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ABSTRACT: A single nucleotide polymorphism of the factor VII activating protease (FSAP), FSAP Marburg I (rs7080536) has been identified as a risk factor for venous thrombosis, but its clinical role has so far been controversial in part due to small cohort sizes. The aim of the present case-control study was to elucidate the impact of the FSAP Marburg I polymorphism (FSAP-MI) on the development of venous thromboembolic disease (VTE) with other known sequence variations, including Factor V Leiden (rs6025) and Factor II G20210A (rs1799963).
The study included 891 patients (312 male and 579 female) with a history of deep venous thrombosis (DVT) and/or pulmonary embolism (PE) and 1283 healthy blood donors with no history of venous thromboembolic disease.
We found that besides to the well-established aforementioned sequence variations of FV and Prothrombin, the FSAP Marburg I (FSAP-MI) polymorphism was significantly associated with the development of DVTs (1.65 (1.16-2.34) OR (95% CI)) and recurrent thromboembolic events (DVT and PE) (2.13 (1.35-3.36) OR (95% CI)). Comparing patients displaying one or more events FSAP-MI was still associated with the development of recurrent thromboembolic events (1.64 (1- 2.69) OR (95% CI)).
We conclude that FSAP Marburg-I genotyping may be used to determine the risk for thromboembolic disorders in patients with suspected thrombophilia and known DVT or PE.
Thrombosis Research 03/2012; 130(3):441-4. · 2.44 Impact Factor
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Cerebrovascular Diseases 12/2011; 32(6):616-9. · 2.72 Impact Factor
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ABSTRACT: An upregulation of platelet CD40 ligand (CD40L) and CD62P has been described in atherosclerotic cardiovascular diseases and among patients with acute cerebral ischemia. Correlation between platelet and monocyte activation and the etiology of ischemic stroke were examined in 41 patients with acute ischemic stroke. Compared to 10 controls, all patients with stroke showed a significantly elevated platelet expression of CD40L (P < .001) and had significantly higher amounts of platelet-monocyte aggregates (P = .002). Plasma levels of interleukin 7 were significantly lower in patients with stroke compared to controls (P = .006). Patients with small artery disease had a significantly higher platelet CD40L expression than patients with cardioembolic stroke (P = .029). Plasma levels of soluble CD40L were significantly higher in patients with large artery disease compared to patients with cardioembolic stroke (P = .047). In conclusion, patients with acute ischemic stroke show an upregulation of platelet CD40L and an activation of cellular coagulation with highest activation in the large artery disease subgroup.
Clinical and Applied Thrombosis/Hemostasis 07/2011; 18(1):87-91. · 1.33 Impact Factor
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Tom Oberheiden,
Christian Blahak,
Xuan Duc Nguyen,
Marc Fatar,
Elif Elmas,
Nicole Morper, Carl-Erik Dempfle,
Hansjörg Bäzner,
Michael Hennerici,
Martin Borggrefe,
Thorsten Kälsch
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ABSTRACT: Platelets and monocytes play a pivotal role in the initiation and progression of large-vessel atherosclerosis. An up-regulation of various platelet and coagulation activation markers has been described in cardiovascular diseases and in patients with acute cerebral ischemia. In the present study the role of platelets and cellular coagulation activation in cerebral small-vessel disease (cSVD) was assessed. In 24 patients with cSVD but without established large-vessel disease, whole blood samples were obtained. Patients were divided into three subgroups (Fazekas 1, 2 and 3) according to extent of cSVD based on morphological magnetic resonance imaging criteria. Surface expression of CD40L and CD62P on platelets, tissue-factor exposition on monocytes and platelet-monocyte aggregates were measured with flow cytometry. Plasma levels of soluble CD40L, interleukin (IL)-6 and IL-7 were assessed by ELISA. Patients with cSVD show a significantly elevated expression of platelet CD40L (P < 0.001) and CD62P (P < 0.023), significantly elevated amounts of platelet-monocyte aggregates (P < 0.004), a significantly enhanced tissue-factor exposition on monocytes (P < 0.019) and significantly lower plasma levels of IL-7 compared to 10 healthy controls. However, this platelet and monocyte activation did not correlate with the severity of cSVD. Patients with cSVD show an up-regulation of the platelet CD40L and CD62P system and an activation of cellular coagulation which might contribute to the initiation and progression of cSVD.
Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 09/2010; 21(8):729-35. · 1.25 Impact Factor
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ABSTRACT: Disseminated intravascular coagulation in sepsis is associated with microvascular thrombosis and organ dysfunction. It was expected that prothrombotic disposition such as factor V Leiden (FVL) mutation would worsen clinical outcome. Astonishingly, clinical trial and animal experimental data indicate that FVL can be associated with improved survival. This study investigated the effect of FVL on the response to endotoxin of the coagulation and fibrinolytic system in humans. Fourteen healthy male subjects without FVL and 15 healthy males with heterozygous FVL received an intravenous bolus dose of endotoxin, 2 ng/kg of body weight. Blood samples were drawn before and 1, 2, 4, 6, and 24 hours after administration of the endotoxin. Injection of endotoxin led to a more pronounced increase in soluble fibrin in patients with FVL than in controls. Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activator-induced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogen- and fibrin-degradation products.
Blood 08/2010; 116(5):801-5. · 9.90 Impact Factor
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ABSTRACT: The cobas h 232 point-of-care analyzer by Roche is the instrument successor of the Cardiac reader allowing the quantitative determination of troponin T, creatine kinase MB, myoglobin, NT-proBNP and D-dimer.
In this study 1329 patients with acute coronary syndromes, heart failure, thromboembolic or other diseases and 945 healthy donors were assessed. Comparisons versus central laboratory methods were carried out with 2379 samples from these individuals; out of these, 1591 samples gave quantitative results within the measuring range and were included in the evaluation.
The point-of-care assays for creatine kinase MB, myoglobin, NT-proBNP and D-dimer were within a relative bias range of -5.9 to +6.9% compared to the laboratory assay. The troponin T assay showed a bias of -11.0% and after change of the calibration procedure of +1.9%. None of the five point-of-care assays had a relative difference between the new system and the precursor device that was higher than +5.0%. Within-series coefficients of variation of patient samples were found in a range from 4.8 to 14.8%. No significant interference was observed with lipemic, hemolytic and icteric blood or at different hematocrit values.
Due to its good analytical agreement with the laboratory methods and with its precursor device, the cobas h 232 system can be reliably used to support on-site decision making for cardiovascular patients in acute and non-acute settings.
Clinical laboratory 01/2010; 56(1-2):37-49. · 0.90 Impact Factor
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ABSTRACT: Treatment with HMG-CoA reductase inhibitors (statins) reduces the morbidity and mortality of coronary artery disease (CAD). In addition to their lipid-lowering actions, pleiotropic effects of statins have been demonstrated.
The aim of the present study was to assess if atorvastatin therapy has an impact on haemostasis, fibrinolysis and inflammation in normocholesterolaemic patients with CAD.
Fifty-four patients with CAD who had received atorvastatin treatment for at least 8 weeks (mean dosage 30 mg/day) and 54 patients with CAD who had not received atorvastatin therapy were selected from a larger prospective, randomized, double-blind study for inclusion in this post hoc analysis. Patients were matched by their total cholesterol levels. All patients were normocholesterolaemic.
In the atorvastatin-treated patients significantly lower plasma levels of thrombin-antithrombin complexes (p < 0.05), plasminogen activator inhibitor-1 activity (PAI-1) [p < 0.05], soluble vascular cell adhesion molecule-1 (p < 0.05), soluble platelet selectin (p < 0.05) and high-sensitivity C-reactive protein (p < 0.05) were measured compared with patients not on atorvastatin therapy. Additionally, a strong trend towards lower soluble intercellular adhesion molecule-1 plasma levels was detected in patients treated with atorvastatin. No differences were found in tissue-type plasminogen activator antigen, plasmin-plasmin inhibitor complexes, fibrinogen, D-dimer and activated factor XII values.
Atorvastatin appears to have an effect on coagulation activation, fibrinolysis and inflammation in patients with CAD. Reduction in PAI-1 and reduced thrombin formation may have an impact on cardiovascular morbidity and mortality in patients with CAD.
Clinical Drug Investigation 01/2010; 30(7):453-60. · 1.82 Impact Factor
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ABSTRACT: The widespread use of primary coronary intervention (PCI) has significantly improved the prognosis of men presenting with acute coronary syndromes, but the cardiovascular event rate among women has either levelled off or increased. The purpose of the present prospective study was to compare the clinical outcome of women and men presenting with ST-elevation myocardial infarction (STEMI) undergoing primary PCI with concomitant usage of GP IIb/IIIa inhibitors.
Between January 2006 and December 2007, 297 consecutive patients presenting with STEMI were prospectively included in this single center investigation. Overall, 82 (27.6%) women and 215 (72.4%) men were treated by PCI with additional bare metal stent implantation and a GP IIb/IIIa inhibitor.
Women were significantly older (65 ± 10 vs 60 ± 12 years, p = 0.04), presented with a smaller reference luminal diameter (2.83 ± 0.51 vs 2.94 ± 0.43, p = 0.03) and had a higher prevalence of hypertension (68% vs 53%, p = 0.025) and obesity (30% vs 18%, p = 0.03). The incidence of major adverse cardiac events (MACE, defined as death, re-myocardial infarction, target lesion revascularization and coronary artery bypass graft) during long-term follow-up was similar in women and men (20% vs 26%, p = 0.29). Age, C-reactive protein, platelet count and cardiogenic shock were identified as independent predictors for MACE, whereas gender was not predictive.
In this study, female gender did not emerge as an independent predictor for MACE, but women presenting with STEMI had a higher cardiovascular risk profile; this emphasizes the need for a more extensive therapeutic strategy. Combination therapy with primary PCI and GP IIb/IIIa inhibitors might mitigate gender-related differences in clinical outcomes.
Cardiology journal 01/2010; 17(6):580-6. · 1.31 Impact Factor
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ABSTRACT: Monitoring of anti-factor Xa activity is often performed during treatment with low-molecular-weight heparins (LMWHs) in pregnancy because the anticoagulant effect may decrease as pregnancy progresses, but assays for anti-factor Xa activity are unavailable in many clinical institutions caring for pregnant women. Heptest-STAT is a new clotting assay for monitoring of LMWHs, which has been optimised for use in near-patient laboratory instrumentation. It has been suggested that monitoring of LMWHs requires the use of individual calibration curves for each LMWH. We compared the dose response of four conventional LMWHs and fondaparinux in normal plasma, and plasma from women in first, second and third trimester of pregnancy. Three concentrations of LMWHs, fondaparinux, or unfractionated heparin were added to pooled plasma samples from non-pregnant women (n=10), and pregnant women in first (n=10), second (n=10) and third (n=10) trimester of pregnancy. Heptest results are not influenced by the stage of pregnancy. In contrast, dose-related aPTT prolongation declines during pregnancy. All LMWHs tested, as well as fondaparinux, display a similar dose-response in Heptest compared to the chromogenic anti-factor Xa assay. Heptest-STAT can be used with the same standard calibration for non-pregnant and pregnant patients and for all LMWHs under investigation, including fondparinux. No individual calibrations are necessary.
Thrombosis and Haemostasis 11/2009; 102(5):1001-6. · 5.04 Impact Factor
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ABSTRACT: Low antithrombin levels may compromise the anticoagulant effect of heparin and heparin-related compounds, such as fondaparinux.
We compared the anticoagulant effect of 10 concentrations of fondaparinux added to plasma samples with normal range (n = 25, antithrombin 95.4% +/- 9.2%) and low antithrombin (n = 22, antithrombin 45.5% +/- 13.2%) levels, using the Heptest coagulation assay.
Heptest clotting time was shorter at any given fondaparinux concentration in the antithrombin-deficient samples, indicating less anticoagulant effect than in the group with normal antithrombin levels. At a high fondaparinux concentration, a saturation effect is observed with no further increase in Heptest clotting time. Addition of antithrombin concentrates results in a shift of the dose-response curve. When antithrombin concentrate was added, Heptest clotting time increased up to a fondaparinux concentration of 10 microg/mL.
In the conventional prophylactic and therapeutic dose range, not only treatment with antithrombin concentrates but also an increase in fondaparinux dose normalizes the anticoagulant effect. A saturation effect is observed at high fondaparinux concentrations. Higher levels of antithrombin lead to an exaggerated effect of fondaparinux on Heptest.
Anesthesia and analgesia 10/2009; 109(3):712-6. · 3.08 Impact Factor
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ABSTRACT: A 30-year-old female experienced three miscarriages in early pregnancy. Extensive laboratory screening showed a low plasma fibrinogen level of approximately l g/l detected by PT-derived fibrinogen assay. The fibrinogen level in the immunological assay was 3 g/l. The functional Clauss assay yielded an intermediate result of 1.78 g/l. During her fourth and fifth pregnancy, the patient received fibrinogen concentrates (Haemocomplettan, CLS Behring, Marburg, Germany), starting with 4 grams of human fibrinogen, followed by 2 grams every second day until the 15(th) week of pregnancy. The further course of these pregnancies was uneventful. SDS-PAGE and immunoblotting showed doublet bands in the positions of the high-molecular weight (HMW)- and low-molecular-weight (LMW)-fibrinogen, a single LMW' fibrinogen band, plus additional bands with higher molecular weight than HMW-fibrinogen, which were also reactive with anti-human serum albumin (HSA) antiserum. These bands correspond to variant fibrinogen conjugated with albumin. Reduced SDS-PAGE and immunoblotting using polyclonal anti-fibrinopeptide A antiserum disclosed one additional Aalpha-chain band with lower molecular weight. Amplification and sequencing of exon 5 of the alpha gene indicated heterozygosity for a novel single nucleotide deletion at codon Aalpha494 (C1537delA). His494 is replaced by Pro and this is followed by 23 (LMKLPSSTLPQLEKHSQ VSSHLC) new amino acids before premature truncation after Cys517, yielding a free C-terminal cysteine, which may link with albumin. This new fibrinogen mutation, leads to a balanced array of homo- and heterodimeric fibrinogen molecules, some of which are conjugated to albumin.
Thrombosis and Haemostasis 08/2009; 102(1):29-34. · 5.04 Impact Factor
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ABSTRACT: AIMS: Sudden cardiac death (SCD) is frequently caused by ventricular fibrillation (VF) occurring in the course of acute myocardial infarction (AMI). It has not been investigated yet, to what extent markers of coagulation activation and inflammation differ between patients with and without VF in the acute phase of AMI.
International journal of cardiology 07/2009; 145(1):118-9. · 7.08 Impact Factor
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Critical care medicine 06/2009; 37(5):1823-4. · 6.37 Impact Factor
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ABSTRACT: Abciximab immunobubbles have been introduced recently for ultrasonographic molecular imaging of human thrombus. This study investigates the potential of using these novel bubbles for enhancing sonothrombolysis. In particular, it addresses the question of whether ligand targeting of bubbles with abciximab improves the effectiveness of lysis with ultrasound. A partial thrombotic occlusion of the right common carotid artery of 16 rats was produced by insertion of human clot material via an external carotid artery catheter. Rats received abciximab immunobubbles, non-specific control immunobubbles or saline intravenously over 30 minutes in combination with pulsed 2 MHz ultrasound. Blood samples were taken at baseline and 5, 10, 20, 30 and 60 minutes after beginning treatment. Human D-dimer levels for quantification of thrombolysis were analysed by ELISA. Only animals treated with abciximab immunobubbles and ultrasound showed a significant increase of D-dimer levels over time (p = 0.043, linear trend p = 0.037), whereas in the other two groups, no significant increase over time was found. Overall, animals in the abciximab immunobubbles group showed higher plasma D-dimer levels than animals treated with non-specific immunobubbles (p = 0.049) and animals treated with ultrasound alone (p = 0.017). In histological sections, thrombi treated with abciximab immunobubbles and ultrasound showed clear signs of disintegration in contrast to thrombi in both control groups. 2 MHz ultrasound in combination with abciximab immunobubbles induces thrombolysis without lytic agents that is superior to insonation of non-specific immunobubbles.
Thrombosis Research 05/2009; 124(1):70-4. · 2.44 Impact Factor
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ABSTRACT: Clinical and epidemiological trials often involve central laboratory analyses of coagulation tests, including fibrinogen, which requires freezing of the plasma samples. Although rapid freezing by immersion of sample tubes in liquid nitrogen and storage at -70 degrees C is recommended, plasma samples are often transferred directly to the storage compartments, and stored at -20 degrees C. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen using a kinetic fibrinogen assay, PT-derived fibrinogen, and an immunoassay were measured in fresh plasma samples from 16 healthy blood donors. In addition, four sets of aliquots were prepared. Set A was transferred directly to a -20 degrees C storage compartment, set B was first snap-frozen in liquid nitrogen and then transferred to the -20 degrees C compartment. Set C was transferred directly to a -70 degrees C freezer, set D was first snap-frozen in liquid nitrogen and then stored at -70 degrees C. Aliquots were thawed after one, two, three and four months storage and laboratory assays repeated. PT and aPTT were strongly influenced by freezing and storage. In contrast, freezing had little effect on fibrinogen levels. Differences were below three percent for all variants. Changes were smaller for samples stored at -70 degrees C compared to -20 degrees C, and for snap-frozen compared to not snap-frozen samples. Frozen and thawed samples generated slightly higher fibrinogen levels compared to fresh samples. Prothrombin time and aPTT should be measured in fresh samples, since freezing has an inconstant and unpredictable effect on the results. In contrast, freezing and storage has little effect on results of fibrinogen assays. A limitation of the study is that only samples from healthy blood donors were used. Plasma samples with abnormal fibrinogen concentration, or with abnormal concentrations of coagulation factors might behave differently.
Thrombosis Research 02/2009; 124(1):121-6. · 2.44 Impact Factor
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ABSTRACT: Percutaneous coronary intervention (PCI) with stent implantation is considered to be the standard treatment in patients presenting with ST-elevation myocardial infarction (STEMI). According to the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for STEMI, there is a class IIa recommendation (treatment reasonable) for platelet glycoprotein (GP) IIb/IIIa inhibitors. This study aims to compare the clinical outcome of patients with and without diabetes, presenting with STEMI undergoing primary PCI with concomitant usage of GP IIb/IIIa inhibitors in real clinical practice.
Over the course of three years (2004-2006) 394 consecutive patients presenting with STEMI were included in this single centre experience. There were 95 patients (24%) with, and 299 patients (76%) without, diabetes. A GP IIb/IIIa inhibitor was administered to all patients without contraindications (316 patients, 80%).
Patients with diabetes were significantly older, more often suffered from hypertension and had a higher incidence of obesity. The rate of administration of GP IIb/IIIa inhibitors was similar in both groups (74% vs. 82%, p = 0.14). The in-hospital incidence of major adverse cardiac events (MACE, defined as death, re-myocardial infarction, target lesion revascularisation and coronary artery bypass graft) was similar in both patient groups (18 [19%] diabetics vs. 51 [17%] non-diabetics, p = 0.65). Hypertension, age and obesity were identified as predictors for MACE, whereas diabetes was not predictive.
In this single centre experience, in diabetic and non-diabetic patients presenting with STEMI, combination therapy with primary PCI and GP IIb/IIIa inhibitors might have contributed to a similar clinical outcome.
Cardiology journal 02/2009; 16(3):234-40. · 1.31 Impact Factor
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Thrombosis Research 01/2009; 124(3):375-6. · 2.44 Impact Factor
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ABSTRACT: Fibrinogen concentration influences mechanical and functional properties of the clot. The purpose of the present study was to identify threshold concentrations of fibrinogen resulting in relevant changes in whole blood clot elastic modulus and platelet contractile force, as well as plasma prothrombin time and activated partial thromboplastin time. We measured clot elastic modulus, platelet contractile force, and other hemostasis parameters in whole blood samples from 552 patients admitted to a surgical intensive care unit. Platelet contractile force and clot elastic modulus were measured using the Hemodyne apparatus. Fibrinogen levels were between less than 0.10 and 9.44 g/l, with a mean of 2.41 g/l. Mean platelet count was 203 x 10(9) l(-1), with a range of 16 x 10(9) l(-1) to 682 x 10(9) l(-1). High levels of fibrinogen result in improved mechanical stability and improved interaction of platelets with the fibrin network. Clot elastic modulus and platelet contractile force are correlated positively with plasma fibrinogen concentration. However, there was no threshold concentration or ceiling effect concerning the mechanical properties of the clots. In contrast, clotting time assays such as prothrombin time, thrombin time, or activated partial thromboplastin time are influenced by the fibrinogen concentration only at levels below 1 g/l. In linear regression analysis, clot elastic modulus was mainly influenced by fibrinogen concentration (F = 185.4, P < 0.0001), whereas platelet contractile force was influenced by fibrinogen (F = 197.0, P < 0.0001) and platelet count (F = 104.7, P < 0.0001). The present data show that 1 g/l is a threshold fibrinogen concentration for an effect on coagulation assays such as prothrombin time, thrombin time, or activated partial thromboplastin time, but increasing fibrinogen concentrations above this level results in further continuous improvement of mechanical properties of the whole blood clot.
Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 12/2008; 19(8):765-70. · 1.25 Impact Factor
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ABSTRACT: Point of care assays for various analytes have been established in critical care, including blood gas analysis, glucose, electrolytes, and markers for cardiac ischemia. Coagulation assays can also be adapted to the critical care environment by using whole blood as sample material and instruments optimized for point of care analysis. Available assays include the conventional coagulation assays, such as prothrombin time and activated partial thromboplastin time, fibrinogen, assays for monitoring of anticoagulant drugs, global coagulation assays based on thrombelastography and viscosimetry, platelet function assays, and D-dimer assays. The main problem in point of care coagulation diagnostics is quality control. Point of care coagulation assays help in rapidly establishing a diagnosis, clarifying causes of bleeding, and monitoring therapy. Thrombelastography and similar assays extend the scope of coagulation diagnostics by visualizing the process of clot formation and extending the observation period to provide an estimate of clot stability versus mechanical and proteolytic attack.
Seminars in Thrombosis and Hemostasis 08/2008; 34(5):445-50. · 4.52 Impact Factor
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Thrombosis and Haemostasis 08/2008; 100(1):9-10. · 5.04 Impact Factor
