Thrombosis and haemostasis最新文献

Venom-induced consumption coagulopathy (VICC) is a common complication of snakebite that is associated with hypofibrinogenemia, bleeding, disability, and death. In remote tropical settings, where most snakebites occur, the 20-minute whole blood clotting test is used to diagnose VICC. Point-of-care (POC) coagulation devices could provide an accessible means of detecting VICC that is better standardized, quantifiable, and more accurate. In this scoping review, the mechanistic reasons that previously studied POC devices have failed in VICC are considered, and evidence-based recommendations are made to prioritize certain devices for clinical validation studies. Four small studies have evaluated a POC international normalized ratio (INR) device in patients with Australian Elapid, Daboia russelii, and Echis carinatus envenoming. The devices assessed in these studies either relied on a thrombin substrate endpoint, which is known to underestimate INR in patients with hypofibrinogenemia, have been recalled due to poor accuracy, or have since been discontinued. Sixteen commercially available POC devices for measuring INR, activated clotting time, activated partial thromboplastin time, fibrinogen, D-dimer, and fibrin(ogen) degradation products have been reviewed. POC INR devices that detect fibrin clot formation, as well as a novel POC device that quantifies fibrinogen were identified, which show promise for use in patients with VICC. These devices could support more accurate allocation of antivenom, reduce the time to antivenom administration, and provide improved clinical trial outcome measurement instruments. There is an urgent need for these promising POC coagulation devices to be validated in prospective clinical snakebite studies.

Direct oral anticoagulants (DOACs) have transformed the landscape of antithrombotic therapy in the past two decades. However, there is uncertainty about when they should or should not be used for treatment or prevention of thromboembolic events. DOACs have largely replaced warfarin for many patients with atrial fibrillation or venous thromboembolism who require anticoagulant therapy. In addition to noninferior efficacy, fewer drug-drug and food-drug interactions and improved convenience; DOACs have been shown to reduce the risk of intracranial hemorrhage. They have also received new indications compared with warfarin, such as cardiovascular risk reduction in patients with stable atherosclerotic diseases. However, there are some scenarios in which DOACs are associated with inferior efficacy or worse safety compared with standard treatment, such as warfarin. These include patients with mechanical heart valves, thrombotic antiphospholipid syndrome, and others. Although DOACs offer a streamlined and convenient option for the management of many patients with or at risk of thromboembolic events, their use should be avoided in certain high-risk scenarios. This minireview summarizes such conditions and those in which there is uncertainty for use of DOACs for particular diseases or particular patient subgroups.

Background:  Accuracy in diagnoses recorded using the International Classification of Diseases (ICD) coding is the most important element ensuring the foundation of research using real-world data analyses.

Objective:  To evaluate the validity of ICD coding for diagnoses of disseminated intravascular coagulation (DIC) using the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria and the Japanese Association for Acute Medicine (JAAM) DIC criteria as reference standards.

Methods:  This retrospective observational study included adult hospitalized patients diagnosed as having diseases potentially causing DIC extracted from a part of a large-scale database in Japan. The index test was a diagnosis of DIC based on the ICD-10 codes. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using ISTH overt DIC criteria and JAAM-2 DIC criteria as the reference standards. We also conducted subgroup analyses according to the underlying diseases.

Results:  We included 84,300 patients in this study. In the overall study population, sensitivity, specificity, PPV, and NPV of the ICD-based diagnosis for ISTH criteria were 26.28, 98.10, 35.12, and 97.14%, respectively. In subgroup analyses according to the underlying disease, sensitivity ranged from 9.48 to 52.08%, and specificity ranged from 96.94 to 99.47%. The accuracy of the ICD-based diagnosis for JAAM-2 criteria was similar to that for ISTH criteria.

Conclusion:  Identification of DIC patients using ICD-10 codes had relatively low sensitivity but very high specificity for DIC diagnostic criteria. Approximately 65% of patients identified by ICD coding are likely to meet the JAAM-2 DIC criteria.

The present work evaluates the predictive value of low-density-granulocytes (LDG) for the development of cardiovascular disease (CVD) and/or bone deterioration (BD) in a six-year prospective study in Systemic Lupus Erythematosus (SLE). Considering the high SLE-LDG capacity to form Neutrophil Extracellular Traps (NETs), circulating levels of total cell-free DNA (cirDNA) and relative amounts of mitochondrial and nuclear DNA (mtDNA and nDNA, respectively) were tested as LDG-associated biomarkers to identify SLE patients at risk of CVD and BD. To this end, the frequency of total blood LDGs, as well as the CD16negCD14neg (nLDG) and CD16posCD14low (pLDG) subsets, was quantified by flow cytometry in 33 controls and 144 SLE patients. Total cirDNA and relative amounts of mitochondrial (mtDNA) and nuclear (nDNA) cell-free DNA were measured by fluorometry or qPCR in plasma from a subgroup of 117 patients and 23 controls at enrolment. Our findings showed increased blood levels of SLE-nLDGs at enrolment associated with prospective CVD development (pCVD) and the presence of BD, thus revealing LDG expansion as a predictor of both comorbidities in SLE progression. The amounts of the different types of circulating DNA analysed were increased in patients, especially those presenting traditional CV-risk factors or subclinical atheromatosis. Similar to nLDGs, the nDNA concentration could predict the development of pCVD in SLE, supporting the quantification of cirDNA levels as a surrogate marker of LDGs in clinical practice.

Background:  Many platelet agonists mediate their cellular effects through G protein-coupled receptors (GPCRs) to induce platelet activation, and GPCR kinases (GRKs) have been demonstrated to have crucial roles in most GPCR functions in other cell types. Here, we investigated the functional role of GRK3 and the molecular basis for the regulation of GPCR desensitization by GRK3 in platelets.

Methods:  We used mice lacking GRK3 as well as β-arrestin2, which has been shown to be important in GPCR function in platelets.

Results:  Platelet aggregation and dense granule secretion induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in both GRK3 -/- and β-arrestin2 -/- platelets compared with wild-type (WT) platelets, whereas non-GPCR agonist collagen-induced platelet aggregation and secretion were not affected. We have previously shown that GRK6 is not involved in the regulation of G_q-coupled 5HT_2A and G_z-coupled α_2A adrenergic receptors. Interestingly, in contrast to GRK6, platelet aggregation induced by costimulation of serotonin and epinephrine, which activate 5-HT_2A and α_2A adrenergic receptors, respectively, was significantly potentiated in GRK3 -/- platelets, suggesting that GRK3 is involved in general GPCR regulation. In addition, platelet aggregation in response to the second challenge of adenosine diphosphate was restored in GRK3 -/- platelets, whereas restimulation of the agonist failed to induce aggregation in WT platelets, confirming that GRK3 contributes to general GPCR desensitization. Furthermore, 2-MeSADP- and AYPGKF-induced AKT and ERK phosphorylation were significantly potentiated in GRK3 -/- platelets. Finally, GRK3 -/- mice showed shorter tail bleeding times compared with WT, indicating that GRK3 -/- mice is more susceptible to hemostasis.

Conclusion:  GRK3 plays a crucial role in the regulation of platelet activation through general GPCR desensitization in platelets.