Relapsing Thrombotic Thrombocytopenic Purpura Research Articles

Phase II Study of Danazol with Plasma Exchange and Corticosteroids for the Treatment of Thrombotic Thrombocytopenic Purpura

Background: Ahn and colleagues reported a decrease in plasma exchange (PE)/plasma infusion requirement with danazol in seven cases of thrombotic thrombocytopenic purpura (TTP) (Ahn Blood 2006;108(11):1057a). We reported an increase in platelet count (PLT) within 24 hours with danazol in two of three cases of human immunodeficiency virus-associated TTP resistant to PE (Torri Transfusion 2010;50:86a). In 2009, we initiated a phase II study of danazol with PE and corticosteroids (CS) for the treatment of TTP. This trial was approved by the institutional review board and was registered at ClinicalTrials.gov (ID# NCT00953771). We report the final results. Aims: To determine if danazol reduces number of PE's, time to remission (TR), and length of stay (LOS) when administered with standard therapy for the initial treatment of TTP. Methods: Experimental Group (EG): Patients with TTP (PLT < 100,000/µL and microangiopathy) receive daily PE, prednisone 1 mg/kg, and danazol 600 mg. Following remission (PLT > 150,000/µL for three consecutive days), PE is tapered to every other day for one week then stopped. Then prednisone is tapered weekly over four weeks then stopped. After one week danazol is tapered by 200 mg weekly then stopped. Historical controls (HC): Patients treated for TTP at St. Luke's-Roosevelt Hospital Center with PE with or without CS from 2000 to 2007 (n=20). Relapse definition: PLT < 100,000/µL with microangiopathy > 30 days after remission. Total number of PE's, TR, LOS, and continuous response rates are compared between the 2 groups. Accrual target: 16 patients to detect a 40% decrease in the number of PE's with 80% power and a level of significance of 0.05.The study was terminated in 2018 due to low accrual. Results: Nine patients were enrolled. Mean number of PE's (days) was 14.8 (EG) and 16.1 (HC), mean TR (days) was 11.4 (EG) and 11 (HC), and mean LOS (days) was 27.3 (EG) and 24.9 (HC), p > 0.05. Four patients in HC had a total of 6 relapses at our institution at a median of 28.25 months, range 2.75 to 97 months after the initial event. One patient in EG relapsed 43 months after study enrollment. One patient in EG died from an unrelated cause. None of the additional seven patients in EG have relapsed during a median follow-up of 49 months, range 12 to 125 months. One episode of pulmonary edema and one episode of hypotension occurred in EG, for which treatment was not discontinued. Discussion: Our study shows that danazol does not reduce PE requirement, TR, or LOS during treatment of TTP, but may prevent relapse. This pattern of response is similar to that which has been observed with rituximab. In a phase 2 study of rituximab in conjunction with PE and CS for the treatment of TTP (Scully Blood 2011), in which results were compared with historical controls who did not receive rituximab, median number of PE's (days) and median LOS (days) were 16.5 and 16.5 in the rituximab group versus 18.0 and 20 in the historical control group, p=ns. Ten percent of patients relapsed at a median of 27 months in the rituximab group whereas 57% of patients relapsed at a median of 18 months in the historical control group. Of interest, the cost of rituximab 375 mg/m 2 weekly for 4 weeks as given would have been approximately $ 25,366.50. The cost of danazol in our protocol would have been approximately $ 2196.00. Caplacizumab is a humanized monoclonal antibody fragment that inhibits von Willebrand factor binding to platelet glycoprotein lb-IX-V. In a phase 3 study (Scully N Engl J Med 2019), caplacizumab in conjunction with PE and CS for the treatment of TTP led to reduced PE's, time to normalization of platelet counts, and LOS, but increased relapses in comparison with placebo. In 2020, the International Society on Thrombosis and Haemostasis strongly recommended adding CS to PE for the treatment of TTP and conditionally recommended adding rituximab and caplacizumab to PE and CS (Zheng J Thromb Haemost 2020). Conclusion: Danazol in conjunction with PE and CS may be a low-cost option to prevent relapses of TTP.

The challenging follow-up of pregnancy in women with known thrombotic thrombocytopenic purpura: a single-center experience of a preemptive management protocol.

Although thrombotic thrombocytopenic purpura frequently affects women of childbearing age, there is no clear recommendation for the management of subsequent pregnancies in women with established thrombotic thrombocytopenic purpura. This single-center, retrospective, observational study included all women with hereditary thrombotic thrombocytopenic purpura or immune thrombotic thrombocytopenic purpura who had had at least one subsequent pregnancy after thrombotic thrombocytopenic purpura diagnosis between 2003 and 2022. The strategy comprised weekly surveillance of platelet count during pregnancy (and quarterly monitoring of ADAMTS13 activity) for women with immune thrombotic thrombocytopenic purpura, without any routine prophylactic treatment. In case of thrombocytopenia < 150,000/mm3 (with or without hemolysis relapse), women with hereditary thrombotic thrombocytopenic purpura systematically received plasma infusions twice weekly until platelet count normalized. A total of 13 patients were included (7 with hereditary thrombotic thrombocytopenic purpura and 6 with immune thrombotic thrombocytopenic purpura, with 20 planned pregnancies (11 and 9, respectively). All pregnancies resulted in live births, and all mothers survived.There was a marked improvement in pregnancy terms in the hereditary thrombotic thrombocytopenic purpura group compared to index pregnancies (37 [35;39] versus 31 [24;38] weeks, p = 0.037) and birth weights (3265 [3029;3410] versus 2160 [1240;2705] grams, p = 0.016), with need for plasma support mostly starting during the third trimester (5/7 patients, 7/11 pregnancies). A single hereditary thrombotic thrombocytopenic purpura relapse occurred, with rapid resolution after plasma support intensification. There were no relapses in the immune thrombotic thrombocytopenic purpura group, with ADAMTS13 activity systematically above 40% during all monitored pregnancies. These real-life data support the feasibility of a preemptive approach to pregnancy monitoring in women with known thrombotic thrombocytopenic purpura who undergo active surveillance within a multidisciplinary network.

Clinical Features and Risk Factors of Relapse and Mortality in Thrombotic Thrombocytopenic Purpura Patients: A Seven-Year Experience.

Background: Thrombotic thrombocytopenic purpura (TTP) is associated with microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis. No comprehensive report exists on clinical characteristics and risk factors of relapse and mortality in Iranian TTP patients. In this study, we aimed to report clinical features of Iranian TTP patients, to evaluate disease relapse and mortality rate and their associated risk factors. Materials and Methods: This study was a cohort study of patients diagnosed with microangiopathic hemolytic anemia admitted to the Shariati Hospital, Tehran, a referral center for TTP patients, from 2010 to 2017. Demographic, clinical, and laboratory data were recorded and patients were followed for 3 years regarding disease relapse and mortality. Results: 114 patients (80 females, 34 males) with a mean age of 39.3 ± 14.99 years were included. Hematologic and neurologic symptoms were the most common manifestations. Abnormal laboratory findings at the presentation included thrombocytopenia, anemia, and elevated LDH. All patients were treated with plasma exchange, and 75.5% of them had a response to treatment, while the 3-year relapse and mortality rate was 23.6 and 26.3%. Lower platelet count was a predictor of disease relapse. Age, hematological, or neurological initial presentation were associated with TTP mortality. Conclusion: Based on the largest study of TTP patients ever in Iran, the demographic and clinical characteristics of Iranian TTP patients are similar to other existing reports. Knowledge of the risk factors for TTP relapse and mortality could be useful to alert hematologists for prompt therapeutic actions when necessary.

Relapse in thrombotic thrombocytopenic purpura

Relapse in thrombotic thrombocytopenic purpura

Refractory thrombotic thrombocytopenic purpura treated successfully with monoclonal antibody (rituximab)

Thrombotic thrombocytopenic purpura (TTP) is a nonimmune, microangiopathic hemolytic anemia, associated with thrombocytopenia, fever, neurologic, or renal dysfunction. Plasma exchange (PEX) with or without steroids constitutes first-line therapy in TTP. However, a subset of the patients may be refractory to PEX. Rituximab appears to be an alternative effective therapy for refractory or relapsing TTP. Here, we report a case of TTP in a 43-year-old female presented with fever, generalized weakness, headache, vomiting, and ecchymotic patches over forearms and upper chest for 7 days along with one episode of seizure. The laboratory evaluation revealed severe thrombocytopenia, anemia, and indirect hyperbilirubinemia with peripheral blood smear showing schistocytes (fragmented red blood cells). Initial therapy with multiple PEXs along with parenteral corticosteroids resulted in only minimal improvement of platelet count. Subsequently, rituximab was administered which helped in normalization of platelet count and overall clinical improvement. This case highlights the importance of timely utilization of second-line drugs such as rituximab in refractory TTP.

Adolescent acquired thrombotic thrombocytopenic purpura: An analysis of the Pediatric Health Information System database

The outcomes and characteristics of acquired thrombotic thrombocytopenic purpura (TTP) in adolescents is poorly understood due to an absence of studies focused on this population. To better understand the life-threatening disorder in this age, we performed an analysis of adolescent patients (ages 10–21) with TTP in the Pediatric Health Information Systems database from 2009 to 2020. The primary outcomes evaluated were in-hospital mortality and rate of TTP relapse. Secondary outcomes included rates of hemorrhagic and thrombotic complications during hospitalizations for TTP. Patients were included if they had a thrombotic microangiopathy diagnostic code, ADAMTS13 lab obtained, and received therapeutic plasmapheresis. Patients that received treatment for other non-TTP microangiopathies were excluded. A total of 99 patients with 123 hospitalizations for TTP treatment were identified. In-patient mortality occurred in 6 % (n = 6) and TTP relapse in 20 % (n = 20) of the cohort. Median time from initial admission to relapse was 33 days (IQR 15, 92). A hemorrhagic complication was identified in 29 % (n = 36) and thrombotic complication in 15 % (n = 19) of the cohort. The presence of underlying comorbidities was not associated with TTP relapse and only a diagnosis of cancer was associated with increased mortality. The rate of mortality and relapse in adolescent TTP is lower than that seen in adult registries. Long term prospective studies are needed to understand the long-term consequences of adolescent onset acquired TTP.

Real-World Variability in ADAMTS13 Assay Methods May Impact upon Follow up for Patients with Thrombotic Thrombocytopenic Purpura (TTP)

IntroductionADAMTS13 activity (ADAMTS13:Ac) measurement is an important diagnostic marker in acute TTP (defined as a level of <10%). Increasing numbers of commercial assays have been developed (ELISA, FRET and chemiluminesence) for diagnostic purposes. The International Council for Standardization in Haematology have not made specific recommendations on ADAMTS13 assay selection in a recent publication in 2020.ADAMTS13:Ac has traditionally been used for diagnostic purposes but can also be useful for monitoring disease status and relapse risk. Patients between levels of 10-50% may require increased monitoring and subsequently treatment to avoid frank relapse, with an inverse relationship between ADAMTS13:Ac levels and intensity of clinical monitoring.We seek to compare the differences between different commercial assays available to measure the ADAMTS13:Ac in patients who have a history of TTP and whether this influences clinical practice.MethodsPatients with an acute diagnosis of TTP as an inpatient or outpatient surveillance with past history of TTP were reviewed at Guy's and St Thomas' Hospital, London, UK, and samples were taken to measure ADAMTS13:Ac as part of disease monitoring between February and July 2021. A comparison was performed between an ELISA (Technozym ADAMTS13 activity, Technoclone) and FRET (Technofluor, Technoclone), with all samples processed in parallel. With no international consensus, broadly, levels of <10% were defined as either active TTP or relapse; patients with 10-30% required more intensive outpatient monitoring to detect for relapse and >50% was defined as within the normal range.Results47 samples from 31 known or newly diagnosed TTP patients were processed over a six month period. Intra- and inter-assay CV for both ELISA and FRET on laboratory testing was as expected from manufacturers guidelines.Figure 1 plots the ADAMTS13:Ac ELISA vs FRET, with a Pearson correlation of p=0.949 across all samples. Ranges were for ELISA (0 - 109.3) and FRET (1.6 - 130.3). Mean ADAMTS13:Ac difference was 16±13.5%, with consistent positive bias in favour of the FRET assay. Higher levels demonstrated greater variability as demonstrated in Table 1, with the mean difference between ELISA and FRET increasing with increasing levels.Based on the above definitions as in the methods, there were 14/47 (29%) samples which had discordant results between the ELISA and FRET methods: 3 discordant samples on diagnosis of relapse, 8 discordant for where the ELISA detected levels <30% and FRET >30%; and 2 discordant for where ELISA <50% and FRET >50%.ConclusionReal-world clinical testing demonstrates substantial variability within a single manufacturer between two separate methods and demonstrates an impact on patient follow up and implications in decisions on follow-up intervals and treatment. There was a consistent positive bias in ADAMTS13:Ac by FRET measurement as compared with the ELISA. Greater consistency was demonstrated at the lower end of testing, where there was good concordance at levels of <10%, confirming that both assays were effective at determining a diagnosis or relapse of TTP. Further interrogation of other commercial platforms is warranted to establish the variability of results to inform on clinical practice in the monitoring of patients with TTP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Single-Center Experience of the Utility of a Rapid ADAMTS13 Assay

Introduction: Antibody-mediated thrombotic thrombocytopenic purpura (TTP) is a rare disease with significant morbidity and mortality, requiring prompt diagnosis and intervention. The advent of rituximab use (off-label) for TTP in 2002 not only established a novel therapy for refractory disease, but also raised the possibility of prophylactic therapy. Prophylactic rituximab was found by Westwood et al. to be effective in normalizing ADAMTS13 when activity dropped ≤15% in a retrospective cohort study (Blood Advances, 2017). Treatment paradigms in TTP are changing as evidence builds for prophylactic therapy, but we remain without large, randomized data to guide who would benefit most from prophylactic rituximab.The use of a rapid assay for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) has been shown to significantly reduce therapeutic plasma exchange (TPE) by ruling-in or -out suspected cases of TTP (Connell et al., Transfusion 2016). The role of rapid ADAMTS13 testing in assessment of response to TPE in acute TTP as well as surveillance of TTP patients in remission continues to be explored. We describe the utilization of a rapid ADAMTS13 assay and its role in the decision to use early or prophylactic rituximab in patients with TTP at the largest referral center for TTP in Rhode Island.Methods: Following IRB approval, demographic data for patients who underwent rapid ADAMTS13 testing from 1/1/13-2/28/17 at Rhode Island Hospital (Providence, RI) was obtained. Patients were deemed to have TTP if they had thrombocytopenia with microangiopathic hemolytic anemia (MAHA) and ADAMTS13 ≤ 10%, or thrombocytopenia with MAHA and a history of TTP. Each patient admission for TTP was recorded as a separate event. Data analysis was performed using Wilcoxon rank sum and Fisher's exact tests.Results: Ninety patients had ADAMTS13 testing from 1/1/13 to 2/28/17. Seven patients were excluded due to age less than 18 years. The remaining 83 patient charts were reviewed. Sixteen events of acquired TTP were diagnosed in 11 patients. Pregnancy-associated TTP did not occur, although 1 relapse of TTP had a history of post-partum TTP. Of the remaining patients, 5 had a history of TTP and underwent surveillance testing of ADAMTS13. One patient had congenital TTP. Diagnoses other than TTP were characterized in 66 patients (Figure 1). The most common other diagnosis found in patients who underwent ADAMTS13 testing was sepsis (n=12).When comparing patients who received rituximab during acute event (n=9) to those that did not (n=7) in 16 TTP events, we observed no statistically significant correlation between rituximab use and age, sex, presenting platelet count, presenting ADAMTS13 activity, presenting ADAMTS13 inhibitor value, days to platelet count normalization, or days of TPE (Table 1). We also observed no significant difference in days of TPE or days to platelet count normalization when comparing patients who received rituximab ≤ 5 days of diagnosis (n=5) versus those who received rituximab > 5 days from diagnosis but during the event (n=4). There was no significant change in rapid ADAMTS13 activity assay use, TPE use or rituximab use by year, from 2013-2016.In three patients with a history of acquired TTP, routine follow-up ADAMTS13 activity assay revealed decreased activity prior to the development of thrombocytopenia. These patients had an ADAMTS13 activity of 1%, 22%, 57% with platelet counts of 166k, 334k, 224k respectively. These patients had a history of 4, 7 and 8 prior events of TTP, respectively. Following the administration of 4 doses of weekly rituximab 375mg/m2, all had improvement in ADAMTS13 activity to >95%, none requiring TPE. These patients are recurrence-free after 7 months, 19 months, and 3 months of follow-up.Conclusions: In our single center retrospective study, early use of rituximab does not appear to confer immediate benefit through reduction of TPE or days to platelet normalization. Routine monitoring of ADAMTS13 activity by rapid assay, in conjunction with rituximab therapy as needed, has been shown to effectively normalize ADAMTS13 activity and possibly prevent relapse in three patients with history of relapsed TTP. Our experience provides evidence against the inpatient use of rituximab in relapsed TTP, and provides justification for the development of a protocol for the routine follow-up of TTP patients with implementation of prophylactic rituximab. [Display omitted] DisclosuresReagan:Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Speakers Bureau.

Decreased vision as a presenting symptom of acquired thrombotic thrombocytopenic purpura relapse

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life‐threatening, blood disorder caused by a severe deficiency in von Wildebrand factor cleaving protease activity due to inhibitory an...

Inhibitory anti ADAMTS13 antibodies with a new rapid fully automated CLiA assay

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by severe ADAMTS13 deficiency. The acquired form is associated with autoantibodies directed against ADAMTS13. Both noninhibitory and inhibitory autoantibodies can be detected by ELISA assay, while only inhibitory autoantibodies are detected by Bethesda assay. Due to its short TAT and good performance, chemiluminescence (CliA) ADAMTS13 activity (HemosIL Acustar) has proven to be a good choice in the diagnosis of TTP in emergency settings. Aim of this study was to analyse the performance of the CliA ADAMTS13 activity assay in detecting inhibitory ADAMTS13 antibodies using the Bethesda assay. A method comparison study was performed on 69 stored samples: 11 acute TTPs, 38 TTP follow-ups, 5 TTP relapses, 1 congenital TTP, 10 HUS, 4 suspected TTPs. We retrieved the results of tests previously run in ELISA for both activity and autoantibodies. At the same time, we reran new tests including ELISA and CliA activity, ELISA autoantibodies, and ELISA and CliA Bethesda assays on thawed frozen samples. Very good correlation was observed between ELISA and CliA activity assay results (r=0.96) and between archived ELISA and CliA activity results (r=0.93). Agreement between the anti-ADAMTS13 assays ranged from good (k=0.63) to very good (k=0.92). CliA and ELISA Bethesda assays showed very good agreement with samples run at the same time using ELISA ADAMTS13-autoantibody assay. Albeit more expensive, the CliA Bethesda assay identified inhibitory anti-ADAMTS13 within almost the same TAT as ELISA, but with better automation and limited operator involvement.

Diagnosis and treatment of thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease in which platelets are consumed and thrombotic microangiopathy develops in multiple organs due to a severe deficiency of the metalloproteinase, ADAMTS13. TTP should be suspected in any case associated with thrombocytopenia and hemolytic anemia; TTP can be diagnosed in cases of profound reduction in ADAMTS13 activity (to <10% of the normal level). Congenital TTP involves mutations in the ADAMTS13 gene, whereas acquired or autoimmune TTP results from the actions of inhibitory autoantibodies against the ADAMTS13 protein. Plasma exchange together with corticosteroids is an effective treatment for acquired TTP; plasma exchange removes autoantibodies and provides ADAMTS13 supplementation, whereas corticosteroids further suppress autoantibody generation. Rituximab was recently approved in Japan for use in refractory or relapsing TTP. Likewise, caplacizumab, an anti-von Willebrand factor, may contribute to disease control and overall survival by preventing ongoing thrombosis and acute end-organ damage.

Describing the Point Prevalence and Characteristics of Venous Thromboembolism in Patients with Thrombotic Thrombocytopenic Purpura

Background: Thrombotic thrombocytopenic purpura (TTP) presents with microangiopathic hemolytic anemia, thrombocytopenia and microvascular thrombosis. Arterial thromboembolic events are relatively common and well-described in these patients. However, the literature describing venous thromboembolism (VTE) in this patient population is scarce and outdated. We hypothesize that patients with TTP are at greater risk for VTE due to the use of central venous catheters and use of solvent-detergent plasma (SDP) for plasma exchange (PLEX). Methods: Eligible patients from a single tertiary care centre were identified through apheresis records, and a retrospective chart review was conducted. The criteria for TTP diagnosis included the presence of accepted clinical/laboratory criteria and ADAMTS13 activity &lt;10%. We considered the diagnosis of VTE if any of the following were present: pulmonary embolism (PE), deep vein thrombosis (DVT) or superficial vein thrombosis (SVT). Data were analyzed using simple descriptive statistics. Institutional research ethics board approval was obtained. Results: We identified 77 consecutive patients with 123 episodes of TTP between January 1, 2008 and December 31, 2018. 51 patients (66%) were female, and 74 (96%) had immune TTP. Standard of care was daily PLEX and high-dose steroids, while rituximab was used for relapsed/refractory disease. In addition, 6 patients received caplacizumab. 13 of the 77 patients (17%) experienced a VTE (14 events: 6 PE, 5 DVT, 3 SVT), all of which were acute and associated with admission for either first presentation or relapse of TTP. None of the VTEs were catheter related. 8/13 patients were female, and all had immune TTP. Median age at diagnosis of VTE was 45 years (IQR: 36.0-56.5 years). 10/14 events were symptomatic; diagnosis was confirmed a median of 1.5 days after VTE symptom onset (IQR: 1-3 days). All patients were treated with PLEX, receiving a median of 17 exchanges (IQR: 10-23 exchanges). In addition, 13/14 TTP episodes were treated with corticosteroids, 9 with rituximab, and no patients received caplacizumab. 8 patients experienced a VTE while receiving daily PLEX; the majority (6/8) were being exchanged with SDP. VTE was diagnosed a median of 13.5 days after initiation of PLEX (IQR: 9.2-23.5 days). At TTP presentation, median platelet count was 11 x 109/L (IQR: 7-16 x 109/L), and median LDH was 894 U/L (IQR: 508-1272 U/L). At VTE diagnosis, the median platelet and LDH levels were 170 x 109/L (IQR: 126-248 x 109/L), and 232 U/L (IQR: 176-254 U/L) respectively. No patients had D-dimer testing at VTE symptom onset or diagnosis. Of the 6 patients with PE, 3 had elevated troponin levels (&gt;0.040 ug/L) at VTE diagnosis. In terms of VTE risk factors, median BMI was 30.0 (IQR: 28.7-32.1); the majority of patients (7/13) were obese (BMI&gt;30). 4/13 patients were active cigarette smokers. No patients had a history of lupus or antiphospholipid antibody syndrome. 2 patients had a past history of VTE, one was associated with a prior TTP episode. Most VTEs (8/14) occurred while patients were not on any pharmacologic thromboprophylaxis. For the remaining patients, dalteparin (3), ASA (2) and rivaroxaban (1) were used. VTE events were treated with direct oral anticoagulants (DOACs) including rivaroxaban and apixaban, in 10 cases. 7 of these patients were started on a DOAC after a brief initial period of low molecular weight or unfractionated heparin, 3 patients were given DOAC as upfront therapy. 4 cases were treated with warfarin (3 bridged with heparin and 1 following rivaroxaban). One distal DVT was not treated. None of the VTEs were fatal. Discussion: The point prevalence of VTE was 17% over one decade amongst patients with TTP; this is higher than previously reported in the literature. Our data also suggests that TTP patients may be at greater risk for VTE compared to general hospitalized medical patients. The majority of affected patients on PLEX were receiving SDP at VTE diagnosis. SDP contains reduced levels of proteins C and S and may have a pro-thrombotic effect. Almost all VTEs occurred after platelet recovery and normalization of hemolytic markers, suggesting a different pathophysiology than arterial thrombosis in this setting. VTE thromboprophylaxis was uncommon since it was often held due to thrombocytopenia and not resumed upon platelet recovery. Our findings suggest the need to implement VTE thromboprophylaxis earlier in patients admitted with TTP. Disclosures Sholzberg: Novartis: Honoraria; Amgen: Honoraria, Research Funding. Pavenski:Ablynx: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Shire: Honoraria; Octapharma: Research Funding; Bioverativ: Research Funding.

Impact of Residual Effects and Complications of Thrombotic Thrombocytopenic Purpura (TTP) on Daily Living: A Qualitative Study

Introduction: Adverse health outcomes following recovery from thrombotic thrombocytopenic purpura (TTP) are under-recognized. The Oklahoma (OK) TTP Registry has documented that patients have residual complications following recovery. TTP survivors have an increased prevalence of major depression, decreased quality of life, minor cognitive impairment, and a decreased life expectancy compared to the general population. Additionally, Chaturvedi et. al (2017), reported that 32% of TTP survivors met the provisional diagnosis of post-traumatic stress disorder related to their TTP. Yet studies have failed to assess the significance of residual complications from the survivor's perspective. The goal of this study was to determine from the survivor's perspective, long-term outcomes that impact daily activities during remission. Patients: TTP survivors were recruited from the OK Registry and the Ohio State University (OSU) TTP Research Program. Eligibility included: 1) age &amp;gt;18 years, 2) documented ADAMTS13 deficiency, 3) in clinical remission from TTP, and 4) able to read and understand English. A non-probabilistic purposive sampling approach was utilized to select survivors from whom the most could be learned. To understand the full range of health challenges during remission, we intentionally included &amp;gt; 1 person who had experienced a TTP relapse in each focus group. Methods: Qualitative focus groups were conducted using a semi-structured discussion guide to facilitate and standardize the discussion. Prior to use, the discussion guide was pilot-tested and revised accordingly. All the focus groups were conducted in-person and moderated by the first author. During the focus group, TTP survivors described symptoms following recovery. All of the mentioned symptoms were transferred to index cards and given to each person. Patients individually sorted the cards into 'high', 'medium', and 'low' impact on daily living. Next, patients discussed views on what makes a symptom high, medium, or low impact. Additionally, patients were asked to list their top 3 symptoms on an index card (regardless of if it had been previously mentioned). Patients were also asked about discussions with their physicians regarding these symptoms. Frequencies were calculated for quantitative responses. Qualitative data were analyzed for themes. Results: Focus groups (4 in OK; 3 in OSU) were conducted from May-Oct. 2018, were 54-94 minutes, and digitally recorded. Overall, there were 25 patients (76% female, 52% black, median age 46 years) (Table 1). Eighty percent of patients were &amp;gt;5 years from their last episode, 52% had experienced a TTP relapse. The top 2 symptoms listed on the cards were: cognitive impairment 19/25 (76%) and fatigue 17/25 (68%). These symptoms were ranked as high in patients who were both &amp;lt; and &amp;gt;5 years from their last episode. High-impact symptoms occurred daily and negatively affected self-esteem, relationships, and careers. In 6/7 focus groups, survivors described high-impact symptoms caused feelings of being a burden, embarrassment, depression, and anxiety. Fatigue kept survivors from activities with loved ones and the hobbies they enjoyed prior to TTP. Cognitive impairment was described as difficulty 'getting the right words out', forming complete thoughts, and problems with memory and concentration. Cognitive impairment often resulted in arguing and frustration with loved ones. In 4/7 focus groups, memory and concentration problems were detrimental to marriages/long-term relationships. In 5/7 focus groups, cognitive impairment significantly impacted a person's ability to do their job. In 1 focus group, patients who worked in healthcare stated they changed careers because they feared their memory problems would negatively impact the health of others. Yet, many patients were hesitant to discuss these symptoms with a physician because they: 1) did not want to complain, 2) did not want to be prescribed additional medication, and 3) did not think these symptoms were relevant to their 'blood doctor'. Conclusion: Cognitive impairment and fatigue have serious impacts on daily living even &amp;gt;5 years after TTP. Yet, patients were often hesitant to discuss the issues with their doctor and failed to connect these symptoms with the TTP recovery process. Phase II of this study is currently underway, the goal is to identify from the TTP survivor's perspective, preferred ways to assess and manage these symptoms. Disclosures Terrell: National Institutes of Health: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Panepinto:NIH: Research Funding.

Rituximab in Relapsing acquired Thrombotic Thrombocytopenic Purpura: Experience and Evidence

Thrombotic Thrombocytopenic Purpura (TTP), first described in the early twentieth century, was fatal in the majority of cases until the advent of plasma therapy. Mortality has declined dramatically since the 1980s, and in the 1990s the pathophysiology was elucidated through the discovery and understanding of the central role of a deficiency of the metalloprotease ADAMTS13. The vast majority of cases occur due to an autoimmune process, with a minority of cases due to an underlying mutation. Since the turn of this century, Rituximab, a monoclonal antibody targeting CD20 expressed on B-lymphocytes, has become widely used to treat patients with a wide spectrum of autoimmune diseases, including TTP. However, Rituximab remains “off-label” in the setting of TTP. We recently encountered a patient with chronic relapsing TTP, whose clinical relapses have responded to Rituximab-based therapy without need to resort to plasmapheresis. The clinical course of this patient is described, and the literature focusing on the use of Rituximab in prophylaxis to prevent recurrent TTP is reviewed.

Cost Effectiveness of Rituximab As Adjunctive Therapy in Reducing Apheresis Procedures and Hospital Length of Stay in Relapsed Thrombotic Thrombocytopenic Purpura

Introduction: Rituximab at standard dosing (375 mg/m2 weekly for 4 weeks) is effective in preventing thrombotic thrombocytopenic purpura (TTP) relapse and is recommended as a therapy of choice along with plasmapheresis (PLEX) in the UK expert-based guidelines on TTP (category IB), although it is not yet universally viewed as standard of care. There is also emerging data for low dose rituximab (100 mg weekly for 4 weeks) in the treatment of relapsing TTP with mixed data on efficacy as compared to standard dose rituximab. With this in mind, we conducted a retrospective chart review to examine the financial cost of treating a patient hospitalized for a TTP relapse with rituximab, PLEX and steroids compared to PLEX and steroids only. The purpose of this study was to determine an average savings per patient of utilizing rituximab as an adjunctive agent in the inpatient setting.Methods: Chart records for patients admitted to a major academic center with a diagnosis of TTP, defined as laboratory and smear evidence of microangiopathy with ADAMTS13 level of 10% or less or evidence of microangiopathy in a patient with a prior established diagnosis of TTP, were reviewed. The clinical course of all patients including treatments received and length of stay (LOS) for each hospitalization was recorded. TTP relapse was defined as hospitalization for TTP more than 30 days after hospital discharge. An average hospital cost per patient with a relapsed episode of TTP was calculated utilizing average costs for LOS and for PLEX during their hospitalization for TTP relapse. The average wholesale price of a fixed dose of rituximab for one cycle (defined as four doses of 375 mg/m2) was utilized to calculate the total cost of rituximab treatment. A cost superiority determination per patient was calculated by comparing the total cost of relapsed TTP hospitalizations versus the cost of rituximab administered in the inpatient setting. All costs are listed in United States Dollar (USD).Results: A total of 28 patients spanning 25 years were hospitalized for a TTP exacerbation. The median age of these patients was 40.7 with ADAMTS13 level of 6.5% at diagnosis and 3.2% at relapse. Of 28 patients, 15 patients had relapsed TTP for a total of 50 hospitalizations. All 15 relapsed patients were treated with PLEX and steroids during every hospitalization. The average number of inpatient PLEX procedures performed on patients admitted for relapsed TTP was 7.1 with an average hospital LOS of 9.6 days. 13 of the 15 relapsed patients received a total of 15 cycles of rituximab while 2 patients did not receive any rituximab. Of the 13 rituximab-treated patients, 10 received one cycle of rituximab, with 9 achieving a sustained remission and the other patient experiencing a relapse of TTP that was not treated with any additional rituximab; 2 received a second cycle, with both achieving a sustained remission, although 1 had an allergic reaction during the second cycle that led to discontinuation of rituximab. In total, 11 of 15 episodes of relapsed TTP were treated with rituximab with 73% achieving a sustained remission over a median follow up time of 36 months.In our study cohort, use of rituximab would have led to a reduction in 182 total hospitalization days and 135 total PLEX procedures, yielding a cost savings of $59,918.40 per relapse of TTP. This would be offset by a cost of $30,894 for each cycle of standard dose rituximab, for a net cost savings of $29,024.40 per occurrence of TTP relapse treated with rituximab. A similar cost analysis utilizing low dose rituximab yielded a net cost savings of $55,582.40 per relapse of TTP, assuming similar efficacy of low and standard dose rituximab.Conclusions: The addition of rituximab to PLEX and steroids in treatment of relapsed TTP is more cost effective than PLEX and steroids alone, owing to the high efficacy of rituximab and the cumulative costs of PLEX and hospital LOS. This cost superiority of rituximab holds both for standard and low dose rituximab, assuming similar efficacy of the latter. Although not calculated in our analysis, administration of rituximab in the outpatient rather than inpatient setting would result in further cost savings. Therefore, from a cost efficiency standpoint, rituximab should be incorporated into treatment paradigms for relapsed TTP. DisclosuresNo relevant conflicts of interest to declare.

Predictors of Relapse and Efficacy of Rituximab in Autoimmune Thrombotic Thrombocytopenic Purpura (TTP): A Multi-Institutional Registry-Based Analysis

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a distinct and lethal subtype of thrombotic microangiopathy (TMA) requiring treatment with therapeutic plasma exchange (TPE). However, a significant proportion of patients suffer relapses of TTP, and predictors of relapse remain unclear. Whether rituximab (RTX) affects relapse rates in TTP is uncertain. We employed a multi-institutional, registry-based approach to study the effect of RTX on relapse in autoimmune TTP and identify predictors of relapse.Methods: Consecutive adult patients presenting with acute autoimmune TTP (thrombocytopenia (<150 x 109 platelets/L) and schistocytes associated with an ADAMTS13 activity level of ≤10%) at 5 academic medical centers between 2004 and 2017 were studied. We recorded demographic information, laboratory parameters, treatment, and outcomes, including complications of TPE, death, and relapse. Extended Cox proportional hazards regression was used to identify variables associated with hazard of relapse. Kaplan-Meier survival analysis was used to study the impact of RTX on risk of relapse.Results: Within our combined dataset, we identified 124 patients with autoimmune TTP. Patients were treated with a median (IQR) of 14 (8-22) TPE treatments until clinical remission was achieved. Seventy-five percent of patients experienced at least one complication from TPE; most common were mild urticarial reactions, but more serious allergic reactions including anaphylaxis occurred in 19% of TPE courses, and one patient died as the result of line-associated bacteremia during TPE. Of the 109 patients with 90-day or more follow up data, 8 (7.3%) died following presentation with TTP; five of these 8 deaths occurred in patients who presented in a moribund state or did not received TPE within the first 24 hours of hospitalization. Thirty-four patients (27%) subsequently relapsed, with a median time to relapse of 1.75 years. RTX was given to 48% of patients. The median time to the first dose of RTX was 12 (7-23) days following presentation. We observed a 3.6% increase per year in the proportion of patients presenting for the first time with acute TTP who were treated with RTX. Kaplan Meier analysis performed on the entire cohort did not show an overall difference in relapse free survival between patients who received RTX and those who did not (Figure 1) but did suggest the presence of a short-term benefit from RTX. A sensitivity analysis using only patients who presented with a first episode of TTP yielded similar results. Extended Cox multivariate analysis showed that the following parameters were independently associated with increased risk of relapse: younger age (HR=2.94, 95% CI: 1.2-7.2, P=0.018), non-O blood group (HR=2.11, 95% CI: 1.03-4.3, P=0.041), and history of a prior episode of TTP (HR=3.05, 95% CI: 1.4-6.6, P=0.005). By contrast, RTX reduced the risk of relapse (HR=0.15, 95% CI 0.03-0.68) but this protective effect appeared to diminish over time. ADAMTS13 inhibitor titer at initial presentation did not predict relapse.Conclusions: Although a significant number of patients experienced complications from treatment with TPE, death from TTP was infrequent and generally associated with delay in seeking medical care or initiating treatment. Use of RTX was associated with short-term protection from relapse but not long-term relapse free survival. Age, non-O blood group, and prior TTP were significantly associated with an increased risk of relapse. Further studies in independent datasets are required to validate the role of these risk factors in identifying patients who would benefit most from therapies directed at prevention of relapse in TTP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Description of the First Cases with ADAMTS13 Mutations in Hungary

INTRODUCTIONLow ADAMTS13 activity is associated with an increased risk of thrombotic thrombocytopenic purpura (TTP). This may be caused by the presence of inhibitory autoantibody (immune-mediated TTP) or genetic deficiency of the enzyme. The latter condition is also known as Upshaw-Schulman syndrome (USS), the extremely rare congenital form of TTP. The clinical picture typically presents during infancy or early childhood but an increasing number of late-onset cases are detected. OBJECTIVEClinical and laboratory characterization of the first 5 Hungarian cases with ADAMTS13 mutations. PATIENTSDuring the last 4 years, 5 cases with ADAMTS13 gene mutations were recognized in Hungary. All were adults, 4 females and 1 male. Two patients (Pts) showed an immune-mediated TTP like clinical picture, while 3 Pts were examined in conjunction with their pregnancies. The first Pt was an 18 years old girl, initially presenting with stroke and isolated cerebral vasculitis. She responded promptly to plasma exchange (PE) combined with immunosuppressive treatment (ISU) and acetylsalicylate (AS). However, severe headache with progressively decreasing platelet (PLT) count into the low normal range and repeatedly deficient ADAMTS13 activity returned after one week of PE cessation necessitating further treatment. ISU was stopped when cerebral vasculitis was excluded. There were several, plasma (PE/infusion) responsive severe headache+bradycardia episodes without hematologic manifestation in the follow-up period. The first TTP episode of the only male Pt occurred at age of 25 and the later clinical course highly resembled autoimmune relapsing (intermittent type) TTP. The Pt received several series of PEs, ISU, even splenectomy, before having the correct diagnosis. Interestingly, this Pt had unclassified HUS in the childhood. The 3rd case was a 40 years old woman with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) needing an immediate cesarean section (CS) in the 25th week of gestation. She achieved a spontaneous remission and remained symptom-free. The fourth Pt a 29 years old female had typical HUS at 3 years of age. Her kidney function slowly declined without HUS flares to end-stage kidney failure necessitating kidney transplantation. She had deep venous thrombosis (DVT) and intrauterine fetal death at 20 weeks of gestation. The workup showed decreased but not severely deficient ADAMTS13 activity. She received AS + low molecular weight heparin (LMWH) and increasing dose of plasma treatment starting at the 10th week of gestation of her next pregnancy. CS was done due to progressive hypertension and worsening placental circulation at the 30th week of gestation. The last Pt was a 41-year-old pregnant woman with recurrent abortions in her history. She received AS and LMWH only. The pregnancy was terminated by CS due to severe vaginal bleeding at the 30th week of gestation. RESULTSPts 1 and 2 with TTP clinical phenotype and Pt 3 with HELLP syndrome had deficient ADAMTS13 activity (0-0-8%, respectively). The activity was decreased but not deficient in Pts 4 and 5 (13-35%). All deficient Pts were compound heterozygous for ADAMTS13 mutations: c.3178C>T and c.4143-4144dupA (Pt1), c.1016_1017delCA and c.3199T>A (Pt2), c.1261C>T and c.3283C>T (Pt3). Three of these mutations were described in patients with USS, 1 in Pts with DVT, whereas 2 mutations are novel. By family study, we could demonstrate the association of c.1261C>T mutation described in DVT and one USS Pts with reduced ADAMTS13 activity. The two non-deficient cases were heterozygous for one of the following mutations: c.3178C>T and c.2839C>T. The previous was identified in late-onset USS, the latter has not yet been described, its association with reduced ADAMTS13 activity was also proven by family study. CONCLUSIONSClinical and molecular characterization of the first 5 Hungarian cases with ADAMTS13 mutations was presented. Compound heterozygous, damaging ADAMTS13 mutations with deficient plasma ADAMTS13 activity were associated with serious clinical consequences. In case of thrombotic microangiopathy in young patients with stroke, or HELLP syndrome, complete workup for ADAMTS13 activity and inhibitors is necessary, and genetic analysis should be considered. Three new ADAMTS13 mutations (c.1016_1017delCA, c.3199T>A , c.2839C>T) were identified and shown to be associated with decreased plasma ADAMTS13 activity. DisclosuresKremer Hovinga:Ablynx: Other: Member of Advisory Board; Shire: Other: Member of Advisory Board, Research Funding. Masszi:AbbVie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Janssen-Cilag: Consultancy; BMS: Consultancy; Pfizer: Consultancy.

Efficacy and safety of rituximab-contained regimen for refractory and relapsing thrombotic thrombocytopenic purpura: a retrospective study of 10 cases

Efficacy and safety of rituximab-contained regimen for refractory and relapsing thrombotic thrombocytopenic purpura: a retrospective study of 10 cases

HIV Infection Increases the Risk of Thrombotic Thrombocytopenic Purpura

An association between HIV infection and Thrombotic Thrombocytopenic Purpura (TTP) remains controversial.We conducted a cross-sectional analysis of 39 consecutive, non-referral cases of TTP encountered over 9 years ata single institution. Thirteen cases had HIV infection. The patients were treated with daily plasma exchange untilremission. The mean (standard deviation) duration of follow-up was 48 (37) months. Seven patients died. TTPcaused 3 of the 4 deaths in the HIV- group but none of the 3 deaths in the HIV+ groups. The age and sex adjustedincidence rate of TTP was 14.5 cases per 106 person-years. The relative risk of TTP was 38.5 (95% confidenceinterval, 19.7-75.0) for HIV infection, 2.7 (1.3-5.7) for female gender and was not increased for the black race.Neither HIV infection nor gender affect the overall and relapse free survivals. While relapse continued to occurthroughout the follow-up period in the HIV- group, it did not occur in the HIV+ group after the first year. We concludethat HIV infection is a major risk factor of TTP. The risk of late TTP relapse is low in HIV infected patients treatedwith anti-retroviral therapies.

Maintenance treatment using the purine-synthesis inhibitor mizoribine in a patient with relapsing thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening disease. Although plasma exchange (PE) therapy and corticosteroids are standard remission induction and maintenance therapies, some patients are easily refractory and frequently relapse under treatment with this therapy, and require additional treatment. However, there are limited data about additional treatment interventions. We report a case of 56-year-old man who was hospitalized for fever, general fatigue and hemoglobinuria. Owing to the symptoms and the laboratory findings of hemolysis, he was diagnosed with TTP. He was treated with PE therapy and corticosteroids, and the TTP went into remission. However, his TTP relapsed and remission induction was attempted again. As a remission maintenance treatment, we used combination therapy with the purine-synthesis inhibitor mizoribine (MZR) and corticosteroids. The administration of MZR maintained disease activity with no adverse event for long periods and allowed us to gradually reduce the corticosteroids dose. Hence, we propose that MZR is an effective treatment for TTP maintenance.