Prevention of perioperative venous thromboembolism: 2024 guidelines from the French Working Group on Perioperative Haemostasis (GIHP) developed in collaboration with the French Society of Anaesthesia and Intensive Care Medicine (SFAR), the French Society of Thrombosis and Haemostasis (SFTH) and the French Society of Vascular Medicine (SFMV) and endorsed by the French Society of Digestive Surgery (SFCD), the French Society of Pharmacology and Therapeutics (SFPT) and INNOVTE (Investigation Network On Venous ThromboEmbolism) network.

BACKGROUND: Any surgical procedure carries a risk for venous thromboembolism (VTE), albeit variable. Improvements in medical and surgical practices and the shortening of care pathways due to the development of day surgery and enhanced recovery after surgery, have reduced the perioperative risk for VTE. OBJECTIVE: A collaborative working group of experts in perioperative haemostasis updated in 2024 the recommendations for the Prevention of perioperative venous thromboembolism published in 2011. METHODS: The addressed questions were defined by 40 experts (GIHP, SFAR, SFTH and SFMV) and formulated in a PICO format. They performed the literature review and formulated recommendations according to the Grading of GRADE system. Recommendations were then validated by a vote determining the strength of each recommendation. Of note, these recommendations do not cover all surgical specialties. Especially, thromboprophylaxis in cardiac surgery, neurosurgery and obstetrics is not addressed. RESULTS: 78 recommendations were formalized into 17 sections, including patient-related VTE risk factors, types of surgery, extreme body weight, renal impairment, mechanical prophylaxis, distal deep vein thrombosis; 27 were found to have a high level of evidence (GRADE 1) and 41 a low level of evidence (GRADE 2) and 10 were expert opinion. All had strong agreement among the experts. CONCLUSIONS: These guidelines help to weigh the perioperative risk for VTE (which includes the risk associated to surgery and the patient-related risk) against the adverse effects of thromboprophylaxis, either pharmacological or mechanical. This includes particularly the bleeding risk induced by antithrombotic drugs as well as costs.

Management of anticoagulation and factor XIII replacement in a patient with severe factor XIII deficiency and recurrent venous thromboembolic disease: case report and review of literature.

Background: Thrombotic events in congenital factor (F)XIII deficiency are extremely rare. To our knowledge, we describe the first case of severe congenital FXIII deficiency associated with recurrent venous thrombotic events. Key Clinician Question: How to deal with anticoagulation treatment in patients with severe FXIII deficiency? Clinical Approach: The patient was treated with rivaroxaban and plasma-derived FXIII substitution therapy as prophylaxis without bleeding complications. We aimed at FXIII trough levels of 50% during the loading doses of rivaroxaban, then 30% during the maintenance dose of rivaroxaban, and finally 20% during the long-term use of prophylactic dose of rivaroxaban. Conclusion: Treatment of thrombotic events with rivaroxaban in patients with severe bleeding disorders seems to be safe, requiring an adaptation of the intensity of the replacement therapy.

[Angiology and hemostasis: what's new in 2023]. / Angiologie et hémostase: ce qui a changé en 2023.

We discuss four topics among the angiology and hemostasis studies of importance in 2023. The BASIL-2 study provides new data for the management of chronic limb-threatening ischemia by comparing surgical and endovascular treatment. The new classification of antiphospholipid antibody (aPL) syndrome integrates new clinical elements and gives a different weight among the isotype and titer of aPL. Concizumab, an antibody targeting the tissue factor pathway inhibitor, broadens the therapeutic arsenal for hemophilia A and B as evidenced by the results of the EXPLORER 7 study. The PREVENT-CLOT and CASTING study focus on the prevention of thrombosis after trauma, by testing the role of aspirin or the lack of thromboprophylaxis, respectively.

Parmi les sujets d'angiologie et d'hémostase qui ont marqué l'année 2023, quatre ont retenu notre attention. L'étude BASIL-2 apporte de nouvelles données pour la prise en charge de l'ischémie critique des membres inférieurs en comparant les traitements chirurgical et endovasculaire. La nouvelle classification du syndrome des anticorps antiphospholipides (aPL) intègre de nouveaux items cliniques et donne un poids différent aux isotypes et titres des aPL. Le concizumab, un anticorps ciblant l'inhibiteur de la voie du facteur tissulaire, vient élargir l'arsenal thérapeutique pour les hémophilies A et B comme en témoignent les résultats de l'étude EXPLORER 7. Les études PREVENT-CLOT et CASTING s'intéressent à la prévention de la thrombose après traumatisme, en testant la place de l'aspirine ou l'absence de thromboprophylaxie.

Longitudinal profile of estrogen-related thrombotic biomarkers after cessation of combined hormonal contraceptives.

ABSTRACT: The persistence of risk of venous thromboembolism (VTE) due to combined hormonal contraceptives (CHCs), after their cessation, is unknown but important to guide clinical practice. The objective of this prospective cohort study was to define the time until normalization of estrogen-related thrombotic biomarkers after CHC cessation. We enrolled women aged 18 to 50 years who had decided to stop their CHC, excluding those with a personal history of VTE, anticoagulation, or pregnancy. The study started before cessation of CHC, with 6 visits afterwards (at 1, 2, 4, 6, and 12 weeks after cessation). Primary outcomes were normalized sensitivity ratios to activated protein C (nAPCsr) and to thrombomodulin (nTMsr), with sex hormone-binding globulin (SHBG) as a secondary end point. We also included control women without CHC. Among 66 CHC users, from baseline until 12 weeks, average levels of nAPCsr, nTMsr, and SHBG decreased from 4.11 (standard deviation [SD], 2.06), 2.53 (SD, 1.03), and 167 nmol/L (SD, 103) to 1.27 (SD, 0.82), 1.11 (SD, 0.58), and 55.4 nmol/L (SD, 26.7), respectively. On a relative scale, 85.8%, 81.3%, and 76.2% of the decrease from baseline until 12 weeks was achieved at 2 weeks and 86.7%, 85.5%, and 87.8% at 4 weeks after CHC cessation, respectively. Levels were not meaningfully modified throughout the study period among 28 control women. In conclusion, CHC cessation is followed by a rapid decrease in estrogen-related thrombotic biomarkers. Two to 4 weeks of cessation before planned major surgery or withdrawal of anticoagulants in patients with VTE appears sufficient for the majority of women. The trial is registered at www.clinicaltrials.gov as #NCT03949985.

Apixaban and rivaroxaban's physiologically-based pharmacokinetic model validation in hospitalized patients: A first step for larger use of a priori modeling approach at bed side.

When used in real-world conditions, substantial interindividual variations in direct oral anticoagulant (DOAC) plasma concentrations are observed for a given dose, leading to a risk of over- or under-exposure and clinically significant adverse events. Physiologically-based pharmacokinetic (PBPK) models could help physicians to tailor DOAC prescriptions in vulnerable patient populations, such as those in the hospital setting. The present study aims to validate prospectively PBPK models for rivaroxaban and apixaban in a large cohort of elderly, polymorbid, and hospitalized patients. In using a model of geriatric population integrating appropriate physiological parameters into models first optimized with healthy volunteer data, observed plasma concentration collected in hospitalized patients on apixaban (n = 100) and rivaroxaban (n = 100) were adequately predicted (ratio predicted/observed area under the concentration curve for a dosing interval [AUCtau ] = 0.97 [0.96-0.99] geometric mean, 90% confidence interval, ratio predicted/observed AUCtau = 1.03 [1.02-1.05]) for apixaban and rivaroxaban, respectively. Validation of the present PBPK models for rivaroxaban and apixaban in in-patients represent an additional step toward the feasibility of bedside use.

Clinicians' adherence to guidelines for the preoperative management of direct oral anticoagulants in a tertiary hospital: a retrospective study.

INTRODUCTION: Despite clear, relatively easy-to-use guidance, many clinicians find the preoperative management of direct oral anticoagulants (DOACs) challenging. Inappropriate management can delay procedures and lead to haemorrhagic or thromboembolic complications. We aimed to describe preoperative management practices regarding DOACs in a tertiary hospital and clinicians' adherence to in-house recommendations. METHOD: We included all patients being treated with DOACs who underwent elective surgery in 2019 and 2020 (n = 337). In-house recommendations for perioperative management were largely comparable to the 2022 American College of Chest Physicians guidelines. RESULTS: Typical patients were older adults with multiple comorbidities and high thrombotic risk stratification scores, and 65.6% (n = 221) had not undergone recommended preoperative anticoagulation management protocols. Patients operated on using local anaesthesia (adjusted OR = 0.30, 95%CI 0.14-0.66; p < 0.01) were less likely to have been treated following institutional recommendations, but no association between their procedure's bleeding risk and adherence was found. Clinicians' failures to adhere to recommendations mostly involved late or non-indicated interruptions of anticoagulation treatment (n = 89, 26.4%) or inappropriate heparin bridging (n = 54, 16.0%). Forty-five (13.3%) procedures had to be postponed. Incorrect preoperative anticoagulation management was directly responsible for 12/45 postponements (26.7% of postponements). CONCLUSION: This study highlights clinicians' low adherence rates to institutional recommendations for patients treated with DOACs scheduled for elective surgery in a tertiary hospital centre. To the best of our knowledge, this is the first clinical study addressing the issue of clinicians' adherence to guidelines for the preoperative management of DOACs. Going beyond the issue of whether clinicians are knowledgeable about guidelines or have them available, this study questions how generalisable guidelines are in a tertiary hospital managing many highly polymorbid patients. Further studies should identify the causes of poor adherence.

Population pharmacokinetics of apixaban in a real-life hospitalized population from the OptimAT study.

This study aimed to characterize apixaban pharmacokinetics (PKs) and its variability in a real-world clinical setting of hospitalized patients using a population PK (PopPK) approach. Model-based simulations helped to identify factors that affect apixaban exposure and their clinical significance. A classic stepwise strategy was applied to determine the best PopPK model for describing typical apixaban PKs in hospitalized patients from the OptimAT study (n = 100) and evaluating the associated variability and influencing factors. Apixaban exposure under specific conditions was assessed using the final model. A two-compartment model with first-order absorption and elimination best described the data. The developed PopPK model revealed a major role of renal function and a minor role of P-glycoprotein phenotypic (P-gp) activity in explaining apixaban variability. The final model indicated that a patient with stage 4 chronic kidney disease (creatinine clearance [CLcr] = 15-29 mL/min) would have a 45% higher drug exposure than a patient with normal renal function (CLcr >90 mL/min), with a further 12% increase if the patient was also a poor metabolizer of P-gp. A high interindividual variability in apixaban PKs was observed in a real-life setting, which was partially explained by renal function and by P-gp phenotypic activity. Target apixaban concentrations are reached under standard dosage regimens, but overexposure can rapidly occur in the presence of cumulative factors warranting the development of a predictive tool for tailoring apixaban exposure and its clinical utility in at-risk patients.

Recommendations for the use of andexanet alfa in the management of bleeding in patients on oral factor Xa inhibitors in Switzerland: Guideline from the Working Party Hemostasis of the Swiss Society of Hematology

Anticoagulants are essential in preventing and treating thrombosis. Unfortunately, their use is accompanied by an enhanced risk of bleeding. Since the introduction of direct oral anticoagulants (DOACs), the risk of major bleeding has been reduced but not eliminated. Major bleeding events related to the use of factor Xa inhibitors can be challenging to manage. In recent years, four-factor prothrombin complex concentrates have been used in patients with severe bleeding taking oral direct factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). Andexanet alfa (OndexxyaTM, AstraZeneca AG) is a specially designed recombinant version of human factor Xa that acts as a decoy receptor to reverse the effects of factor Xa inhibitors. Since 2 December 2020, andexanet alfa has been used in Switzerland for adult patients receiving apixaban or rivaroxaban when reversal of anticoagulation is required because of life-threatening or uncontrolled bleeding. However, the use of andexanet alfa remains a challenge owing to its cost, the reported thrombotic complications and the fact that its efficacy mainly relates to intracranial haemorrhage. Moreover, the use of nonspecific reversal agents together with andexanet alfa is controversial. The present recommendations on the use of andexanet alfa in the management of bleeding in patients on factor Xa inhibitors in Switzerland were developed by a group of Swiss experts from the Working Party Hemostasis of the Swiss Society of Hematology. These recommendations aim to provide support to clinicians in their decision-making in the management of patients with major bleeding receiving factor Xa inhibitors.

Multicenter evaluation of light transmission platelet aggregation reagents: communication from the ISTH SSC Subcommittee on Platelet Physiology.

BACKGROUND: Light transmission aggregation (LTA) is used widely by the clinical and research communities. Although it is a gold standard, there is a lack of interlaboratory harmonization. OBJECTIVES: The primary objective was to assess whether sources of activators (mainly adenosine diphosphate [ADP], collagen, arachidonic acid, epinephrine, and thrombin receptor activating peptide6) and ristocetin contribute to poor LTA reproducibility. The secondary objective was to evaluate interindividual variability of results to appreciate the distribution of normal values and consequently better interpret pathologic results. METHODS: An international multicenter study involving 28 laboratories in which we compared LTA results obtained with center-specific activators and a comparator that we supplied. RESULTS: We report variability in the potency (P) of activators in comparison with the comparator. Thrombin receptor activating peptide 6 (P, 1.32-2.68), arachidonic acid (P, 0.87-1.43), and epinephrine (P, 0.97-1.34) showed the greatest variability. ADP (P, 1.04-1.20) and ristocetin (P, 0.98-1.07) were the most consistent. The data highlighted clear interindividual variability, notably for ADP and epinephrine. Four profiles of responses were observed with ADP from high-responders, intermediate-responders, and low-responders. A fifth profile corresponding to nonresponders (5% of the individuals) was observed with epinephrine. CONCLUSION: Based on these data, the establishment and adoption of simple standardization principles should mitigate variability due to activator sources. The observation of huge interindividual variability for certain concentrations of activators should lead to a cautious interpretation before reporting a result as abnormal. Confidence can be taken from the fact that difference between sources is not exacerbated in patients treated with antiplatelet agents.

Determination of Anti-Xa Inhibitor Plasma Concentrations Using a Universal Edoxaban Calibrator.

A universal calibrator for the determination of all anti-Xa inhibitors would support laboratory processes. We aimed to test the clinical performance of an anti-Xa assay utilizing a universal edoxaban calibrator to determine clinically relevant concentrations of all anti-Xa inhibitors. Following a pilot study, we enrolled 553 consecutive patients taking rivaroxaban, edoxaban, or apixaban from nine study centers in a prospective cross-sectional study. The Technochrom® anti-Xa assay was conducted using the Technoview® edoxaban calibrator. Using ultra-high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), anti-Xa inhibitor drug concentrations were determined. Sensitivities and specificities to detect three clinically relevant drug concentrations (30 µgL-1, 50 µgL-1, 100 µgL-1) were determined. Overall, 300 patients treated with rivaroxaban, 221 with apixaban, and 32 with edoxaban were included. The overall correlation coefficient (rs) was 0.95 (95% CI 0.94, 0.96). An area under the receiver operating characteristic curve of 0.96 for 30 µgL-1, 0.98 for 50 µgL-1, and 0.99 for 100 µgL-1 was found. The sensitivities were 92.3% (95% CI 89.2, 94.6), 92.7% (89.4, 95.1), and 94.8% (91.1, 97.0), respectively (specificities 82.2%, 93.7%, and 94.4%). In conclusion, the clinical performance of a universal, edoxaban-calibrated anti-Xa assay was solid and most drug concentrations were predicted correctly.

Coexpression of factor VIII and factor von Willebrand variants in a woman with heavy menstrual bleeding.

Heavy menstrual bleeding is one of the most common causes of consultation in haematology. We present the clinical case of a 20-year-old woman referred by her gynaecologist due to heavy menstrual bleeding since menarche, complicated by iron deficiency anaemia. Haemostasis work-up was initially suggestive of a von Willebrand disease type 1. Genetic analyses by whole exome sequencing lead to a fortuitous discovery of haemophilia by identifying a heterozygous missense mutation in F8 , exon 8 c.1127T>G:p.Val376Gly, previously reported in a patient with mild haemophilia A. The bleeding phenotype worsened by concomitant low von Willebrand factor (VWF) due to VWF variants influencing VWF levels. Our case highlights how whole exome sequencing can help to correct an erroneous diagnosis and identify polymorphisms that eventually contribute to the overall haemostatic balance.

Thrombophilia and outcomes of venous thromboembolism in older patients.

Background: Limited data exist on thrombophilic risk factors and clinical outcomes in the elderly with venous thromboembolism (VTE). Objectives: To describe the prevalence of laboratory thrombophilic risk factors and their association with VTE recurrence or death in a cohort of elderly people with VTE. Methods: In 240 patients aged ≥65 years with acute VTE without active cancer or an indication for extended anticoagulation, we performed laboratory thrombophilia testing 1 year after the index VTE. Recurrence or death was assessed during the 2-year follow-up. Results: A total of 78% of patients had ≥1 laboratory thrombophilic risk factor(s). Elevated levels of von Willebrand factor, homocysteine, coagulant activity of factor VIII (FVIII:C), fibrinogen, FIX:C, and low antithrombin activity were the most prevalent risk factors (43%, 30%, 15%, 14%, 13%, and 11%, respectively). Additionally, 16.2% of patients experienced VTE recurrence and 5.8% of patients died. Patients with a von Willebrand factor of >182%, FVIII:C level >200%, homocysteine level >15µmol/L, or lupus anticoagulant had a significantly higher rate of recurrence than those without these risk factors (15.0 vs. 6.1 [P = .006], 23.5 vs. 8.2 [P = .01], 17.0 vs. 6.8 [P = .006], and 89.5 vs. 9.2 [P = .02] events per 100 patient-years, respectively). Furthermore, patients with a high fibrinogen level or hyperhomocysteinemia with a homocysteine level ≥30 µmol/L had significantly higher mortality than patients with normal levels (18.5 vs. 2.8 [P = .049] and 13.6 vs. 2 [P = .002] deaths per 100 patient-years, respectively). After adjustments for relevant confounders, these associations remained unchanged. Conclusion: Laboratory thrombophilic risk factors are common in elderly people with VTE and allow for the identification of a population at the risk of worse clinical outcomes.

[Angiology and hemostasis : what's new in 2022]. / Angiologie et hémostase : ce qui a changé en 2022.

In this article, we have selected four topics that particularly caught our attention during the year 2022, and which are related to anticoagulation, its bleeding complications, and hemophilia. Thus, we discuss the issue of the treatment with rivaroxaban of atrial fibrillation associated with rheumatic valvulopathy, which has been studied in a randomized trial, the intensity of thromboprophylaxis in COVID outpatients and inpatients, and the bleeding risk of anticoagulation in patients with cerebral tumors. Finally, recent data on gene therapy in severe hemophilia A, an upcoming treatment, are discussed.

Dans cet article, nous avons sélectionné 4 sujets qui ont particulièrement retenu notre attention durant l'année 2022, en lien avec l'anticoagulation, ses complications hémorragiques et l'hémophilie. Ainsi, nous abordons le traitement par rivaroxaban de la fibrillation atriale associée à une valvulopathie rhumatismale qui a fait l'objet d'une étude randomisée, l'intensité de la thromboprophylaxie chez les patients hospitalisés ou traités en ambulatoire avec un Covid dont les données se sont bien étoffées, le risque associé à l'anticoagulation chez les patients avec une néoplasie cérébrale et, finalement, la thérapie génique dans l'hémophilie A sévère qui devrait apparaître sur le marché très prochainement.

Prothrombotic biomarkers during controlled ovarian stimulation for assisted reproductive technology.

OBJECTIVE: To assess the impact of 3 different ovarian stimulation protocols on surrogate biomarkers of coagulation. DESIGN: Observational multicenter cohort study. SETTING: The study was conducted in assisted reproductive technology (ART) units. PATIENTS: Infertile women undergoing ART in 2017-2019 were included. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Our primary outcome was the endogenous thrombin potential (ETP) assessed by the calibrated automated thrombogram. The ETP was measured at baseline (T1), on the day of ovulation triggering (T2), and 7 days after triggering (T3). Three protocols were prescribed according to the standards used and without hormonal before treatment: agonist protocol with human chorionic gonadotropin (hCG) trigger (ag-hCG), antagonist protocol with hCG trigger (atg-hCG), or GnRH agonist trigger. The evolution of ETP was compared among groups using a mixed-effects linear regression model. RESULT(S): Sixty-four women with a mean age of 37.8 years participated in the study: of which 24, 16, 24 received ag-hCG, atg-hCG, and GnRH agonist triggers, respectively. As expected, the mean serum estradiol levels in GnRH agonist trigger were statistically higher at T2 and lower at T3 than that for both ag-hCG and atg-hCG. Overall, the ETP evolution over time was statistically different between the groups. Values were similar between groups at T1 and increased at T2 in each group. The greatest difference occurred between T2 and T3 in each group. The ETP continued to increase at T3 in ag-hCG (+110 nM/L × min) and atg-hCG (+171 nM/L × min), but it remained stable in GnRH agonist trigger (-2 nM/L × min). Sex hormone-binding globulin showed persistent increase at T3 despite the fall in estradiol levels, particularly in the GnRH agonist trigger group. CONCLUSION(S): The ag-hCG and atg-hCG groups were associated with a higher hypercoagulable state at T3 than the GnRH agonist trigger group. However, our results show the persistence of a hypercoagulable state after the GnRH agonist triggering despite a sharp drop in estradiol levels. These findings may support the use of GnRH agonist trigger protocol in patients with high thrombotic risk and gives new insight into the fact that coagulation parameters could be disturbed for long time periods. CLINICAL TRIAL REGISTRATION NUMBER: NCT04188444.

Applicability of the European Society of Cardiology Guidelines on the management of acute coronary syndromes to older people with haemophilia A - A modified Delphi consensus by the ADVANCE Working Group.

INTRODUCTION: As people with haemophilia (PWH) receive better treatment and live longer they are more likely to encounter cardiovascular disease (CVD) and other comorbidities. ESC guidelines for the acute management of patients presenting with acute coronary syndrome (ACS) are based on the non-haemophilia population. AIM: To review the guidelines and propose relevant adaptations for PWHA without inhibitors who are treated with prophylaxis and present with ACS. METHODS: As part of the ADVANCE Group, 20 European haemophilia experts used a modified Delphi approach to develop and gain consensus on proposed adaptations of the ESC guidelines for PWHA without inhibitors. RESULTS: Of the 32 Class I recommendations across both guidelines, adaptions were considered necessary and proposed for 15. The adaptions highlight the need to provide sufficient FVIII trough levels at the time of antithrombotic treatment in people with haemophilia A (HA) without inhibitors. Patients receiving emicizumab prophylaxis and requiring oral anticoagulation therapy or combined single antiplatelet plus oral anticoagulation therapy will require additional FVIII replacement therapy. CONCLUSION: In the absence of high-quality clinical evidence, the combined expert opinion used to develop these adaptions to the current ESC guidelines may help to guide clinicians in their treatment decisions when a PWHA presents with ACS.