Sridharan, Meera

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 (< 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 (>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 < 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 < 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 <10%. 16/18 patients had an ISTH DIC score ≥5. 18/20 patients had a creatinine > 2 mg/dL or were receiving renal replacement therapy the time of ADMS13: AC. 7/20 patients had total or direct bilirubin of >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 <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.

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is defined by thrombocytopenia and microangiopathic hemolytic anemia without an alternative explanation, confirmed by severely deficient ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) to <10%. It is caused by autoantibodies against the ADAMTS13 protease. Pregnancy can precipitate iTTP, but the diagnosis and treatment are challenging, since it is often difficult to differentiate from other TMAs associated with pregnancy The aim of this study was to describe the clinical presentation, treatment, and outcomes of pregnancy related iTTP. Methods: Data was obtained from the USTMA retrospective database, including 15 large USTMA referral centers. Patients were identified based on the diagnosis of iTTP provoked by pregnancy between 9/6/1990 and 6/18/2018. The study cohort included participants with a clinical diagnosis of iTTP, confirmed by ADAMTS13 activity <10% who had a pregnancy or recent delivery within 30 days of presenting with iTTP. For participants diagnosed before the ADAMTS13 assay was developed (2006), the iTTP diagnosis was based on the clinical course and absence of alternative causes. iTTP exacerbation was defined as clinical disease recurrence within 30 days of PLEX (plasma exchange) discontinuation, and clinical relapse was defined as disease recurrence after 30 days of last PLEX. Maternal and fetal outcomes were additionally collected from 7/15 sites. Results: 42 patients had 55 iTTP episodes provoked by pregnancy. Median age for patients was 29. Sixteen (38.1%) were white, 20 (47.6%) were black. The most common presenting symptoms were headache and fatigue in 11/55 (20%) episodes. Thirty nine (70.9%) episodes had a platelet count <30 x10 9/L, and 46 (83.6%) had laboratory findings concerning for hemolysis as evidenced by elevated lactate dehydrogenase (LDH) and/or schistocytes present on peripheral smear. Only 5 (9%) episodes presented with a creatinine >2 mg/dL. ADAMTS13 activity was documented in 33 (60%) episodes and was <10% in 30 (90.9%) (Table 1). Treatment with PLEX was described in 30 (54.5%) episodes with a median duration of 6 days (2-26 days). Further immunosuppression included prednisone in 38 (69.1%) episodes and rituximab in 11 (20%), of which 7 (63.6%) had no future exacerbations or relapses during the study period.Seventeen (40.5%) patients had a prior diagnosis of iTTP. There were 10 exacerbations in 8 patients (19%), and 34 relapses in 13 (30%) patients after the 55-pregnancy provoked iTTP episodes. Five of those relapses were triggered again by pregnancy. Pregnancy related outcomes were obtained in 16 patients. Twenty five percent (4/16) of patients had a prior history of iTTP; median time of last iTTP to current presentation was 34 months (10-108). Of 16 patients, iTTP occurred with first pregnancy in 8 patients. Of the remaining eight patients, iTTP occurred in the eleventh (n=1), ninth (n=1), sixth (n=1), fifth (n=1), fourth (n=2), and unknown (n=2) pregnancy. Only 13 of 16 patients had further pregnancy specific outcomes available (Table 2). Preeclampsia was noted in 3 patients. Seven and 1 patients, presented with iTTP within 30 days postpartum or after miscarriage, respectively. The remaining patients (n=5) developed iTTP during the antepartum period. Of these, 2 pregnancies were terminated due to iTTP (second trimester and third trimester). One of the three remaining pregnancies resulted in fetal demise at 24 weeks. The latter two patients delivered healthy infants. There were no maternal deaths in our cohort. Conclusions: This is first multicenter descriptive analysis of pregnancy related iTTP from the USTMA registry. The clinical presentation of this cohort is consistent with iTTP triggered by other causes, and the low rate of acute kidney injury is helpful in identifying iTTP from other TMAs in pregnancy. We observed that pregnancy is a risk not only for acute episodes of iTTP in first pregnancy, but also in subsequent pregnancies and in the relapse setting of those with previous diagnosis of iTTP. While there was a 20% and 30% exacerbation and relapse rate respectively, maternal mortality was not observed. Rituximab did not affect maternal mortality. Fetal mortality was affected by iTTP in the antepartum period. These findings will serve as bases of prospective USTMA study for standardize management of this population.

Background: Warm autoimmune hemolytic anemia (WAIHA) is mostly IgG mediated (IgG+C3-), which may at times fix complement (IgG+C3+). Whether the clinical outcome of complement-fixing (C3+) WAIHA is different from that of non-complement fixing (C3-) WAIHA remains unclear. The goal of this retrospective study was to describe and compare the clinical characteristics and treatment outcomes of patients with C3+ and C3- WAIHA. Methods: We included adult WAIHA patients seen at our institution from 2001-2023 who met all of the following criteria: A) age >18 years; B) direct antiglobulin test [DAT] IgG+ + C3+ with no cold agglutinin; and C) biochemical evidence of hemolysis. Response to treatment was based on the international consensus criteria: complete (CR; normal Hb or Hb ≥12 g/dL, with resolution of hemolysis); partial (PR; Hb >10 but <12 g/dL or Hgb >12 g/dL without resolution of hemolysis); or no response (neither CR nor PR). 223 WAIHA patients were found, and 132 patients were ultimately included. The most common reason for exclusion was a lack of complete DAT that included C3 testing. Results: There were 59 patients with C3- WAIHA and 73 patients with C3+ WAIHA, reflecting 44.7% and 55.3% of total patients respectively. Pertinent demographic, clinical, and treatment information are shown in Table 1. Slightly over half (52.3%) were males and the mean age (SD) was 63.9 years (18.1). Concomitant lymphoproliferative disease was present in 34.1% of the patients. The 3 most common treatments were steroids (97%), rituximab (66.7%), and splenectomy (18.2%). The median follow-up from diagnosis was 20.0 months (range, 1.0-251.8 months), and 14.4% of patients had died at the time of this analysis with no difference between the groups (P=0.82). There was no significant difference in the demographic composition, clinical findings, and treatment received in both groups. The number of treatments received were similar between C3- and C3+ WAIHA groups (Table 1). After first line of treatment, response was achieved in 86.4% and 94.4% of the C3- and C3+ groups (P=0.12), respectively. Additionally, 62.7% of the C3- group and 80.8% of the C3+ group were in PR or CR by their most recent CBC (P=0.02). 33.9% and 43.8% of the C3- and C3+ groups relapsed at least once (P=0.25). In those who relapsed, there was an average of 2.6 relapse events in the C3- WAIHA group compared to 1.8 relapse events in the C3+ WAIHA group (P=0.03). However, there was no difference in time to first relapse between the groups (P=0.51), shown in Figure 1. Conclusion: There have been retrospective descriptions of multiple AIHA subtypes and response rates to different therapies; however, this is one of the first studies to our knowledge to focus specifically on outcomes between complement subgroups. In our large group of patients with C3- and C3+ WAIHA, the clinical presentation, treatments utilized, and response to treatment were similar. Our data suggest that C3- and C3+ WAIHA can be approached and treated similarly.

101 Background: In the US, minority patients are underrepresented in cancer clinical trials. This is due to multiple factors, including socioeconomic barriers, limited medical insurance coverage and restrictive clinical trial eligibility, e.g., ANC cutoff. For the latter, conservative ANC cutoff disadvantages Black patients. Two-in-three Black individuals have a Duffy-null phenotype, that is associated with lower ANC with 5% prevalence of ANC <1,500 cells/µl. To improve Black patient accrual to cancer clinical trials, lowering the ANC cutoff was proposed as a potential solution over a decade ago. Its implementation is not known. This study evaluates the ANC cutoff values as part of the eligibility criteria for cancer clinical trials. Methods: We accessed the Clinicaltrials.gov website on 5/25/2023 and obtained the ANC cutoff of cancer clinical trials conducted in the US. We included adult therapeutic trials in the phases of recruiting, not yet recruiting, enrolling by invitation, and active-not yet recruiting. Trials with drug interventions were selected. Those focusing on surgical, behavioral, nutritional and radiotherapeutic interventions were excluded. All ANC cutoff values were converted to “cells/µl” for analysis. Results: A total of 911 trials were evaluated, and 470 met the eligibility criteria. Of the 470 trials, 366 (78%) involved solid malignancies, and 104 (22%) involved hematologic malignancies. Hematologic trials have significantly lower ANC cutoffs compared to solid tumor trials with median ANC cutoff of 1,000 (range, 250-2000) vs. 1,500 (range 250-3,000); p=<0.001. In all, 323 trials (68.7%) required patients to have ANC >1,500, and 116 trials (24.6%), primarily hematologic, required patients to have ANC >1,000. For myeloma and prostate cancer, two cancers with higher incidence among Blacks, 12.9% and 86.4% of the trials require ANC >1,500, respectively. All genitourinary, breast, head & neck, sarcoma, lung, skin, and neuroendocrine tumor trials excluded patients with ANC <1,000. Conclusions: Most hematologic malignancy trials have a more liberal ANC cutoff allowing patients with ANC <1,500 to participate. However, solid tumor trials remain more conservative, with 4 in 5 trials requiring an ANC cutoff of >1,500. A strict ANC cutoff remains a barrier to minority accrual.[Table: see text]

Abstract Objectives To determine the impact of residual platelets on dilute Russell’s viper venom time (DRVVT) assay in frozen-thawed plasma submitted for lupus anticoagulant (LAC) testing. Methods We measured platelet counts in frozen-thawed samples submitted for LAC testing and evaluated the association between platelet count and the DRVVT screening time and ratios. We also spiked platelets into a LAC-positive sample to observe the effect on the DRVVT. Results Progressive increase in platelet count resulted in a statistically significant shortening of the DRVVT assay results on plasma after 1 freeze-thaw cycle. A similar effect was noted on the LAC-positive sample. Conclusions Residual platelets in plasma samples result in shortening of DRVVT assay after 1 freeze-thaw cycle. This may result in a false-negative LAC test result.

AbstractPatients with thrombophilia remain concerned about venous thromboembolism (VTE) risk with COVID‐19 vaccinations. The aim of this study was to examine VTE outcomes in patients with inherited or acquired thrombophilia who were vaccinated for COVID‐19. Vaccinated patients ≥18 years between November 1, 2020 and November 1, 2021 were analyzed using electronic medical records across the Mayo Clinic enterprise. The primary outcome was imaging confirmed acute VTE occurring 90 days before and after the date of the first vaccine dose. Thrombophilia patients were identified through laboratory testing results and ICD‐10 codes. A total of 792 010 patients with at least one COVID‐19 vaccination were identified. Six thousand sixty‐seven of these patients were found to have a thrombophilia, among whom there was a total of 39 VTE events after compared to 51 VTE events before vaccination (0.64% vs. 0.84%, p = .20). In patients with Factor V Leiden or prothrombin gene mutation, VTE occurred in 27 patients before and in 29 patients after vaccination (0.61 vs. 0.65%, p = .79). In patients with antiphospholipid syndrome, VTE occurred in six patients before and four patients after vaccination (0.59% vs. 0.39%, p = .40). No difference was observed in the overall VTE rate when comparing the postvaccination 90 days to the prevaccination 90 days, adjusted hazard ratio 0.81 (95% confidence interval: 0.53–1.23). In this subgroup of COVID‐19 vaccinated patients with thrombophilia, there was no increased risk for acute VTE postvaccination compared to the prevaccination timeframe. These results are consistent with prior studies and should offer additional reassurance to patients with inherited or acquired thrombophilia.