TH open : companion journal to thrombosis and haemostasis最新文献

Background: Approximately 20% of patients with cancer will have cancer-associated venous thromboembolism (CAT), which is associated with significant morbidity and mortality. Despite its clinical importance, CAT awareness in cancer patients and caregivers remains low. We sought to assess the patients' knowledge of CAT through a national survey.

Materials and methods: A survey assessing knowledge of different aspects of CAT was developed by a steering committee including four clinicians with expertise in CAT and a patient partner with lived experience. Survey dissemination among patients with cancer occurred through the Environics network, the Thrombosis Canada member network, the Thrombosis Canada social media platforms, and was advertised through Instagram and Facebook, and the Canadian Cancer Survivor Network newsletter.

Results: Out of the 312 patients with cancer or survivors who responded to the survey, 179 (57.4%) were female, and 118 (37.8%) were over 65 years old. Overall, 119 patients (38.1%, 95% confidence interval [CI]: 37.7-49.8%) reported having no knowledge of CAT. Only 84 (26.9%, 95% CI: 22.1-32.2%) and 94 (30.1%, 95% CI: 25.1-35.6%) patients reported receiving education about their underlying risk of CAT or education about signs and symptoms of venous thromboembolism, respectively. A total of 66 (21%, 95% CI: 16.8-26.1%) patients reported being informed by a health care professional about considering thromboprophylaxis. Patients were interested in learning more about the risk of CAT, its associated risk factors, and the benefits and potential side effects of thromboprophylaxis.

Conclusion: Many patients with cancer lack awareness or knowledge of CAT. Our results highlight ongoing education and awareness of the CAT burden.

Direct oral anticoagulants such as edoxaban are standard of care in current treatment of venous thromboembolism (VTE). However, phase III trial data need confirmation in real-world settings. We extracted data from the prospective, noninterventional multiple-indication DRESDEN NOAC REGISTRY to evaluate outcome rates during VTE treatment with edoxaban. Patients were included in this analysis, if they had acute VTE and if patient enrolment and edoxaban initiation occurred within 30 days after VTE diagnosis. Patient characteristics, treatment persistence, and clinical outcomes were centrally adjudicated using standard definitions. Until December 31, 2023, 323 acute VTE patients (median age 67 years, 56.7% male) were enrolled and initiated edoxaban within 7.8 ± 4.9 days (mean) for isolated deep vein thrombosis (DVT) (57.6%) or pulmonary embolism (PE) ± DVT (42.4%). Mean duration of follow-up was 3.9 ± 1.9 years with a mean duration of edoxaban exposure of 1.5 ± 1.7 years. During ongoing edoxaban therapy, 3/323 patients (0.9%) experienced recurrent VTE (0.6/100 patient-years); 141/323 (43.7%) patients reported clinically relevant International Society on Thrombosis and Haemostasis (ISTH) nonmajor bleeding and 16 reported ISTH major bleeding (5.0%; 3.2/100 patient-years). Death was observed in 53 patients (4.1/100 patient-years). At 6 months, 78.2% were still taking edoxaban, 2% were electively switched to dose-reduced secondary prophylaxis with apixaban 2.5 mg twice a day or rivaroxaban 10 mg once daily. The remaining patients had a scheduled end of VTE treatment (11.4%) or were switched to nonedoxaban therapeutic anticoagulation (6.2%). Our results indicate effectiveness of edoxaban in acute VTE treatment with excellent persistence in the treatment and low rates of unplanned discontinuation. Bleeding was frequently observed, but rates of major bleeding were low and comparable to phase III data.

Objective: This study reviewed the management and outcomes of traumatic brain injury (TBI) patients who developed venous thromboembolism (VTE) during hospitalization, focusing on the timing of VTE diagnosis and anticoagulation initiation.

Methods: This retrospective, single-center study utilized data from the University of Texas Trauma Database. Patients were categorized based on VTE diagnosis timing (early ≤7 days, late >7 days). The primary outcome was in-hospital mortality. Secondary outcomes included mortality specifically among patients who were receiving anticoagulation treatment, hemorrhagic complications, predictors associated with early anticoagulation initiation (defined as ≤ 7 days from VTE diagnosis), and whether anticoagulation timing influenced mortality.

Results: Among 237 patients (early: 145, late: 92), the mean age was 59 ± 20 years vs. 55 ± 20 years ( p  = 0.133). Males comprised 68% vs. 78% ( p  = 0.038). Subdural hematomas were the predominant injury (63% vs. 68%, p  = 0.443). In-hospital mortality was similar (10% vs. 13%, p  = 0.524) and did not differ between anticoagulated and non-anticoagulated patients ( p  = 0.94). Among patients who died, 73% in the early group and 100% in the late group had received anticoagulation ( p  = 0.053). Hemorrhage expansion was more frequent in early VTE patients (40% vs. 0%, p  = 0.046). Pulmonary embolism was associated with early anticoagulation (OR = 1.86, 95% CI: 1.09-3.17, p  = 0.023), while severe neurologic injury (GCS <9) reduced its likelihood (OR = 0.53, 95% CI: 0.28-0.98, p  = 0.042).

Conclusion: In-hospital mortality did not differ by VTE timing or anticoagulation status. However, hemorrhage expansion was more frequent in early VTE patients, particularly those with subdural hematomas, emphasizing the need for individualized anticoagulation strategies.

Objective: To assess real-world treatment patterns and outcomes in previously treated patients ≥12 years old with severe haemophilia A treated with marketed factor VIII (FVIII) replacement products.

Methods: Data were collected prospectively between 25 January 2019 and 30 November 2020 across 45 sites in 17 countries. Primary endpoint was annualized bleed rate (ABR). Secondary endpoints included factor consumption, bleed treatment, joint health, and safety. Exploratory endpoints included pain and quality of life outcomes.

Results: A total of 157 patients received ≥1 FVIII injection (prophylaxis n  = 139, on-demand n  = 19). Mean (standard deviation; SD) observation period was 43.1 (13.3) weeks. Median (quarter [Q]1, Q3) ABR was 2.0 (0.0, 5.7) for those on prophylaxis. Those receiving standard half-life FVIII products or extended half-life FVIII products had a median (IQR) ABR of 2.2 (0.0, 6.1) and 1.3 (0.0, 5.0), respectively. Still, only 35% of patients on prophylaxis experienced zero bleeds and 18% had five or more bleeds in a year. Approximately 23% of bleeding episodes required >1 FVIII dose for resolution. The mean (SD) number of routine prophylaxis injections/week was 2.2 (1.1). Median (Q1, Q3) annualized factor consumption for patients on prophylaxis was 4,106.4 (3,151.6, 5,291.2) IU/kg/year. No changes in Haemophilia Joint Health Score (mean [SD] of 16.1 [19.3] versus 15.7 [17.7]), PROMIS pain intensity 3a T-score (mean [SD] 41.6 [8.2] versus 40.9 [9.1]), or Haem-A-QoL (mean [SD] 30.6 [17.3] versus 29.5 [17.4]) were observed between baseline and the end of the observation period for those using prophylaxis.

Conclusions: Prophylaxis using standard or extended half-life FVIII replacement therapies achieves adequate haemostatic control in only about half of patients, with some experiencing very poor outcomes. Real-world data highlight the urgent need to optimize prophylaxis to enhance haemostatic control, ideally achieving a zero ABR and its associated benefits.

The development of inhibitors to von Willebrand factor (VWF) is a rare but potentially serious complication of VWF replacement therapy in patients with von Willebrand disease (VWD). Patients who develop VWF inhibitors may become unresponsive and/or may develop severe anaphylactic reactions to VWF concentrates. Data on inhibitor development and management in VWD remain limited, and better understanding of inhibitor development is an important goal in VWD management. The WIL-31 study demonstrated the efficacy and safety of prophylaxis with wilate, a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate, in children and adults with VWD of all types. The annualized bleeding rate (ABR) was reduced by 84% with wilate prophylaxis compared with on-demand treatment, and prophylaxis was well tolerated. No inhibitors developed during the WIL-31 study. Here, we report two brothers with type 3 VWD who at the 6-month visit were found to have VWF inhibitors, which on further investigation were found to have already been present before the study. Despite the presence of inhibitors, neither patient showed any clinical symptoms, and prophylaxis with wilate led to a ≥85% reduction in ABR in both boys compared with on-demand treatment.

Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone encoded by the SERPINH1 gene, has emerged as a groundbreaking focus in thrombosis research. Recent findings published in "Science" have revolutionized our understanding of thrombosis, identifying HSP47 as a critical mediator in a new thrombosis target for treatment. This discovery not only unveils a novel pathway in thrombosis but also opens new avenues for therapeutic intervention. HSP47's significance extends beyond thrombosis, influencing pathological processes such as fibrosis and cancer. In fibrosis, its upregulation promotes collagen deposition, while its dysregulation in osteogenesis imperfecta (OI) Type X underscores the protein's indispensable role in collagen biosynthesis. The therapeutic challenge lies in balancing HSP47 inhibition to reduce fibrotic burden without impairing its essential physiological functions. In cancer, HSP47 plays dual roles. It supports tumor progression through collagen stabilization and metastasis facilitation while contributing to tissue repair under hyperthermia treatment combined with radiotherapy or chemotherapy. However, its overexpression can exacerbate tumor aggressiveness via mechanisms such as angiogenesis and epithelial-mesenchymal transition. This review emphasizes the pivotal discovery of HSP47's thrombogenic role and its broader implications in disease biology. These findings mark a paradigm shift in thrombosis research and underscore the potential of HSP47 as a target in diverse pathological contexts, from platelet-driven diseases to fibrotic and oncological disorders.

Background: Venous thromboembolism (VTE) can considerably limit patients' functioning and quality of life. Using patient-reported outcome measures (PROMs), the full impact of VTE on individual patients can be captured.

Methods: To evaluate the experiences of patients and healthcare professionals with the routine use of PROMs for VTE patients visiting the outpatient clinic, a mixed-methods study was performed at Leiden University Medical Center, the Netherlands. VTE PROMs were incorporated into routine care since March 2023, through a digital application sending patients invitations to complete PROMs. Quantitative and qualitative data were obtained from semi-structured interviews with patients and involved healthcare professionals. The NoMAD (normalization measure development) questionnaire was used to assess the implementation process from the professionals' perspective. Patients aged ≥18 years who experienced VTE and completed PROMs at two follow-up time points during ≥3 months follow-up and VTE patients who did not complete PROMs at both time points were asked to participate.

Results: Eight patients (five completed PROMs; three did not) and four professionals were interviewed. Both patients and professionals experienced the use of PROMs as neutral to predominantly positive (lower limit 3 on a scale of 1-5). All professionals valued the effects of PROMs on their work. Most patients felt the questionnaires contained too many questions. Suggestions to improve the completion rate, accessibility, PROMs content, and the digital tool were shared.

Conclusion: PROMs were believed to provide additional value during preparation for the appointment and during the consultation. The first experiences of patients and professionals, tending toward positive, can be used to improve PROMs application and support implementation in routine thrombosis care.

Objective: To describe an innovative anticoagulation strategy in a 20-year-old woman with innate jejunal atresia and ultrashort bowel syndrome who was dependent on long-term parenteral nutrition and suffered from multiple venous thrombotic events and bleeding complications since infancy.

Design: Single-patient case report.

Setting: Dresden University Hospital, Dresden, Germany.

Patient: Being fully CVC-dependent since birth, our patient repeatedly developed catheter-related thrombosis (CRT) since infancy and was treated with daily low-molecular-weight heparin injections for more than 15 years. Despite this, clotting, severe gastrointestinal bleeding, and osteoporosis remained a persistent problem, causing numerous hospitalizations over the years, significant developmental delays, and a decline in the patient's body mass index (BMI). A short period of rivaroxaban treatment had to be stopped owing to acute gastrointestinal bleeding. After the failure of all approved anticoagulant concepts, compassionate use access was granted to the investigational drug osocimab, a human monoclonal antibody inhibitor of factor XIa. Hereditary FXI deficiency as well as FXI inhibition in animal models have been shown to reduce arterial and venous thrombosis without increasing bleeding. Consistent with this, short-term osocimab treatment has shown clinical efficacy in preventing postoperative venous thromboembolism after knee replacement surgery and in reducing dialysis conduit clotting compared with placebo in patients undergoing hemodialysis, without increasing the rate of clinically relevant bleeding versus comparators. After initiating osocimab, the patient experienced no further clotting complications, and bleeding decreased in frequency and severity. The patient's BMI decline immediately stopped; her weight increased by over 10% in the subsequent 20 months, and menstruation started 3 months later without signs of menorrhagia. Now, with 2.5 years of uninterrupted exposure outside of a clinical trial, this patient has experienced the longest duration of factor XIa inhibition to date. She continues to receive osocimab under the compassionate use program and maintains a positive change in her well-being and quality of life.

Background: Patients taking direct oral anticoagulants (DOACs) often present complicated scenarios following major bleeding, stroke, or emergency surgery. Rapid whole blood assays of DOAC levels would aid clinical decisions such as the need for DOAC reversal.

Methods: We developed a single-use, storage-stable, eight-channel microfluidic device to estimate factor Xa (FXa) inhibitor (apixaban or rivaroxaban) levels in venous thromboembolism or atrial fibrillation patients. The assay simultaneously measured whole blood clotting dynamics on collagen/tissue factor (TF; wall shear rate, 200 ^-1 ) under four ex vivo conditions: no-treatment control, high dose Factor Xa inhibition, low dose or high dose FXa reversal agent (andexanet alfa). Fibrin and platelet deposition dynamics were monitored via two-color epifluorescence microscopy. Plasma samples were also evaluated by LC-MS/MS for DOAC concentrations.

Results: Experiments with healthy volunteer blood spiked with DOAC verified device performance (DOAC IC ₅₀ ∼120 nM) and confirmed that andexanet alfa added to healthy donor blood had no off-target effect on platelet or fibrin signal. Patient whole blood monitored for 15 to 25 minutes (17 minutes mean runtime) allowed calculation of functional DOAC concentrations ranging from 2 to 500 nM that correlated well with LC-MS/MS determination of apixaban or rivaroxaban (R ²  = 0.7 or 0.9, respectively). Platelet dysfunction was not observed in any patient on DOAC. For a threshold of 100 nM DOAC, the area under the curve (AUC) was found to be 0.881 for apixaban and 0.933 for rivaroxaban.

Conclusion: Microfluidic testing of whole blood can provide a rapid estimate of DOAC levels over the on-therapy range.

Background: Hypercoagulability is a risk factor for venous thromboembolism (VTE). Thrombin generation (TG) is a global coagulation assay that measures an individual's clotting tendency. We hypothesise that slow-onset TG (achieved by using a low procoagulant stimulus or an inhibitor of coagulation) is the optimal responsive TG method for detecting hypercoagulability.This study aimed to compare different TG assay conditions with respect to VTE risk and assess the risk of the first VTE.

Materials and methods: Basal TG at low tissue factor (TF) concentration and high TF concentration in the presence and absence of activated protein C (APC) were measured in plasma samples from 2,081 patients with first VTE and 2,908 healthy controls from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study. TG parameters and normalised activated protein C sensitivity ratio (nAPCsr) were categorised into quartiles as measured in the controls. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) of the first VTE for different TG categories.

Results: Under all assay conditions the thrombin peak height was associated with VTE risk: peak height of >75th percentile, at low TF OR 6.8 (95% CI 5.5-8.3), at high TF, OR 3.0 (95% CI 2.5-3.6), and at high TF + APC, OR 3.8 (95% CI 3.2-4.5), all compared with a peak height of <25th percentile obtained in controls. An increased nAPCsr (higher resistance to APC) was also associated with VTE risk, OR 3.4 (95% CI 2.8-4.1).

Conclusion: Increased TG is associated with the risk of first VTE, particularly when triggered with a low procoagulant stimulus.