Background and Purpose— One of the reasons for the failure of trials of neuroprotection in stroke may be the lack of white matter (WM) protection. However, whether patients entered into typical neuroprotection trials have WM involved in the ischemic process is unknown. We studied patients who were enrolled in neuroprotection trials at our center and used a neuroimaging coregistration approach to determine whether final infarcts involved WM and, if so, in what proportion. We also aimed to provide the first in vivo volume distribution of gray matter (GM) and WM in normal stroke-aged brains. Methods— Patients enrolled in trials of neuroprotection had late computed tomography or magnetic resonance scans coregistered in standard stereotaxic coordinate space after segmentation of symptomatic cerebral infarcts. These were then superimposed on a probabilistic map of GM and WM, which was developed from age-matched normal controls in whom GM and WM volumes were assessed. Results— Forty-two patients (mean age, 73.7±10.5 years) were studied from 6 trials of neuroprotection. WM formed 41.7% of the brain volume in 37 control subjects (mean age, 73.5±8.4 years). In the segmented infarcts, WM comprised a median of 49% (interquartile range, 36.5 to 77.9) of the infarct volume. Ninety-five percent of infarcts had some involvement of WM tracts. Conclusions— WM occupies ≈42% by volume of the normal stroke-aged brain. Patients entered into typical trials of neuroprotection may have significant WM volumes involved in the ischemic process, thus providing a rationale for the development of neuroprotectants for this compartment.

Direct oral anticoagulants (DOACs) are increasingly being used, primarily due to their drug stability and patient convenience. Although these drugs have been evaluated to be well tolerated in numerous clinical trials, their impact on in-vivo anticoagulation effect, variability and therapeutic drug level remains unknown. Hence, we aim to study the effect and variability of DOACs on thrombin generation via the calibrated automated thrombogram. Anonymized coagulation specimens from outpatients on warfarin were collected. Pooled normal plasma samples were spiked with increasing concentrations of dabigatran, rivaroxaban and apixaban. Similarly, plasma samples with normal coagulation profiles were spiked with two concentrations each of dabigatran, rivaroxaban and apixaban. Thrombin generation via calibrated automated thrombogram was run using the above samples and compared with a dataset of normal controls. Increasing international normalized ratio was associated with a reduction of endogenous thrombin potential (ETP) and thrombin peak and increasing lag time. Factor Xa inhibitors produced a flattened thrombin generation curve with a reduction of thrombin peak and relative preservation of ETP. Direct thrombin inhibitors produced a reduction of both ETP and thrombin peak and increasing lag time. Seventy-one citrated plasma samples (26 dabigatran, 21 rivaroxaban and 24 apixaban) were evaluated. The two concentrations produced a reduction of thrombin generation parameters with significant interindividual variability compared with neat plasma of 35–93, 13–31 and 18–71% and for dabigatran, rivaroxaban and apixaban, respectively. Thrombin generation can measure the anticoagulation effect of commonly used DOACs, with each drug having a unique thrombin generation profile. The variability noted using the same concentration suggests significant interindividual pharmacodynamic differences, which maybe relevant with respect to efficacy as well as bleeding side effects. Further delineation of the modifiers of interindividual differences is required in the in-vivo setting.

Direct oral anticoagulants (DOACs) have changed the paradigm of anticoagulation management, improving patient convenience as well as possibly reducing the incidence of spontaneous intracranial hemorrhage. However, concerns remain with these agents because of the lack of monitoring capacity and availability of readily accessible specific antidotes. This is particularly pertinent in the older population, specifically the frail older adults who have multiple comorbidities, higher risk of falls, and increased bleeding risk. This group has not been specifically studied in the DOAC randomized controlled trials and, hence, extrapolation of these data into this population should be done cautiously. We provide a review of the use of DOACs in the older frail population from both hematological and geriatric perspectives, as well as propose an algorithm for how these agents may be used in this frail population.

Cardiovascular disease remains the leading cause of death in the era of modern medicine despite major advancements in this field. Current available clinical surrogate markers and blood tests do not adequately predict individual risk of cardiovascular disease. A more precise and sophisticated tool that can reliably predict the thrombosis and bleeding risks at an individual level is required in order for clinicians to confidently recommend early interventions with a favorable risk–benefit profile. Critical to the development of this tool is the assessment and understanding of Virchow’s triad and its complex interactions between hypercoagulability, endothelial dysfunction and vessel flow, a fundamental concept to the development of thrombosis. This review explores the pathophysiology of cardiovascular disease stemming from the triad of factors and how individualized risk assessment can be improved through the multimodal use of tools such as global coagulation assays, endothelial biomarkers and vessel flow assessment.