Journal of Thrombosis and Haemostasis最新文献

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.

Background: The mitochondrial calcium uniporter (MCU), a selective intracellular calcium (Ca²⁺) channel, mediates mitochondrial Ca²⁺ uptake, supporting Ca²⁺ homeostasis and mitochondrial bioenergetics. While cytosolic Ca²⁺ flux from the dense tubular system (DTS) and store-operated Ca²⁺ entry are known to drive platelet activation, the role of mitochondrial Ca²⁺ handling in platelet function and thrombosis is not well understood.

Objectives: This study examined whether targeting MCU-dependent Ca²⁺ flux could attenuate platelet activation and arterial thrombosis.

Methods: Susceptibility to arterial thrombosis was assessed using the FeCl₃-induced carotid injury model in wild-type and MCU^-/- mice. Mitochondrial and cytosolic Ca²⁺ levels were measured in Rhod-2- and Fura-2-loaded platelets by fluorometry, and platelet bioenergetics were analyzed using a Seahorse extracellular flux analyzer.

Results: Genetic ablation of MCU inhibited agonist-induced platelet functions, including aggregation, fibrinogen binding to integrin α_IIbβ₃, granule secretion, and spreading on fibrinogen. MCU^-/- mice were less susceptible to in vivo arterial thrombosis with unaltered tail bleeding time, suggesting normal hemostasis. Mechanistically, these effects were associated with disruption of Ca²⁺ homeostasis mediated by reduced mitochondrial Ca²⁺ uptake, altered release of Ca²⁺ from dense tubular system, and impaired store-operated Ca²⁺ entry in agonist-stimulated MCU^-/- platelets. Consistent with this, Ca²⁺-dependent glycoprotein VI signaling events such as phospholipase γ2 and protein kinase C substrate phosphorylation were significantly reduced in collagen-stimulated MCU^-/- platelets. Furthermore, disruption of mitochondrial Ca²⁺ uptake significantly impaired mitochondrial respiration and associated adenosine triphosphate production in agonist-stimulated MCU^-/- platelets.

Conclusion: MCU facilitates platelet activation and thrombosis by regulating calcium flux (mitochondrial and cytosolic), thereby establishing its potential as a target for antithrombotic therapeutic intervention.

Background: Pain is a burden for people with hemophilia (PwH) and is often underdiagnosed. Therefore, it is crucial to develop accurate tools for pain assessment.

Objectives: Pain pressure thresholds (PPTs) are valuable in the diagnosis of pain sensitivity. The meaning and influencing factors in PwH were evaluated in this study.

Methods: We investigated PPTs in 327 PwH and 121 healthy controls to compare differences, examine the influence of age on PPT testing, and explore correlations between PPTs and numeric rating scale (NRS) categories or joint status. PPTs were measured bilaterally at hemophilia-specific joints (elbow/knee/ankle) and reference landmarks (sternum/forehead). Joint status was assessed via the Hemophilia Joint Health Score. NRS categories were used to evaluate current, mean, and maximum pain over the last 4 weeks.

Results: PPTs varied significantly across hemophilia-specific joints, such as the knees and ankles, compared with controls (P < .001), but showed no significant differences at the elbows (P ≥ .123) or at reference landmarks (P ≥ .621). Age did not influence PPTs in either group. In contrast, age-related effects were observed across nearly all NRS categories (current/mean/maximum) in both groups. Correlations between PPTs and NRS categories were low (r ≤ -.212), indicating that they measure different dimensions of pain.

Conclusion: This study demonstrates that PPT measurement is an important method of pain assessment in PwH. Joint-specific PPT values are independent of age and correlate with the presence of affected joints, potentially reflecting the local joint condition, while NRS categories likely represent the overall pain status. Therefore, PPT is a useful tool for pain assessment in PwH, particularly for the diagnosis of joint-specific pain sensitivity.

Background: Thrombin is generated from its precursor prothrombin by sequential cleavage at Arg320 and Arg271 by the prothrombinase complex, composed of factor (F)Xa and FVa on phospholipid (PL) surfaces. The affinity of human FXa for FVa is low in the absence of PL. However, FXa orthologs from the venom of group D snakes bind to FVa with high affinity, forming an active complex without PL. We previously characterized the properties of the FXa ortholog hopsarin D (HopD) from Hoplocephalus stephensii.

Objectives: In this study, we set out to create a PL-independent human prothrombinase by making mutations to FXa, guided by a model of the prothrombinase complex and the sequence differences between human FXa and HopD.

Methods: We assessed the contribution of individual domains of FXa to its binding to FVa by swapping each with the corresponding domain of HopD. We then chose 3 loops in the serine protease domain predicted to be in contact with FVa to swap to those of HopD. Eventually, 10 residues from the 3 loops in the serine protease domain and 7 from the epidermal growth factor 2 domain were selected for mutation.

Results: The resulting M17 FXa variant bound to FVa with a dissociation constant of 21 nM, similar to HopD, and together efficiently processed prothrombin through the meizothrombin intermediate in the absence of PL.

Conclusion: We conclude that the role of PL membranes in prothrombinase assembly and function is limited to improving the affinity of FXa for FVa and that the M17-FVa complex is likely to be structurally equivalent to human prothrombinase.

Background: Postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT), with residual venous obstruction (RVO) as a key contributing factor. Oxerutin, a venoactive drug, has the potential to promote DVT resolution, thereby reducing RVO and possibly preventing PTS.

Objectives: This pilot study aimed to estimate the effect of oxerutin therapy on RVO.

Methods: A single-center, patient-unblinded, physician-blinded, assessor-blinded, randomized controlled trial was conducted in adults with acute proximal DVT. Patients were randomized within 48 hours to receive 2-month oxerutin therapy plus standard treatment or standard treatment alone. The primary outcome was RVO at 3 months, defined as a transversal diameter ≥2mm on compressive ultrasound, with sensitivity analysis at ≥4 mm. Secondary outcomes included PTS at 3 months and biomarkers at 5 timepoints. The study was approved by the ethics committee. All patients gave written informed consent.

Results: A total of 44 patients were randomized to oxerutin or standard treatment. At 3 months, the proportion of RVO was lower in the oxerutin group, both for ≥2 mm (42.9% vs 59.1%; odds ratio [OR], 0.34; 95% CI, 0.08-1.28) and ≥4 mm (28.6% vs 54.5%; OR, 0.21; 95% CI, 0.04-0.85), adjusted for DVT extent. A lower proportion of PTS was observed in the oxerutin group (28.6% vs 40.9%; OR, 0.38; 95% CI, 0.08-1.53). Biomarker levels of intercellular adhesion molecule-1 and interleukin-6 were persistently lower in the oxerutin group.

Conclusion: Oxerutin therapy might reduce RVO by promoting DVT resolution. These preliminary findings support further investigation in a large-scale trial to assess the long-term prevention of PTS.