TH Open: Companion Journal to Thrombosis and Haemostasis最新文献

Background  With a trend toward greater virtual care in selected clinical settings, perioperative anticoagulant management appears well suited for this care delivery model. We explored the potential for virtual care among patients who are receiving anticoagulant therapy and require perioperative management around the time of an elective surgery/procedure. Methods  We undertook a retrospective review of patients who were receiving anticoagulant therapy, either a direct oral anticoagulant (DOAC) or warfarin, assessed in a perioperative anticoagulation-bridging clinic over a 5-year period from 2016 to 2020. Using prespecified criteria, we determined the proportion of patients who likely would be suitable for virtual care (receiving a DOAC or warfarin and having a minimal- or low-/moderate-bleed-risk surgery/procedure), those who likely would be suitable for in-person care (receiving warfarin and requiring heparin bridging for a mechanical heart valve), and patients who would be suitable for either care delivery model (receiving a DOAC or warfarin, but not with a mechanical heart valve, and requiring a high-bleed-risk surgery/procedure). Results  During the 5-year study period, there were 4,609 patients assessed for perioperative anticoagulant management in whom the most widely used anticoagulants were warfarin (37%), apixaban (30%), and rivaroxaban (24%). Within each year assessed, 4 to 20% of all patients were undergoing a minimal-bleed-risk procedure, 76 to 82% were undergoing a low-/moderate-bleed-risk surgery/procedure, and 10 to 39% were undergoing a high-bleed-risk surgery/procedure. The proportion of patients considered suitable for virtual, in-person, or either virtual or in-person management was 79.6, 7.1, and 13.3%, respectively. Conclusion  In patients who were assessed in a perioperative anticoagulation clinic, there was a high proportion of patients in whom a virtual care model might be suitable.

Envenomings by Russell's viper ( Daboia russelii ), a species of high medical importance in India and other Asian countries, commonly result in hemorrhage, coagulopathies, necrosis, and acute kidney injury. Although bleeding complications are frequently reported following viper envenomings, thrombotic events occur rarely (reported only in coronary and carotid arteries) with serious consequences. For the first time, we report three serious cases of peripheral arterial thrombosis following Russell's viper bites and their diagnostic, clinical management, and mechanistic insights. These patients developed occlusive thrombi in their peripheral arteries and symptoms despite antivenom treatment. In addition to clinical features, computed tomography angiography was used to diagnose arterial thrombosis and ascertain its precise locations. They were treated using thrombectomy or amputation in one case that presented with gangrenous digits. Mechanistic insights into the pathology through investigations revealed the procoagulant actions of Russell's viper venom in standard clotting tests as well as in rotational thromboelastometry analysis. Notably, Russell's viper venom inhibited agonist-induced platelet activation. The procoagulant effects of Russell's viper venom were inhibited by a matrix metalloprotease inhibitor, marimastat, although a phospholipase A ₂ inhibitor (varespladib) did not show any inhibitory effects. Russell's viper venom induced pulmonary thrombosis when injected intravenously in mice and thrombi in the microvasculature and affected skeletal muscle when administered locally. These data emphasize the significance of peripheral arterial thrombosis in snakebite victims and provide awareness, mechanisms, and robust strategies for clinicians to tackle this issue in patients.

Heparin is typically extracted from domestic pigs, which may carry zoonotic adventitious agents. Prion and viral safety cannot be assured by testing the active pharmaceutical ingredient itself; instead for the evaluation of the adventitious agent (i.e., viruses/prions) safety of heparin and heparinoid (e.g., Orgaran or Sulodexide) therapeutics, a risk assessment is required. An approach is presented which provides a quantitative estimation of the worst-case potential residual adventitious agent (i.e., GC/mL or ID ₅₀ ) present in a maximum daily dose of heparin. This estimation is based on the input (determined by prevalence, titer, and amount of starting material to prepare a maximum daily dose) and validated reduction by the manufacturing process, resulting in an estimation of the worst-case potential level of adventitious agent present in a maximum daily dose. The merits of this quantitative, worst-case approach are evaluated. The approach described in this review provides a tool for a quantitative risk evaluation of the viral and prion safety of heparin.

Background  Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor. Objective  Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran. Methods  The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses. Results  Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 ( p  < 0.01; n  = 5), and 66.9 ± 4.8% ( p  < 0.001; n  = 6) versus vehicle at 0.25 + 0.17, 1.0 + 0.67, and 4.0 ± 2.68 mg/kg bolus + mg/kg/h infusion, respectively. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23-, and 3.12-fold increases from baseline upon the AV shunt start), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight and clotting assays was also demonstrated for both apixaban and dabigatran as the references for the model validation. Conclusion  Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study.

Background  Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis even when they do not have antiphospholipid syndrome (APS). Interactions between complement activation and activated platelets have been suggested in SLE and APS and could play a role in the increased thrombosis risk. Objectives  To explore factors potentially related to the prothrombotic pathophysiology in patients with SLE, primary APS, and healthy controls, by investigating lectin pathway proteins (LPPs), complement activation, platelet aggregation, and platelet activation. Methods  This cross-sectional cohort study included 20 SLE patients, 17 primary APS, and 39 healthy controls. Flow cytometry and light transmission aggregometry were used to assess platelet activation and aggregation. Using time-resolved immunofluorometric assays, the plasma concentrations of 11 LPPs and C3dg, reflecting complement activation, were measured. Results  H-ficolin plasma concentrations were higher in SLE and APS patients than in controls ( p  = 0.01 and p  = 0.03). M-ficolin was lower in SLE than in APS ( p  = 0.01) and controls ( p  = 0.03). MAp19 was higher in APS patients than in SLE patients ( p  = 0.01) and controls ( p  < 0.001). In APS patients, MASP-2 and C3dg correlated negatively with platelet activation. Platelet-bound fibrinogen after agonist stimulation and C3dg concentrations correlated negatively with platelet activation. Conclusion  We observed significant differences between SLE and APS patients regarding complement proteins and platelet activation. Particularly the negative correlations between MASP-2 and C3dg with platelet activation only observed in APS patients suggest that interactions between complement activation and platelets differ in SLE and APS.

Background  Intermittent fasting is becoming more popular as health benefits are described in recent literature. Various forms of fasting exist, one of them involving a zero-calorie diet and drinking only water. However, the safety of water-only fasting is still not well established. We report a case of a man who developed a lower limb deep vein thrombosis at the end of a 2-week water-only fasting and characterized by an initial period of 5 days of no food and no water intake. We reviewed literature regarding potential links between fasting and venous thromboembolism (VTE). Clinical Approach  We believe that fasting can induce important dehydration, leading to hypercoagulability and then contribute to the development of a venous thrombosis. The patient was treated with apixaban for 3 months as is recommended in patients with a provoked event caused by a transient risk factor. No thrombotic recurrence was observed during the 6-month follow-up. Conclusion  The public needs to be aware of the potential life-threatening complications associated with important dehydration in the setting of medically unsupervised fasting, and these might include VTE. Whether a VTE with dehydration as the only identified risk factor should be approached as a low recurrence risk situation or not still needs to be clarified.

Introduction  Response to ADP P2Y ₁₂ receptor inhibition by clopidogrel can be evaluated by various techniques. Here, we compared a functional rapid point-of-care technique (PFA-P2Y) with the degree of biochemical inhibition assessed by the VASP/P2Y ₁₂ assay. Methods  Platelet response to clopidogrel was investigated in 173 patients undergoing elective intracerebral stenting (derivation cohort n  = 117; validation cohort n  = 56). High platelet reactivity (HPR) was defined as PFA-P2Y occlusion time <106 seconds or VASP/P2Y ₁₂ platelet reactivity index (PRI) >50%. Results  In the derivation cohort, receiver operator characteristics analysis for the ability of PFA-P2Y to detect biochemical HPR showed high specificity (98.4%) but poor sensitivity (20.0%) and a very low area under the curve (0.59). The VASP/P2Y ₁₂ assay revealed two coexisting platelet populations with different levels of vasodilator-stimulated phosphoprotein (VASP) phosphorylation: a fraction of highly phosphorylated, inhibited platelets and another of poorly phosphorylated, reactive platelets. Analysis of the PFA-P2Y curve shape revealed different types, categorized by time of occlusion (<106 seconds, 106 to 300 seconds, >300 seconds), and pattern (regular, irregular, and atypical). Noteworthy, curves with late occlusion and permeable curves with an irregular or atypical pattern correlated with VASP-PRI >50% and smaller sizes of the inhibited platelet subpopulation. Considering the PFA-P2Y shape of the curve for the detection of HPR improved sensitivity (72.7%) and preserved specificity (91.9%), with a rather high AUC (0.823). The validation cohort confirmed the VASP/P2Y ₁₂ assay data and the usefulness of considering the PFA-P2Y curve shape. Conclusion  In patients treated with acetylsalicylic acid and clopidogrel for 7-10 days, the VASP/P2Y ₁₂ assay reveals two coexisting subpopulations of differentially inhibited platelets, whose relative sizes predict global PRI and distinct PFA-P2Y curve patterns, indicating incomplete clopidogrel efficacy. The detailed analysis of both VASP/P2Y ₁₂ and PFA-P2Y is necessary for optimal detection of HPR.

Background  The efficacy, safety, and immunogenicity of each of Octapharma's factor VIII (FVIII) products, Nuwiq, octanate, and wilate, have been investigated in previously untreated patients (PUPs) with severe hemophilia A in prospective clinical trials. The aim of the Protect-NOW study is to evaluate the effectiveness, safety, and utilization patterns of Nuwiq, octanate, and wilate in PUPs and minimally treated patients (MTPs; <5 exposure days [EDs] to FVIII concentrates or other blood products containing FVIII) with severe hemophilia A in a real-world setting. Real-world data provide valuable information that complement data obtained from interventional clinical trials. Methods  Protect-NOW (ClinicalTrials.gov identifier: NCT03695978; ISRCTN identifier: 11492145) is a real-world study in PUPs and MTPs treated with either the human cell line-derived recombinant FVIII Nuwiq (simoctocog alfa) or a plasma-derived FVIII concentrate containing von Willebrand factor (octanate or wilate). It is a prospective and (partly) retrospective, observational, international, noncontrolled, noninterventional study. A total of 140 PUPs and MTPs with severe hemophilia A will be enrolled across around 50 specialized centers worldwide and followed for either 100 EDs or a maximum period of 3 years from ED1. The primary objectives are to assess effectiveness in the prevention and treatment of bleeding episodes and overall safety, including inhibitor development. The secondary objectives are to assess utilization patterns (including dosage and frequency of administration) and the effectiveness in surgical prophylaxis. Conclusions  The Protect-NOW study will provide information on the treatment of PUPs and MTPs in routine clinical practice, which will help guide clinical decision making for treating these patients in the future.

Background  Geographical mapping of variations in the treatment and outcomes of a disease is a valuable tool for identifying inequity. We examined international and intranational variations in initiating oral anticoagulation (OAC) therapy and clinical outcomes among patients with atrial fibrillation (AF) in Nordic countries. We also tracked real-world trends in initiating OAC and the clinical outcomes. Methods  We conducted a registry-based multinational cohort study of OAC-naive patients with an incident hospital diagnosis of AF in Denmark ( N  = 61,345), Sweden ( N  = 124,120), and Finland ( N  = 59,855) and a CHA ₂ DS ₂ -VASc score of ≥1 in men and ≥2 in women between 2012 and 2017. Initiation of OAC therapy was defined as dispensing at least one prescription between 90 days before and 90 days after the AF diagnosis. Clinical outcomes included ischemic stroke, intracerebral hemorrhage, intracranial bleeding, other major bleeding, and all-cause mortality. Results  The proportion of patients initiating OAC therapy ranged from 67.7% (95% CI: 67.5-68.0) in Sweden to 69.6% (95% CI: 69.2-70.0) in Finland, with intranational variation. The 1-year risk of stroke varied from 1.9% (95% CI: 1.8-2.0) in Sweden and Finland to 2.3% (95% CI: 2.2-2.4) in Denmark, with intranational variation. The initiation of OAC therapy increased with a preference for direct oral anticoagulants over warfarin. The risk of ischemic stroke decreased with no increase in intracranial and intracerebral bleeding. Conclusion  We documented inter- and intranational variation in initiating OAC therapy and clinical outcomes across Nordic countries. Adherence to structured care of patients with AF could reduce future variation.