Fibrin polymerization is a necessary part of hemostasis but clots can obstruct blood vessels and cause heart attacks and strokes. The polymerization reactions are specific and controlled, involving strong knob-into-hole interactions to convert soluble fibrinogen into insoluble fibrin. It has long been assumed that clots and thrombi are stable structures until proteolytic digestion. On the contrary, using the technique of fluorescence recovery after photobleaching, we demonstrate here that there is turnover of fibrin in an uncrosslinked clot. A peptide representing the knobs involved in fibrin polymerization can compete for the holes and dissolve a preformed fibrin clot, or increase the fraction of soluble oligomers, with striking rearrangements in clot structure. These results imply that in vivo clots or thrombi are more dynamic structures than previously believed that may be remodeled as a result of local environmental conditions, may account for some embolization, and suggest a target for therapeutic intervention.
Atrial fibrillation, the commonest cardiac arrhythmia, predisposes to thrombus formation and consequently increases risk of ischaemic stroke. Recent years have seen approval of a number of novel oral anticoagulants. Nevertheless, warfarin and aspirin remain the mainstays of therapy. It is widely appreciated that both these agents increase the likelihood of bleeding: there is a popular conception that this risk is greater with warfarin. In fact, well-managed warfarin therapy (INR 2-3) has little effect on bleeding risk and is twice as effective as aspirin at preventing stroke. Patients with atrial fibrillation and a further risk factor for stroke (CHA2DS2-VASc >0) should therefore either receive warfarin or a novel oral agent. The remainder who are at the very lowest risk of stroke are better not prescribed antithrombotic therapy. For stroke prevention in atrial fibrillation; aspirin is rarely the right choice.
Background Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. Methods We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. Results The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). Conclusions Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391 .).
To the Editor: In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), investigators found that rivaroxaban was noninferior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation.(1) In December 2014, four years after completion of the trial, the Food and Drug Administration (FDA) issued a recall notice for a medical device correction of the Alere INRatio Monitor System (formally known as the Hemosense INRatio device). The recall correction notice was issued because the FDA-approved and European . . .
The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial.
Thrombin is a serine protease and regulator of haemostasis that plays a critical role in the formation of obstructive blood clots, or thrombosis, that is a life-threatening condition associated with numerous diseases such as atherosclerosis and stroke. To detect thrombi in living animals, we design and conjugate thrombin-sensitive peptide substrates to the surface of nanoparticles. Following intravenous infusion, these ‘synthetic biomarkers’ survey the host vasculature for coagulation and in response to substrate cleavage by thrombin, release ligand-encoded reporters into the host urine. To detect the urinary reporters, we develop a companion 96-well immunoassay that utilizes antibodies to bind specifically to the ligands, thus capturing the reporters for quantification. Using a thromboplastin-induced mouse model of pulmonary embolism, we show that urinary biomarker levels differentiate between healthy and thrombotic states and correlate closely with the aggregate burden of clots formed in the lungs. Our results demonstrate that synthetic biomarkers can be engineered to sense vascular diseases remotely from the urine and may allow applications in point-of-care diagnostics.
To assess the risk of pulmonary embolism, ischaemic stroke, and myocardial infarction associated with combined oral contraceptives according to dose of oestrogen (ethinylestradiol) and progestogen.
Blood clotting is a precise cascade engineered to form a clot with temporal and spatial control. Current control of blood clotting is achieved predominantly by anticoagulants and thus inherently one-sided. Here we use a pair of nanorods (NRs) to provide a two-way switch for the blood clotting cascade by utilizing their ability to selectively release species on their surface under two different laser excitations. We selectively trigger release of a thrombin binding aptamer from one nanorod, inhibiting blood clotting and resulting in increased clotting time. We then release the complementary DNA as an antidote from the other NR, reversing the effect of the aptamer and restoring blood clotting. Thus, the nanorod pair acts as an on/off switch. One challenge for nanobiotechnology is the bio-nano interface, where coronas of weakly adsorbed proteins can obscure biomolecular function. We exploit these adsorbed proteins to increase aptamer and antidote loading on the nanorods.
Findings From 12-lead Electrocardiography That Predict Circulatory Shock From Pulmonary Embolism: Systematic Review and Meta-analysis
- Academic emergency medicine : official journal of the Society for Academic Emergency Medicine
- Published over 2 years ago
Treatment guidelines for acute pulmonary embolism (PE) recommend risk stratifying patients to assess PE severity, as those at higher risk should be considered for therapy in addition to standard anticoagulation to prevent right ventricular (RV) failure, which can cause hemodynamic collapse. The hypothesis was that 12-lead electrocardiography (ECG) can aid in this determination. The objective of this study was to measure the prognostic value of specific ECG findings (the Daniel score, which includes heart rate > 100 beats/min, presence of the S1Q3T3 pattern, incomplete and complete right bundle branch block [RBBB], and T-wave inversion in leads V1-V4, plus ST elevation in lead aVR and atrial fibrillation suggestive of RV strain from acute pulmonary hypertension), in patients with acute PE.
Background: Trauma is a global disease with over 2.5 million deaths annually from haemorrhage and coagulopathy. Overt hyperfibrinolysis is rare in trauma and associated with massive fatal injuries. Paradoxically, clinical trials suggest a much broader indication for antifibrinolytics. Objective: To determine the incidence and magnitude of fibrinolytic activation in trauma patients and its relationship to clot lysis as measured by thromboelastometry. Methods: Prospective cohort study of 303 consecutive trauma patients admitted between January 2007 and June 2009. Blood was drawn on arrival for thromboelastometry (TEM) and coagulation assays. Follow-up was until hospital discharge or death. TEM hyperfibrinolysis was defined as maximum clot lysis (ML) >15%. Fibrinolytic Activation (FA) measured by plasmin-antiplasmin complex (PAP) and D-dimer levels. Data were collected on demographics, mechanism, severity of injury and baseline vital signs. Outcome Measure(s): 28-day mortality. Secondary: 28-day ventilator-free days and 24-hour transfusion requirement. Results: Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of ‘moderate’ fibrinolysis with PAP levels elevated over twice normal (>1500μg/L) without lysis on TEM. TEM only detected clot lysis when PAP levels were increased 30 times normal (p<0.001) and antiplasmin levels were less than 75% of normal. Patients with FA had increased 28-day mortality compared with no FA (12% vs 1%, p<0.001), fewer ventilator-free days and longer hospital stay. Conclusions: FA occurs in the majority of trauma patients and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional thromboelastometry, an insensitive measure of endogenous fibrinolytic activity. © 2012 International Society on Thrombosis and Haemostasis.