Georg Endler

Evidence of a U‐shaped association between factor XII activity and overall survival

Summary.  Introduction: The clinical relevance of decreased coagulation factor XII (FXII) plasma activity as a risk factor for both venous and arterial thrombosis is still discussed controversially. The current study evaluated the predictive value of FXII levels for all‐cause mortality in a large Viennese patient cohort. Patients and methods: Individuals, whose FXII activity levels were determined for suspected coagulation disorders or thrombophilia screening between 1991–2003 were included in this study (n = 8936, 51% male, 49% female, median age 43 years). Death/survival was determined by record linkage with the Austrian Death Registry. The median observation period was 5 years covering a total of 46 400 person years; the death rate was 17.1%. For Cox regression analysis, FXII plasma activity was divided into 11 categories of 10% steps with the category of > 100% FXII serving as a reference category. Results: With decreasing FXII plasma activity, hazard ratios for all‐cause mortality gradually increased linearly from 1.0 in the > 100% category to 1.5 (95% CI: 1.2–1.9) in the 80–90% category to 4.7 (95% CI: 3.4–6.5) in the 10–20% category. Similar results were obtained, when only vascular mortality or death as a result of ischemic heart disease was considered. No significant increase in all‐cause mortality (HR: 1.4, 95%CI 0.7–2.8) was observed in the small group of FXII‐deficient subjects [0–10% category (n = 58)]. Conclusions: This study first demonstrates a strong and almost linear association of FXII plasma activity between 90% and 10% with all‐cause mortality in a large Viennese patient cohort. Interestingly, mortality rates are not increased when FXII activity is below 10%, resulting in a U‐shaped survival curve.

Fasting Plasma Total Homocysteine Levels and Mortality and Allograft Loss in Kidney Transplant Recipients: A Prospective Study

Homocysteine is implicated to be an atherogenic amino acid and has been associated with increased risk of adverse cardiovascular outcomes. The prognostic significance of plasma total homocysteine (tHcy) levels for mortality and allograft loss in kidney transplant recipients has not been established. A total of 733 kidney transplant recipients who were seen for a routine visit at this transplant clinic in 1996 to 1998 were studied prospectively. During that visit, clinical information was collected and blood was drawn for laboratory evaluation. Information on the previous transplant procedure and the organ donor was obtained from the Eurotransplant Foundation database. Patients were followed prospectively using the Austrian Dialysis and Transplant Registry. With the use of proportional-hazards regression, the independent relations of fasting plasma tHcy levels to the risk of death from any cause and kidney allograft loss were examined. During a median follow-up of 6.1 yr, 154 participants died and 260 kidney allografts were lost. After adjustment for several important risk factors, elevated tHcy levels (>/=12 micromol/L) were associated with 2.44 times the mortality risk of patients with normal tHcy levels (hazards ratio 2.44; 95% confidence interval 1.45 to 4.12; P < 0.001). Similarly, elevated tHcy levels were associated with 1.63 times increased risk of kidney allograft loss (hazards ratio 1.63; 95% confidence interval 1.09 to 2.44; P = 0.02). In this single-center sample, baseline fasting plasma tHcy levels were independently associated with the risk of death and kidney allograft loss. The clinical utility of homocysteine-lowering therapy, such as multivitamin therapy, to reduce the rates of these end points needs to be studied.

A microsatellite polymorphism in the heme oxygenase‐1 gene promoter is associated with risk for melanoma

Heme oxygenase‐1 (HO‐1) has been demonstrated to play an important role in the regulation of signaling systems, which are involved in the control of cell cycle progression and apoptosis. Recently, a (GT)n dinucleotide repeat polymorphism in the HO‐1 promoter was shown to modulate HO‐1 gene expression. Short (<25 GT) repeats are associated with an increased HO‐1 upregulation after stimulation than are longer repeats. Malignant melanoma (MM) is the most serious cutaneous malignancy with high tendency to aggressive growth and resistance to apoptosis. Therefore, we sought to study the influence of this polymorphism on the progression of MM. We determined the HO‐1 promoter genotype in 152 patients with MM and 398 healthy controls and studied their association in regard to susceptibility to MM, Breslow thickness and disease‐free survival. In our study, the homozygous short allele with <25 (GT)n repeats (S/S) was found more frequently in the melanoma group compared to the healthy control population (21 and 12%, respectively). The calculated risk for acquiring primary MM in S/S carriers was 2‐fold higher compared to those with L‐allele types (95% confidence interval: 1.2–2.4, p = 0.03). Additionally, the S/S genotype was significantly associated with primary tumors with deeper Breslow thickness compared to L‐allele (>25 repeats) carriers (mean Breslow thickness: 4.0 ± 2.9 mm versus 3.1 ± 1.7 mm, p = 0.03). These data suggest that HO‐1 might render a higher risk for MM in S/S genotype individuals and could represent an important candidate gene in the pathogenesis and growth of malignant melanoma.

Routinely available biomarkers improve prediction of long-term mortality in stable coronary artery disease: the Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score.

AIMS Previous risk assessment scores for patients with coronary artery disease (CAD) have focused on primary prevention and patients with acute coronary syndrome. However, especially in stable CAD patients improved long-term risk prediction is crucial to efficiently apply measures of secondary prevention. We aimed to create a clinically applicable mortality prediction score for stable CAD patients based on routinely determined laboratory biomarkers and clinical determinants of secondary prevention. METHODS AND RESULTS We prospectively included 547 patients with stable CAD and a median follow-up of 11.3 years. Independent risk factors were selected using bootstrapping based on Cox regression analysis. Age, left ventricular function, serum cholinesterase, creatinine, heart rate, and HbA1c were selected as significant mortality predictors for the final multivariable model. The Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score based on the aforementioned variables demonstrated an excellent discriminatory power for 10-year survival with a C-statistic of 0.77 (P < 0.001), which was significantly better than an established risk score based on conventional cardiovascular risk factors (C-statistic = 0.61, P < 0.001). Net reclassification confirmed a significant improvement in individual risk prediction by 34.8% (95% confidence interval: 21.7-48.0%) compared with the conventional risk score (P < 0.001). External validation of the risk score in 1275 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up of 9.8 years) achieved similar results (C-statistic = 0.73, P < 0.001). CONCLUSION The VILCAD score based on a routinely available set of risk factors, measures of cardiac function, and comorbidities outperforms established risk prediction algorithms and might improve the identification of high-risk patients for a more intensive treatment.

4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia

Summary.  Background: Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor‐1 (PAI‐1) is a characteristic feature of meningococcal sepsis. We and others have reported an association between mortality and the functional 4G/5G promoter polymorphism of the PAI‐1 gene in children with meningococcal sepsis. Objective: Multicenter study to investigate the association of the 4G/5G PAI‐1 polymorphism and disseminated intravascular coagulation (DIC) in children with meningococcal disease in a Central European population. Patients/Methods: Blood samples and clinical information of 326 previously healthy children with meningococcal infection were collected from 95 pediatric hospitals in Germany, Switzerland, Italy, and Austria from 2000 to 2002. Results: DIC, defined as platelet counts below 100 G L−1, increased D‐dimer levels and prolonged prothrombin time, was significantly associated with the 4G4G genotype [31 of 63 (49%) vs. 55 of 175 (31%), P = 0.014], resulting in a hazard ratio (HR) of 1.5 (95% confidence interval 1.1–2.1) to develop DIC. Carriers of the 4G4G genotype showed significantly lower platelet counts (183 G L−1 vs. 227 G L−1, P = 0.009) on admission. Fibrinogen and C‐reactive protein levels were not associated with the PAI‐1 4G/5G polymorphism, nor were white blood cell counts. Conclusions: Our data show a correlation between the 4G4G genotype of the PAI‐1 gene and development of DIC in meningococcal infection.

Classification of chronic kidney disease by estimated glomerular filtration rate

Background  Serum creatinine concentration alone as a marker of kidney function is inadequate. Thus several equations for estimating glomerular filtration rate (eGFR) have been proposed within the last years.

Polymorphism in the tissue factor region is associated with basal but not endotoxin-induced tissue factor-mRNA levels in leukocytes

Summary.  Objective: Tissue factor (TF) plays a central role during disseminated intravascular coagulation (DIC) in sepsis. We hypothesized that a frequent D/I polymorphism, at nucleotide position −1208 in the promoter region, could influence TF‐mRNA and downstream coagulation. Methods: Basal‐ and lipopolysaccharide (LPS)‐induced TF‐mRNA expression, microparticle‐associated TF‐procoagulant activity and coagulation were determined in healthy men (n = 74) before and after endotoxin (LPS) infusion (2 ng kg−1). Basal values of TF‐mRNA ranged between 34 and >37.5 cycles. Results: Baseline TF‐mRNA levels significantly differed between genotypes: I/I carriers had almost 2‐fold higher TF‐mRNA levels compared to D/D carriers at baseline (P < 0.01). In accordance, higher levels of microparticle‐associated TF‐procoagulant activity could be seen in I/I carriers. However, the genotype did not affect basal or LPS‐induced levels of prothrombin fragment F1+2, D‐dimer or cytokines including tumor necrosis factor and interleukin‐6. Conclusion: The TF–1208 polymorphism is functional in that it regulates basal TF‐mRNA in circulating monocytes and circulating microparticle‐associated TF‐procoagulant activity in vivo, but does not influence the relative increase in TF‐mRNA or coagulation activation during low‐grade endotoxemia.

Sex differences in the association between albumin and all-cause and vascular mortality

Background  Low serum albumin levels are associated with cardiovascular disease and mortality risk. This study evaluated the predictive value of low serum albumin for all‐cause‐mortality in a large Viennese patient cohort and investigated sex differences in the association between serum albumin and mortality.

Nerve compression and pain in human volunteers with narrow vs wide tourniquets

AIM To assess the clinical effects and the morphological grade of nerve compression. METHODS In a prospective single-center randomized, open study we assessed the clinical effects and the morphological grade of nerve compression during 20 min of either a silicon ring (group A) or pneumatic tourniquet (group B) placement variantly on the upper non-dominant limb in 14 healthy human volunteers. Before and during compression, the median and radial nerves were visualized in both groups by 3 Tesla MR imaging, using high resolutional (2.5 mm slice thickness) axial T2-weighted sequences. RESULTS In group A, Visual analog pain scale was 5.4 ± 2.2 compared to results of group B, 2.9 ± 2.5, showing a significant difference (P = 0.028). FPS levels in group A were 2.6 ± 0.9 compared to levels in group B 1.6 ± 1, showing a significant difference (P = 0.039). Results related to measureable effect on median and radial nerve function were equal in both groups. No undue pressure signs on the skin, redness or nerve damage occurred in either group. There was no significant difference in the diameters of the nerves without and under compression in either group on T2 weighted images. CONCLUSION Based on our results, no differences between narrow and wide tourniquets were identified. Silicon ring tourniquets can be regarded as safe for short time application.

Coagulation factor VIII levels are associated with long-term survival – interactions with gender in a large hospital-based cohort

ZusammenfassungHINTERGRUND: In der Literatur ist eine gesteigerte Faktor VIII Aktivität mit einem erhöhten Risiko für arterielle und venöse Thrombosen assoziiert. Die vorliegende Studie untersucht den Einfluss von Faktor VIII Spiegeln auf die Gesamtmortalität unter Berücksichtigung geschlechtsspezifischer Unterschiede in einer groß angelegten Studie in Österreich. PATIENTEN UND METHODE: In dieser Studie wurden zwischen 1991 und 2003, 11203 Patienten eingeschlossen. Der durchschnittliche Beobachtungszeitraum betrug 5 Jahre mit insgesamt 46000 Personenjahren. Insgesamt sind während des Beobachtungszeitraumes 17,1 % der Studienpopulation verstorben. ERGEBNISSE: Im Vergleich zu Patienten in der Referenzkategorie (FVIII: C <94 %) stiegen die Hazard Ratios von 1,4 (95 % CI: 1,1 – 1,8) in der 152 – 170 % Kategorie (5th Dezile) auf letztlich 4,4 (95 % CI: 3,5 – 5,5) in der >313 % Kategorie (höchste Dezile, alle p < 0,05). Die Assoziation zwischen FVIII: C Spiegeln und Mortalität bleibt unverändert hinsichtlich nicht Krebs-assoziierte Mortalität, vaskuläre Mortalität und ischämischer Herzerkrankungen. Im Vergleich zu Männern, haben Frauen mit erhöhten FVIII: C Spiegeln ein schlechteres Outcome, resultierend in höheren Hazard Ratios 6,8 (95 % CI: 4,6 – 9,9) im Vergleich zu Männern (HR: 3,4 (95 % CI: 2,6 – 4,5)). SCHLUSSFOLGERUNGEN: In unserer groß angelegten Studie konnten wir erstmals zeigen, dass FVIII: C Plasma Aktivität mit einer erhöhten Gesamtmortalität assoziiert ist. Außerdem scheint es auch eine geschlechtsspezifische Interaktion von FVIII: C zu geben. Vor allem bei Frauen mit erhöhten FVIII: C Spiegeln dürfte es daher hilfreich sein Hochrisikogruppen zu identifizieren, die von individuellen Präventionsstrategien profitieren würden.SummaryINTRODUCTION: Elevated coagulation factor VIII activity has been associated with increased risk for both venous and arterial thrombosis. The current study evaluated the influence of Factor VIII levels and interactions with gender on all cause mortality in a large Austrian cohort. PATIENTS AND METHODS: During 1991 and 2003, 11203 individuals, first ever request for laboratory analyses of FVIII: C, age ≥18 years, were included in this study. The median observation period was 5 years covering a total of 46000 person-years. The death rate was 17.1%. RESULTS: Compared to individuals within the reference category (FVIII: C <94%) hazard ratios gradually increased from 1.4 (95% CI: 1.1–1.8) in the 152–170% category (5th decile) to finally 4.4 (95% CI: 3.5–5.5) in the >313% category (highest decile, all p < 0.05). The association between FVIII: C levels and mortality remained essentially unchanged when considering non-cancer mortality, all cause vascular mortality or mortality due to ischemic heart disease. Compared to males females with elevated FVIII: C had a worse outcome resulting in higher hazard ratios reaching 6.8 (95% CI: 4.6–9.9) within the highest decile compared to males (HR: 3.4 (95% CI: 2.6–4.5)). CONCLUSIONS: In our large patient cohort we might be able to demonstrate for the first time that FVIII: C plasma activity is strongly associated with all cause mortality. Additionally, FVIII: C appears to interact with gender. Especially in women FVIII: C might help identifying high-risk cohorts, which might benefit from individualized prevention strategies.