Doctor of Medicine, Universitat Leipzig (2007)
Philip Tsao, Postdoctoral Faculty Sponsor
Thromboembolism and bleeding after mechanical heart valve replacement are still unsolved problems, particularly for patients requiring anticoagulative bridging therapy. The aim of this study was to investigate whether rivaroxaban, a new oral selective and direct coagulation factor Xa inhibitor, is as effective as enoxaparin and unfractionated heparin (UFH) in preventing thrombus formation on mechanical heart valves using an in vitro system. Blood from healthy male donors was anticoagulated with either UFH, enoxaparin, rivaroxaban at 300 ng/ml, (n = 10 each), or rivaroxaban at 30 ng/ml (n = 3). Mechanical aortic valve prostheses were placed into the in vitro testing system THIA II and exposed to the anticoagulant blood mixtures at a pulsatile flow for 60 min. Overall thrombus weight, coagulation parameters, and electron microscopic features of thrombus formation on the valve surface were quantified as endpoints. The mean thrombus weights were 163 ± 64 mg for group 1 (UFH), 341 ± 63 mg for the group 2 (enoxaparin), 238 ± 83 mg for group 3 (rivaroxaban 300 ng/ml) and 1.739 ± 16 mg for group 4 (rivaroxaban 30 ng/ml). Whereas high-dosed rivaroxaban showed no significant differences compared to UFH or enoxaparin, low-dosed rivaroxaban generated a massive thrombus generation, thus differing significantly from all other treatment groups regarding the thrombus weight. We hypothesize that high-dose rivaroxaban is a competitive oral available alternative to UFH and LMWH's, that might be a worthwhile alternative for patients in need of anticoagulative bridging therapy. Prospective studies have to evaluate if rivaroxaban might even overcome the limitations of OAC in patients after implantation of artificial heart valves.
View details for DOI 10.1007/s11239-011-0621-6
View details for Web of Science ID 000295330000005
View details for PubMedID 21773837
Interruption of oral anticoagulation is discussed often, particularly in the outpatient setting. We present a 66- year-old woman who developed a thrombus in the left atrial appendage under bridging therapy with fondaparinux. With this case report we would like to emphasize that off-label use of fondaparinux should not be administered to patients at high risk for systemic embolism.
View details for PubMedID 22122396
Lifelong oral anticoagulation (OAC) therapy is required for the prevention of thromboembolic events after implantation of an artificial heart valve. Thromboembolism and anticoagulant-related bleedings account for approximately 75% of all complications experienced by heart valve recipients (2-9% of patients per year). The present study investigated the efficacy of dabigatran, a new direct thrombin inhibitor for oral use, as compared to unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in preventing thrombus formation on mechanical heart valves in vitro.Blood (230 ml) from healthy young male volunteers was anticoagulated either by dabigatran (1 micromol/l), UFH (150 IU), or LMWH (100 IU). Mechanical heart valve prostheses were placed in an in vitro thrombosis tester and exposed to the anticoagulated blood samples under continuous circulation at a rate of 75 beats per minute.In whole blood with no anticoagulant, the apparatus completely clotted in 15-20 minutes. When blood was treated with dabigatran, the mean thrombus weight was 164+/-55 mg, in the UFH group 159+/-69 mg, and in the LMWH group 182+/-82 mg (p-value: 0.704). Electron microscopy showed no significant difference in thrombus formation in any group.Dabigatran was as effective as UFH and LMWH in preventing thrombus formation on mechanical heart valves in our in vitro investigation. Thus, we hypothesize that dabigatran etexilate might potentially be a useful and competitive orally administered alternative to UFH and LMWH for recipients of alloplastic heart valve prostheses.
View details for DOI 10.1016/j.thromres.2010.06.011
View details for Web of Science ID 000281386000024
View details for PubMedID 20659761
Patients with cardiogenic shock (CS) are currently treated with acute coronary revascularization, mechanical support (i.e., IABP), and in addition with vasopressor and inotropic support. Among medical treatment dobutamine and norepinephrine are drugs of first choice. Nowadays, intravenous levosimendan, a new calcium sensitizer and K-ATP channel opener, has emerged as an alternative option of pharmacologic inotropic support in patients with cardiogenic shock. Recent reports on levosimendan's use in cardiogenic shock demonstrated more favorable effects when compared with conventional inotropic agents. Clearly, levosimendan is able to archieve profound increase of cardiac index and cardiac power index in combination with reduced systemic and pulmonary resistance reduction compared to conventional therapy. Further, levosimendan is able to improve hemodynamic parameters more rapidly compared to intraaortic ballon counter pulsation. Similar, in patients with low cardiac output syndrome upon cardiovascular surgery, levosimendan is able to improve cardiac performance when administered prior or after cardiac surgery. In the light of cardiogenic shock, the myocardial protective effects of levosimendan might be important to reduce reperfusion injury and myocardial stunning following ischemia and reperfusion. This review summarizes the evidence from current scientific literature including our recent trials regarding the mechanism of action, efficiency and the use of levosimendan in CS patients.
View details for PubMedID 20938415
Owing to its beneficial pharmacological profile, the low-molecular-weight heparin (LMWH) enoxaparin is increasingly being taken as an alternative to UFH in the treatment of ACS with an early invasive strategy and in elective percutaneous coronary interventions (PCI). Insufficient anticoagulation increases the risk of catheter thrombus formation during PCI. The aim of the present study was to test in vitro the hypotheses that (i) inhibiting thrombin or thrombin generation by administering LMWH is a critical intervention in preventing catheter thrombus formation and (ii) other LMWH such as certoparin or dalteparin are as effective as enoxaparin. Blood pre-treated with the anticoagulants of interest was continuously circulated through a guiding catheter by using a roller pump for a maximum experimental period of 60 min or until the catheter became occluded. Overall thrombus weight, anti-Xa activity and electron microscopic features such as deposits of platelets, erythrocytes and fibrin on the catheter surface were quantified as endpoints. All LMWH tested significantly reduced catheter thrombus generation comparable to UFH treatment whereas there was no difference between the specific LMWH with respect to catheter thrombus formation or deposition of platelets, erythrocytes and fibrin. Thrombus generation was found to negatively correlate with anti-Xa activity. The additional use of eptifibatide did not affect thrombus formation. These data suggest that modulating plasmatic coagulation by employing LMWH is critical for preventing catheter thrombus formation and at the same time offer a potential for administering LMWH other than enoxaparin, such as certoparin or dalteparin, in the setting of PCI.
View details for DOI 10.1007/s11239-009-0355-x
View details for Web of Science ID 000275555100001
View details for PubMedID 19517216
The direct thrombin inhibitor argatroban offers some significant advantages over unfractionated heparin (UFH) and is recommended as an alternative anticoagulant during percutaneous coronary interventions (PCI). The impact of argatroban on cardiac catheter thrombosis--a severe potential complication of PCI--has not been systematically studied yet. The aim of the present study was to test in vitro the hypothesis that argatroban is equivalent to the more established anticoagulants UFH and enoxaparin in preventing catheter thrombus formation. Blood pretreated with the anticoagulants of interest was continuously circulated through a guiding catheter by using a roller pump for a maximum experimental period of 60 minutes. In an alternate model, coagulation was mechanically induced by a magnetic stirrer. Coagulation parameters, overall thrombus weight and electron microscopic features (deposits of platelets and fibrin on the catheter surface) were quantified as endpoints. Argatroban (administered as bolus or continuous infusion), UFH (bolus), and enoxaparin (bolus) significantly reduced catheter thrombus formation compared to untreated controls. Here, neither overall thrombus weight nor platelet/fibrin deposition was different among the specific anticoagulants. Declining ACT (activated clotting time) levels--which were found in the argatroban bolus group--could be prevented by continuous infusion. In magnetic stirrer-induced coagulation, thrombus weight was lower following bolus treatment with UFH and enoxaparin compared to argatroban. These data suggest that the potential for argatroban in preventing catheter thrombosis is comparable to that of UFH and enoxaparin. However, the anticoagulatory efficacy varied, depending on the model of coagulation activation, which demonstrates the necessity for specific testing.
View details for DOI 10.1160/TH09-07-0456
View details for Web of Science ID 000277031700018
View details for PubMedID 20174756
Plasma phospholipid transfer protein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Animal studies have shown that it is closely related to the development of atherosclerosis. Although many studies have indicated that PLTP activity is increased in diabetes mellitus, the role of PLTP in diabetes is still unclear. To evaluate the influence of a high-fat meal on PLTP activity, 50 nondiabetic patients with coronary heart disease (CHD), 50 insulin-treated Type 2 diabetics, and 50 healthy controls were included. We determined PLTP activity before and 4 and 8 h after a high-fat meal. As expected, serum PLTP activity was significantly higher in CHD patients than in healthy controls (71.0 +/- 46.2 vs. 54.0 +/- 33.8 pmol/microl/h, P = 0.032) at baseline. More importantly, we found that serum PLTP activity increased to its maximum 4 h after fat loading and then decreased to nearly basal levels after 8 h both in controls and CHD patients. In contrast, PLTP activity continuously increased during this time period in the diabetic patients. With regards to the data from this study we hypothesize that serum PLTP is involved in the clearance of postprandial lipoproteins and this process is attenuated in diabetes. Since postprandial lipoproteins are atherogenic, the delay in clearance of these particles could play an important role in the development of atherosclerosis in patients with diabetes mellitus.
View details for DOI 10.1007/s11745-010-3384-5
View details for Web of Science ID 000274333300003
View details for PubMedID 20108050
Prevention of valve thrombosis in patients after prosthetic mechanical heart valve replacement and heparin-induced thrombocytopenia (HIT) is still an open issue. The aim of the present in-vitro study was to investigate the efficacy of argatroban and bivalirudin in comparison to unfractionated heparin (UFH) in preventing thrombus formation on mechanical heart valves. Blood (230 ml) from healthy young male volunteers was anticoagulated either by UFH, argatroban bolus, argatroban bolus plus continuous infusion, bivalirudin bolus, or bivalirudin bolus plus continuous infusion. Valve prostheses were placed in a newly developed in-vitro thrombosis tester and exposed to the anticoagulated blood samples. To quantify the thrombi, electron microscopy was performed, and each valve was weighed before and after the experiment. Mean thrombus weight in group 1 (UFH) was 117 + 93 mg, in group 2 (argatroban bolus) 722 + 428 mg, in group 3 (bivalirudin bolus) 758 + 323 mg, in group 4 (argatroban bolus plus continuous infusion) 162 + 98 mg, and in group 5 (bivalirudin bolus plus continuous infusion) 166 + 141 mg (p-value <0.001). Electron microscopy showed increased rates of thrombus formation in groups 2 and 3. Argatroban and bivalirudin were as effective as UFH in preventing thrombus formation on valve prostheses in our in-vitro investigation when they were administered continuously. We hypothesise that continuous infusion of argatroban or bivalirudin are optimal treatment options for patients with HIT after mechanical heart valve replacement for adapting oral to parenteral anticoagulation or vice versa.
View details for DOI 10.1160/TH08-09-0571
View details for Web of Science ID 000267218700028
View details for PubMedID 19492162
Alveolar epithelial and endothelial cell death caused by mechanical over-distension is likely to contribute to ventilator-induced lung injury (VILI). Consequently, the search for cytoprotective interventions is of interest. We investigated the effect of the mTOR inhibitor rapamycin on human pulmonary microvascular endothelial cell (HMVEC-L) viability in a model of high-amplitude mechanical stretch. Cyclic mechanical stretch (30% increase in membrane surface area, cycling frequency 40/min), employed for 24 h induced apoptosis in HMVEC-L. This effect was reduced by rapamycin treatment. Focusing on possible mechanisms of action we demonstrated that the stretch-induced reduction in the anti-apoptotic messenger pAkt could be restored by rapamycin treatment. Furthermore, we observed rapamycin-induced modifications in the HMVEC-L actin cytoskeleton architecture and global cellular f-actin content which functionally resulted in an increased global cellular mechanical stability - as indicated by an increased HMVEC-L osmomechanical resistance - thereby possibly desensitizing HMVEC-L to mechanical stimulation. According to the data from the present study, rapamycin represents a promising cytoprotective agent under mechanically challenging conditions such as mechanical ventilation.
View details for DOI 10.1016/j.mvr.2009.01.012
View details for Web of Science ID 000265430200009
View details for PubMedID 19323970
Phospholipid transferprotein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Although many studies have investigated the role of PLTP in atherogenesis, the role of PLTP in atherosclerotic diseases is unclear. We investigated the association of serum PLTP activity with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and its relation to other markers of atherosclerosis in 1,085 patients with angiographically documented coronary artery disease (CAD). In the median follow-up of 5.1 years, 156 patients had suffered from the combined endpoint of myocardial infarction or cardiovascular death including 47 of 395 patients who were on statins at baseline. In Kaplan-Meyer analyses serum PLTP activity was not associated with the combined endpoint in all patients. However, in the subgroup of patients receiving statins at baseline, PLTP was shown to be a significant predictor of cardiovascular outcome (P = 0.019), and this also remained stable in univariate (P = 0.027) and multivariate cox regression analyses (P = 0.041) including potential confounders (classical risk factors, HDL cholesterol (HDL-C), and others). We showed in our study that, under statin treatment, high plasma PLTP activity was related to fatal and nonfatal cardiovascular events in CAD patients.
View details for DOI 10.1194/jlr.M800414-JLR200
View details for Web of Science ID 000264283800015
View details for PubMedID 19001358
The chemokine and adhesion molecule fractalkine and its receptor CX(3)CR1 have emerged as interesting regulators in inflammation and related atherosclerosis. The pro-inflammatory status may be counteracted by appropriate treatment, such as in rehabilitation. We compared serum fractalkine concentrations of 46 patients with coronary heart disease (CHD) and 47 insulin-dependent diabetic patients (IDDM) following rehabilitation with those of 50 control subjects. Following rehabilitation serum fractalkine levels (477 + or - 225 pg/mL) in CHD patients were similar to those in control subjects (572 + or - 205 pg/mL; P = 0.303), whereas fractalkine levels were lower in IDDM patients (430 + or - 256 pg/mL; P = 0.042). No significant difference between CHD and IDDM patients was present (P = 0.319). Postprandial hyperlipemia may influence inflammation; thus, we investigated fractalkine levels four and eight hours after inducing postprandial hyperlipemia. However, we did not find any significant alterations in CHD and diabetic patients, whereas the fractalkine levels in controls were reduced. In vitro, lipofundin used as a hyperlipemic stimulus was added to vessel wall cells and reduced fractalkine levels. Low fractalkine levels in patients attending rehabilitation indicate a beneficial effect of the rehabilitation procedure on innate inflammatory pathways, such as the chemokine and adhesion molecule fractalkine.
View details for PubMedID 19851523
Atrial fibrillation (AF) is the most common cardiac arrhythmia sustained and frequently occurs in patients with coronary heart disease. Thus, a large number of patients requiring percutaneous coronary intervention (PCI) also suffer from AF. An anticoagulant regimen has not been standardized for patients with AF after coronary stent implantation.The authors investigated data from 159 patients with AF who underwent PCI in their department. Baseline variables and incidence of a combined endpoint (stroke, myocardial infarction, cardiovascular death, severe bleeding) were compared in patients receiving clopidogrel and acetylsalicylic acid (ASA; group 1) versus patients receiving the combination of clopidogrel and ASA with low-molecular-weight heparin (LMWH; group 2) versus patients receiving the combination of clopidogrel and ASA with oral anticoagulation (OAC; group 3) at discharge.Patients discharged with triple therapy including OAC seemed to be at higher risk: patients in group 3 had decreased left ventricular ejection fraction and increased inflammatory state as measured by plasma fibrinogen and C-reactive protein. Moreover, previous OAC treatment and strokes were found more often in this subgroup of patients. In a median follow-up of 1.4 years, two severe bleeding events (both in group 1), four myocardial infarctions (all in group 1), 13 strokes (nine in group 1, four in group 2), and nine cardiovascular deaths (three in group 1, five in group 2, one in group 3) occurred.In this analysis, no treatment regimen seemed to be clearly superior. It underlines the importance of prospective, randomized trials to investigate the optimal antithrombotic/antiplatelet treatment for patients with AF after PCI.
View details for DOI 10.1007/s00063-008-1101-4
View details for Web of Science ID 000259482400003
View details for PubMedID 18813885