Journal of Thrombosis and Haemostasis最新文献

Diagnosing inherited thrombophilia as the cause of venous thromboembolism is important for patient management. Deficiencies in antithrombin, protein C, and protein S are usually diagnosed by plasma-based assays. Genetic testing can confirm the congenital nature of these deficiencies. Factor V Leiden can be detected using activated protein C resistance assays, followed by or replaced by molecular confirmation, whereas prothrombin G20210A can only be detected genetically. During the last decade, molecular techniques have evolved from single-gene sequencing to multigene sequencing panels. To understand current thrombophilia testing practices, a questionnaire was designed focusing on thrombophilia testing in coagulation laboratories and how genetic testing is placed in the diagnostic workflow. All International Society on Thrombosis and Haemostasis members and participants in external quality control schemes on thrombophilia testing were invited to complete the survey. Eighty-two unique responses were received. This international survey showed that laboratories perform plasma-based thrombophilia testing, but 42% restrict it to requests from thrombosis/hemostasis specialists, patients without anticoagulant treatment, or those with a strong personal of familial history of venous thrombosis. However, phenotypic testing is not always performed according to published guidelines. More specifically, the transference of reference intervals from manufacturers or literature is often suboptimal. For results interpretation, anticoagulant use and acquired causes were considered the most. Genetic testing is not systematically included in the diagnostic work-up algorithms and is mostly restricted to single-variant testing. Multigene panel testing is only performed by a minority of laboratories. Our results highlight the necessity for recommendations on how and when to perform this kind of testing.

Background: In traumatic hemorrhage, transfusion of donor-derived platelets improve hemostasis and survival, but their availability is often limited by supply constraints and short shelf-life. To address this, we have developed SynthoPlate (SP), a synthetic platelet nanotechnology that mimics the primary hemostatic functions of natural platelets, and have recently advanced its manufacturing into a shelf-stable, lyophilized powder for rapid aqueous-reconstitution and on-demand use.

Objectives: We aimed to evaluate the feasibility, safety, and efficacy of administering SP intraosseously in a rat model of traumatic hemorrhage, considering the critical clinical relevance of intraosseous access in prehospital and combat medicine.

Methods: We first assessed SP's hemostatic cooperativity with rat platelets using a microfluidic assay. Next, SP was administered intraosseously in rats to evaluate safety and biodistribution. Finally, 0.5 mg/kg of SP was administered intraosseously in a rat liver laceration model to assess effects on hemodynamics, blood loss, and survival.

Results: Microfluidic studies confirmed SP's hemostatic capability in platelet-depleted rat plasma. In pilot safety studies, intraosseously administered SP was well tolerated at doses up to 20 mg/kg, 40 times the proposed effective dose. In efficacy studies, rats treated with SP showed significantly reduced blood loss and improved survival compared with controls. SP-treated rats also exhibited higher mean arterial pressure postinjury, shorter durations of hypotension, and faster mean arterial pressure recovery.

Conclusion: This first-in-kind study demonstrates the feasibility of administering SP intraosseously to enhance hemostasis and survival in traumatic hemorrhage, supporting its potential as a rapidly deployable, shelf-stable platelet surrogate for use in emergency and austere settings.

Background: Adherence to oral anticoagulants (OACs) for atrial fibrillation (AF) stroke prevention is traditionally defined as taking 80% of doses as prescribed, but this threshold has not been clinically validated.

Objectives: We identified OAC adherence thresholds maximally associated with risk of clinical events in patients with AF and compared them with the conventional 80% threshold.

Methods: This was a cohort study using retrospective data of patients newly diagnosed with AF who were new OAC users from 1996 to 2019, based on population-based administrative data from British Columbia, Canada. We used Cox proportional hazards models with OAC proportion of days covered (PDC) as the main exposure captured during 90 days before outcome events or at the end of follow-up, then applied least absolute shrinkage and selection operator-estimated coefficient paths to identify candidate thresholds, and identified which were optimal in terms of outcomes.

Results: A total of 44 172 patients were included. For all outcomes, vitamin K antagonist (VKA) optimal thresholds were between PDC 0.85 and 0.95, and the direct OAC (DOAC) optimal threshold was PDC 0.9. Above vs below threshold outcome hazard reduction was greater for DOACs than for VKAs (DOACs: 19%-52% stroke risk reduction; VKAs: not significant for most outcomes). The PDC 0.8 threshold had inferior model fit and outcome effect compared with the optimal thresholds identified.

Conclusion: Optimal adherence thresholds are higher than conventionally assumed and, especially for DOACs, are strongly associated with clinical outcomes. These results provide a basis for considering updating the definition of OAC nonadherence to PDC <0.9 for DOACs and to PDC <0.9 or <0.95 for VKAs, depending on the outcome.

Background: Anticonvulsants vary in their theoretical propensity to interact with direct oral anticoagulants (DOACs). Coprescription may reduce DOAC efficacy and increase risk of thromboembolism.

Objectives: To evaluate the risk of clinical outcomes - thromboembolism, major bleeding, and death - among patients who were receiving a DOAC and newly treated with an interacting anticonvulsant relative to those newly treated with a non-interacting anticonvulsant.

Methods: We undertook 3 cohort studies using administrative health care data for Ontarians aged ≥66 years who were using a DOAC and newly prescribed 1 of 3 groups of anticonvulsants with declining theoretic propensity for interaction: group 1 (strongly interacting); group 2 (mildly interacting); and group 3 (potentially interacting). Each cohort was compared with a reference group of patients who were newly coprescribed a DOAC with a presumed noninteracting anticonvulsant. The primary outcome was hospitalization for thromboembolism. Secondary outcomes were major bleeding, death, and a composite of thromboembolism or death. Analysis was by propensity score inverse probability of treatment weighted competing risk Fine-Gray regression models.

Results: We studied 17 325 patients: 878 in group 1; 313 in group 2; 943 in group 3; and 15 191 in the reference group. After inverse probability of treatment weighted, we did not observe an association with thromboembolism or major bleeding in groups 1 to 3. The Cox proportional hazards ratio for death in those prescribed group 1 anticonvulsants was 2.21 (95% CI, 1.77-2.75).

Conclusion: In patients using a DOAC and newly prescribed a group 1, 2, or 3 anticonvulsant, we did not observe an increased risk of thromboembolism. In patients newly coprescribed a DOAC with a group 1 anticonvulsant, the observed increased risk of death is likely due to residual confounding.

Background: Emicizumab provides effective prophylaxis for hemophilia A (HA), but its cost puts a burden on health care systems. Pharmacokinetic (PK)-pharmacodynamic analyses suggest that emicizumab is effective at lower trough concentrations (Ctrough) than the mean 55 μg/mL reported with conventional dosing.

Objectives: To perform an interim analysis comparing bleeding control during 6 months of conventional emicizumab dosing vs PK-guided dosing in participants with HA, targeting a Ctrough of 25-35 μg/mL.

Methods: The DosEmi study (NCT06320626) is an ongoing multicenter, open-label, crossover Dutch trial. Eligible participants were aged ≥16 years using emicizumab for ≥12 months with good bleeding control (≤2 treated bleeds/6 months, none spontaneous). This planned interim analysis compared 6 months' bleeding on conventional dosing with PK-guided dosing. Study continuation criteria were ≤15% decrease in the proportion of participants without treated bleeds, maximum of 2 spontaneous bleeds overall, and <1.0 increase in bleeds/y (annualized bleeding rate).

Results: In 26 participants with severe HA, PK-guided dosing reduced emicizumab consumption by 39% (range, 13%-50%). The proportion of participants without treated bleeds was 69% with conventional dosing vs 58% with PK-guided dosing (risk difference, +11%; P = .254); the proportion without joint bleeds remained stable at 85% vs 88%, respectively (risk difference, -4%; P = .500). The annualized bleeding rate remained low (0.7 vs 0.9; P = .132), including 1 spontaneous muscle bleed (emicizumab concentration 52.5 μg/mL).

Conclusion: These interim results suggest that bleeding control with PK-guided reduced emicizumab dosing (target Ctrough 25-35 μg/mL) is similar to conventional dosing. All prespecified criteria for study continuation and inclusion of participants aged <16 years were met.

Recent advances in cancer treatment have improved outcomes for patients across a wide variety of cancers. However, despite the introduction of more targeted therapies, including those that harness the body's natural immune system, cancer-associated thrombosis, particularly during therapy, is a significant clinical problem associated with poorer outcomes. Although venous thromboembolism is more common, arterial events cause significant morbidity and are frequently fatal. In addition to the well-established chemotherapeutic regimens, multiple therapies are now used in the first-line setting, including antibody-based treatments, immunotherapy, and hormone receptor modulators. Many cancers are now being managed as chronic diseases with long-term maintenance therapies in an increasingly older patient population with significant comorbidities. With this change in the treatment landscape, predictive biomarkers are needed to effectively identify patients and treatments associated with the highest risk of thrombosis in the current cancer population. Although cancer-associated thrombosis has been extensively studied, the specific mechanisms by which cancer therapy causes thrombosis remain poorly understood. The pathogenesis of immunothrombosis associated with cancer treatments in particular is poorly defined. Focusing on solid tumors, the aim of this narrative review is to explore our current understanding of the pathogenesis of thrombotic effects of systemic cancer treatment. These include coagulation activation, vascular endothelial damage, procoagulant effects of material from dead and dying tumor cells, as well as the role of inflammatory mediators. Greater understanding of pathogenesis of treatment-related cancer-associated thrombosis will lead to the identification of more effective biomarkers to guide thromboprophylaxis.

We report the first case of immune-mediated thrombotic thrombocytopenic purpura (iTTP) successfully treated with recombinant ADAMTS13 (rhADAMTS13) during pregnancy. A 36-year-old woman with a history of severe iTTP and persistently undetectable ADAMTS13 activity despite multiple immunosuppressive therapies, remained relapse free for 10 years. In the 33rd week of pregnancy, she showed the first signs of relapse, whereupon rhADAMTS13 40 IU/kg was administered twice daily. ADAMTS13 activity and platelet count recovered rapidly, allowing a healthy newborn to be delivered safely by cesarean section. No adverse event was observed. rhADAMTS13 could represent an effective, well-tolerated therapeutic alternative for patients with iTTP and clinical or ADAMTS13 relapse. During pregnancy, where plasma exchange or caplacizumab are undesirable and recommendations are uncertain, this strategy could represent a promising therapeutic alternative in selected cases.

Background: Patients with renal cell carcinoma (RCC) and tumor thrombus (TT) are at significant risk of venous thromboembolism (VTE).

Objectives: This systematic review aimed to assess the role of anticoagulation in ambulatory patients with RCC and TT.

Methods: Inclusion criteria were diagnosis of RCC with TT, reporting of VTE, major bleeding and/or arterial thromboembolism, as well as exposure to anticoagulation. Studies with <30 patients were excluded. Studies were also excluded if anticoagulation status was not reported per outcome stratum. A comprehensive search was conducted in PubMed and other databases. Risk of bias was assessed in accordance with the Scottish Intercollegiate Guidelines Network bias quality assessment tool.

Results: Six observational studies containing 659 patients were included. All studies had considerable risk of bias. Anticoagulation use ranged from 3.9% to 50%. Two studies reported a lower VTE incidence in anticoagulated patients than in non-anticoagulated patients: 7.3% (1.2-21) vs 20% (6.9-37) after 1 year, and 18% (1.5-49) vs 24% (14-36) after 2 years. In anticoagulated patients, major bleeding incidence was 12% (2.8-27) after 1 year and 33% (8.2-60) after 2 years. For non-anticoagulated patients the incidence was 19% (6.6-36) after 1 year and 12% (5.1-22) after 2 years. Importantly, none of the studies were management studies, and confidence intervals of our outcomes were wide.

Conclusion: Anticoagulation in patients with RCC with TT may lower VTE risk. Bleeding risk is high in both anticoagulated as well as non-anticoagulated patients. Current evidence remains inconclusive due to study heterogeneity and risk of bias.

Background: Protein disulfide isomerases (PDIs) are a family of thiol oxidoreductases that catalyze the oxidation, reduction, and isomerization of disulfide bonds. While some PDIs enhance arterial thrombosis, their roles in coagulation system remain largely unknown.

Methods: The effect of a thiol blocker N-ethylmaleimide and a reducing agent dithiothreitol on factor XII activity was measured by chromogenic assay, activated partial thromboplastin time and thrombin generation assay. Redox states of FXII disulfides were determined by thiol labeling and mass spectrometry. Functional disulfides were evaluated through cysteine mutagenesis of FXII and predicting structural function via molecular dynamics simulations. Thiol modification and kinetic trapping were used to identify ERp46 substrates. The inferior vena cava stenosis model assessed the roles of ERp46 and FXII in venous thrombosis.

Results: N-ethylmaleimide significantly prolonged activated partial thromboplastin time and inhibited FXIIa chromogenic activity, while dithiothreitol inhibited clotting, thrombin generation, and substrate HK cleavage. Of the PDIs tested, only oxidized ERp46 enhanced FXII activity. Screening identified Cys513-Cys529 and Cys540-Cys571 as crucial disulfides for FXII function. Notably, half of Cys540-Cys571 were in partially disulfide-bonded form. ERp46 oxidized Cys540-Cys571 and increased FXII activity. In vivo, ERp46 deficiency reduced venous thrombus growth, with no additive effect observed in mice with combined ERp46 and FXII deficiency. Only wild-type FXII protein, not FXII/C540S-C571S mutant, restored venous thrombus growth in FXII-deficient mice.

Conclusion: These findings reveal a novel redox-regulatory mechanism for FXII activity and identify the critical role of ERp46 in oxidization of Cys540-Cys571 disulfide, facilitating the activation of FXII and intrinsic coagulation pathway.