Multiple Anticoagulants Research Articles

Literature review of spinal hematoma case reports: causes and outcomes in pediatric, obstetric, neuraxial and pain medicine cases

BackgroundThe risk of spinal epidural hematoma (SEH) has been described in the literature but the impact in various patient populations has not been assessed in the same study. We identified...

Multistage Anticoagulant Surfaces: A Synergistic Combination of Protein Resistance, Fibrinolysis, and Endothelialization.

Anticoagulant surface modification of blood-contacting materials has been shown to be effective in preventing thrombosis and reducing the dose of anticoagulant drugs that patients take. However, commercially available anticoagulant coatings, that is, both bioinert and bioactive coatings, are typically based on a single anticoagulation strategy. This puts the anticoagulation function of the coating at risk of failure during long-term use. Considering the several pathways of the human coagulation system, the synergy of multiple anticoagulation theories may provide separate, targeted effects at different stages of thrombosis. Based on this presumption, in this work, negatively charged poly(sodium p-styrenesulfonate-co-oligo(ethylene glycol) methyl ether methacrylate) and positively charged poly(lysine-co-1-adamantan-1-ylmethyl methacrylate) were synthesized to construct matrix layers on the substrate by electrostatic layer-by-layer self-assembly (LBL). Amino-functionalized β-cyclodextrin (β-CD-PEI) was subsequently immobilized on the surface by host-guest interactions, and heparin was grafted. By adjusting the content of poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA), the interactions between modified surfaces and plasma proteins/cells were regulated. This multistage anticoagulant surface exhibits inertness at the initial stage of implantation, resisting nonspecific protein adsorption (POEGMA). When coagulation reactions occur, heparin exerts its active anticoagulant function in a timely manner, blocking the pathway of thrombosis. If thrombus formation is inevitable, lysine can play a fibrinolytic role in dissolving fibrin clots. Finally, during implantation, endothelial cells continue to adhere and proliferate on the surface, forming an endothelial layer, which meets the blood compatibility requirements. This method provides a new approach to construct a multistage anticoagulant surface for blood-contacting materials.

Anticoagulants: A Short History, Their Mechanism of Action, Pharmacology, and Indications.

Anticoagulant drugs antagonize coagulation and are used to prevent or cure (recurrent) venous thromboembolism (VTE). Drugs to prevent clotting have been used for more than a century, and, nowadays, physicians possess a broad panel of multiple anticoagulants to meet the individual needs of a patient. Within this review, we aimed to revise the history of the different anticoagulants that are currently prescribed in the clinic. In addition, we compared their pharmacological properties, medical indications, and the difficulties in implementing new anticoagulants in vulnerable patient populations. Since the introduction of unfractionated heparin in the 1930s, major advances in the mechanistic understanding and the medical use of anticoagulants have allowed for significant improvements to treat VTE patients. However, a new generation of anticoagulants is currently being tested in clinical trials, with the goal of further optimizing medical care.

Cardiac troponin T degradation in end-stage renal disease patients appears to occur in vivo

Abstract Background Cardiac troponin T (cTnT) is a cornerstone biomarker for diagnosing myocardial infarction (MI). However, since the introduction of the high-sensitivity assays, cardiac troponins are also measured in pathologies with cardiac risk factors, such as end-stage renal disease (ESRD), making it more difficult for clinicians to diagnose MI. Previous studies of our group identified specific larger cTnT proteoforms for the acute phase of MI, while a study in serum of ESRD patients showed solely small cTnT fragments. However, others allocated the small cTnT fragments in serum of ESRD patients to a pre-analytic effect due to abundant thrombin generation in serum, as thrombin is known to cause fragmentation of cTnT. Purpose This study investigated the effect of multiple anticoagulation methods on cTnT proteoforms in vitro and in the blood of ESRD patients. Methods First, cTnT negative serum and lithium-heparinized (LH), ethylenediaminetetraacetic-acid (EDTA), and hirudin plasma tubes were spiked with human cTnT standard, incubated at 37°C till 48 hours, and analysed with Western Blotting using anti-cTnT Roche antibodies. Second, similar blood tubes were collected from ESRD patients (n=10) conform the Declaration of Helsinki, patient samples and spiked cTnT standards were separated using gel filtration chromatography (GFC) and cTnT was subsequently analysed using the Cobas 6000 analyser. Results After 48 hours of in vitro incubation of cTnT in hirudin plasma, no cTnT degradation was observed, while LH only showed minor degradation of 10% from intact 40 kDa cTnT to 29 kDa fragments (figure 1). Also, for both EDTA and serum, a time-dependent degradation from 40 kDa cTnT to 29 kDa fragments to 15–18 kDa fragments was observed. Moreover, in ESRD patients, GFC elution profiles of all blood tubes revealed that 85–98% of cTnT corresponded to small 15–18 kDa fragments (41–42 mL), while 2–15% were 29/40 kDa cTnT forms (27–28 mL). For comparison, standards of ternary T-I-C complex and intact cTnT eluted at 21 mL and 28 mL, respectively. Conclusions The extent of cTnT degradation in vitro is dependent on the anticoagulation method of the blood tubes, with absence of degradation exclusively in hirudin plasma. Since in ESRD patients for all blood tubes mainly small 15–18 kDa cTnT fragments were found, including hirudin plasma, cTnT degradation appears to occur in vivo. This observation supports the hypothesis that larger cTnT proteoforms might indeed be specific for the acute phase of MI, thereby supporting the opportunity for developing a more specific cTnT method. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ZonMw Veni grant

Perioperative Bleeding Associated With Ibrutinib in Dermatologic Surgery: A Case-Control Study.

Ibrutinib, an irreversible Bruton tyrosine kinase inhibitor, has been associated with an increased risk of bleeding. There is a paucity of data on the risk of bleeding in patients on ibrutinib undergoing dermatologic surgery. To determine the frequency of bleeding complications associated with ibrutinib in patients undergoing dermatologic surgery. A retrospective, single-center, case-control study of patients on ibrutinib undergoing skin surgery between January 2013 and March 2020 compared with sex, disease, and age-matched control patients undergoing cutaneous surgeries. A total of 75 surgeries performed on 37 case patients and 116 surgeries performed on 64 control patients were included. Ibrutinib was associated with a statistically significant increased rate of bleeding events (6/75 [8%] vs 1/116 [0.8%], p -value = .02). Compared with ibrutinib patients who did not have a bleeding event, those on ibrutinib who suffered bleeding were all men, older (mean age 82.7 vs 73.0, p -value= .01), and had lower mean platelet counts (104.0 vs 150.5 K/μL, p -value = .03). Ibrutinib may be associated with increased risk of bleeding in patients with hematologic malignancies, particularly older men with lower platelet levels and on multiple anticoagulants. Transient discontinuation of ibrutinib should be considered for dermatologic surgeries.

Anticoagulant Therapy Post-COVID in the Perioperative Setting

A post-COVID patient with a high D-dimer Value (>5000 IU) was posted for total knee replacement. She was on multiple anticoagulants including the novel oral anticoagulants that started to reduce thrombotic risk. This case highlights the importance of continuing the anticoagulants and provides insights on the proper timing to stop and restart various anticoagulants after surgery in post-COVID patients.

Equivalent VTE rates after total joint arthroplasty using thromboprophylaxis with aspirin versus potent anticoagulants: retrospective analysis of 4562 cases across a diverse healthcare system

BackgroundGuidelines support aspirin thromboprophylaxis for primary total hip and knee arthroplasty (THA and TKA) but supporting evidence has come from high volume centers and the practice remains controversial.MethodsWe studied 4562 Medicare patients who underwent elective primary THA (1736, 38.1%) or TKA (2826, 61.9%) at 9 diverse hospitals. Thirty-day claims data were combined with data from the health system’s electronic medical records to compare rates of venous thromboembolism (VTE) between patients who received prophylaxis with: (1) aspirin alone (47.3%), (2) a single, potent anticoagulant (29%), (3) antiplatelet agents other than aspirin or multiple anticoagulants (21.5%), or (4) low-dose subcutaneous unfractionated heparin or no anticoagulation (2.2%). Sub-analyses separately evaluating THA, TKA and cases from lower volume hospitals (n = 975) were performed.ResultsThe 30-day VTE incidence was 0.6% (29/4562). VTE rates were equal in patients receiving aspirin and those receiving a single potent anticoagulant (0.5% in both groups). Patients with VTE were significantly older than patients without VTE (mean 76.5 vs. 73.1 years, P = 0.04). VTE rate did not associate with sex or hospital case volume. On bivariate analysis considering age, aspirin did not associate with greater VTE risk compared to a single potent anticoagulant (OR = 2.1, CI = 0.7–6.3) with the numbers available. Odds of VTE were increased with use of subcutaneous heparin or no anticoagulant (OR = 6.4, CI = 1.2–35.6) and with multiple anticoagulants (OR = 3.6, CI = 1.1–11.2). THA and TKA demonstrated similar rates of VTE (0.5% vs. 0.7%, respectively, P = 0.43). Of 975 cases done at lower volume hospitals, 387 received aspirin, none of whom developed VTE.ConclusionsThis study provides further support for aspirin as an effective form of pharmacological VTE prophylaxis after total joint arthroplasty in the setting of a multi-modal regimen using 30-day outcomes. VTE occurred in 0.7% of primary joint arthroplasties. Aspirin prophylaxis did not associate with greater VTE risk compared to potent anticoagulants in the total population or at lower volume hospitals.

Optimal Anticoagulant Dosing in Patients with COVID-19, a Retrospective Review

BackgroundHospitalized patients with coronavirus disease 2019 (COVID-19) infection have higher rates of venous thromboembolism (VTE).Higher mortality rates have been reported in severe cases of COVID-19 including those who have elevated D-dimer levels and have thromboembolic phenomena.ObjectiveThe objective of this retrospective and observational study was to ascertain which type and dosages of anticoagulation provide a mortality benefit and decrease the risk of developing VTE.MethodsWe evaluated the risk factors for VTEs in patients with a confirmed polymerase chain reaction test positive for COVID-19 who were admitted to our facility from April 1 to July 1, 2020. In addition, we performed a logistic regression to examine the relationship between mortality and intensive care unit (ICU) admission, specific risk factors outlined in the study, D-dimer, ferritin, prothrombin time (PT) and international normalized ratio (INR). Patients with a history of VTE, those already on anticoagulation (AC) prior to hospitalization, and patients on comfort care were excluded from study.ResultsThere were originally 331 patients in the data set. Of those, 111 patients were excluded based on exclusion criteria and 4 additional patients were removed as they were the only individual patients in their specific AC covariant group. The analysis was performed on the remaining 216 patients. We divided the AC medications administered to the patients into five separate covariates: 1. enoxaparin 40 mg subcutaneous (sq) daily, 2. enoxaparin 40 mg sq every 12 hours (q12h), 3. heparin 5000 mg sq q12h, 4. heparin 5000 mg sq every 8 hours (q8h), 5. Patients taking multiple AC or deep venous thrombosis (DVT) prophylaxis medications. 6. No AC and examined them via logistic regression for mortality at 28 days and 60 days (Table 1). Patients in enoxaparin 40 mg daily group had statistically significant lower 28 day mortality. There was no statistically significant relationship between the use of enoxaparin 40 mg q12h and 28 day mortality rate. Patients in both heparin groups did not have significantly lower 28 day mortality rates. Patients in groups 5 & 6 had significantly higher 28 day mortality rates (Table 1). It is important to note that 33 patients underwent a pulmonary computed tomography angiography due to concern for pulmonary embolism and 38 patients underwent an ultrasound of their lower extremities to rule out the development of DVT.For patients with additional risk factors defined as chronic kidney disease, chronic obstructive pulmonary disease, organ transplant recipient, obesity (BMI > 30), cardiac disease (heart failure, coronary artery disease or cardiomyopathy), sickle cell disease, diabetes mellitus and smoking history, the odds of death at 28 days increased by a factor of 1.71, at 60 days by a factor of 1.63 and being admitted to the ICU by a factor of 1.41. Patients with 3-5 risk factors are 2.48 times more likely to be admitted to the ICU than patients with 0-2 risk factors. Patients with 4 or 5 risk factors are 3.56 times more likely to be admitted to the ICU than patients with 0-3 risk factors (Table 2). Predictably, patients that were admitted to the ICU had a significantly increased rate of mortality compared to those who were not (Table 3).Per our analysis, there was no relationship between PT or INR and mortality. At 28 days and 2 months, the D-dimer > 4000 was indicative of a higher odds of death versus patients with a D-dimer < 4000. An increased ferritin was also indicative of a higher mortality rate (Table 4).ConclusionPatients receiving enoxaparin 40 mg daily benefited more than any other AC regimen with respect to the development of VTE at both 28 days and 2 months. Increasing the dosing to twice daily did not decrease mortality. Additionally, patients receiving heparin did not have a decreased mortality. It is important to note that there was no standard protocol used to determine which patients received daily or twice daily dosing. The type and dose of AC was determined based on the clinical judgment of intensivists in each case. It is also possible that patients with severe COVID-19 infection were more likely to be given twice daily dosing which could account for the lack of mortality benefit with more frequent dosing. We did not report bleeding rates in AC groups in our study and this can be a possible reason for no mortality benefit among higher dose AC groups. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ex Vivo Assessment of Different Oral Anticoagulant Regimens on Pump Thrombosis in a HeartWare Ventricular Assist Device

In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents. A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity. Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes, P=0.02. There were similar changes in lactate dehydrogenase levels and other secondary end points. In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.

Global biochemical analysis of plasma, serum and whole blood collected using various anticoagulant additives.

Analysis of blood for the evaluation of clinically relevant biomarkers requires precise collection and sample handling by phlebotomists and laboratory staff. An important consideration for the clinical application of metabolomics are the different anticoagulants utilized for sample collection. Most studies that have characterized differences in metabolite levels in various blood collection tubes have focused on single analytes. We define analyte levels on a global metabolomics platform following blood sampling using five different, but commonly used, clinical laboratory blood collection tubes (i.e., plasma anticoagulated with either EDTA, lithium heparin or sodium citrate, along with no additive (serum), and EDTA anticoagulated whole blood). Using an untargeted metabolomics platform we analyzed five sample types after all had been collected and stored at -80°C. The biochemical composition was determined and differences between the samples established using matched-pair t-tests. We identified 1,117 biochemicals across all samples and detected a mean of 1,036 in the sample groups. Compared to the levels of metabolites in EDTA plasma, the number of biochemicals present at statistically significant different levels (p<0.05) ranged from 452 (serum) to 917 (whole blood). Several metabolites linked to screening assays for rare diseases including acylcarnitines, bilirubin and heme metabolites, nucleosides, and redox balance metabolites varied significantly across the sample collection types. Our study highlights the widespread effects and importance of using consistent additives for assessing small molecule levels in clinical metabolomics. The biochemistry that occurs during the blood collection process creates a reproducible signal that can identify specimens collected with different anticoagulants in metabolomic studies. In this manuscript, normal/healthy donors had peripheral blood collected using multiple anticoagulants as well as serum during a fasted blood draw. Global metabolomics is a new technology being utilized to draw clinical conclusions and we interrogated the effects of different anticoagulants on the levels of biochemicals from each of the donors. Characterizing the effects of the anticoagulants on biochemical levels will help researchers leverage the information using global metabolomics in order to make conclusions regarding important disease biomarkers.

Improving anticoagulation in sub-Saharan Africa: What are the challenges and how can we overcome them?

Patients in sub‐Saharan Africa generally have poor anticoagulation control. We review the potential reasons for this poor control, as well as the potential solutions. Challenges include the affordability and centralisation of anticoagulation care, problems with access to medicines and international normalised ratio monitoring, the lack of locally validated standardized dosing protocols, and low levels of anticoagulation knowledge among healthcare workers and patients. Increasing numbers of patients will need anticoagulation in the future because of the increasing burden of noncommunicable disease in the region. We propose that locally developed “warfarin care bundles” which address multiple anticoagulation challenges in combination may be the most appropriate solution in this setting currently.

Eculizumab for Refractory Thrombosis in Antiphospholipid Syndrome

Introduction:Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis in the presence of antiphospholipid antibodies. Recently, derangement in the complement pathway has been implicated in APS pathophysiology. Refractory cases of APS with recurrent and potentially fatal thrombosis have prompted use of the monoclonal antibody eculizumab, which inhibits generation of the terminal complement complex. We present the successful use of eculizumab in controlling and preventing recurrent thrombosis in a refractory case of APS. Case Description:An 18-year-old female received a diagnosis of antiphospholipid syndrome after developing extensive unprovoked deep vein thrombosis of axillary, inferior vena caval and brachiocephalic veins. Thrombophilia evaluation revealed triple positivity for lupus anti-coagulant (LA), beta-2 glycoprotein I (GP) IgG 84.9 SGU Units, IgM 76.5 SMU Units, IgA 66.7 SAU Units and strongly positive anti-cardiolipin (aCL) antibodies (each &amp;gt;&amp;gt;40U/mL) with persistent positive titers after 12 weeks of initial evaluation. She was refractory with trials of multiple anticoagulants alone and with antiplatelet and adjunctive therapies. Anticoagulants used were enoxaparin, fondaparinux, apixaban, rivaroxaban, and warfarin; antiplatelet agents used were aspirin and clopidogrel; and adjunctive therapies included hydroxychloroquine, immunosuppression with steroids and rituximab, and plasmapheresis. Despite these interventions, she continued to develop recurrent thrombosis of subclavian, femoral, common femoral, iliac, popliteal and saphenous veins. She additionally developed a potentially life-threatening hepatic infarction and pulmonary embolism, and 6 weeks of plasma exchange failed to decrease antiphospholipid antibody titers. Following this event, eculizumab (600mg weekly x 4 weeks, followed by 900mg once on week 5, followed by 900mg every 2 weeks) was initiated in combination with fondaparinux, aspirin, clopidogrel, and hydroxychloroquine. She has remained on this regimen with additional anticoagulation and antiplatelet therapy without recurrence of thrombosis over the subsequent year. Discussion:Recent evidence has shown complement activation playing a role in pathophysiology of antiphospholipid syndrome. This is thought to occur through C3 and C5a causing platelet and endothelial activation, leading to microvascular thrombosis. Histological evidence of such processes is supported by the demonstration of anti-beta-2 GP1 IgG-C5b-9 immune complexes in microvascular organ thrombi in individuals with APS leading to thrombotic microangiopathy and multiorgan failure. Such evidence of complement induced thrombosis in antiphospholipid syndrome led us to use eculizumab following failure of available therapies including anticoagulation, antiplatelet therapy, immune modulation and plasmapheresis in a potentially life-threatening event. Absence of recurrent thrombotic events over approximately one year with eculizumab combined with anticoagulation and antiplatelet therapy highlights the potential role of complement inhibition in preventing thrombosis in APS. While the role of complement in thrombosis continues to be elucidated, we have observed no decline in antiphospholipid antibody levels in a span of one year in our patient. Importantly, there has been no recurrent thrombosis during this time. Our case suggests that eculizumab may have a role as a therapeutic option in refractory thrombosis in APS. Chronology of Events:Eculizumab initiated on 9/5/2019. No evidence of venous or arterial thrombosis since 10/2019 to present. Figure Disclosures Tarantino: Pfizer:Other;Genentech:Membership on an entity's Board of Directors or advisory committees;Octapharma:Membership on an entity's Board of Directors or advisory committees;Dova:Membership on an entity's Board of Directors or advisory committees;CDC:Membership on an entity's Board of Directors or advisory committees;Grifols:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen:Membership on an entity's Board of Directors or advisory committees;Biomarin:Membership on an entity's Board of Directors or advisory committees;NovoNordisk:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Takeda:Research Funding;HRSA:Membership on an entity's Board of Directors or advisory committees;Spark:Membership on an entity's Board of Directors or advisory committees;Sobi:Membership on an entity's Board of Directors or advisory committees.McCrae:Rigel:Consultancy;Novartis:Honoraria;Momenta Pharmaceuticals:Consultancy;Dova:Consultancy.Chaturvedi:Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees;Alexion:Honoraria, Membership on an entity's Board of Directors or advisory committees.Roberts:Octapharma:Consultancy, Speakers Bureau;uniQure:Consultancy;Sanofi:Consultancy, Speakers Bureau;Novo Nordisk:Consultancy, Speakers Bureau;Pfizer:Consultancy;Takeda:Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: eculizumab for treatment of refractory thrombosis in antiphospholipid syndrome

Early Death in Patients with Disseminated Intravascular Coagulation during Induction Therapy for Acute Promyelocytic Leukemia: A Nationwide Analysis

Background: Real-world data studies showed poorer outcomes in patients with acute promyelocytic leukemia (APL) than randomized controlled trials, because elderly patients were excluded in such trials. Reportedly, the main cause of death was severe bleeding due to disseminated intravascular coagulation (DIC) during induction therapy for APL. The management of DIC was therefore crucially important especially in elderly patients. This study aimed to clarify factors associated with in-hospital death in all patients, and elderly patients with DIC during induction therapy for APL. Study Design and Methods: We retrospectively identified 1,463 patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and March 2018 from a nationwide inpatient database in Japan. In-hospital death was evaluated with multivariable logistic regression models in all patients, and in ≥60 year-old patients. Anticoagulants included recombinant human soluble thrombomodulin, delteparin (low molecular weight heparin), danaparoid sodium, gabexate mesilate, and nafamostat mesilate which were administered within three days from admission. Patients who died within three days from the admission were excluded from the study to avoid immortal time bias. Results: We identified a total of 1,138 (78%) patients who developed DIC. We excluded 23 patients who died within three days from the admission. The remaining 1,115 patients were analyzed. During hospitalization, 172 (15%) patients died at a median of 13 days (interquartile range: 7-30). Compared with younger patients (20 to 39 years old), elderly patients were significantly associated with higher in-hospital mortality (60 to 79 years old: odds ratio 5.58 [95% confidence interval 3.05-10.22], 80 years or older: 13.51 [6.07-30.08]). Patients who received ATRA monotherapy had significantly higher incidence of in-hospital death (2.48 [1.54-4.01]). Delayed initiation of ATRA was significantly associated with higher mortality (1.60 [1.11-2.30]). A total of 699 patients (63%) received anticoagulant therapies, but none of these were significantly associated with lower mortality. Use of multiple anticoagulants was significantly associated with higher in-hospital mortality (2.47 [1.16-5.26]). Subgroup analyses in patients ≥60 years old were then conducted. During hospitalization, 122 of 416 (29%) patients died at a median of 13 days (interquartile range: 7-29). Both late initiation of conventional chemotherapy and no conventional chemotherapy were significantly associated with higher in-hospital mortality (1.88 [1.01-3.49], 3.25 [1.74-6.06], respectively). Use of recombinant human soluble thrombomodulin and use of multiple anticoagulants were significantly associated with higher mortality (1.91 [1.09-3.35], 2.64 [1.01-6.90], respectively). Conclusions: Elderly patients who developed DIC during induction therapy for APL were significantly associated with higher in-hospital mortality. Immediate initiation of ATRA and early initiation of conventional chemotherapy may have contributed to preferable outcomes. Disclosures Matsuda: Kyowa Kirin: Speakers Bureau. Jo:Tsumura: Other: Belongs to joint program with Tsumura, Research Funding. Toyama:Bristol-Myers Squibb: Speakers Bureau; Eisai: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Chugai Pharmaceutical,: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Kurokawa:Ono: Research Funding, Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Teijin: Research Funding; Eisai: Research Funding, Speakers Bureau; Shire Plc: Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Bioverativ Japan: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

Underutilization of gastrointestinal prophylaxis in high-risk chronic nonsteroidal anti-inflammatory drug users in Korea.

Background The increasing use of antithrombotic therapies in older patients has led to an increased risk of gastrointestinal (GI) bleeding in chronic nonsteroidal anti-inflammatory drug (NSAID) users. Therefore, there is a pressing need for GI prophylaxis in these high-risk patients. Objective To analyze prescribing patterns and factors associated with the use of gastroprotective agents (GPAs) among high-risk, chronic NSAID users. Setting National claims database including 20% of the total Korean population aged ≥ 65years. Method In this cross-sectional study, we identified older adults prescribed traditional NSAIDs for > 90days and classified them into high- and ultra-high-risk groups if they had one or two or more GI risk factors, respectively. Proton pump inhibitors or misoprostol prescribed for more than 80% of traditional NSAID treatment days was regarded as appropriate GI prophylaxis. Main outcome measure Prevalence and associated factors with appropriate GI prophylaxis. Results Among 69,992 chronic traditional NSAID users, 38.8% and 9.4% belonged to the high and ultra-high-risk groups; 13.2% and 19.9% received appropriate GI prophylaxis, respectively. The most frequently used GPA was histamine H2 antagonists. Multiple NSAID use, concomitant antiplatelets and anticoagulants, and prior GI ulcer history increased the likelihood of receiving appropriate GI prophylaxis. Advanced age (≥ 85years), indications other than arthritis, and neurology specialists negatively affected appropriate GI prophylaxis use. Conclusion Approximately one in five chronic NSAID users, considered ultra-high risk, are prescribed appropriate GI prophylaxis in Korea. Advanced age, indications, and specialties of the prescriber all need to be considered when selecting target populations for interventions.

Correlation Among Antifactor Xa, Activated Partial Thromboplastin Time, and Heparin Dose and Association with Pediatric Extracorporeal Membrane Oxygenation Complications.

Anticoagulation is essential during extracorporeal membrane oxygenation (ECMO) to prevent catastrophic circuit clotting. Several assays exist to monitor unfractionated heparin (UFH), the most commonly used anticoagulant during ECMO, but no single test or combination of tests has consistently been proven to be superior. This retrospective observational study examines the correlation among antifactor Xa level, activated partial thromboplastin time (aPTT), and UFH dose and the association between antifactor Xa level and aPTT with survival and hemorrhagic and thrombotic complications. Sixty-nine consecutive neonatal and pediatric ECMO patients from September 2012 to December 2014 at a single institution were included. Spearman rank correlation was used to compare antifactor Xa level, aPTT, and UFH dose. Significant but poor correlation exists between antifactor Xa level and UFH dose ρ = 0.1 (p < 0.0001) and aPTT and UFH dose ρ = 0.26 (p < 0.0001). Antifactor Xa level and aPTT were weakly correlated to each other ρ = 0.38 (p < 0.0001). In an univariate analysis, there was no difference between survival and antifactor Xa level, aPTT, or UFH dose. Multiple anticoagulation tests may be superior to a single test during ECMO.

A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers

AbstractAs with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor–induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

Feline aortic thromboembolism: Presentation, diagnosis, and treatment outcomes of 15 cats.

Background:Feline aortic thromboembolism (FATE) is a fatal disease where a blood clot gets lodged into the aortic trifurcation.Methods:Fifteen cats with a sudden onset of hind limb paresis/paralysis, vocalization, and pain were admitted to the surgery clinic. A full case history was obtained and clinical, orthopedic, neurologic, radiographic, electrocardiographic, and echocardiographic examinations were performed for each cat. The treatment protocol included daily administration of multiple anticoagulant drugs with different mode of actions and meloxicam for 7 successive days. Prophylactic anticoagulant therapy (clopidogrel and acetylsalicylic acid) was continued for 6 months. All data were statistically analyzed and the correlation between time of admission and treatment outcome was tested using Pearson’s correlation coefficient.Results:The case history and clinical, orthopedic, and neurologic examinations revealed a sudden onset of hind limb paralysis (n = 12) or paresis (n = 3) associated with vocalization and pain, absence of trauma, cold and pale paws of hind limbs (n = 13, 86.7%) or cyanosed hind paws (n = 2, 13.3%), absence of femoral pulsation, shallow and rapid open-mouth respiration (61 ± 8 breaths/minutes), hypothermia (37.9°C ± 0.6°C) and tachycardia (155 ± 12 beats/minutes), with a muffled heart sound in four cats (26.7%). Radiography revealed no abnormalities in the hind limbs, pelvis, and spines, cardiomegaly in five cats (33.3%), mild pleural effusion and vascular pattern of the lung in six cats (40%), and Valentine’s heart shape in four cats (26.7%). Electrocardiography (ECG) revealed an R-wave< 0.9 mV, prolongation of QRS interval in five cats (33.3%), and conduction disturbance in four cats (26.7%). Echocardiography was consistent with hypertrophic cardiomyopathy (HCM) in five cats (33.3%). A statistically significant (p= 0.023) strong negative correlation (r= -0.6) was reported between time of admission and subsequent early treatment and recovery from clinical signs. The treatment was successful in nine cats (60%), while four cats (26.7) were euthanized and two cats (13.3%) were subjected to hind limb amputation, at the owners’ requests.Conclusion:Clinical signs, radiography, ECG, and echocardiography are valuable for diagnosis of FATE. The outcome of the multiple anticoagulants therapy depends mainly upon early diagnosis and treatment within the first 6 hours from the onset of clinical signs.

Current Strategies for the Management of Bleeding Associated with Direct Oral Anticoagulants and a Review of Investigational Reversal Agents.

The management of life-threatening bleeding in patients who are receiving direct oral anticoagulants (DOACs) is a serious medical concern. This review provides a concise, balanced overview of the current and future approaches for reversing the anticoagulation effects of DOACs, particularly factor Xa (FXa) inhibitors. The anticoagulant activity of the direct thrombin inhibitor dabigatran can be reversed by idarucizumab, but until recently, options for the management of major bleeding in patients who were receiving FXa inhibitors were limited to nonspecific strategies, including supplementation of clotting factors with prothrombin complex concentrates (PCCs) or activated PCCs for attenuating anticoagulation effects. They appear as a treatment option in many hospital guidelines despite the lack of approval by the U.S. Food and Drug Administration and the lack of rigorous medical evidence supporting their use in this setting. The development of specific reversal agents may provide improved strategies for the management of bleeding. Andexanetalfa is a modified FXa molecule approved in the United States to reverse the anticoagulant effects of FXa inhibitors (rivaroxaban and apixaban) in patients with life-threatening or uncontrolled bleeding. Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects. The current guidelines for management of DOAC-associated bleeding are being updated to reflect that the reversal agent for rivaroxaban and apixaban is now available. For other FXa inhibitors, in the absence of a reversal agent, nonspecific strategies that include PCCs are recommended. The population of patients anticoagulated with DOACs is growing, and we hope that specific reversal agents will improve the approach to management of major bleeding in this population.

Activated Clotting Times Demonstrate Weak Correlation With Heparin Dosing in Adult Extracorporeal Membrane Oxygenation.

The optimal monitoring strategy for anticoagulation management in extracorporeal membrane oxygenation (ECMO) remains a clinical controversy. The Extracorporeal Life Support Organization Anticoagulation Guidelines suggest that multiple anticoagulation assays may be needed but do not specify a preferred management strategy. In adult ECMO patients, which anticoagulation assays demonstrate the highest correlation with unfractionated heparin (UFH) dose requirements? We performed a retrospective chart review of adult patients cannulated to ECMO between February 2013 and July 2015. The primary outcome was the correlation between activated clotting time (ACT), activated partial thromboplastin time (aPTT), and anti-Xa and UFH dose. Secondary outcomes included correlations between anticoagulation assays. Correlations were calculated for the entire cohort, with subgroup analysis of venoarterial and venovenous ECMO patients. Forty-eight patients were included in the analysis, 26 initially cannulated to venoarterial ECMO and 22 to veno-venous ECMO. The median duration of ECMO therapy was 7 days. Mean UFH requirements were 1149 units/h or 15.3 units/kg/h. Total UFH dose was most correlated with anti-Xa levels (r = 0.467), whereas weight-based heparin dose was most correlated with aPTT (0.405). For correlations between anticoagulation assays, anti-Xa and aPTT were more highly correlated with each other (r = 0.633) compared with ACT. In adult patients requiring ECMO, anti-Xa and aPTT monitoring were correlated more closely with UFH dosing than ACT.

Abstract 110: Clinical Characteristics and Anticoagulant Transition Patterns of Hospitalized Patients with Venous Thromboembolism: A Retrospective Analysis Using Electronic Health Record Data

Objective: Describe the clinical characteristics and anticoagulant use of patients with venous thromboembolism (VTE) transitioning from a hospital setting using an electronic health care (EHR) database. Methods: This retrospective EHR study analyzed adults (18+ years) with a VTE diagnosis code during a hospital encounter (emergency department [ED], observation [OBS] area, or inpatient [IP] stay) between 1/1/2012-8/31/2017 (ID period). The first VTE hospital encounter (from admission to discharge) during the ID period was defined as the index VTE encounter. Patients with evidence of atrial fibrillation/flutter, pregnancy, or multiple oral anticoagulants during the index VTE encounter were excluded. Clinical characteristics and anticoagulants administered during the index VTE encounter and ordered on the discharge date were reported descriptively. Results: Among the 282,978 patients identified, the mean age (SD) age was 61 (17) years; 48% (136,155 of 282,978) were male; 78% (221,120 of 282,978) were Caucasian; 59% (167,628 of 282,978) had deep vein thrombosis without a pulmonary embolism; 18% (49,596 of 282,978) had evidence of cancer; and 7% (19,447 of 282,978) had evidence of a provoked etiology (hormonal therapy, lower extremity fracture/trauma, pelvic/orthopedic surgery) during the index VTE encounter. Nearly three-quarters (199,568 of 282,978) were admitted for an IP stay with a median length of stay of 6 days; the remaining 29% (83,410 of 282,978) were treated in an ED or OBS area only. Overall, 73% (207,640 of 282,978) were discharged home, 19% (54,283 of 282,978) were discharged to another IP facility, and 7% (21,055 of 282,978) had other or unknown discharge status. During the index VTE encounter, 67% (188,271 of 282,978) received heparin (low molecular weight or unfractionated), 34% (95,090 of 282,978) received warfarin, 12% (34,540 of 282,978) received a non-vitamin K oral anticoagulant (DOAC), and 27% (76,877 of 282,978) had no record of anticoagulant administration. Of those with heparin, 41% (76,471 of 188,271) received heparin only. More than half of those with an order for a DOAC or warfarin on the discharge date had received the same anticoagulant during the index VTE encounter, namely, 65% (22,344 of 34,540) with a DOAC during the index VTE encounter received a discharge order for a DOAC and 58% (55,369 of 95,090) with warfarin during the index VTE encounter received a discharge order for warfarin. Among those with heparin only during the index VTE encounter, approximately 18% (13,759 of 76,471) received an order for heparin, 6% (4,217 of 76,471) received an order for a DOAC, and 5% (3,810 of 76,471) received an order for warfarin on discharge. Conclusion: This EHR study observed that a sizable proportion of hospitalized patients with VTE were either prescribed a different anticoagulant on discharge or discharged without an anticoagulant prescription.