Biomedical subjects
S Konstantinides
Publications and source records attributed to S Konstantinides.
[Diagnosis and therapy of pulmonary embolism].
Management of venous thromboembolism has long been characterized by a high degree of complexity and a disappointing lack of both efficacy and efficiency. The non-specific clinical signs of acute pulmonary embolism (PE) and the limitations of earlier imaging procedures such as the lung scan and pulmonary angiography led to the development of numerous sophisticated, multi-step diagnostic algorithms which, however, have proved extremely difficult to implement in clinical practice. As a result, the diagnosis of potentially life-threatening PE was frequently missed in many patients who subsequently died of the disease without receiving appropriate treatment, while other patients unnecessarily underwent a battery of invasive, time consuming procedures due to a vague, poorly documented clinical suspicion. Recently, the development of structured models for assessment of clinical pre-test probability, the widespread use of D-dimer testing in the outpatient setting, and particularly the technical advances of multidetector-row CT scan, had an enormous impact on our strategy for approaching patients with suspected PE. Contemporary diagnostic algorithms based on the above modalities are not only efficient and reliable but also simple and practicable. Furthermore, the importance of right ventricular (RV) dysfunction, even in the absence of overt hemodynamic instability, was recognized, and a number of studies demonstrated the value of echocardiography and laboratory biomarkers for risk stratification of PE. At present, low molecular weight heparins are increasingly becoming established as the treatment of choice for hemodynamically stable patients without RV dysfunction (non-massive PE), while consensus exists that patients with massive PE and cardiogenic shock necessitate emergency removal of pulmonary thrombus using thrombolytic agents, surgical embolectomy, or catheter-based thrombus aspiration. On the other hand, the treatment of stable patients with RV dysfunction (submassive PE) remains the subject of debate, and a large randomized trial is urgently needed to address the possible clinical benefits of thrombolysis in this setting.
Distinct antithrombotic consequences of platelet glycoprotein Ibalpha and VI deficiency in a mouse model of arterial thrombosis.
BACKGROUND: Collagen and von Willebrand factor (VWF) are considered essential to initiate platelet deposition at sites of vascular injury, but their respective roles remain to be elucidated. METHODS: We used a model of carotid artery thrombosis induced by a ferric chloride injury to compare the time to first occlusion and occlusion rate at 25 min postinjury in mice lacking the collagen receptor, glycoprotein (GP) VI, or the ligand-binding domain of the VWF receptor, GP Ibalpha. RESULTS: In normal mice used as controls (n = 12), a complete obstruction of blood flow developed within 8.05 +/- 0.47 min (mean +/- SEM), and the occlusion rate was 100%. The results were variable in 26 GP VI(-/-) mice. The artery never occluded in eight mice, but the time to first occlusion in the remaining 18 (8.36 +/- 0.27 min) was not different from normal (P = 0.556). Nonetheless, the occlusion rate was 42%, because in seven mice the occluded artery reopened and stayed patent at 25 min. In contrast, the artery never occluded in 12 mice lacking GP Ibalpha. In ex vivo perfusion experiments, GP VI(-/-) platelets failed to form thrombi onto collagen type I fibrils, but formed thrombi of normal size when exposed to endothelial or fibroblast extracellular matrix. CONCLUSIONS: Absence of GP Ibalpha function has a more profound antithrombotic effect in vivo than absence of the GP VI-dependent pathway of collagen-induced adhesion/activation. Components of the extracellular matrix may elicit a thrombogenic response in the absence of GP VI but not GP Ibalpha.
[Acute ST-elevation myocardial infarction: is primary PCI superior to thrombolysis?].
Thrombolysis is an established treatment of acute myocardial infarction with persistent ST elevation (STEMI). Thrombolytic agents are most effective in patients who can be treated within two hours of symptom onset. On the other hand, the efficacy of mechanical recanalization (PCI) was consistently shown to be superior to thrombolysis regardless of the duration of symptoms. Recent studies further suggest that it may be preferable for small hospitals to rapidly transfer patients with acute STEMI to a PCI center rather than perform on-site thrombolysis. Therefore, this novel strategy is principally recommended in the updated guidelines of German and international cardiac societies. However, it is emphasized that the transfer-related delay of treatment should not exceed 60-90 minutes.
Thrombotic phenotype of mice with a combined deficiency in plasminogen activator inhibitor 1 and vitronectin.
OBJECTIVE: The role of vitronectin (VN) in thrombosis is not fully understood, primarily because this adhesive glycoprotein not only stabilizes plasminogen activator inhibitor 1 (PAI-1) and thus protects fibrin from premature lysis, but also because it binds to platelet integrins and may influence platelet aggregation. The absence of quantitative approaches to characterize the thrombi formed in animal models under different conditions further complicates this analysis. METHODS: In this report, we describe a more comprehensive approach to assess the stability of thrombi formed in mice deficient in PAI-1 (PAI-1(-/-)), VN (VN(-/-)) or both (PAI-1(-/-)/VN(-/-)). RESULTS: We observed that all deficient mice developed unstable thrombi compared with wild type (WT) mice. Thus, only 31% of the thrombi formed in WT mice were unstable compared with 74% of PAI-1(-/-), 80% of VN(-/-), and 87% of PAI-1(-/-)/VN(-/-) mice. In this regard, the average number of emboli per WT mouse was significantly lower (0.55) compared with VN(-/-) (2.66), PAI-1(-/-) (2.1), and VN(-/-)/PAI-1(-/-) (2.35) mice. Finally, the total duration of complete vascular occlusion was higher and the rate of vascular patency was lower in the WT mice compared with the deficient mice. CONCLUSIONS: Taken together, these observations indicate that the thrombotic phenotype of mice with a combined deficiency in PAI-1 and VN does not differ significantly from the phenotype of mice with deficiencies in only PAI-1 or VN. This observation suggests that PAI-1 and VN may influence thrombus stability by regulating a common pathway.
[Acute cor pulmonale in pulmonary embolism. An important prognostic factor and a critical parameter for the choice of a therapeutic strategy].
Venous thromboembolism remains one of the most frequent and threatening acute cardiovascular syndromes. Its incidence has remained constant over the last several years, both in Europe and the United States, accounting for approximately 1.5 cases per 1000 inhabitants per year. Every year about 100 cases of venous thromboembolism per 100,000 inhabitants are admitted to the hospital, and 10% of these patients die during the hospital stay. Particularly alarming is the fact that in 50-70% of all patients who die from an acute pulmonary embolism the diagnosis is only made after death. These facts emphasize not only the relevance of the problem of "acute pulmonary embolism," but also the need for optimization of current diagnostic and therapeutic strategies. Rapid identification of acute cor pulmonale with echocardiography and cardiac biomarkers has recently proven to be especially helpful in this regard.
PAI-1 and vasculopathy: the debate continues.
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Thrombolysis in submassive pulmonary embolism? Yes.
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Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice.
BACKGROUND: The origin and contribution of plasminogen activator inhibitor-1 (PAI-1) and its cofactor vitronectin (VN) to arterial thrombosis/thrombolysis in vivo is controversial. METHODS AND RESULTS: Ferric chloride was used to induce carotid artery injury in 97 wild-type (WT), 84 PAI-1-/-, and 84 VN-/- mice. Complete thrombotic occlusion was observed in 70% of PAI-1-/- mice versus 92% of WT (P:<0.001) and 87% of VN-/- (P:=0.015) mice. In vessels that occluded, mean times to occlusion were significantly longer in PAI-1-/- than in WT or VN-/- mice. The initial thrombotic response of VN-/- mice was similar to that of WT mice, but their thrombi were unstable and frequently embolized. As a result, the patency rate of carotid vessels 30 minutes after injury was as high in VN-/- mice (36%) as in PAI-1-/- mice (which demonstrate progressive thrombolysis) and significantly higher than that of WT mice (12%; P:=0.013). Histochemical and reverse transcription-polymerase chain reaction studies revealed an early upregulation of PAI-1 mRNA and protein expression in the thrombus and the vessel wall, which persisted for >/=1 week. VN protein also accumulated after injury, but VN mRNA levels remained low at all times. CONCLUSIONS: PAI-1 and VN participate in the thrombotic response to arterial injury by preventing premature thrombus dissolution and embolization. The accumulation of PAI-1 in the thrombus/vessel wall after injury may result, at least in part, from local synthesis, whereas the VN protein appears to be derived from plasma.
Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice.
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Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity.
Obesity is associated with increased cardiovascular morbidity and mortality and with elevated circulating levels of the satiety factor leptin. This study provides evidence for a direct link between leptin and the risk for thrombotic complications in obese individuals. For example, although arterial injury provokes thrombosis in both lean and obese (ob/ob) mice, the time to complete thrombotic occlusion is significantly delayed in the ob/ob mice, and the thrombi formed are unstable and frequently embolize. The ob/ob mice lack leptin, and intraperitoneal administration of leptin to these mice before injury restores the phenotype of lean mice by shortening the time to occlusion, stabilizing the thrombi, and decreasing the patency rate. The thrombi that form when leptin receptor-deficient obese (db/db) mice are injured also are unstable. However, in this instance, leptin has no effect. Platelets express the leptin receptor, and leptin potentiates the aggregation of platelets from ob/ob but not db/db mice in response to known agonists. These results reveal a novel receptor-dependent effect of leptin on platelet function and hemostasis and provide new insights into the molecular basis of cardiovascular complications in obese individuals. The results suggest that these prothrombotic properties should be considered when developing therapeutic strategies based on leptin.
The prothrombotic effects of leptin possible implications for the risk of cardiovascular disease in obesity.
Human obesity is associated with leptin resistance, elevated leptin levels in the circulation, and increased risk of arterial and venous thrombotic disease. Our studies suggest that elevated leptin levels may directly promote arterial thrombosis in vivo. We found that leptin-deficient ob/ob mice had prolonged times to thrombosis after arterial injury with ferric chloride and that exogenously administered leptin corrected their phenotype in a dose-dependent manner. These effects appear to result from a direct, receptor-mediated effect of leptin on platelets, because leptin stimulated the aggregation of murine (wild-type and ob/ob) and human platelets, but it had no effect on platelets from leptin receptor-deficient db/db mice. Moreover, db/db mice had an attenuated thrombotic response to ferric chloride injury (indistinguishable from that of the ob/ob mice), which was unaffected by exogenous leptin. Our results raise the possibility that elevated plasma levels of leptin may contribute to the risk of atherothrombotic complications in human obesity.
[Patent foramen ovale: conservative or surgical therapy?].
Notwithstanding the difficulties in definitely confirming paradoxical embolism, the association between patent foramen ovale (PFO) and cryptogenic stroke has repeatedly been demonstrated in clinical studies. Moreover, the recurrence rate of cerebral ischemia in patients with PFO and an unexplained stroke was found to be 3-4% per year in two recently published series. With the exception of right atrial pressure elevation in the setting of major pulmonary embolism, a reliable risk stratification of patients with PFO based on clinical or echocardiographic findings is not yet possible. The presence of atrial septal aneurysm, a wide opening of the defect during the cardiac cycle and a large atrial shunt have been implicated as risk factors by some investigators. Long-term prevention of paradoxical embolism with oral anticoagulants seems to be of questionable benefit. Besides, these agents are poorly tolerated and carry the risk of significant or fatal bleeding at a rate of 2-5% per year. Surgery of the atrial septum has been performed for many decades in patients with atrial septal defect and evidence accumulates that it is a safe and highly effective procedure in patients with PFO. At present, surgical closure of the PFO appears to be the treatment of choice for secondary prevention of paradoxical embolism. However, further studies are needed to define the appropriate candidates for surgical treatment. Devices for catheter-based sealing of PFO are also available and are currently being evaluated in clinical trials. However, experience with their use remains confined to specialized centers. Furthermore, further technical improvements of these systems are needed in order to optimize successful delivery and positioning, increase their long-term stability, and reduce periprocedural complications.
[Current status of diagnosis and therapy of acute pulmonary embolism].
Diagnosing pulmonary embolism (PE) remains a challenge due to the often confusing clinical presentation of the disease. Plasma D-dimer testing with ELISA is increasingly becoming part of the initial diagnostic work up. Due to the high specificity of the assay, a negative test can reliably exclude PE. Importantly, massive PE can be promptly diagnosed or excluded by echocardiography which is a particularly valuable noninvasive method for detection of right ventricular dysfunction at the bedside. High-risk patients can thus be identified and treated immediately without further time-consuming examinations. Confirmation of PE in patients with inconclusive or normal echocardiograms is often based on lung scans, but diagnostic uncertainty is common with this procedure. The popularity of pulmonary angiography is decreasing due to its invasiveness, whereas spiral CT appears to be a promising alternative. Search for (residual) deep vein thrombosis is useful for guiding therapy in stable patients with small pulmonary emboli, since their risk is determined by the potential for PE recurrence. Recent evidence confirmed that right ventricular dysfunction predicts an unfavorable prognosis and might therefore justify thrombolytic treatment of massive PE regardless of systemic hemodynamics. On the other hand, simplified anticoagulation regimens with low-molecular weight heparins have yielded very promising results in stable patients. These diagnostic and therapeutic principles based on cardiovascular risk stratification will hopefully result in a more effective approach to patients with venous thromboembolism in the future.
Cerebral and renal embolization after lymphography in a patient with non-Hodgkin lymphoma: case report.
An unusual case of lipid embolization to brain and kidney after lymphography in a patient with non-Hodgkin lymphoma of the upper anterior mediastinum is reported. Contrast material-enhanced echocardiography demonstrated a right-to-left shunt to the left atrium without evidence of a patent foramen ovale. Echo contrast particles were transiently present within the tumor surrounding the great vessels.
Submassive and massive pulmonary embolism: a target for thrombolytic therapy?
Thrombolytic agents have been consistently demonstrated to dissolve pulmonary thrombi much more rapidly and effectively than heparin alone. Rapid resolution of pulmonary embolism (PE) is accompanied by a significant decrease in pulmonary artery pressure and an improvement in right ventricular function. However, it is no longer than 7 days until the findings of patients treated with heparin improve to a similar extent. Previous studies were not designed to determine whether this short-lasting difference in favor of thrombolysis can indeed affect the prognosis of patients with PE and thus justify the 1% (or even higher) risk of cerebral or fatal bleeding. Recently, two large registries demonstrated the importance of right ventricular dysfunction assessed by echocardiography as an independent predictor of mortality. Thrombolytic treatment was shown in one of these registries to be associated with a 50% reduction of death risk in clinically stable patients with right ventricular enlargement. It was thus possible to identify a group of patients with massive PE who are most likely to benefit from early thrombolysis. These findings now have to be confirmed by a prospective randomized trial which will compare thrombolysis with heparin alone in this high-risk patient population, focusing on clinical end points such as overall and event-free survival in the acute phase of PE.
Comparison of alteplase versus heparin for resolution of major pulmonary embolism.
Complete resolution of major pulmonary embolism (PE) treated with heparin alone can often take > 3 weeks. Thrombolytic agents effectively resolve pulmonary artery thrombi within a few hours. However, the effect of the 2 types of treatment on recovery of right ventricular function has not yet been followed for periods of > 24 hours. We prospectively examined 40 consecutive patients with documented major PE (symptoms being present for < or = 8 weeks). After diagnosis, 27 patients (68%) were treated with alteplase plus heparin and 13 (32%) with heparin alone. There was no significant difference between the 2 groups with regard to baseline parameters. At 12 hours, systolic pulmonary artery pressure decreased from 56 +/- 20 to 37 +/- 21 mm Hg in the alteplase group, and from 50 +/- 11 to 46 +/- 12 mm Hg in the heparin group (significantly more; p = 0.016). On echocardiographic follow-up, a decrease in end-diastolic dimensions of the right ventricle and an increase in left ventricular dimensions was significantly more pronounced in the alteplase group (p <0.001 and p = 0.05, respectively). The incidence of right ventricular dilation and paradoxical septal wall motion decreased significantly only in the thrombolyis group. However, at 1-week follow-up, no difference was seen between the 2 groups regarding the overall change in right or left ventricular dimensions or the final values of other echocardiographic parameters. Thus, echocardiography is particularly useful for hemodynamic follow-up of major PE. Thrombolysis may rapidly reduce pulmonary artery pressure, but resolution of right ventricular pressure overload also occurs within 1 week in patients treated with heparin alone.
Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism.
BACKGROUND: Right-to-left shunt through a patent foramen ovale is frequently diagnosed by contrast echocardiography and can be particularly prominent in the presence of elevated pressures in the right side of the heart. Its prognostic significance in patients with pulmonary thromboembolism, however, is unknown. METHODS AND RESULTS: The present prospective study included 139 consecutive patients with major pulmonary embolism diagnosed on the basis of clinical, echocardiographic, and cardiac catheterization criteria. All patients underwent contrast echocardiography at presentation. The end points of the study were overall mortality and complicated clinical course during the hospital stay defined as death, cerebral or peripheral arterial thromboembolism, major bleeding, or need for endotracheal intubation or cardiopulmonary resuscitation. Patent foramen ovale was diagnosed in 48 patients (35%). These patients had a death rate of 33% as opposed to 14% in patients with a negative echo-contrast examination (P=.015). Logistic regression analysis demonstrated that the only independent predictors of mortality in the study population were a patent foramen ovale (odds ratio [OR], 11.4; P<.001) and arterial hypotension at presentation (OR, 26.3; P<.001). Patients with a patent foramen ovale also had a significantly higher incidence of ischemic stroke (13% versus 2.2%; P=.02) and peripheral arterial embolism (15 versus 0%; P<.001). Overall, the risk of a complicated in-hospital course was 5.2 times higher in this patient group (P<.001). CONCLUSIONS: In patients with major pulmonary embolism, echocardiographic detection of a patent foramen ovale signifies a particularly high risk of death and arterial thromboembolic complications.