Research and Practice in Thrombosis and Haemostasis最新文献

Background

In lung transplant patients, direct oral anticoagulants are often taken in combination with immunosuppressive drugs such as tacrolimus. Since tacrolimus is a substrate and inhibitor of the efflux protein ABCB1, also transporting direct oral anticoagulants, a possible drug–drug interaction mediated by competition for this transporter needs to be investigated.

Objectives

To determine the in vitro effect of tacrolimus on ABCB1-mediated rivaroxaban transport in order to support clinician practice.

Methods

Recombinant cell line models, based on human embryonic kidney 293 cells, were generated by a stable transfection process to overexpress ABCB1 or not (control cells). The impact of tacrolimus on ABCB1-mediated rivaroxaban transport was assessed by accumulation experiments.

Results

ABCB1 expression decreased the cellular accumulation of rivaroxaban and tacrolimus at their respective clinically relevant concentrations when compared with control cells. This confirms the involvement of ABCB1 in the active transport of tacrolimus and rivaroxaban. However, tacrolimus had no significant influence on rivaroxaban disposition at those clinically relevant concentrations.

Conclusion

Our study does not provide evidence for a possible interaction between tacrolimus and rivaroxaban when used together in practice.

Background

People with hemophilia often experience pain and suffer from comorbidities related to their bleeding disorder. Consequently, unemployment due to disability is prevalent among people with hemophilia.

Objectives

To explore associations between unemployment due to disability and treatment while adjusting for known risk factors for unemployment.

Methods

Collecting data from 20 hemophilia centers from 15 European countries, the Age-related DeVelopments ANd ComorbiditiEs in hemophilia study recruited 785 participants aged 40 years and over with hemophilia A or B. A comprehensive electronic case report form included items related to patient characteristics, demographic information, past and current treatment regimens, and medical history, including a lifelong history of comorbidities. Baseline data from the Age-related DeVelopments ANd ComorbiditiEs in hemophilia study was analyzed using descriptive statistics and logistic regression models.

Results

Employment status was available for 756 of 785 participants aged 40 to 88 years (median, 53 years). We used regression analysis to compare people with hemophilia who were fully employed with those who were unemployed due to disability. This analysis included 424 participants. Using multivariable logistic regression, we found that age (odds ratio [OR], 1.07; P < .01), severe hemophilia (OR, 10.81; P < .01), current smoker (OR, 2.53; P < .01), and psychiatric disorder (OR, 4.18; P = .02) were associated with increased odds of unemployment due to disability. In contrast, prophylactic treatment (OR, 0.44; P = .01) was associated with decreased odds.

Conclusion

Our analysis suggests that by maintaining factor levels above a critical threshold (3%-5%), prophylactic treatment for people with hemophilia could help avoid unemployment due to disability. While prophylaxis is more costly and can be burdensome, the benefits to material well-being and quality of life could be substantial.

Background

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) may lead to microvascular thrombosis and mortality, despite patients receiving appropriate standard of care treatment (immunosuppressive therapy and therapeutic plasma exchange). Caplacizumab directly inhibits von Willebrand factor–platelet interaction and consequently prevents microthrombi formation.

Objectives

This study aimed to determine the efficacy and safety of caplacizumab in diverse, clinically relevant patient subgroups.

Methods

In this post hoc analysis of phase 3 HERCULES study (NCT02553317), patients were categorized by clinically relevant subgroups (prior iTTP history, iTTP severity at presentation, and initial immunosuppression regimen).

Results

In patients with previous acute iTTP episodes, less severe disease at presentation, or those who received a corticosteroid-only initial immunosuppression regimen, time to platelet count response was shorter with caplacizumab vs placebo. Across all subgroups, fewer patients experienced a composite outcome of iTTP-related death, exacerbation, or major thromboembolic event on caplacizumab vs placebo. Placebo-treated patients remained at risk of exacerbations and refractoriness on either initial immunosuppression regimen (ie, corticosteroids only or corticosteroids plus rituximab). In the corticosteroids plus rituximab group, no exacerbations were reported in caplacizumab-treated patients, but 8 of the 16 (50%) patients experienced exacerbations in the placebo group. Safety outcomes were consistent with the findings of the main HERCULES study.

Conclusion

Caplacizumab treatment of acute iTTP, in combination with therapeutic plasma exchange and immunosuppression, was safe and effective regardless of prior iTTP history, severity, or initial immunosuppression regimen and improved patient outcomes across clinically diverse subgroups. These findings emphasize the need for treatments with rapid onset of action that can reduce mortality and iTTP-related complications.

Background

Previous studies have shown that thiol isomerases such as ERp46 positively regulate platelet function by reducing integrin αIIbβ3 disulfides, and the transmembrane thiol isomerase TMX1 negatively regulates integrin αIIbβ3 activation. However, whether and how the positive and negative thiol isomerases interact with each other and their interactions participate in platelet activation remain unknown.

Objectives

To investigate whether and how TMX1 regulates the effect of ERp46 on platelet function.

Methods

Using ERp46- and TMX1-deficient platelets, anti-TMX1 antibody, and wild-type TMX1 (TMX1-CPAC, TMX1-SS) and inactive TMX1 (TMX1-SPAS, TMX1-OO) proteins, we studied the antagonistic effect of TMX1 on ERp46 in platelet aggregation, clot retraction, and integrin αIIbβ3 signaling. The underlying mechanisms were further determined using thiol labeling, reductase activity, and other assays.

Results

Anti-TMX1 antibody and TMX1-OO reversed the decreased aggregation of ERp46-deficient platelets induced by thrombin, convulxin, and U46619. Anti-TMX1 antibody reversed the attenuated integrin αIIbβ3 function of ERp46-deficient platelets. TMX1 inhibited ERp46 reductase activity in a concentration-dependent manner. TMX1 oxidized thiols of ERp46 and those of integrin αIIbβ3 generated by ERp46. Moreover, TMX1 deficiency increased free thiols of ERp46 in platelets, which was reversed by the addition of wild-type TMX1 protein. Besides, anti-TMX1 antibody increased free thiols of ERp46 in wild-type activated platelets.

Conclusion

TMX1 not only oxidizes integrin αIIbβ3 disulfides that are reduced by ERp46 but also directly oxidizes ERp46 to suppress its reduction of integrin αIIbβ3. Thus, TMX1 is critical for maintaining platelets in a quiescent state and counterbalancing the effect of ERp46 to prevent platelet overactivation.

Background

Platelet function is driven by the expression of specialized surface markers. The concept of distinct circulating subpopulations of platelets has emerged in recent years, but their exact nature remains debatable.

Objectives

To design a spectral flow cytometry–based phenotyping workflow to provide a more comprehensive characterization, at a global and individual level, of surface markers in resting and activated healthy platelets, and to apply this workflow to investigate how responses differ according to platelet age.

Methods

A 14-marker flow cytometry panel was developed and applied to vehicle- or agonist-stimulated platelet-rich plasma and whole blood samples obtained from healthy volunteers, or to platelets sorted according to SYTO-13 (Thermo Fisher Scientific) staining intensity as an indicator of platelet age. Data were analyzed using both user-led and independent approaches incorporating novel machine learning–based algorithms.

Results

The assay detected differences in marker expression in healthy platelets, at rest and on agonist activation, in both platelet-rich plasma and whole blood samples, that are consistent with the literature. Machine learning identified stimulated populations of platelets with high accuracy (>80%). Similarly, machine learning differentiation between young and old platelet populations achieved 76% accuracy, primarily weighted by forward scatter, cluster of differentiation (CD) 41, side scatter, glycoprotein VI, CD61, and CD42b expression patterns.

Conclusion

Our approach provides a powerful phenotypic assay coupled with robust bioinformatic and machine learning workflows for deep analysis of platelet subpopulations. Cleavable receptors, glycoprotein VI and CD42b, contribute to defining shared and unique subpopulations. This adoptable, low-volume approach will be valuable in deep characterization of platelets in disease.

Background

Ascertaining accurately the exposure to antithrombotic medications for both research and quality initiatives has been challenging due to a multitude of reasons: aspirin, the most commonly used antithrombotic, is available over the counter in the United States. Additionally, antithrombotic medications are frequently interrupted for bleeding and procedures.

Objectives

We aimed to develop and validate an algorithm to capture accurately the longitudinal exposure to antithrombotic medications including aspirin using the electronic health record.

Methods

We used the Medical Inpatient Thrombosis and Hemostasis cohort, which consists of primary care patients at a university medical center followed for a median of 6.2 years. Exposure to antithrombotic medications was captured using the medication reconciliation data linked to each ambulatory encounter. We developed an algorithm that used the taking “yes” or “no” tab as well as start and stop dates to define the duration of exposure for each medication. Eighty charts were reviewed and compared with results of the algorithm for validation. We estimated the sensitivity, specificity, and positive and negative predictive values.

Results

The algorithm was 97% (95% CI, 94%-100%) sensitive and 95% (95% CI, 90%-100%) specific in identifying exposure to any antithrombotic medication. This translated to a 93% (95% CI, 85%-100%) positive predictive value and 98% (95% CI, 96%-100%) negative predictive value. When looking at aspirin alone, the sensitivity and the positive predictive value were 95% (95% CI, 88%-100%) and 87% (95% CI, 71%-100%).

Conclusion

This current algorithm provides a new and easily adaptable strategy to capture accurately exposure to aspirin and other antithrombotic medications.

Venous thromboembolic disease (VTE) is a significant medical problem in cancer patients, as it is associated with substantial morbidity and increased mortality. Cancer survivors with VTE experience important changes in their health-related quality of life (HRQOL). Over the past few years, HRQOL and its measurement have been incorporated in clinical studies of anticoagulation therapy, as well as in qualitative and quantitative studies for the examination of the impact of VTE in cancer patients. While there are several tools available to assess HRQOL, few are specific to cancer patients and VTE. More importantly, those same tools are yet to be incorporated in routine clinical practice. The purpose of this review is to describe the available tools for the assessment of HRQOL in cancer patients with a focus on VTE, as well as the characteristics of those tools, their strengths, limitations, and potential applicability in clinical practice.

Background

Critically ill medical patients face a heightened risk of developing venous thromboembolism. In Thailand, routine thromboprophylaxis is not employed. The incidence of deep vein thrombosis (DVT) in the medical intensive care unit (ICU) has not been elucidated in the Thai population.

Objectives

The aims were to evaluate the incidence of DVT and identify associated risk factors in critically ill medical patients.

Methods

A single-center, prospective cohort study was conducted from 2019 to 2020. Consecutive patients underwent screening for proximal DVT by duplex ultrasound of both legs.

Results

A total of 200 patients were enrolled, with 115 being male (57%). The mean (SD) age was 66.5 (16.4) years. The mean (SD) Acute Physiology and Chronic Health Evaluation II score was 27 (8). The cumulative incidence of DVT over 5 days was 7% (95% CI, 3.4%-10.6%). No clinically or radiologically diagnosed pulmonary embolism occurred in patients with DVT. No independent risk factor associated with DVT was identified. Hospital mortality in those with and those without DVT was 42.9% and 32.3%, respectively. There was no significant difference in the length of ICU or hospital stay or inpatient mortality between those with and those without DVT.

Conclusion

Without thromboprophylaxis, the incidence of DVT in the Thai population remains low. A strategy of screening ultrasound 5 to 7 days after admission to the ICU may be a suitable alternative to anticoagulant prophylaxis in critically ill Thai patients without symptoms of venous thromboembolism.

Background

Hemophilia significantly impacts joint health, necessitating innovative strategies for early detection and management of joint damage.

Objectives

This study assessed the impact of incorporating musculoskeletal ultrasound (MSKUS) into shared decision-making processes on prophylaxis regimens for patients with hemophilia over a 3-year period.

Methods

The “Joint Damage Monitoring by Ultrasonography in Patients with Hemophilia in Japan” study was a long-term prospective observational study conducted at Ogikubo Hospital, Tokyo, Japan. It enrolled 174 participants with moderate-to-severe hemophilia A or B. Participants underwent 6 monthly MSKUS evaluations, generating 3582 images from 682 joints; the findings guided adjustments of prophylaxis.

Results

Over the 3-year period, 69.3% of participants adjusted their prophylaxis regimen at least once. Adherence, defined as the ratio of the prescribed to the actual frequency of prophylaxis administration as agreed upon by physicians and patients, was high at the beginning of the study, with an average of 91.6%, and remained high after 3 years at 94.7%. The HEAD-US scores for elbows, knees, and ankles significantly improved (all P < .0001). The spontaneous annual joint bleeding rate and Hemophilia Joint Health Scores also significantly improved (P = .001 and P = .004, respectively). Synovitis detection decreased from 12.9% to 1.6%, with the majority of identified synovitis being subclinical (11.7%) and not associated with bleeding events in the 6 months preceding detection.

Conclusion

Integrating MSKUS into hemophilia care as a shared decision-making tool significantly facilitates the early detection of joint damage and supports personalized prophylaxis adjustments, markedly improving patient outcomes.

Background

Early thromboprophylaxis does not prevent hospital admissions and death among outpatients with symptomatic COVID-19. Its impact on long-term outcomes, including long COVID symptoms and performance status, is unknown.

Objectives

To assess the long-term effects of thromboprophylaxis given at the time of acute COVID-19 in outpatients.

Methods

The OVID (enoxaparin for outpatients with COVID-19) trial randomized outpatients older than 50 years with acute COVID-19 to receive either subcutaneous enoxaparin 40 mg once daily for 14 days or standard of care (no thromboprophylaxis). In this follow-up study, we assessed the 2-year outcomes, including all-cause hospitalization and death, cardiovascular events, long COVID symptoms, and functional limitations based on the Post–COVID-19 Functional Status (PCFS) scale and EuroQol-5 Dimensions-5 Levels scale.

Results

Of 469 potentially eligible patients, 468 survived, of whom 439 (mean age 59 years; 54% men) participated in the Post-OVID study. There was no difference in terms of hospitalization and death (8.3% in the treatment group vs 10% in controls; relative risk, 0.83; 95% CI, 0.5-1.5) and of cardiovascular events between groups. The risk of presenting with long COVID symptoms was similar in the 2 groups (44% in the treatment group vs 47% in the standard of care group), with no difference between groups also concerning individual symptoms. A PCFS grade of 1 to 3, indicating light-to-moderate functional limitation, was recorded in 15% of patients in each group (odds ratio, 0.98; 95% CI, 0.6-1.7). No patients reported severe limitations (PCFS grade 4). Median EuroQol visual analog scale score was 85 on 100 points (IQR, 80-90 for the standard of care group and 75-90 for the enoxaparin group).

Conclusion

Early thromboprophylaxis does not improve long-term, 2-year clinical and functional outcomes among symptomatic ambulatory patients with acute COVID-19.