Thrombotic Thrombocytopenic Purpura Patients Research Articles

Distinguishing thrombotic thrombocytopenic purpura from primary immune thrombocytopenia accompanied by anemia using the carbon monoxide breath test

ABSTRACT Objectives Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening hematological disorder. Early differentiation between TTP and primary immune thrombocytopenia (ITP) accompanied by anemia is crucial to initiate an appropriate therapeutic strategy. The objective of this study was to evaluate the predictive value of red blood cell lifespan (RBCLS), determined using the carbon monoxide breath test, in the differential diagnosis of these two diseases. Methods We conducted a retrospective analysis of 23 patients with TTP and 32 patients with ITP accompanied by anemia. RBCLS measurements were compared and evaluated between these two patient groups. Results TTP patients had a significantly shorter mean RBCLS (20 ± 8 days) than patients with ITP accompanied by anemia (77 ± 22 days, P < 0.001) and healthy controls (114 ± 25 days, P < 0.001). In TTP patients, RBCLS showed a significant negative correlation with reticulocyte percentage and lactic dehydrogenase levels (P < 0.001). When using a standard baseline of 75 days, RBCLS demonstrated a sensitivity of 100% and specificity of 53.1% in identifying TTP. The diagnostic accuracy could reach 93% by excluding the impact of gastrointestinal bleeding. By employing the Receiver Operator Characteristics (ROC) curve, the area under the curve for RBCLS was 0.985 (95% CI: 0–1, P < 0.01) in predicting TTP, with an optimal cut-off value of 32 days, and sensitivity and specificity of 95.7% and 96.9%, respectively. Conclusions Our study proposes a simple and accessible method for evaluating RBCLS to differentiate between TTP and ITP accompanied by anemia.

Peak ADAMTS13 activity to assess ADAMTS13 conformation and risk of relapse in immune-mediated thrombotic thrombocytopenic purpura

AbstractPrevious studies have demonstrated that >38% of patients with immune-mediated thrombotic thrombocytopenic purpura in remission with activity >50% had an open ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) conformation. We assessed ADAMTS13 conformation in remission (ADAMTS13 activity >60%), focusing on peak ADAMTS13 activity levels and longitudinal assessment in 420 samples across 157 patients. Fewer cases had an open conformation at peak ADAMTS13 activity than unselected remission samples with ADAMTS13 activity >60% (23% vs 43%). Patients with a closed ADAMTS13 conformation at peak ADAMTS13 activity had an eightfold lower relapse rate in the subsequent year (9% vs 46%) and a fivefold lower relapse rate within 2 years (23% vs 62%) compared with cases with an open conformation. Patients with an open conformation at peak ADAMTS13 activity required preemptive anti-CD20 treatment earlier than those with a closed conformation (median, 10 vs 25 months). Longitudinally, an open conformation was evident at, and often preceded relapse. When the conformation was already open before relapse, an increase in the conformation index at relapse was seen despite the undetectable anti-ADAMTS13 immunoglobulin G (IgG) antibody. In cases with detectable anti-ADAMTS13 IgG antibody, these became undetectable before achieving a closed conformation, highlighting the relapse risk even with undetectable anti-ADAMTS13 IgG antibody and the clinical utility of open/closed during monitoring. To our knowledge, this is the first study to show an association between relapse risk and ADAMTS13 conformation when activity levels are at a peak. The open conformation identifies antibody-mediated subclinical disease that is not detectable by the current ADAMTS13 testing.

Stress-induced hyperglycemia is associated with the mortality of thrombotic thrombocytopenic purpura patients

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy with a rapid progression and high mortality rate. We aimed to explore early risk factors for mortality in patients with TTP.MethodsWe conducted a retrospective analysis of 42 TTP patients that were admitted to our hospital between 2000 and 2021, with a median age of 49 (29–63) years. Risk factors for mortality were evaluated using multivariate logistic regression. Receiver operating characteristic curve analysis was used to determine the cut-off value of glucose for predicting mortality in patients, which was validated by comparison to a similar cohort in the published literature.ResultsElevated glucose level and reduced red blood cells (RBC) counts were risk factors for mortality in patients with TTP (glucose, odds ratio and 95% confidence interval: 2.476 [1.368–4.484]; RBC, odds ratio and 95% confidence interval: 0.095 [0.011–0.799]). The area under the curve of glucose was 0.827, and the cut-off value was 9.2 mmol/L, with a sensitivity of 75.0% and specificity of 95.8%. A total of 26 cases from the validation cohort had a sensitivity of 71.0% and a specificity of 84.0%. The change trends of the TTP-related laboratory indices differed during hospitalization.ConclusionHyperglycemia at admission and unstable blood glucose levels during hospitalization may be potential predictors of mortality for TTP patients. The improved prognosis was associated with the recovery of platelet counts and a significant decrease in serum lactate dehydrogenase after five days of treatment.

Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis

Abstractvon Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. Here, we describe the development of a variable domain of heavy-chain-only antibody (VHH)-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in patients with TTP during acute attacks of thrombotic microangiopathy but not in those in remission. Finally, we show that therapeutic plasminogen activation in a mouse model of TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion.

Nivolumab-induced Thrombotic Thrombocytopenic Purpura in Patients with Gastric Tube Cancer.

Recently, immune checkpoint inhibitors (ICIs) have been used to treat several cancer types. ICIs have been reported to cause a wide variety of immune-related adverse events, including endocrine, neurologic, gastrointestinal, and cutaneous disorders. Thrombotic thrombocytopenic purpura (TTP) is an autoimmune hematologic disorder characterized by the presence of autoantibodies against a disintegrin and metalloprotease with thrombospondin-1, member 13. Several previous cases of TTP were thought to have been caused by ICI treatment. We herein report a rare case of TTP that developed after long-term treatment with an ICI (nivolumab) for gastric tube cancer.

Outcomes of thrombotic thrombocytopenic purpura patients submitted to therapeutic plasma exchange in a single center in Brazil

IntroductionImmune thrombotic thrombocytopenic purpura (iTTP) is characterized by acute systemic microvascular thrombosis and is associated with a high morbidity and mortality, especially in delayed diagnosis (later than 6–7 days from symptoms). iTTP data in Brazil is scarce, so we aimed to characterize the clinical presentation and identify predictors of death risk in patients with this disease in Brazil. MethodsIn this single-center retrospective study the patients who underwent therapeutic plasma exchange (TPE) for presumptive or confirmed iTTP were evaluated regarding the epidemiological, clinical, laboratorial characteristics and management. ResultsA total of 50 patients (90 % female), with median age (IQR) of 34.1 (27–47) years, were enrolled, of which 12 (24 %) died. The most frequent symptoms were neurological (96 %), bleeding (76 %), gastrointestinal (52 %), fever (38 %), and cardiovascular (22 %). Neurological focal deficit and cardiovascular symptoms were more frequently observed in the non-survivor group (P = 0.0019 and P = 0.007, respectively). The mean ± SD number of days from beginning of symptoms to first TPE was 12.22 ± 7.91. We identified an association regarding mortality rate with a score MITS ≥ 2 points (P = 0.04), a higher indirect bilirubin (P = 0.0006), a higher number of transfused red blood cell units (P = 0.025), and platelet transfusion (P = 0.027). ConclusionDelayed diagnosis appears to be associated with a higher frequency of neurological symptoms and mortality. Intensity of hemolysis and signs of organ ischemia, such as cardiovascular symptoms and focal neurological deficit, are indicators of death risk.

Proof-of-Concept in a Murine Model of Treatment of Thrombotic Thrombocytopenic Purpura Using Engineered Red Blood Cells Expressing Fragments of ADAMTS13 on Their Membrane

Thrombotic Thrombocytopenic Purpura (TTP) is due to congenital or acquired deficiency in A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13 (ADAMTS13), a metalloproteinase responsible for the cleavage of the pro-coagulant glycoprotein von Willebrand Factor (vWF). Lack of ADAMTS13 activity causes induction of systemic platelet aggregation and microthrombi in small blood vessels by vWF multimers. Current treatment of TTP consists of daily plasma exchange and immune suppression but is costly and associated with high morbidity. A recombinant ADAMTS13 treatment for the congenital form is in advanced clinical trials but alternative treatment methodologies remain needed. We have developed methods to generate genetically engineered cultured red blood cells (cRBCs) from iPSCs which can be used as drug delivery vectors. We hypothesize that generating cRBCs with membrane-bound variants of ADAMTS13 could be a potential method of treatment for TTP. We have inserted at AAVS1, in human erythroid cells, constructs that contain globin-LCR driven MDTCS ADAMTS13 fusion transgenes with or without gain-of function mutations that confer resistance to ADAMTS13 auto-antibodies. We have shown using flow cytometry and a FRET assay that these erythroid cells express these fusion proteins at high levels and that membrane bound ADAMTS13 is enzymatically active. We have also shown that, as expected, the enzymatic activity of erythroid cells carrying the MDTCS fragment of ADAMTS13 with gain-of-function mutations is resistant to inhibition by plasma from TTP patients, while the wildtype version of the same fragment is not. To obtain an in vivo proof-of-concept that such erythroid cells can prevent TTP, we have generated rosa26 knock-ins and transgenic mice expressing the wildtype or gain-of-function variants of MDTCS ADAMTS13 and observed that RBCs from these animals have normal half-lives, and, as shown via FACS and FRET assays, express significant amounts of catalytically active ADAMTS13 on their RBC membranes. ADAMTS13 knock-out mice inoculated with large amounts of recombinant human vWF (rhvWF) have been shown to exhibit typical TTP symptoms including platelet drops, schistocytes formation and cardiac abnormalities providing a useful murine model for TTP. To determine if ADAMTS13 expressing RBCs could be used to prevent TTP symptoms, we transfused ADAMTS13 knock-out mice with either wild-type or ADAMTS13-RBCs up to 24 hours prior to inoculation with rhvWF. Mice transfused with ADAMTS13-RBCs displayed a significant reduction of ADAMTS13 symptoms including drastically reduced platelet drops, lack of schistocytes formation and absent cardiac abnormalities. We conclude that the membrane-bound MDTCS fragment of ADAMTS13 is capable of cleaving the full-length rhvWF in the presence of flow, in vivo. The above data provide a proof-of-concept that RBCs expressing membrane-bound ADAMTS13 fusion proteins can be used as a therapeutic for congenital and acquired TTP. Experiments are in progress to determine in vivo, the TTP antibody resistance of these cells in the presence of anti-ADAMTS13 auto-antibodies from TTP patients.

The ‘Weekend Effect’ on Immune Cytopenia: Insights from the National Inpatient Sample Database

Introduction: Outcomes for weekend versus weekday admissions for immune cytopenias including immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and autoimmune hemolytic anemia (AIHA)/Evan's Syndrome are explored in this abstract. Methods: A query of the 2012-2019 National Inpatient Sample was performed for primary hospitalizations with immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and autoimmune hemolytic anemia (AIHA)/Evan's Syndrome using ICD-9/10 codes. Demographics, comorbidities, and outcomes were identified. Univariate analysis with t-tests or chi-square performed as appropriate. A 1:1 nearest neighbor propensity score matched cohorts was generated for each of the ITP, TTP and AIHA/Evan's hospitalization dataset. Variables with standardized mean differences &amp;gt;0.1 used in multivariate regression to generate adjusted odds ratios (AOR)/β-coefficients for weekend admission status on outcomes. Significance was set at an alpha level of &amp;lt;0.05. All analysis performed in SPSS versions 26. Results: 24,325, 2992,and 7,609 hospitalizations were included with 4592, 656, and 1468 weekend admissions in ITP, TTP, and AIHA/Evan's respectively. Propensity matched cohorts were generated adjusting for age, sex, race, median household income and co-morbidities including DM, CHF, CKD/ESRD, and liver disease. The results showed significantly higher, almost two-fold, in-hospital mortality in AIHA for weekend admissions (Odds ratio (OR): 1.85, CI 1.20-2.85, p-value=0.005). In addition, there was significantly higher risk of circulatory shock and mechanical ventilation requirement for weekend admissions in AIHA along with significantly increased length of hospital stay and total hospital charges. TTP patients also showed similar trend towards higher mortality with significantly higher incidence of AKI and increased length of stay for weekend admissions. There was no significant difference seen in ITP. The results are summarized in table 1. These results are partly in agreement with findings of Manadan et al study, which showed lower rate of procedures and higher adjusted mortality for general inpatient admissions in weekends. Conclusion: Weekend admissions showed poorer outcomes especially in AIHA and TTP. Although the exact reasons are unknown, decreased staffing and procedural availability may be responsible for such findings. Further studies are needed to clarify the steps needed to decrease adverse outcomes for weekend admissions.

Plasmin-Cleaved Von Willebrand Factor As a Biomarker for Microvascular Thrombosis

Von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. We developed a V HH-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in TTP patients during acute attacks of thrombotic microangiopathy, but not in remission. Finally, we show that therapeutic plasminogen activation in a mouse model for TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion.

Cryoprecipitate-Poor Plasma Instead of Fresh Frozen Plasma As Replacement Therapy in Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition characterized by the presence of small-vessel thrombi enriched with platelets, leading to thrombocytopenia, thrombotic microangiopathy (TMA), and on occasion, resulting in end-organ damage. The standard therapeutic plasma exchange (TPE) approach, initiated after suspicion of TTP, is done with fresh frozen plasma (FFP). Yet, the use of cryoprecipitate-poor plasma (CPP) has been suggested as alternative in recent decades given its absence of von Willebrand factor, which would benefit the pathophysiology of TTP. However, its efficacy over FFP remains unclear. Therefore, we aimed to conduct a meta-analysis to compare the safety and efficacy of CPP versus FFP in patients with TTP. Methods: We systematically searched PubMed, Cochrane Central and Embase for clinical studies published up to June 2023, comparing CPP to FFP as replacement fluids in TPP or TMA patients. Outcomes assessed were overall mortality, relapse rate, response to treatment and number of TPE sessions. We pooled outcomes as odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI). We also performed a subgroup analysis with randomized controlled trials (RCTs). Statistical analysis was performed with Review Manager version 5.4.1. Heterogeneity was assessed with I 2 statistics. The protocol was registered in PROSPERO (ID: CRD42023440665). Results: A total of eight articles met inclusion criteria, of which three were RCTs. The combined dataset involved 290 patients, of which 144 (49.7%) were in CPP group and 146 (50.3%) in the FFP group. CPP significantly reduced overall mortality compared to FFP (OR 0.27; 95% CI 0.13-0.59; p=0.001; I 2=0%; Figure 1A). However, our subgroup analysis of RCTs showed no significant difference in overall mortality between groups (OR 0.49; 95% CI 0.13-1.84; p=0.29; I 2=0%; Figure 1B). Additionally, there were no significant differences between groups regarding relapses (OR 0.81; 95% CI 0.37-1.77; p=0.60; I 2=0%; Figure 1C), response to treatment (OR 2.20; 95% CI 0.69-7.07; p=0.18; I 2=44%; Figure 1D) or number of TPE sessions (MD 1.63; 95% CI -2.83 - 6.08; p=0.47; I 2=55%; Figure 1E). Conclusion: Our meta-analysis shows that the safety and efficacy of CPP in TTP patients is at least similar to FFP in reducing mortality, relapse rate, and improving response to treatment. The reduced mortality with CPP found in the whole pool of studies, along with the trend towards reduced mortality found in the RCT-only analysis indicates the potential benefit of CPP over FFP. However, larger population-based randomized trials should contribute to narrow confidence intervals and decrease bias of observational studies, providing clearer conclusions for treatment efficacy in the future.

Validation of the Plasmic Score and Development of a Novel Predictive Model for Thrombotic Thrombocytopenic Purpura: Exploring Socioeconomic Disparities and Outcomes

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy with a mortality rate up to 90% if left untreated. The PLASMIC score is a clinical prediction tool used to estimate the pretest probability of severe ADAMTS13 deficiency. Female sex, black ethnicity, and obesity have been identified as potential risk factors for TTP, however, definitive evidence for this is lacking. Our goal was to externally validate the PLASMIC score at our institution, explore the role of socioeconomic factors on TTP outcomes, and potentially identify a more accurate predictive model for TTP. Methods: We conducted a retrospective analysis of patients admitted to our institution in Cleveland, Ohio with suspected TTP between January 2000 and January 2023. Any patient who had an ADAMTS13 test ordered was included in the study. The PLASMIC score was retrospectively calculated based on admission labs and correlated with ADAMTS13 levels. Logistic regression analysis was performed to identify potential predictors of TTP with effect measured by odds ratio (OR) and its 95% confidence interval (CI). The performance of 5 predictive models was summarized using the area under the curve (AUC) and compared using Delong's test (Figures 1.1&amp;1.2). We also examined the relationship between age, race, average income, and underlying chronic diseases with TTP outcomes including length of hospital stay, number of blood transfusions, treatment options, lowest hemoglobin level during admission, and lowest platelet count during admission. Overall survival (OS) was calculated from admission to death or last follow-up for surviving patients and was evaluated using Kaplan-Meier method and Cox model. Results: We identified a cohort of 47 patients who underwent ADAMTS13 testing. The average age was 50 years old with 62% females and 44.7% identifying as African American. A total of 47% of patients were diagnosed with TTP and had ADAMTS13 levels below 10%. Our analysis revealed that the PLASMIC score was predictive of TTP with OR = 3.05 (P=0.003). When the PLASMIC score was dichotomized into a low-intermediate range (0-5) and a high range (6-7), the model predicted severe ADAMTS13 deficiency (at cutoff point -0.1088028) with a positive predictive value of 75%, negative predictive value of 69.6%, sensitivity of 72%, and specificity of 72.7%. Among the five predictive models compared (Figures 1.1 &amp; 1.2) the final multivariable model that included sex and four components of the PLASMIC score (Active Cancer, Mean Corpuscular Volume, International Normalized Ratio, and Creatinine) was found to be the most accurate in predicting TTP, with an AUC 0.88. In patients with TTP, 94% received plasma exchange and 100% received systemic steroids as treatment. Only 6 TTP patients (31.5%) received rituximab, and 2 patients (10.5%) received intravenous immunoglobulin. The use of multiple treatment options was significantly higher in older patients (P=0.017), obesity (P=0.002), and those with higher average income (per 1% increase, P=0.006). The length of hospital stay was associated with older age (P=0.015), hyperlipidemia (P=0.037), and the presence of underlying autoimmune disease (P=0.009). There was no statistically significant correlation between race and any of the adverse outcomes. Patients diagnosed with TTP had a significantly better OS compared to patients without TTP (P=0.011). The OS of patients who underwent plasmapheresis was slightly better, although the difference was not statistically significant (P=0.067). Conclusion: Our study validates the original PLASMIC score as a reliable predictor of severe ADAMTS13 deficiency. However, we propose a new multivariable model that incorporates sex and four components of the original PLASMIC score (Active Cancer, Mean Corpuscular Volume, International Normalized Ratio, and Creatinine) as a better predictor for TTP. Further multicenter studies with larger sample sizes are necessary to validate this new model. We also identified socioeconomic disparities, such as patients with higher income who received multiple lines of treatment compared to lower income patients. Notably, patients diagnosed with TTP had lower mortality possibly due to prompt diagnosis and effective management at our institution and/or the presence of more severe alternative diagnoses in the non-TTP group.

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.

Comparative Analysis of Hospital Outcomes for Thrombotic Thrombocytopenic Purpura between 2018 and 20120: A National Inpatient Sample Database Study

Background: Thrombotic Thrombocytopenic Purpura (TTP) is a rare, life-threatening hematological emergency with a mortality rate of up to 20%. While plasma exchange and immunosuppression have long been the “pillars” of therapy, since 2019, a novel targeted therapy, caplacizumab, has become available. This study aims to analyze hospital outcomes before and after 2019 to assess the potential impact of this therapeutic advancement. Methods: A retrospective analysis of the United States (US) National Inpatient Sample (NIS) database was conducted using International Classification of Diseases (ICD-10) codes to identify TTP patients in 2018 and 2020. The data were analyzed using STATA version MP14.2. Fischer's exact test, student's t-test, and multivariate regression analysis were used to compare proportions and continuous variables and calculate the adjusted odds ratio. The database, however, did not consistently specify which patients received specific therapeutics like rituximab and caplacizumab and which patients did not. Results: The study included 1120 TTP hospitalization in 2018 and 975 in 2020. The majority of patients were African Americans (52.1% in 2018, 46.4% in 2020) and females (67.9% in 2018, 68.7% in 2020); 1.6% had COVID-19 infection in 2020, with a mean Charlson comorbidity Index (CCI) of 1.28 in 2018 vs. 1.34 in 2020. The multivariate analysis after controlling age, sex, CCI, and primary payer, revealed no significant change in the rates of stroke (AOR: 0.94, 95% CI: 0.64-1.40, P = 0.77), myocardial infarction (AOR: 1.01, 95% CI: 0.70-1.46, P = 0.95), acute kidney injury (AOR: 0.91, 95% CI: 0.72-1.14, P = 0.398), acute bleeding (AOR: 0.74, 95% CI: 0.51-1.09, P = 0.13), packed red blood cell transfusion (AOR: 0.95, 95% CI: 0.74-1.23, P = 0.71), and platelet transfusion (AOR: 1.20, 95% CI: 0.88-1.62, P = 0.25) in 2020 compared to 2018. Additionally, there were no significant changes in the mortality rate (AOR: 0.83, 95% CI: 0.52-1.33, P = 0.43) and mean length of hospital stay (12 vs. 11 days) in 2020. However, a significant increase in mean hospital cost ($189,749.9 vs. $267,835 US dollars, P&amp;lt;0.001), adjusted for inflation, was observed in 2020. A subgroup analysis was conducted for 50 patients who received caplacizumab in 2020, revealing higher average hospital costs ($465,665 vs. $241,665) and an increased rate of intracranial bleeding (10% vs. 1.6%) compared to patients whose caplacizumab usage was unknown. Mortality was observed in none of the known caplacizumab-treated samples, while 6.5% mortality was recorded among those without known caplacizumab use. Conclusion: Compared to 2018, 2020 hospitalizations had a substantial increase in costs without a significant change in patient outcomes. This probability is related to the COVID-19 pandemic and the advent of caplacizumab use in the US. We were unable to sort out the impact of other costly therapeutics like rituximab. However, it would be given less frequently. Further study is needed to explore this indirect inference from the NIS database analysis and the attendant cost-benefit implications in the management of TTP and its impact on patient outcomes.

Immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura — diagnostic difficulties and errors

Introduction. When establishing a diagnosis of thrombotic thrombocytopenic purpura (TTP) for the first time, other diseases occurring with thrombocytopenia may be misdiagnosed. Aim: to analyze diagnostic difficulties and errors of TTP. Materials and methods. In total, 54 patients (44 women and 10 men) aged 18 to 83 years (median 33 years), who were diagnosed TTP from 2019 to 2023, were included in the study. Anamnesis, baseline hemoglobin, platelets, erythrocytes, lactate dehydrogenase and bilirubin serum concentrations, pre-established diagnoses, treatment, and outcomes were analyzed. Results. Initially TTP was suspected only in 19 (35 %) patients. In 12 out of 54 patients immune thrombocytopenia (ITP) was initially misdiagnosed. Fisher-Evans syndrome was initially suspected in 3 patients. In sporadic cases, myelodysplastic syndrome, systemic lupus erythematosus / antiphospholipid syndrome, autoimmune hemolytic anemia were initially suspected. Among 15 women with associated with pregnancy TTP in 8 (53.3 %), HELLP syndrome was initially misdiagnosed. In total, 12 (22.2 %) of 54 TTP patients died. In 11/12 non-survival patients, TTP treatment was never started, because the doctors were waiting for the ADAMTS13 test results. A case report of Sequential Immune Thrombocytopenia (ITP) and TTP in the same Patient is described. Conclusion. When thrombocytopenia is combined with hemolysis and in the absence of multiple organ pathology, it is difficult to differentiate ITP and TTP without examining the plasma activity of ADAMTS113. With a combination of ITP and TTP in the same patient, the study of ADAMTS13 plasma activity makes it possible to identify the leading mechanism of thrombocytopenia and choose treatment tactics.

Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura

ABSTRACTCongenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of ADAMTS13 activity. DNA sequence analysis revealed two mutations on chromosome 9 (1.9q34.2) in the patient’s ADAMTS13 gene. One mutation was a non-synonymous mutation (exon 5: c.A530G: p.Y177C), while the other was a nonsense mutation (exon 21: c.G2651A: p.W884X). Both mutations were found to be heterozygous. The patient’s parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient’s father was a heterozygote for the nonsense mutation of the ADAMTS13 gene (exon 21: c.G2651A: p.W884X), while the mother was a heterozygote for the non-synonymous mutation of the ADAMTS13 gene (exon 5: c.A530G: p.Y177C). To investigate the mechanism behind ADAMTS13 deficiency in this patient, wild type (WT), ADAMTS13 p.Y177C, and ADAMTS13 p.W884X were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated ADAMTS-13 proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments.

Identification of 8 Rare Deleterious Variants in ADAMTS13 by Next-generation Sequencing in a Chinese Population with Thrombotic Thrombocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare and fatal disease caused by a severe deficiency in the metalloprotease ADAMTS13 and is characterized by thrombotic microangiopathy. The present study aimed to investigate the genes and variants associated with TTP in a Chinese population. Target sequencing was performed on 220 genes related to complements, coagulation factors, platelets, fibrinolytic, endothelial, inflammatory, and anticoagulation systems in 207 TTP patients and 574 controls. Subsequently, logistic regression analysis was carried out to identify the TTP-associated genes based on the counts of rare deleterious variants in the region of a certain gene. Moreover, the associations between common variants and TTP were also investigated. ADAMTS13 was the only TTP-associated gene (OR = 3.77; 95% CI: 1.82-7.81; P=3.6×10ȡ4) containing rare deleterious variants in TTP patients. Among these 8 variants, 5 novel rare variants that might contribute to TTP were identified, including rs200594025, rs782492477, c.T1928G (p.I643S), c.3336_3361del (p.Q1114Afs*20), and c.3469_3470del (p.A1158Sfs*17). No common variants associated with TTP were identified under the stringent criteria of correction for multiple testing. ADAMTS13 is the primary gene related to TTP. The genetic variants associated with the occurrence of TTP were slightly different between the Chinese and European populations.

Acute myocardial infarction in a patient with thrombotic thrombocytopenic purpura: a case report and literature review

Acute myocardial infarction (AMI) induced by thrombotic thrombocytopenic purpura (TTP) has been previously reported, but comorbidity with autoimmune hemolytic anemia is rare. The index patient, a 55-year-old woman, presented with acute ST-elevation myocardial infarction (STEMI). A diagnosis of TTP was established on the presence of thrombocytopenia, microangiopathic hemolytic anemia, acute kidney injury, fever, and neurologic symptoms (ischemic stroke); autoimmune hemolytic anemia was established based on Comboost test. Percutaneous coronary intervention and dual antiplatelet therapy were not initiated due to elevated risk of bleeding. Instead, the patient was treated with glucocorticosteroid and plasmapheresis. Despite the treatment, the patient suffered a watershed acute cerebral infarction, and finally died of gastrointestinal bleeding. This case highlights the challenges in managing STEMI in TTP patients.

Immune thrombotic thrombocytopenic purpura in patients over 60 years of age: Diagnostic pitfalls and treatment strategy.

Real-world registry studies of older patients with iTTP highlight diagnostic difficulties in comparison to patients less than 60 years of age with greater risk of renal injury, atypical neurological features and less profound cytopenia, which can result in diagnostic delays. However, there is no clear signal of significantly increased toxicity from full active treatment. Commentary on: Gómez-Seguí et al. Immune thrombotic thrombocytopenic purpura in older patients: results from the Spanish TTP Registry (REPTT). Br J Haematol 2023;203:860-871.

Immunosuppressive Therapy of Antibody-Mediated aHUS and TTP.

The recent classification of pediatric thrombotic microangiopathies (TMA) takes into consideration mechanisms of disease for guidance to targeted therapies. We present our experience with seven patients with antibody mediated atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). Five children had aHUS with antibodies against complement factor H (CFH-ab) and two with TTP with antibodies against metalloproteinase ADAMTS13. In the aHUS cases diagnosed and treated before the eculizumab era, CFH-ab was detected using the ELISA assay. Mutational analysis of selected complement genes was performed. TTP was diagnosed if, in addition to microangiopathic hemolytic anemia and thrombocytopenia, ischemic organ involvement and severe deficiency in ADAMTS13 activity were present. Treatment protocol consisted of plasma exchanges (PE) and steroid pulses, followed by the combination of cyclophosphamide and rituximab to achieve long-term immunosuppression. Four patients with CFH-ab and the TTP patients with ADAMTS13 antibodies came into sustained remission. After a median follow-up of 11.7 (range 7.7-12.9) years without maintenance therapy, no disease recurrence was observed; nevertheless, six patients, two had hypertension and two had proteinuria as a late consequence. One patient, with late diagnosis of CFH-ab and additional genetic risk factors who was treated only with PE and plasma substitution, reached end-stage renal disease and was later successfully transplanted using eculizumab prophylaxis. In the cases of antibody-mediated TMAs, PE and early immunosuppressive treatment may result in sustained remission with preserved kidney function. Further data are needed to establish optimal treatment of anti-FH antibody-associated HUS.

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

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