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.

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.

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IntroductionThe interactions between the plasma membrane and the cytoskeleton are essential for a wide variety of cellular processes such as endocytosis, cell morphology, cell adhesion, formation of cell-cell contacts and cell motility. These interactions are regulated by signaling complexes formed by the assembly of transmembrane and cytosolic proteins and lipids (Engqvist-Goldstein and Drubin, 2003;Fais and Malorni, 2003;Sechi and Wehland, 2000). These complexes are thought to participate in the control of the elongation of actin filaments leading to the formation of membrane protrusions, or in the contraction of the actomyosin network leading to membrane retraction. Blood platelets represent an attractive model to investigate these mechanisms as the actin cytoskeleton and its interactions with the plasma membrane are critical for their physiological functions (Hartwig et al., 1999). Indeed, platelets must respond rapidly to a vessel injury by a series of coordinated events including adhesion, shape change, spreading, aggregation and clot retraction. αIIbβ3 is the most prominent platelet integrin, and, upon activation by 'insideout' signaling, is capable of binding to several adhesive proteins, including fibrinogen, to support platelet aggregation. During aggregation, αIIbβ3 is also involved in transmitting an 'outside-in' signal leading to the formation of a network of signaling and structural proteins strongly interacting with the newly remodeled actin cytoskeleton (Hartwig et al., 1999). These protein complexes were previously co-isolated with the cytoskeleton as a Triton X-100 insoluble pellet obtained at low speed centrifugation (15,000 g) from aggregated platelets (Fox, 1993). The characterization of this cellular fraction led to the identification of several key signaling molecules recruited to αIIbβ3-based cytoskeletal structures, where they are thought to play an essential role in stabilization of platelet aggregation (Hartwig et al., 1999).At the sites of interaction with the cytoskeleton, the plasma membrane is subjected to important mechanical forces, especially during platelet fibrin clot retraction, a postaggregation event involved in the maintenance of hemostasis. During retraction, integrins take part in the formation of a transmembrane linkage between proteins from the extracellular matrix and from the actomyosin filament network, allowing the transmission of contractile forces. It is currently hypothesized that the areas of membrane interacting with the cytoskeleton have a specific lipid composition adapted to these forces. In this context, cholesterol and sphingolipid enriched membrane microdomains, known as detergent resistant membranes (DRMs) or lipid rafts, are of major interest. Their lipid composition confers a restricted fluidity state called a liquid ordered phase to these membrane microdomains (Brown and London, 2000). Although the existence of rafts has been 759 Dynamic connections between actin filaments and the plasma membrane are crucial for the regulation of blood platelet funct...

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SummaryVenous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 ± 4 and 65 ± 3 yrs) and creati-nine clearance (114 ± 15 and 62 ± 6 ml · min –1). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 ± 11 yrs and creatinine clearance of 76 ± 8 ml · min –1. Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg–1 for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the begining and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.

The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.

and the French Working Group on Perioperative Hemostasis * 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. Highdose 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 COVID-19 patients without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results.