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.

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.

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The glycoprotein VI (GPVI)/FcR␥ complex is a key receptor for platelet activation by collagen. We describe, for the first time, 2 genetic abnormalities in one patient. This 10-year-old girl presented ecchymoses since infancy, a prolonged bleeding time despite a normal platelet count and no antiplatelet antibodies. Collagen-induced platelet activation was null, whereas GPVI quantification by flow cytometry evidenced an incomplete deficiency. Immunoblotting showed an abnormal migration of residual GPVI, and no FcR␥ defect. GPVI DNA sequencing revealed (1) an R38C mutation in exon 3 of one allele and IntroductionCollagen is a major thrombogenic constituent of the vessel wall. Platelets principally react with collagen via integrin ␣2␤1 and glycoprotein VI (GPVI), 1 a member of the immunoglobulin receptor family. 2,3 GPVI plays a major role in platelet activation through signaling mediated by the noncovalently associated immunoreceptor tyrosine-based activation motif-containing FcR␥ chain. 1,4 The extracellular domain of GPVI is composed of 2 Ig-like domains important for collagen binding and receptor dimerization, respectively. 5-8 GPVI deficiencies 9 have been described mostly in patients with immune thrombocytopenic purpura, where autoantibodies are assumed to induce GPVI shedding. 10,11 We report the first case of congenital GPVI deficiency with a mild bleeding disorder. This patient, whose platelets failed to respond to collagen, is a compound heterozygote for 2 GPVI mutations: one leads to an incomplete protein deficiency, and the second is a loss of function Arg to Cys substitution in the first GPVI Ig-like loop. MethodsThe supplemental data contain information on methods (available on the Blood website; see the Supplemental Materials link at the top of the online article). PatientsThe patient is a 10-year-old girl who consulted for easy bruising since infancy. Her parents were nonconsanguineous, and there was no family history of bleeding. She had a prolonged bleeding time (Ivy Ͼ 15 minutes, PFA-100 closure time on collagen/epinephrine 210 seconds), a normal platelet count (280 G/L), no morphologic abnormalities on blood smears, and no detectable antiplatelet antibodies. von Willebrand factor exploration was in the normal range. All studies were performed with written informed consent according to the Declaration of Helsinki and with approval of the ethical board of Hôpital Necker (Assistance Publique-Hopitaux de Paris). Platelet function studiesPlatelet aggregation was measured on platelet-rich plasma (PRP) and washed platelets. 12 Dense granule secretion was quantified using an adenosine triphosphate determination kit. Platelet adhesion to collagen under flow conditions and thrombin generation were measured mainly as described. 13,14 GPVI expression was analyzed by flow cytometry and immunoblot using the monoclonal antibody 3J24.2 or 9O12.2 and a human polyclonal antibody. Genetic studiesEach of the 8 exons and intron-exon junctions of GPVI were amplified by polymerase chain reaction; products were sequenc...

Introduction: Emicizumab (Hemlibra ® ) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data. Aim:The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures.

To cite this article: Lillo-Le Louë t A, Boutouyrie P, Alhenc-Gelas M, Le Beller C, Gautier I, Aiach M, Lasne D. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004; 2: 1882-8.See also Matthai Jr WH, Cines DB. Towards a diagnosis of heparin-induced thrombocytopenia after cardiopulmonary bypass. This issue, pp 1879-81.Summary. Heparin-induced thrombocytopenia (HIT) occurs in nearly 3% of patients treated with heparin after cardiopulmonary bypass (CPB). HIT carries a risk of severe thrombotic complications, and must be diagnosed rapidly. To identify simple criteria for estimating the probability of HIT after CPB, we retrospectively analyzed the files of 84 patients with suspected HIT after CPB and we analyzed the usefulness of several variables collected at the time of HIT suspicion to estimate HIT probability. HIT was confirmed in 35 cases and ruled out in 49 cases, on the basis of a platelet increment after heparin withdrawal, detection of heparin-dependent antibodies, and absence of other clear cause of thrombocytopenia. A biphasic platelet count from CPB to the first day of suspected HIT, an interval of ‡ 5 days from CPB to the first day of suspected HIT, and a CPB duration of £ 118 min were independent risk factors for HIT. These variables were combined to create a post-CPB HIT probability score. The score correctly identified 34/35 HIT patients and 28/49-non-HIT patients. This score, which can be applied as soon as HIT is suspected after CPB, has very good negative predictive value (97%). Prospective studies are required to confirm these findings.

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Infection by SARS-CoV-2 is associated with a high risk of thrombosis. The laboratory documentation of hypercoagulability and impaired fibrinolysis remains a challenge. Our aim was to assess the potential usefulness of viscoelastometric testing (VET) to predict thrombotic events in COVID-19 patients according to the literature. We also (i) analyzed the impact of anticoagulation and the methods used to neutralize heparin, (ii) analyzed whether maximal clot mechanical strength brings more information than Clauss fibrinogen, and (iii) critically scrutinized the diagnosis of hypofibrinolysis. We performed a systematic search in PubMed and Scopus databases until December 31st, 2020. VET methods and parameters, and patients’ features and outcomes were extracted. VET was performed for 1063 patients (893 intensive care unit (ICU) and 170 non-ICU, 44 studies). There was extensive heterogeneity concerning study design, VET device used (ROTEM, TEG, Quantra and ClotPro) and reagents (with non-systematic use of heparin neutralization), timing of assay, and definition of hypercoagulable state. Notably, only 4 out of 25 studies using ROTEM reported data with heparinase (HEPTEM). The common findings were increased clot mechanical strength mainly due to excessive fibrinogen component and impaired to absent fibrinolysis, more conspicuous in the presence of an added plasminogen activator. Only 4 studies out of the 16 that addressed the point found an association of VETs with thrombotic events. So-called functional fibrinogen assessed by VETs showed a variable correlation with Clauss fibrinogen. Abnormal VET pattern, often evidenced despite standard prophylactic anticoagulation, tended to normalize after increased dosing. VET studies reported heterogeneity, and small sample sizes do not support an association between the poorly defined prothrombotic phenotype of COVID-19 and thrombotic events.