Acute Phase Of Pulmonary Embolism Research Articles

Circulating miR-let7a levels predict future diagnosis of chronic thromboembolic pulmonary hypertension

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54–0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH.

Changes in Pulmonary Vascular Resistance and Obstruction Score Following Acute Pulmonary Embolism in Pigs.

To investigate the contribution of mechanical obstruction and pulmonary vasoconstriction to pulmonary vascular resistance (PVR) in acute pulmonary embolism (PE) in pigs. Controlled, animal study. Tertiary university hospital, animal research laboratory. Female Danish slaughter pigs (n = 12, ~60 kg). None. PE was induced by infusion of autologous blood clots in pigs. CT pulmonary angiograms were performed at baseline, after PE (first experimental day [PEd0]) and the following 2 days (second experimental day [PEd1] and third experimental day [PEd2]), and clot burden quantified by a modified Qanadli Obstruction Score. Hemodynamics were evaluated with left and right heart catheterization and systemic invasive pressures each day before, under, and after treatment with the pulmonary vasodilators sildenafil (0.1 mg/kg) and oxygen (Fio2 40%). PE increased PVR (baseline vs. PEd0: 178 ± 54 vs. 526 ± 160 dynes; p < 0.0001) and obstruction score (baseline vs. PEd0: 0% vs. 45% ± 13%; p < 0.0001). PVR decreased toward baseline at day 1 (baseline vs. PEd1: 178 ± 54 vs. 219 ± 48; p = 0.16) and day 2 (baseline vs. PEd2: 178 ± 54 vs. 201 ± 50; p = 0.51). Obstruction score decreased only slightly at day 1 (PEd0 vs. PEd1: 45% ± 12% vs. 43% ± 14%; p = 0.04) and remained elevated throughout the study (PEd1 vs. PEd2: 43% ± 14% vs. 42% ± 17%; p = 0.74). Sildenafil and oxygen in combination decreased PVR at day 0 (-284 ± 154 dynes; p = 0.0064) but had no effects at day 1 (-8 ± 27 dynes; p = 0.4827) or day 2 (-18 ± 32 dynes; p = 0.0923). Pulmonary vasoconstriction, and not mechanical obstruction, was the predominant cause of increased PVR in acute PE in pigs. PVR rapidly declined over the first 2 days after onset despite a persistent mechanical obstruction of the pulmonary circulation from emboli. The findings suggest that treatment with pulmonary vasodilators might only be effective in the acute phase of PE thereby limiting the window for such therapy.

External validation of the PE-SARD risk score for predicting early bleeding in acute pulmonary embolism in the RIETE Registry

IntroductionThe PE-SARD score (syncope, anemia, renal dysfunction) was developed to predict the risk of major bleeding in the acute phase of pulmonary embolism (PE). MethodsWe analyzed data from 50,686 patients with acute PE included in the RIETE registry to externally validate the PE-SARD score. We calculated the overall reliability of the PE-SARD score, as well as discrimination and calibration for predicting the risk of major bleeding at 30 days. The performance of PE-SARD was compared to the BACS and PE-CH models. ResultsDuring the first 30 days, 640 patients (1.3 %) had a major bleeding event. The incidence of major bleeding within 30 days was 0.6 % in the PE-SARD-defined low-risk group, 1.5 % in the intermediate-risk group, and 2.5 % in the high-risk group, for an OR of 2.22 (95 % CI, 2.02–2.43) for the intermediate-risk group (vs low-risk group), and 3.94 for the high-risk group (vs low-risk group). The corresponding sensitivity was 81.1 % (intermediate/high vs low risk), and specificity was 85.9 % (95 % CI, 85.8–86.1) (low/intermediate vs high risk). The applicability of PE-SARD was consistent across clinically relevant patient subgroups and over shorter time periods of follow-up (i.e., 3 and 7 days). The C-index was 0.654 and calibration was excellent. The PE-SARD bleeding score improved the major bleeding risk prediction compared with the BACS and PE-CH scores. ConclusionsThe PE-SARD score identifies PE patients with a higher risk of bleeding, which could assist providers for potentially adjusting PE management, in a framework of shared decision-making with individual patients.

Acute Pulmonary Embolism and Immunity in Animal Models.

Venous thromboembolism, encompassing acute pulmonary embolism (APE) and deep vein thrombosis (DVT), is a potentially fatal disease with complex pathophysiology. Traditionally, the Virchow triad provided a framework for understanding the pathogenic contributors to thrombus formation, which include endothelial dysfunction, alterations in blood flow and blood hypercoagulability. In the last years, it has become apparent that immunity plays a central role in thrombosis, interacting with classical prothrombotic mechanisms, oxidative stress and vascular factors. Thrombosis amplifies inflammation, and exaggerated inflammatory processes can trigger thrombosis mainly due to the activation of leukocytes, platelets, and endothelial cells. APE-related endothelium injury is a major trigger for immune system activation. Endothelium is also a key component mediating inflammatory reaction and it is relevant to maintain vascular permeability. Exaggerated right ventricular wall stress and overload, with coexisting systemic hypotension and hypoxemia, result in myocardial injury and necrosis. Hypoxia, tissue factor activation and cytokine storm are engaged in the thrombo-inflammatory processes. Thrombus development is characterized by inflammatory state vascular wall caused mainly by an early extravasation of leukocytes and intense selectins and cytokines production. Nevertheless, immunity of DVT is well described, little is known about potential chemokine and cellular differences between thrombus that develops in the vein and thrombus that detaches and lodges in the pulmonary circulation being a cause of APE. There is a paucity of data considering inflammatory state in the pulmonary artery wall during an acute episode of pulmonary embolism. The main aim of this review is to summarize the knowledge of immunity in acute phase of pulmonary embolism in experimental models.

Pulmonary vasoconstriction plays a major role in the acute phase of pulmonary embolism in pigs

Abstract Background Pulmonary vascular resistance (PVR) increases in acute pulmonary embolism (PE) due to both mechanical obstruction and pulmonary vasoconstriction. Attenuation of adverse pulmonary vasoconstriction has shown promise as a treatment of acute PE in experimental studies. However, clinical trials have failed to replicate these beneficial effects in PE patients. Time may be a factor in this discrepancy between experimental and clinical studies. In experimental PE studies, PVR acutely increases and decreases within hours. Meanwhile in clinical trials, the time from symptom onset to study inclusion is often days, at which time PVR may already be decreased. Whether this decrease in PVR is due to reduced mechanical obstruction by endogenous fibrinolysis or attenuation of adverse pulmonary vasoconstriction is unknown. Purpose To investigate the contribution of the mechanical obstruction and pulmonary vasoconstriction to PVR in two days following PE in pigs. Methods In a controlled animal study, using an estabilished model of autologous PE in pigs (PE, n=12 ∼60 kg), changes in pulmonary hemodynamics and clot burden were evaluated. CT pulmonary angiograms were performed at baseline (BL), after acute PE and the following two days, quantifying clot burden using the Qanadli Obstruction Score. Hemodynamics were evaluated with real-time biventricular catheterization and systemic invasive pressures. To evaluate the vasoactive component, pulmonary vasodilators sildenafil (bolus 0.1 mg/kg) and oxygen (inspired fraction of oxygen 40%) were administered. Results Following PE, both mean PVR (Figure 1A) and pulmonary obstruction scores (Figure 1B) increased. PVR decreased at day one and remained unchanged at day two (Figure 1A). Meanwhile, mean obstruction score decreased slightly at day one but remained elevated throughout the study (Figure 1B). Vasodilatation induced by sildenafil and oxygen (SIL+OXY) decreased PVR at day zero but displayed no effect on the subsequent days (Figure 1A). Conclusion Pulmonary vasoconstriction and mechanical obstruction both contributed to the increase in PVR during the acute phase of PE. PVR decreased towards levels of baseline already day one and remained unchanged at day two. The contribution of pulmonary vasoconstriction decreased at day one and two, while the mechanical obstruction remained significantly increased. Accordingly, the effects of pulmonary vasodilators were only present in the acute phase of PE.Figure 1

Two-year quality of life after acute pulmonary embolism: results from the FOCUS study

Abstract Background/Introduction No firm prospective evidence exists on the long-term course of disease-specific and generic quality of life (QoL) or their determinants in patients with acute pulmonary embolism (PE). Reliable data on this topic is essential for early identification of patients at risk of deviating from the expected course and prevention of clinical events affecting QoL recovery after PE. Purpose We examined the two-year course of QoL and the impact of events occurring after the acute phase of PE in patients from the prospective multicentre FOllow-up after aCUte pulmonary emboliSm (FOCUS) study. Methods All patients with complete QoL assessment at 3, 12 and 24 months (N=462) were included in the analysis of the two-year course of QoL; all patients with QoL assessment at 12 months, 24 months, or both (N=740) contributed to a multivariable linear mixed-effects regression for the investigation of determinants of long-term QoL. Disease-specific QoL was assessed with the Pulmonary Embolism Quality of Life (PEmb-QoL) instrument (global score: 0 = best, 100 = worst QoL), generic health-related QoL with the Euro Quality of life group (EuroQol) five-dimensions utility index (EQ-5D-5L; 0 = worst, 1 = best QoL) and the EuroQol visual analogue scale (0 = worst, 100 = best QoL). Incident events (recurrent PE, bleeding, stroke, new cancer diagnosis, and re-hospitalization) were modelled as time-varying covariates from discharge to month 12 and from month 12 to month 24. Results Among 462 patients with complete QoL assessment [200 (43.3%) women, median age 61.5 (IQR: 49–72) years, high-risk PE 15/462 (3.2%)], the median (IQR) PEmb-QoL score at 3, 12, and 24 months was 20 (9–36), 14 (5–30) and 13 (5–28), with a similar trend across all sub-dimensions (Figure 1); the mean (95% CI) EQ-5D-5L utility index 0.86 (0.84–0.88), 0.88 (0.87–0.90) and 0.87 (0.85–0.89); the mean (95% CI) EuroQoL visual analogue scale 74.2 (72.5–75.9), 76.8 (75.2–78.4) and 76.3 (74.6–78.0). Upon multivariable analysis in 740 patients with QoL data at 12 or 24 months, QoL according to all three scales was worse in women, patients of older age, with cardiopulmonary disease, with higher BMI, and in smokers, but did not change significantly at 24 vs 12 months. Incident PE recurrence or stroke did not considerably affect any of the QoL dimensions, whereas re-hospitalization for any cause worsened disease-specific QoL, a new cancer diagnosis worsened both scales of generic QoL, and bleeding worsened generic QoL as assessed by the Visual Analogue Scale (Table 1). Conclusion Generic and disease-specific QoL after PE improved in the first year and then plateaued in the second year. Disease-specific QoL was adversely affected by re-hospitalization for any cause but was robust to new cancer diagnosis and bleedings, which instead worsened generic QoL. These findings may support long-term management of patients with PE and contribute to design and interpretation of interventional studies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer Health Care

Surgical treatment for chronic thromboembolic pulmonary hypertension: an historical perspective.

Chronic thrombotic occlusion of the pulmonary arteries that results in pulmonary hypertension is now recognized as being relatively common, and surgical treatment of the condition is being increasingly applied throughout the world. However, the condition was not described until 90 years ago, and just 60 years ago less than 200 cases of the syndrome had been reported. At that time the condition was thought to be inoperable. Surgery for the acute phase of pulmonary embolism was attempted beginning 100 years ago, with minimal success until cardiopulmonary bypass was developed and could be used to stabilize the patient during induction of anesthesia and the surgical removal of the embolus. Pulmonary endarterectomy was suggested as a possible surgical approach to the chronic condition in 1956, and the first planned pulmonary endarterectomy was performed in 1957. Over the next thirty years several operations were attempted in Europe and the United States. By 1989 it is likely that fewer than 250 cases of pulmonary endarterectomy had been attempted, with a mortality rate of greater than 20%. Some cases of pulmonary endarterectomy had been carried out successfully at the University of California, San Diego (UCSD), beginning in 1970. The technique of the operation was refined, and in 2003 the results of 1,500 of these operations performed at UCSD were described, with a mortality rate of less than 5%. The good results obtained in San Diego encouraged other groups internationally to start their own programs and the operation is now well established, with good results. The following discourse traces the development of surgery, first for acute pulmonary embolism, and also, growing out of that experience, an operation for chronic pulmonary embolism.

Fibrinogen β chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism.

Prothrombotic fibrin clot properties, including increased clot density, are in part genetically determined. We investigated whether fibrinogen alpha-chain gene (FGA) c.991A>G (rs6050), fibrinogen beta chain gene (FGB) -455G>A (rs1800790) and factor XIII gene (F13) c.103G>T (rs5985) polymorphisms affect plasma fibrin clot properties in patients with acute pulmonary embolism (PE). As many as 126 normotensive patients with PE, free of cancer, were genotyped by TaqMan assay. Fibrin clot permeability (Ks ), clot lysis time (CLT) and endogenous thrombin potential (ETP) were assessed on admission. The minor allele frequencies were as follows: FGA rs6050 (n=62, 0.31), FGB rs1800790 (n=40, 0.17) and F13 rs5985 (n=49, 0.23). There were no differences related to any of the polymorphisms with regard to demographic, clinical and laboratory data, except for fibrinogen concentration, which was higher in carriers of F13 rs5985 polymorphism (p=.024), and PE combined with deep-vein thrombosis, which was less prevalent in FGB rs1800790 polymorphism carriers (p=.004). Carriers of FGB rs1800790 A allele and F13 rs5985T allele had lower Ks , prolonged CLT and higher ETP compared with major homozygotes (all p<.05). After adjustment for fibrinogen, all differences remained significant (all p<.01). There were no associations between the FGA rs6050 polymorphism and Ks , CLT or ETP. Our study showed that FGB rs1800790 and F13 rs5985 polymorphisms contribute to the prothrombotic fibrin clot phenotype and these effects are strong enough to be observed in the acute phase of PE.

Evaluation of right ventricular function in acute pulmonary embolism by 3D ejection fraction and longitudinal strain echocardiography in acute phase and follow-up

Abstract Background Assessment of right ventricular (RV) function by transthoracic echocardiography (TTE) in acute pulmonary embolism (PE) has an essential role to severity stratification. However, there is no reliable information on RV function about the clinical utility of advanced TTE parameters in follow-up. Purpose We aimed to assess the clinical utility of 3D RV ejection fraction (3DEF) and free wall longitudinal strain (FWLS) compared to conventional parameters in evaluating RV function in patients with acute PE at time of diagnosis and after follow-up and the relation with adverse outcomes. Methods We prospectively recruited 86 patients with intermediate-high and high-risk bilateral PE from 2018 to 2020 in our centre. Patients underwent TTE during admission and at 6 to 12 months follow-up that included conventional RV parameters (pulsed Doppler S wave (S'), TAPSE, and fractional area change (FAC)). 3DEF and FWLS were obtained as well. Normal values were stablished according to European guidelines. Results Mean age was 63.7±16.5 years, 58% males. Reperfusion treatment was performed in a 26,8%. In-hospital mortality was 4,7% (3 patients in the acute phase of PE and 1 due to rePE. The median follow-up was 1.3 years (IQR 1–2.5). 9 patients died (2 due to PE, 3 due to respiratory failure and 5 due to cancer). Patients with adverse events had a greater severity in PESI scale and worse RV function assessed by 3DEF and 3D volumes. There were no significant differences between groups in FAC, S' and TAPSE (Table 1). Baseline echocardiographic parameters were analyzed in the acute phase during admission and at 6–12 month follow-up (Table 2). There was a significant improvement in conventional parameters (TAPSE and FAC) and a reversal of FWLS values (P=0,01) at follow-up. 3DEF improved, but was not statistically significant (p=0,06). There was a greater reversal in end-systolic volume compared to end-diastolic volume. Conclusion Advanced RV function assessment by 3DEF and FWLS is useful in the acute phase and follow-up. FWLS showed and early normalization after PE resolution, whereas 3DEF improved but remained pathological at 6–12 months follow-up. Funding Acknowledgement Type of funding sources: None. Table 1Table 2

Available bleeding scoring systems poorly predict major bleeding in the acute phase of pulmonary embolism

Abstract Background Bleeding prediction scores may help to guide acute management of patients with pulmonary embolism (PE). However, existing scoring systems have not been validated for in-hospital assessment. We aimed to compare 6 available bleeding scores, in a real-life cohort for the prediction of major in-hospital bleeding. Methods We recorded in-hospital characteristics of 2,754 PE patients included in a prospective observational multicenter cohort study contributing 18,028 person-days of follow-up. We assessed the VTE-BLEED, RIETE, ORBIT, HEMORRA2HAGES, ATRIA, and HAS-BLED scores at baseline. ISTH-defined bleeding events were independently adjudicated. The accuracy of the scores for the prediction of in-hospital bleeding was evaluated and compared. Results We observed 82 first in-hospital major bleeding events (3.0% (95% CI, 2.4–3.7)). Overall, the predictive power of bleeding scores was poor, with a C index ranging from 0.57 to 0.69 (Figure 1). The RIETE score had the numerically highest model fit and best discriminatory capacity, but without reaching statistical significance versus the ORBIT, HEMORR2HAGES, and ATRIA scores. The VTE-BLEED and HAS-BLED scores had significantly lower C indices, integrated discrimination improvement, and net reclassification improvement compared to the four others. Conclusion Currently available scoring systems have insufficient accuracy for the prediction of in-hospital major bleeding in patients with acute PE. The development of acute-PE-specific risk scores is needed to optimally target patients that warrant bleeding-prevention strategies. Funding Acknowledgement Type of funding sources: None. Figure 1

Available Bleeding Scoring Systems Poorly Predict Major Bleeding in the Acute Phase of Pulmonary Embolism.

We aimed to compare six available bleeding scores, in a real-life cohort, for prediction of major bleeding in the early phase of pulmonary embolism (PE). We recorded in-hospital characteristics of 2754 PE patients in a prospective observational multicenter cohort contributing 18,028 person-days follow-up. The VTE-BLEED (Venous Thrombo-Embolism Bleed), RIETE (Registro informatizado de la enfermedad tromboembólica en España; Computerized Registry of Patients with Venous Thromboembolism), ORBIT (Outcomes Registry for Better Informed Treatment), HEMORR2HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol) scores were assessed at baseline. International Society on Thrombosis and Haemostasis (ISTH)-defined bleeding events were independently adjudicated. Accuracy of the overall original 3-level and newly defined optimal 2-level outcome of the scores were evaluated and compared. We observed 82 first early major bleedings (3.0% (95% CI, 2.4–3.7)). The predictive power of bleeding scores was poor (Harrel’s C-index from 0.57 to 0.69). The RIETE score had numerically higher model fit and discrimination capacity but without reaching statistical significance versus the ORBIT, HEMORR2HAGES, and ATRIA scores. The VTE-BLEED and HAS-BLED scores had significantly lower C-index, integrated discrimination improvement, and net reclassification improvement compared to the others. The rate of observed early major bleeding in score-defined low-risk patients was high, between 15% and 34%. Current available scoring systems have insufficient accuracy to predict early major bleeding in patients with acute PE. The development of acute-PE-specific risk scores is needed to optimally target bleeding prevention strategies.

Plasma fibrin clot proteomics in patients with acute pulmonary embolism: Association with clot properties

It has been reported that 476 proteins can be detected in plasma fibrin clots from patients with venous thromboembolism. Plasma fibrin clots proteomic composition in relation to their properties has not been studied in acute pulmonary embolism (PE). Clots generated from plasma of 20 PE patients and 20 healthy controls were assessed using mass spectrometry, clot permeability (Ks), and clot lysis time (CLT). The proteomic composition of plasma fibrin clots from acute PE patients differed from that of control subjects in regard to 198 clot-bound proteins. In the acute PE group, we observed increased clot-bound fibrinogen, apolipoprotein B-100, platelet glycoprotein Ib, lipopolysaccharide-binding protein, and histones H3 + 4 and reduced fibronectin, α2-antiplasmin, α2-macroglobulin, factor (F)XIII, histidine-rich glycoprotein, antithrombin, von Willebrand Factor, plasminogen, and prothrombin. Among PE patients, low Ks (≤3.83 × 10−9 cm2) was associated with increased clot-bound C-reactive protein, kininogen-1, protein S, β-2-microglobulin, and thromboxane-A synthase when compared with patients having Ks > 3.83 × 10−9 cm2. Ks correlated inversely with FIX and FV, thrombin-activatable fibrinolysis inhibitor, complement C1s, C7, C8, and apolipoprotein A-I. The specific protein composition in plasma fibrin clots from acute PE patients is associated with denser clot formation. Several proteins unrelated to the coagulation system can modulate fibrin phenotype in acute thrombotic states. SignificanceOur study significantly advances the field of thrombosis and hemostasis. The plasma fibrin clot proteomics findings fill the gap of knowledge about the presence and the role of other proteins to the plasma fibrin clot in the acute phase of pulmonary embolism, aside fibrinogen, which is the main component of fibrin. The reported methodology, which involves the sample preparation using Multienzyme Digestion-Filter Aided Sample Preparation (MED FASP), data acquisition with the Quadrupole-Orbitrap mass spectrometer, and data analysis using the advanced tools such as MaxQuant, Total Protein Approach and Perseus, allows to gain not only the qualitative, but also the quantitative insights into the microworld of proteins entangled among the fibrin network. By comparing the clots formed from plasma of patients with acute pulmonary embolism with the clots from healthy control, we provide the specific protein composition associated with unfavorable clot properties observed in this disease. Moreover, our findings emphasize that several proteins unrelated to the coagulation system, can modulate fibrin phenotype in acute thrombotic states.

Inhaled nitric oxide has pulmonary vasodilator efficacy both in the immediate and prolonged phase of acute pulmonary embolism.

Inhaled nitric oxide (iNO) effectively reduces right ventricular afterload when administered in the immediate phase of acute pulmonary embolism (PE) in preclinical animal models. In a porcine model of intermediate-risk PE, we aimed to investigate whether iNO has pulmonary vasodilator efficacy both in the immediate and prolonged phase of acute PE. Anesthetized pigs (n = 18) were randomized into three subgroups. An acute PE iNO-group (n = 6) received iNO at 40 ppm at one, three, six, nine and 12 hours after onset of PE. Vehicle animals (n = 6) received PE, but no active treatment. A third group of sham animals (n = 6) received neither PE nor treatment. Animals were evaluated using intravascular pressures, respiratory parameters, biochemistry and intracardiac pressure-volume measurements. The administration of PE increased mean pulmonary artery pressure (mPAP) (vehicle vs sham; 33.3 vs 17.7 mmHg, p < 0.0001), pulmonary vascular resistance (vehicle vs sham; 847.5 vs 82.0 dynes, p < 0.0001) and right ventricular arterial elastance (vehicle vs sham; 1.2 vs 0.2 mmHg/ml, p < 0.0001). Significant mPAP reduction by iNO was preserved at 12 hours after the onset of acute PE (vehicle vs iNO; 0.5 vs -3.5 mmHg, p < 0.0001). However, this response was attenuated over time (p = 0.0313). iNO did not affect the systemic circulation. iNO is a safe and effective pulmonary vasodilator both in the immediate and prolonged phase of acute PE in an in-vivo porcine model of intermediate-risk PE.

Right ventricular adaptation in the critical phase after acute intermediate-risk pulmonary embolism.

The haemodynamic response following acute, intermediate-risk pulmonary embolism is not well described. We aimed to describe the cardiovascular changes in the initial, critical phase 0-12 hours after acute pulmonary embolism in an in-vivo porcine model. Pigs were randomly allocated to pulmonary embolism (n = 6) or sham (n = 6). Pulmonary embolism was administered as autologous blood clots (20 × 1 cm) until doubling of mean pulmonary arterial pressure or mean pulmonary arterial pressure was greater than 34 mmHg. Sham animals received saline. Cardiopulmonary changes were evaluated for 12 hours after intervention by biventricular pressure-volume loop recordings, invasive pressure measurements, arterial and central venous blood gas analyses. Mean pulmonary arterial pressure increased (P < 0.0001) and stayed elevated for 12 hours in the pulmonary embolism group compared to sham. Pulmonary vascular resistance and right ventricular arterial elastance (right ventricular afterload) were increased in the first 11 and 6 hours, respectively, after pulmonary embolism (P < 0.01 for both) compared to sham. Right ventricular ejection fraction was reduced (P < 0.01) for 8 hours, whereas a near-significant reduction in right ventricular stroke volume was observed (P = 0.06) for 4 hours in the pulmonary embolism group compared to sham. Right ventricular ventriculo-arterial coupling was reduced (P < 0.05) for 6 hours following acute pulmonary embolism despite increased right ventricular mechanical work in the pulmonary embolism group (P < 0.01) suggesting right ventricular failure. In a porcine model of intermediate-risk pulmonary embolism, the increased right ventricular afterload caused initial right ventricular ventriculo-arterial uncoupling and dysfunction. After approximately 6 hours, the right ventricular afterload returned to pre-pulmonary embolism values and right ventricular function improved despite a sustained high pulmonary arterial pressure. These results suggest an initial critical and vulnerable phase of acute pulmonary embolism before haemodynamic adaptation.

Fonction ventriculaire droite après un premier épisode d’embolie pulmonaire : apport du strain 2D

BackgroundAnalysis of right ventricular (RV) function during the acute phase of pulmonary embolism (PE) was widely reported in the literature. However, few studies analysed its function long term after the acute phase. Our aim was to evaluate the RV function long term after a first episode of PE. MethodsIn this study, we compared echocardiographic parameters of right ventricular function in 25 patients with a first episode of non-severe PE for more than six months with 25 healthy controls subject. ResultsIn the study of RV function, we noted that the mean values of the standard parameters were significantly lower in the EP group compared to the control group but their values remained within the normal range. The global RV longitudinal strain had a mean value lower than the control group statistically significant (−21±4,8% vs. −25±2,4%; P=0,28). The longitudinal strain of the free wall of the RV was altered in the EP group, however, there was no significant difference between the EP group and the control group (−19,4±16% vs. −24±17%; P=0,28). ConclusionThis study has shown that there is a systolic dysfunction late after a first episode of PE and this despite the absence of the symptoms and pulmonary hypertension.

Тест генерации тромбина в оценке адаптационных возможностей системы гемокоагуляции у пациентов с дегенеративно-дистрофическими заболеваниями суставов

Введение. Поиски методов оценки функционального состояния системы гемокоагуляции у пациентов, которые ожидают выполнения эндопротезирования крупных суставов нижних конечностей, обоснованы высокой частотой встречаемости у них тромбоэмболических осложнений. Цель исследования: изучение теста генерации тромбина (ТГТ) с позиции оценки адаптационных возможностей системы гемокоагуляции у больных с дегенеративнодистрофическими заболеваниями крупных суставов нижних конечностей. Материалы и методы. Обследован 141 больной с дегенеративнодистрофическими поражениями тазобедренных и коленных суставов (35 мужчин, 106 женщин), средний возраст 62,6 9,9 лет. Контрольную группу составили 30 условно здоровых доноров, средний возраст 49,7 6,5 лет. Исследовали коагуляционные свой ства крови рутинными методами и регистрировали кривую процесса тромбинообразования в ТГТ, анализируя параметры: tlag латентное время тромбинообразования, ttpeak время достижения максимума тромбина, peak максимальное количество тромбина, VI индекс скорости тромбинообразования, AUC площадь под кривой. Больные были разделены на 2 группы в зависимости от характера изменения временных параметров ТГТ в ответ на инициацию тромбиногенеза активаторами с концентрацией тканевого фактора 2 пмоль/мл (активатор RB) и 5 пмоль/мл (активатор RClow). Результаты. В 1й группе значения параметров tlag и ttpeak в ответ на действие активатора RClow были меньше, чем на действие активатора RB, реакцию системы гемокоагуляции расценивали как адекватную. Во 2й группе значения tlag и ttpeak при использовании активатора RClow превышали величины аналогичных параметров при инициации тромбообразования активатором RB, а корреляционный анализ отразил ослабление связей между параметрами ТГТ, что свидетельствовало об адаптационной перестройке системы на фоне высокого тромбогенного потенциала и повышенном риске развития гемокоагуляционных осложнений у больных 2й группы. Заключение. ТГТ с использованием активаторов RB и RClow ерспективный инструмент выявления больных с высоким риском развития послеоперационных гемокоагуляционных осложнений. Introduction. The search of methods for assessing of hemocoagulation functional state in patients that are waiting endoprosthesis replacement of large joints of lower extremities is justified by the high incidence of thromboembolic complications. Aim: to study thrombin generation assay (TGA) for assessment of hemocoagulation adaptive potential in patients with degenerativedystrophic diseases of the large joints of lower extremities. Materials and methods. We examined 141 patients with degenerativedystrophic lesions of hip and knee joints (35 men, 106 women), average age was 62.6 9.9 years. Control group consisted of 30 relatively healthy donors, average age was 49.7 6.5 years. We investigated blood coagulation properties by routine methods and recorded the curve of thrombin formation by TGA. We analyzed next parameters: tlag is the latent time of thrombin formation, ttpeak is the time to reach the maximum of thrombin, peak is the maximum amount of thrombin, VI is the index of thrombin formation speed, AUC is the area under the curve. Patients were divided into 2 groups according TGA parameters in response to thrombinogenesis initiation by activators with different tissue factor concentrations 2 pmol/ml (RB activator) and 5 pmol/ml (RClow activator). Results. In the 1st group, tlag and ttpeak values in TGA with RClow activator were less than with RB activator, the hemocoagulation response was regarded as adequate. In the 2nd group, tlag and ttpeak values with RClow activator were higher than with RB activator and correlation analysis revealed the weakening of the relationships between TGA parameters. This indicated about system adaptation at a time of high thrombogenic potential and about increased risk of developing hemocoagulation complications in patients of the 2nd group. Conclusion. TGA with RB and RClow activators is a promising tool for identifying patients with a high risk of postoperative hemocoagulation complications.

Развитие синдрома такоцубо в период госпитализации по поводу тромбоэмболии легочной артерии: клиническое наблюдение

The clinical case of the Takotsubo syndrome (TT) developed in process of treatment pulmonary embolism (PE) in old woman is described. A feature of this observation is the occurrence of TT not in the acute phase of PE, but in a month after the debut of the disease and in a week after the start of successful treatment.

Prevention of early complications and late consequences after acute pulmonary embolism: Focus on reperfusion techniques

Pulmonary embolism (PE) is a major cause of acute cardiovascular mortality and long-term morbidity. Right ventricular (RV) dysfunction is the key determinant of prognosis in the acute phase of PE, and residual RV dysfunction is associated with the development of post-PE functional impairment, chronic thromboembolic disease, and higher costs of treatment over the long term. Patients with clinically overt RV failure, i.e. hemodynamic collapse at presentation (high-risk PE), necessitate immediate thrombolytic treatment to relieve the obstruction in the pulmonary circulation; surgical or catheter-directed removal of the thrombus can be an alternative option. For patients with a high risk of bleeding or active hemorrhage, or for normotensive patients with intermediate-risk PE, systemic (intravenous) standard-dose thrombolysis is not recommended since the risks of treatment outweigh its benefits. In such cases, rescue thrombolysis should be considered only if hemodynamic decompensation develops while on heparin anticoagulation. For survivors of acute PE, little is known on the possible effects of thrombolytic treatment on the risk of chronic functional and hemodynamic impairment. Catheter-directed, ultrasound-assisted, low-dose thrombolysis leads to recovery of RV dysfunction, and its safety profile appears promising. However, adequately powered prospective trials focusing on both short- and long-term clinical outcomes are needed to establish novel interventional techniques in the treatment of PE.

Risk-adapted management of pulmonary embolism

The presence and severity of right ventricular (RV) dysfunction is a key determinant of prognosis in the acute phase of pulmonary embolism (PE). Risk-adapted treatment strategies continue to evolve, tailoring initial management to the clinical presentation and the functional status of the RV. Beyond pharmacological and, if necessary, mechanical circulatory support, systemic thrombolysis remains the mainstay of treatment for hemodynamically unstable patients; in contrast, it is not routinely recommended for intermediate-risk PE. Catheter-directed pharmacomechanical reperfusion treatment represents a promising option for minimizing bleeding risk; for reduced-dose intravenous thrombolysis, the data are still preliminary. Non-vitamin K-dependent oral anticoagulants, directly inhibiting factor Xa (rivaroxaban, apixaban, edoxaban) or thrombin (dabigatran), have simplified initial and long-term anticoagulation for PE while reducing major bleeding risk. Use of vena cava filters should be restricted to selected patients with absolute contraindications to anticoagulation, or PE recurrence despite adequately dosed anticoagulants.

Systemic Thrombolytic Therapy for Acute Pulmonary Embolism: Who Is a Candidate?

Pulmonary embolism (PE) is a major cause of both acute and long-term morbidity for a large number of patients worldwide, and massive PE is frequently fatal. Right ventricular (RV) dysfunction is a key determinant of prognosis in the acute phase of PE. Patients with clinically overt RV failure, that is, with cardiogenic shock or persistent hypotension at presentation (acute high-risk PE), are clearly in need of immediate reperfusion treatment with systemic thrombolysis or, alternatively, surgical or catheter-directed techniques. On the other hand, within the large group of patients presenting without hemodynamic instability, the bleeding risk of full-dose intravenous thrombolytic treatment has been shown to outweigh its benefits, even if they present with evidence of both RV dysfunction and myocardial injury. Thus, current guidelines agree in proposing a strategy of effective anticoagulation and "watchful waiting" (with initial hemodynamic monitoring notably over the first 48-72 hours) in intermediate-risk PE, with an indication for rescue thrombolysis if signs of hemodynamic decompensation appear. Recently published trials suggest that catheter-directed, ultrasound-assisted, low-dose local fibrinolysis may provide an effective and particularly safe treatment option for some of these patients. Ongoing or planned studies are expected to resolve the controversy on the efficacy and safety or reduced-dose systemic thrombolysis and to address the possible impact of thrombolytic therapy on long-term outcomes after acute PE.