Low ectonucleotidase activity and increased neutrophil-platelet aggregates in patients with antiphospholipid syndrome.

ABSTRACT: Many patients with antiphospholipid syndrome had decreased ectonucleotidase activity on neutrophils and platelets, which enabled extracellular nucleotides to trigger neutrophil-platelet aggregates. This phenotype was replicated by treating healthy neutrophils and platelets with patient-derived antiphospholipid antibodies or ectonucleotidase inhibitors.

Prevalence of Guideline-Discordant Aspirin Use and Associated Adverse Events in Patients on Warfarin for Mechanical Valve Replacement.

BACKGROUND: For patients on warfarin for mechanical heart valve replacement, the 2020 American College of Cardiology and American Heart Association Guidelines recommend only adding aspirin in patients with a specific indication for antiplatelet therapy. This contrasts with prior guidelines, which recommended concomitant aspirin therapy. We sought to assess the prevalence of guideline-discordant aspirin use among patients on warfarin for mechanical heart valve replacement and to compare adverse event rates among patients with and without concomitant aspirin. METHODS: Patients on warfarin for mechanical heart valve replacement were identified from the Michigan Anticoagulation Quality Improvement Initiative registry. Patients with myocardial infarction, percutaneous coronary intervention, or coronary artery bypass within the past 12 months were excluded. Patients were divided into 2 groups based on aspirin use. Patient characteristics and bleeding and thromboembolic outcomes were compared. RESULTS: Four hundred forty-four patients met the inclusion criteria, with 341 (76.8%) on concomitant aspirin. The aspirin group was older (50.6 vs 46.3 years, P = .028) and had more hypertension (57.8% vs 46.6%, P = .046) but other patient characteristics were similar. The aspirin group had a higher rate of bleeding events (28.3 vs 13.3 per 100 patient-years, P < .001) and bleed-related emergency department visits (11.8 vs 2.9 per 100 patient-years, P = .001) compared with the non-aspirin group. There was no observed difference in rates of ischemic stroke (0.56 vs 0.48 per 100 patient-years, P = .89). CONCLUSIONS: A significant proportion of patients on warfarin for mechanical heart valve replacement are on guideline-discordant aspirin. Aspirin deprescribing in select patients may safely reduce bleeding events.

Calprotectin Impairs Platelet Survival in Patients With Primary Antiphospholipid Syndrome.

OBJECTIVE: While thrombosis and pregnancy loss are the best-known clinical features of antiphospholipid syndrome (APS), many patients also exhibit "extra-criteria" manifestations, such as thrombocytopenia. The mechanisms that drive APS thrombocytopenia are not completely understood, and no clinical biomarkers are available for predicting antiphospholipid antibody (aPL)-mediated thrombocytopenia. Calprotectin is a heterodimer of S100A8 and S100A9 that is abundant in the neutrophil cytoplasm and released upon proinflammatory neutrophil activation. Here, we sought to evaluate the presence, clinical associations, and potential mechanistic roles of circulating calprotectin in a cohort of primary APS and aPL-positive patients. METHODS: Levels of circulating calprotectin were determined in plasma by the QUANTA Flash chemiluminescent assay. A viability dye-based platelet assay was used to assess the potential impact of calprotectin on aPL-mediated thrombocytopenia. RESULTS: Circulating calprotectin was measured in 112 patients with primary APS and 30 aPL-positive (without APS criteria manifestations or lupus) patients as compared to patients with lupus (without APS), patients with unprovoked venous thrombosis (without aPL), and healthy controls. Levels of calprotectin were higher in patients with primary APS and aPL-positive patients compared to healthy controls. After adjustment for age and sex, calprotectin level correlated positively with absolute neutrophil count (r = 0.41, P < 0.001), positively with C-reactive protein level (r = 0.34, P = 0.002), and negatively with platelet count (r = -0.24, P = 0.004). Mechanistically, we found that calprotectin provoked aPL-mediated thrombocytopenia by engaging platelet surface toll-like receptor 4 and activating the NLRP3-inflammasome, thereby reducing platelet viability in a caspase-1-dependent manner. CONCLUSION: These data suggest that calprotectin has the potential to be a functional biomarker and a new therapeutic target for APS thrombocytopenia.

Development and validation of a risk model for hospital-acquired venous thrombosis: the Medical Inpatients Thrombosis and Hemostasis study.

BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race. CONCLUSION: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.

Accuracy of Electronic Health Record-Documented Aspirin for Primary Prevention in Adult Outpatients.

This quality improvement study examines the accuracy of electronic health record (EHR) documentation of aspirin use for primary prevention of atherosclerotic cardiovascular disease in adult outpatients.

Assessment of an Intervention to Reduce Aspirin Prescribing for Patients Receiving Warfarin for Anticoagulation.

Importance: For some patients receiving warfarin, adding aspirin (acetylsalicylic acid) increases bleeding risk with unclear treatment benefit. Reducing excess aspirin use could be associated with improved clinical outcomes. Objective: To assess changes in aspirin use, bleeding, and thrombosis event rates among patients treated with warfarin. Design, Setting, and Participants: This pre-post observational quality improvement study was conducted from January 1, 2010, to December 31, 2019, at a 6-center quality improvement collaborative in Michigan among 6738 adults taking warfarin for atrial fibrillation and/or venous thromboembolism without an apparent indication for concomitant aspirin. Statistical analysis was conducted from November 26, 2020, to June 14, 2021. Intervention: Primary care professionals for patients taking aspirin were asked whether an ongoing combination aspirin and warfarin treatment was indicated. If not, then aspirin was discontinued with the approval of the managing clinician. Main Outcomes and Measures: Outcomes were assessed before and after intervention for the primary analysis and before and after 24 months before the intervention (when rates of aspirin use first began to decrease) for the secondary analysis. Outcomes included the rate of aspirin use, bleeding, and thrombotic outcomes. An interrupted time series analysis assessed cumulative monthly event rates over time. Results: A total of 6738 patients treated with warfarin (3160 men [46.9%]; mean [SD] age, 62.8 [16.2] years) were followed up for a median of 6.7 months (IQR, 3.2-19.3 months). Aspirin use decreased slightly from a baseline mean use of 29.4% (95% CI, 28.9%-29.9%) to 27.1% (95% CI, 26.1%-28.0%) during the 24 months before the intervention (P < .001 for slope before and after 24 months before the intervention) with an accelerated decrease after the intervention (mean aspirin use, 15.7%; 95% CI, 14.8%-16.8%; P = .001 for slope before and after intervention). In the primary analysis, the intervention was associated with a significant decrease in major bleeding events per month (preintervention, 0.31%; 95% CI, 0.27%-0.34%; postintervention, 0.21%; 95% CI, 0.14%-0.28%; P = .03 for difference in slope before and after intervention). No change was observed in mean percentage of patients having a thrombotic event from before to after the intervention (0.21% vs 0.24%; P = .34 for difference in slope). In the secondary analysis, reducing aspirin use (starting 24 months before the intervention) was associated with decreases in mean percentage of patients having any bleeding event (2.3% vs 1.5%; P = .02 for change in slope before and after 24 months before the intervention), mean percentage of patients having a major bleeding event (0.31% vs 0.25%; P = .001 for change in slope before and after 24 months before the intervention), and mean percentage of patients with an emergency department visit for bleeding (0.99% vs 0.67%; P = .04 for change in slope before and after 24 months before the intervention), with no change in mean percentage of patients with a thrombotic event (0.20% vs 0.23%; P = .36 for change in slope before and after 24 months before the intervention). Conclusions and Relevance: This quality improvement intervention was associated with an acceleration of a preexisting decrease in aspirin use among patients taking warfarin for atrial fibrillation and/or venous thromboembolism without a clear indication for aspirin therapy. Reductions in aspirin use were associated with reduced bleeding. This study suggests that an anticoagulation clinic-based aspirin deimplementation intervention can improve guideline-concordant aspirin use.

A survey of internists' recommendations for aspirin in older adults and barriers to evidence-based use.

Recent trials suggest that aspirin for primary prevention may do more harm than good for some, including adults over 70 years of age. We sought to assess how primary care providers (PCPs) use aspirin for the primary prevention in older patients and to identify barriers to use according to recent guidelines, which recommend against routine use in patients over age 70. We surveyed PCPs about whether they would recommend aspirin in clinical vignettes of a 75-year-old patient with a 10-year atherosclerotic cardiovascular disease risk of 25%. We also queried perceived difficulty following guideline recommendations, as well as perceived barriers and facilitators. We obtained responses from 372 PCPs (47.9% response). In the patient vignette, 45.4% of clinicians recommended aspirin use, which did not vary by whether the patient was using aspirin initially (p = 0.21); 41.7% believed aspirin was beneficial. Perceived barriers to guideline-based aspirin use included concern about patients being upset (41.6%), possible malpractice claims (25.0%), and not having a strategy for discussing aspirin use (24.5%). The estimated adjusted probability of rating the guideline as "hard to follow" was higher in clinicians who believed aspirin was beneficial (29.4% vs. 8.0%; p < 0.001) and who worried the patient would be upset if told to stop aspirin (26.7% vs. 12.5%; p = 0.001). Internists vary considerably in their recommendations for aspirin use for primary prevention in older patients. A high proportion of PCPs continue to believe aspirin is beneficial in this setting. These results can inform de-implementation efforts to optimize evidence-based aspirin use.

Update on Guidelines for the Prevention of Cancer-Associated Thrombosis.

Patients with cancer are at high risk of developing arterial and venous thromboembolism (VTE). They constitute 15% to 20% of the patients diagnosed with VTE. Depending on the type of tumor, cancer therapy, and presence of other risk factors, 1% to 25% of patients with cancer will develop thrombosis. The decision to start patients with cancer on primary thromboprophylaxis depends on patient preference, balancing risk of bleeding versus risk of thrombosis, cost, and adequate organ function. Currently, guidelines recommend against the use of routine primary thromboprophylaxis in unselected ambulatory patients with cancer. Validated risk assessment models can accurately identify patients at highest risk for cancer-associated thrombosis (CAT). This review summarizes the recently updated NCCN Guidelines for CAT primary prophylaxis, with a primarily focus on VTE prevention. Two main clinical questions that providers commonly encounter will also be addressed: which patients with cancer should receive primary thromboprophylaxis (both surgical and medical oncology patients) and how to safely choose between different anticoagulation agents.

Factors Associated With Inferior Vena Cava Filter Placement and Retrieval for Patients With Cancer-Associated Thrombosis.

BACKGROUND: Venous thromboembolism is a leading cause of death in patients with cancer. Inferior vena cava filters are utilized to mitigate the risk of pulmonary embolism for patients who have contraindication to, or failure of, anticoagulation. METHODS: We reviewed an insurance claims database to identify adults receiving cancer-directed therapy and had a new diagnosis of venous thromboembolism. We then evaluated clinical and sociodemographic characteristics in patients with and without filter placement and retrieval. RESULTS: There were 25,788 patients (mean [SD] age: 68.3 [12.7] years) who met the study inclusion criteria, with 2111 individuals (8.2%) undergoing filter placement. Filter placement was associated with the type of thrombosis, malignancy, recent surgery, comorbidities, and income. A total of 137 patients (6.5%) newly started anticoagulation within 3 days of filter placement, and 612 (29%) patients received anticoagulation within 30 days after filter placement. Despite this, only 159 (7.5%) patients had their filters retrieved during the study period. Patients with income of $75-99K (odds ratio 2.13, P = .012) or above $100K (odds ratio 1.8, P = .038) were more likely to have filter retrieval compared with those with income <$50K. Filter retrieval was also more likely in younger patients and those with fewer comorbidities or without central nervous system or lung malignancies. CONCLUSIONS: Inferior vena cava filter placement and retrieval are associated with several sociodemographic factors. Filter retrieval rates are low despite re-initiation of anticoagulation in many patients. Efforts are needed to address disparities in filter use and improve retrieval rates.

How to Choose An Appropriate Anticoagulant for Cancer-Associated Thrombosis.

Venous thromboembolic disease can be a fatal complication of cancer. Despite advances in prevention, thousands of patients require treatment of cancer-associated thrombosis (CAT) each year. Guidelines have advocated low-molecular-weight heparin (LMWH) as the preferred anticoagulant for CAT for years, based on clinical trial data showing LMWH to be associated with a lower risk of recurrent thrombosis when compared with vitamin K antagonists. However, the potentially painful, subcutaneously administered LMWH injections can be expensive, and clinical practice has not been consistent with guideline recommendations. Recently, studies have compared LMWH to the direct oral anticoagulants (DOACs) for the management of CAT. Based on promising trial results outlined in this review, DOACs are now preferred anticoagulants for CAT occurring in patients without gastric or gastroesophageal lesions. For patients with gastrointestinal cancers, who may be at higher risk of hemorrhage with the DOACs, LMWH remains the anticoagulant of choice. Applying the latest data from this rapidly evolving field to care for diverse patient groups can be challenging. This article provides an evidence-based review of outpatient anticoagulant selection for lower-extremity deep vein thrombosis or pulmonary embolism in the setting of cancer, and takes into account special populations with cancer.

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication.

Importance: It is unclear how many patients treated with a direct oral anticoagulant (DOAC) are using concomitant acetylsalicylic acid (ASA, or aspirin) and how this affects clinical outcomes. Objective: To evaluate the frequency and outcomes of prescription of concomitant ASA and DOAC therapy for patients with atrial fibrillation (AF) or venous thromboembolic disease (VTE). Design, Setting, and Participants: This registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019. Eligible participants were adults undergoing treatment with a DOAC for AF or VTE, without a recent myocardial infarction (MI) or history of heart valve replacement, with at least 3 months of follow-up. Exposures: Use of ASA concomitant with DOAC therapy. Main Outcomes and Measures: Rates of bleeding (any, nonmajor, major), rates of thrombosis (stroke, VTE, MI), emergency department visits, hospitalizations, and death. Results: Of the study cohort of 3280 patients (1673 [51.0%] men; mean [SD] age 68.2 [13.3] years), 1107 (33.8%) patients without a clear indication for ASA were being treated with DOACs and ASA. Two propensity score-matched cohorts, each with 1047 patients, were analyzed (DOAC plus ASA and DOAC only). Patients were followed up for a mean (SD) of 20.9 (19.0) months. Patients taking DOAC and ASA experienced more bleeding events compared with DOAC monotherapy (26.0 bleeds vs 31.6 bleeds per 100 patient years, P = .01). Specifically, patients undergoing combination therapy had significantly higher rates of nonmajor bleeding (26.1 bleeds vs 21.7 bleeds per 100 patient years, P = .02) compared with DOAC monotherapy. Major bleeding rates were similar between the 2 cohorts. Thrombotic event rates were also similar between the cohorts (2.5 events vs 2.3 events per 100 patient years for patients treated with DOAC and ASA compared with DOAC monotherapy, P = .80). Patients were more often hospitalized while undergoing combination therapy (9.1 vs 6.5 admissions per 100 patient years, P = .02). Conclusion and Relevance: Nearly one-third of patients with AF and/or VTE who were treated with a DOAC received ASA without a clear indication. Compared with DOAC monotherapy, concurrent DOAC and ASA use was associated with increased bleeding and hospitalizations but similar observed thrombosis rate. Future research should identify and deprescribe ASA for patients when the risk exceeds the anticipated benefit.

Clinical and sociodemographic factors associated with anticoagulant use for cancer associated venous thromboembolism.

Cancer associated thrombosis (CAT) is a leading cause of death among patients with cancer. It is not clear if non-clinical factors are associated with anticoagulation receipt. We conducted a retrospective cohort study of Optum's de-identified Clinformatics® Database of adults with cancer diagnosed between 2009 and 2016 who developed CAT, treated with an outpatient anticoagulant (warfarin, low molecular weight heparin (LMWH), or a direct oral anticoagulant (DOAC)). Of 12,622 patients, three months after an episode of CAT, 1,485 (12%) were on LMWH, 1,546 (12%) on DOACs, and 9,591 (76%) were on warfarin. When controlling for other factors, anticoagulant use was significantly associated with socioeconomic factors, region, co-morbidities, type of thrombosis, and cancer subtype. Patients with a bachelor's degree or greater level of education were less likely to receive warfarin (OR: 0.77; 95% CI: [0.59, 0.99]; p < 0.046) or DOACs (OR: 0.67; 95% CI: [0.55, 0.82]; p < 0.001) compared to LMWH. Patients with higher income levels were more likely to receive LMWH or DOACs compared to warfarin, while patients across all income levels were equally likely to receive LMWH or DOACs. Non-clinical factors including income, education, and region, are associated with anticoagulation receipt three months after an episode of CAT. Sociodemographic factors may result in some patients receiving suboptimal care and contribute to non-guideline concordant care for CAT.

A provider's guide to primary myelofibrosis: pathophysiology, diagnosis, and management.

Although understanding of the pathogenesis and molecular biology of primary myelofibrosis continues to improve, treatment options are limited, and several biological features remain unexplained. With an appropriate clinical history, exam, laboratory evaluation, and bone marrow biopsy, the diagnosis can often be established. Recent studies have better characterized prognostic factors and driver mutations in myelofibrosis, facilitated by use of next-generation sequencing. These advances have facilitated development of a management strategy that is based on both risk factors and clinical phenotype. For low-risk patients, treatment will depend on symptom severity. For patients with higher-risk disease, several treatments are available including JAK inhibitors, allogeneic hematopoietic stem cell transplant, and clinical trials using novel molecularly targeted therapies and rational drug combinations. In this review, we outline what is known about the disease pathogenesis, discuss an approach to reaching the diagnosis, review the prognosis of myelofibrosis, and detail current therapeutic strategies.

Anticoagulant medication adherence for cancer-associated thrombosis: A comparison of LMWH to DOACs.

Essentials It is not clear if patients are less adherent to low molecular weight heparin (LMWH) compared to direct oral anticoagulants (DOACs) for cancer-associated thrombosis (CAT). We evaluated medication adherence among two propensity-matched groups of patients with CAT by comparing the proportion of days covered (PDC). Median treatment persistence on DOACs was more than 80 days longer than LMWH. Medication adherence was high (~95%) and was similar with LMWH compared to DOACs. ABSTRACT: Background Low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs) are used to treat cancer-associated thrombosis (CAT). It is not clear if patients are less adherent to LMWH compared to DOACs. Objectives To compare medication persistence and adherence between LMWH and DOACs. Patients/Methods We analyzed Optum's de-identified Clinformatics® Data Mart Database of privately insured adults with cancer diagnosed between January 2009 and October 2015 who were undergoing chemotherapy, immunotherapy, targeted or hormonal therapies; developed CAT; and were treated with an outpatient anticoagulant. The proportion of days covered (PDC) was calculated from the date of anticoagulant prescription until the anticoagulant was switched, stopped, or the study end. Medication adherence was defined as PDC ≥ 80%, ≥95%, and by comparing the mean PDC. Results Two propensity-matched groups of 1128 patients were identified. Patient persistence was higher with DOACs compared to LMWH (median 116 days versus 34 days). With adherence defined as PDC ≥ 80%, we found no significant difference (95.6% versus 94.6% adherence with DOACs versus LMWH, P = .33). The mean difference of PDC between the two groups was also similar. With medication adherence defined as PDC ≥ 95%, adherence was evident in 73% of DOAC users and 81% of patients on LMWH (P < .001). Prescription copayments were higher on average for LMWH compared to DOACs (mean $153.61 versus 40.67; standard deviation $306.74 versus $33.11). Conclusion Patients remain on DOACs longer than LMWH, but medication adherence is similar with LMWH.

Pure erythroid leukemia.

The diagnosis of pure erythroid leukemia (PEL) can be challenging. Prompt identification of CD45+, CD34-, CD71+, CD117+, and E-cadherin+ erythroblasts is important. The differential diagnosis is broad and includes megaloblastic anemia.