GFHT proposals on the practical use of argatroban - With specifics regarding vaccine-induced immune thrombotic thrombocytopaenia (VITT).

Argatroban is a direct anti-IIa (thrombin) anticoagulant, administered as a continuous intravenous infusion; it has been approved in many countries for the anticoagulant management of heparin-induced thrombocytopaenia (HIT). Argatroban was recently proposed as the non-heparin anticoagulant of choice for the management of patients diagnosed with Vaccine-induced Immune Thrombotic Thrombocytopaenia (VITT). Immunoglobulins are also promptly intravenously administered in order to rapidly improve platelet count; concomitant therapy with steroids is also often considered. An ad hoc committee of the French Working Group on Haemostasis and Thrombosis members has worked on updated and detailed proposals regarding the management of anticoagulation with argatroban, based on previously released guidance for HIT, and adapted for VITT. In case of VITT, the initial dose to be preferred is 1.0 µg × kg-1 × min-1, with further dose-adjustments based on iterative and frequent clinical and laboratory assessments. It is strongly advised to involve a health practitioner experienced in the management of difficult cases in haemostasis. The first laboratory assessment should be performed 4 h after the initiation of argatroban infusion, with further controls at 2-4-h intervals until steady state, and at least once daily thereafter. Importantly, full anticoagulation should be rapidly achieved in case of widespread thrombosis. Cerebral vein thrombosis (which is typical of VITT) should not call for an overly cautious anticoagulation scheme. Argatroban administration requires baseline laboratory assessment and should rely on an anti-IIa assay to derive argatroban plasma levels using a dedicated calibration, with a target range between 0.5 and 1.5 µg/mL. Target argatroban plasma levels can be refined based on meticulous appraisal of risk factors for bleeding and thrombosis, on frequent reassessments of clinical status with appropriate vascular imaging, and on the changes in daily platelet counts. Regarding the use of aPTT, baseline value and possible causes for alterations of the clotting time must be taken into account. Specifically, in case of VITT, an aPTT ratio (patient's/mean normal clotting time) between 1.5 and 2.5 is suggested, to be refined according to the sensitivity of the reagent to the effect of a direct thrombin inhibitor. The sole use of aPTT is discouraged: one has to resort to a periodical check with an anti-IIa assay at least, with the help of a specialised laboratory if necessary. Dose modifications should proceed in a stepwise manner with 0.1 to 0.2 µg × kg-1 × min-1 up- or downward changes, taking into account the initial dose, laboratory results, and the whole individual setting. Nomograms are available to adjust the infusion rate. Haemoglobin level, platelet count, fibrinogen plasma level and liver tests should be periodically checked, depending on the clinical status, the more so when unstable.

Prévention du risque thromboembolique veineux et surveillance de l’hémostase chez les patients hospitalisés pour COVID-19 : propositions réactualisées (avril 2021). Groupe d’intérêt en hémostase périopératoire (GIHP) et groupe d’étude sur l’hémostase et la thrombose (GFHT) Prevention of venous thromboembolism and haemostasis monitoring in patients with COVID-19: Updated proposals (April 2021): From the French working group on perioperative haemostasis (GIHP) and the French study group on thrombosis and haemostasis (GFHT), in collaboration with the French society of anaesthesia and intensive care (SFAR)

<h4>Contexte</h4> La COVID-19 est associée à un risque thromboembolique veineux élevé, en particulier chez les patients sévères. Depuis les premières propositions GIHP/GFHT publiées en avril 2020, de nouvelles connaissances sont apparues. L’objet du présent travail était de réactualiser ces propositions. <h4>Méthodes</h4> Un groupe de travail a défini sept questions et effectué une revue critique de la littérature. Les propositions ont été formulées après consensus entre les membres du groupe de travail et les autres membres du GIHP/GFHT. <h4>Résultats</h4> Chez les patients hospitalisés non sévères et certains patients ambulatoires à risque, nous suggérons l’administration d’une thromboprophylaxie à dose standard. Chez les patients sévères, nous suggérons une thromboprophylaxie à dose intermédiaire ou thérapeutique selon le taux de D-dimères et son évolution. Sept à dix jours après l’admission, nous suggérons de revenir à une dose standard pour réduire le risque hémorragique. Chez les patients présentant un très haut risque thrombotique, ayant reçu une thromboprophylaxie à dose thérapeutique, nous suggérons un dépistage systématique de la thrombose avant la désescalade. Nous suggérons d’ajuster l’anticoagulation au poids des patients. Nous suggérons un monitorage régulier des paramètres d’hémostase, incluant les D-dimères, chez les patients sévères. Nous suggérons un monitorage de l’anticoagulation à dose intermédiaire et thérapeutique par l’activité anti-Xa. <h4>Conclusion</h4> Les propositions réactualisées suivent une approche standard de la thromboprophylaxie, visant à diminuer l’incidence des évènements thromboemboliques veineux symptomatiques. Chez les patients sévères, nous proposons une stratégie séquentielle tenant compte de la relation temporelle entre le risque thrombotique et le risque hémorragique.

Prévention du risque thromboembolique veineux et surveillance de l’hémostase chez les patients hospitalisés pour COVID-19 : propositions réactualisées (avril 2021). Groupe d’intérêt en hémostase périopératoire (GIHP) et groupe d’étude sur l’hémostase et la thrombose (GFHT)

Résumé Contexte La COVID-19 est associée à un risque thromboembolique veineux élevé, en particulier chez les patients sévères. Depuis les premières propositions GIHP/GFHT publiées en avril 2020, de nouvelles connaissances sont apparues. L’objet du présent travail était de réactualiser ces propositions. Méthodes Un groupe de travail a défini sept questions et effectué une revue critique de la littérature. Les propositions ont été formulées après consensus entre les membres du groupe de travail et les autres membres du GIHP/GFHT. Résultats Chez les patients hospitalisés non sévères et certains patients ambulatoires à risque, nous suggérons l’administration d’une thromboprophylaxie à dose standard. Chez les patients sévères, nous suggérons une thromboprophylaxie à dose intermédiaire ou thérapeutique selon le taux de D-dimères et son évolution. Sept à dix jours après l’admission, nous suggérons de revenir à une dose standard pour réduire le risque hémorragique. Chez les patients présentant un très haut risque thrombotique, ayant reçu une thromboprophylaxie à dose thérapeutique, nous suggérons un dépistage systématique de la thrombose avant la désescalade. Nous suggérons d’ajuster l’anticoagulation au poids des patients. Nous suggérons un monitorage régulier des paramètres d’hémostase, incluant les D-dimères, chez les patients sévères. Nous suggérons un monitorage de l’anticoagulation à dose intermédiaire et thérapeutique par l’activité anti-Xa. Conclusion Les propositions réactualisées suivent une approche standard de la thromboprophylaxie, visant à diminuer l’incidence des évènements thromboemboliques veineux symptomatiques. Chez les patients sévères, nous proposons une stratégie séquentielle tenant compte de la relation temporelle entre le risque thrombotique et le risque hémorragique.

Impact of High-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19 Pneumonia.

BACKGROUND: Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. RESEARCH QUESTION: What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? STUDY DESIGN AND METHODS: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. RESULTS: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75). INTERPRETATION: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04405869; URL: www.clinicaltrials.gov.

Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring.

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 µg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.