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.

Unexpected acute pulmonary embolism in an old COVID-19 patient with warfarin overdose: a case report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 disease is strongly associated with a high incidence of thrombotic events. Anticoagulation could be a cornerstone in successfully managing severe forms of coronavirus disease 2019 (COVID-19). However, optimal anticoagulant dosing in elderly patients is challenging because of high risk of both thrombosis and bleeding. CASE SUMMARY: We present here the case of an 89-year-old patient receiving warfarin for atrial fibrillation and valvular heart disease, admitted to the intensive care unit for respiratory failure due to COVID-19. The patient presented with a severe epistaxis associated with warfarin overdose [international normalized ratio (INR) > 10]. After a successful initial reversal using vitamin K per os, INR values greatly fluctuated up to 10, requiring repeated administrations of vitamin K. Despite starting low-molecular-weight heparin therapy at therapeutic dose as soon as INR value was below 2.0, the patient further developed an acute bilateral and proximal pulmonary embolism concomitantly with a sharp D-dimer increase. The combination of azithromycin intake, a known inhibitor of CYP2C9, with the presence of CYP2C9*2 and -1639G>A VKORC1, two variants associated with warfarin hypersensitivity, have likely contributed to explain the warfarin overdose and the difficulty to reverse warfarin effect in this patient. DISCUSSION: This case report illustrates the complexity of COVID-19 pathophysiology and its management for physicians, especially in patients receiving vitamin K antagonists (VKAs). Infection, concurrent medication use, and pharmacogenetic factors involved in VKA metabolism and pharmacodynamics may lead to a loss of control of anticoagulation. Pulmonary embolism should still be considered in COVID-19 patients even with effective or overdosed anticoagulant therapy.

White blood count, D-dimers, and ferritin levels as predictive factors of pulmonary embolism suspected upon admission in noncritically ill COVID-19 patients: The French multicenter CLOTVID retrospective study.

BACKGROUND: A high prevalence of pulmonary embolism (PE) has been described during COVID-19. Our aim was to identify predictive factors of PE in non-ICU hospitalized COVID-19 patients. METHODS: Data and outcomes were collected upon admission during a French multicenter retrospective study, including patients hospitalized for COVID-19, with a CT pulmonary angiography (CTPA) performed in the emergency department for suspected PE. Predictive factors significantly associated with PE were identified through a multivariate regression model. RESULTS: A total of 88 patients (median [IQR] age of 68 years [60-78]) were analyzed. Based on CTPA, 47 (53.4%) patients were diagnosed with PE, and 41 were not. D-dimer ≥3000 ng/mL (OR 8.2 [95% CI] 1.3-74.2, sensitivity (Se) 0.84, specificity (Sp) 0.78, P = .03), white blood count (WBC) ≥12.0 G/L (29.5 [2.3-1221.2], Se 0.47, Sp 0.92, P = .02), and ferritin ≥480 µg/L (17.0 [1.7-553.3], Se 0.96, Sp 0.44, P = .03) were independently associated with the PE diagnosis. The presence of the double criterion D-dimer ≥3000 ng/mL and WBC ≥12.0 G/L was greatly associated with PE (OR 21.4 [4.0-397.9], P = .004). CONCLUSION: The white blood count, the D-dimer and ferritin levels could be used as an indication for CTPA to confirm PE on admission in non-ICU COVID-19 patients.

D-Dimer Level and Neutrophils Count as Predictive and Prognostic Factors of Pulmonary Embolism in Severe Non-ICU COVID-19 Patients.

The incidence of pulmonary embolism (PE) is high during severe Coronavirus Disease 2019 (COVID-19). We aimed to identify predictive and prognostic factors of PE in non-ICU hospitalized COVID-19 patients. In the retrospective multicenter observational CLOTVID cohort, we enrolled patients with confirmed RT-PCR COVID-19 who were hospitalized in a medicine ward and also underwent a CT pulmonary angiography for a PE suspicion. Baseline data, laboratory biomarkers, treatments, and outcomes were collected. Predictive and prognostics factors of PE were identified by using logistic multivariate and by Cox regression models, respectively. A total of 174 patients were enrolled, among whom 86 (median [IQR] age of 66 years [55-77]) had post-admission PE suspicion, with 30/86 (34.9%) PE being confirmed. PE occurrence was independently associated with the lack of long-term anticoagulation or thromboprophylaxis (OR [95%CI], 72.3 [3.6-4384.8]) D-dimers ≥ 2000 ng/mL (26.3 [4.1-537.8]) and neutrophils ≥ 7.0 G/L (5.8 [1.4-29.5]). The presence of these two biomarkers was associated with a higher risk of PE (p = 0.0002) and death or ICU transfer (HR [95%CI], 12.9 [2.5-67.8], p < 0.01). In hospitalized non-ICU severe COVID-19 patients with clinical PE suspicion, the lack of anticoagulation, D-dimers ≥ 2000 ng/mL, neutrophils ≥ 7.0 G/L, and these two biomarkers combined might be useful predictive markers of PE and prognosis, respectively.

Pathophysiological Processes Underlying the High Prevalence of Deep Vein Thrombosis in Critically Ill COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) predisposes to deep vein thrombosis (DVT) and pulmonary embolism (PE) particularly in mechanically ventilated adults with severe pneumonia. The extremely high prevalence of DVT in the COVID-19 patients hospitalized in the intensive care unit (ICU) has been established between 25 and 84% based on studies including systematic duplex ultrasound of the lower limbs when prophylactic anticoagulation was systematically administrated. DVT prevalence has been shown to be markedly higher than in mechanically ventilated influenza patients (6-8%). Unusually high inflammatory and prothrombotic phenotype represents a striking feature of COVID-19 patients, as reflected by markedly elevated reactive protein C, fibrinogen, interleukin 6, von Willebrand factor, and factor VIII. Moreover, in critically ill patients, venous stasis has been associated with the prothrombotic phenotype attributed to COVID-19, which increases the risk of thrombosis. Venous stasis results among others from immobilization under muscular paralysis, mechanical ventilation with high positive end-expiratory pressure, and pulmonary microvascular network injuries or occlusions. Venous return to the heart is subsequently decreased with increase in central and peripheral venous pressures, marked proximal and distal veins dilation, and drops in venous blood flow velocities, leading to a spontaneous contrast "sludge pattern" in veins considered as prothrombotic. Together with endothelial lesions and hypercoagulability status, venous stasis completes the Virchow triad and considerably increases the prevalence of DVT and PE in critically ill COVID-19 patients, therefore raising questions regarding the optimal doses for thromboprophylaxis during ICU stay.