Research and Practice in Thrombosis and Haemostasis最新文献

Background

Implantation of a left ventricular assist device (LVAD) is a crucial therapeutic option for selected end-stage heart failure patients. However, major bleeding (MB) complications postimplantation are a significant concern.

Objectives

We evaluated current risk scores’ predictive accuracy for MB in LVAD recipients.

Methods

We conducted an observational, single-center study of LVAD recipients (HeartWare or HeartMate-3, November 2010-December 2022) in the Netherlands. The primary outcome was the first post-LVAD MB (according to the International Society on Thrombosis and Haemostasis [ISTH] and Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS], and INTERMACS combined with intracranial bleeding [INTERMACS+] criteria). Mortality prior to MB was considered a competing event. Discrimination (C-statistic) and calibration were evaluated for the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke score, Anticoagulation and Risk Factors in Atrial Fibrillation score, Outpatient Bleeding Risk Index, venous thromboembolism score, atrial fibrillation score, and Utah Bleeding Risk Score (UBRS).

Results

One hundred four patients were included (median age, 64 years; female, 20.2%; HeartWare, 90.4%; HeartMate-3, 9.6%). The cumulative MB incidence was 75.7% (95% CI 65.5%-85.9%) by ISTH and INTERMACS+ criteria and 67.0% (95% CI 56.0%-78.0%) per INTERMACS criteria over a median event-free follow-up time of 1916 days (range, 59-4521). All scores had poor discriminative ability on their intended prediction timeframe. Cumulative area under the receiving operator characteristic curve ranged from 0.49 (95% CI 0.35-0.63, venous thromboembolism-BLEED) to 0.56 (95% CI 0.47-0.65, UBRS) according to ISTH and INTERMACS+ criteria and from 0.48 (95% CI 0.40-0.56, Anticoagulation and Risk Factors in Atrial Fibrillation) to 0.56 (95% CI 0.47-0.65, UBRS) per INTERMACS criteria. All models showed poor calibration, largely underestimating MB risk.

Conclusion

Current bleeding risk scores exhibit inadequate predictive accuracy for LVAD recipients. There is a need for an accurate risk score to identify LVAD patients at high risk of MB who may benefit from patient-tailored antithrombotic therapy.

The management of hemophilia, von Willebrand disease (VWD), and rare coagulation disorders traditionally relied on replacement therapies, such as factor concentrates, to address clotting factor deficiencies. However, in recent years, the emergence of nonreplacement therapies has shown promise as an adjunctive approach, especially in hemophilia, and also for patients with VWD and rare bleeding disorders.

This review article offers an overview of nonreplacement therapies, such as FVIII-mimicking agents and drugs aimed at rebalancing hemostasis by inhibiting natural anticoagulants, particularly in the management of hemophilia. The utilization of nonreplacement therapies in VWD and rare bleeding disorders has recently attracted attention, as evidenced by presentations at the International Society on Thrombosis and Haemostasis 2023 Congress. Nonreplacement therapies provide alternative methods for preventing bleeding episodes and enhancing patients’ quality of life, as many of them are administered subcutaneously and allow longer infusion intervals, resulting in improved quality of life and comfort for patients.

Background

Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR.

Objectives

To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics.

Methods

Moderate or severe MR patients (n = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed.

Results

At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%).

Conclusion

Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients.

Background

Venous thromboembolism (VTE) is associated with various long-term complications.

Objectives

We aimed to investigate the association of clinical characteristics at VTE diagnosis with functional limitations 3 and 12 months afterward.

Methods

We conducted a prospective cohort study of VTE patients, excluding patients with cancer, pregnancy, and postpartum period. Functional limitations were assessed with the post-VTE functional status (PVFS) scale (range, 0-4) within 21 days of diagnosis, after 3 and 12 months (prospectively), and 1 month before diagnosis (retrospectively). Twelve-month follow-up was only performed in patients on anticoagulation. We fitted 2 proportional odds logistic regression models for the 3- and 12-month follow-ups and computed odds ratios (ORs) with 95% bootstrap percentile confidence intervals (CIs).

Results

We included 307 patients (42% female, median age 55.6 years) with a median (IQR) PVFS scale grade of 2 (2-3) at study inclusion and 0 (0-0) before diagnosis. After 3 months, PVFS scale grade in 269 patients was 1 (0-2). Female sex (OR, 2.15; 95% CI, 1.26-4.14), body mass index (OR per 1 kg/m² increase, 1.05; 95% CI, 1.00-1.10), functional limitations at baseline, and older age were associated with functional limitations. After 12 months, PVFS scale grade in 124 patients was 1 (0-2). Female sex (OR, 4.47; 95% CI, 2.11-16.00), history of cardiovascular/pulmonary disease (OR, 2.36; 95% CI, 1.01-6.89), and functional limitations at baseline were associated with functional limitations.

Conclusion

Functional limitations in VTE patients improved 3 and 12 months after diagnosis but did not return to pre-VTE values. We identified clinical characteristics that could help identify patients at risk of persisting functional limitations after VTE.

Background

Venous thromboembolic events have been reported in persons with hemophilia A who received emicizumab and activated prothrombin complex concentrate (APCC) concomitantly, but the relevant mechanism(s) remains unclear. We speculated that activated protein C (APC) and antithrombin (AT) resistance might be associated with these adverse events.

Objectives

To investigate APC and AT resistance in factor (F)VIII–deficient (FVIIIdef) plasma in the presence of emicizumab and APCC.

Methods

In pooled normal plasma or FVIIIdef plasma samples mixed with emicizumab (50 μg/mL) and FVIII-bypassing agents, including recombinant FVIIa (2.2 μg/mL), APCC (1.3 IU/mL), or plasma-derived FVIIa/FX (1.5 μg/mL), the suppression effect of AT (0-2.4 μM) and APC (0-16 nM) was assessed by tissue factor–triggered thrombin generation assay. The APC effects in FVIIIdef plasma with the copresence of emicizumab, FII (1.3 μM), and/or FIXa (280 pM) were also examined.

Results

The AT resistance in emicizumab and each bypassing agent was not observed. Moreover, APC dose-dependent suppression effect was observed in pooled normal plasma or FVIIIdef plasma mixed with emicizumab and recombinant FVIIa or plasma-derived FVIIa/FX. However, APC-catalyzed inactivation had little effect on thrombin generation assay potential in FVIIIdef plasma spiked with emicizumab and APCC. The addition of FIXa to emicizumab in FVIIIdef plasma could lead to partial APC resistance. Furthermore, FVIIIdef plasma spiked with emicizumab, FIXa, and FII was markedly resistant to APC-mediated inactivation.

Conclusion

FII and FIXa in APCCs were key clotting factors for APC resistance in FVIIIdef plasma supplemented with emicizumab and APCCs. The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events.

The topic of this review is venous thromboembolism (VTE) during pregnancy and postpartum. The following topics will be addressed: epidemiology and pathophysiology of VTE in pregnancy and postpartum, diagnostic considerations for VTE in pregnancy, indications for prophylactic and therapeutic anticoagulation in pregnancy and postpartum, choice of anticoagulation in pregnancy and breastfeeding, anticoagulation management during labor and delivery, and anticoagulation considerations for assisted reproductive technology.

Background

Cardiac surgery is a high-risk setting for heparin-induced thrombocytopenia (HIT). However, large differences in its incidence, rate of thrombotic complications, and mortality have been reported in this context. Few studies address the pharmacologic management of HIT specifically in this setting.

Objectives

To describe the incidence, outcomes, and management of patients with HIT in our cohort and to compare them with patients presenting platelet factor 4/heparin antibodies but without platelet-activating capacity.

Methods

A retrospective observational study was conducted over a period of 10 years and 6 months on 13,178 cardiac operations in a single high-volume cardiac surgery center.

Results

HIT was diagnosed in 0.22% of patients. HIT with associated thromboembolic complications occurred in 0.04% of cases. Two deaths at 30 days were registered, both in patients with associated thrombosis. The 4T score showed a 99.9% negative predictive value. The immunoglobulin G-specific chemiluminescence test positivity rate was highly predictive of HIT. Warfarin was often started early after surgery, and although it was rarely stopped when the diagnosis of HIT was made, no new thromboembolic complications subsequently occurred. Thrombocytopenia appeared to be a poor prognostic sign, whatever the cause.

Conclusion

Although rare, HIT is characterized by high mortality in this setting, especially if thrombotic complications occur. Large multicentric studies or an international registry should be created to enhance the scientific evidence on HIT diagnosis and management in this context.

Background

Overuse of antiplatelet therapy and underuse of gastroprotection contribute to preventable bleeding in patients taking anticoagulants.

Objectives

(1) Determine the feasibility of a factorial trial testing patient activation and clinician outreach to reduce gastrointestinal (GI) bleeding risk in patients prescribed warfarin–antiplatelet therapy without proton pump inhibitor gastroprotection and (2) assess intervention acceptability.

Methods

Pragmatic 2 × 2 factorial cluster-randomized controlled pilot comparing (1) a patient activation booklet vs usual care and (2) clinician notification vs clinician notification plus nurse facilitation was performed. The primary feasibility outcome was percentage of patients completing a structured telephone assessment after 5 weeks. Exploratory outcomes, including effectiveness, were evaluated using chart review, surveys, and semistructured interviews.

Results

Among 47 eligible patients, 35/47 (74.5%; 95% CI, 58.6%-85.7%) met the feasibility outcome. In the subset confirmed to be high risk for upper GI bleeding, 11/29 (37.9%; 95% CI, 16.9%-64.7%) made a medication change, without differences between intervention arms. In interviews, few patients reported reviewing the activation booklet; barriers included underestimating GI bleeding risk, misunderstanding the booklet’s purpose, and receiving excessive health communication materials. Clinicians responded to notification messages for 24/47 patients (51.1%; 95% CI, 26.4%-75.4%), which was lower for surgeons than nonsurgeons (22.7% vs 76.0%). Medical specialists but not surgeons viewed clinician notification as acceptable.

Conclusion

The proposed trial design and outcome ascertainment strategy were feasible, but the patient activation intervention is unlikely to be effective as designed. While clinician notification appears promising, it may not be acceptable to surgeons, findings which support further refinement and testing of a clinician notification intervention.

Background

To overcome deficiencies of the traditional von Willebrand factor (VWF) ristocetin cofactor activity assay (VWF:RCo), several automated assays for VWF platelet-binding activity have been developed. Information on the performance of these assays and their diagnostic utility remains limited.

Objectives

To validate the VWF:glycoprotein IbM assay INNOVANCE VWF Ac and compare it with an automated VWF:RCo assay as well as with an automated assay and a manual VWF:Ab assay and to generate reference ranges and analyze reproducibility of the VWF:glycoprotein IbM assay.

Methods

Clinical sites enrolled healthy subjects and patients representing the intended use population; VWF activity assays were performed, and results were analyzed. The performance of the INNOVANCE VWF Ac assay was also compared between the BCS XP System and the CS-2500 and CS-5100 analyzers.

Results

The INNOVANCE VWF Ac assay correlated well with the VWF:RCo assay and the automated HemosIL VWF:Ab assay, with Pearson coefficients of >.9 and a predicted bias of ≤5.0 IU/dL at VWF levels of 30 IU/dL and ≤5.8 IU/dL at the levels of 50 IU/dL, but correlation and bias were not as good when compared with the REAADS manual VWF:Ab assay. Reference ranges observed for healthy subjects correlated well with previously published findings. Reproducibility of the INNOVANCE VWF Ac assay on the BCS XP System and the CS analyzers was excellent, as was correlation among devices.

Conclusion

The characteristics of the INNOVANCE VWF Ac assay regarding comparability with other VWF activity assays, reference ranges, and precision support the use of this assay for evaluation of patients with concern for von Willebrand disease.

Background

Biomarkers of fibrinolysis are elevated during acute immunologic reactions (allergic reactions and angioedema), although it is unclear whether fibrinolysis is associated with disease severity.

Objectives

We investigated a possible association between maximum lysis (ML) measured by thromboelastography and the severity of acute immunologic reactions.

Methods

We recruited patients with acute immunologic reactions at a high-volume emergency department. Clinical disease severity at presentation and at the end of the emergency department stay was assessed using a 5-grade scale, ranging from local symptoms to cardiac arrest. We determined ML on admission by thromboelastography (ROTEM's extrinsic [EXTEM], and aprotinin [APTEM] tests), expressed as ML%. Hyperfibrinolysis was defined as an ML of >15% in EXTEM, which was reversed by adding aprotinin (APTEM). We used exact logistic regression to investigate an association between ML% and disease severity (grades 1 and 2 [mild] vs 3-5 [severe]) and between hyperfibrinolysis and disease severity.

Results

We included 31 patients (71% female; median age, 52 [IQR, 35-58] years; 10 [32%] with a severe reaction). ML% was higher in patients with severe symptoms (21 [IQR, 12-100] vs 10 [IQR, 4-17]). Logistic regression found a significant association between ML% and symptom severity (odds ratio, 1.07; 95% CI, 1.01-1.21; P = .003). Hyperfibrinolysis was detected in 6 patients and found to be associated with severe symptoms (odds ratio, 17.59; 95% CI, 1.52-991.09; P = .02). D-dimer, tryptase, and immunoglobulin E concentrations increased with the severity of immunologic reactions.

Conclusion

ML, quantified by thromboelastography, is associated with the severity of acute immunologic reactions.