Summary
Introduction
Little is known about the natural history of clot resolution in the initial weeks of anticoagulant therapy in patients with acute pulmonary embolism (PE). Clot resolution of ...acute PE was assessed with either computed tomography pulmonary angiography scan (CT‐scan) or perfusion scintigraphy scan (Q‐scan) after 3 weeks of treatment.
Methods
This was a predefined safety analysis of the Einstein PE study, including PE patients, randomized to either enoxaparin with vitamin K antagonist (VKA) or rivaroxaban. A similar scan as at baseline was repeated after 3 weeks. The percentage of vascular obstruction (PVO) was calculated on the basis of a weighted semiquantitative estimation of obstruction. Clot resolution was assessed blindly by calculating the relative change after 3 weeks.
Results
PE was diagnosed in 264 patients with CT‐scan and in 83 with Q‐scan. Baseline characteristics were similar. At baseline, the mean PVO assessed with CT‐scan (PVO‐CT) and the mean PVO assessed with Q‐scan (PVO‐Q) were both 21% (standard deviation SD 13%) (P = 0.9). The mean relative decrease in PVO was 71% (SD 33%) for PVO‐CT, and 62% (SD 36%) for PVO‐Q (P = 0.02); complete resolution was observed in 44% (116/264; 95% confidence interval CI 38–50%) and 31% (26/83; 95% CI 22–42%) with CT‐scan and Q‐scan, respectively (P = 0.04). No difference in clot resolution between enoxaparin/VKA and rivaroxaban was found.
Conclusion
In patients with acute PE, only 3 weeks of anticoagulant treatment leads to complete clot resolution in a considerable proportion of patients, and normalization is more often observed with CT‐scan than with Q‐scan.
Essentials
Heparin‐induced thrombocytopenia (HIT) is a thrombogenic condition that is difficult to treat.
We evaluated rivaroxaban as a treatment option in patients with suspected or confirmed HIT.
...One patient had recurrent thrombosis and 9/10 patients with thrombocytopenia had platelet recovery.
Rivaroxaban may be an effective and safe treatment option for HIT.
Summary
Background
Rivaroxaban is a direct oral anti‐Xa inhibitor that has the potential to greatly simplify treatment of heparin‐induced thrombocytopenia (HIT).
Objectives
To evaluate the efficacy and safety of rivaroxaban in this patient population, we conducted a multicenter, single‐arm, prospective cohort study of patients with suspected or confirmed HIT.
Patients/Methods
Twenty‐two consecutive adults with suspected or confirmed HIT received rivaroxaban 15 mg bid until a local HIT assay result was available. Participants with a positive local assay result continued rivaroxaban 15 mg bid until platelet recovery (or until day 21 if they had acute thrombosis at study entry), then stepped down to rivaroxaban 20 mg daily until day 30.
Results and Conclusions
The primary outcome measure, incidence of new symptomatic, objectively‐confirmed venous and arterial thromboembolism at 30 days, occurred in one HIT‐positive participant (4.5%; 95% confidence interval CI, 0–23.5%) and one HIT‐positive participant required limb amputation despite platelet recovery. Platelet recovery was achieved in nine out of 10 HIT‐positive patients with thrombocytopenia. Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision.
Summary
Background
Post‐thrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis (DVT). Its diagnosis is based on clinical characteristics. However, symptoms and signs of ...PTS are non‐specific, and could result from concomitant primary venous insufficiency (PVI) rather than DVT. This could bias evaluation of PTS.
Methods
Using data from the REVERSE multicenter study, we assessed risk factors for PTS in patients with a first unprovoked unilateral proximal DVT 5–7 months earlier who were free of clinically significant PVI (defined as absence of moderate or severe venous ectasia in the contralateral leg).
Results
Among the 328 patients considered, the prevalence of PTS was 27.1%. Obesity (odds ratio OR 2.6 95% confidence interval (CI) 1.5–4.7), mild contralateral venous ectasia (OR 2.2 95% CI 1.1–4.3), poor International Normalized Ratio (INR) control (OR per additional 1% of time with INR < 2 during anticoagulant treatment of 1.018 95% CI 1.003–1.034) and the presence of residual venous obstruction on ultrasound (OR 2.1 95% CI 1.1–3.7) significantly increased the risk for PTS in multivariable analyses. When we restricted our analysis to patients without any signs, even mild, of contralateral venous insufficiency (n = 244), the prevalence of PTS decreased slightly to 24.6%. Only obesity remained an independent predictor of PTS (OR 2.6 95% CI 1.3–5.0). Poor INR control and residual venous obstruction also increased the risk, but the results were no longer statistically significant (OR 1.017 95% CI 0.999–1.035 and OR 1.7 95% CI 0.9–3.3, respectively).
Conclusions
After a first unprovoked proximal DVT, obese patients and patients with even mild PVI constitute a group at increased risk of developing PTS for whom particular attention should be paid with respect to PTS prevention. Careful monitoring of anticoagulant treatment may prevent PTS.
Whether to continue oral anticoagulant therapy beyond 6 months after an "unprovoked" venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are ...at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants.
In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5-7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule.
We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%-11.3%). Men had a 13.7% (95% CI 10.8%-17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer > or = 250 microg/L while taking warfarin; body mass index > or = 30 kg/m(2); or age > or = 65 years. These women had an annual risk of 1.6% (95% CI 0.3%-4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%-17.3%).
Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men.
Functional mitral regurgitation (FMR) is a consequence of mitral annular enlargement, leaflet tethering and reduced co-aptation. The importance of the left atrium (LA) as a cause of mitral ...regurgitation (MR) is less clear. We applied a co-aptation index using three-dimensional (3D) transoesophageal echocardiography to FMR and MR secondary to LA dilatation (atrial mitral regurgitation, AMR).
Seventy-two patients underwent comprehensive 3D echo studies: FMR (n = 19); AMR (n = 33); and 20 controls. We recorded: LV size and function; LA dimensions; mitral annular area (MVA); and leaflet area in early and late systole. MVA fractional change was defined: (MVA late systole - MVA early systole)/MVA late systole × 100%; the co-aptation index was defined: (leaflet area early systole - leaflet area late systole)/leaflet area early systole × 100%. Despite normal LV size and function in AMR, MVA was increased similarly to FMR (AMR 12.86 cm(2) vs. FMR 12.33 cm(2), P = ns; both P < 0.01 vs. controls 8.83 cm(2)), and MVA fractional change similarly reduced (AMR 5.1% vs. FMR 6.3%; P = ns; both P < 0.001 vs. controls 14.6%). The co-aptation index was reduced in both MR groups (FMR 6.6% vs. AMR 7.0%, P = ns; both P < 0.001 vs. controls 19.6%). After multivariate analysis, the co-aptation index (χ(2) = 41.2) and MVA fractional change (χ(2) = 22.1) remained the strongest predictors of MR (both P < 0.001 for the model). A co-aptation index of ≤13% was 96% sensitive and 90% specific for the presence of MR.
LA dilatation leads to MVA enlargement, reduced leaflet co-aptation and MR even without LV dilatation. A co-aptation index describes this in vivo. This work provides insights into the mechanism of AMR.
Caspases are a family of proteases found in all metazoans, including a dozen in humans, that drive the terminal stages of apoptosis as well as other cellular remodeling and inflammatory events. ...Caspases are named because they are cysteine class enzymes shown to cleave after aspartate residues. In the past decade, we and others have developed unbiased proteomic methods that collectively identified ~2000 native proteins cleaved during apoptosis after the signature aspartate residues. Here, we explore non-aspartate cleavage events and identify 100s of substrates cleaved after glutamate in both human and murine apoptotic samples. The extended consensus sequence patterns are virtually identical for the aspartate and glutamate cleavage sites suggesting they are cleaved by the same caspases. Detailed kinetic analyses of the dominant apoptotic executioner caspases-3 and -7 show that synthetic substrates containing DEVD↓ are cleaved only twofold faster than DEVE↓, which is well within the 500-fold range of rates that natural proteins are cut. X-ray crystallography studies confirm that the two acidic substrates bind in virtually the same way to either caspases-3 or -7 with minimal adjustments to accommodate the larger glutamate. Lastly, during apoptosis we found 121 proteins cleaved after serine residues that have been previously annotated to be phosphorylation sites. We found that caspase-3, but not caspase-7, can cleave peptides containing DEVpS↓ at only threefold slower rate than DEVD↓, but does not cleave the unphosphorylated serine peptide. There are only a handful of previously reported examples of proteins cleaved after glutamate and none after phosphorserine. Our studies reveal a much greater promiscuity for cleaving after acidic residues and the name 'cacidase' could aptly reflect this broader specificity.
Abstract
Background
A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The ...endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD).
Methods
After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema).
Results
Our results showed a significant improvement in gas exchange elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03) in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control.
Conclusions
These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.
On 2017 September 22, the IceCube Neutrino Observatory reported the detection of the high-energy neutrino event IC 170922A, of potential astrophysical origin. It was soon determined that the neutrino ...direction was consistent with the location of the gamma-ray blazar TXS 0506+056 (3FGL J0509.4+0541), which was in an elevated gamma-ray emission state as measured by the Fermi satellite. Very Energetic Radiation Imaging Telescope Array System (VERITAS) observations of the neutrino/blazar region started on 2017 September 23 in response to the neutrino alert and continued through 2018 February 6. While no significant very-high-energy (VHE; E > 100 GeV) emission was observed from the blazar by VERITAS in the two-week period immediately following the IceCube alert, TXS 0506+056 was detected by VERITAS with a significance of 5.8 standard deviations ( ) in the full 35 hr data set. The average photon flux of the source during this period was (8.9 1.6) × 10−12 cm−2 s−1, or 1.6% of the Crab Nebula flux, above an energy threshold of 110 GeV, with a soft spectral index of 4.8 1.3.
PDF
