The use of 1E12, a monoclonal anti-platelet factor 4 antibody, to improve the diagnosis of vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a complication of adenoviral-based vaccine against SARS-CoV-2 due to prothrombotic immunoglobulin (Ig) G antibodies to platelet factor 4 (PF4) and may be difficult to distinguish from heparin-induced thrombocytopenia (HIT) in patients treated with heparin. OBJECTIVES: We assessed the usefulness of competitive anti-PF4 enzyme immunoassays (EIAs) in this context. METHODS: The ability of F(ab')2 fragments of 1E12, 1C12, and 2E1, 3 monoclonal anti-PF4 antibodies, to inhibit the binding of human VITT or HIT antibodies to PF4 was evaluated using EIAs. Alanine-scanning mutagenesis was performed to define the amino acids involved in the interactions between the monoclonal antibodies and PF4. RESULTS: A strong inhibition of VITT IgG binding to PF4 was measured with 1E12 (median inhibition, 93%; n = 8), whereas it had no effect on the binding of HIT antibodies (median, 6%; n = 8). In contrast, 1C12 and 2E1 inhibited VITT (median, 74% and 76%, respectively) and HIT antibodies (median, 68% and 53%, respectively) binding to PF4. When a competitive anti-PF4 EIA was performed with 1E12 for 19 additional VITT samples, it strongly inhibited IgG binding to PF4, except for 1 patient, who had actually developed HIT according to the clinical history. Epitope mapping showed that 1E12 interacts with 5 key amino acids on PF4, of which 4 are also required for the binding of human VITT antibodies, thus explaining the competitive inhibition. CONCLUSION: A simple competitive anti-PF4 EIA with 1E12 could help confirm VITT diagnosis and distinguish it from HIT in patients when both diagnoses are possible.

Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants?

Given the growing number of patients receiving direct oral anticoagulant (DOAC), patients requiring rapid neutralization is also increasing in case of major bleedings or urgent surgery/procedures. Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote. Other antidotes or hemostatic agents are still under preclinical or clinical development, the most advanced being ciraparantag. DOAC plasma levels measurement allows to appropriately select patient for antidote administration and may prevent unnecessary prescription of expensive molecules in some acute clinical settings. However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes.

Impact of Intraoperative Allogeneic Platelet Transfusion on Healthcare-Associated Infections in Cardiac Surgery: Insights From a Large Single-Center Cohort Study.

OBJECTIVES: Despite significant improvement in patient blood management, cardiac surgery remains a high hemorrhagic risk procedure. Platelet transfusion is used commonly to treat thrombocytopenia-associated perioperative bleeding. Allogeneic platelet transfusion may induce transfusion-related immunomodulation. However, its association with postoperative healthcare-associated infections is still a matter of debate. The objective was to evaluate the impact of allogeneic platelet transfusion during cardiac surgery on postoperative healthcare-associated infection incidence. DESIGN: Retrospective cohort study. SETTING: Tertiary referral academic center. PARTICIPANTS: Patients undergoing cardiac surgery from 2012 to 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intraoperative platelet transfusion was defined as exposure in a causal model. The primary outcome was the incidence of healthcare-associated infections comprised of bloodstream infection, hospital-acquired pneumonia, and surgical-site infection. Among 7,662 included patients, 528 patients (6.8%) were exposed to intraoperative platelet transfusion, and 329 patients (4.3%) developed 454 postoperative infections. Bloodstream infection affected 106 patients (1.4%), hospital-acquired pneumonia affected 174 patients (2.3%), and surgical-site infection affected 148 patients (1.9%). Intraoperative platelet transfusion was associated with an increased risk of bloodstream infection after adjustment by multivariable logistic regression (odds ratio [OR] 2.85; 95% CI 1.40-5.8; p = 0.004; n = 7,662), propensity score matching (OR 3.95; 95% CI 1.57-12.0), p = 0.007; n = 766), and propensity score overlap weighting (OR 3.04; 95% CI 1.51-6.1, p = 0.002; n = 7,762). Surgical-site infection and hospital-acquired pneumonia were not significantly associated with platelet transfusion. CONCLUSIONS: These results suggested that intraoperative allogeneic platelet transfusion is a risk factor for bloodstream infection after cardiac surgery. These results supported the development of patient blood management strategies aimed at minimizing perioperative platelet transfusion in cardiac surgery.

Factors Influencing Unfractionated Heparin Pharmacokinetics and Pharmacodynamics During a Cardiopulmonary Bypass.

BACKGROUND: Unfractionated heparin (UFH) is commonly used during cardiac surgery with a cardiopulmonary bypass to prevent blood clotting. However, empirical administration of UFH leads to variable responses. Pharmacokinetic and pharmacodynamic modeling can be used to optimize UFH dosing and perform real-time individualization. In previous studies, many factors that could influence UFH pharmacokinetics/pharmacodynamics had not been taken into account such as hemodilution or the type of UFH. Few covariates were identified probably owing to a lack of statistical power. This study aims to address these limitations through a meta-analysis of individual data from two studies. METHODS: An individual patient data meta-analysis was conducted using data from two single-center prospective observational studies, where different UFH types were used for anticoagulation. A pharmacodynamic/pharmacodynamic model of UFH was developed using a non-linear mixed-effects approach. Time-varying covariates such as hemodilution and fluid infusions during a cardiopulmonary bypass were considered. RESULTS: Activities of UFH's anti-activated factor/anti-thrombin were best described by a two-compartment model. Unfractionated heparin clearance was influenced by body weight and the specific UFH type. Volume of distribution was influenced by body weight and pre-operative fibrinogen levels. Pharmacodynamic data followed a log-linear model, accounting for the effect of hemodilution and the pre-operative fibrinogen level. Equations were derived from the model to personalize UFH dosing based on the targeted activated clotting time level and patient covariates. CONCLUSIONS: The population model effectively characterized UFH's pharmacokinetics/pharmacodynamics in cardiopulmonary bypass patients. This meta-analysis incorporated new covariates related to UFH's pharmacokinetics/pharmacodynamics, enabling personalized dosing regimens. The proposed model holds potential for individualization using a Bayesian estimation.

Comparisons between diluted thrombin time, ecarin chromogenic assays, and UPLC-MS for plasma level dabigatran quantification: Results from DRIVING study.

INTRODUCTION: The knowledge of dabigatran levels is helpful for decision-making in specific situations such as urgent surgery or when the question of reversal arises (uncontrolled bleeding, eligibility for thrombolysis). However, a limited number of observational studies are available regarding comparisons between quantification methods. The objective of the study was to compare dabigatran plasma levels using three assays including the reference method (high-performance liquid chromatography coupled with mass spectrometry), focusing on the agreement around the 30-50 ng/mL clinically relevant thresholds. METHODS: Sixty healthy volunteers from DRIVING trial (NCT01627665) were given a single 300-mg dabigatran etexilate dose. Serial blood samplings were performed at pre-defined time points (0 to 24 h). We analyzed plasma samples using ultra-performance-liquid chromatography coupled with tandem mass spectrometry (UPLC-MS) (dabigatran reference method); ii/diluted thrombin time (dTT) (Hemoclot-DTI-Hyphen-Biomed); iii/ecarin-based chromogenic assay (ECA-II-Stago). RESULTS: Nine hundred sixty samples were analyzed using the three assays (2759 values). dTT and ECA-II values were highly correlated with those of UPLC-MS (Deming regression). Most values >50 ng/mL were higher using dTT and ECA-II compared to UPLC-MS: biases were constant, +14% and +16% with dTT and ECA-II, respectively (Bland-Altman plots), suggesting that active metabolites accounted for ~15% of thrombin inhibition. Regarding values <30 ng/mL, 30-50 ng/mL, or ≥50 ng/mL, the agreement probability between dTT and ECA-II was of 90.6% [88.4-92.5] (Cohen's kappa coefficient 0.84). CONCLUSION: dTT and ECA-II assays rapidly provide accurate dabigatran-level results for clinical practice, both assays being suitable in emergency, taking into account the thrombin inhibitory effect of dabigatran metabolites.

Factors Influencing Anti-Xa Assays: A Multicenter Prospective Study in Critically Ill and Noncritically Ill Patients Receiving Unfractionated Heparin.

BACKGROUND: The presence of dextran sulfate (DS) in reagents and the type of blood collection tube (citrate/citrated-theophylline-adenosine-dipyridamole [CTAD]) can lead to discrepancies between unfractionated heparin (UFH) anti-Xa levels. OBJECTIVES: To evaluate the extent of the effect (1) of different reagents containing or not containing DS and (2) of the blood collection tubes, on UFH anti-Xa levels, in various clinical situations (NCT04700670). METHODS: We prospectively included patients from eight centers: group (G)1, cardiopulmonary bypass (CPB) after heparin neutralization (n = 39); G2, cardiothoracic intensive care unit (ICU) after CPB (n = 35); G3, medical ICU (n = 53); G4, other medical inpatients (n = 38). Blood was collected into citrated and CTAD tubes. Chromogenic anti-Xa assays were centrally performed, using seven reagent/analyzer combinations including two without DS. The association between anti-Xa levels and covariates was tested using a linear mixed-effects model. RESULTS: We analyzed 4,546 anti-Xa values from 165 patients. Median anti-Xa levels were systematically higher with reagents containing DS, whatever the patient group, with the greatest effect observed in G1 (0.32 vs. 0.05 IU/mL). Anti-Xa levels were slightly higher in CTAD than in citrate samples, irrespective of the assay. The model showed: (1) a significant dextran-patient group interaction (p < 0.0001), the effect of DS on anti-Xa levels varying from 30.9% in G4 to 296% in G1, and (2) a significant effect of CTAD, varying between patient groups (p = 0.0302). CONCLUSION: The variability of anti-Xa levels with a great overestimation of the values, using a reagent containing DS, can lead to different treatment decisions, especially after heparin neutralization by protamine. Clinical consequences of these differences remain to be demonstrated.

Impact of age on in vitro metabolism of clopidogrel: a potential explanation for high on-treatment platelet reactivity in the elderly?

Background: High on-treatment platelet reactivity has been reported in 30% of patients on clopidogrel and 50% in elderly patients; however, little is known about the mechanisms of this biological resistance. One hypothesis is an age-related impaired hepatic metabolism of the prodrug clopidogrel, leading to a lower formation of its active metabolite (clopidogrel-AM). Objectives: To compare the levels of clopidogrel-AM formed in vitro using "old" and "young" human liver microsomes (HLMs) and their consequences on platelet functions. Methods: We developed an in vitro model using "old" (73.6 ± 2.3 years) and "young" (51.2 ± 8.5 years) HLMs, added to platelet-rich plasma from 21 healthy donors with or without clopidogrel (50 µM) and incubated at 37 °C for 30 (T30) and 45 minutes (T45). Clopidogrel-AM was quantified by liquid chromatography-mass spectrometry/mass spectrometry method. Platelet aggregation was performed by light transmission aggregometry. Results: The generation of clopidogrel-AM increased over time and reached concentrations comparable with those reported in treated patients. At T30, mean clopidogrel-AM concentrations were significantly higher with "young" (8.56 µg/L; 95% CI, 5.87-11.24) than with "old" HLMs (7.64 µg/L; 95% CI, 5.14-10.14; P = .002); and at T45, 11.40 µg/L; 95% CI (7.57-15.22) vs 10.63 µg/L, 95% CI (7.10-14.15), P = .02 (n = 21). Despite a significant inhibition of platelet aggregation, no significant difference was found in light transmission aggregometry (adenosine diphosphate, 10 µM) after clopidogrel metabolism by "old" or "young" HLMs, probably because of low sensitivity of the method to small variations of clopidogrel-AM. Conclusion: In this original model combining metabolic and functional approaches, less clopidogrel-AM was produced with HLMs from older patients. This provides support for a decreased CYP450 activity that may contribute to high on-treatment platelet reactivity in elderly patients.

Assessment of DOAC in GEriatrics (Adage Study): Rivaroxaban/Apixaban Concentrations and Thrombin Generation Profiles in NVAF Very Elderly Patients.

BACKGROUND: Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions, and polypharmacy receive direct oral anticoagulants (DOACs), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients. AIMS: To investigate: (1) DOAC concentration-time profiles; (2) thrombin generation (TG); and (3) clinical outcomes 6 months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban. METHODS: Adage-NCT02464488 was an academic prospective exploratory multicenter study, enrolling AF in-patients aged ≥80 years, receiving DOAC for at least 4 days. Each patient had one to five blood samples at different time points over 20 days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen). RESULTS: We included 215 patients (women 71.1%, mean age: 87 ± 4 years), 104 rivaroxaban and 111 apixaban, and 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (coefficient of variation) whatever the regimen, at C max [49-46%] and C min [75-61%] in 15 mg rivaroxaban and 2.5 mg apixaban patients, respectively. The dose regimen was associated with C max and C min plasma concentrations in apixaban (p = 0.0058 and p = 0.0222, respectively), but not in rivaroxaban samples (multivariate analysis). Moreover, substantial variability of thrombin peak height (STG-ThromboScreen) was noticed at a given plasma concentration for both xabans, suggesting an impact of the underlying coagulation status on TG in elderly in-patients. After 6-month follow-up, major bleeding/thromboembolic event/death rates were 6.7%/1.0%/17.3% in rivaroxaban and 5.4%/3.6%/18.9% in apixaban patients, respectively. CONCLUSION: Our study provides original data in very elderly patients receiving DOAC in a real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings.

Induced forms of α2-macroglobulin neutralize heparin and direct oral anticoagulant effects.

Alpha2-macroglobulin (α2M) is a physiological macromolecule that facilitates the clearance of many proteinases, cytokines and growth factors in human. Here, we explored the effect of induced forms of α2M on anticoagulant drugs. Gla-domainless factor Xa (GDFXa) and methylamine (MA)-induced α2M were prepared and characterized by electrophoresis, immunonephelometry, chromogenic, clot waveform and rotational thromboelastometry assays. Samples from healthy volunteers and anticoagulated patients were included. In vivo neutralization of anticoagulants was evaluated in C57Bl/6JRj mouse bleeding-model. Anticoagulant binding sites on induced α2M were depicted by computer-aided energy minimization modeling. GDFXa-induced α2M neutralized dabigatran and heparins in plasma and whole blood. In mice, a single IV dose of GDFXa-induced α2M following anticoagulant administration significantly reduced blood loss and bleeding time. Being far easier to prepare, we investigated the efficacy of MA-induced α2M. It neutralized rivaroxaban, apixaban, dabigatran and heparins in spiked samples in a concentration-dependent manner and in samples from treated patients. Molecular docking analysis evidenced the ability of MA-induced α2M to bind non-covalently these compounds via some deeply buried binding sites. Induced forms of α2M have the potential to neutralize direct oral anticoagulants and heparins, and might be developed as a universal antidote in case of major bleeding or urgent surgery.

Comparative Analysis of a French Prospective Series of 144 Patients with Heparin-Induced Thrombocytopenia (FRIGTIH) and the Literature.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature. METHODS: The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis. RESULTS: Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis, p = 0.03). CONCLUSION: This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.

P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation.

The P2Y12 receptor is a key player in platelet activation and a major target for antithrombotic drugs. The beneficial effects of P2Y12 receptor antagonists might, however, not be restricted to the primary and secondary prevention of arterial thrombosis. Indeed, it has been established that platelet activation also has an essential role in inflammation. Additionally, nonplatelet P2Y12 receptors present in immune cells and vascular smooth muscle cells might be effective players in the inflammatory response. This review will investigate the biological and clinical impact of P2Y12 receptor inhibition beyond its platelet-driven antithrombotic effects, focusing on its anti-inflammatory role. We will discuss the potential molecular and cellular mechanisms of P2Y12-mediated inflammation, including cytokine release, platelet-leukocyte interactions and neutrophil extracellular trap formation. Then we will summarize the current evidence on the beneficial effects of P2Y12 antagonists during various clinical inflammatory diseases, especially during sepsis, acute lung injury, asthma, atherosclerosis, and cancer.

Strategies of neutralization of the direct oral anticoagulants effect: review of the literature.

Many neutralizing agents of anticoagulant effect of factor Xa or thrombin inhibitors (xabans and dabigatran, respectively) have been developed since the commercialization of direct oral anticoagulants (DOAC) in 2008. Idarucizumab is a specific antidote of dabigatran commercialised since 2016. An antidote of xabans, andexanet-α, was very recently approved by the Food and Drug Administration (FDA). Other antidotes of DOAC are under pre-clinical or clinical development; the most advanced being the aripazine in addition to γ-thrombine S195A and GDFXa-α2M complex. Prothrombin complex concentrates activated or not, are part of the pro-hemostatic agents suggested for DOAC handling in case of haemorrhage or preceeding urgent surgery or invasive procedures. Other pro-hemostatic agents (FXaI16L, FX (a)-C, superFVa) are in pre-clinical stage. The efficacy of these different agents in DOAC reversal and mortality reduction is still controversal in the light of the sparse results of in vitro, ex vivo, pre-clinical and clinical studies.

Ticagrelor reversal: in vitro assessment of four haemostatic agents.

AIM: Management of ticagrelor-induced bleeding is challenging as platelet transfusion is ineffective. An effective strategy is needed. This study aimed to investigate in vitro the efficacy of four haemostatic drugs (HDs), namely recombinant activated factor VII (rFVIIa), fibrinogen concentrate (Fib), tranexamic acid (TXA) and factor XIII concentrate (FXIII) to improve the haemostatic capacity in the presence of ticagrelor. METHODS: Blood was spiked with ticagrelor then supplemented by either HD or control. Several assays were performed: ADP-induced platelet aggregation measured by impedance aggregometry, light transmission and two global assays, thrombolastography with the platelet mapping device (TEG-PM) and a platelet-dependent thrombin generation assay (TGA). RESULTS: Ticagrelor inhibited ADP-induced platelet aggregation and decreased the clot strength maximum amplitude (MA) in TEG-PMADP. None of the HDs corrected these parameters. However, rFVIIa shortened the coagulation time R using TEG-PMthrombin and the time to peak prolonged by ticagrelor in TGA. Fib increased MAthrombin and FXIII decreased LY30. TXA had no effects. CONCLUSIONS: Whereas none of the HDs corrected ticagrelor-induced platelet inhibition, rFVIIa shortened coagulation times, Fib increased clot firmness and FXIII decreased fibrinolysis. Consequently, they may bypass ticagrelor effects by acting on fibrin formation or fibrinolysis. Further studies are needed to confirm these data in vivo.

The effectiveness of platelet supplementation for the reversal of ticagrelor-induced inhibition of platelet aggregation: An in-vitro study.

BACKGROUND: Management of ticagrelor-induced bleeding is challenging, as no antidote is currently available. Platelet transfusion, usually proposed to reverse antiplatelet drugs, has been suggested to be ineffective but few data are available. OBJECTIVE: To assess the efficacy of platelet supplementation to restore platelet aggregation inhibited by ticagrelor. DESIGN: In vitro study. SETTING: Blood samples were obtained from the French Blood Bank Institute. PARTICIPANTS: Healthy blood donors. INTERVENTIONS: Whole blood from healthy donors was spiked with ticagrelor or aspirin (used as a positive control). MAIN OUTCOME MEASURES: Platelet aggregation was investigated with impedance aggregometry on whole blood [expressed in ohms (V)] and light transmission aggregometry (expressed in %) on platelet-rich plasma using ADP or arachidonic acid as agonists for ticagrelor or aspirin, respectively. Platelet supplementation was defined as the addition of washed platelet suspension increasing at least 60% of whole blood platelet count. RESULTS: Ticagrelor (3.25 mM) inhibited ADP-induced platelet aggregation compared with control either in whole blood (2 vs. 13 V, P < 0.05) or in platelet-rich plasma (15 vs. 75% P < 0.05). Aspirin (25 mM) inhibited arachidonic acid-induced aggregation (1 vs. 7.5 V, P < 0.05 in whole blood and 5 vs. 77.5%, P = 0.01 in platelet-rich plasma). Platelet supplementation completely restored arachidonic acid-induced platelet aggregation in whole blood (10 vs. 1 V, P = 0.008) and platelet-rich plasma (73 vs. 5%, P < 0.01) in aspirin-treated samples, whereas it failed to correct ADP-induced aggregation (2 vs. 2 V in whole blood and 13.5 vs. 15% in platelet-rich plasma, P > 0.05) in ticagrelor-treated samples. We also report a case of a ticagrelor-treated patient in whom platelet transfusion failed to restore ADP-induced platelet aggregation. CONCLUSION: Platelet supplementation restored platelet aggregation in aspirin-spiked but not in ticagrelor-spiked samples. These results do not support the use of platelet transfusion to reverse the effects of ticagrelor.

Peri-procedural management of dabigatran and rivaroxaban: Duration of anticoagulant discontinuation and drug concentrations.

BACKGROUND: Peri-procedural management of direct oral anticoagulants (DOAC) is challenging. The optimal duration of pre-procedural discontinuation that guarantees a minimal DOAC concentration ([DOAC]) at surgery is unknown. The usual 48-hour discontinuation might not be sufficient for all patients. OBJECTIVES: To test the hypothesis that a 48-hour DOAC discontinuation is not sufficient to ensure a minimal per-procedural [DOAC], defined as [DOAC]<30ng/mL. To investigate the factors associated with per-procedural [DOAC]. To evaluate the ability of normal PT and aPTT to predict [DOAC]<30ng/mL. METHODS: Patients treated with dabigatran or rivaroxaban, and requiring any invasive procedure were included in this multicentre, prospective, observational study. [DOAC], PT and aPTT were measured during invasive procedure. RESULTS: Sixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168h. Per-procedural [DOAC] ranged from <30 to 466ng/mL. [DOAC]<30ng/mL occurred more frequently after 48-hour discontinuation than after a shorter delay. [DOAC] remained ≥30ng/mL in 36% and 14% of measurements performed 24-48h and 48h-120h after discontinuation, respectively. According to ROC curve, a cut-off value of 120hours for DOAC discontinuation had a better specificity than a cut-off value of 48hours to predict [DOAC]<30ng/mL. Normal PT and aPTT ratios had good specificity and positive predictive value, but limited sensitivity (74%) and negative predictive value (73%) to predict [DOAC]<30ng/mL. CONCLUSIONS: A 48-hour discontinuation does not guarantee a [DOAC]<30ng/mL in all patients. Normal PT and aPTT are flawed to predict this threshold and could not replace specific assays. Further studies are needed to define the relationship between per-procedural [DOAC] and clinical outcomes.

[Non-VKA oral anticoagulants: an update for the clinical biologists]. / Anticoagulants directs oraux : actualités pour les biologistes.

Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulator's level. These compounds are usually given at fixed doses without routine coagulation monitoring. However, new data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of, at least dabigatran. Therefore, in certain patient populations, i.e. acute or chronic renal impairment or multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This article aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.