Acute Episode Of Thrombotic Thrombocytopenic Purpura Research Articles

The Highs and Lows of ADAMTS13 Activity.

Severe deficiency of ADAMTS13 (<10 iu/dL) is diagnostic of thrombotic thrombocytopenic purpura (TTP) and leads to accumulation of ultra-large vWF multimers, platelet aggregation, and widespread microthrombi, which can be life-threatening. However, the clinical implications of a low ADAMTS13 activity level are not only important in an acute episode of TTP. In this article, we discuss the effects of low ADAMTS13 activity in congenital and immune-mediated TTP patients not only at presentation but once in a clinical remission. Evidence is emerging of the clinical effects of low ADAMTS13 activity in other disease areas outside of TTP, and here, we explore the wider impact of low ADAMTS13 activity on the vascular endothelium and the potential for recombinant ADAMTS13 therapy in other thrombotic disease states.

Thrombotic Thrombocytopenic Purpura (TTP) Survivors Exhibit Impaired Stress Perfusion on Cardiac MRI

Introduction: Thrombotic thrombocytopenic purpura (TTP) survivors have increased rates of cardiovascular morbidity and mortality when compared with the general population. In this prospective pilot study, we sought to further characterize the long-term cardiovascular sequelae of TTP survivors through pharmacologic stress cardiac magnetic resonance imaging (CMR). Stress CMR has been increasingly utilized to detect clinical and subclinical structural and functional changes. A CMR biomarker of myocardial remodeling is extracellular volume (ECV); an increase in ECV may indicate the development of interstitial myocardial fibrosis. ECV was chosen for structural assessment as it has been implicated with diastolic dysfunction and other cardiac issues in other hematologic diseases, like sickle cell anemia. Methods: Adult patients (age ≥18 years of age) with TTP (immune-mediated or congenital) in the Ohio State University (OSU) TTP registry were prospectively consented and enrolled from March 2023 through July 2023 to undergo adenosine stress CMR at standard clinical dosing. All patients in the TTP cohort had confirmed diagnosis based on ADAMTS13 activity &amp;lt;15% during an acute episode and were in clinical remission at the time of CMR testing. Standard baseline and stress CMR parameters were obtained and compared with an age and sex matched control population, selected from patients without TTP who underwent identical stress CMR protocol for other indications and demonstrated normal stress perfusion. Patients in the control cohort predominantly had diagnoses of arrhythmia, stable angina, or heart failure. We collected data on patient demographics, details of TTP history, and underlying comorbidities. On CMR standard structural measurements were evaluated, and ECV was calculated (normal range 25.3 ± 3.5%). Perfusion was measured per standard protocols via global myocardial blood flow (MBF) as ml/min/g. Differences between the TTP and control populations were tested using the Fischer's exact test for categorical variables and Mann-Whitney U test for continuous variables. Results: A total of 10 TTP patients (9 immune-mediated, 1 congenital) were enrolled between March and July 2023. Median age at enrollment was 44.5 years (IQR 40.8-49.5) and 80% (8/10) were female. Patients were in documented clinical and ADAMTS13 activity remission with median ADAMTS13 activity of 68% (64.0-84.5), excluding the activity level of the congenital patient. Median time from initial diagnosis was 15 years (range 0.5 - 41 years) and median number of acute TTP episodes was 2 (IQR 1.0-4.5). Characteristics of the study (n= 10) and control cohort (n = 13) are summarized in Table 1. There were no significant differences in the TTP and control cohorts with respect to age, sex, race, and presence of hypertension or diabetes. Patients in the TTP cohort had significantly higher BMI (median 34.5 mg/m 2 vs 26.5 mg/m 2, p = .012), diastolic blood pressure (94 mmHg vs 82 mmHg, p = .003), and a lower rate of known cardiac disease (10% vs 85%, p&amp;lt;.001). Stress CMR showed reduced myocardial perfusion in TTP survivors: Nine out of 10 (90%) TTP survivors had evidence of structural or perfusion deficits on CMR. The median ECV in the TTP cohort (28.5%, 24.8 - 31.5) was increased compared with controls (26%, 23.5 - 27.5) though it did not reach significance (p = .08). There were no significant differences in median global MBF at rest in the TTP group (1.30, 1.16 - 1.37) compared with controls (1.18, 1.07 - 1.31, p = .210). However, TTP survivors had significantly reduced stress MBF (3.28, 2.21 - 3.53) vs controls (4.1, 3.88 - 4.22, p &amp;lt;.001) with adenosine. Reductions in quantitative stress perfusion in the TTP cohort was primarily noted in the subendocardium as shown in Figure 2. Conclusion: Asymptomatic structural changes and reduction in quantitative perfusion are common in TTP survivors. The study is ongoing to recruit more patients to ensure clinical significance and generalizability of these preliminary findings. Stress CMR may detect subclinical myocardial damage in TTP survivors who otherwise do not exhibit overt cardiovascular symptoms until a later time and may provide the basis to understand increased cardiovascular morbidity and mortality in this population.

Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura

BackgroundSevere deficiency in ADAMTS-13 (<10%) and the loss of von Willebrand factor–cleaving function can precipitate microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Patients with immune-mediated TTP (iTTP) have anti-ADAMTS-13 immunoglobulin G antibodies that inhibit ADAMTS-13 function and/or increase ADAMTS-13 clearance. Patients with iTTP are treated primarily by plasma exchange (PEX), often in combination with adjunct therapies that target either the von Willebrand factor-dependent microvascular thrombotic processes (caplacizumab) or the autoimmune components (steroids or rituximab) of the disease. ObjectivesTo investigate the contributions of autoantibody-mediated ADAMTS-13 clearance and inhibition in patients with iTTP at presentation and through the course of the PEX therapy. Patients/MethodsAnti-ADAMTS-13 immunoglobulin G antibodies, ADAMTS-13 antigen, and activity were measured before and after each PEX in 17 patients with iTTP and 20 acute TTP episodes. ResultsAt presentation, 14 out of 15 patients with iTTP had ADAMTS-13 antigen levels of <10%, suggesting a major contribution of ADAMTS-13 clearance to the deficiency state. After the first PEX, both ADAMTS-13 antigen and activity levels increased similarly, and the anti-ADAMTS-13 autoantibody titer decreased in all patients, revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP. Analysis of ADAMTS-13 antigen levels between consecutive PEX treatments revealed that the rate of ADAMTS-13 clearance in 9 out of 14 patients analyzed was 4- to 10-fold faster than the estimated normal rate of clearance. ConclusionThese data reveal, both at presentation and during PEX treatment, that antibody-mediated clearance of ADAMTS-13 is the major pathogenic mechanism that causes ADAMTS-13 deficiency in iTTP. Understanding the kinetics of ADAMTS-13 clearance in iTTP may now enable further optimization of treatment of patients with iTTP.

Recombinant ADAMTS13 for Hereditary Thrombotic Thrombocytopenic Purpura

SummaryA 27-year-old patient with a history of severe obstetrical complications and arterial thrombosis received a diagnosis of hereditary thrombotic thrombocytopenic purpura (TTP) due to severe ADAMTS13 deficiency when she presented with an acute episode in the 30th week of her second pregnancy. When the acute episode of hereditary TTP became plasma-refractory and fetal death was imminent, weekly injections of recombinant ADAMTS13 at a dose of 40 U per kilogram of body weight were initiated. The patient’s platelet count normalized, and the growth of the fetus stabilized. At 37 weeks 1 day of gestation, a small-for-gestational-age boy was delivered by cesarean section. At the time of this report, the patient and her son were well, and she continued to receive injections of recombinant ADAMTS13 every 2 weeks. (Funded by the Swiss National Science Foundation.)

Retrospective Analysis of the Efficacy of Solvent/Detergent Treated Pooled Plasma As Compared to Fresh Frozen Plasma in Thrombotic Thrombocytopenic Purpura: A Single Center Experience

Background : Plasma exchange is the primary treatment for acute episodes of Thrombotic Thrombocytopenic Purpura (TTP), a rare condition characterized by the formation of thromboses in small blood vessels, resulting in thrombocytopenia, hemolytic anemia and multi-organ failure. Plasma exchange replacement fluids in TTP include Fresh Frozen Plasma (FFP) and solvent/detergent treated pooled plasma (SDP), such as Octaplas. SDP is a virus-inactivated, pooled human plasma product with standardized plasma protein content, including ADAMTS13, that has been used in the treatment of TTP. This study evaluates the effectiveness of SDP as compared to FFP in the treatment of acute TTP episodes. Study Design and Methods : A retrospective analysis was conducted comparing SDP- to FFP-treated patients with suspected acute TTP episodes as a primary admitting diagnosis between December 2014 and December 2019. A total of 16 patients were included in this study. The FFP group consisted of 9 patients (6M/3F, median age 44 years), three of whom had relapsed TTP. The SDP cohort had 7 patients (2M/5F, median age 38 years), one of whom had relapsed TTP. The primary outcomes measured included reported thromboembolic and major bleeding events. Secondary outcomes included number of plasma exchange procedures, adverse effects including neurological changes, transfusion of other blood products, ICU and hospital length of stay (LOS), and changes in laboratory values. Results : There were no adverse transfusion reactions reported in either group. 12 bleeding events were reported from 6 patients in the FFP group and 8 bleeding events from 4 patients in the SDP group (p=0.397). No significant differences were detected in ICU stay, hospital LOS, number of plasma units transfused, daily percentage of change of laboratory values, or changes in neurological status. Conclusions:These data confirm the previously reported efficacy of SDP for treating suspected/confirmed TTP.There were no significant differences in thromboembolic or bleeding events between patients who received FFP as compared to SDP. The non-significant differences observed in laboratory values throughout the duration of plasma exchange procedures as well as adverse reactions and clinical outcomes between both groups confirm the safety of SDP when used interchangeably with FFP for the treatment of TTP. Table Disclosures Blumberg: CSL Behring: Consultancy. Refaai:CSL Behring: Consultancy; Octapharma: Research Funding; Instrumentation Laboratory: Research Funding; iLine Microsystems: Research Funding; Diagnostica Stago: Consultancy.

Efficacy of albumin and compounded plasma for plasma exchange in acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic microangiopathy. Therapeutic plasma exchange (TPE) is the first-line treatment for TTP. In our institution, albumin plus plasma (fresh frozen plasma [FFP] and/or cryoprecipitate-reduced plasma [CRP]) has been used as replacement fluid since 2014. We aimed to evaluate the efficacy of albumin combined with plasma as TPE for TTP. We retrospectively evaluated 20 patients admitted to our institution due to an acute episode of TTP between January 1, 2014 and February 1, 2019. They were divided into two groups according to the replacement fluid protocols: (a) albumin plus FFP (1:1) and (b) albumin plus mixed plasma [ie, albumin and FFP with CRP (2:1:1)] groups. Data on patient characteristics, replacement parameters, outcome, and hemorrhage risk were collected and analyzed. There were no significant differences in treatment outcomes between the two groups (P > .05). However, the albumin plus mixed plasma group tended to require fewer plasma exchanges (median, 4) and shorter time to response (median, 15 days) compared to albumin plus FFP group (median, 6; 31 days). Although the cumulative survival of the albumin plus mixed plasma group was higher than the other group starting from day 23 after treatment, we did not observe significant difference (P = .50). No significant increase in the risk for hemorrhage was observed in either group. The therapeutic efficacy of albumin and mixed plasma (2:1:1) is not inferior to that of albumin and FFP (1:1), and it can be used in treating TTP.

Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors

AbstractWith timely and effective treatment, most patients with thrombotic thrombocytopenic purpura (TTP) survive the acute TTP episode. In addition to the risk of relapse, TTP survivors have higher all-cause mortality than the general population and increased rates of chronic morbidities, including hypertension, depression, and mild cognitive impairment. We conducted this retrospective-prospective cohort study to determine the incidence and prevalence of stroke after recovery from acute TTP and to test the hypothesis that lower ADAMTS13 activity after recovery from TTP is associated with an increased risk of stroke during remission. Of 170 consecutive patients treated for TTP at The Johns Hopkins Hospital from 1995 through 2018, 14 (8.2%) died during the index episode and 19 were observed for less than 1 month after recovery. Of the remaining 137 patients, 18 (13.1%) developed stroke unrelated to an acute TTP episode over a median observation period of 3.08 years, which is fivefold higher than the expected prevalence of 2.6% from an age- and sex-matched reference population (P = .002). ADAMTS13 activity during remission was measured in 52 patients and was >70% in 44.2%, 40% to 70% in 23.1%, 10% to 39% in 25%, and <10% in 7.7%. Stroke after recovery from acute TTP occurred in 0% (0 of 22) of patients with normal remission ADAMTS13 activity (>70%) and in 27.6% (8 of 29) of patients with low ADAMTS13 activity (≤70%; P = .007). In conclusion, stroke is common after recovery from TTP and is associated with reduced ADAMTS13 activity during remission.

Long-term neuropsychological sequelae, emotional wellbeing and quality of life in patients with acquired thrombotic thrombocytopenic purpura.

Neurological symptoms related to microthrombosis are the hallmark of acute manifestations of acquired thrombotic thrombocytopenic purpura (TTP). Despite the achievement of hematological remission, patients may report persisting neurological impairment that affects their quality of life. To assess the long-term neuropsychological consequences of acute TTP, we recruited 35 acquired TTP patients (77% females, median age at onset 41 years, interquartile range: 35–48) regularly followed at our out-patient clinic of thrombotic microangiopathies in Milan (Italy) from December 2015 to October 2016. Patients underwent a psychological evaluation of memory and attentional functions, emotional wellbeing and health-related quality of life at least three months after their last acute TTP event (median 36 months, interquartile range: 17–54). During the psychological consultation, 17 patients (49%) referred persisting subjective neurological impairment in the frame of a remission phase, with at least one symptom as disorientation, loss of concentration, dizziness, lack of balance, headache and diplopia. Neuropsychological assessment revealed lower scores than the Italian general population pertaining to direct, indirect and deferred memory. A higher degree of impairment of memory domains was found in patients with neurological involvement at the time of presentation of the first acute TTP episode. Anxiety and depression were detected in seven (20%) and 15 (43%) patients, respectively. Health-related quality of life was lower than the Italian general population, with mental domains more impacted than physical domains (mean difference 58.43, 95% confidence interval: 71.49–45.37). Our study demonstrates compromised memory and attention functions, persisting anxiety/depression symptoms and a generally reduced quality of life in patients recovering from acute acquired TTP. New clinical strategies should be considered to improve these symptoms.

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) AND MODERN APPROACH TO ITS INVESTIGATION AND TREATMENT

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia linked to disseminated microvascular platelet rich-thrombi. TTP is specifically related to a severe deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the specific von Willebrand factor-cleaving protease. ADAMTS13 deficiency is most frequently acquired via ADAMTS13 autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13 gane. The first acute episode of TTP usually occurs during adulthood, with a predominant anti – ADAMTS13 autoimmune etiology. In rare cases, however, TTP begins as soon as childhood, with frequent inherited forms. TTP is 2 – fold more frequent in women, and its outcome is characterized by a relapsing tendency.

Prevention of relapse in patients with acquired thrombotic thrombocytopenic purpura undergoing elective surgery: a case series

Essentials Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. Surgery is a possible trigger of acute TTP episodes and no guidelines are available. Six patients with severe ADAMTS-13 deficiency during remission underwent elective surgery. Patients were prophylactically treated to restore ADAMTS-13 activity and no relapses occurred. SUMMARY: Background Severe ADAMTS-13 deficiency has been recognized as the main risk factor for recurrence of thrombotic thrombocytopenic purpura (TTP). Several conditions, including surgery, may influence the levels of ultra-large von Willebrand factor and ADAMTS-13, acting as a trigger for an acute TTP event. Objectives To report our experience of management of six patients with acquired TTP who underwent elective surgery after prophylactic treatment to restore ADAMTS-13 activity levels. Patients Six patients followed for acquired TTP with severe ADAMTS-13 deficiency during remission were candidates for seven elective surgeries (inguinal hernioplasty, cholecystectomy, laparoscopic hysterectomy, oophorectomy, parotidectomy and two total hip arthroplasties). Results Four patients were treated with prophylactic plasma exchange (PEX) therapy immediately before surgery. One patient was treated with PEX therapy before her first surgery and with preemptive rituximab once her second surgery was scheduled. Because rituximab increased ADAMTS-13 levels only partially, she required one PEX procedure the day before her second surgery. One patient was treated with azathioprine after rituximab failure, obtaining a progressive increase of ADAMTS-13 activity to more than 40%. This level allowed her to undergo total hip arthroplasty without additional treatment. All surgeries were successful and no complications or relapses occurred. Conclusions Six patients with acquired TTP underwent seven successful surgical procedures using prophylaxis to restore ADAMTS-13 activity. Further observational studies or randomized clinical trials are needed to confirm whether prophylactic PEX could be the key factor in preventing relapse.

Lysine Histone-Induced Thrombocytopenia in Zebrafish Depends on Endothelial Von Willebrand Factor

Thrombotic thrombocytopenic purpura (TTP), a potentially fatal blood disorder, is caused by severe deficiency of plasma ADAMTS13 activity, primarily resulting from acquired autoantibodies that inhibit ADAMTS13's ability to cleave von Willebrand factor (VWF). However, severe deficiency of plasma ADAMTS13 activity alone is often not sufficient to cause an acute episode of TTP; additional environmental or genetic factors may be required for the development of acute TTP. Here, we report a creation and characterization of a novel zebrafish model of TTP and use the model to identify a potential mechanistic link between an innate immunity and onset of TTP. Using CRISPR/cas9, we generated adamts13-/-,vwf-/-, and adamts13-/-vwf-/-zebrafish on a double transgenic (Fli1-eGFP/Gata1-dsRed) background in which erythrocytes, thrombocytes, and endothelial cells were uniquely labeled with an endogenously expressed fluorescent protein. Our results demonstrated that adamts13-/-zebrafish larvae (5-dpf) had an increased rate of developing occlusive thrombi in the caudal venues after FeCl3 injury; also, adamts13-/- adult zebrafish (3-4 months) exhibited ~27% reduction of their total or mature thrombocyte counts with a significantly increased number of fragmented erythrocytes; moreover, an intraperitoneal administration of a lysine-rich histone resulted in severe and more persistent thrombocytopenia with an increased mortality in adamts13-/-zebrafish than their wild-type littermate; finally, both spontaneous and histone-induced thrombocytopenia and thrombotic microangiopathy in adamts13-/-was eliminated when endothelial vwf was genetically deleted from zebrafish. Together, these results provide experimental evidences to support a mechanistic link of acute infection or inflammation to acute onset of TTP in patients lacking plasma ADAMTS13 activity. DisclosuresZheng:Alexion: Research Funding, Speakers Bureau.

Amplified endogenous plasmin activity resolves acute thrombotic thrombocytopenic purpura in mice

Background Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening pathology, caused by occlusive von Willebrand factor (VWF)-rich microthrombi that accumulate in the absence of ADAMTS-13. We previously demonstrated that plasmin can cleave VWF and that plasmin is generated in patients during acute TTP. However, the exact role of plasmin in TTP remains unclear. Objectives Investigate if endogenous plasmin-mediated proteolysis of VWF can influence acute TTP episodes. Results In mice with an acquired ADAMTS-13 deficiency, plasmin is generated during TTP as reflected by increased plasmin-α2-antiplasmin (PAP)-complex levels. However, mice still developed TTP, suggesting that this increase is not sufficient to control the pathology. As mice with TTP also had increased plasminogen activator inhibitor 1 (PAI-1) levels, we investigated whether blocking the plasmin(ogen) inhibitors would result in the generation of sufficient plasmin to influence TTP outcome in mice. Interestingly, when amplified plasmin activity was allowed (α2-antiplasmin-/- mice with inhibited PAI-1) in mice with an acquired ADAMTS-13 deficiency, a resolution of TTP signs was observed as a result of an increased proteolysis of VWF. In line with this, in patients with acute TTP, increased PAP-complex and PAI-1 levels were also observed. However, neither PAP-complex levels nor PAI-1 levels were related to TTP signs and outcome. Conclusions In conclusion, endogenous plasmin levels are increased during acute TTP, although limited via suppression through α2-antiplasmin and PAI-1. Only when amplified plasmin activity is allowed, plasmin can function as a back-up for ADAMTS-13 in mice and resolve TTP signs as a result of an increased proteolysis of VWF.

Natural History of Patients Affected with Thrombotic Thrombocytopenic Purpura: Milan TTP Registry

Introduction: thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy, with a reported incidence of 2-6 cases/million/year and a 10-20% mortality. TTP is associated with the severe deficiency of the von Willebrand factor cleaving protease, ADAMTS13, due to congenital defects in the ADAMTS13 gene (congenital TTP) or to the development of autoantibodies against ADAMTS13. The Milan TTP Registry is a digital database developed and curated at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy), including demographic, clinical and laboratory data of patients with a confirmed diagnosis of congenital or acquired thrombotic thrombocytopenic purpura (TTP).Aims: to report the natural history of patients affected with acquired TTP enrolled in the Milan TTP Registry, including demographic, clinical and laboratory data.Methods: acquired TTP patients enrolled in the Milan TTP Registry for an acute episode of TTP occurred between January 2002 and November 2015, and followed until May 2016, were included in this study. Acquired TTP was defined as the occurrence of thrombocytopenia and microangiopathic hemolytic anemia, in the absence of alternative causes. Patients with acquired TTP secondary to cancer and bone-marrow transplant were excluded from this analysis. Demographic and disease-related information were collected by a standardized clinical questionnaire. ADAMTS13-related measurements were performed in a centralized laboratory in Milan. Remission of an acute TTP episode was defined as two days after normalization of the platelet count (≥150 x 109/l).Results: 416 patients with a confirmed diagnosis of acquired TTP were included in the Milan TTP Registry, for a total of 837 acute events. Demographic, clinical and laboratory data are reported in Tables 1 and 2. The majority of patients were female (77%), of white ethnicity (98%) and Italian origin (82%). The median age at the first TTP episode was 40 years (interquartile range [IQR] 30-52). A history of other autoimmune diseases, cancer (non-active at the time of the TTP event), HIV infection and other diseases such as stroke, acute myocardial infarction and hypertension was reported in 34% of the patients. Among potential triggers of acute episodes (defined as occurring within three months before onset), infections were the most prevalent (22% of all patients), followed by the assumption of estroprogestinic drugs (5%). At TTP episode onset, systemic, bleeding and neurological signs and symptoms were present in 70%, 68% and 44% of acute events, respectively, whereas a lower prevalence of renal (19%) and cardiovascular (10%) signs and symptoms was observed. Clinical characteristics and hematologic laboratory parameters were less severe in relapsing episodes compared with first episodes (Table 2). Almost all acute events were treated by plasma exchange procedures and steroids. Rituximab therapy was administered in 12% of acute TTP episodes. In 197 acute TTP episodes with available ADAMTS13-related measurements at baseline, ADAMTS13 activity was severely reduced (<10%) in 85%, moderately reduced (10% to lower limit of normal range) in 12% and normal in 3% of events, respectively. Anti-ADAMTS13 antibodies were positive in 93% of acute TTP. The TTP-related mortality in our population of acquired TTP patients was 5%. In survivors, the median time to remission was 13 days (IQR 7-24, n=313), shorter for relapses than first events (median difference 8 days, 95% confidence interval 5-11). In 348 patients who survived the first TTP episode and had a follow-up period of at least 6 months, 178 (51%) experienced only one episode of acquired TTP, whereas 170 (49%) developed a recurrent form of the disease. This results might be overestimated due to the tertiary nature of our center.Conclusions: acquired TTP is a rare, potentially fatal disease, which may require a long hospitalization and presents in a recurrent form in nearly half of the patients. Digital registries, such as the Milan TTP Registry, represent a powerful and necessary tool to systematically collect epidemiologic, clinical and laboratory data which may ultimately improve our understanding and management of acquired TTP. Our registry, in collaboration with those of other international centers, might answer the most relevant questions in this field. [Display omitted] [Display omitted] DisclosuresPeyvandi:Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau; SOBI: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Bayer: Speakers Bureau; Grifols: Speakers Bureau; LFB: Consultancy; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding.

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.

ADAMTS13-specific circulating immune complexes as potential predictors of relapse in patients with acquired thrombotic thrombocytopenic purpura

BackgroundAcquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy due to the development of autoantibodies against the VWF-cleaving protease ADAMTS13. ADAMTS13-specific circulating immune complexes (CICs) have been described in patients with acquired TTP, but their clinical relevance remained to be established. The aim of this study was to assess the association between ADAMTS13-specific CICs and ADAMTS13-related measurements, clinical and laboratory markers of disease severity, and occurrence of TTP relapse, in autoimmune TTP patients. Material and methodsWe measured ADAMTS13-specific CICs in 51 patients with severe ADAMTS13 deficiency and anti-ADAMTS13 autoantibodies, at the first episode of acquired TTP. The associations between ADAMTS13-specific CICs and the variables of interest were assessed by linear, logistic and Cox proportional hazard regression models, where appropriate. ResultsThe prevalence of ADAMTS13-specific CICs in patients experiencing the first TTP episode was 39% (95% confidence intervals [CI]: 26–52%). ADAMTS13-specific CICs were not associated neither with laboratory markers of disease severity, nor with patterns of clinical presentation. Conversely, among 45 survivors, a positive association was found between the presence of ADAMTS13-specific CICs and the risk of recurrence within 2years after the first TTP episode (adjusted hazard ratio, 3.4 [95% CI: 0.9 to 13.5]). ConclusionsADAMTS13-specific CICs seem to be able to predict the recurrence of acute TTP episodes in the first 2years after disease onset. Therefore, their measurement might be used as a tool to stratify the risk of disease relapse, with potential influence on surveillance and therapeutic choices during remission phase.

Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura

BackgroundAcquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high.MethodsCaplacizumab, an anti–von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, we randomly assigned patients with acquired TTP to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses.ResultsSeventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group.ConclusionsCaplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo. (Funded by Ablynx; ClinicalTrials.gov number, NCT01151423.)

Temperature-Dependent Irreversible Conformational Change of ADAMTS13 upon Metal Ion Chelation

Thrombotic thrombocytopenic purpura (TTP) is characterized by a functional deficiency in the plasma metalloprotease ADAMTS13, caused by mutations in the ADAMTS13 gene or by autoantibody inhibition. ADAMTS13 is the key regulator of the hemostatic activity of von Willebrand factor (VWF), accomplished by cleavage of a single site within the A2 domain of VWF. The catalytic domain of ADAMTS13 possesses various binding sites for metallic cations including one Zn2+ binding site composed of three histidine residues within the sequence HEXXHXXGXXHD and up to three putative calcium ion-binding sites. The dependence of ADAMTS13 activity on zinc and calcium ions is reflected in its inactivation by chelating agents such as EDTA and doxycycline. Although replenishment with an appropriate metallic cation is thought to fully restore the proteolytic activity of the enzyme, the stability of ADAMTS13 in a Ca2+-depleting environment has not yet been explored. This aspect, however, is clinically relevant, as citrated human plasma serves as the standard source for testing ADAMTS13-specific parameters, where the chelator citrate not only prevents activation of the coagulation cascade, but also renders ADAMTS13 inactive.Here, we addressed the stability of plasma ADAMTS13 in the presence or absence of citrate (0.38%) at various temperatures. While ADAMTS13 proved stable at 4-8°C and at room temperature for up to 24 h irrespective of the presence of citrate, a time-dependent decrease in activity was observed at 37°C in the presence but not in the absence of citrate. No decrease in activity was seen when heparinized plasma was used as source of ADAMTS13, but the addition of 0.38% citrate again caused ADAMTS13 instability at 37°C. Similar results were observed when using the purified recombinant protein as source for ADAMTS13. Higher order structural analyses using Fourier-transformed infrared spectroscopy and dynamic light scattering demonstrated citrate-dependent structural changes in ADAMTS13 at 37°C that are typical for less-ordered protein structures. Addition of 5 mM Ca2+, Zn2+, or both metal ions prior to incubation completely restored ADAMTS13 stability, but these compounds failed to restore activity when added post incubation even after prolonged periods, suggesting that the loss in activity was irreversible.We conclude that Zn2+ and/or Ca2+ ions are required to stabilize the structure of ADAMTS13 at physiological temperature. This finding needs to be considered when using citrated plasma as source of ADAMTS13 in clinical settings such as for plasma exchange to treat acute episodes of TTP. DisclosuresGrillberger:Baxalta Innovations GmbH: Employment. Kaufmann:Baxalta Innovations GmbH: Employment. Kink:Baxalta Innovations GmbH: Employment. Matthiessen:Baxalta Innovations GmbH: Employment. Plaimauer:Baxalta Innovations GmbH: Employment. Scheiflinger:Baxalta Innovations GmbH: Employment. Rottensteiner:Baxalta Innovations GmbH: Employment.

Thrombotic Thrombocytopenic Purpura (TTP) Patient Attitudes Regarding Depression Management: a Qualitative Study

▪Introduction: Recovery from an acute episode of TTP was previously thought to be complete except for a risk for relapse. However, the Oklahoma TTP-HUS Registry has documented that patients have multiple health problems that persist following recovery, including an increased prevalence of major depression (Blood122:2023;2013). Untreated major depression impacts daily functioning, quality of life and is a risk factor for suicide. Recognizing depression and establishing effective treatment should be a critical part of TTP follow-up care. The objective of our study was to identify TTP patient attitudes regarding treatments for depression.Methods: The study was based on the theoretical framework of the Theory of Planned Behavior (TPB). The theory suggests that intention is the immediate predictor of behavior. Intention is determined by 3 factors: attitude toward a behavior, subjective norms, and perceived behavioral control. This study focused on attitude; therefore, patients were primarily asked if there were any advantages or disadvantages of treating depression with either pharmacotherapy or counseling.One-on-one semi-structured interviews were conducted by the first author. Interviews were transcribed verbatim and content analysis was conducted by 3 qualitative researchers and facilitated by using the NVivo 10 software. A codebook was developed to guide the data analysis. Similar beliefs were grouped into themes and key ideas.Patients: Registry patients whose initial episode was associated with severe ADAMTS13 deficiency (<10%), 1995-2012, and who had major depression on at least 1 screening evaluation from 2004-2012. Qualitative purposeful sampling was used instead of random sampling. Patients were stratified by previous/current or no pharmacotherapy treatment regardless of counseling history.Results: Fifty-six ADAMTS13-deficient patients in clinical remission had been screened for depression; 50 patients were alive in 2013; 24 had a score of major depression at least once. Of the 24 patients, 12 (50%) had taken pharmacotherapy for their depression and 12 (50%) patients had never taken pharmacotherapy.Data saturation was achieved after interviewing 16 patients (9 pharmacotherapy; 7 no pharmacotherapy). Fourteen patients (88%) were women, 9 (56%) were black, and the median age was 49 years (range 28-69). Patients were a median of 8.5 years from their most recent TTP episode (range 2-17 years), 5 (31%) had relapsed, and 7 (44%) had been treated with rituximab.Interviews among all patients revealed that a TTP diagnosis was 'life-altering’ and 'traumatic’. Many patients felt the residual effects of TTP (a fear of relapsing, fatigue, and mild cognitive impairment) were related to their depression. A major theme across groups was that patients had a positive attitude toward counseling and believed counseling could be an effective way to treat depression. However, a history of a negative counseling experience seemed to discourage many patients from continuing counseling. Additionally, regardless of previous counseling experience, a key idea across groups was mistrust toward the mental healthcare provider’s ability. However, this mistrust was only a perception among those who had never tried counseling. Within the pharmacotherapy group, patients believed that medication was an effective way to treat depression; however, many patients reported side effects (feeling 'sluggish’ and 'not caring about anything’) as the reasons for stopping the medication. On the contrary, among the non-pharmacotherapy group patients were unsure if pharmacotherapy actually worked-'Uh, I guess it kind of would keep you steady-minded I guess’. The fear of side effects and the fear of addiction were the biggest barriers among the non-pharmacotherapy group for using pharmacotherapy.Conclusion:Hematologists need to recognize that TTP is a long-term life-altering diagnosis following recovery. Identifying and managing depression is a critical issue that can save lives. TTP patients seem to have a positive attitude toward counseling and a mixed attitude toward pharmacotherapy. Whether these fears are valid is beyond the scope of this study; however, it is imperative that hematologists discuss the issue of depression in depth with their patients and address the barriers to acceptance of treatment. This study is a first step in identifying barriers to depression treatment in TTP survivors. 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.

The Role of ADAMTS13-Specific Circulating Immune Complexes in Prediction of Recurrence of Acquired Thrombotic Thrombocytopenic Purpura

Introduction. Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy due to the development of autoantibodies against the VWF-cleaving protease ADAMTS13. We recently developed and validated a new ELISA method for the detection of ADAMTS13-specific circulating immune complexes (CICs) in acquired TTP patients. This study aims at investigating the clinical relevance of ADAMTS13-specific CICs at disease presentation in a large cohort of acquired TTP patients.Methods. We measured ADAMTS13-specific CICs by ELISA in 51 patients from the Milan TTP Registry, at the first episode of acquired TTP. All patients presented anti-ADAMTS13 autoantibodies by western blotting and severe ADAMTS13 deficiency (i.e., <10% of normal) by FRETS-VWF73 or CBA assays. We studied the associations between ADAMTS13-specific CICs levels and (i) ADAMTS13-related measurements (i.e., ADAMTS13 antigen, anti-ADAMTS13 IgG), (ii) clinical and laboratory markers of disease severity (i.e., muco-cutaneous bleeding, neurological, renal and cardiovascular symptoms, number of platelets, LDH, hemoglobin, creatinine), (iii) short- and long-term clinical outcomes (i.e., number of plasma exchange procedures required to attain remission, recurrence). Statistical analyses were performed using linear, logistic and Cox regression models.Results. The prevalence of ADAMTS13-specific CICs in patients experiencing a first episode of acquired TTP was 39% (95% confidence intervals [CI]: 26-52%). ADAMTS13-specific CICs were only associated with ADAMTS13 antigen levels at regression analyses (beta per 10% increase in ADAMTS13 antigen, 95% CI: 0.05, 0.02-0.08). The presence of ADAMTS13-specific CICs was associated with more than a four-fold increase in the risk of recurrence at 2 years after the first TTP episode (hazard ratio, 95%CI: 4.2, 1.1-16.4).Conclusions. ADAMTS13-specific CICs are neither a biomarker of disease severity, nor a predictor of clinical outcome during acute phase. Conversely, ADAMTS13-specific CICs seem to have relevance in predicting the recurrence of acute TTP episodes. DisclosuresPeyvandi:NovoNordisk: Research Funding; Kedrion : Research Funding; NovoNordisk: Speakers Bureau; CSL Behring : Speakers Bureau; Baxter: Speakers Bureau; Bayer: Speakers Bureau.