PLASMIC Score Research Articles

Vitamin B12 Deficiency in Thrombotic Thrombocytopenic Purpura-Like Cases.

Thrombotic microangiopathies (TMA) are characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage which occur in the setting of endothelial damage and platelet activation. Vitamin B12 (cobalamin) deficiency could lead to a picture that resembles TMA, termed metabolic mediated TMA (MM-TMA). A 60-year-old female was brought to the hospital after she was found unresponsive. On presentation, she was pale, lethargic, tachycardic, and febrile. Laboratory investigations revealed normocytic anemia, thrombocytopenia, and elevated bilirubin. Blood smear revealed schistocytes and tear drop cells. Given the presence of hemolytic anemia, thrombocytopenia, acute renal failure, and altered mental status, a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) was made with a PLASMIC score of 7 indicating high risk. She received plasma exchange, caplacizumab, and intravenous methylprednisolone. Given the patient's low level of vitamin B12, she was initiated on intramuscular cyanocobalamin 1000 μg daily. The encephalopathy resolved and renal function improved. On day 6, ADAMTS13 activity was normal ruling out the diagnosis of TTP. Accordingly, plasmapheresis, steroids, and caplacizumab were discontinued. With continued aggressive B12 replacement, hemolysis resolved indicating severe vitamin B12 deficiency was the likely culprit of this patient's microangiopathic hemolytic anemia. This case serves to highlight the variable presentation of vitamin B12 deficiency. Severe vitamin B12 deficiency can even mimic TTP. If patients have markers of hemolysis, a low vitamin B12 level, and low reticulocyte count we should consider vitamin B12 deficiency as a likely cause of microangiopathic hemolytic anemia as early detection allows for early initiation of appropriate management. Vitamin B12 deficiency can be a cause of thrombotic microangiopathy.

Role of therapeutic plasma exchange in dengue-related microangiopathy

Abstract: Thrombotic microangiopathies (TMAs) are a group of disorders characterized by microangiopathic hemolytic anemia and thrombocytopenia, leading to ischemic tissue injury. We, hereby, describe an interesting case of TMA secondary to dengue along with dengue encephalitis. Dengue-related TMA is rarely described. Treatment was initiated with standard-volume (1.5 plasma volume) therapeutic plasma exchange (TPE) by centrifugation method on a multifunctional cell separator (Spectra Optia, Terumo BCT, USA) within a few hours of admission based on high PLASMIC score, which led to improvement in hemolytic parameters and kidney injury. This case highlights the role of early diagnosis and early initiation of TPE is key in the management of dengue-related TMAs.

Risk factors of death or chronic renal replacement therapy requirements in patients with thrombotic microangiopathies without ADAMTS-13 deficiency.

Thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multisystem organ dysfunction, is a life-threatening disease. Patients with TMA who do not exhibit a severe ADAMTS-13 deficiency (defined as a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 activity ≥10%: TMA-13n) continue to experience elevated mortality rates. This study explores the prognostic indicators for augmented mortality risk or necessitating chronic renal replacement therapy (composite outcome: CO) in TMA-13n patients. We included 42 TMA-13n patients from January 2008 to May 2018. Median age of 41 years and 60% were female. At presentation, 62% required dialysis, and 57% warranted intensive care unit admission. CO was observed in 45% of patients, including a 9-patient mortality subset. Multivariate logistic regression revealed three independent prognostic factors for CO: early administration of eculizumab (median time from hospitalization to eculizumab initiation: 5 days, range 0-19 days; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.94), presence of neuroradiological lesions (OR, 6.67; 95% CI, 1.12-39.80), and a PLASMIC score ≤4 (OR, 7.39; 95% CI, 1.18-46.11). In conclusion, TMA-13n patients exhibit a heightened risk of CO in the presence of low PLASMIC scores and neuroradiological lesions, while early eculizumab therapy was the only protective factor.

Cost-effectiveness of rapid vs in-house vs send-out ADAMTS13 testing for immune thrombotic thrombocytopenic purpura

AbstractWhile awaiting confirmatory results, empiric therapy for patients suspected to have immune thrombotic thrombocytopenic purpura (iTTP) provides benefits and also accrues risks and costs. Rapid assays for ADAMTS13 may be able to avoid the cost and risk exposure associated with empiric treatment. We conducted, to our knowledge, the first cost-effectiveness evaluation of testing strategies with rapid vs traditional ADAMTS13 assays in patients with intermediate- to high-risk PLASMIC scores, with and without caplacizumab use. We built a Markov cohort simulation with 4 clinical base-case analyses: (1) intermediate-risk PLASMIC score with caplacizumab; (2) intermediate-risk PLASMIC score without caplacizumab; (3) high-risk PLASMIC score with caplacizumab; and (4) high-risk PLASMIC score without caplacizumab. Each of these evaluated 3 testing strategies: (1) rapid assay (<1-hour turnaround); (2) in-house fluorescence resonance energy transfer (FRET)–based assay (24-hour turnaround); and (3) send-out FRET-based assay (72-hour turnaround). The primary outcome was the incremental net monetary benefit reported over a 3-day time horizon and across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). While accruing the same amount of QALYs, the rapid assay strategy saved up to $46 820 (95% CI, $41 961-$52 486) per patient tested. No parameter variation changed the outcome. In probabilistic sensitivity analyses, the rapid assay strategy was favored in 100% (3 base cases and scenario analyses) and 99% (1 base-case and scenario analysis) across 100 000 Monte Carlo iterations within each. Rapid ADAMTS13 testing for patients with intermediate- or high-risk PLASMIC scores yields significant per patient cost savings, achieved by reducing the costs associated with unnecessary therapeutic plasma exchange and caplacizumab therapy in patients without iTTP.

HLA-DR-DQ associations, combined with PLASMIC score, are reliable predictors of acquired thrombotic thrombocytopenic purpura (aTTP) and aid in differentiating aTTP from other thrombotic microangiopathies

BackgroundThrombotic microangiopathies (TMA) are a group of disorders with overlapping clinical features that require urgent intervention. Treatment is based on the recognition of the TMA type, which is often challenging. The aim of this study was to identify specific HLA associations with different TMA types to aid rapid diagnosis and appropriate treatment, since the HLA assay can be completed within five hours. MethodsAll 86 consecutive patients who presented to the University of Arkansas for Medical Sciences between May 2013 and January 2021 with a presumptive diagnosis of TMA were included in this study. HLA typing was performed and correlated with other clinical and laboratory studies. ResultsIn comparison with other types of TMA, patients with acquired thrombotic thrombocytopenic purpura (aTTP) showed increased frequencies of HLA-DRB1*11, HLA-DQB1*03:01/19, HLA-DRB1*08 and HLA-DRB3. Combining the presence of these HLA associations with a PLASMIC score of 6 or more achieved a higher positive predictive value (90%) for identifying aTTP than the PLASMIC score alone (69%). In comparison with other TMA types, patients with aTTP showed decreased frequencies of HLA-DRB4, HLA-DRB1*07, HLA-DQB1*02. The HLA-DRB1*07/DQB1*02 was not observed in any aTTP patients (negative predictive value: 100%), and thus the presence of this haplotype essentially rules out aTTP. Further, HLA-DRB1*11/DQB1*03:01/19 was absent in atypical hemolytic uremic syndrome patients. ConclusionHLA alleles can be used as an adjunct for the rapid assessment of TMA and can help to differentiate it from other primary and secondary forms of TMA, allowing for earlier definitive therapy.

Immune Thrombotic Thrombocytopenic Purpura in Elderly Patients: The Roles of PLASMIC and French Scores

In recent years, new developments have been incorporated into daily practice in the management of immune thrombotic thrombocytopenic purpura (iTTP). In particular, clinical scoring systems could help clinicians with clinical decision-making and early recognition. However, older patients frequently present with more organ involvement and in unusual ways. The ways in which age could affect these clinical prediction scoring systems remain unclear. We evaluated the use of PLASMIC and French scores in patients over 60 years of age. We performed a retrospective cross-sectional analysis of patients over 60 years of age with a presumptive diagnosis of iTTP between 2014 and 2022 at 10 centers. We calculated PLASMIC and French scores and compared our data with a single-center analysis of younger patients presenting with thrombotic microangiopathy. Our study included 30 patients over 60 years of age and a control group of 28 patients younger than 60 years. The diagnostic sensitivity and specificity of a French score of ≥1 were lower in older patients compared to the control group (78.9% vs. 100% and 18.2% vs. 57.1%, respectively). The diagnostic sensitivity and specificity of a PLASMIC score of ≥5 were 100% vs. 95% and 27.3% vs. 100% for the study group and control group, respectively. Our study showed a higher mortality rate in older patients compared to the control group (30% vs. 7.1%, p=0.043). For a limited number of patients (n=6), our results showed that rituximab can reduce mortality. Given that the reliability of clinical prediction scores for iTTP in older patients may be lower, more caution must be undertaken in interpreting their results.

Cost-Effectiveness of Rapid Hemosil Versus in-House and Send-out ADAMTS13 Activity Testing in the Care of Patients with Immune Thrombotic Thrombocytopenic Purpura

INTRODUCTION Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy requiring immediate treatment when the pretest probability is intermediate or high, a probability determined with the use of the PLASMIC and/or French clinical scores. Ruling out iTTP with a biomarker ADAMTS13 activity level can take several days at most hospital systems in the United States, all the while empiric treatment for iTTP accrues risks and costs. The newly developed rapid turnaround and fully automated, chemiluminescent immunoassay (HemosIL) reveals high concordance with chromogenic ELISA and FRET-based assays, the diagnostic standard-of-care. Unlike rapid in-house testing requiring technical expertise, the HemosIL assay can abrogate the cost and risk exposure associated with treating patients for iTTP whose biomarker activity level later rules out this diagnosis. Despite existing concerns of testing cost, we hypothesized that rapid and fully automated diagnostic testing would be cost-saving with similar quality-adjusted life-expectancy, as compared to both in-house FRET-based evaluation and send-out FRET-based evaluation. We further posited that this effect would be greater in the context of 1) intermediate- versus high-probability PLASMIC scores, and 2) patients treated with caplacizumab versus without. We sought to fill these gaps by conducting the first cost-effectiveness evaluation of the HemosIL assay in patients treated with and without caplacizumab. METHODS For this independent analysis free of industry influence, we built a Markov simulation of patients with intermediate- (PLASMIC score =5) or high- (PLASMIC score 6-7) pretest probability for iTTP empirically treated while awaiting results under three testing strategies: 1) HemosIL rapid turnaround (&amp;lt;1 hour), 2) 24-hour in-house, FRET-based evaluation, and 3) 72-hour send-out, FRET-based evaluation. For transition probabilities, our model was informed by extensive literature published on test characteristics, as well as derivation and validation cohorts for the PLASMIC score. Adverse events for therapeutic plasma exchange (TPE) and caplacizumab were informed from clinical trial data and real-world data, with costs in 2023 US dollars sourced from the Centers for Medicare and Medicaid Services. Utilities were informed by literature on critically ill adults hospitalized in the medical intensive care unit and were originally derived with validated EuroQol methodology. Age- and sex-adjusted background mortality were employed. The primary outcome was the incremental cost-effectiveness ratio (ICER) or, the incremental net monetary benefit (iNMB) if the intervention (HemosIL) was found to be cost-saving, reported over a 3-day time-horizon and across accepted willingness-to-pay thresholds in USD per quality-adjusted life-year (QALY). Four scenario analyses were examined: 1) PLASMIC 5 with caplacizumab, 2) PLASMIC 5 without caplacizumab, 3) PLASMIC 6-7 with caplacizumab, 4) 6-7 PLASMIC without caplacizumab. We concluded by executing deterministic and probabilistic sensitivity analyses, varying all parameter estimates +/-50% and capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo simulations. RESULTS Across all scenario analyses, testing with HemosIL was cost saving and accrued the same amount of QALYs (Table 1). These savings with HemosIL ranged from $2,900 (PLASMIC 6-7, without caplacizumab) through $44,700 (PLASMIC 5, with caplacizumab) per-patient-tested versus send-out, and from $800 to $19,800 versus in-house testing. No parameter variation changed the outcome of any scenario to favoring a non-HemosIL testing strategy in deterministic sensitivity analysis. In probabilistic sensitivity analyses across accepted willingness-to-pay thresholds in the United States, HemosIL was favored in 100% of iterations in the PLASMIC 5 context (with and without caplacizumab), and 99.9% and 98.6% in the PLASMIC 6-7 context with and without caplacizumab use, respectively (Table 2). CONCLUSION Despite cost concerns, HemosIL testing for patients with intermediate- or high-risk PLASMIC score produces significant cost savings for each patient tested and empirically treated. This is achieved by reducing the costs associated with unnecessary therapeutic plasma exchange and caplacizumab therapy.

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.

Low ADAMTS13 Activity in Patients with Liver Disease- Thrombotic Thrombocytopenic Purpura or Not?

Introduction: Patients with liver injury have hemostatic defects including reduced ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). Severe deficiency of ADAMTS13 (ADMS13) activity (&amp;lt; 10%) is pathognomonic for thrombotic thrombocytopenic purpura (TTP), a rare thrombotic microangiopathy (TMA). Differentiating TTP from severe liver injury is complex for multiple reasons including 1) low baseline ADMS13 2) concomitant coagulopathies complicating differentiation from disseminated intravascular coagulation (DIC) 3) ADMS13 activity (ADMS13:AC) assay interference (hyperbilirubinemia (&amp;gt;30mg/dL) can cause artifactual reduction of ADMS13:AC). Here we sought to characterize the clinical presentation, management, and outcomes of patients with liver injury presenting with thrombocytopenia (TCP), microangiopathic hemolytic anemia (MAHA) and low ADMS13:AC at our institution. Methods: In this retrospective study, after IRB approval, electronic medical records (EMR) of institutional patients who had ADMS13:AC and inhibitor profile performed in our special coagulation laboratory between 2018 and July 17, 2023, were reviewed. Eligible patients had ADMS13:AC ≤20% were ≥ 18 years and had evidence of liver injury at time of ADMS13. Liver injury was defined as ALT or AST elevations greater than two times the upper level of normal within one month prior to ADMS13:AC testing, history of end stage liver disease or cirrhosis, or liver transplant with evidence of graft dysfunction. Details regarding clinical presentation, management and outcomes were extracted from the EMR. PLASMIC and ISTH DIC scores were retrospectively calculated. Results: 70 patients had at least one ADMS13:AC &amp;lt; 20% during the study period. 28/70 patients met liver injury inclusion criteria and 20/28 had TCP and MAHA. Of those 20 patients, median age at initial ADMS13:AC was 56.5 years (29-85). Most patients (n=14) had ADMS13:AC of 10-20%. ADMS13:AC was &amp;lt; 5% and 5-10% in 3 patients each. Eleven patients had a positive inhibitor with a median Bethesda titer of 1.85 BU (0.5-3.9). Etiology of liver included: ischemic hepatopathy (n=8), liver graft failure (n=4), liver metastasis (n=3), cirrhosis (n=2), alcoholic hepatitis (n=1), unknown (n=2). Median hemoglobin and platelet (plt) count at time of ADMS13 was 7 g/dL (6.4-13.2) and 30 x10 9/L (3-98), respectively. 7/20 patients had a PLASMIC score of ≥5; PLASMIC score was ≥5, in 2/6 patients with ADMS13:AC &amp;lt;10%. 16/18 patients had an ISTH DIC score ≥5. 18/20 patients had a creatinine &amp;gt; 2 mg/dL or were receiving renal replacement therapy the time of ADMS13: AC. 7/20 patients had total or direct bilirubin of &amp;gt;30mg/dL. Eight/20 patients were treated with plasma exchange (PEX) for a median duration of 7 days (2-13). 66.7% of pts with ADMS13:AC &amp;lt;10% received PEX. Glucocorticoids and Rituximab were used with the intent to treat TTP in 7 and 3 patients, respectively. Caplacizumab was used in 2 patients. 3/8 (37.5%) patients receiving PEX demonstrated normalization of MAHA. One of these patients demonstrated improvement but not normalization of plts (Table 1B, case 5). All patients had recurrence of hematologic abnormalities after PEX was stopped. One patient was treated with plasma infusion with stabilization in plt count. There were 13 and 15 deaths within 1 and 6 months of first ADMTS13:AC, respectively. One death was potentially attributable to management of TTP (Table 1B, case 1). There was no difference in time to death or mortality with the use of PEX. Repeat ADMS13:AC remote from PEX, TCP and MAHA was available for 1/5 surviving patients. This patient (Table1, case 2) had normalization of ADMS:AC after undergoing liver transplant. Conclusion: The differential diagnosis of TCP and MAHA in patients with liver injury includes hepatic dysfunction, DIC and TMA. In the current cohort, 89% of evaluable patients met criteria for overt DIC per ISTH criteria. Due to a low ADMTS13:AC, 40% of patients underwent a trial of PEX with 37.5% demonstrating improvement in MAHA that was not sustained upon discontinuation of PEX due to persistent liver dysfunction. Six-month mortality was 75% and use of PEX did not affect mortality. Given the high mortality, further studies evaluating which patients with TMA and liver injury are more likely to benefit from therapies typically used to treat TTP are necessary.

A Real-World Analysis of Immune Thrombotic Thrombocytopenic Purpura: Comparing Clinical Outcomes of Conventional Treatment Vs Addition of Caplacizumab, a Single-Center Experience

Introduction Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy that causes systemic platelet-rich microthrombi with multiorgan damage. Caplacizumab is an anti-von Willebrand factor humanized nano-antibody, thereby blocking platelet binding and it is the first targeted therapy approved for the treatment of iTTP, in conjunction with plasma exchange (PLEX) and immunosuppression. Two pivotal randomized controlled trials have provided positive results where the use of Caplacizumab is associated with faster platelet count recovery, decrease relapse rates significantly and reduce mortality and recurrence rates compared with placebo. Likewise, published real-life studies support the positive results; however, today the controversy continues to exist whether Caplacizumab should be used first line or in refractory or relapsed disease. Methods We performed a single-center retrospective, observational analysis of clinic-biological and survival outcomes of conventional treatment alone vs addition of Caplacizumab in adult patients (≥18 years old) with confirmed diagnosis by ADAMTS13 activity of acquired iTTP (first or relapsed episode) who were treated at our institution between April 2008 and June 2023. Baseline demographic and clinical data and laboratory values were collected at the time of diagnosis. The PLASMIC score was determined retrospectively. Day 0 was defined as the day of diagnosis as indicated by the treating physician, beginning of iTTP-specific therapy, or a reported ADAMTS13 activity measurement of less than 10%. Time to normalization of platelet count after the start of iTTP-specific treatment was defined as the first day with a count ≥150×10 9/L (clinical response). Clinical remission, exacerbation, refractory disease, and relapse were defined according to the criteria published by Cuker et al in 2021 for the International Working Group for TTP. Results Patient characteristics, initial disease presentation, treatment modalities, individual courses, and outcome data are shown in Tables 1 and 2. Thirty-three patients were included, 24 received conventional treatment and 9 additional Caplacizumab. In 39.4% of the cases (13 of 33 episodes), iTTP was presented with a disease relapse. An initial ADAMTS13 activity of &amp;lt;10% was reported in all patients of Caplacizumab group (median 0%; range, 0-7%); in the conventional treatment group, in 6 patients the ADAMTS13 activity was not available at diagnosis for data consultation, in the rest of the group, ADAMTS13 activity was &amp;lt;10% in all cases (median 0,3%; range, 0-9%). The median initial thrombocyte count was 12×10 9/L (range, 4-161). Troponin levels were measured in 14 patients (42,4%) at the time of diagnosis; 10 of 14 patients (71,4%) showed increased levels suggesting concomitant myocardial damage. Due to the severity of symptoms 8 of 33 patients (24.2%), were initially treated on intensive care units. Patients were discharged from the hospital after 15 days (range, 4-75). Thirty-two patients (96.9%) received glucocorticoids and PEX, with a median of 8 PEX treatments (range, 2-59), only one patient did not receive any treatment due to death in the first hours after hospital admission, with significant neurological and cardiac involvement. Caplacizumab treatment was started with a median of 1 day after diagnosis (range, 0-12) and the drug was used as a frontline agent in 7 of 9 patients (77.8%). Twenty-four patients (72,7%) were treated with rituximab. Ten patients received additional immunosuppressants. Platelet counts normalized to above 150×10 9/L in a median of 9 days (range, 3-30) in the conventional treatment group versus 5 days (range; 2-57) in the Caplacizumab group ( p=0.243). Clinical remission was achieved in 31 patients. Two patients, died of iTTP complications after achieve clinical response. No differences were observed in the median time to relapse between patients treated with conventional treatment vs additional Caplacizumab (Figure 1). Conclusions In our experience, the use of Caplacizumab improves the clinical response rate, achieves faster platelet count recovery, and decreases relapse; another benefit is an important alleviation in the burden of care, by reducing the number of PEX sessions to achieve remission, as well as a reduction in hospital stay, although not significantly, probably limited by the number of patients included in the study.

The Use of Caplacizumab in COVID-19-Related TTP

Introduction Thrombotic Thrombocytopenic Purpura (TTP) is a rare but feared hematological disorder encountered in the inpatient setting. COVID-19-associated TTP is a lesser understood phenomenon, with slightly different symptomology and clinical course. Prompt identification is essential since TTP is a medical emergency which carries a 90% risk of mortality if untreated. Several aspects of treatment, including the use of agents like caplacizumab as monotherapy and therapy duration, are poorly defined in the literature. In this case report, we discuss one such case of post-COVID TTP and explore the therapeutic challenges that clinicians should be aware of when using caplacizumab. Case A 49-year-old female presented with brief changes in mentation and confusion, as well as an associated headache, sore throat, myalgias, and fever for 10 days. The patient tested positive for the COVID-19 antigen 3 days prior to presentation. The patient was hemodynamically stable on arrival, although tachycardic to 94 beats per minute. Initial labs revealed acute normocytic anemia (Hb 7.4 g/dl from a baseline of 12.1 g/dl) and acute, severe thrombocytopenia (9 K/ul from a baseline of 217 K/ul) with schistocytes present on peripheral blood smear. Elevated lactate dehydrogenase (LDH) and low haptoglobin suggested hemolysis. PT, INR, PTT, d-dimer, fibrinogen, and fibrin degradation product (FDP) did not suggest disseminated intravascular coagulation (DIC). TTP was highly suspected with a PLASMIC score of 7. Therapeutic plasma exchange (TPE) was started emergently on day of admission. Additional treatments that were administered include methylprednisolone (1g daily for 3 days), rituximab (375mg/m2), and caplacizumab (11mg before and after TPE on Day 1, then 11 mg daily thereafter). Caplacizumab was administered daily through Day 4, then stopped because our hospital pharmacy could not procure the drug. Nevertheless, by day 4, platelets had improved to &amp;gt;150 K/ul and LDH to &amp;lt;200 IU/l for 2 consecutive days. From Day 4 to Day 10, TPE was given every other day. However, on day 10 the platelets decreased to 11 K/ul. Both daily TPE and caplacizumab was re-initiated. ADAMTS 13 level was &amp;lt;2% at admission and Day 9, later increased to 54.1% on Day 15. ADAMTS 13 antibody levels were &amp;gt;164 U/ml on the day of admission, 67 U/ml on Day 9, and undetectable on Day 15. The patient was discharged on Day 22 and completed a 30-day course of caplacizumab. Follow-up showed sustained remission at 2.5 months with ADAMSTS13 level of 90.8%, platelet count 130 K/ul and the LDH level of 136 U/l. Discussion Caplacizumab is a bivalent anti-VWF immunoglobulin approved in 2019 for treating acquired TTP in conjunction with TPE and other immunosuppressive therapies. The TITAN trial showed significantly lower 30-day exacerbations in the caplacizumab group compared to the placebo group, but a higher rate of relapse in the caplacizumab group in the following month. Patients in the caplacizumab group received fewer TPE sessions overall. Paradoxically HERCULES trial showed 67% lower recurrence in the caplacizumab group. These results in the HERCULES trial were attributed to caplacizumab treatment lengths that could be expanded based on ADAMTS13 activity &amp;lt;10%. In our case, given the high bleeding risk and lack of cost-effectiveness while inpatient, caplacizumab was discontinued and TPE decreased to alternate day dosing following adequate clinical response. It is difficult to predict whether premature discontinuation of caplacizumab or early weaning of TPE triggered recurrence, since both therapies were discontinued on Day 5. This case demonstrates a clinical conundrum of whether caplacizumab can lead to early discontinuation of TPE with inadequate clearance of ADAMTS13 antibody, leading to early relapses. A review of current literature and our experience suggest that Caplacizumab may be very effective in improving platelet count and reducing relapse rates, especially when decisions to discontinue the drug are based on ADAMTS-13 levels. However, lack of cost-effectiveness is a limiting factor, and high bleeding risks must be considered before deciding to start caplacizumab in patients with refractory or severe TTP.

Immune Thrombotic Thrombocytopenic Purpura in Elderly Patients; the Role for PLASMIC and French Scores.

Immune Thrombotic Thrombocytopenic Purpura in Elderly Patients; the Role for PLASMIC and French Scores.

HTRS2023.O8A.1 Plasmic (PLASMICkid) score for pediatric thrombotic thrombocytopenic purpura

HTRS2023.O8A.1 Plasmic (PLASMICkid) score for pediatric thrombotic thrombocytopenic purpura

A validation and modification of PLASMIC score by adjusting the criteria of mean corpuscular volume and international normalized ratio.

The PLASMIC score was developed for distinguishing thrombotic thrombocytopenic purpura (TTP) from other types of thrombotic microangiopathy. However, two components of the PLASMIC score, mean corpuscular volume (MCV) and international normalized ratio (INR), showed non-significant differences between TTP and non-TTP patients in previous validations. Here, we validate the PLASMIC score and aim to modify it by adjusting the criteria of MCV and INR. A retrospective validation of suspected TTP patients was performed by reviewing electronic medical records from two medical centers in Taiwan. The performance of different modified types of the PLASMIC score was carried out. Among 50 patients included in the final analysis, 12 were diagnosed with TTP based on deficiency of ADAMTS13 activity and clinical judgement. When stratified by high (score ≥ 6) and low-intermediate risk (score < 6), the positive predictive value (PPV) of the PLASMIC score to predict TTP was 0.45 (95% confidence interval [CI]: 0.29-0.61). The area under curve (AUC) was 0.70 (95% CI: 0.56-0.82). When adjusting the criteria of the PLASMIC score from MCV < 90 fL to MCV ≥ 90 fL, the PPV increased to 0.57 (95% CI: 0.37-0.75). The AUC was 0.75 (95% CI: 0.61-0.87). When adjusting the INR from >1.5 to >1.1, the PPV increased to 0.56 (95% CI: 0.39-0.71). The AUC was 0.81 (95% CI: 0.68-0.90). MCV ≥ 90 fL and/or INR > 1.1 might be suitable modifications for PLASMIC score but should be validated in a larger sample size.

#3479 RISK FACTORS OF DEATH OR CHRONIC RENAL REPLACEMENT THERAPY REQUIREMENTS IN PATIENTS WITH THROMBOTIC MICROANGIOPATHIES WITHOUT ADAMTS-13 DEFICIENCY

Abstract Background and Aims Thrombotic microangiopathy without severe ADAMTS-13 deficiency activity levels (TMA-13n) has a high mortality rate. Early recognition of patients at higher risk of dying or needing chronic renal replacement therapy (composite outcome: CO) has become of paramount importance since treatments such as eculizumab could ameliorate the prognosis of this group of patients. Plasmic score have been shown to predict severe ADAMTS-13 deficiency; however, its role as a prognostic factor of CO in TMA-13n is unknown. Method We retrospectively evaluate the potential factors associated with the risk of CO. Patients diagnosed with TMA-13n (defined by microangiopathic anaemia, thrombocytopenia, organ damage and ADAMTS-13 activity ≥ 10%) from January 2008 to May 2018 in our centre were included in the study. Results Forty-two consecutive patients were included. Mean (SD) age: 41(20) years. Twenty-five (60% were females. Mean (SD) ADAMTS-13 activity: 69 (24%). Twenty-six (62%) patients required dialysis at admission. Nineteen (45%) met CO (10 patients died). Higher age, lower lactate dehydrogenase, PLASMIC score values ≤ 4, neuroradiological damage and early eculizumab use [median (IQR): 4 (0-16) days from hospital admission: 5] were factors associated with the risk for developing CO. Only three factors were independently associated with CO mortality by logistic regression: early use of eculizumab (OR: 0.14; 95% CI: 0.02-0.94) and neuroradiological damage (OR: 6.67; 95% CI: 1.12-39.80) and PLASMIC score ≤ 4 (OR: 7.39; 95% CI: 1.18-46.11). Conclusion In TMA-13n patients, neuroradiological damage, low PLASMIC score and early use of eculizumab were independent prognostic factors of death and chronic renal replacement therapy requirements.

Potential modifications of the PLASMIC scoring system for predicting thrombotic thrombocytopenic purpura: Sometimes, less is more.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening occlusive disease of the microcirculation characterized by systemic platelet plugs, organ ischemia, deep thrombocytopenia, and fragmentation of erythrocytes. One of the widely used scoring system to determine the clinical probability of TTP is the PLASMIC scoring system. This study aimed to evaluate the contribution of PLASMIC score modifications to sensitivity and specificity in patients with microangiopathic hemolytic anemia (MAHA) undergoing plasma exchange with a prediagnosis of TTP at our center. The data of patients who were hospitalized with a previous diagnosis of MAHA and TTP and underwent plasma exchange at Bursa Uludag University, Faculty of Medicine, Department of Hematology between January 2000 and January 2022 were retrospectively analyzed. Overall, 33 patients (including 15 and 18 with and without TTP, respectively) were included in this study. Receiver operating characteristic (ROC) analysis revealed that the area under the curve (AUC) for the original PLASMIC score was 0.985 (95% confidence interval [95% CI]: 0.955-1.000), and AUC for the PLASMIC score without mean corpuscular volume (MCV) was 0.967 (95% CI: 0.910-1.000), which is close to the original AUC. With the removal of MCV from the scoring system, the sensitivity decreased from 100% to 93%, whereas the specificity increased from 33% to 78%. Based on the results of this validation study, removing MCV from the PLASMIC score led to the categorization of eight non-TTP cases in the low-risk category, and this could avoid unnecessary plasma exchange. However, in our study increasing the specificity was at the expense of the sensitivity by missing one patient with this new scoring system without MCV. Further multicenter studies with large sample sizes are required owing to the fact that different parameters may be effective in TTP prediction among different populations.

Utility of Different Scoring Systems for the Diagnosis of Thrombotic Microangiopathies.

To investigate the appropriateness of Bentley and plasmic scores and ADAMTS-13 activity to distinguish between primary thrombotic microangiopathies (TMA) syndromes and other thrombotic microangiopathies, as well as primary thrombotic microangiopathies (TTP, complement-related TMA, etc). Descriptive study. Place and Duration of the Study: Department of Hematology, Faculty of Medicine, from February 2013 to February 2020. Data of patients with non-immune hemolytic anaemia (MAHA) and thrombocytopenia who had ADAMTS-13 test, were analysed. Clinical and laboratory findings, Bentley and plasmic scores, and ADAMTS activity levels were compared. The patients were grouped as primary (n = 27) and secondary (n = 28) TMA, the age was median 38.0 (18-63) years in the primary TMA group and 49.5 (20-84) years in the secondary TMA group. Neurological findings were less in the secondary TMA group (p = 0.008). Plasmic score, lactate dehydrogenase, and total and indirect bilirubin levels were high and D-dimer levels were low in the primary TMA group. In the primary TMA group, a greater number of patients with high plasmic scores were found, whereas all patients in the secondary TMA group had low risk according to Bentley score. Calcium levels were high and platelet levels were low in those with ADAMTS activity level <10% (p = 0.006). The evaluation of primary TMAs demonstrated significant differences in platelet, urea, creatinine, and sodium values between the two groups. Laboratory data and clinical scores are valuable in differentiating primary and other TMA. Bentley score, Complement, Plasmic score, Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura, ADAMTS-13.

Validating lactate dehydrogenase (LDH) as a component of the PLASMIC predictive tool (PLASMIC-LDH).

The PLASMIC score is a convenient tool for predicting ADAMTS13 activity of <10%. Lactate dehydrogenase (LDH) is widely used as a marker of haemolysis in thrombotic thrombocytopenic purpura (TTP) monitoring, and could be used as a replacement marker for lysis. We aimed to validate the PLASMIC score in a multi-centre Asia Pacific region, and to explore whether LDH could be used as a replacement marker for lysis. Records of patients with thrombotic microangiopathy (TMA) were reviewed. Patients' ADAMTS13 activity levels were obtained, along with clinical/laboratory findings relevant to the PLASMIC score. Both PLASMIC scores and PLASMIC-LDH scores, in which LDH replaced traditional lysis markers, were calculated. We generated a receiver operator characteristics (ROC) curve and compared the area under the curve values (AUC) to determine the predictive ability of each score. 46 patients fulfilled the inclusion criteria, of which 34 had ADAMTS13 activity levels of <10%. When the patients were divided into intermediate-to-high risk (scores 5‒7) and low risk (scores 0‒4), the PLASMIC score showed a sensitivity of 97.1% and specificity of 58.3%, with a positive predictive value (PPV) of 86.8% and negative predictive value (NPV) of 87.5%. The PLASMIC-LDH score had a sensitivity of 97.1% and specificity of 33.3%, with a PPV of 80.5% and NPV of 80.0%. Our study validated the utility of the PLASMIC score, and demonstrated PLASMIC-LDH as a reasonable alternative in the absence of traditional lysis markers, to help identify high-risk patients for treatment via plasma exchange.

Thrombotic thrombocytopenic purpura-adifferential diagnostic challenge in an emergency

Thrombotic thrombocytopenic purpura (TTP), which comprises thrombocytopenia, elevated lactate dehydrogenase levels, and anemia in the combination of organ involvement, is a rare but life-threatening condition associated with an extremely high lethality in the acute phase if left untreated. Using the example of a 49-year-old woman admitted to the hospital with unexplained abdominal symptoms and subfebrile temperatures, recommendations for the emergency situation are presented. Increased awareness of the disease and targeted further diagnostics with determination of the PLASMIC score or ADAMTS13 activity may lead directly to diagnosis of TTP; delayed diagnosis is usually associated with secondary complications.

The Combination of the Lactate Dehydrogenase/Hemoglobin Ratio with the PLASMIC Score Facilitates Differentiation of TTP from Septic DIC Without Identification of Schistocytes.

In some cases, differentiating thrombotic thrombocytopenic purpura (TTP) from septic disseminated intravascular coagulation (DIC) without measuring ADAMTS13 activity is critical for urgent lifesaving plasma exchange. To investigate whether PLASMIC score without identifying the presence of schistocytes, D-dimer, fibrin/fibrinogen degradation products (FDP), FDP/D-dimer ratio, prothrombin time-international normalized ratio (PT-INR), lactate dehydrogenase (LD), hemoglobin (Hb), and LD/Hb ratio are useful in differentiating patients with TTP from those with septic DIC. Retrospective analysis was conducted on the medical records of the patients with septic DIC (32 patients) or TTP (16 patients). The PLASMIC score and other laboratory measurements all were helpful in differentiating TTP from septic DIC. When dichotomized between high risk (scores 6-7) and intermediate-low risk (scores 0-5), the PLASMIC score predicted TTP with a sensitivity of 75.0% and a specificity of 100%. However, 4 of 16 patients with TTP and 19 of 32 patients with septic DIC showed comparable PLASMIC scores of 4 or 5, making it difficult to distinguish between the two by PLASMIC score alone. Among the measurements examined, the LDH/Hb ratio was the most useful for differentiation. Receiver operating characteristic analysis of the LD/Hb ratio for predicting TTP revealed a cutoff of 53.7 (IU/10 g) (sensitivity 0.94, specificity 0.91). If the LD/Hb ratio was less than 53.7, it was unlikely that the patient had TTP. A combination of the LD/Hb ratio and the PLASMIC score may be useful for distinguishing between TTP and DIC and identifying patients who need rapid plasma exchange or caplacizumab administration.