New Therapeutic Targets for the Prevention and Treatment of Venous Thromboembolism With a Focus on Factor XI Inhibitors.

FXI (factor XI) and FXII (factor XII) have emerged as targets for new anticoagulants that have the potential to be both more efficacious and safer than the currently available direct oral anticoagulants for the prevention and treatment of venous thromboembolism. In this review, we discuss the role of FXI and FXII in the pathogenesis of venous thromboembolism, explain why FXI is a better target, and explain why FXI inhibitors have potential advantages over currently available anticoagulants. Finally, we describe the FXI inhibitors under development and discuss their potential to address unmet needs in venous thromboembolism management.

Clinical Studies with Anticoagulants that Have Changed Clinical Practice.

Anticoagulant therapy is the cornerstone of treatment and prevention of arterial and venous thromboembolism. Taking a historical perspective, starting in the 1960s, and progressing through to 2022, we discuss key clinical trials of anticoagulants that have changed clinical practice, and examine obstacles encountered in bringing these anticoagulants to the clinic. The design of some of the early studies that shaped clinical practice was poor by current standards, but their results were influential because nothing better was available. Both heparin and vitamin K antagonists had been in clinical use for several decades before well-designed trials in the 1980s optimized their dosing and enhanced their safety and efficacy. Low-molecular-weight heparin then replaced unfractionated heparin because it had a more predictable dose-response and a longer half-life, thereby allowing it to be used conveniently in out-of-hospital settings. More recently, direct oral anticoagulants became the oral anticoagulants of choice for most indications because they were shown to be at least as safe and effective as vitamin K antagonists when used in fixed doses without the need for laboratory monitoring. The design of the trials that led to the approval of the direct oral anticoagulants was excellent, but further studies are required to optimize their dosing in selected patients who were underrepresented in these trials.

Novel antithrombotic strategies for treatment of venous thromboembolism.

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular death after heart attack and stroke. Anticoagulation therapy is the cornerstone of VTE treatment. Despite such therapy, up to 50% of patients with DVT develop postthrombotic syndrome, and up to 4% of patients with PE develop chronic thromboembolic pulmonary hypertension. Therefore, better therapies are needed. Although direct oral anticoagulants are more convenient and safer than warfarin for VTE treatment, bleeding remains the major side effect, particularly in cancer patients. Factor XII and factor XI have emerged as targets for new anticoagulants that may be safer. To reduce the complications of VTE, attenuation of thrombin activatable fibrinolysis inhibitor activity is under investigation in PE patients to enhance endogenous fibrinolysis, whereas blockade of leukocyte interaction with the vessel wall is being studied to reduce the inflammation that contributes to postthrombotic syndrome in DVT patients. Focusing on these novel antithrombotic strategies, this article explains why safer anticoagulants are needed, provides the rationale for factor XII and XI as targets for such agents, reviews the data on the factor XII- and factor XI-directed anticoagulants under development, describes novel therapies to enhance fibrinolysis and decrease inflammation in PE and DVT patients, respectively, and offers insights into the opportunities for these novel VTE therapies.

In pregnant women with suspected VTE and low/intermediate or unlikely pretest probability, D-dimer rules out VTE at 3 mo.

SOURCE CITATION: Bellesini M, Robert-Ebadi H, Combescure C, et al. D-dimer to rule out venous thromboembolism during pregnancy: a systematic review and meta-analysis. J Thromb Haemost. 2021;19:2454-67. 34161671.

How I manage anticoagulant therapy in older individuals with atrial fibrillation or venous thromboembolism.

Anticoagulant therapy is the most effective strategy to prevent arterial and venous thromboembolism, but treating older individuals is challenging, because increasing age, comorbidities, and polypharmacy increase the risk of both thrombosis and bleeding. Warfarin and non-vitamin K antagonist oral anticoagulants are underused and often underdosed in the prevention of stroke in older patients with atrial fibrillation because of concerns about the risk of bleeding. Poor adherence to anticoagulant therapy is also an issue for older patients with atrial fibrillation and those at risk of recurrent pulmonary embolism. In this review, we present 5 clinical cases to illustrate common challenges with anticoagulant use in older patients and discuss our approach to institute safe and effective antithrombotic therapy.

Antithrombotic Agents.

Recent advances in our understanding of the contribution of thrombin generation to arterial thrombosis and the role of platelets in venous thrombosis have prompted new treatment paradigms. Nonetheless, bleeding remains the major side effect of such treatments spurring the quest for new antithrombotic regimens with better benefit-risk profiles and for safer anticoagulants for existing and new indications. The aims of this article are to review the results of recent trials aimed at enhancing the benefit-risk profile of antithrombotic therapy and explain how these findings are changing our approach to the management of arterial and venous thrombosis. Focusing on these 2 aspects of thrombosis management, this article discusses 4 advances: (1) the observation that in some indications, lowering the dose of some direct oral anticoagulants reduces the risk of bleeding without compromising efficacy, (2) the recognition that aspirin is not only effective for secondary prevention of atherothrombosis but also for prevention of venous thromboembolism, (3) the finding that dual pathway inhibition with the combination of low-dose rivaroxaban to attenuate thrombin generation plus aspirin to reduce thromboxane A2-mediated platelet activation is superior to aspirin or rivaroxaban alone for prevention of atherothrombosis in patients with coronary or peripheral artery disease, and (4) the development of inhibitors of factor XI or XII as potentially safer anticoagulants.

Comparison of Peripapillary Vessel Density of Acute Nonarteritic Anterior Ischemic Optic Neuropathy and Other Optic Neuropathies With Disc Swelling Using Optical Coherence Tomography Angiography: A Pilot Study.

BACKGROUND: The purpose of this study is to quantitatively compare the peripapillary vessel density (PPVD), measured with optical coherence tomography angiography (OCT-A), between acute nonarteritic anterior ischemic optic neuropathy (NAION) and other causes of disc swelling ("others"). METHODS: In this prospective comparative case series, patients with unilateral disc swelling due to acute NAION (n = 7) and "others" (n = 7) underwent OCT-A scanning of the optic nerve head with a swept-source OCT (Triton DRI-OCT), in addition to functional assessment. OCT-A images were analyzed using an automated customized MATLAB program. Comparison was made between total and 6 sectoral PPVD (radial peripapillary capillary [RPC] and choroid layers) of affected and fellow eyes; and between the 2 groups' affected eyes. Five NAION patients had repeated assessments at 1, 3, and 6 months. RESULTS: Acute NAION eyes had a significantly lower total and superonasal PPVD (both layers) compared to fellow eyes. No such difference was observed in "others" group for the RPC layer. NAION eyes also had significantly lower total RPC PPVD than affected eyes in the "others" group. Over 6 months, NAION eyes had persistently lower RPC PPVD compared to fellow eyes but the reduced choroidal PPVD resolved by 1 month. CONCLUSION: The study demonstrated reduced superonasal and total RPC PPVD in acute NAION, which persisted over 6 months. Because there is currently no single diagnostic test for NAION, use of OCT-A images to analyze RPC PPVD may potentially help distinguish acute NAION from other causes of disc swelling by quantitatively demonstrating capillary dropout in the RPC layer.

Advances in Antithrombotic Therapy.

Thrombosis remains a major cause of morbidity and mortality. Consequently, advances in antithrombotic therapy are needed to reduce the disease burden. This article focuses on 2 such advances. First, the prevention of atherothrombosis in patients with coronary or peripheral artery disease, which has been enhanced by the finding that the combination of low-dose rivaroxaban plus aspirin is superior to aspirin alone for prevention of recurrent ischemic events. However, this benefit comes at the cost of increased bleeding albeit not fatal bleeding. To overcome this problem, the second advance is the identification of factor XI as a target for new anticoagulants that are potentially safer than those currently available.

Utility of a Nurse-Led Pathway for Patients with Acute Venous Thromboembolism Discharged on Rivaroxaban: A Prospective Cohort Study.

The highest risk of adverse events for patients with acute venous thromboembolism (VTE) is during the early anticoagulation period. However, no established model exists for early clinical monitoring of patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). The authors' aim was to evaluate the utility of a nurse-led pathway to minimize adverse events in acute VTE patients starting on rivaroxaban. The rivaroxaban VTE treatment pathway is a prospective cohort study of consecutive patients with objectively confirmed VTE between July 2015 and May 2017. Primary outcome was the proportion of patients identified at major risk of adverse events (bleeding or recurrent VTE). Secondary outcomes were rates of interventions, major or clinically relevant nonmajor bleeding (CRNMB), recurrent VTE, and all-cause mortality at 90 days. Among 304 participants, 5% (n = 15) were identified to be at major and 9% (n = 28) at possible risk for adverse events. Appropriate interventions to prevent harm were required in 40 patients. Rates of major bleeding, CRNMB, recurrence, and all-cause mortality were 0.3% (95% confidence interval [CI]: 0.1-1.8), 7.2% (95% CI: 4.8-10.7), 1.0 (95% CI: 0.3-2.9), and 1.6% (95% CI: 0.7-3.8), respectively. In conclusion, following discharge of acute VTE patients, a nurse-led pathway identified one in seven (14%) patients at major or possible risk of adverse events. Preemptive interventions to reduce harm translated into the low rates of bleeding and recurrence. The authors' experience highlights the feasibility and importance of a structured clinical surveillance pathway for acute VTE patients initiating NOAC therapy.

Evolving Treatments for Arterial and Venous Thrombosis: Role of the Direct Oral Anticoagulants.

The direct oral anticoagulants (DOACs) represent a major advance in oral anticoagulant therapy and have replaced the vitamin K antagonists as the preferred treatment for many indications. By simplifying long-term anticoagulant therapy and improving its safety, the DOACs have the potential to reduce the global burden of thrombosis. Postmarketing studies suggest that the favorable results achieved with DOACs in the randomized controlled trials can be readily translated into practice, but highlight the need for appropriate patient, drug and dose selection, and careful follow-up. Leveraging on their success to date, ongoing studies are assessing the utility of DOACs for the prevention of thrombosis in patients with embolic stroke of unknown source, heart failure, coronary artery disease, peripheral artery disease, antiphospholipid syndrome, and cancer. The purpose of this article is to (1) review the pharmacology of the DOACs, (2) describe the advantages of the DOACs over vitamin K antagonists, (3) summarize the experience with the DOACs in established indications, (4) highlight current challenges and limitations, (5) highlight potential new indications; and (6) identify future directions for anticoagulant therapy.

Quantifying immature platelets as markers of increased platelet production after coronary artery bypass grafting surgery.

OBJECTIVES: An increased rate of platelet production is a possible cause of reduced antithrombotic response to once-daily aspirin. Markers of immature platelets (IPs), such as immature platelet count (IPC), immature platelet fraction (IPF), and mean platelet volume (MPV) might be useful for identifying patients who have an increase in their rate of platelet production. However, their potential as markers of platelet production has not been rigorously evaluated. We aimed to investigate the utility of the IPC, IPF, and MPV as surrogates for increased platelet production using coronary artery bypass grafting (CABG) as a model of enhanced thrombopoiesis. METHODS: Daily changes in platelet count, IPC, IPF, and MPV were followed in 45 patients undergoing CABG. RESULTS: The rise in IP markers preceded that in the platelet count. IPC (16% per day increase from nadir) but not IPF or MPV showed a significant and sustained rise, which paralleled the pattern observed with platelet count (18% per day increase from nadir). CONCLUSIONS: Of the 3 markers, IPC was the most promising as surrogates for platelet production. Future studies should evaluate the utility of the IPC to identify patients with cardiovascular disease with reduced response to aspirin who might benefit from twice-daily aspirin.

Proceedings of the Neuro-Ophthalmology Program of the 33rd Asia-Pacific Academy of Ophthalmology Congress, Hong Kong, 8-11 February 2018.

The 33rd Asia-Pacific Academy of Ophthalmology (APAO) Congress was held on Feb 8-11, 2018 in Hong Kong. This report summarized the highlights of the neuro-ophthalmology program of the Congress, including the scientific symposia (invited and submitted) and the social activities.

The use of optical coherence tomography in neuro-ophthalmology.

PURPOSE OF REVIEW: In the last decade, with the advances of optical coherence tomography (OCT) technology, different imaging protocols and analysis algorithms have been introduced to maximize the potential of this diagnostic tool in the evaluation of different eye diseases. This review aims to provide an update on these additional features, with respect to the management of a diverse range of neuro-ophthalmologic conditions. RECENT FINDINGS: Macular ganglion cell complex (mGCC) analysis has been shown to be superior to peripapillary retinal nerve fiber layer (pRNFL) analysis in certain settings, such as differentiating Leber's hereditary optic neuropathy from functional visual loss; monitoring neurodegenerative diseases or multiple sclerosis; and predicting visual loss in nonarteritic ischemic optic neuropathy. mGCC analysis also demonstrates high correlation with perimetry and might serve as an early structural indicator of irreversible neuronal loss. Compared to pRNFL, retinal thickness analysis of the optic nerve head demonstrates better correlation with the severity of papilledema, thus enabling its possible application in detecting raised intracranial pressure, especially in the pediatric group. Upcoming research on emerging OCT technologies including OCT-angiography, enhanced depth imaging, retinal single-layer analysis and portable systems will hopefully further enhance the utility of OCT in the field. SUMMARY: It is crucial for neuro-ophthalmologists to be updated and familiar with these newer OCT imaging protocols and to make appropriate choices for different clinical scenarios, in order to optimize the diagnostic sensitivity and specificity.

Optic Disc and Macular Imaging in Blind Eyes from Non-glaucomatous Optic Neuropathy: A Study with Spectral-domain Optical Coherence Tomography.

The purpose of this study was to determine and compare the optic disc and macular thickness measurements using two spectral-domain optical coherence tomography (SD-OCT) instruments in long-standing blind eyes diagnosed with non-glaucomatous optic neuropathies (NGON). A prospective observational case-series design was used. Twelve eyes from 12 NGON patients with no light perception for at least 6 months underwent optic disc and macular imaging with Cirrus HD-OCT and Spectralis OCT. The correlation between the peripapillary retinal nerve fibre layer (PRNFL) and macular ganglion cell layer and inner plexiform layer (GCL+IPL) thicknesses, and between the duration of no light perception (NLP) and PRNFL/GCL+IPL thicknesses were determined using Spearman's correlation analysis. The mean average PRNFL thickness was 55.9 ± 4.8 µm for Cirrus HD-OCT, which was significantly thicker than that measured by Spectralis OCT (31.9 ± 7.4 µm; p < 0.001). The mean central macular thickness on Cirrus HD-OCT was normal, but there was global thinning at the other macular areas. The mean average GCL+IPL thickness on Cirrus HD-OCT was 51.8 ± 5.8 µm. There was a good correlation between average PRNFL thickness and GCL+IPL thickness (r = 0.830, p = 0.002); however, there was no significant correlation between the duration of NLP to the average PRNFL thickness (on either instruments) or GCL+IPL thickness on Cirrus HD-OCT (p > 0.7). These results show that there was residual PRNFL thickness in NGON eyes with NLP, which varied significantly between SD-OCT instruments. The values of the residual PRNFL and GCL+IPL thicknesses in blind eyes (the "floor" effect) may be useful for prognostic purposes for patients with partial optic atrophy.

Laboratory measurement of the direct oral anticoagulants.

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot® and ecarin-based assays can be used to quantify dabigatran level and calibrated chromogenic anti-FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available.