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Immune TTP (iTTP) survivors have increased risk of cardiovascular disease including stroke, and report persistent cognitive difficulties during remission. We conducted this prospective study of iTTP survivors in clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neuro-deficits, during clinical remission. We also tested the hypothesis that SCI is associated with cognitive impairment assessed using the NIH ToolBox cognition battery. We used fully corrected T scores adjusted for age, sex, race, and education. Based on DSM-5 criteria, we defined mild and major cognitive impairment as T-scores that are 1-2 SD and > 2 SD below the mean on at least one test, respectively. Forty-two patients have been enrolled, with 36 completing MRI.SCI was present in 50% (18) , of which 8 (44.4%) had prior overt stroke including during acute iTTP. Patients with SCI had higher rates of cognitive impairment (66.7% vs. 27.7%, P=0.026) including major cognitive impairment (50% vs. 5.6%, P=0.010). In separate logistic regression models, SCI was associated with any (mild or major) cognitive impairment [OR 10.5 (95% CI 1.45 - 76.63); P = 0.020] and major cognitive impairment [OR 7.98 (95% CI 1.11 - 57.27); P = 0.039] after adjusting for history of stroke and Beck depression inventory scores. In summary, MRI evidence of brain infarction is common in iTTP survivors; the strong association of SCI with impaired cognition suggests that these 'silent' infarcts are neither silent nor innocuous.

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.

The 4Ts and HIT-Expert Probability (HEP) scoring tools for heparin-induced thrombocytopenia (HIT) have not been validated in cardiac surgery patients, and the reported sensitivity and specificity of the Post-Cardiopulmonary Bypass (CPB) scoring tool vary widely in the 2 available analyses. It remains unclear which of the available scoring tools most accurately predicts HIT in this population. Forty-nine HIT-positive patients who underwent on-pump cardiac surgery within a 6-year period were loosely matched to 98 HIT-negative patients in a 1:2 case-control design. The 4Ts, HEP, and CPB scores were calculated for each patient. Sensitivity and specificity of each tool were calculated using standard cut-offs. The Youden method was utilized to determine optimal cut-offs within receiver operating characteristic (ROC) curves of each score, after which sensitivities and specificities were recalculated. Using standard cut-offs, the sensitivities for the CPB, HEP, and 4Ts scores were 100%, 93.9%, and 69.4%, respectively. Specificities were 51%, 49%, and 71.4%, respectively. The AUC of the scoring tool ROC curves were 0.961 for the CPB score, 0.773 for the HEP score, and 0.805 for the 4Ts score. Using the Youden method-derived optimal cut-off of ≥3 points on the CPB score, sensitivity remained 100% with improved specificity to 88.9%. The CPB score is the preferred HIT clinical scoring tool in adult cardiac surgery patients, whereas the 4Ts score performed less effectively. A cut-off of ≥ 3 points on the CPB score could increase specificity while preserving high sensitivity, which should be validated in a prospective evaluation.

Acquired von Willebrand disease (aVWD) is a rare disorder associated with a reduction in von Willebrand factor (VWF) activity, leading to increased bleeding risk. Monoclonal gammopathy of undetermined significance (MGUS) is the most common cause of lymphoproliferative disorder-associated aVWD and is caused by accelerated clearance of circulating VWF. Standard VWF replacement protocols for congenital VWD based on intermittent bolus dosing are typically less effective for aVWD because of antibody-mediated clearance. Intermittent bolus dosing of VWF concentrates often leads to inadequate peak response and profoundly shortened VWF half-life in aVWD. Intravenous immune globulin (IVIG) has demonstrated efficacy in aVWD; however, treatment effect is delayed up to 4 days, limiting its efficacy in acutely bleeding patients. We report the successful use of continuous-infusion VWF concentrate (with or without concomitant IVIG) in 3 patients with MGUS-associated aVWD who had demonstrated an inadequate response to bolus dosing. VWF concentrate doses required in this cohort were higher than typical doses for bleeding treatment in congenital VWD. This report illustrates that continuous-infusion VWF concentrate administration with or without intravenous immunoglobulin rapidly achieves target ristocetin cofactor activity and provides adequate hemostasis in aVWD associated with immunoglobulin G MGUS.

BACKGROUND AND OBJECTIVES Health services research often relies on readily available data, originally collected for administrative purposes and used for public reporting and pay-for-performance initiatives. We examined the prevalence of underreporting of diagnostic procedures for acute myocardial infarction (AMI), deep venous thrombosis (DVT), and pulmonary embolism (PE), used for public reporting and pay-for-performance initiatives. METHOD We retrospectively identified procedures for AMI, DVT, and PE in the National Inpatient Sample (NIS) database between 2012 and 2016. From January 1, 2012, through September 30, 2015, the NIS used the International Classification of Diseases, Ninth Revision (ICD-9) coding scheme. From October 1, 2015, through December 31, 2016, the NIS used the International Classification of Diseases, Tenth Revision (ICD-10) coding scheme. We grouped the data by ICD code definitions (ICD-9 or ICD-10) to reflect these code changes and to prevent any confounding or misclassification. In addition, we used survey weighting to examine the utilization of venous duplex ultrasound scan for DVT, electrocardiogram (ECG) for AMI, and chest computed tomography (CT) scan, pulmonary angiography, echocardiography, and nuclear medicine ventilation/perfusion () scan for PE. RESULTS In the ICD-9 period, by primary diagnosis, only 0.26% (n = 5930) of patients with reported AMI had an ECG. Just 2.13% (n = 7455) of patients with reported DVT had a peripheral vascular ultrasound scan. For patients with PE diagnosis, 1.92% (n = 12 885) had pulmonary angiography, 3.92% (n = 26 325) had CT scan, 5.31% (n = 35 645) had cardiac ultrasound scan, and 0.45% (n = 3025) had scan. In the ICD-10 period, by primary diagnosis, 0.04% (n = 345) of reported AMI events had an ECG and 0.91% (n = 920) of DVT events had a peripheral vascular ultrasound scan. For patients with PE diagnosis, 2.08% (n = 4805) had pulmonary angiography, 0.63% (n = 1460) had CT scan, 1.68% (n = 3890) had cardiac ultrasound scan, and 0.06% (n = 140) had scan. Small proportions of diagnostic procedures were observed for any diagnoses of AMI, DVT, or PE. CONCLUSIONS Our findings question the validity of using NIS and other administrative databases for health services and outcomes research that rely on certain diagnostic procedures. Unfortunately, the NIS does not provide granular data that can control for differences in diagnostic procedure use, which can lead to surveillance bias. Researchers and policy makers must understand and acknowledge the limitations inherent in these databases, when used for pay-for-performance initiatives and hospital benchmarking.

Evidence suggests that an apixaban-based strategy to treat acute venous thromboembolism (VTE) in patients with End-Stage Kidney Disease (ESKD) may be safer than a warfarin-based strategy. Apixaban has an additional advantage of not requiring bridging with heparin which often necessitates long hospitalizations for patients with ESKD. We sought to determine if an apixaban-based strategy is associated with less healthcare utilization than a warfarin-based strategy.We employed a new-user, active-comparator retrospective cohort study using inverse probability of treatment weights (IPTW) to adjust for confounding demographic and clinical variables. Patients with ESKD newly initiated on either apixaban or warfarin for an acute VTE between 2014 and 2018 in the United States Renal Data System were included. Outcomes were presence of index hospitalization, length of index hospitalization, total hospital days, total hospital days excluding index hospitalization, total emergency department (ED) visits that did not result in hospitalization, and total skilled nursing facility days.At six months, patients who received apixaban were less likely to have an index hospitalization, had a shorter index hospitalization (median of 4.0 vs 8.0 days, p 0.001), and had fewer total hospital days. The IPTW and index year-adjusted incidence rate ratios of total hospital days at one, three, and six months were 0.83 (95 % confidence intervals (CI) 0.79-0.86), 0.84 (95 % CI 0.81-0.88), and 0.88 (95 % CI 0.83-0.92) for apixaban compared to warfarin.Among patients with ESKD and VTE, resource utilization for an apixaban-based strategy appears to be lower than for a warfarin-based strategy.

Background An antithrombotic stewardship program was implemented to reduce IV DTI use and increase fondaparinux and direct oral anticoagulant (DOAC) use for suspected or confirmed Heparin-induced thrombocytopenia (HIT). Objectives This study evaluated the impact of an antithrombotic stewardship program on IV DTI utilization in patients with HIT. Methods A retrospective analysis of adults receiving IV DTIs or fondaparinux from July 2016 to July 2017 (pre-stewardship) and October 2017 to July 2019 (post-stewardship) was conducted. Results The median duration of IV DTI administration was not significantly different in HIT-negative patients between the pre- and post-stewardship cohorts (1.6 days (25th percentile (p25), 75th percentile (p75): .5, 3.3) vs 1.7 days (p25, p75: .9, 3.9), P = .31). The median duration of IV DTI administration in HIT-positive patients was 9.9 days (p25, p75: 7.6, 21.0) pre-stewardship and 7.3 days (p25, p75: 4.8, 16.5) post-stewardship ( P = .18). For HIT-positive patients, the time from HIT diagnosis to discharge was 12.8 days (p25, p75: 8.9, 24.9) and 9.2 days (p25, p75: 4.0, 18.1) in the pre- and post-stewardship cohorts, respectively ( P = .07). Fondaparinux and DOAC prescribing rates were 40.7% and 62.2% in the pre- and post-stewardship cohorts, respectively ( P = .09). The percentage of patients with no contraindications to IV DTI alternatives receiving these agents increased from 31.2% to 78.6% ( P = .01) following stewardship implementation. Conclusions Intravenous DTI alternative utilization increased significantly after stewardship implementation. Stewardship implementation was associated with a non-statistically significant trend towards decreased IV DTI utilization and decreased length of stay for HIT-positive patients.

Patients with end-stage kidney disease (ESKD) are at significantly increased risk for both thrombosis and bleeding relative to those with normal renal function. The optimal therapy of venous thromboembolism (VTE) in patients with ESKD is unknown.To compare the safety and effectiveness of apixaban relative to warfarin in patients with ESKD and acute VTE.New-user, active-comparator retrospective United States population-based cohort with inverse probability of treatment weighting, using the United States Renal Data System data from 2014 to 2018. We included adults with ESKD on hemodialysis or peritoneal dialysis who were newly initiated on apixaban or warfarin for an acute VTE.The coprimary outcomes were major bleeding, recurrent VTE, and all-cause mortality within 6 months of anticoagulant initiation. Secondary outcomes were intracranial hemorrhage and gastrointestinal bleeding. The primary analyses were based on intent-to-treat defined by the first drug received and accounted for competing risks of death. Sensitivity analyses included varied follow-up time, as-treated analyses, and dose-specific apixaban subgroups.The apixaban and warfarin cohorts included 2302 and 9263 patients, respectively. Apixaban was associated with a lower risk of major bleeding (hazard ratio [HR] 0.81, 95% confidence interval [CI]: 0.70-0.94), intracranial bleeding (HR 0.69, 95% CI 0.48-0.98), and gastrointestinal bleeding (HR 0.82, 95% CI 0.69-0.96). Recurrent VTE and all-cause mortality were not significantly different between the groups.Apixaban was associated with a lower risk of bleeding relative to warfarin when used to treat acute VTE in patients with ESKD on dialysis.

Background: During pregnancy and in the postpartum period women are at increased risk of venous thromboembolism (VTE) owing to hypercoagulability and mechanical issues, as well as nonpregnancy conditions including inherited and acquired thrombophilia. Although guidelines exist for the use of thromboprophylaxis in this setting, there are differences in the specifics of the recommendations among expert societies. We assessed the current practice patterns of North American providers in the prevention of pregnancy-associated VTE in women with thrombophilia. Methods: A survey was created and distributed with case studies and questions addressing VTE prevention during the antepartum and postpartum periods. Results: Surveys were completed by 28% of adult providers queried, with broad geographic representation. There was consistent use of a prophylactic dose of low-molecular weight heparin (LMWH) ante- and postpartum for individuals with low-risk thrombophilia and past estrogen-provoked VTE but a lack of a consensus of anticoagulant (AC) use and dose in individuals with higher risk thrombophilia. There was variability in the dose selection and monitoring of AC when using induction versus spontaneous labor, with 47% of providers switching from LMWH to unfractionated heparin for those not having a scheduled delivery, and there were differences in the duration of postpartum prophylaxis based upon delivery mode. Conclusion: In this survey of North American experienced specialists' responses to a variety of commonly encountered scenarios of thrombophilia and pregnancy and the management of AC were not always consistent with published guidelines.

Aims Patients with cancer are at high risk of venous thromboembolism (VTE), which entails a high economic burden. The risk of cancer-associated VTE can be assessed using the Khorana score (KS), a validated VTE risk prediction algorithm. This study compared healthcare costs associated with different KS in a population of patients newly diagnosed with cancer. Methods The Optum® Clinformatics® DataMart database (01/01/2012-09/30/2017) was used to select adult patients with ≥1 hospitalization or ≥2 outpatient claims with a cancer diagnosis (index date) initiated on systemic therapy or radiation therapy. Patients were classified in mutually exclusive cohorts based on KS (i.e., KS =0, 1, 2 or ≥3). The observation period spanned from index to the earliest among end of data availability, death, end of insurance coverage, or 12 months. Results In total 6,194 patients (KS =0: 2,488; KS =1: 2,125; KS =2: 1,074; KS ≥3: 507) were included. On average, patients were aged 68 years, 48-52% were female, and the Quan-Charlson comorbidity index ranged between 1.1 and 1.4. Over the observation period, all-cause total healthcare costs per patient per month (PPPM) were $8,826 (KS =0), $11,598 (KS =1), $14,028 (KS =2), and $16,211 (KS ≥3). Using the KS =0 cohort as reference, adjusted PPPM costs were $2,506, $4,775, and $6,452 higher in the KS =1, KS =2 cohort, and KS ≥3 cohorts, respectively. Hospitalization and outpatient costs were the main drivers of these differences. Similar results were found for VTE-related costs, which represented 4-11% of the total all-cause cost difference between KS cohorts. Limitations Residual confounders; results may not be generalized to patients with other insurance plans or those who received treatments other than systemic therapy or radiation therapy. Conclusions This real-world analysis found that cancer patients at higher risk of VTE (based on KS) incurred significantly greater all-cause and VTE-related healthcare costs compared with cancer patients at lower risk of VTE.

Evidence regarding the safety and efficacy of anticoagulant thromboprophylaxis among pediatric patients hospitalized for coronavirus disease 2019 (COVID-19) is limited. We sought to evaluate safety, dose-finding, and preliminary efficacy of twice-daily enoxaparin as primary thromboprophylaxis among children hospitalized for symptomatic COVID-19, including primary respiratory infection and multisystem inflammatory syndrome in children (MISC).We performed a phase 2, multicenter, prospective, open-label, single-arm clinical trial of twice-daily enoxaparin (initial dose: 0.5mg/kg per dose; max: 60mg; target anti-Xa activity: 0.20-0.49IU/mL) as primary thromboprophylaxis for children18 years of age hospitalized for symptomatic COVID-19. Study endpoints included: cumulative incidence of International Society of Thrombosis and Haemostasis-defined clinically relevant bleeding; enoxaparin dose-requirements; and cumulative incidence of venous thromboembolism within 30-days of hospital discharge. Descriptive statistics summarized endpoint estimates that were further evaluated by participant age (±12 years) and clinical presentation.Forty children were enrolled and 38 met analyses criteria. None experienced clinically relevant bleeding. Median (interquartile range) dose to achieve target anti-Xa levels was 0.5 mg/kg (0.48-0.54). Dose-requirement did not differ by age (0.5 [0.46-0.52] mg/kg for age ≥12 years versus 0.52 [0.49-0.55] mg/kg for age12 years, P = .51) but was greater for participants with MISC (0.52 [0.5-0.61] mg/kg) as compared with primary COVID-19 (0.48 [0.39-0.51] mg/kg, P = .010). Two children (5.3%) developed central-venous catheter-related venous thromboembolism. No serious adverse events were related to trial intervention.Among children hospitalized for COVID-19, thromboprophylaxis with twice-daily enoxaparin appears safe and warrants further investigation to assess efficacy.

Cancer-associated thrombosis (CAT) is a major cause of morbidity and mortality in patients with cancer. Over the past 2 decades, enormous advances have been made in the management of CAT. The growing evidence base informing practice has led to the publication of a number of guidelines and guidance documents on the diagnosis and treatment of CAT. The goal of this review is to examine the latest versions of evidence-based guidelines, highlighting the differences and similarities in their methodology, their disease-specific content, and recommendations for management. Our analysis shows that for most clinical topics, the different guidelines provide roughly similar management advice. However, there are a number of important clinical topics in CAT that are not currently covered by the existing guidelines. We think inclusion of these topics in future versions of the guidelines will facilitate ongoing efforts to optimize the care of patients with CAT. Implications for Practice Cancer-associated thrombosis (CAT) is a common complication in patients with cancer. This review examines the differences and similarities of the current CAT guidelines methods and recommendations. Current guidelines largely agree on many aspects of CAT management. However, there are a number of topics in CAT that are not currently included in guidelines where evidence-based guidance would be very helpful for clinicians. Coverage of these topics in future guidelines is encouraged to optimize clinical practice.

As the Coronavirus disease 2019 (COVID-19) pandemic spread to the US, so too did descriptions of an associated coagulopathy and thrombotic complications. Hospitals created institutional protocols for inpatient management of COVID-19 coagulopathy and thrombosis in response to this developing data. We collected and analyzed protocols from 21 US academic medical centers developed between January and May 2020. We found greatest consensus on recommendations for heparin-based pharmacologic venous thromboembolism (VTE) prophylaxis in COVID-19 patients without contraindications. Protocols differed regarding incorporation of D-dimer tests, dosing of VTE prophylaxis, indications for post-discharge pharmacologic VTE prophylaxis, how to evaluate for VTE, and the use of empiric therapeutic anticoagulation. These findings support ongoing efforts to establish international, evidence-based guidelines., Highlights • COVID-19 protocols agreed on heparin-based venous thromboembolism prophylaxis. • Disagreement on thrombosis risk and diagnosis, D-dimer, empiric anticoagulation • Cumulative incidence of COVID-19 did not correlate with specific recommendations. • Framework for frontline providers and hospitals to evaluate practices and outcomes

Background Venous thromboembolism (VTE) is a leading cause of preventable harm in hospitalized patients. However, many doses of prescribed pharmacologic VTE prophylaxis are frequently missed. We investigated the effect of a patient-centered education bundle on missed doses of VTE prophylaxis in a community hospital. Methods We performed a pre-post analysis examining missed doses of VTE prophylaxis in a community hospital. A real-time alert from the electronic health record system facilitated the delivery of a patient education bundle intervention. We included all patient visits on a single floor where at least 1 dose of VTE prophylaxis was prescribed during pre- (January 1, 2018, - November 31, 2018) and post- (January 1 - June 31, 2019) intervention periods. Outcomes included any missed dose (primary) and reasons for missed doses (refusal, other [secondary]) and were compared between both periods. Results 1,614 patient visits were included. The proportion of any missed dose significantly decreased (13.8% vs. 8.2% [OR, 0.56; 95% CI, 0.48, 0.64]) between the pre-post intervention periods. Patient refusal was the most frequent reason for missed doses. In the post-intervention period, patient refusal significantly decreased from 8.8% to 5.0% (OR, 0.54; 95% CI, 0.46, 0.64). Similarly, other reasons for missed doses significantly decreased from 5.0% to 3.2% (OR, 0.62; 95% CI, 0.51, 0.77). Conclusions A real-time alert-triggered patient-centered education bundle developed and tested in an academic hospital, significantly reduced missed doses of prescribed pharmacologic VTE prophylaxis when disseminated to a community hospital.

Background The Khorana score (KS) clinical algorithm is used to predict VTE risk in cancer patients. The study objective was to evaluate VTE and survival rates among patients newly diagnosed with cancer and stratified by KS in a real‐world population. Methods Data from the Optum® Clinformatics® DataMart database between 01/01/2012–09/30/2017 was used to identify adults with ≥ 1 hospitalization or ≥ 2 outpatient claims with a cancer diagnosis (index date). Only patients who were initiated on chemotherapy or radiation therapy were included. Patients were classified based on KS (KS = 0, 1, 2 or ≥ 3). Time‐to‐first VTE and survival were evaluated from the index date to the earliest among end of data availability or insurance coverage, death, or 12 months post‐index using Kaplan‐Meier (KM) analyses. Results A total of 2,488 (KS = 0); 2,125 (KS = 1), 1,074 (KS = 2), and 507 (KS ≥ 3) cancer patients were included. The 12‐month KM rates of VTE were 3.1%, 5.4%, 7.9%, and 14.9% (associated median time to VTE of 2.7, 3.0, 1.4, and 1.7 months) among KS = 0, 1, 2, and ≥ 3 cohorts, respectively. Corresponding adjusted hazard ratios (95% CIs) relative to the KS = 0 cohort were 1.72 (1.25‐2.38), 2.46 (1.73‐3.50), and 4.99 (3.40‐7.31) for the KS = 1, 2, and ≥ 3 cohorts, respectively (all P, This cohort study evaluated the risk of VTE and survival rates among patients newly diagnosed with cancer and stratified by Khorana score (KS) in a real‐world population. The present findings indicate that the rates of VTE significantly increased with KS, confirming its predictive ability. Moreover, VTE was associated with lower survival rates within each KS cohort.

In the 5 months since initial reports of COVID-19 came to light, the death toll due to SARS-CoV-2 has rapidly increased. The morbidity and mortality of the infection varies based upon patient age, comorbid conditions, viral load, and the availability of effective treatments. Findings from limited autopsies, clinical observations, and laboratory data suggest that high cytokine levels and a procoagulant state can precipitate acute respiratory distress syndrome and multi-organ dysfunction syndrome in critically ill patients. To complicate matters, comorbidities may affect the response to medical treatments currently in use, all of which are still in trial phase. Therapeutic plasma exchange (TPE) merits consideration in the treatment of critically ill COVID-19 patients and is an avenue for clinical trials to pursue. If efficacious, faster recovery of patients may lead to shorter intensive care unit stays and less time on mechanical ventilation. Herein, we briefly discuss some of the various approaches currently being investigated for the treatment of SARS-CoV-2 with a focus on potential benefits of TPE for selected critically ill patients.

There may be many predictors of venous thromboembolism (VTE) and bleeding in hospitalized medical patients, but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify prognostic factors for VTE and bleeding in hospitalized medical patients and searched Medline and EMBASE from inception through May 2018. We considered studies that identified potential prognostic factors for VTE and bleeding in hospitalized adult medical patients. Reviewers extracted data in duplicate and independently and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. Of 69 410 citations, we included 17 studies in our analysis: 14 that reported on VTE, and 3 that reported on bleeding. For VTE, moderate-certainty evidence showed a probable association with older age; elevated C-reactive protein (CRP), D-dimer, and fibrinogen levels; tachycardia; thrombocytosis; leukocytosis; fever; leg edema; lower Barthel Index (BI) score; immobility; paresis; previous history of VTE; thrombophilia; malignancy; critical illness; and infections. For bleeding, moderate-certainty evidence showed a probable association with older age, sex, anemia, obesity, low hemoglobin, gastroduodenal ulcers, rehospitalization, critical illness, thrombocytopenia, blood dyscrasias, hepatic disease, renal failure, antithrombotic medication, and presence of a central venous catheter. Elevated CRP, a lower BI, a history of malignancy, and elevated heart rate are not included in most VTE risk assessment models. This study informs risk prediction in the management of hospitalized medical patients for VTE and bleeding; it also informs guidelines for VTE prevention and future research.

Introduction In the CASSINI study, rivaroxaban thromboprophylaxis significantly reduced primary venous thromboembolism (VTE) endpoints during the intervention period, but several thromboembolic events designated as secondary efficacy endpoints were not included in the primary analysis. This study was aimed to evaluate the full impact of rivaroxaban thromboprophylaxis on all prespecified thromboembolic endpoints occurring on study. Methods CASSINI was a double-blind, randomized, placebo-controlled study in adult ambulatory patients with cancer at risk for VTE (Khorana score ≥2). Patients were screened at baseline for deep-vein thrombosis (DVT) and randomized if none was found. The primary efficacy endpoint was a composite of lower extremity proximal DVT, symptomatic upper extremity, or lower extremity distal DVT, any pulmonary embolism, and VTE-related death. This analysis evaluated all prespecified thromboembolic endpoints occurring on study to determine the full benefit of rivaroxaban prophylaxis. All endpoints were independently adjudicated. Results Total thromboembolic events occurred in fewer patients randomized to rivaroxaban during the full study period (29/420 [6.9%] and 49/421 [11.6%] patients in rivaroxaban and placebo groups, respectively [hazard ratio (HR) = 0.57; 95% confidence interval (CI): 0.36–0.90; p = 0.01]; number needed to treat [NNT] = 21). Similarly, fewer patients randomized to rivaroxaban experienced thromboembolism during the intervention period (13/420 [3.1%] patients) versus placebo (38/421 [9.0%] patients; HR = 0.33; 95% CI: 0.18–0.62; p < 0.001; NNT = 17). Conclusion Our findings confirm the substantial benefit of rivaroxaban thromboprophylaxis when considering all prespecified thromboembolic events, even after excluding baseline screen-detected DVT. The low NNT, coupled with prior data demonstrating a high number needed to harm, should assist clinicians in determining the risk/benefit of thromboprophylaxis in high-risk patients with cancer.

Background Venous thromboembolism (VTE) is a cause of considerable morbidity and mortality in hospitalized patients. An evidence-based algorithm was developed and implemented at our institution to guide perioperative VTE prophylaxis management. Objective We evaluated compliance with prescription of risk-appropriate VTE prophylaxis and administration of prescribed VTE prophylaxis in neurosurgery patients. Methods This was a retrospective analysis of postoperative neurosurgery patients at a single institution with subsequent diagnosis of acute VTE during their inpatient stay. Descriptive statistics were used to characterize pharmacologic VTE prophylaxis and prescribing patterns. Results The incidence of VTE in our neurosurgery population was 248/13,913 (1.8%). Of the 123 patients, the median time to VTE diagnosis was 96 hours after surgery (interquartile range [IQR], 58–188 hours). A total of 108 patients (87.8%) were prescribed risk-appropriate VTE prophylaxis, among whom 61 (56.5%) received all doses as prescribed. Fifty-three patients (43.1%) missed ≥1 dose of prescribed prophylaxis and the median missed doses was 3 (IQR, 0–3). The median time to first dose of pharmacologic VTE prophylaxis was 42 hours (IQR, 28–51). More than half (n = 63, 51.2%) of the VTE risk assessments contained ≥1 error, of which 15 (23.8%) would have resulted in a change in recommendation. Conclusions Our evidence-based VTE prophylaxis algorithm was not accurately completed in more than half of patients. Many patients who developed VTE had a defect in their VTE prophylaxis management during their inpatient stay. Research to improve optimal VTE prevention practice in neurosurgery patients is needed.

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies, including anti-β2-glycoprotein-I (anti-β2GPI), that are considered central to APS pathogenesis. Based on animal studies showing a role of complement in APS-related clinical events, we used the modified Ham (mHam) assay (complement-dependent cell killing) and cell-surface deposition of C5b-9 to test the hypothesis that complement activation is associated with thrombotic events in APS. A positive mHam (and corresponding C5b-9 deposition) were present in 85.7% of catastrophic APS (CAPS), 35.6% of APS (and 68.5% of samples collected within 1 year of thrombosis), and only 6.8% of systemic lupus erythematosus (SLE) sera. A positive mHam assay was associated with triple positivity (for lupus anticoagulant, anticardiolipin, and anti-β2GPI antibodies) and recurrent thrombosis. Patient-derived anti-β2GPI antibodies also induced C5b-9 deposition, which was blocked completely by an anti-C5 monoclonal antibody, but not by a factor D inhibitor, indicating that complement activation by anti-β2GPI antibodies occurs primarily through the classical complement pathway. Finally, patients with CAPS have high rates of rare germline variants in complement regulatory genes (60%), compared with patients with APS (21.8%) or SLE (28.6%) or normal controls (23.3%), and have mutations at a rate similar to that of patients with atypical hemolytic uremic syndrome (51.5%). Taken together, our data suggest that anti-β2GPI antibodies activate complement and contribute to thrombosis in APS, whereas patients with CAPS have underlying mutations in complement regulatory genes that serve as a “second hit,” leading to uncontrolled complement activation and a more severe thrombotic phenotype.

Venous thromboembolism (VTE) is a frequent cause of preventable harm among hospitalized patients. Many prescribed prophylaxis doses are not administered despite supporting evidence. We previously demonstrated a patient-centered education bundle improved VTE prophylaxis administration broadly; however, patient-specific factors driving nonadministration are unclear. We examine the effects of the education bundle on missed doses of VTE prophylaxis by sex.We performed a post-hoc analysis of a nonrandomized controlled trial to evaluate the differences in missed doses by sex. Pre-intervention and intervention periods for patients admitted to 16 surgical and medical floors between 10/2014-03/2015 (pre-intervention) and 04/2015-12/2015 (intervention) were compared. We examined the conditional odds of (1) overall missed doses, (2) missed doses due to patient refusal, and (3) missed doses for other reasons.Overall, 16,865 patients were included (pre-intervention 6853, intervention 10,012), with 2350 male and 2460 female patients (intervention), and 6373 male and 5682 female patients (control). Any missed dose significantly reduced on the intervention floors among male (odds ratio OR 0.55; 95% confidence interval CI, 0.44-0.70, P 0.001) and female (OR 0.59; 95% CI, 0.47-0.73, P 0.001) patients. Similar significant reductions ensued for missed doses due to patient refusal (P 0.001). Overall, there were no sex-specific differences (P-interaction0.05).Our intervention increased VTE prophylaxis administration for both female and male patients, driven by decreased patient refusal. Patient education should be applicable to a wide range of patient demographics representative of the target group. To improve future interventions, quality improvement efforts should be evaluated based on patient demographics and drivers of differences in care.

Using the Vaccine Adverse Event Reporting System, the number and demographic characteristics of cases of thrombosis with thrombocytopenia syndrome occurring after receipt of COVID-19 vaccines in the United States were determined., Visual Abstract. Thrombosis With Thrombocytopenia Syndrome After COVID-19 Vaccination. Using the Vaccine Adverse Event Reporting System, the number and demographic characteristics of cases of thrombosis with thrombocytopenia syndrome occurring after receipt of COVID-19 vaccines in the United States were determined. Visual Abstract. Thrombosis With Thrombocytopenia Syndrome After COVID-19 Vaccination. Using the Vaccine Adverse Event Reporting System, the number and demographic characteristics of cases of thrombosis with thrombocytopenia syndrome occurring after receipt of COVID-19 vaccines in the United States were determined., Background: Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. It presents similarly to spontaneous heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis after vaccination with the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson) have previously been described. Objective: To describe surveillance data and reporting rates of all reported TTS cases after COVID-19 vaccination in the United States. Design: Case series. Setting: United States. Patients: Case patients receiving a COVID-19 vaccine from 14 December 2020 through 31 August 2021 with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction) reported to the Vaccine Adverse Event Reporting System. If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for antiplatelet factor 4 antibodies or functional heparin-induced thrombocytopenia platelet test result was required. Measurements: Reporting rates (cases per million vaccine doses) and descriptive epidemiology. Results: A total of 57 TTS cases were confirmed after vaccination with Ad26.COV2.S (n = 54) or a messenger RNA (mRNA)–based COVID-19 vaccine (n = 3). Reporting rates for TTS were 3.83 per million vaccine doses (Ad26.COV2.S) and 0.00855 per million vaccine doses (mRNA-based COVID-19 vaccines). The median age of patients with TTS after Ad26.COV2.S vaccination was 44.5 years (range, 18 to 70 years), and 69% of patients were women. Of the TTS cases after mRNA-based COVID-19 vaccination, 2 occurred in men older than 50 years and 1 in a woman aged 50 to 59 years. All cases after Ad26.COV2.S vaccination involved hospitalization, including 36 (67%) with intensive care unit admission. Outcomes of hospitalizations after Ad26.COV2.S vaccination included death (15%), discharge to postacute care (17%), and discharge home (68%). Limitations: Underreporting and incomplete case follow-up. Conclusion: Thrombosis with thrombocytopenia syndrome is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The different demographic characteristics of the 3 cases reported after mRNA-based COVID-19 vaccines and the much lower reporting rate suggest that these cases represent a background rate. Primary Funding Source: Centers for Disease Control and Prevention.

BackgroundThrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. TTS presents similarly to autoimmune heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis following Janssen/Johnson & Johnson (Ad26.COV2.S) COVID-19 vaccination have been described.ObjectiveDescribe surveillance data and reporting rates of TTS cases following COVID-19 vaccination.DesignCase series.SettingUnited StatesPatientsCase-patients reported to the Vaccine Adverse Event Reporting System (VAERS) receiving COVID-19 vaccine from December 14, 2020 through August 31, 2021, with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction). If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for anti-platelet factor 4 antibody was required.MeasurementsReporting rates (cases/million vaccine doses) and descriptive epidemiology.Results52 TTS cases were confirmed following Ad26.COV2.S (n=50) or mRNA-based COVID-19 (n=2) vaccination. TTS reporting rates were 3.55 per million (Ad26.COV2.S) and 0.0057 per million (mRNA-based COVID-19 vaccines). Median age of patients with TTS following Ad26.COV2.S vaccination was 43.5 years (range: 18–70); 70% were female. Both TTS cases following mRNA-based COVID-19 vaccination occurred in males aged >50 years. All cases following Ad26.COV2.S vaccination involved hospitalization including 32 (64%) with intensive care unit admission. Outcomes of hospitalizations following Ad26.COV2.S vaccination included death (12%), discharge to post-acute care (16%), and discharge home (72%).LimitationsUnder-reporting and incomplete case follow-up.ConclusionTTS is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The different demographic characteristics of the two cases reported after mRNA-based COVID-19 vaccines and the much lower reporting rate suggest that these cases represent a background rate.Funding SourceCDC

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.

The optimal regimen for prevention and treatment of venous thromboembolism in bariatric surgical patients remains controversial. Direct oral anticoagulants are potentially advantageous over other agents, but inadequate evidence exists regarding their effects in bariatric surgical patients.To investigate single-dose pharmacokinetic (PK) and pharmacodynamic (PD) parameters of apixaban when administered to patients undergoing vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB) and to determine whether the PK and PD parameters are affected by type of bariatric surgery and weight loss in the immediate and postoperative period up to 12 months.University Hospital and A Bariatric Center of Excellence, Baltimore, Maryland.Adults with a body mass index ≥35 kg/mgov). Apixaban PK and PD parameters were measured after a single 5 mg dose of the drug was given preoperatively and at 1, 6, and 12 months postoperatively in patients undergoing VSG and RYGB. Change in PK parameters was assessed as maximum concentration, time to maximum concentration, elimination half-life, and area under the concentration-time curve from 0-72 hours and change in PD parameters were assessed by chromogenic factor X activity.Of 33 patients enrolled, 28 (14 VSG, 14 RYGB) completed all visits and were analyzed. Most patients (89%) were female, with a mean age of 43.8 years and a body mass index of 48.7 kg/mThe effect of either VSG or RYGB on apixaban PK and PD parameters is minimal. Factor X activity after 5 mg apixaban was lower in postoperative versus preoperative bariatric patients, but this effect appears to be primarily the result of a decrease in factor X activity from bariatric surgery itself and not a postoperative change in apixaban PK and PD parameters. Future studies should investigate the safety, efficacy, and clinical outcomes of apixaban and other direct oral anticoagulants perioperatively and beyond 12 months following bariatric surgery.

Background Prophylactic anticoagulation with rivaroxaban significantly reduced the risk of cancer-associated thrombosis during the intervention period in the CASSINI trial. Direct oral anticoagulants may increase the risk of gastrointestinal (GI) tract bleeding in patients with an in situ GI tract cancer or lesion. Objective This post hoc analysis characterized the efficacy and safety of rivaroxaban in patients with and without gastric/gastroesophageal junction (G/GEJ) tumors. Methods Primary and secondary efficacy end points and adjudicated bleeding events, including bleeding sites, were analyzed for the intent-to-treat population by cancer type (G/GEJ vs non-G/GEJ) for the 180-day observation period. Results In patients with G/GEJ tumors, the rates for the primary efficacy end point were 3.4% for rivaroxaban versus 6.9% for placebo (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.11-1.80). In patients with non-G/GEJ tumors, the rivaroxaban group had a lower risk of the primary end point (6.6% vs 9.3%; HR, 0.70; 95% CI, 0.40-1.21). Rates of major bleeding in patients with G/GEJ tumors were 4.6% (4/88) versus 1.2% (1/85) for rivaroxaban and placebo; rates in patients with non-G/GEJ tumors were 1.3% (4/317) versus 0.9% (3/319), respectively. Conclusions Excluding patients with G/GEJ tumors resulted in a definable population of cancer patients who achieved an improved benefit-risk balance from rivaroxaban prophylaxis.

Acute Promyelocytic Leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is notably distinguished clinically by a rapidly progressive and fatal course. Due to the acute nature of its presentation, prompt and accurate diagnosis is required to initiate appropriate therapy that can be curative. However, the gold standard genetic tests can take days to confirm a diagnosis and thus therapy is often initiated on high clinical suspicion based on both clinical presentation as well as direct visualization of the peripheral smear. While there are described cellular morphological features that distinguish APL, there is still considerable difficulty in diagnosing APL from direct visualization of a peripheral smear by a hematopathologist. We hypothesized that deep learning pattern recognition would have greater discriminatory power and consistency compared to humans to distinguish t(15;17) translocation positive APL from t(15;17) translocation negative AML. To best tackle the problem of diagnosing APL rapidly from a peripheral smear, study patients with APL and AML were identified via retrospective chart review from a list of confirmed FISH t(15;17)-positive (n = 34) and -negative (n = 72) patients presenting at The Johns Hopkins Hospital (JHH). Additional inclusion criteria included new disease diagnosis, no prior treatment, and availability of peripheral blood smear image uploaded to CellaVision. Patients were separated into a discovery cohort presenting prior to 1/2019 (APL, n = 22; AML, n=60) and a validation cohort presenting on or after 1/2019 (APL, n = 12; AML, n = 12). A multiple-instance deep learning model employing convolutional layers at the per-cell level (Figure 1A) was trained on the discovery cohort and then tested on the independent prospective validation cohort to assess generalizability of the model. When compared to 10 academic clinicians (denoted with red +) who consisted of leukemia-treating hematologists, oncologists, and hematopathologists, the deep learning model was equivalent or outperformed 9/10 readers (Figure 1B) with an AUC of 0.861. We further looked at the performance of using proportion of promyelocytes (per CellaVision classification) as a biomarker of APL which had an AUC of 0.611. Finally, we applied integrated gradients, a method by which to extract per-pixel importance to the classification probability to identify and understand the morphological features the model was learning and using to distinguish APL (Figure 1C). We noted that the appearance of the chromatin in the non-APL leukemias was more dispersed and focused at the edge of the cell whereas in APL, the chromatin was more condensed and focused at the center of the cell. These morphological features, taught to us by the model, have not been previously reported in the literature as being useful for distinguishing APL from non-APL. Our work presents a deep learning model capable of rapid and accurate diagnosis of APL from universally available peripheral smears. In addition, explainable artificial intelligence is provided for biological insights to facilitate clinical management and reveal morphological concepts previously unappreciated in APL. The deep learning framework we have delineated is applicable to any diagnostic pipeline that can leverage a peripheral blood smear, potentially allowing for efficient diagnosis and early treatment of disease. Figure 1. Disclosures Streiff: Bayer: Consultancy, Speakers Bureau; Dispersol: Consultancy; BristolMyersSquibb: Consultancy; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Speakers Bureau; Portola: Consultancy; Boehringer-Ingelheim: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; NovoNordisk: Research Funding; Sanofi: Research Funding. Moliterno:Pharmessentia: Consultancy; MPNRF: Research Funding. DeZern:MEI: Consultancy; Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria. Levis:Astellas: Honoraria, Research Funding; Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria.

This study compared anti-Xa activity in critically ill patients receiving UFH for VTE prophylaxis between two weight groups (100 kg vs ≥100 kg).This prospective, observational study included critically ill patients on UFH 5000 or 7500 units every 8 h. A peak and trough anti-Xa activity assay was ordered for each patient at steady state. Goal peak anti-Xa activity was 0.1-0.3 units/mL.From March 2017 to June 2018, 75 patients were enrolled with 44 in the100 kg group and 31 in the ≥100 kg group. There was no significant difference in the percentage of patients with peak anti-Xa activity within goal range between patients100 kg and ≥ 100 kg (55.3% vs 35.7%, p = 0.12). The odds ratio for achieving peak anti-Xa activity within goal range as weight-based dose increased was 1.03 (95% CI 0.99-1.07). No differences were found in trough anti-Xa activity, VTE, bleeding, length of stay, or death.Though only one-third of patients ≥100 kg had peak anti-Xa activity within goal range, no significant difference was found between the weight groups. Additional prospective studies with adequate sample sizes are warranted to further investigate appropriate weight-based dosing of UFH in critically ill patients.

Essentials Acquired hemophilia A is a rare bleeding disorder often accompanied by other comorbidities. We describe emicizumab use in acquired hemophilia A complicated by acute coronary syndrome. Emicizumab proved safe and effective in a patient with acquired hemophilia A. Emicizumab facilitated successful administration of dual antiplatelet therapy. Abstract We report a patient with a high‐titer factor VIII inhibitor refractory to immunosuppression. He initially presented with myocardial infarction requiring percutaneous coronary intervention (PCI) with bare metal stent placement. Despite Feiba prophylaxis, inadequate hemostasis prompted premature discontinuation of dual antiplatelet therapy (DAPT). Fifteen weeks later, the patient presented with a left anterior descending artery in‐stent restenosis. This case report examines the Key Clinical Question of how to manage in‐stent restenosis in a patient with acquired hemophilia A (AHA). After multidisciplinary discussions including hematology, cardiology, cardiac surgery, laboratory medicine, and pharmacy, emicizumab was initiated to facilitate PCI. Four weeks after emicizumab initiation, the patient underwent successful PCI with drug‐eluting stent placement. Five months after discharge, he remains without signs or symptoms of cardiac disease or bleeding on DAPT and emicizumab. This case provides evidence of the potential of emicizumab for bleeding prophylaxis in AHA.