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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