First Episode Of Thrombotic Thrombocytopenic Purpura Research Articles

Incidence of thrombotic microangiopathies in Quebec: insight from a laboratory centralizing ADAMTS-13 testing

BackgroundThrombotic microangiopathies (TMA) are serious medical conditions requiring a prompt diagnosis to adapt treatment. The determination of ADAMTS-13 activity enables discriminating thrombotic thrombocytopenic purpura (TTP) from other forms of TMA. The purpose of this study was to provide an estimate of the incidence of TTP and TMA in the Canadian Quebec province using data collected from a laboratory centralizing ADAMTS-13 testing for the whole province.ResultsFrom 2012 to 2019, 846 patients were evaluated for plasma ADAMTS-13 activity due to a suspicion of TMA. TTP was identified in 147 patients. Of these, 118 patients with a median age of 51.5 years and a male–female ratio of 1:1.4 had their first episode of TTP during the study period. The number of ADAMTS-13 tests performed and the number of patients with suspected TMA increased annually by 19% and 21% respectively. While the incidence of non-TTP TMA increased annually, that for TTP remained unchanged. This averaged 10.2 (95% CI 5.9–14.4) per million persons per year for suspected non-TTP TMA and 1.8 (95% CI 1.3–2.4) for confirmed TTP. The incidence rate of TMA other than TTP was higher in the age group 70–79 years (21.8; 95% CI 5.4–38.1) for females and in the age group 80–89 years (24.4; 95% CI 7.2–41.7) for males compared to other age groups. The incidence rate of TTP was higher in the age group 40–49 years (4.0; 95% CI 2.0–5.9) for women and in the age group 60–69 years (3.4; 95% CI 1.1–5.6) for men compared to other age groups.ConclusionThe analysis of centralized data measuring ADAMTS-13 activity allowed us to adequately establish the incidence rate and demographic characteristics of TMA, particularly TTP, in Quebec. TTP incidence remained stable while suspected non-TTP TMA steadily increased from 2012 to 2019.

Cardiovascular Disease Is a Leading Cause of Death in Thrombotic Thrombocytopenic Purpura (TTP) Survivors

Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially lethal thrombotic microangiopathy; however, prompt therapy with plasma exchange and immunosuppression leads to survival in over 90% of patients. Though TTP survivors were previously thought to return to baseline levels of health, recent reports suggest that TTP survivors have high rates of adverse health sequelae including hypertension, stroke, cognitive impairment, and poor quality of life as well as higher mortality rates compared with an age, race, and sex matched controls population. We conducted this multi-center cohort study to evaluate long term mortality and causes of death in patients that survived their first TTP episode. Methods: All available patients in The Ohio State University and Johns Hopkins Hospital Thrombotic Microangiopathy (TMA) registries were reviewed. Patients with confirmed iTTP based on ADAMTS13 activity <10% during an acute episode were included for analysis. A total of 238 patients met inclusion criteria, with 38 experiencing death during follow up. We evaluated primary and secondary cause of death where applicable. We also collected data on patient demographics, details of TTP history, and comorbidities including hypertension, diabetes, obesity, heart failure, hyperlipidemia, autoimmune conditions, chronic kidney disease, smoking, etc. Mortality was compared with an age, sex and race standardized US population using indirect standardization methods. A multivariable cox regression analysis was used to evaluate risk factors for reduced survival. Results: A total of 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries between 2003 and 2020, of which 70.3% were female, and median age at enrollment was 42 (IQR [interquartile range] 29, 55) years. There were 38 deaths over a median follow up of 4 (IQR 0, 11) years (and a total of 1318 patient years of follow up). Characteristics of the study cohort are summarized in Table 1. Of the 38 patients that died, 9 died during their first episode of TTP and 29 died after surviving the first TTP episode. Median age at death among those that survived the first TTP episode was 49 (IQR 39, 65) years. Among survivors of acute TTP, cardiovascular disease was the leading primary cause of death (27.6%) followed by relapsed TTP (27.6%), malignancy (20.7%), infection (13.8%), and other/unknown causes (10.3%) (Table 2). Cardiovascular disease was the primary or secondary cause of death in 31% (9 of 29) patients. Cardiovascular causes of death included myocardial infarction, arrhythmia, decompensated heart failure, stroke, and hypertensive emergency. The median age of death from any cardiovascular cause (primary or secondary) was 49 years. Among TTP survivors, male sex [HR 4.39 (95% CI 1.83-10.52, P=0.001), age [HR 1.03 (95% CI 1.01-1.06), P=0.039] and number of TTP episodes [HR 1.12 (96% CI 1.05-1.21), P=0.001] were risk factors for mortality in a Cox regression model also adjusted for hypertension [HR 0.60 (95% CI 0.26-1.37), P=0.228], CKD [HR 1.38 (95% CI 0.61-3.13, P=0.436] and SLE [HR 1.26 (95% CI 1.04-1.21), P=0.771]. The mortality rate in TTP survivors was significantly higher than the expected mortality rate from an age and sex standardized reference US population (2228.3 per 100,000 person years versus 1273.8 per 100,000 person years, P = 0.007) (Figure 1). The median age at death was also lower in TTP survivors compared with the general population (49 versus 78.7 years). Conclusions: TTP survivors have two-fold higher mortality rate than expected rates from a reference US population, adjusted for age, sex and race. Cardiovascular disease is a leading cause of death in patients that survive their first episode of TTP. This may be due to higher rates of cardiovascular risk factors such as hypertension in TTP survivors. Reduced ADAMTS13 activity is a risk factor for all cause and cardiovascular death in the general population (Sonneveld et al.Arterioscler Thromb Vasc Biol. 2016) and may contribute to cardiovascular death in TTP survivors. Our results highlight the need to screen and aggressively manage cardiovascular risk factors in TTP survivors, and for prospective studies examining the vascular sequelae of TTP. Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Chaturvedi:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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.

No Major Differences in Outcomes Between the Initial and Relapse Episodes in Patients with Thrombotic Thrombocytopenic Purpura: The Experience from the Ohio State University Registry

Background:Thrombotic thrombocytopenic purpura (TTP) is characterized by consumptive thrombocytopenia and microangiopathic hemolytic anemia. At least a third of the patients with TTP will have one or more relapses throughout their life. There is very little data regarding the differences, if any, in clinical presentation and outcomes between the initial and subsequent TTP episodes. This information is relevant to understand if patients that present initially and those that present with a relapse can be seen as equal when being considered for clinical trials. Identifying the characteristics of patients that are prone to relapse will help guide the monitoring of patients after an acute episode of TTP to help to prevent relapse.Methods:Between March 2003 and June 2016 we collected clinical and laboratory data on all patients that presented to the Ohio State University with a diagnosis of acquired TTP (aTTP). The diagnostic criteria for aTTP included: thrombocytopenia, and a microangiopathic hemolytic anemia without an alternative explanation. The diagnosis was confirmed by the finding of severely deficient ADAMTS13 activity (<10%). Patients were consented to participate in our TTP registry and the information obtained included initial clinical presentation, platelets, LDH, kidney function, ADAMTS13 activity and inhibitor titer, number of plasma exchange (PEX) to achieve remission (defined as number of PEX needed to obtain a normal platelet count), and the outcome of the episode; clinical response (normal platelet count and LDH), exacerbation (recurrent TTP within 30 days of last PEX procedure), refractory (more than 30 PEX needed to obtain a clinical response), or death.Results:- All the patients enrolled were included in the study, except those with active cancer, leaving a total of 125 episodes from 57 patients.- 36 of the 57 patients had two or more TTP episodes (relapse rate 63.1%), with 21 of the 57 patients having 3 or more episodes. The time between episodes varied greatly, from 2 months to 8 years.- Of the 125 episodes, there were 42 initial and 83 relapses.- The initial group presented with central nervous system (CNS) symptoms more commonly than the relapse group. They also had significantly lower platelets and a higher LDH than the relapse group.- Regarding treatment, there was no significant difference in the number of PEX needed to achieve remission between the 2 groups. However, there was a significant number of patients in the initial group that needed more than 5 PEX to achieve remission, compared to the relapse group (p<0.0001)- There were no significant differences in the main clinical outcomes between the initial and relapse groups in rates of clinical response (p=0.267), exacerbation (p=0.483), refractory (p=0.075) or death (p=0.066)Conclusions:In their first episode of TTP, patients may present more ill than those patients having relapses (with more CNS symptoms, lower platelets and higher LDH), and may also require more PEX sessions to achieve remission. However, these findings do not change outcomes, and patients in their initial presentation and relapses can be seen as equal in terms of clinical response, exacerbation, refractory disease, and mortality rates. The high relapse rate seen in our registry may be due to the prolonged follow up (13 years) which is more than other series reported. Patients may have a relapse even after several years of being stable. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Increased Morbidity during Long Term Follow up of Survivors of Thrombotic Thrombocytopenic Purpura

Background and Objective: The advent of plasma exchange has led to a dramatic improvement in the survival of patients with thrombotic thrombocytopenic purpura (TTP). Recovery from TTP is usually complete, but may be complicated by a significant rate of relapse, particularly in the first year after the acute episode. Recent reports also suggest that survivors of TTP may have a poorer health related quality of life than previously estimated. We followed a cohort of 100 patients diagnosed with TTP to estimate the burden of chronic renal impairment, hypertension, diabetes, stroke, depression and other psychiatric and neurologic conditions in this group.Patients and Methods: A total of 100 consecutive patients treated for TTP at the Cleveland Clinic from January 2000 to March 2012 were identified. Nine patients died and the remaining 91 patients were followed until death or date of last clinical contact. The point prevalence of chronic kidney disease, hypertension, diabetes, stroke, major depression and other neurologic and psychiatric conditions was compared to expected values in the reference US population [based on National Health and Nutrition Examination Survey (NHANES) data] adjusted for age and sex.Results: Of the 91 patients who survived a first episode of TTP, 69 (75.8%) were female, with an age range of 16 to 79 years (median 44 years). Fifty one percent of patients were Caucasian, 45% African American and 2% Hispanic. Sixty three percent of cases occurred without predisposing conditions while 12.1% were associated with autoimmune disease (5 with SLE, 2 with rheumatoid arthritis, one with SLE and rheumatoid arthritis, and one each with Sjogren’s syndrome, dermatomyositis and mixed connective tissue disorder), 8% with pregnancy or the postpartum state, 6.6% with cancer and 5.5% with solid organ transplant.The median follow up time was 59 months (range 1-117 months). During this period, 18 patients suffered relapses (11 patients had 1 relapse, 6 patients had 2 relapses, and 1 had three relapses). Compared to the reference US population, survivors of TTP had a higher prevalence of hypertension (61.5% versus 29.8%), chronic renal disease (26.4% versus 16.8%) and stroke (12.1% versus 1.87%). TTP survivors also had a high prevalence of neurologic disorders including migraines (n=9), multiple sclerosis (n=1), fibromyalgia (n=1) and restless leg syndrome (n=2). There was a five-fold higher incidence of major depression requiring pharmacologic treatment compared to the reference population (26.4% versus 5.4%). We also noted a significant prevalence of other mental health disorders such as anxiety disorders (n=15), bipolar disorder (n=2), adjustment disorder (n=1) and conversion disorder (n=1). The incidence of diabetes was lower than seen in the reference population (6.6% versus 14.4%).Conclusion: Survivors of TTP are at higher risk for poor health outcomes including chronic cardiovascular disease, neurologic disease and psychiatric conditions, all of which impair quality of life. These may be related to persistent organ damage from microvascular dysfunction during the acute episode of TTP, or from co-morbid conditions such as auto-immune diseases that are independent risk factors for poor outcomes. Our results highlight the importance of continued follow up in order to address the long-term health problems associated with TTP survivorship. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Monitoring ADAMTS13 Autoantibody Titer Using a Novel Quantitative Radioimmunoprecipitation Assay In Patients With Acquired Thrombotic Thrombocytopenic Purpura

BackgroundADAMTS13-binding immunoglobulin G (IgG)-type autoantibodies are present in patients with acquired thrombotic thrombocytopenic purpura (TTP), thereby causing severe deficiency of plasma ADAMTS13 activity. Some specific autoantibodies directly inhibit the enzymatic activity by interfering with the access of its substrate, von Willebrand factor (VWF), particularly in the spacer domain, although others bind to almost all of the domains in the molecule, possibly leading to the acceleration of the clearance from blood stream. Not only the inhibitor titer, but the importance of ADAMTS13 autoantibody titer was highlighted by many previous clinical studies, associating with the prognosis such as recurrence rate. ObjectiveWe targeted to establish a novel high-sensitive assay to measure ADAMTS13-binding IgG autoantibody titer using three kinds of radioisotope-labeled antigens, ADAMTS13 whole molecule, MDTCS and T2-8/CUB, and aimed to analyze the association between the autoantibody titer and the clinical characteristics of TTP patients. Materials and MethodsHuman Cell-Free Protein Expression System (Takara #3281, Shiga, Japan) was used to synthesize radioisotope-labeled antigens. ADAMTS13 cDNA corresponding to whole molecule (A13), metalloprotease to spacer domains (MDTCS) and TSP1-2 to CUB2 domains (T2-8/CUB) were cloned into an expression vector pT7-IRES and mixed with Cell Lysate containing T7 RNA polymerase, methionine-free amino acids, ATP, translation enhancement factor and 35S-methionine. The correct synthesis and molecular size of the radiolabeled antigens were checked with SDS-PAGE. To assess the utility as a quantitative assay, each of the antigens was mixed with mouse anti-ADAMTS13 monoclonal antibodies, whose epitopes were determined in our previous study (Thromb Res. 2012; 130(3):e79-83), and the immune complex was precipitated with protein G beads, washed and measured in a liquid scintillation counter. Plasma samples from acquired TTP patients were tested to quantify the autoantibody titers using radiolabeled A13, MDTCS and T2-8/CUB antigens, respectively. As a control, plasma samples from healthy subjects with no histories of autoimmune disease were also tested. ResultsEach of the radiolabeled antigens was detected as a single band at the correct molecular weight size and successfully immnoprecipitated with several mouse anti-ADAMTS13 monoclonal antibodies, indicating the intact molecular conformation of the synthesized proteins using the cell-free protein synthesis system. Moreover, the appropriate dose-dependent escalation curves in accordance with the addition of the monoclonal antibodies were observed, thereby confirming the utility of the assay as a quantitative analysis. We tested TTP patient plasma at onset (n=5) and were able to detect ADAMTS13 autoantibody titers with each of the radiolabeled A13, MDTCS and T2-8/CUB antigens. We next applied this assay for monitoring ADAMTS13 autoantibody titer in a clinical course of TTP patient. The patient developed the first episode of TTP at the age of 2 month and treated with steroid pulse and plasma exchange therapy for six consecutive days. Remission was once achieved but 6 months later from the onset, the second episode of TTP occurred and the patient was treated with 11 plasma exchange and rituximab at the dose of 375 mg/m2 once a week for 4 weeks. Plasma samples at onset, after the first 6 consecutive plasma exchange and after rituximab administration were examined about autoantibody titer using this assay. Interestingly, the titers remained high even after the plasma exchange but declined clearly after the rituximab treatment, whereas no reduction of total IgG level was observed. These findings suggest that the autoantibody titration using this assay might be useful to assess the effect of treatment and associate with the prognosis related to the recurrence. ConclusionWe developed a novel quantitative radioimmunoprecipitation assay to measure ADAMTS13 autoantibody titer related to three antigens, ADAMTS13 whole molecule, MDTCS and TSP2-8/CUB. This assay may serve not only as a diagnostic test but as a monitoring index to evaluate the prognosis of TTP. Disclosures:No relevant conflicts of interest to declare.

Management and outcomes for patients with TTP: analysis of 100 cases at a single institution

The advent of plasma exchange has led to a dramatic improvement in the survival of patients with thrombotic thrombocytopenic purpura (TTP), though approximately 10% of patients still die and a third suffer relapses. Clinical features that identify poor risk patients have not been clearly identified. We reviewed 100 patients who were treated for a first episode of TTP at the Cleveland Clinic between 2000 and 2012 to identify factors predictive of poor outcomes. On multivariate analysis, increasing age, especially age > 60 (RR: 7.08, 95% CI: 2.15-23.39, P = 0.002), severe neurological symptoms at presentation (RR: 18.37, 95% CI: I4.19-80.13, P < 0.001) and a persistently elevated LDH level after two plasma exchanges were predictive of mortality. Patients with ADAMTS13 activity above or below 5% did not differ in terms of clinical presentation or mortality and relapse rates, although ADAMTS13 activity > 5% was an independent predictor of adverse renal outcomes (need for dialysis and progression to chronic kidney disease). These variables may be useful for risk stratification and identification of patients who could potentially benefit from early institution of adjunctive therapy.

First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur?

Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare cause of thrombocytopenia and hemolysis characterized by life-threatening end-organ ischemia due to platelet microthrombi. TTP arises from severe deficiency of ADAMTS13 (< 10% activity). Although neurologic symptoms are considered classical of TTP, they are not present in all patients. Previous studies have described other manifestations in a significant percentage of the patients, related or not to hemolysis and anemia.1 Therefore, physicians must have a high level of suspicion in order to diagnose TTP. Delay to refer a patient for therapeutic plasma exchange (TPE) is potentially fatal.2 Following Institutional Review Board’s approval, we reviewed the records of all adults diagnosed with a first episode of TTP at the University of Alabama at Birmingham (UAB) and the Oklahoma TTP-HUS Registry from January 1, 2007 to June 30, 2010 to answer a specific question: What are the first symptoms of TTP and when do they occur? TTP was defined as thrombocytopenia, microangiopathic hemolytic anemia, and ADAMTS13 activity of < 10% . Patients with underlying conditions such as: pregnancy/postpartum, stem cell transplantation, sepsis, systemic malignancy, autoimmune disease, or a bloody diarrhea prodrome, were excluded, even if their ADAMTS13 activity was <10%. Thirty-four patients met eligibility criteria (23 from UAB and 11 from the OK Registry). Their mean age was 46 years, and 76% were female. Their laboratory data are shown in Table 1. Table 2 displays the initial symptoms and the number of days until the first TPE. While neurologic complaints were the most common (44%), they varied from mild, such as headache or lightheadedness, to serious, such as seizures and focal deficits. The single most common symptom was abdominal pain (23.5%), with or without nausea/vomiting. Less than 10% of patients reported bleeding secondary to thrombocytopenia. The mean number of days prior to TPE was 12, the median was 5.5, and 62% were treated within 7 days. Table 1 Laboratory characteristics of patients with TTP: Table 2 Initial symptoms and time to first therapeutic plasma exchange (TPE): Our data confirm that patients with TTP present with a wide range of symptoms, not immediately suspicious for TTP, such as abdominal pain, nausea and vomiting. We postulate that some of these symptoms reflect an underlying disease that may have triggered TTP. Influenza, for example, has been shown to induce antibodies to ADAMTS13 and clinical TTP.3 Moreover, we suggest that abdominal pain, not considered classic of TTP, represents intra-abdominal ischemia, as it has been rarely described.4-6 In the past year, we have seen two patients with ADAMTS13 deficiency that died with massive gastrointestinal ischemia and hemorrhage, confirmed by autopsy. Unfortunately, the nonspecific nature of signs and symptoms of TTP are likely to hamper a physician’s ability to suspect it on clinical grounds alone. Unless a complete blood cell count is ordered and the combination of severe thrombocytopenia and microangiopathic hemolytic anemia is noted, it is concerning that some patients may experience a delay in diagnosis. We did not collect any information on how many clinic or emergency room visits our patients had prior to being diagnosed with TTP. Anecdotally, we know that many patients are seen by several physicians until the constellation of history, laboratory values and consultation with colleagues in hematology or apheresis medicine eventually leads to the correct diagnosis of TTP. Indeed, patients included in this study had one or more of the following diagnoses prior to being referred for TPE: meningitis, arthritis, gastroenteritis, systemic lupus erythematosus, immune thrombocytopenia, stroke, urosepsis, diabetic non-ketotic hyperosmolar acidosis, pernicious anemia, pancreatitis, and antiphospholipid antibody syndrome, confirming our concerns.

Thrombotic Thrombocytopenic Purpura At the Cleveland Clinic 2000–2012: Review of 100 Cases and Identification of Prognostic Factors

AbstractAbstract 3325 BACKGROUND AND OBJECTIVE:The advent of plasma exchange has led to a dramatic improvement in the survival of patients with Thrombotic Thrombocytopenic Purpura (TTP). However 10–20% of patients do not respond to plasma exchange and up to a third suffer relapses. Recent studies suggest that Rituximab as an adjunct to plasma exchange and corticosteroids may be effective in refractory or relapsing disease, although clinical factors that identify patients at high risk for poor outcomes have not been clearly defined. This concern prompted a retrospective review of all patients with TTP treated at the Cleveland Clinic over the last 12 years in an attempt to identify factors associated with poor prognosis. Records from all patients were reviewed from the date of initial presentation until at least two years afterwards to determine the incidence of refractory disease and relapse. STUDY AND METHODS:A total of 284 patients who were diagnosed with a first episode of thrombotic microangiopathy at the Cleveland Clinic from January 2000 to March 2012 were identified. Records from these patients were reviewed and individuals with other explanations for thrombocytopenia and hemolytic anemia such as DIC, hypertensive crisis or HELLP were excluded. One hundred patients were included in the final analysis. Fischer exact test and t- test were used to compare variables. A p value of <0.05 was considered significant. RESULTS:Of the 100 patients with TTP, 73% were female, with an age range of 16 to 79 years (median 49 years). Fifty percent of patients were Caucasian, 45% African American and 2% Hispanic. Sixty seven percent of cases occurred without predisposing conditions while 12% were associated with autoimmune disease (6 with SLE, 2 with rheumatoid arthritis, one with SLE and rheumatoid arthritis, and one each with Sjogren’s syndrome, dermatomyositis and mixed connective tissue disorder), 8% with pregnancy or the postpartum state, 6% each with cancer and solid organ transplantation and 2% each with bone marrow and stem cell transplant. ADAMTS13 activity was tested in 57% of cases of which 36 (63%) had <5% and 21 (37%) had 8% to 56% activity, respectively. All patients were treated with plasma exchange, and all but 17 received corticosteroids, while some received additional therapies including vincristine (10), rituximab (15) and splenectomy (7) for refractory disease. Mortality after a first episode of TTP was 8%, while 13% of patients had exacerbations (within 30 days) and 18% had relapses (11 patients had a single relapse, 6 patients had 2 relapses and 1 had three relapses).Non survivors were older (p=0.042) with this association particularly striking for patients greater than age 60 (OR 8.75, 95% CI 2.32–33.01, p=0.002). Non-survivors also presented more frequently with severe neurological symptoms including obtundation, focal deficits and seizures (p=0.001). A higher LDH level after 1 or 2 cycles of plasma exchange, i.e. LDH on day 3, 4 or 5 of admission was also strongly associated with mortality (p<0.01) as well as with prolonged duration of plasma exchange.ADAMTS13 activity and levels of inhibitory anti-ADAMTS13 antibodies were comparable between survivors and non-survivors. However, undetectable ADAMTS13 levels were associated with a lower incidence of adverse renal outcomes including need for dialysis during the acute episode (p=0.007) and the development of chronic kidney disease (p=0.033) and/or end stage renal disease at 2 years (p=0.015). CONCLUSION:The most significant independent variables predicting death in TTP were increasing age, especially age>60, severe neurological symptoms at presentation and a persistently high LDH level the second day after diagnosis and initiation of plasma exchange. These variables could be used to identify patients who would benefit from close monitoring and potentially from early institution of adjunctive therapy. Treatment of high risk patients in this manner could limit the duration of plasma exchange, improve outcomes, and decrease associated morbidity and costs. Disclosures:No relevant conflicts of interest to declare.

Letter to the editor Cyclophosphamide-rescued plasmapheresis-unresponsive secondary thrombotic thrombocytopenic purpura caused by Sjögren’s syndrome

Letter to the editor Cyclophosphamide-rescued plasmapheresis-unresponsive secondary thrombotic thrombocytopenic purpura caused by Sjögren’s syndrome

Targeting B cells in severe thrombotic thrombocytopenic purpura–a road to cure?*

Targeting B cells in severe thrombotic thrombocytopenic purpura–a road to cure?*

Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic‐uremic syndromes

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent multiple disorders with diverse etiologies. We compared the gender and race of 335 patients enrolled in the Oklahoma TTP-HUS Registry across 21 years for their first episode of TTP or HUS to appropriate control groups. The relative frequency of women and white race among patients with TTP-HUS-associated with a bloody diarrhea prodrome and the relative frequency of women with quinine-associated TTP-HUS were significantly greater than their control populations. The relative frequency of women and black race among patients with idiopathic TTP and TTP-associated with severe ADAMTS13 deficiency was significantly greater than their control populations. The relative frequency of black race among patients who had systemic lupus erythematosus (SLE) preceding TTP was significantly greater than among a population of patients with SLE, and the relative frequency of black race among patients with other autoimmune disorders preceding TTP was significantly greater than their control population. No significant gender or race disparities were present among patients with hematopoietic stem cell transplantation-associated thrombotic microangiopathy, TTP associated with pregnancy, or TTP associated with drugs other than quinine. The validity of these observations is supported by the enrollment of all consecutive patients across 21 years from a defined geographic region, without selection or referral bias. These observations of different gender and race disparities among the TTP-HUS syndromes suggest the presence of different risk factors and may serve as starting points for novel investigations of pathogenesis.

Rituximab therapy in two children with autoimmune thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare disease among pediatric patients, in whom it may be mistaken for hemolytic uremic syndrome (HUS) and idiopathic thrombocytopenic purpura (ITP). Familial forms are caused by mutations in the ADAMTS13 gene, whereas acquired forms may result from an inhibitory antibody directed against ADAMTS13, a metalloprotease that cleaves very large multimers of Von Willebrand factor (VWF), thereby preventing platelet aggregation in blood vessels. We report two cases of TTP. The first was a 15-year-old girl with her first episode of TTP that failed to respond after 10 days of plasmapheresis and was treated with rituximab; she has remained in remission at 12 months of follow-up. The second was a 6-year-old boy with acquired relapsing TTP previously managed with plasmapheresis and prednisolone, who presented with a third relapse that was treated with plasmapheresis and rituximab; he remains in remission 17 months after treatment. Rituximab has been used by pediatricians for treating B cell malignancy, autoimmune diseases and antibody-mediated diseases, such as the Factor VIII inhibitors in hemophilia A, and may also have a promising role in children with acute refractory or chronic relapsing TTP.

Rituximab in Chronic Relapsing Acquired Thrombotic Thrombocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure and neurological manifestation. It is caused by a severe decreased of Von Willebrand factor cleaving protease activity (ADAMTS-13), leading to persistence of unusually ultra-large Von Willebrand multimers (ULVWF) in the circulation that bind to platelets, causing platelet aggregates, microangiopathic hemolysis and thrombocytopenia. A lack of ADAMTS-13 activity can be caused by autoimmune inhibitors or may be due to a constitutional deficiency of this protein. Recently, the ADAMTS-13 gene that encodes for the ADAMTS-13 protein was found. It was mapped to chromosome 9q34 and consists of 29 exons. Several mutations has been identified in the ADAMTS gene in patient with the congenital form of TTP. Although TTP usually occurs as an acquired form due to autoantibodies against ADAMTS-13.The determination of the activity of ADAMTS-13 and of antibodies against ADAMTS-13 are important part in the workup of patients with TTP.Plasma exchange (PE) with fresh frozen plasma replacement is the standard treatment in the acquired TTP. The efficacy of PE is likely due to the removal of both antibodies and ULVWF and the infution of ADAMTS-13. Additional treatment modalities include glucocorticoids, splenectomy, vincristine, cyclophosphamide, azathioprine, cyclosporin A, combination chemotherapy, intravenous immunoglobulins and, recently, rituximab, a monoclonal antibody against CD20 present on B-limphoid cells. We report a case of chronic relapsing acquired idiopathic TTP successfully treated with rituximab.The patient, an 50-year old woman, developed her first episode of TTP in May 2001. Remission was achieved after 12 sessions of PE, four dose of vincristine at dose of 0,02 mg/kg/die, corticosteroids at dose of 1 mg/kg/die and increased dose of prociclide from 10 to 60 mg /kg/die.From 2001 to 2004, she had six relapses responding to treatment with PE, vincristine, and corticosteroids. The relapse in 2004 was followed by a protracted course despite the addition of cyclosporine A and she become dependent on PE. On May 2004 she was treated with splenectomy.The postoperative course was uneventful. The inhibitors against ADAMTS-13 disappared, but after 8 months the patient relapsed and received six PE and corticosteroids, and then rituximab therapy (four doses of 375 mg/mq weekly). ADAMTS-13 activity and inhibitor levels were monitored.ADAMTS-13 activity was initially, pre-rituximab,<6% (n.v. 46–160%) and inhibitor's titre against ADAMTS-13 was 12 U/ml (n.v. <1 U/ml). After rituximab, the inhibitor against ADAMTS-13 disappeared rapidly after one month, while ADAMTS-13 activity has remained very low (<6%). After six months from rituximab therapy, there wasn't full recovery of ADAMTS-13 activity. Follow up is now 6 months, responses are manteined, ADAMTS-13 activity has remained <6% and inhibitors have not reappeared.Our experience suggests that rituximab, by eliminating an important source of B-lymphocytes producing inhibitory ADAMTS-13 autoantibodies, may be a useful immunomodulating adjunct in the treatment of refractory chronic relapsing acquired TTP, before than others immunosoppressors and/or splenectomy.

Thrombotic Thrombocytopenic Purpura (TTP) and Systemic Lupus Erythematosus (SLE): Distinct but Potentially Overlapping Syndromes.

A systematic literature review suggests that SLE and TTP co-exist: we identified 51 articles reporting 87 patients who were diagnosed with both TTP and SLE. SLE was diagnosed prior to TTP in 53 (61%), subsequent to TTP in 11 (13%) and simultaneously with TTP in 23 (26%) patients. However a critical distinction is that TTP is a rapidly fatal disease without plasma exchange (PE) treatment while SLE is typically a more chronic disease with intermittent acute flares and PE is not an essential treatment. Therefore when TTP is suspected in a patient with an established diagnosis of SLE, the relative benefits and risks of PE are difficult to assess, since the diagnosis of TTP may be unclear and PE is a procedure with risk for major complications and death. The Oklahoma TTP-HUS Registry has collected serum samples on 185 of 206 (90%) of prospectively enrolled patients with a clinical diagnosis of TTP or HUS from 11/13/1995 to 12/31/2003; all patients have been followed to the present time. We compared presenting features and clinical outcomes of the first episode of TTP-HUS between the 14 (7%) patients in whom SLE had been previously diagnosed to the 22 patients in whom the diagnosis of TTP was supported by severely deficient (<5%) ADAMTS13. None of the 14 patients with a previous diagnosis of SLE had severe ADAMTS13 deficiency (range 7–100%, median 50%). SLE disease activity as measured by the SLEDAI score ranged from 3–32, median 10, indicating that SLE manifestations were severe in most patients. Only 2 patients had inactive lupus as indicated by a SLEDAI score <4. SLE was not considered at the time of diagnosis of the first episode of TTP in the 22 patients with severe ADAMTS13 deficiency. Only 1/22 patients has been subsequently diagnosed with SLE; at the time of an apparent relapse of TTP he had serositis and positive serologic tests; his ADAMTS13 activity at that time was 30%. This patient's course documents the potential overlap of these two disorders.SLE-TTP(n=14)TTP (n=22)p-valueAge (years)39390.820Race (% Black)36%45%0.563Gender (% female)100%82%0.140Obesity (BMI ≥ 30 kg/m²)14%55%0.016Severe neurologic abnormalities71%45%0.126Platelet count2190.010Hematocrit22210.660LDH70714310.043Acute renal failure64%5%<0.001Response to PE36%86%0.003Death64%23%0.018Relapse in 30 day survivors0%44%0.031Median values are presented for continuous data. Laboratory data are most abnormal values at diagnosis of TTP-HUS ±7 daysAlthough the demographic (age, race, gender) and some presenting clinical features of patients with SLE and a clinical diagnosis of TTP-HUS were not different from patients with TTP and severe ADAMTS13 deficiency, other presenting features and the outcomes were different. Response to PE was poor, all cause mortality was high, and relapses of TTP have not occurred in patients with a previous diagnosis of SLE. These differences suggest that these 2 groups of patients in our Registry are distinct. Therefore in patients with an established diagnosis of SLE in whom the additional diagnosis of TTP-HUS is considered, more intensive immunosuppressive treatment for SLE is appropriate initial management in addition to considering the relative benefits and risks of PE.

Acquired Deficiency of von Willebrand Factor-Cleaving Protease in a Patient With Thrombotic Thrombocytopenic Purpura

Plasma of patients with thrombotic thrombocytopenic purpura (TTP) has been shown to contain unusually large von Willebrand factor (vWF) multimers that may cause platelet agglutination in vivo. Fresh frozen plasma infusions and plasma exchange represent the most efficient therapy of acute TTP. A specific protease responsible for cleavage of vWF multimers has been recently isolated from normal human plasma and was found to be deficient in four patients with chronic relapsing TTP. We examined the activity of the vWF-cleaving protease in plasma samples collected over a period of 400 days from a further patient with recurrent episodes of TTP who was treated by plasma exchange, plasma infusion, vincristine, corticosteroid therapy, and splenectomy. Complete deficiency of the vWF-cleaving protease was established during the first episode of TTP. The ensuing normalization of the platelet count was associated with the appearance of the protease activity. Three months after remission from the initial TTP event, the vWF-cleaving protease again disappeared and the platelet count gradually decreased. Relapses of severe thrombocytopenia occurred 7 and 11 months after the first acute episode of TTP. Deficient protease activity was associated with the presence in the patient plasma of an inhibitor that was found to be an IgG. Plasma exchange/infusion was followed by a temporary increase in the antibody titer, whereas treatment with vincristine led to a recovery of the platelet count without affecting the inhibitor concentration. Splenectomy and corticosteroid treatment resulted in disappearance of the autoantibody and normalization of the protease activity and of the platelet count. Our data suggest that the thrombocytopenia in this patient with TTP was associated with a lack of the vWF-cleaving protease activity depleted by an autoimmune mechanism. This case, together with our previously reported patients, leads us to conclude that acquired as well as constitutional deficiency of the vWF-cleaving protease may predispose to TTP.

The role of splenectomy in the treatment of relapsing thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a serious disorder of unknown etiology. Clinical findings are the result of vascular occlusions by platelet aggregates. Treatment with plasma exchange, often used in combination with corticosteroids, vincristine, aspirin, and dipyridamole, has reduced mortality to 20%. Relapses may occur even after long disease-free intervals. In this report we describe our experience with splenectomy in patients with relapsing TTP. Between July 1978 and March 1994, 16 patients with TTP were treated in our hospital. Five of the 13 patients surviving the first episode of TTP had relapses. Most relapses were treated as the first episode of TTP with plasma exchange with fresh-frozen plasma, followed by plasma infusions, corticosteroids, and vincristine. Sometimes aspirin and dipyridamole were added. Splenectomy was performed after five relapses in the first two patients and after two and three relapses in the other patients. Before splenectomy the disease-free interval varied from 3 weeks to 27 months and the incidence rate of relapses was 1.5 relapse/patient/year. None of the patients had relapses after splenectomy. The mean follow-up after splenectomy is 39 months with a range of 9-62 months. We conclude that patients with relapsing TTP can benefit from splenectomy, since it seems to increase disease-free intervals. Further investigation is necessary to understand the role of the spleen in the pathogenesis of TTP.