovinga, Bernhard Lämmle, James N George
Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura.
Transfusion. 2009 May;49(5):873-87. doi: 10.1111/j.1537-2995.2008.02082.x. Epub 2009 Feb 6.
Abstract/Text
BACKGROUND: Reports of deterioration and death after platelet (PLT) transfusions in patients with thrombotic thrombocytopenic purpura (TTP) have led to recommendations that they should not be given except for life-threatening hemorrhage.
STUDY DESIGN AND METHODS: Published reports of PLT transfusions in patients with TTP were systematically reviewed and data from the Oklahoma TTP-HUS Registry, an inception cohort of 382 consecutive patients, 1989 through 2007, were analyzed.
RESULTS: A systematic review identified 34 publications describing outcomes of patients with TTP after PLT transfusions: 9 articles attributed complications to PLT transfusions, 4 suggested that they may be safe, and 21 articles did not comment about a relation between PLT transfusions and outcomes. Fifty-four consecutive patients from the Oklahoma TTP-HUS Registry were prospectively analyzed. ADAMTS13 activity was less than 10 percent in 47 patients; also included were 7 patients whose activity was not measured but who may have been deficient. Thirty-three (61%) patients received PLT transfusions. The frequency of death was not different between the two groups (p = 0.971): 8 (24%) patients who received PLT transfusions died (thrombosis, 5; hemorrhage, 1; sepsis, 2) and 5 (24%) patients who did not receive PLT transfusions died (thrombosis, 4; hemorrhage, 1). The frequency of severe neurologic events was also not different (p = 0.190): 17 (52%) patients who received PLT transfusions (in 5 of these 17 patients, neurologic events only occurred before PLT transfusions) and 7 (33%) patients who did not receive PLT transfusions.
CONCLUSION: Evidence for harm from PLT transfusions in patients with TTP is uncertain.
溶血性尿毒症症候群の診断・治療ガイドライン作成班：溶血性尿毒症症候群の診断・治療ガイドライン、東京医学社.
Gema Ariceta, Nesrin Besbas, Sally Johnson, Diana Karpman, Daniel Landau, Christoph Licht, Chantal Loirat, Carmine Pecoraro, C Mark Taylor, Nicole Van de Kar, Johan Vandewalle, Lothar B Zimmerhackl, European Paediatric Study Group for HUS
Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome.
Pediatr Nephrol. 2009 Apr;24(4):687-96. doi: 10.1007/s00467-008-0964-1. Epub 2008 Sep 18.
Abstract/Text
This guideline for the investigation and initial treatment of atypical hemolytic uremic syndrome (HUS) is intended to offer an approach based on opinion, as evidence is lacking. It builds on the current ability to identify the etiology of specific diagnostic sub-groups of HUS. HUS in children is mostly due to infection, enterohemorrhagic Escherichia coli (EHEC), Shigella dysenteriae type 1 in some geographic regions, and invasive Streptococcus pneumoniae. These sub-groups are relatively straightforward to diagnose. Their management, which is outside the remit of this guideline, is related to control of infection where that is necessary and supportive measures for the anemia and acute renal failure. A thorough investigation of the remainder of childhood HUS cases, commonly referred to as "atypical" HUS, will reveal a risk factor for the syndrome in approximately 60% of cases. Disorders of complement regulation are, numerically, the most important. The outcome for children with atypical HUS is poor, and, because of the rarity of these disorders, clinical experience is scanty. Some cases of complement dysfunction appear to respond to plasma therapy. The therapeutic part of this guideline is the consensus of the contributing authors and is based on limited information from uncontrolled studies. The guideline proposes urgent and empirical plasmapheresis replacement with whole plasma fraction for the first month after diagnosis. This should only be undertaken in specialized pediatric nephrology centers where appropriate medical and nursing skills are available. The guideline includes defined terminology and audit points so that the early clinical effectiveness of the strategy can be evaluated.
C M Legendre, C Licht, P Muus, L A Greenbaum, S Babu, C Bedrosian, C Bingham, D J Cohen, Y Delmas, K Douglas, F Eitner, T Feldkamp, D Fouque, R R Furman, O Gaber, M Herthelius, M Hourmant, D Karpman, Y Lebranchu, C Mariat, J Menne, B Moulin, J Nürnberger, M Ogawa, G Remuzzi, T Richard, R Sberro-Soussan, B Severino, N S Sheerin, A Trivelli, L B Zimmerhackl, T Goodship, C Loirat
Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.
N Engl J Med. 2013 Jun 6;368(23):2169-81. doi: 10.1056/NEJMoa1208981.
Abstract/Text
BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease.
METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2).
RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.
CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).
Nay M Tun, Gina M Villani
Efficacy of rituximab in acute refractory or chronic relapsing non-familial idiopathic thrombotic thrombocytopenic purpura: a systematic review with pooled data analysis.
J Thromb Thrombolysis. 2012 Oct;34(3):347-59. doi: 10.1007/s11239-012-0723-9.
Abstract/Text
Idiopathic thrombotic thrombocytopenic purpura (TTP) occurs primarily due to the formation of autoantibody against ADAMTS13, a specific von Willebrand factor-cleaving protease, resulting in low ADAMTS13 activity and subsequent accumulation of large vWF multimers, platelet aggregation and thrombus formation in the microvasculature of tissues. Limited clinical data suggest that the administration of anti-CD20 antibody (rituximab) may be useful in treating acute refractory or chronic relapsing idiopathic TTP. We carried out a systematic review with pooled data analysis using individual patient data to evaluate the efficacy of rituximab in these settings. Fifteen case series and 16 case reports comprising 100 patients were eligible for the study. Median age was 39 years. Male constituted 31 % and female 69 %. Complete remission was seen in 98 %, non-response in 2 % and relapse after complete remission in 9 %. For patients with complete remission, median follow-up was 13 months. Median platelet recovery from the first dose of rituximab was 14 days. ADAMTS13 inhibitor positivity and severe ADAMTS13 deficiency were highly predictive of the response to rituximab, implying that these can be useful markers in predicting response to rituximab in acute refractory or chronic relapsing idiopathic TTP.
Marie Scully, Vickie McDonald, Jamie Cavenagh, Beverley J Hunt, Ian Longair, Hannah Cohen, Samuel J Machin
A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
Blood. 2011 Aug 18;118(7):1746-53. doi: 10.1182/blood-2011-03-341131. Epub 2011 Jun 2.
Abstract/Text
The safety and efficacy of weekly rituximab 375 mg/m(2) (×4), given within 3 days of acute TTP admission, with standard therapy (PEX and steroids) was evaluated. Clinical outcomes were compared to historical controls (n = 40) who had not received rituximab. Within the trial group, 15 of 40 required ICU admission and 15% of all cases with the highest troponin T levels on admission were ventilated. Before the second rituximab infusion, 68% of cases had a platelet count > 50 × 10(9)/L and 38% > 150 × 10(9)/L. Fewer PEX were required in whites compared to nonwhite in the rituximab group (mean 14 vs 21, P = .0095). Inpatient stay was reduced by 7 days in the non-ICU trial cases compared to historical controls (P = .04), especially in whites, with a mean reduction of 7 days (P = .05). Ten percent of trial cases relapsed, median, 27 months (17-31 months), compared to 57% in historical controls, median 18 months (3-60 months; P = .0011). There were no excess infections or serious adverse events with rituximab. In conclusion, rituximab appears a safe and effective therapy. Inpatient stay and relapse are significantly reduced in the rituximab cohort. Rituximab should be considered in conjunction with standard therapy on acute presentation of TTP. This study was registered at www.clinicaltrials.gov as NCT009-3713.
