Acute Renal Thrombotic Microangiopathy Caused by Eltrombopag and Romiplostim in a Patient with Myelodysplastic Syndromes (MDS) and Underlying Antiphospholipid Syndrome.

Romiplostim and eltrombopag are synthetic agonists of the thrombopoietin receptor (TPO-R), commonly used for immune thrombocytopenic purpura (ITP) and sometimes in myelodysplastic syndrome (MDS). They are rarely associated with kidney injury. We report a case of acute kidney injury caused by romiplostim and eltrombopag in an 80-year-old male patient with MDS and ITP. He did not have systemic haemolysis syndrome but isolated acute renal thrombotic microangiopathy confirmed by kidney biopsy. He was treated with steroids, plasmapheresis and anticoagulation, with improvement in renal function. Interestingly, the patient had high antiphospholipid (aPL) antibodies noted upon screening, indicating a possible new antiphospholipid syndrome (APS) diagnosis. In the presence of circulating aPL antibodies, eltrombopag may have served as a trigger, causing endothelial injury and subsequent renal microangiopathy; aPL antibodies were still significantly positive at four weeks of outpatient testing. This case and a few others reported in the literature highlight the importance of screening for aPL antibodies before initiating TPO-R agonists in patients with ITP. We suspect that using TPO-R agonists, rather than underlying aPL, caused renal failure. LEARNING POINTS: Synthetic agonists of the thrombopoietin receptor, such as romiplostim or eltrombopag, can cause acute renal failure.Preexisting antiphospholipid (aPL) antibodies may increase the risk of renal failure.Screening for aPL antibodies should be considered before initiating thrombopoietin-receptor agonists (TPO-R agonists) in patients with immune thrombocytopenic purpura (ITP).

Identifying Neutrophil Extracellular Traps (NETs) in Blood Samples Using Peripheral Smear Autoanalyzers.

Neutrophil Extracellular Traps (NETs) are large neutrophil-derived structures composed of decondensed chromatin, cytosolic, and granule proteins. NETs play an important role in fighting infection, inflammation, thrombosis, and tumor progression processes, yet their fast and reliable identification has been challenging. Smudge cells (SCs) are a subcategory of white cells identified by CellaVision®, a hematology autoanalyzer routinely used in clinical practice that uses digital imaging to generate "manual" differentials of peripheral blood smears. We hypothesize that a proportion of cells identified in the SC category by CellaVision® Hematology Autoanalyzers are actually NETs. We demonstrate that NET-like SCs are not present in normal blood samples, nor are they an artifact of smear preparation. NET-like SCs stain positive for neutrophil markers such as myeloperoxidase, leukocyte alkaline phosphatase, and neutrophil elastase. On flow cytometry, cells from samples with high percent NET-like SCs that are positive for surface DNA are also positive for CD45, myeloperoxidase and markers of neutrophil activation and CD66b. Samples with NET-like SCs have a strong side fluorescent (SFL) signal on the white count and nucleated red cells (WNR) scattergram, representing cells with high nucleic acid content. When compared to patients with low percent SCs, those with a high percentage of SCs have a significantly higher incidence of documented bacterial and viral infections. The current methodology of NET identification is time-consuming, complicated, and cumbersome. In this study, we present data supporting identification of NETs by CellaVision®, allowing for easy, fast, cost-effective, and high throughput identification of NETs that is available in real time and may serve as a positive marker for a bacterial or viral infections.

Thrombosis in myeloproliferative neoplasms: Treatment outcomes of direct oral anticoagulants and vitamin K antagonists.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at an increased risk of recurrent thromboembolic events (TEs) and hemorrhagic complications. Anticoagulation with vitamin K antagonists (VKAs) had been the standard of care until the recent US Food and Drug Administration approval of direct oral anticoagulants (DOACs) for treatment of cancer-associated thrombosis. However, since patients with MPNs were underrepresented in large studies, the use of DOACs in patients with MPN-associated thrombosis remains understudied. OBJECTIVES: The primary objective of this study was to establish the incidence of recurrent TEs and hemorrhagic complications in patients with MPN-associated thrombosis treated with DOACs versus VKAs as first-line therapy. METHODS: Data from 30 patients ≥18 years old with established diagnoses of PV or ET who were treated with either DOACs or VKAs as the first-line anticoagulant for arterial and/or venous thrombosis were reviewed to determine the incidence of recurrent TEs as well as hemorrhagic complications. RESULTS: Nineteen patients were treated with DOACs, and 11 were treated with VKAs. Of those on DOACs, 1 had a recurrent thrombosis, and 4 had bleeding events. Of the 11 patients treated with VKAs, 1 had a recurrent thrombotic event, and 1 had a bleeding event. CONCLUSION: Our data did not demonstrate a significant difference in recurrent TEs or bleeding events in patients with MPN-associated thrombosis anticoagulated with either DOACs or VKAs.

Saddle Pulmonary Embolism: Demographics, Clinical Presentation, and Outcomes.

Saddle pulmonary embolism is an uncommon type of venous thromboembolism that can lead to sudden hemodynamic collapse and death. Saddle pulmonary embolism can be difficult to recognize, and data on its presentation, clinical features, and associated complications are sparse. We sought to characterize patients with saddle pulmonary embolism. DESIGN: The Montage software (Nuance, Burlington, MA) was used to identify patients to create a retrospective cohort study. SETTING: Montefiore Medical Center from January 1, 2012, to December 31, 2018. PATIENTS: All subjects diagnosed with saddle pulmonary embolism in above time period. INTERVENTIONS: Charts were reviewed for demographics, diagnostics, laboratory data, presenting vital signs, inhospital mortality, 6-month survival, and prevalence of recurrent venous thromboembolism. MEASUREMENTS AND MAIN RESULTS: About 120 patients with saddle pulmonary embolism were identified. Median age was 61 years and 57.5% were women. Events were provoked by a transient risk factor in 43.3%. On presentation, median mean arterial pressures were normal (93 mm Hg). Only five of 120 of patients (4.2%) presented with vitals concerning for massive pulmonary embolism. We found a 9.2% inhospital mortality; an additional 8.6% died within 6 months of discharge. Inhospital mortality was higher in women (11.6%), compared with men (3.9%), but this was not significant (p = 0.28). In 10 patients, both ventilation/perfusion scans and computed tomography pulmonary angiogram were performed. None of the ventilation/perfusion scans diagnosed saddle pulmonary embolism. Thrombus was visualized in the right heart in eight of 105 (7.6%), and this group had a higher inhospital mortality (37.5%). Recurrent venous thromboembolism occurred in 13 of 85 of survivors (15.3%). CONCLUSIONS: Despite presenting without the accepted clinical criteria for massive pulmonary embolism, saddle pulmonary embolism has a very high inhospital mortality. Ventilation/perfusion scan is unable to diagnose saddle pulmonary embolism. Visualized right heart thrombi portend an even higher inhospital mortality.

Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality.

BACKGROUND: Mortality in coronavirus disease of 2019 (COVID-19) is associated with increases in prothrombotic parameters, particularly D-dimer levels. Anticoagulation has been proposed as therapy to decrease mortality, often adjusted for illness severity. OBJECTIVE: We wanted to investigate whether anticoagulation improves survival in COVID-19 and if this improvement in survival is associated with disease severity. METHODS: This is a cohort study simulating an intention-to-treat clinical trial, by analyzing the effect on mortality of anticoagulation therapy chosen in the first 48 hours of hospitalization. We analyzed 3,625 COVID-19+ inpatients, controlling for age, gender, glomerular filtration rate, oxygen saturation, ventilation requirement, intensive care unit admission, and time period, all determined during the first 48 hours. RESULTS: Adjusted logistic regression analyses demonstrated a significant decrease in mortality with prophylactic use of apixaban (odds ratio [OR] 0.46, p = 0.001) and enoxaparin (OR = 0.49, p = 0.001). Therapeutic apixaban was also associated with decreased mortality (OR 0.57, p = 0.006) but was not more beneficial than prophylactic use when analyzed over the entire cohort or within D-dimer stratified categories. Higher D-dimer levels were associated with increased mortality (p < 0.0001). When adjusted for these same comorbidities within D-dimer strata, patients with D-dimer levels < 1 µg/mL did not appear to benefit from anticoagulation while patients with D-dimer levels > 10 µg/mL derived the most benefit. There was no increase in transfusion requirement with any of the anticoagulants used. CONCLUSION: We conclude that COVID-19+ patients with moderate or severe illness benefit from anticoagulation and that apixaban has similar efficacy to enoxaparin in decreasing mortality in this disease.

Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data.

BACKGROUND: Because studies of direct oral anticoagulants in patients with venous thromboembolism and non-valvular atrial fibrillation have had minimal representation of morbidly obese patients (ie, body-mass index [BMI] ≥40 kg/m2), their efficacy and safety in this population are unclear. We investigated whether apixaban and rivaroxaban are as effective and safe as warfarin in morbidly obese patients. METHODS: We did a single-centre, retrospective analysis of chart data for all adult patients aged at least 18 years at Montefiore Medical Center (Bronx, NY, USA) with a BMI of at least 40 kg/m2 who were prescribed apixaban, rivaroxaban, or warfarin for either venous thromboembolism or atrial fibrillation between March 1, 2013, and March 1, 2017. Patients who had both venous thromboembolism and atrial fibrillation were excluded, as were patients with indications other than atrial fibrillation and venous thromboembolism. Outcomes of recurrent venous thromboembolism, stroke, and bleeding were measured from the first prescription date to the earliest of a thrombotic event, medication discontinuation, death, or end of study on June 30, 2017. Analyses were stratified by anticoagulation indication and adjusted for comorbidities, CHA2DS2-VASc score, and age where appropriate. Outcome rates were compared using Pearson's χ2 or Fisher's exact test. Time-to-event analyses accounting for length of follow-up were used to compare risks of outcomes. FINDINGS: We obtained data for 795 patients: 150 prescribed apixaban, 326 rivaroxaban, and 319 warfarin. In 366 patients prescribed an anticoagulant for venous thromboembolism, the incidence of recurrent venous thromboembolism was similar between the apixaban, rivaroxaban, and warfarin cohorts (1/47 [2·1%, 95% CI 0·0-6·3], 3/152 [2·0%, 0·0-4·2], and 2/167 [1·2%, 0·0-2·9], respectively; p=0·74). Incidence of major bleeding in this patient group was also similar between the treatment cohorts (1/47 patients on apixaban [2·1%, 95% CI 0·0-6·3], 2/152 on rivaroxaban [1·3%, 0·0-3·1], and 4/167 on warfarin [2·4%, 0·1-4·7]; p=0·77). In 429 patients prescribed an anticoagulant for atrial fibrillation, incidence of stroke was similar between the treatment cohorts (1/103 patients on apixaban [1·0%, 95% CI 0·0-2·9], 4/174 on rivaroxaban [2·3%, 0·1-4·5], and 2/152 on warfarin [1·3%, 0·0-3·1], p=0·71). In this patient group, major bleeding occurred in 3/103 patients on apixaban (2·9%, 95% CI 0·0-6·2), 5/174 on rivaroxaban (2·9%, 0·4-5·4), and 12/152 on warfarin (7·9%, 3·6-12·2); p=0·063. Time-to-event analyses showed that risk of all outcomes in patients with venous thromboembolism, and stroke and composite bleeding in patients with atrial fibrillation, were similar between the anticoagulant cohorts. INTERPRETATION: Our retrospective study provides further evidence of similar efficacy and safety between the direct oral anticoagulants apixaban and rivaroxaban, and warfarin in morbidly obese patients with atrial fibrillation and venous thromboembolism. These data, if confirmed in prospective studies, might enable patients with a BMI of at least 40 kg/m2 to benefit from more convenient, and possibly safer, anticoagulants. FUNDING: None.

Persistent neutrophilia is a marker for an increased risk of venous thrombosis.

In patients with cancer and myeloproliferative disorders, leukocytosis has been associated with an increased venous thromboembolic (VTE) risk. Our goal was to determine whether persistent neutrophilia (PN), not associated with known causes such as malignancies, infections or steroids, is independently associated with VTE. All adult patients with >3 outpatient complete blood counts (CBCs) within 3 years were included. PN was defined as having an absolute neutrophil count >95 % (>2SD) of the population (≥7.8 × 10(9)/L) on at least three CBCs, at least 2 months apart. Separate analyses for neutrophil counts ≥9 × 10(9)/L and ≥10 × 10(9)/L were also performed. Blood counts from inpatients were excluded. Primary outcome was diagnosis of VTE, as determined by ICD-9 codes. Odds ratios were adjusted for diabetes, smoking, obesity, gender, and age. Charlson score was utilized as a morbidity measure. Data on 43,538 outpatients were collected. Although there was no association of VTE with neutrophil counts ≥7.8 × 10(9)/L, patients with ≥9.0 × 10(9)/L neutrophils were twice as likely to be diagnosed with VTE compared to those with normal neutrophil counts (OR 2.0, 95 % CI 1.3, 3.1; p = 0.003). Patients with neutrophil counts ≥10.0 × 10(9)/L were at an even higher risk (OR 2.3, 95 % CI 1.2, 4.8; p = 0.019). Charlson scores significantly modified this risk when incorporated into analysis. Elevated neutrophil counts are associated with an increased risk of venous thrombosis even when they are not due to cancer, infection or steroids. In patients with significant comorbidities, neutrophilia may be a marker of VTE risk.

Treatment with Dalteparin is Associated with a Lower Risk of Bleeding Compared to Treatment with Unfractionated Heparin in Patients with Renal Insufficiency.

BACKGROUND: Low molecular weight heparins (LMWHs) have been cautiously used in patients with chronic kidney disease (CKD) due to fear of accumulation. Dalteparin, however, has shown minimal tendency to accumulate in patients with CKD and may be safe to use in this patient population. OBJECTIVE: We compared the incidence of clinically significant bleeding in patients with CKD receiving therapeutic doses of dalteparin to that of patients with CKD receiving therapeutic doses of UFH. DESIGN: This was a retrospective cohort study. SUBJECTS: Inpatients with CKD (GFR < 60 ml/min) who were treated with therapeutic dalteparin or UFH were included in the study MAIN MEASURES: Primary outcome was major bleeding within 10 days of anticoagulation, identified by ICD-9 code and confirmed by chart review. Demographic characteristics, laboratory values, comorbidities, prior bleeding history and inpatient medications were extracted for each admission from the electronic medical record. Logistic regression models were created to examine the association between choice of anticoagulant and bleeding rates, after adjustment for demographic and clinical characteristics. KEY RESULTS: Dalteparin-treated patients were significantly less likely to experience a major bleed than patients treated with UFH (1.14 % vs. 3.49 %, p < 0.001). The reduced likelihood of bleeding associated with dalteparin treatment remained significant after adjustment for patient characteristics (HR 0.39, 95 % CI: 0.21-0.70, p < 0.0001). A stratified analysis for subgroups with GFR< 30 mL/min and with GFR between 30 and 60 mL/min showed that dalteparin was still associated with lower odds of bleeding compared to treatment with unfractionated heparin, but the difference was nonsignificant for GFR< 30 (HR 0.35, 95 % CI: 0.11-1.15), even after adjustment (OR 0.37, 95 % CI: 0.11-1.22). CONCLUSION: In patients with CKD, treatment with therapeutic dose dalteparin was associated with lower rates of bleeding than treatment with unfractionated heparin. For patients with severe CKD (GFR< 30), dalteparin was shown to be at least as safe as unfractionated heparin.