Padrnos, Leslie

Abstract Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) due to an acquired deficiency in the enzyme ADAMTS13 leads to ultra-large von Willebrand multimers, thrombocytopenia and microangiopathic hemolytic anemia. Complications include microvascular and macrovascular thrombosis. We present an unusual case of a patient with a history of refractory aTTP who experienced relapsed aTTP following COVID-19 vaccine. Case Description: A 57-year-old African-American male with a history of refractory aTTP experienced a relapse following 3 years of remission after receiving COVID-19 vaccination. The patient was initially diagnosed with aTTP in 2016, after presenting with symptoms of dark urine, mild headaches and transient episodes of aphasia and paresthesia. Due to symptoms and persistently low ADAMTS13 levels, he required prolonged and extensive treatment including over 5 weeks of daily therapeutic plasma exchange (TPE), followed by gradual reduction in frequency of TPE sessions, as well as trials of rituximab, eculizumab, steroids, mycophenolate mofetil and bortezomib. Ultimately, he achieved remission after 9 months of intermittent TPE, 3 months of weekly bortezomib 1 mg/m 2, mycophenolate mofetil up-titrated to 1,750 mg twice daily, and then slowly tapered off over a 2-year period. The patient was doing well for 3 years without manifestations of aTTP (2 years off all therapeutics), until he developed a petechial rash 7 weeks after receiving the second dose of the Moderna COVID-19 vaccine. He was found to have acute thrombocytopenia with platelets of 38 x 10 9/L (normal range 135-317 x 109/L), from a baseline of 200-300 x 10 9/L. He was referred to the emergency department, where additional labs were notable for mildly elevated LDH of 508 U/L (normal range 122-222 U/L), hemoglobin of 12.4 g/dL (normal range 13.2-16.6 g/dL), creatinine at baseline, and peripheral blood smear showing 1-3 schistocytes per high-powered field. ADAMTS13 activity level was t <5% (normal >/= 70%), with positive ADAMTS13 inhibitor screen and titer of 1.5 (normal <0.4), consistent with relapsed aTTP. The patient was admitted to the hospital, and initiated on daily TPE, with steroids and diphenhydramine prior to each TPE session. He quickly improved with TPE alone , but given his history of refractory aTTP, he was discharged on weekly rituximab for 4 weeks and caplacizumab 11 mg daily for 30 days. His platelets remained stable within the upper limit of normal during his 30 day course of caplacizumab. However, 3 weeks after completion of caplacizumab, he had an acute drop in his platelets to 23 x 10 9/L. His ADAMTS13 level was again found to be <5%, and inhibitor level was the highest that it had ever been at 11.4. He was again hospitalized and underwent 8 sessions of daily TPE, as well as re-initiation of caplacizumab, mycophenolate mofetil 500 mg bid (with increasing taper), and a prednisone taper. Intravenous Cyclophosphamide 750 mg/m 2 was also added every 3 weeks. With this regimen, patient's platelet count normalized and remain stable, and his ADAMTS13 activity level has reached 52-59%. Discussion: Cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) have been described as a complication following vaccination with formulations containing replication-defective adenoviral vectors (AstraZeneca-Oxford and Johnson&Johnson COVID-19 vaccines)(Arepally and Ortel 2021, Simpson, Shi et al. 2021). VITT and aTTP are both immune-mediated, however, VITT is distinct and pathogenically linked to autoimmune heparin-induced thrombocytopenia (HIT), given the presence of anti-platelet factor 4 antibodies in these patients, whereas aTTP is due to reduction in ADAMTS13 level, secondary to an antibody inhibitor of ADAMTS13 (Arepally and Ortel 2021). Recently, cases have been reported of de novo aTTP developing shortly after COVID-19 vaccination with all available vaccines, except the Moderna (mRNA-1273) vaccine (Al-Ahmad, Al-Rasheed et al. 2021, de Bruijn, Maes et al. 2021, Maayan, Kirgner et al. 2021, Ruhe, Schnetzke et al. 2021, Waqar, Khan et al. 2021, Yocum and Simon 2021). Additionally, cases of relapsed aTTP have been described following only the BNT162B2 (Pfizer-BioNTech) vaccine (Maayan, Kirgner et al. 2021, Sissa, Al-Khaffaf et al. 2021). This is the first case, to our knowledge, reported in the literature of aTTP following vaccination with Moderna's mRNA-1273 vaccine. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: The management of bleeding associated with direct oral anticoagulants (DOACs) is challenging and associated with high risk of morbidity/mortality despite the use of various reversal agents (Gomez-Outes et al. 2021). Routine tests cannot determine the level of DOAC anticoagulation and reversal agents carry potential prothrombotic complications (Garcia & Crowther 2021). We present an unusual case of a patient requiring emergent surgery with significant post-op bleeding due to profoundly delayed apixaban elimination. Case Description: A 63-year-old female presented to the emergency department (ED) with a 10-day history of worsening abdominal pain, distension, nausea and constipation. Her past medical history was notable for right sided heart failure, COVID-19 pneumonia requiring intubation, tissue mitral valve replacement, and post-op atrial fibrillation for which she was prescribed apixaban 5 mg BID. Her last dose of apixaban had been the night prior to ED presentation. In the ED, a CT of the abdomen revealed a 6 cm partially obstructing lesion involving the mid-sigmoid colon. Findings were consistent with evolving peritonitis and the patient underwent an emergent exploratory laparotomy, sigmoid resection, and end colostomy. Pre-op labs revealed WBC 12.4 x10 9/L, hemoglobin (hgb) 9.2 g/dL, and platelets 318 x10 9/L. Coagulation studies revealed a PT of 28 sec and INR of 2.5. The patient was given prothrombin complex concentrate (PCC) 25 units/kg and 1 mg of vitamin K prior to surgery. Postoperatively, the INR remained elevated, 2.0, and her hgb downtrended from 8.8 g/dL to 7.8 g/dL. On post-op day 1 the patient became hypotensive, with increased abdominal pain/distension, she also started bleeding from her ostomy. The INR was 2.4 and her hgb dropped to 6.0 g/dL. Red blood cells were given along with FFP, vitamin K and a 2 nd dose of PCC. The patient continued to decline, was transferred to the ICU where she was intubated and placed on CRRT. Hematology was consulted for the persistently prolonged PT/INR in the setting of bleeding despite multiple interventions to correct the INR. The patient's last dose of apixaban was ~48 h prior to ICU admission. A rapid heparin anti-Xa assay was performed and upon comparison with an in-house nomogram the result, 1.78 IU/mL, correlated to an apixaban dose between 180-200 ng/ml (average peak levels 2-4 h after administration are 171 ng/mL). This result was confirmed the following day by an apixaban anti-Xa assay, 190 ng/mL. A repeat test performed 11 h later showed a minimal decrease in apixaban indicating impaired clearance. Therapeutic plasma exchange (TPE) was considered for rapid removal of apixaban. We performed a 1.0 plasma volume exchange, using plasma as the replacement fluid, to remove apixaban. Pre and post TPE drug levels were 172 and 108 ng/mL, respectively. Due to an elevated apixaban level the next day, a second TPE was performed which dropped the level to 87 ng/mL. The patient began to improve clinically, with hgb stabilization ~10 g/dL. She was extubated and transferred to a medical floor for further management. Apixaban levels were still measurable, 16 ng/mL, on post op day 8, 11 days after her last dose. Discussion: Apixaban is a highly protein-bound drug (~90%) that is rapidly absorbed in the small intestine with a large Vd (21 L) and a t1/2 of ~12 h. Elimination primarily occurs through the fecal route (Byon et al. 2019). The factors impairing the elimination of the drug in this patient were the following: 1. Pre-op constipation resulting in 10 days without a bowel movement; 2. Minimal bowel function post-op; and 3. Renal failure requiring CRRT after admission to the ICU. This case illustrates the profound effect intestinal obstruction/dysfunction can have on apixaban clearance. It also highlights the importance of laboratory test interpretation when managing coagulopathic patients. TPE is an effective way to remove drugs with high protein binding affinity (Mahmoud et al. 2021). TPE significantly reduced apixaban levels in our patient allowing for hemostasis and clinical improvement. To our knowledge, there are only two case reports regarding the effect of TPE on DOACs, one for apixaban, the other rivaroxaban (Hodulik et al. 2019). Conclusion: TPE can be considered as an option for rapid clearance of apixaban, or other highly protein bound anti-Xa inhibitors, in the setting of delayed elimination or when specific reversal agents are not safe/available. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Patients with coronavirus disease 2019 (COVID-19) have an increased risk for venous thromboembolic events. Thrombotic events contribute to the morbidity and mortality associated with COVID-19 infection, and have prompted investigation into strategies for mitigating thrombosis risk in patients hospitalized with COVID-19 infection. Our team reviewed the charts of patients hospitalized with COVID-19 pneumonia at a tertiary hospital in metropolitan Phoenix Arizona between 2020-2021, to assess frequency and efficacy of utilizing a VTE prophylaxis algorithm designed to prevent thrombosis in patients infected with COVID-19. Methods: A total of 846 patients were retrospectively evaluated to determine if they were treated with guideline-appropriate anticoagulation while hospitalized with COVID-19, as well as if they developed venous or arterial thrombotic events, or major or minor bleeds. 317 patients were excluded for taking therapeutic anticoagulation prior to admission, or for having a COVID-19 diagnosis >7 days after admission. Appropriate anticoagulation was determined by an institutionally designed COVID-19 thromboprophylaxis algorithm, based on platelet count, d-dimer, bleeding risk, and level of medical care required. Regimen options included: no anticoagulation, prophylactic enoxaparin (40 mg SQ daily) or heparin in the setting of kidney dysfunction, weight-based dosing of enoxaparin (40 mg SQ BID if BMI>40), intermediate intensity enoxaparin without thrombus (30 mg BID if BMI<40, or 40 mg BID if BMI>40), and therapeutic anticoagulation (for example enoxaparin 1 mg/kg BID) with thrombus. Demographics: Demographic data and clinical characteristics were collected for 529 patients. Average age was 59 years old, and the majority were men (58.4%). Most patients were White (58.3%), followed by Hispanic (17.8%), or Native American (15.7%). Fewer patients had a normal BMI (21.3%; BMI 18.5 - 24.9) compared to those who were overweight (31.2%; BMI 25-29.9) or obese (43.1% BMI > 30). Other comorbidities included Type 1 or Type 2 diabetes mellitus (N= 172, 32.5%), hypertension (N = 271, 51.2%), and hyperlipidemia (N = 176, 33.3%). Results: A total of 42 patients (8%), were diagnosed with a venous thrombosis during hospitalization. Patients admitted to the ICU were significantly more likely to have a thrombotic event of any type compared to non-ICU patients (21.6% to 5.7%; p < 0.001). Specifically, critically ill patients had higher incidences of deep vein thrombosis (9.5% to 0.7%), pulmonary emboli (8.1% to 4.8%), and superficial thrombi (2.7% to 0.2%). Only 1.1% of patients (6/529) experienced any bleeding, of which 3 were classified as a major bleed. Discussion: Among patients hospitalized at our institution with COVID-19, the majority were anticoagulated appropriately according to the COVID-19 thromboprophylaxis algorithm. Overall incidence of thrombosis in the study population was 8%. A significantly higher percent of critically ill patients had thrombi, supporting reports of correlation between severity of illness and thrombosis risk. The two regimens of anticoagulation least adhered to were weight-based and intermediate-based dosing, likely reflecting a departure from the hospital's thromboprophylaxis regimens prior to COVID-19 pandemic. Further studies are needed to characterize whether identifiable risk factors correlate with the incidence of thrombosis, and whether treatment with lower than recommended doses of anticoagulation, based on the COVID-19 thromboprophylaxis algorithm, were associated with thrombosis. Disclosures No relevant conflicts of interest to declare.

Abstract Background: COVID-19 vaccinations in the United States (Janssen, Moderna, and Pfizer) have been deemed generally safe and effective. Rare thrombotic events, now termed vaccine-induced thrombotic thrombocytopenia (VITT), have been reported after the Janssen and Moderna vaccinations. With millions of vaccinations being administered to adults, it is expected that some deep vein thrombosis (DVT) will occur coincidentally with vaccination. Whether COVID-19 vaccinations may contribute to DVT risk more generally (outside of VITT) has not been well studied outside of the initial clinical trials. Aims: Evaluate trends in DVT diagnosis before and after COVID-19 vaccination Methods: Vaccinated patients ≥ 18 years between 11/6/2020 through 6/1/2021 were analyzed using electronic medical records across the Mayo Clinic enterprise. Upper and lower DVT venous Duplex ultrasound (DUS) reports occurring 90 days before and after vaccination date (first dose for Pfizer and Moderna vaccines) were extracted and analyzed with a highly accurate, previously validated, Natural Language Processing (NLP) algorithm for acute DVT. Results: 382,527 patients with at least 1 COVID-19 vaccination were identified. The median age was 61 (IQR 44-72) and 55.3% were male. Pfizer was the most common vaccine administered (n=245,572, 64.2%), followed by Moderna (n=120,683, 31.6%) and Janssen (n=16,272, 4.3%). Most patients (91.5%) receiving vaccinations were from states with Mayo Clinic health services (Minnesota, n=197,834; Wisconsin, n=80,720; Florida, n=42,391; Arizona, n=28,882). The mean age at vaccination was 61.0 (SD 17.7), 56.5 (SD 19.1), and 54.7 (SD 16.3) for Moderna, Pfizer, and Janssen vaccines respectively. Women were most likely to receive the Pfizer (56.3%) compared to Moderna (54.1%) and Janssen (49.5%) vaccines. Non-white patients were most likely to receive Janssen (21%) compared to Moderna (7.7%) and Pfizer (8.2%) vaccines. Among all patients, 7,265 upper and lower venous DUS were performed in 5,960 patients. Figure 1 shows the utilization of DUS before and after COVID-19 vaccination and shows that more patients underwent DUS in the 90 days after vaccination compared to 90 days pre-vaccination. Acute DVT was identified by the NLP algorithm in 808 (714 patients) ultrasounds (11.1%); 656 out of 6136 lower extremity DUS (10.7%) and 152 out of 1129 upper extremity DUS (13.5%). The overall rate of acute DVT (upper and lower) was 1.86 per 1000 patients, consistent with the expected background epidemiologic rate. Figure 2 shows the daily probability of acute DVT by ultrasound report in the 90 days before and after vaccination with a linear regression best fit line showing no overall correlation (R 2 = 0.0). Overall acute DVT post-vaccination occurred on 10.8% of DUS compared to 11.6% pre-vaccination (p=0.28). Among ultrasound reports in Janssen vaccinated patients, 7.0% of post-vaccination compared to 18.0% of pre-vaccination were positive for acute DVT (p=0.003). Among ultrasound reports in Moderna vaccinated patients, 11.0% of post-vaccination compared to 12.7% of pre-vaccination were positive for acute DVT (p=0.15). Among ultrasound reports in Pfizer vaccinated patients, 11.0% of post-vaccination compared to 10.4% of pre-vaccination were positive for acute DVT (p=0.56). Using a Cox proportional hazard model, pre vs post-vaccination time among the same patient cohort was compared for each vaccine. The hazard ratio for DVT post-vaccination was 0.68 (95% CI 0.34-1.38) for Janssen, 1.08 (95% CI 0.86-1.35) for Moderna, and 1.20 (95% CI 0.99-1.46) for Pfizer. After adjusting for age and sex, Pfizer and Janssen's vaccines did not have different risks for DVT compared to Moderna in the 90 days post-vaccination (HR 0.80, 95% CI 0.98-1.25 and HR 0.75, 95% CI 0.42-1.32 respectively). Conclusions: In this large cohort of COVID-19 vaccinated patients, no increased risk for acute DVT post-vaccination was identified for any of the approved vaccinations in the United States. Additionally, no significant difference was seen in the risk for DVT post-vaccination when comparing each vaccine to each other. The probability of acute DVT on ultrasounds in the 90 days post-vaccination was lower than the pre-vaccination period with the Janssen vaccine possibly indicating over-testing in this group. These results provide additional reassurance of the safety of approved COVID-19 vaccines. Figure 1 Figure 1. Disclosures Padmanabhan: Veralox Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pruthi: HEMA Biologics: Honoraria; CSL Behring: Honoraria; Genentech: Honoraria; Instrumentation Laboratory: Honoraria; Bayer Healthcare AG: Honoraria; Merck: Honoraria.

Introduction: Serum folate (SF), vitamin B12 (B12), and iron deficiency (def) are common causes of nutritional anemias (NA). These deficiencies are usually multifactorial, with nutritional and non-nutritional causes playing a role. SF, B12, and iron levels are usually ordered in the setting of anemia, and malnutrition with or without neurologic symptoms. Clinical evidence suggests that these def have a strong dietary component and socioeconomic status (SES). The relationship of NA and area-based SES in the US has not been studied. We aimed to determine the relationship of SES with the prevalence of NA. Methods: We performed a cross-sectional analysis of adult patients with SF, B12 and iron levels at Mayo Clinic Arizona and Florida between 2010 and 2018. Race was classified using the NIH criteria. Normal laboratory values were determined according to our lab reference and the US NHANES III. SF levels (mcg/Lt) were defined as deficient <4, normal ≥4.0, and excess ≥20. B12 levels (ng/L) as deficient <150, borderline 150-400, normal >400-900, and excess ≥900. Iron def was determined by ferritin levels (mcg/L) as low <24, normal 24-336, elevated >336 for men, low <11, normal 11-307, elevated >307 for women. Area-Level SES indicators: Median Household income (MHI), unemployment rate (UR), median gross rent month (MGRM), % uninsured, median house value (MHV), % high school; were geocoded by zip code using the 2014 American Community Survey. Demographics and clinical variables were compared between groups by chi-square test for frequency data or Kruskal Wallis rank-sum test for continuous variables. Results: 202,046 samples from 128,084 patients were analyzed. In the sample-level analysis, there were statistically significant associations between SES and SF def; all SES indicators except UR for B12 def; and no differences for iron def, except % uninsured (Table 1). There was no statistically significant interaction between race and SES for SF def and iron def. Race was a statistically significant modifier between B12 def and MHI (p<0.001), % uninsured (p=0.002), and MHV (p=0.007). Asian and Other race had an increase in odds of B12 def with increasing MHI (Asian OR=1.11 , Other OR=1.18); white race had a decrease in odds of B12 def with increasing MHI (OR=0.95 for a $10,000 increase in MHI). Conclusions: We show significant relationships between SES and NA in the US. Differences were observed between SF def and all the SES indicators without race interactions. There were significant interactions between B12 def, race and SES for pts of White, Asian and Other race. There were no differences between SES and race for iron def. These relationships confirm that NA are related to area-level SES and other social determinants of health. Research regarding the causes of these disparities on a population level are needed. Disclosures No relevant conflicts of interest to declare.

AbstractBackgroundPhiladelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, have severe function‐limiting symptom burden that is experienced by the majority of patients. Previous studies have suggested that depression may be present in over a quarter of MPN patients, but to date no studies have evaluated the relationship between depression and other variables such as symptoms.MethodsA 70‐item internet based survey regarding fatigue and mood symptoms was developed by a multidisciplinary team of MPN investigators, patients and patient advocates including Patient Health Questionnaire and the Myeloproliferative Neoplasm Symptom Assessment Form was completed by over 1300 patients with MPN diagnosis.ResultsThere were 309 respondents (23%) with PHQ‐2 scores ≥ 3. In this analysis, we found worse systemic symptom burden in individuals reporting depressive symptoms.ConclusionThis analysis suggests the importance of depression in contributing to as well as confounding symptomatology in MPN patients, and suggests that this critical variable should also be addressed by clinicians and researchers alike when comprehensively assessing symptom burden etiologies.