Episodes 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.

Rising total leukocyte counts correspond with rising platelet counts in thrombotic thrombocytopenic purpura

AbstractThrombotic thrombocytopenic purpura (TTP) is a rare disorder involving pathological platelet–von Willebrand factor interaction, resulting in microvascular thrombosis. The consumption of platelets in TTP microthrombi results in severe thrombocytopenia which resolves with resolution of the microvascular thrombosis. Over the course of treatment, patient platelet counts often rise and fall multiple times before stable remission is achieved. On casual inspection, we noted that total leukocyte counts follow a pattern that appears to correspond to platelet counts. To explore whether changing leukocyte counts track significantly with changing platelet counts, we examined paired daily platelet counts and total leukocyte counts in 27 episodes of TTP in 13 patients across 2 institutions comprising 423 days of data. We modeled the nonlinear behavior in the data using a threshold mixed-effects regression model, in which we found a significant temporal relationship between total leukocyte counts and platelet counts. The model proved that, on a day when platelet counts were rising in previous days, the total leukocyte count is predictive of the rise in platelet count. The higher the total leukocyte count, the greater the rise in platelet count. Our results support the hypothesis that leukocytes play a role in the resolution of TTP microvascular thrombosis.

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.

Therapeutic modalities in thrombotic thrombocytopenic purpura management among Jehovah’s Witness patients: A review of reported cases

IntroductionDevout members of the Jehovah’s Witness faith flatly refuse transfusions of white blood cells, red blood cells, platelets, and plasma. The latter agent is a mainstay in the treatment of thrombotic thrombocytopenic purpura (TTP). Alternative treatment options for Jehovah’s Witness patients are needed and reviewed herein. MethodsCases of TTP treatment among Jehovah’s Witnesses were obtained from the published literature. Key baseline and clinical data were extracted and summarized. ResultsA total of 13 reports spanning a 23-year period and 15 TTP episodes were identified. Median (IQR) age was 45.5 (29.0–57.5) and 12/13 (93%) patients were female. Neurologic symptoms were present in 7/15 (47%) episodes at presentation. Disease confirmation with ADAMTS13 testing was present in 11/15 (73%) of episodes. Corticosteroids and rituximab were employed in 13/15 (87%) and 12/15 (80%) of cases, respectively, with apheresis-based therapy employed in 9/15 (60%) episodes. For eligible cases, caplacizumab was used in 4/5 (80%) episodes; average time to platelet response was shortest in these cases. Sources of exogenous ADAMTS13 accepted by patients in this series included cryo-poor plasma, FVIII concentrate, and cryoprecipitate. Conclusions: Successful management of TTP within the boundaries of the Jehovah’s Witness faith is possible.

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.)

The perfect storm: Thrombotic thrombocytopenic purpura (TTP) associated with COVID-19, a clinical case series and review.

This is a case series of three patients in our hospital system who developed acquired thrombotic thrombocytopenic purpura (aTTP) after testing positive for COVID-19 infection. Two patients had acute COVID-19 infections, and one had COVID-19 IgG antibodies consistent with prior COVID-19 infection. Twelve additional cases of aTTP after COVID-19 infection were found in the literature. COVID-19 creates alterations in the vWF-ADAMTS-13 axis with reduced ADAMTS-13 in acute illness that may lead those patients who are predisposed into fulminant aTTP. Further genetic studies are necessary to uncover why some patients with COVID-19 can have concurrent aTTP. For those with a prior COVID-19 infection, molecular mimicry with autoantibodies to ADAMTS-13 is likely the predominant trigger, but having an underlying predisposition (prior episode of TTP, genetic predisposition to autoimmune conditions, or breast cancer history) creates an environment that could be a possible trigger for aTTP.

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.

Diagnostic uncertainty presented barriers to the timely management of acute thrombotic thrombocytopenic purpura in the United Kingdom between 2014 and 2019

BackgroundAcute thrombotic thrombocytopenic purpura (TTP) is a life‐threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality. ObjectivesTo compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX. Patients/MethodsThe trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP. ResultsData on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on‐site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two‐thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation. ConclusionsThis is the first multi‐center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life‐saving intervention.

Factors Associated with Mortality in Immune-Mediated Thrombotic Thrombocytopenic Purpura: Results from the United States Thrombotic Microangiopathy TTP Registry

Background: Thrombotic Thrombocytopenic Purpura (TTP) is a life threatening microangiopathy used by a deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). ADAMTS13 cleaves von Willebrand factor, and ADAMTS13 deficiency leads to an excess of high molecular weight multimers of von Willebrand factor which, in turn, causes platelet aggregation and congestion in small arteries and organ damage. TTP occurs in two forms: inherited due to a congenital defect in either production or function of the protein, and immune-mediated due to autoantibody formation either leading to immune clearance or inhibition of the function of the enzyme. TTP is a medical emergency and if untreated carries a mortality rate of approximately 90 percent. Current therapies (plasma exchange, immunomodulatory agents) have improved outcome in this disease, but mortality remains unacceptably high at approximately 10 percent. Attempts have been made to identify factors placing patients at higher risk for adverse outcomes, perhaps signaling the need for more aggressive treatment in these patients.Design and Methods: We queried the United States Thrombotic Microangiopathy (USTMA) immune-mediated TTP registry which currently contains data from 181 patients with 316 distinct episodes of TTP in order to evaluate the French TMA consortium predictive model and identify additional factors associated with mortality.(Benhamou, 2012) There were 269 TTP episodes in 149 patients with sufficient data available to calculate the prognostic scoring system under review. Clinical and demographic variables from episodes resulting in death less than thirty days from diagnosis were compared with those in which patients survived. In the group of patients succumbing to the disease (n=13), 3 had multiple episodes of TTP captured in the registry. For two patients, episodes of TTP were separated by greater than 12 months. For a third patient, the initial episode of TTP was followed by an early relapse resulting in death 29 days after the first day of the first event. This death was counted once and attributed to the second episode.Results: There were thirteen deaths in the cohort, yielding a mortality of 4.8%. Demographic factors associated with mortality were increasing age (mean age 55 vs. 44, p=0.01), and male gender (46% vs. 25%, p=0.30). Precipitating factors (surgery, infection, new medication) were more often present in those succumbing to the disease than those surviving (46% vs. 27%, p=0.20). Presenting symptoms seen more frequently in the mortality group were fever (38% vs. 13%, p=0.02) and neurologic symptoms (77% vs. 47%, p=0.02). Patients in the mortality cohort were more likely to have abnormal renal function with a higher mean creatinine (1.91 vs. 1.23, p=0.0004) and a higher proportion of patients with a creatinine over 1.3 (61% vs. 32%, p=0.04). Elevated troponin was also more common in the mortality group (39% vs. 16%, p=0.05). A mortality risk score using LDH 10 times normal, CNS involvement and age was calculated for each patient. When applied to our patient population, we found this score to have a sensitivity (% non-survivors with score ≥ 3) of 23% compared to 52% previously reported. We calculate a specificity (% of survivors scoring < 3) of 87% which is similar to previous reports of 90%. The positive predictive value for mortality with a score greater than or equal to 3 was 8%, and the negative predictive value of a score less than 3 was found to be 96% in the USTMA registry, compared to 41% and 93% reported by the French TMA consortium.Conclusion: We find lower rates of mortality in our patient population as compared to previously reported series. Increasing age, neurologic involvement, renal dysfunction, and cardiac involvement seem to herald increase risk of early mortality. Sensitive tools to identify those at highest risk remain elusive. DisclosuresSadler:23andMe: Consultancy; BioMarin: Consultancy; Genentech: Consultancy; Ablynx: Consultancy.

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 &amp;lt;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.

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.

Cost Effectiveness of Caplacizumab in Acquired Thrombotic Thrombocytopenic Purpura

Introduction: Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab +/- other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery, reduce TPE treatments and hospital length of stay, decrease exacerbations and increase relapses in TTP patients treated in the TITAN and HERCULES trials. Given the efficacy of caplacizumab in the TITAN and HERCULES trials, we conducted a cost effectiveness analysis (CEA) of caplacizumab in acquired TTP, representing the first-ever CEA in TTP. Methods: We built decision tree models to evaluate the cost effectiveness of SOC plus caplacizumab versus SOC in acquired TTP based on the results of each of the phase II TITAN trial at 12-month follow-up and the phase III HERCULES trial at 1-month follow-up. Costs were assessed from the health system perspective. For each trial, the SOC cost was calculated as the sum of TPE sessions, hospital length-of-stay (LOS), intensive care unit (ICU) stay, and rituximab use, while the cost of the SOC plus caplacizumab arm included the SOC cost plus the list price of caplacizumab (USD $270,000 per TTP episode). Effectiveness was calculated in quality-adjusted life years (QALY). Cost effectiveness of each treatment arm was calculated as the ratio of cost divided by QALYs. The incremental cost effectiveness ratio (ICER) of adding caplacizumab to SOC was calculated as the difference between the costs of the two treatment arms divided by the difference in QALYs; the ICER was then compared against the 2019 US willingness-to-pay (WTP) threshold of $195,300 USD as a measure of overall cost effectiveness. To avoid potential confounding factors that might inadvertently bias our analysis against the addition of caplacizumab, all values used in our models were selected to maximize cost in the SOC arm and minimize cost in the SOC plus caplacizumab arm in the two clinical trials. We also created a Markov model comparing cost effectiveness of SOC plus caplacizumab versus SOC in acquired TTP with a 5-year time horizon. We performed one-way sensitivity analyses for all models varying parameters including LOS, ICU stay, number of TPE sessions, rituximab use, utilities of the well and diseases states, and caplacizumab cost. Results: In the decision tree models, caplacizumab use yielded a higher cost of treatment compared to SOC alone in both trials (TITAN: $325,647 for caplacizumab plus SOC, versus $89,750 for SOC; HERCULES: $323,547 for caplacizumab plus SOC, versus $83,634 for SOC). An improvement in QALYs with the addition of caplacizumab was noted as compared to SOC in both trials (0.07 in TITAN and 0.26 in HERCULES). The ICER for adding caplacizumab to SOC versus SOC alone was $3.7 million in the TITAN trial and $0.9 million in the HERCULES trial, well above the US WTP threshold. The 5-year horizon Markov model yielded higher cost of caplacizumab treatment compared to SOC alone ($551,878 versus $151,947) and an improvement in QALYs (3.19 versus 2.92). The ICER for adding caplacizumab to SOC was $1.5 million (95% confidence interval $1.25-$1.72 million) with SOC favored in 100% of 10,000 Monte Carlo simulations in a probabilistic sensitivity analysis. Among all parameters, decreasing the cost of caplacizumab had the greatest impact on decreasing the ICERs in all models. The price of caplacizumab treatment for one TTP episode to meet the 2019 US WTP would have to be $46,424 and $80,848 in the TITAN and HERCULES decision tree models, respectively, and $65,106 in a Markov model with a 5-year horizon. Conclusion: The addition of caplacizumab to SOC treatment is not cost effective at its current drug pricing. As our models are designed to maximize the cost effectiveness of caplacizumab, it is very likely that the actual costs incurred by this medication will be much higher than what we report here. Compared to CEA studies of other orphan drugs that, unlike caplacizumab, alter long-term disease course, the costs incurred by caplacizumab treatment in acquired TTP are at the higher end of the spectrum. Additional studies utilizing longer-term follow-up data are warranted to assess the full impact of caplacizumab on the cost of treating TTP. Figure Disclosures No relevant conflicts of interest to declare.

Describing the point prevalence and characteristics of venous thromboembolism in patients with thrombotic thrombocytopenic purpura

BackgroundArterial thromboembolic events are relatively common and well‐described in patients with thrombotic thrombocytopenic purpura (TTP). However, the literature describing venous thromboembolism (VTE) in TTP is scarce. MethodsSingle‐institution retrospective chart review was conducted in TTP patients over a 10‐year period to describe the point prevalence of VTE. Data were analyzed using descriptive statistics. ResultsWe identified 77 consecutive patients with 123 episodes of TTP. Of these patients, 14 (18%) experienced 16 VTEs (6 pulmonary embolisms, 6 deep vein thromboses, 4 superficial vein thromboses [SVT]). Excluding SVT, the point prevalence of VTE was 14%. All were acute and associated with admission for acute TTP. All patients were treated with plasma exchange (PLEX); 6/8 patients on concurrent PLEX at VTE diagnosis were exchanged with solvent‐detergent plasma (SDP). Platelet and lactate dehydrogenase levels at time of VTE diagnosis had largely normalized from presentation values (median 175 × 109 U/L [interquartile range 130.75, 250] and 232 U/L [interquartile range 178.75, 263.5], respectively). Most VTEs (9/16) occurred while patients were not on pharmacologic thromboprophylaxis. All but one VTE was treated with anticoagulation. No VTEs were fatal or massive. ConclusionsOur data provide additional evidence that TTP patients may be at risk for VTE. It is possible that SDP exerted a prothrombotic effect. TTP‐associated VTEs may be pathophysiologically distinct from arterial thromboses because they occur following hematological recovery. VTE thromboprophylaxis was not commonly used. Our findings suggest the need to implement VTE thromboprophylaxis earlier in hospitalized patients with TTP.

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.

Association of Plasmic Score with Neurological Symptoms in Patients with Thrombotic Thrombocytopenic Purpura (TTP)

The PLASMIC score was recently developed for rapid diagnosis of thrombotic thrombocytopenic purpura (TTP) and therapeutic decision, as ADAMTS13 is frequently unavailable. The score consists of a scale from 1 to 7 that considers clinical and laboratory factors. PLASMIC score 6 - 7, 4 - 5 and below 4 are associated with high, intermediate and low probability of ADAMTS13 deficiency, respectively. Although the PLASMIC score is validated to predict ADAMTS13 values, its role as a predictor of adverse clinical outcomes in TTP is not established. The primary aim of this study was to evaluate whether the PLASMIC score is associated with neurological complications during TTP episodes. We also evaluated the association of the score with treatment outcomes, such as number of plasma exchange procedures, need for a second line immunosuppression therapy, days in hospital and death. In the present study, we retrospectively applied the PLASMIC score at the time of diagnosis of TTP episodes treated at the UNICAMP Clinical Hospital (University of Campinas - Brazil) between 1995 and 2016. All clinical data were retrieved from medical charts. We grouped the episodes according to the PLASMIC score, calculated at diagnosis, and compared the occurrence of neurological symptoms and other clinical manifestation between the PLASMIC score groups. The association between the PLASMIC score and neurological symptoms was evaluated by regression analysis. A total of 50 episodes of TTP were identified, of these 47 episodes, and 34 patients, were included in the study. Three episodes were excluded due to lack of clinical data. Twenty-seven (79.4%) patients were women, and the mean age was 35.7 years (SD 12.7). At the diagnosis, the mean PLASMIC score was 6, no PLASMIC score below 4 was detected, and the most common clinical features were thrombocytopenia (mean platelet count = 21,029 x 109 / L [SD 18,371 x 109]) and reticulocytosis (mean count = 7.83% [SD 5.29]). Plasma exchange was the main treatment in 98% of the episodes and an immunosuppression therapy was used in 94% of the cases. In 74.5% of the episodes, the patients presented with neurological symptoms at diagnosis or during hospitalization. Clinical features at diagnosis and during hospitalization of all TTP episodes, and of TTP episodes grouped according to the initial PLASMIC score, are presented in Table 1. The incidence of neurological symptoms was higher in PLASMIC score 7 (n= 14 [87, 5%]) and 6 (18 [81, 8%]) when compared with scores 5 (n=1, [16.7%) and 4 (n= 2 (66.7%]). The neurological complications tended to be more severe in PLASMIC scores 6 and 7. Personality change was reported in 2 (9%) TTP episodes in which the PLASMIC score was 6, in 4 (25%) episodes in which the PLASMIC score was 7 and was not reported in PLASMIC scores 4 and 5. Sensitivity loss was reported in 1 (16%) TTP episode in which the PLASMIC score was 5, in 11 (50%) episodes in which the PLASMIC score 6, and in 10 (62%) episodes in which the PLASMIC score was 7 . Seizures were reported in 3 (13.6%) TTP episodes in which the PLASMIC score was 6, in 5 (31.2%) episodes in PLASMIC score 7 and was not reported in PLASMIC scores 4 and 5. Stupor or coma were reported only in PLASMIC scores 6 [n=7 (31%]) and 7 (n= 9 [56%]). The mean number of plasma exchange procedures was 10.67 (SD=4.93) in PLASMIC score 4, 5 (SD=4.94) in PLASMIC score 5, 18.38 (10.61) in PLASMIC score 6 and 7.94 (SD=5.27) in PLASMIC score 7. The length of hospitalization and the days in intensive care unit were similar between groups. Deaths during hospitalization occurred only in cases with PLASMIC score 6 or 7. In the regression analysis, the risk of neurological complications was 9.0-fold increased (95%CI 1.6 - 52.3) in PLASMIC score 6 and was 14-fold increased (95%CI 1.8 - 106.5) in PLASMIC score 7, when compared with PLASMIC score 4 and 5. The risk of severe neurological complications was also higher in PLASMIC score 6 (odds ratio 12.0, 95% CI 1.7 - 83.5) and 7 (odds ratio 18.0, 95% CI 2.0 - 161.0) as compared to PLASMIC score 4 and 5. In conclusion, the frequency and severity of neurological injuries increased with higher PLASMIC scores. These observations suggest that further attention to neurological complications are needed when PLASMIC score is 6 or 7. Awareness of the risk of neurological complications may also improve treatment. Therefore, the PLASMIC score may be an important tool not only to predict ADAMTS13 values but also to provide information on prognosis from a neurological point of view. Disclosures No relevant conflicts of interest to declare.

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

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

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.