Research and Practice in Thrombosis and Haemostasis最新文献

Background

Patient-reported outcomes (PROs) reflect patient perceptions of disease and treatment and are important for evaluating new therapies.

Objectives

Evaluate the effects of once-daily concizumab prophylaxis on health-related quality of life (HRQoL), treatment burden, and treatment preference in males aged ≥12 years with hemophilia A/B with inhibitors.

Methods

Patients enrolled in the multicenter, open-label explorer7 phase 3 study (ClinicalTrials.gov identifier: NCT04083781) were randomized to receive no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or were nonrandomly allocated to concizumab prophylaxis (arms 3 and 4). The study included questionnaires to assess patients’ perception of HRQoL (Haemophilia Quality of Life Questionnaire for Adults), treatment burden (Hemophilia Treatment Experience Measure), and treatment preference (Haemophilia Patient Preference Questionnaire).

Results

The estimated treatment difference between patients receiving concizumab prophylaxis vs no prophylaxis at week 24 for Haemophilia Quality of Life Questionnaire for Adults “total score” was −22.6 points (95% CI, −42.5; −2.7), directionally favoring patients receiving concizumab prophylaxis. For Hemophilia Treatment Experience Measure “total score,” the estimated treatment difference was −19.9 points (95% CI, −34.3, −5.6) in favor of concizumab vs no prophylaxis. The majority of patients receiving concizumab expressed a preference for concizumab over their previous treatment, the main reasons being “fewer bleeds,” “require less time,” and “less painful to inject.” Across all PROs, there were less responses collected than anticipated, limiting interpretations.

Conclusion

PROs collected during the explorer7 study showed improvements in some domains of HRQoL, treatment burden, and patient treatment preference in persons with hemophilia A or B with inhibitors receiving concizumab prophylaxis compared with no prophylaxis.

Clinical prediction modeling has become an increasingly popular domain of venous thromboembolism research in recent years. Prediction models can help healthcare providers make decisions regarding starting or withholding therapeutic interventions, or referrals for further diagnostic workup, and can form a basis for risk stratification in clinical trials. The aim of the current guide is to assist in the practical application of complicated methodological requirements for well-performed prediction research by presenting key dos and don’ts while expanding the understanding of predictive research in general for (clinical) researchers who are not specifically trained in the topic; throughout we will use prognostic venous thromboembolism scores as an exemplar.

Background

For the relationship between obesity and venous thromboembolism (VTE), nonalcoholic fatty liver disease (recently termed metabolic dysfunction–associated steatotic liver disease) is of interest given the hepatic role in hemostasis.

Objectives

We aimed to assess the association between the fatty liver index (FLI), as a proxy for nonalcoholic fatty liver disease, and VTE risk in a population-based cohort.

Methods

Data from the Tromsø 4 (1994-1995) and 6 (2007-2008) surveys were used to calculate the FLI in 9870 participants. All VTEs were recorded up to December 31, 2020. We used Cox regression to estimate hazard ratios for VTE with 95% CIs by FLI groups defined according to clinical cut-offs (<30, 30-59, and ≥60). Because waist circumference and body mass index (BMI) are main determinants for FLI calculation, we assessed the potential contribution of FLI to VTE risk beyond these body fat measures.

Results

During a median follow-up of 13.1 years, 507 incident VTEs occurred. Compared with the reference group (FLI < 30), the hazard ratios for VTE were 1.5 (95% CI, 1.1-1.9) and 1.8 (95% CI, 1.4-2.3) for the FLI 30-59 and ≥60 groups, respectively, in models adjusted for age, sex, alcohol intake, educational level, and physical activity. The association of FLI with VTE was no longer observed, with risk estimates close to unity, when participants were stratified by clinical categories of waist circumference and BMI.

Conclusion

Higher values of the FLI were associated with a higher VTE risk. This association was explained by waist circumference and BMI, which reflect excessive body fat deposition and are determinants of the FLI.

Acquired hemophilia A (AHA) is a rare autoimmune disease resulting from the development of autoantibodies directed against endogenous factor (F)VIII, leading to bleeding manifestations that can be life-threatening. The current standard hemostatic treatment involves the use of bypassing agents that circumvent FVIII (recombinant activated FVII, activated prothrombin complex concentrate, and recombinant porcine FVIII) that must be administered intravenously and possess a short half-life. These limitations and the risk of potentially fatal bleeding complications justify the early initiation of immunosuppressive treatment (IST) aimed at promptly eradicating the autoantibodies. IST is not without side effects, sometimes severe and possibly fatal, especially in persons with AHA who are generally older and have multiple comorbidities. Emicizumab, a bispecific antibody that mimics the action of FVIII, has emerged as an effective hemostatic therapy among persons with congenital hemophilia, whether complicated by the presence of anti-FVIII antibodies or not. Numerous arguments from recent clinical experiences suggest positioning emicizumab as a first-line treatment for AHA. This strategy has the potential to reduce bleeding complications and, importantly, the side effects associated with IST, which can be delayed and tailored to each patient.

Background

Joint bleeding can lead to synovitis and arthropathy in people with hemophilia, reducing quality of life. Although early diagnosis is associated with improved therapeutic outcomes, diagnostic ultrasonography requires specialist experience. Artificial intelligence (AI) algorithms may support ultrasonography diagnoses.

Objectives

This study will research, develop, and evaluate the diagnostic precision of an AI algorithm for detecting the presence or absence of hemarthrosis and synovitis in people with hemophilia.

Methods

Elbow, knee, and ankle ultrasound images were obtained from people with hemophilia from January 2010 to March 2022. The images were used to train and test the AI models to estimate the presence/absence of hemarthrosis and synovitis. The primary endpoint was the area under the curve for the diagnostic precision to diagnose hemarthrosis and synovitis. Other endpoints were the rate of accuracy, precision, sensitivity, and specificity.

Results

Out of 5649 images collected, 3435 were used for analysis. The area under the curve for hemarthrosis detection for the elbow, knee, and ankle joints was ≥0.87 and for synovitis, it was ≥0.90. The accuracy and precision for hemarthrosis detection were ≥0.74 and ≥0.67, respectively, and those for synovitis were ≥0.83 and ≥0.74, respectively. Analysis across people with hemophilia aged 10 to 60 years showed consistent results.

Conclusion

AI models have the potential to aid diagnosis and enable earlier therapeutic interventions, helping people with hemophilia achieve healthy and active lives. Although AI models show potential in diagnosis, evidence is unclear on required control for abnormal findings. Long-term observation is crucial for assessing impact on joint health.

Background

Factor (F)XI deficiency is a rare bleeding disorder with a poor correlation between bleeding tendency and FXI level. Management of pregnant women with FXI deficiency is not clearly established, especially regarding neuraxial analgesia (NA).

Objectives

A retrospective multicenter observational study was conducted in French hemostasis centers on pregnant women with FXI of <60 IU/dL.

Methods

Data to report were (i) FXI levels before pregnancy and at time of delivery, (ii) type of NA and delivery management modalities, and (iii) possible complications related to NA and bleeding complications.

Results

Three hundred fourteen pregnancies in patients with FXI deficiency of <60 IU/dL were reported (from 20 centers); among them, 199 NA procedures have been completed (137 epidurals and 61 spinals, 1 had both). The period of childbirth was mostly from 2014 to 2020 (281/314; 89.5%). Congenital FXI deficiency was established with certainty by investigators in 32.8% patients (n = 103). Previous bleedings were described in 20.4% of the patients (64/314; 45.3% cutaneous, 31.3% gynecologic, and 15.6% postsurgical). Thirteen deliveries had an NA procedure with FXI of <30 IU/dL, 42 with FXI of 30-40 IU/dL, and 118 with FXI of 40-60 IU/dL. Median FXI levels at delivery in the epidural and spinal groups were not significantly different but were significantly lower in the group without NA by medical staff contraindications. There were no complications related to NA. A 17.5% postpartum hemorrhage or excessive postpartum bleeding incidence was reported, which is consistent with previous data.

Conclusion

Our data support the use of a 30 IU/dL FXI threshold for NA, as suggested by the French proposals published in August 2023.

Background

Thrombin activatable fibrinolysis inhibitor (TAFI) is one of the most important physiological fibrinolysis inhibitors. Its inhibitory efficacy under physiological conditions remains uncertain.

Objectives

Elucidate the role of soluble thrombomodulin (sTM)/TAFI axis in the regulation of fibrinlysis.

Methods

Since thrombin is required to generate activated TAFI (TAFIa) that targets the C-terminal lysine of partially digested fibrin, a clot lysis assay is suitable for evaluating its function. Using tissue-type plasminogen activator-induced plasma clot lysis time (tPA-PCLT) together with TAFIa inhibitor and recombinant sTM (rsTM), we evaluated the specific function of TM/TAFI in the plasma milieu.

Results

tPA-PCLT values were significantly shortened by the TAFIa inhibitor. rsTM supplementation prolonged tPA-PCLT, which was shortened by the TAFIa inhibitor to a time similar to that obtained without rsTM and with the TAFIa inhibitor. Plasma obtained from patients treated with rsTM showed prolonged tPA-PCLT, which was shortened by the TAFIa inhibitor but not further prolonged by rsTM. However, no significant correlation was observed between tPA-PCLT and parameters of TM/TAFI system in the plasma.

Conclusion

The role of the TM/TAFI system in regulating fibrinolysis was successfully evaluated using TAFIa inhibitor and rsTM. Trace amounts of soluble TM in normal plasma appeared sufficient to activate TAFI and inhibit fibrinolysis. Further, a therapeutic dose of rsTM appeared sufficient to activate TAFI and regulate fibrinolysis in the plasma milieu.

Background

Multiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is frequently recommended but underutilized partly due to the absence of studies assessing bleeding risk.

Objectives

To determine the rate of severe (hospitalized) bleeding from thromboprophylaxis in patients treated for MM and identify clinical risk factors for bleeding in this population.

Methods

Using the MarketScan database, we analyzed 6656 patients treated for MM between 2013 and 2021. Concomitant thromboprophylaxis was defined using prescription claims. Hospitalized bleeding was identified through the Cunningham algorithm. Bleeding rates were compared by thromboprophylaxis status, and Cox regression identified risk factors for bleeding.

Results

Anticoagulant thromboprophylaxis was used in 6.6% (436) patients treated for MM. Patients on thromboprophylaxis had a higher rate of immunomodulatory-based therapy (63.8% vs 46.7%; P < .01) and lower rate of antiplatelet use (2.1% vs 4.7%; P < .01). Bleeding occurred in 1.4% of them during median follow-up of 1.3 years. Rate of severe bleeding was not different between those on prophylaxis (7.8 per 1000 person-years) and those not on prophylaxis (10.1 per 1000 person-years). No association was identified between thromboprophylaxis and bleeding. Factors associated with increased bleeding included age (hazard ratio [HR], 1.38 per 10 years increase in age), comorbidity index (HR, 1.18 per SD increase), history of bleeding (HR, 1.54), hypertension (HR, 1.87), and renal disease (HR, 1.56).

Conclusion

Risk of serious bleeding from thromboprophylaxis in patients treated for MM was low, and concomitant anticoagulant therapy did not result in increased bleeding risk. Clinical risk factors for bleeding included age, comorbidity index, bleeding history, hypertension, and renal disease.

Background

For patients anticoagulated with direct oral anticoagulants (DOACs) or warfarin and on aspirin (ASA) for nonvalvular atrial fibrillation and/or venous thromboembolism, it is unclear if bleeding outcomes differ.

Objectives

To assess bleeding rates for ASA with DOACs vs warfarin and one another.

Methods

Registry-based cohort study of patients followed by a 6-center quality improvement collaborative in Michigan using data from 2009 to 2022. The study included adults on ASA with warfarin or DOACs for atrial fibrillation and/or venous thromboembolism without a recent myocardial infarction or heart valve replacement.

Results

After propensity matching by anticoagulant class, we compared 2 groups of 1467 patients followed for a median of 18.0 months. Any bleeding and nonmajor bleeding was increased with DOACs + ASA compared with warfarin + ASA (32.2 vs 27.8 and 27.1 vs 22.9 events/100 patient-years; relative risks [RRs], 1.1 and 1.2; 95% CIs, 1.1-1.2 and 1.1-1.3, respectively). After matching by drug, patients on apixaban + ASA vs warfarin + ASA had more bleeding (31.2 vs 27.8 events/100 patient-years; RR, 1.1; 95% CI, 1.0-1.2) and nonmajor bleeding but less major bleeding (3.8 vs 4.7 events/100 patient-years; RR, 0.8; 95% CI, 0.6-1.0) and emergency room visits for bleeding. Patients on rivaroxaban + ASA vs warfarin + ASA had more bleeding (39.3 vs 26.3 events/100 patient-years, RR, 1.5; 95% CI, 1.3-1.6), nonmajor bleeding, and thrombosis. Patients on apixaban + ASA vs rivaroxaban + ASA had significantly less bleeding (22.5 vs 39.3/100 patient-years; RR, 0.6; 95% CI, 0.5-0.7), nonmajor bleeding, major bleeding (2.1 vs 5.5 events/100 patient-years; RR, 0.4; 95% CI, 0.2-0.6), emergency room visits for bleeding, and thrombotic events.

Conclusion

Patients on DOAC + ASA without a recent myocardial infarction or heart valve replacement had more nonmajor bleeding but otherwise similar outcomes compared with warfarin + ASA. Patients treated with rivaroxaban + ASA experienced more adverse clinical events compared with warfarin + ASA or apixaban + ASA.

Background

Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited.

Objectives

To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B.

Methods

Inhibitor development in PTPs was collected since 2008 from 97 centers participating in European HAemophilia Safety Surveillance. Per concentrate, inhibitors were reported quarterly and the number of PTPs treated annually. Incidence rates (IRs)/1000 treatment years with 95% CIs were compared between concentrate types (plasma derived FVIII/FIX, standard half-life recombinant FVIII/FIX, and extended half-life recombinant (EHL-rFVIII/IX) concentrates using IR ratios with CI. Medians and IQRs were calculated for inhibitor characteristics.

Results

For severe haemophilia A, inhibitor rate was 66/65,200 treatment years, IR 1.00/1000 years (CI 0.80-1.30), occurring at median 13.5 years (2.7-31.5) and 150 EDs (80-773). IR on plasma-derived pdFVIII (IR, 1.13) and standard half-life recombinant FVIII (IR, 1.12) were similar, whereas IR on EHL-rFVIII was lower at 0.13 (incidence rate ratio, 0.12; 95% CI, <0.01-0.70; P < .01).

For severe hemophilia B, inhibitor rate was 5/11,160 treatment years and IR was 0.45/1000 years (95% CI, 0.15-1.04), at median 3.7 years (95% CI, 2.1-42.4) and 260 EDs (95% CI, 130 to >1000). Data were insufficient to compare by type of FIX concentrates.

Conclusion

Low inhibitor rates were observed for PTPs with severe hemophilia A and B. Data suggested reduced inhibitor development on EHL-rFVIII, but no significant difference between plasma-derived FVIII and standard half-life recombinant FVIII. FIX inhibitor rates were too low for robust statistical analysis.