Journal of Thrombosis and Haemostasis最新文献

Background: Many research investigations for pulmonary embolism (PE) rely on the International Classification of Diseases 10th Revision (ICD-10) codes for analyses of electronic databases. The validity of ICD-10 codes in identifying PE remains uncertain.

Objectives: The objective of this study was to validate an algorithm to efficiently identify pulmonary embolism using ICD-10 codes.

Methods: Using a prespecified protocol, patients in the Mass General-Brigham hospitals (2016-2021) with ICD-10 principal discharge codes for PE, those with secondary codes for PE, and those without PE codes were identified (n = 578 from each group). Weighting was applied to represent each group proportionate to their true prevalence. The accuracy of ICD-10 codes for identifying PE was compared with adjudication by independent physicians. The F1 score, which incorporates sensitivity and positive predictive value (PPV), was assessed. Subset validation was performed at Yale-New Haven Health System.

Results: A total of 1712 patients were included (age: 60.6 years; 52.3% female). ICD-10 PE codes in the principal discharge position had sensitivity and PPV of 58.3% and 92.1%, respectively. Adding secondary discharge codes to the principal discharge codes improved the sensitivity to 83.2%, but the PPV was reduced to 79.1%. Using a combination of ICD-10 PE principal discharge codes or secondary codes plus imaging codes for PE led to sensitivity and PPV of 81.6% and 84.7%, respectively, and the highest F1 score (83.1%; P < .001 compared with other methods). Validation yielded largely similar results.

Conclusion: Although the principal discharge codes for PE show excellent PPV, they miss 40% of acute PEs. A combination of principal discharge codes and secondary codes plus PE imaging codes led to improved sensitivity without severe reduction in PPV.

Introduction: Long term-recurrence risk following a pregnancy associated venous thromboembolism (VTE) is sparsely assessed.

Objective: To determine the rate of recurrence after a pregnancy associated VTE, and identify associated risk factors.

Method: Five hundred and eighty-seven women with a history of first VTE occurring during pregnancy or until 3 months after delivery were referred to La Timone Hospital, Marseille, France. Women were consecutively included between 2000 and 2015. VTE characteristics and biological parameters were collected at inclusion. During the 2016-2019 period, patients were recontacted to gather information on post-inclusion VTE. A weighted Cox model, adapted to the study's ambispective design, was used to analyse pre- and post-inclusion VTE recurrences.

Results: After quality controls, 583 women were analyzed. Incidence of recurrent VTE was 2.4% person-years. Cumulative risk of VTE recurrence was 38% (n=221), with a median follow-up of 31 years (95%CI [27-35]); 6%, 13%, 17%, 30% at 2, 5, 10 and 30 years respectively. Pulmonary embolism (PE) at first event was associated with a 2-fold increased risk of PE at recurrence compared with isolated deep venous thrombosis (DVT, Hazard Ratio (HR)=2.63, 95%CI [1.44-4.82]). Risk factors significantly associated with recurrence were: interrupted pregnancies (HR=1.85, 95%CI [1.18-2.90]; lower limb DVT (HR=2.95, 95%CI [1.16-7.49] and AB blood group (HR=1.71, 95%CI [1.06-2.77]).

Conclusion: Although the recurrence risk is low within the first 10 years after a pregnancy associated VTE, 1/3 patients experienced a new event over a 30-year period. Interrupted pregnancies, lower limb DVT, and AB blood group were associated with higher risk of recurrence.

Background: Guidelines recommend using risk assessment tools to identify ambulatory patients with cancer at high risk of venous thromboembolism (VTE).

Objective: We aimed to validate a new cancer-associated thrombosis (CAT) risk score in a population-based healthcare setting.

Methods: We used healthcare registry data and electronic medical records from the Central Denmark Region to calculate the new CAT risk score and the guideline-recommended Khorana score in patients with a first-time cancer diagnosis who initiated systemic cancer therapy. Patients were followed for six months after initiation of therapy. The outcome was any VTE identified through hospital discharge diagnoses. Discrimination was assessed using c-statistics.

Results: We included 12,471 patients from 2012 through 2020. Of these, 416 (3.3%) developed VTE. The c-statistic was 0.71 (95% confidence interval [CI]: 0.68-0.74) for the new CAT score and 0.66 (95% CI: 0.63-0.70) for the Khorana score. The six-month cumulative VTE incidence was 5.0% in 6,175 patients classified as high risk by the new CAT score, compared with 1.7% in 6,296 patients classified as low risk. The six-month cumulative VTE incidence was 5.2% in 4,263 patients classified as high risk by the Khorana score, compared with 2.4% in 8,208 patients classified as low risk.

Conclusion: The new CAT score had a discriminatory ability similar to that reported in the derivation study. The c-statistic was numerically higher than that of the Khorana score. Our findings support implementation of the new CAT score to identify ambulatory patients with cancer who are at high risk of VTE.

The availability of direct oral anticoagulants (DOACs) rapidly changed the landscape of anticoagulation between 2010-present. Randomized controlled trials demonstrating efficacy with similar or superior safety compared to warfarin led to widespread use of DOACs in male and female patients of all ages. Years later, post-marketing data demonstrated a markedly increased rate of heavy menstrual bleeding (HMB) with rivaroxaban that had gone undetected in registry trials. Factor XI (FXI) inhibitors are currently being investigated as another alternative to available anticoagulation agents. While generally mild, the phenotype of inherited FXI deficiency includes bleeding in tissues with enhanced fibninolysis, including HMB. Thus, we aimed to perform a systematic review of published studies on FXI inhibitors in order to estimate rates of HMB. However, we found that few studies included menstruating individuals and even fewer specifically reported on uterine bleeding, highlighting once again a flaw in our approach to conducting trials of new anticoagulants.

Background and aims: Hypertrophic synovium (HS) is a marker of disease activity in patients with haemophilia (PwH). Although some recommendations suggest intensifying prophylaxis in PwH with HS, no validated schedules are available. We explored the efficacy of intensive Factor VIII (FVIII) replacement treatment in PwH with HS.

Methods: In a randomized, open-label study, PwH with HS were randomized to receive pharmacokinetics-driven prophylaxis targeting a FVIII through level of 8%-12% (intensive treatment arm [ITA]) or 3-5% (standard treatment arm [STA]). The primary outcome was HS reduction/resolution in the two treatment arms.

Results: A total of 39 PwH were randomized to ITA and 36 to STA. During the study, we found a lower Annual Bleeding Rate (ABR) and a higher rate of ABR zero in the ITA than in the STA. HS reduction/resolution was reported by 35.9% of cases in the ITA and by 8.4% in the STA. In detail, in the ITA 10.3% achieved HS reduction and 25.6% complete HS resolution, as compared to 5.6% and 2.8% in the STA. A COX regression showed that ITA was associated to HS reduction/resolution (Hazard ratio [HR]: 4.75, 95% confidence interval [CI]: 1.36-16.57, p=0.014) and to HS complete resolution (HR: 10.79, 95%CI: 1.38-84.45, p=0.023). The analysis on the 127 joints with HS (54 elbows, 41 knees and 32 ankles) consistently confirmed similar results.

Conclusions: In this randomized study, we found a ∼5-fold higher rate of HS reduction/resolution and a ∼10-fold higher rate of HS resolution in the ITA as compared to the STA.

Background: The most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobin G (IgG), termed inhibitors, against factor VIII (FVIII) which prevent FVIII replacement therapy. Low titers of FVIII-specific immunoglobin M (IgM) have been identified in hemophilia A patients with and without inhibitors, as well as healthy individuals. However, the duration and influence of IgM on the immune response to FVIII remains unclear.

Objective: To characterize the binding interactions of persistently secreted FVIII-specific IgM in hemophilia A mice and assess their effect on IgG antibody development.

Methods: Splenic-derived monoclonal antibodies (MAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase ELISA and computational modeling with HADDOCK to account for weak IgM binding.

Results: Sixteen porcine cross-reactive and non-inhibitory FVIII-specific IgM MAbs were identified. RNA sequencing of FVIII-specific IgM revealed 13 unique VDJ/VJ sequences indicating derivation from 13 unique B cell clones. IgM demonstrated polyclonal and polyreactive binding to FVIII in vitro and in silico. Molecular docking studies with reconstructed IgM VDJ/VJ regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215 or K2249 within the FVIII A2 and C2 domains. Injections of individual IgM prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect de novo FVIII antibody production.

Conclusion: Persistent FVIII-specific IgM are polyclonal but preferentially bind the A2 and C2 domains and FVIII/IgM immune complex formation do not significantly alter inhibitor development.

Background: The Kids-DOTT multinational randomized clinical trial (RCT) revealed non-inferiority of a six-week versus three-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old, in regard to net clinical benefit at one year.

Objective: To evaluate non-inferiority at two years.

Patients/methods: Patients whose repeat imaging six weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation versus receive a total three-month course and followed for two years for the occurrence of symptomatic recurrent (SR-) VTE (efficacy outcome) and clinically-relevant bleeding (CRB, safety outcome). Outcomes were centrally adjudicated and net clinical benefit was compared between treatment arms via a pre-specified bivariate non-inferiority boundary, using 95% confidence intervals (CIs) in absolute risk differences (ARDs) between treatment arms.

Results: Kaplan-Meier estimates of two-year cumulative incidences in the six-week and three-months arms of the intention-to-treat (ITT) population (n=417) were 1.7% (95% CI: 0%, 3.7%) and 2.9% (95% CI: 0.3%, 5.4%) for SR-VTE and 1.1% (95% CI: 0%, 2.5%) and 3.2% (95% CI: 0.6%, 5.7%) for CRB. Bivariate analysis of the ARDs in the ITT population demonstrated that a six-week anticoagulation duration was non-inferior to a three-month course.

Conclusions: These findings support durability of the Kids-DOTT RCT findings of net clinical benefit at two years.