Thrombosis and haemostasis最新文献

Introduction:  Platelets link thrombosis and inflammation, but how platelets handle the endogenous intraplatelet inflammatory machinery is less well understood. NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) is the central component of the interleukin (IL)-1-producing inflammasome. Elucidating the cell type-specific mechanism of NLRP3 in platelets may improve our understanding of thrombotic diseases.

Methods:  Ferric chloride-induced mesenteric arteriole thrombosis models, tail bleeding models, and microfluidic whole-blood perfusion were used to study thrombosis and hemostasis. Additionally, we utilized aggregometry, flow cytometry, immunoprecipitation, and western blotting to investigate glycoprotein (GP)Ib-IX-mediated platelet function and signaling.

Results:  NLRP3^-/- mice exhibited severely impaired thrombosis and hemostasis, whereas apoptosis-associated speck-like protein containing a CARD (ASC)^-/-, caspase-1^-/-, and Nlrp3 ^A350V/+ CrePF4 mice did not exhibit such changes. NLRP3^-/- platelets exhibited reduced adhesion to injured vessel walls and collagen and impaired von Willebrand factor (vWF)-dependent translocation and rolling behavior. NLRP3 deficiency decreased botrocetin-induced platelet aggregation and the phosphorylation of key signaling molecules in the GPIb-IX pathway. Mechanistically, decreased cAMP/PKA activity led to reduced phosphorylation of NLRP3, thereby enabling the interaction between NLRP3 and filamin A. This interaction accelerated the dissociation of filamin A from GPIbα, which allowed a 14-3-3ζ-dependent increase in GPIb-IX affinity to vWF. Finally, platelet NLRP3 was found to largely regulate thrombotic disease models, such as models of stroke and deep vein thrombosis.

Conclusion:  NLRP3 promoted the function of the major platelet adhesion receptor GPIb-IX without involving NLRP3 inflammasome assembly or IL-1β production.

Background:  Oral anticoagulants (OAC) may exacerbate menstrual bleeding in women of childbearing age; however, the existing literature on this issue has several limitations.

Materials and methods:  This study investigates abnormal uterine bleeding in women of childbearing age taking OAC-vitamin K antagonists or direct oral anticoagulants-for venous thromboembolism through a retrospective analysis of prospectively collected data. Uterine bleeding was assessed using the Pictorial Blood Assessment Chart (PBAC) and hemoglobin (Hb) values during anticoagulation compared with prior therapy. The number of unplanned medical visits for bleeding complications was also calculated.

Results:  From June 2014 to November 2023, 110 women were recruited (median age, 36 years). PBAC scores correlated with Hb values at baseline and during therapy (analysis of variance [ANOVA], p < 0.01), with a significant difference in Hb values before and during anticoagulant therapy (delta Hb) among groups (ANOVA, p.0.034). Seventeen women (15.5%) reported uterine fibroids, experiencing a greater reduction in Hb values during anticoagulant administration than women without uterine fibroids (delta 0.3, interquartile range [IQR]: 0.8, 2.9 vs. 0.5, IQR 1.2, 0.3; p.0.012). Women with selfreported uterine fibroids required more frequent unplanned medical consultations for bleeding (mean visits 5 vs. 4, respectively; Poisson regression, p < 0.05). Among women with uterine fibroids, those taking apixaban showed smaller Hb changes than those on other oral anticoagulants (ANOVA, p.0.047). This difference persisted even after adjusting for potential confounders (multiple ANOVA, p.0.004).

Conclusion:  Women of childbearing age taking OAC frequently experience changes in Hb values and PBAC scores during treatment, with uterine fibroids playing a significant role.

Background:  Although most patients with atrial fibrillation (AF) receiving a direct oral anticoagulant (DOAC) do not require drug concentration measurements, there are situations where such information could be useful. Existing guidance documents provide usual on-therapy ranges for drug concentrations, but these have important limitations.

Methods:  This is a systematic review and meta-analysis of studies reporting trough and peak levels of DOAC regimens approved for stroke prevention in AF. We used random effects models and the quantile estimation method to estimate the median and a usual on-therapy range (10^th and 90^th percentiles).

Results:  Of 4,822 unique publications, 53 studies met eligibility (29,266 trough and 12,103 peak levels). Usual on-therapy ranges for trough levels were 38 to 155 and 58 to 206 ng/mL for apixaban 2.5 and 5 mg twice daily; 35 to 138 and 33 to 151 ng/mL for dabigatran 110 and 150 mg twice daily; 8 to 54 and 13 to 66 ng/mL for edoxaban 30 and 60 mg daily; and 16 to 74 and 19 to 72 ng/mL for rivaroxaban 15 and 20 mg daily. The corresponding range for peak levels were 96 to 251 and 132 to 343; 65 to 223 and 76 to 285; 57 to 219 and 127 to 407; 131 to 384, and 169 to 313 ng/mL, respectively.

Conclusion:  This systematic review and meta-analysis provides updated and more representative usual on-therapy ranges of DOAC levels in patients with AF.

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.