Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease.

Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study.

BACKGROUND: Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. OBJECTIVES: This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. METHODS: Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. RESULTS: In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). CONCLUSION: Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

Four years into the pandemic, managing COVID-19 patients with acute coagulopathy: what have we learned?

Coagulopathy alongside micro- and macrovascular thrombotic events were frequent characteristics of patients presenting with acute COVID-19 during the initial stages of the pandemic. However, over the past 4 years, the incidence and manifestations of COVID-19-associated coagulopathy have changed due to immunity from natural infection and vaccination and the appearance of new SARS-CoV-2 variants. Diagnostic criteria and management strategies based on early experience and studies for COVID-19-associated coagulopathy thus require reevaluation. As many other infectious disease states are also associated with hemostatic dysfunction, the coagulopathy associated with COVID-19 may be compounded, especially throughout the winter months, in patients with diverse etiologies of COVID-19 and other infections. This commentary examines what we have learned about COVID-19-associated coagulopathy throughout the pandemic and how we might best prepare to mitigate the hemostatic consequences of emerging infection agents.

Current Gaps in the Provision of Safe and Effective Anticoagulation in Atrial Fibrillation and the Potential for Factor XI-Directed Therapeutics.

The global prevalence of atrial fibrillation is rapidly increasing, in large part due to the aging of the population. Atrial fibrillation is known to increase the risk of thromboembolic stroke by five times, but it has been evident for decades that well-managed anticoagulation therapy can greatly attenuate this risk. Despite advances in pharmacology (such as the shift from vitamin K antagonists to direct oral anticoagulants) that have increased the safety and convenience of chronic oral anticoagulation in atrial fibrillation, a preponderance of recent observational data indicates that protection from stroke is poorly achieved on a population basis. This outcomes deficit is multifactorial in origin, stemming from a combination of underprescribing of anticoagulants (often as a result of bleeding concerns by prescribers), limitations of the drugs themselves (drug-drug interactions, bioaccumulation in renal insufficiency, short half-lives that result in lapses in therapeutic effect, etc.), and suboptimal patient adherence that results from lack of understanding/education, polypharmacy, fear of bleeding, forgetfulness, and socioeconomic barriers, among other obstacles. Often this adherence is not reported to treating clinicians, further subverting efforts to optimize care. A multidisciplinary, interprofessional panel of clinicians met during the 2023 International Society of Thrombosis and Haemostasis Congress to discuss these gaps in therapy, how they can be more readily recognized, and the potential for Factor XI-directed anticoagulants to improve the safety and efficacy of stroke prevention. A full appreciation of this potential requires a re-evaluation of traditional teaching about the "coagulation cascade" and decoupling the processes that result in (physiologic) hemostasis and (pathologic) thrombosis. The panel discussion is summarized and presented here.

When Direct Oral Anticoagulants Should Not Be Standard Treatment: JACC State-of-the-Art Review.

For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves, thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for conditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis, and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring further research.

Finding a common definition of heparin resistance in adult cardiac surgery: communication from the ISTH SSC subcommittee on perioperative and critical care thrombosis and hemostasis.

Ensuring adequate anticoagulation for patients requiring cardiac surgery and cardiopulmonary bypass (CPB) is important due to the adverse consequences of inadequate anticoagulation with respect to bleeding and thrombosis. When target anticoagulation is not achieved with typical doses, the term heparin resistance is routinely used despite the lack of uniform diagnostic criteria. Prior reports and guidance documents that define heparin resistance in patients requiring CPB and guidance documents remain variable based on the lack of standardized criteria. As a result, we conducted a review of clinical trials and reports to evaluate the various heparin resistance definitions employed in this clinical setting and to identify potential standards for future clinical trials and clinical management. In addition, we also aimed to characterize the differences in the reported incidence of heparin resistance in the adult cardiac surgical literature based on the variability of both target-activated clotting (ACT) values and unfractionated heparin doses. Our findings suggest that the most extensively reported ACT target for CPB is 480 seconds or higher. Although most publications define heparin resistance as a failure to achieve this target after a weight-based dose of either 400 U/kg or 500 U/kg of heparin, a standardized definition would be useful to guide future clinical trials and help improve clinical management. We propose the inability to obtain an ACT target for CPB of 480 seconds or more after 500 U/kg as a standardized definition for heparin resistance in this setting.

Early Time Courses of Recurrent Venous Thromboembolism and Bleeding during Apixaban or Dalteparin Therapy for Patients with Cancer.

BACKGROUND: In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE. METHODS: The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding. RESULTS: In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group. CONCLUSION: The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE.

Impact of as needed heparin boluses on supratherapeutic activated partial thromboplastin time in patients managed with extracorporeal membrane oxygenation.

INTRODUCTION: Brigham and Women's Hospital (BWH) historically used titratable weight-based heparin nomograms with as needed boluses managed by extracorporeal membrane oxygenation (ECMO) specialists to achieve a pre-determined goal activated partial thromboplastin time (aPTT). Due to concern amongst providers that as needed boluses may lead to supratherapeutic aPTT's and subsequent bleeding, new nomograms without as needed boluses were implemented. The purpose of this retrospective observational analysis is to provide a comparison in safety and efficacy between the heparin nomograms with as needed boluses and the new nomograms without boluses. METHODS: Adult patients who were cannulated on ECMO and initiated on an approved heparin bolus nomogram (January 1, 2018-December 31, 2019) or an approved heparin no bolus nomogram (October 20, 2020-March 31, 2021) were screened for inclusion. The major endpoint evaluated was the percentage of supratherapeutic aPTTs, defined as an aPTT above the upper limit of the specified nomogram goal, within the first 72 hours. RESULTS: A total of 23 patients were included in the bolus nomogram cohort and 9 patients in the no-bolus nomogram cohort. Within the first 72 hours of initiation, there were 11.5% supratherapeutic aPTTs in the bolus group and 5.1% in the no-bolus group (p=0.101). Overall there was one bleeding event in the no-bolus group (11.1%) and seven in the bolus group (30.4%) (p=0.26). There were no thromboembolic events in either group. CONCLUSION: Overall, there was no difference found in percentage of supratherapeutic aPTTs within the first 72 hours of heparin initation between the bolus and no-bolus nomograms.

Avatrombopag for adults with early versus chronic immune thrombocytopenia.

Avatrombopag is a newer thrombopoietin receptor agonist (TPO-RA) currently approved to treat chronic ITP (duration >12 months). No studies have yet evaluated the safety and effectiveness of avatrombopag in newly diagnosed ITP (duration <3 months) or persistent ITP (duration 3-12 months), and so its use in these populations is presently off-label worldwide. We hypothesize that avatrombopag has similar safety and effectiveness irrespective of ITP disease phase. To evaluate this, we performed a multicenter observational cohort study of adults with ITP treated with avatrombopag, comparing patient outcomes by disease phase (newly diagnosed/persistent versus chronic). Seventy-five patients were included, 23 with newly diagnosed/persistent ITP (17.7 patient-years of avatrombopag treatment) and 52 with chronic ITP (65.3 patient-years of avatrombopag treatment). On avatrombopag, 91% of newly diagnosed/persistent patients versus 96% of chronic patients (p = .58) achieved a platelet response (≥50 × 109 /L) and 86% versus 81% of patients (p = .78) achieved a complete response (≥100 × 109 /L). Median platelet counts on avatrombopag were similar between the two groups (165 × 109 /L vs. 129 × 109 /L, p = .57). Response durability was high and similar in both groups. No patients in the newly diagnosed/persistent group had a major bleeding event, thromboembolic event or avatrombopag discontinuation for adverse events, compared with 4, 1, and 2, respectively, in the chronic group. Thrombocytosis (platelets ≥400 × 109 /L) incidence was similar in the two groups. No other drug-related adverse events occurred in either group. Avatrombopag was safe and effective in patients with newly diagnosed and persistent ITP, with outcomes numerically, statistically, and clinically similar to patients receiving avatrombopag for chronic ITP.

How to manage ITP with life-threatening bleeding.

While immune thrombocytopenia often presents with mild bleeding manifestations or surprising findings of thrombocytopenia on routine complete blood counts in patients without symptoms, some patients can present with new thrombocytopenia and life-threatening bleeding. Emergent assessment and treatment are needed to prevent substantial morbidity and even mortality. These patients present to the emergency room with bleeding, and hematologists are subsequently consulted. Understanding the approach to making the diagnosis and excluding other life-threatening illnesses is essential, as is rapid initiation of treatment in the bleeding patient even when the diagnosis of immune- mediated thrombocytopenia is tentative. Using a case-based format, we review how to approach and treat patients presenting with new thrombocytopenia and bleeding.

Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure: The ARIES-HM3 Randomized Clinical Trial.

IMPORTANCE: Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety. OBJECTIVE: To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding. DESIGN, SETTING, and PARTICIPANTS: This international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months. Intervention: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen. MAIN OUTCOMES AND MEASURES: The composite primary end point, assessed for noninferiority (-10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months. The principal secondary end point was nonsurgical bleeding events. RESULTS: Of the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (74%) vs those taking aspirin (68%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, -1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events, a finding consistent among diverse subgroups of patient characteristics. CONCLUSIONS AND RELEVANCE: In patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04069156.

Acute myocardial infarction in von Willebrand disease: characteristics and outcomes.

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder. As treatments have improved prognosis of VWD, age-related diseases, including acute myocardial infarction (AMI), have become more prevalent. The treatment of AMI includes antithrombotic therapies, which increase the risk of bleeding. Current guidelines suggest weighing risks/benefits of antithrombotic therapy in patients with VWD. However, data to inform these discussions are lacking. Objective: To characterize outcomes of patients with VWD after AMI. Methods: We conducted a retrospective cohort study utilizing the National Readmissions Database of patients with and without VWD admitted with AMI in 2017 and 2018. Primary outcomes were 90-day any-cause, bleeding-related, and arterial thrombosis-related readmissions. Case-control matching was performed for age, sex (male or female), ST-elevation myocardial infarction, percutaneous coronary intervention, diabetes, and chronic kidney disease. Time-to-event analysis was performed after matching using Cox proportional hazards regression. Results: A total of 136 patients with VWD were matched with 3400 controls without VWD. At 90 days, there were no differences in all-cause (10.7% vs 11.5%; P = 1.00), arterial thrombosis (1.9% vs 3.1%; P = .77), and bleeding (1.9% vs 0.4%; P = .083) readmission in patients with VWD. VWD was associated with increased risk of 90-day bleeding (hazard ratio [HR], 4.75; 95% CI, 1.05-21.66) but not all-cause (HR, 0.91; 95% CI, 0.50-1.67) or arterial thrombosis (HR, 0.54; 95% CI, 0.39-2.19) readmission. Conclusion: Among patients admitted with AMI, VWD was associated with higher risk of 90-day readmission for bleeding but not any-cause and arterial thrombosis-related readmissions. Further studies are needed to balance bleeding and thrombotic risks post-AMI in patients with VWD.

What Role Does Microthrombosis Play in Long COVID?

Soon after the outbreak of coronavirus disease 2019 (COVID-19), unexplained sustained fatigue, cognitive disturbance, and muscle ache/weakness were reported in patients who had recovered from acute COVID-19 infection. This abnormal condition has been recognized as "long COVID (postacute sequelae of COVID-19 [PASC])" with a prevalence estimated to be from 10 to 20% of convalescent patients. Although the pathophysiology of PASC has been studied, the exact mechanism remains obscure. Microclots in circulation can represent one of the possible causes of PASC. Although hypercoagulability and thrombosis are critical mechanisms of acute COVID-19, recent studies have reported that thromboinflammation continues in some patients, even after the virus has cleared. Viral spike proteins and RNA can be detected months after patients have recovered, findings that may be responsible for persistent thromboinflammation and the development of microclots. Despite this theory, long-term results of anticoagulation, antiplatelet therapy, and vascular endothelial protection are inconsistent, and could not always show beneficial treatment effects. In summary, PASC reflects a heterogeneous condition, and microclots cannot explain all the presenting symptoms. After clarification of the pathomechanisms of each symptom, a symptom- or biomarker-based stratified approach should be considered for future studies.

Defining heparin resistance: communication from the ISTH SSC Subcommittee of Perioperative and Critical Care Thrombosis and Hemostasis.

The term heparin resistance (HR) is used by clinicians without specific criteria. We performed a literature search and surveyed our SSC membership to better define the term when applied to medical and intensive care unit patients. The most common heparin dosing strategy reported in the literature (53%) and by survey respondents (80.4%) was the use of weight-based dosing. Heparin monitoring results were similar based on the proportion of publications and respondents that reported the use of anti-Xa and activated partial thromboplastin time. The most common literature definition of HR was >35 000 U/d, but no consensus was reported among survey respondents regarding weight-based and the total dose of heparin when determining resistance. Respondent consensus on treating HR included antithrombin supplementation, direct thrombin inhibitors, or administering more heparin as the strategies available for treating HR. A range of definitions for HR exist. Given the common use of heparin weight-based dosing, future publications employing the term HR should include weight-based definitions, monitoring assay, and target level used. Further work is needed to develop a consensus for defining HR.