C Mannhalter

Medical University of Vienna, Wien, Vienna, Austria

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Publications (179)878.23 Total impact

  • Gajalakshmi Ramanathan · Christine Mannhalter
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    ABSTRACT: Members of the transient receptor potential (TRP) family of cation conducting channels are found in several tissues and cell types where they have different physiological functions. The canonical TRP channel 6 (TRPC6) is present on the platelet membrane and appears to participate in calcium influx during platelet activation. However, limited information is available on the importance of TRPC channels in megakaryocytes (MKs), the precursor cells of platelets. We determined the mRNA and protein expression of TRPC family members and investigated the role of TRPC6 for proliferation and differentiation of human MKs derived from CD34+ progenitor cells. TRPC6 transcripts were highly expressed during the differentiation of MKs and TRPC6 protein was detectable in MK cytoplasm by confocal staining. TRPC6 channel activity was modulated by pharmacological approaches using flufenamic acid (FFA) for activation and SKF96365 for inhibition. Upon FFA stimulation in MKs, an increase in intracellular calcium was observed which was blocked by SKF96365 at 10 µM concentration. Incubation of MKs with SKF96365 resulted in a reduction in thrombopoietin-stimulated cell proliferation. Our results suggest a role of TRPC6 in calcium homeostasis during MK development, particularly for cell proliferation.
    No preview · Article · Oct 2015 · Cell Biology International
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    ABSTRACT: In haemophilia A patients factor VIII (FVIII) recovery and half-life can vary substantially. There are parameters known to modulate FVIII pharmacokinetics (PK), but they explain only about 34% of the variability. The aim of this study was to identify new parameters that influence FVIII PK and thus to expand the current knowledge. FVIII PK were determined in 42 haemophilia A patients (37 severe, 5 moderate) without inhibitor. Patients' characteristics and laboratory parameters were evaluated for an association with FVIII PK. We analysed plasma levels of low-density lipoprotein receptor-related protein 1 (LRP1) and protein C (PC) activity, which had been hypothesized to influence FVIII activity. Furthermore, four variations in intron 6 of the LRP1 gene, which had been shown to influence LRP1, were investigated. FVIII half-life differed widely from 6.2 to 20.7 h, with a median of 10.0 h. Patients with blood group O had shorter FVIII half-life compared to patients with non-O blood group (median FVIII half-life 9.0 h vs. 10.4 h, P = 0.018). Age was significantly associated with FVIII half-life (r = 0.32, P = 0.035). Besides age, also VWF antigen (r = 0.52, P < 0.001) and blood group (r = −0.37, P = 0.015) was associated with FVIII half-life. No correlation was found with FVIII- or LRP1-genotype, LRP1 or PC concentrations. Our data showed large differences in FVIII PK between individual patients and revealed age, blood group and VWF levels as important determining factors for FVIII half-life. FVIII genotype or levels of LRP1 or PC had no influence on FVIII PK.
    No preview · Article · Dec 2014 · Haemophilia
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    ABSTRACT: The formation of leukocyte-platelet aggregates (LPA), through the P-selectin - P-selectin glycoprotein ligand (PSGL)-1 axis, plays a pivotal role in atherothrombosis. In order to investigate the influence of platelet (pP-selectin) and soluble P-selectin (sP-selectin), and of variations in the genes encoding for P-selectin (SELP) and PSGL-1 (SELPLG) on LPA formation, we assessed monocyte (MPA)- and neutrophil-platelet aggregates (NPA) as well as pP-selectin by flow cytometry in 263 patients undergoing angioplasty and stenting. sP-selectin was determined by ELISA, the SELP Pro715 allele and the SELPLG Ile62 allele were determined by allele specific PCR. The Pro715 allele was significantly associated with lower levels of in vivo pP-selectin and sP-selectin, while agonists´ inducible pP-selectin was not influenced by the Pro715 allele. PP-selectin was significantly associated with MPA and NPA formation. The in vivo formation of MPA and NPA depended to 19 % and 7.4 %, respectively, on in vivo pP-selectin, irrespective of the Pro715 allele and the Ile62 allele carrier status. TRAP-6 inducible MPA and NPA depended to 34 % and 27 %, respectively, on TRAP-6 inducible pP-selectin, but were independent of the Pro715 allele and the Ile62 allele carrier status. Carriers of the Ile62 allele showed a stronger correlation between TRAP-6 inducible pP-selectin and TRAP-6 inducible MPA/NPA than non-carriers. Furthermore, TRAP-6 inducible NPA were higher in Ile62 allele carriers, which suggests higher thrombin sensitivity. In conclusion, our findings point to the significant role of pP-selectin for MPA and NPA formation, while other variables like sP-selectin, the SELP Pro715 allele and the SELPLG Ile62 allele have less influence.
    No preview · Article · Nov 2014 · Thrombosis and Haemostasis
  • Christine Mannhalter

    No preview · Article · Sep 2014 · Thrombosis and Haemostasis

  • No preview · Article · Sep 2014 · Wiener klinische Wochenschrift
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    ABSTRACT: Background and objectiveCentral venous lines (CVL) are the major exogenous risk factor for deep venous thrombosis (DVT) in children. Study objective was to assess whether endogenous prothrombotic conditions contribute to the risk of CVL-related DVT in children.Methods Cohort study of consecutive children with heart disease requiring CVL for perioperative care. CVL were inserted percutaneously in the upper venous system and patients received prophylaxis with continuous unfractionated heparin (50 u/kg/d). Blood samples to test for prothrombotic conditions were collected prospectively and assayed in blinded fashion. Outcome assessment was by screening for DVT by venography, venous ultrasound, and echocardiography.ResultsThe study population consisted of 90 children, median age 2.7 years (0 months - 18 years). Prevalences of antithrombin deficiency, protein C deficiency, protein S deficiency, heterozygous Factor V Leiden, prothrombin G20210A mutation, methylentetrahydrofolate C677TT genotype, hyperhomocysteinemia, lupus anticoagulant, anticardiolipin antibodies, increased levels of lipoprotein (a) were within the range reported for the general population. At least one prothrombotic condition was present in 38% children and combined abnormalities in 8%. The incidence of DVT was 28% (25/ 90), most of which were asymptomatic. None of the prothrombotic conditions showed a significant association with DVT. The population attributable risk, i.e. the risk of DVT in the overall population attributable to a specific condition, did not exceed 2.2%.Conclusion Prothrombotic conditions did not have an important impact on the risk of DVT in children with short-term CVL. The results of the study suggest that screening for prothrombotic conditions is not justified in this setting.This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2014 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: Background and ObjectivesP-selectin is stored in the alpha granules of platelets and in the Weibel Palade bodies of endothelial cells; upon activation, it is translocated to the cell surface and released into the plasma in soluble form. One variant of the P-selectin gene, the Thr715Pro polymorphism, is strongly associated with the plasma levels of soluble P-selectin. In platelet concentrates soluble P-selectin can be regarded mainly platelet derived. Materials and Methods The relation of the genotype with soluble P-selectin, platelet expressed P-selectin and the sum of all forms of P-selectin - comprising soluble P-selectin, platelet surface P-selectin and P-selectin from the alpha granules - was assessed in fresh whole blood and in apheresis platelets suspended in 35% plasma/65% SSP+ obtained from 89 platelet donors. ResultsLevels of total P-selectin were genotype associated (P=0025); likewise, in fresh whole blood there was an association of soluble P-selectin with genotype (P=002). In platelets suspended in additive solution, however, levels of the storage-associated or TRAP-6 agonist induced increase of platelets' P-selectin were not associated with the genotype. A correlation between levels of soluble P-selectin and surface expression of P-selectin was observed on day 3 of storage in Thr715Thr individuals (P<00001), but not in heterozygotes (Thr715Pro, P=02). Conclusion The donors' genotype has only little influence on levels of soluble P-selectin in apheresis platelets suspended in 35% plasma/65% SSP+.
    No preview · Article · Jun 2014 · Vox Sanguinis
  • C Mannhalter
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    ABSTRACT: The haemostatic system maintains the blood in a fluid state, but allows rapid clot formation at sites of vascular injury to prevent excessive bleeding. Unbalances within the haemostatic system can lead to thrombosis. Inspite of successful research our understanding of the disease pathogenesis is still incomplete. There is great hope that genetic, genomic, and epigenetic discoveries will enhance the diagnostic capability, and improve the treatment options. During the preceding 20 years, the identification of polymorphisms and the elucidation of their role in arterial and venous thromboses became an important area of research. Today, a large body of data is available regarding associations of single nucleotide polymorphisms (SNPs) in candidate genes with plasma concentrations and e. g. the risk of ischaemic stroke or myocardial infarction. However, the results for individual polymorphisms and genes are often controversial. It is now well established that besides acquired also hereditary risk factors influence the occurrence of thrombotic events, and environmental factors may add to this risk. Currently available statistical methods are only able to identify combined risk genotypes if very large patient collectives (>10 000 cases) are tested, and appropriate algorithms to evaluate the data have yet to be developed. Further research is needed to understand the functional effects of genetic variants in genes of blood coagulation proteins that are critical to the pathogenesis of arterial and venous thrombotic disorders. In this review genetic variants in selected genes of the haemostatic system and their relevance for arterial and venous thrombosis will be discussed.
    No preview · Article · May 2014 · Hamostaseologie
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    ABSTRACT: KIT D816V is present in a majority of patients with systemic mastocytosis (SM). We determined the KIT D816V allele burden by quantitative real-time PCR in bone marrow and peripheral blood of 105 patients with mastocytosis. KIT D816V was detected in 92/105 patients (88%). Significant differences in the median allele burden were observed between disease subgroups: cutaneous mastocytosis (0.042%), indolent SM (0.285%), smoldering SM (5.991%), aggressive SM (9.346%), and SM with associated hematologic non-mast cell lineage disease (3.761%) (P < 0.001). The KIT D816V burden also correlated with serum tryptase (R = 0.5, P < 0.005) but not with mast cell infiltration in bone marrow or mediator symptoms. Moreover, the allele burden was of prognostic significance regarding survival (P < 0.01). Patients responding to cytoreductive therapy showed a significant decrease in KIT D816V (P < 0.05). To conclude, the KIT D816V burden correlates with the variant of mastocytosis, predicts survival, and is a valuable follow-up parameter in SM.
    No preview · Article · Apr 2014 · Allergy
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    ABSTRACT: The single nucleotide polymorphism (SNP) rs342293 has been shown to influence platelet number and mean platelet volume (MPV). We investigated the association between the rs342293 polymorphism and cardiovascular outcome in a prospective cohort study. The rs342293 polymorphism was analysed in 404 patients with coronary artery disease undergoing percutaneous coronary intervention. The rates of cardiac adverse events were recorded during two years of follow-up. The polymorphism was associated with MPV (median 10.1 fL, interquartile range [IQR]: 9.6 to 10.6 in patients with the CC-allele vs 10.4 fL, IQR: 9.9 to 11.1 in G>C SNP carriers; p<0.001), but not with platelet count. Survival analysis indicated that carriers of the rs342293 G variant had a substantially higher risk to develop cardiac adverse events compared with wild type carriers during two years of follow-up (33% vs 22%; adjusted hazard ratio = 1.63, 95% confidence interval = 1.06-2.52, p=0.027). The rs342293 SNP could explain 2.9% of the variability in MPV (p=0.01). In conclusion, patients undergoing coronary stenting who carry the G-variant of the rs342293 SNP which is associated with larger MPV are at higher risk for adverse cardiovascular outcome.
    Full-text · Article · Mar 2014 · Thrombosis and Haemostasis
  • J. Scheibelhofer · T. Sliwa · C. Mannhalter · C. Rupp · K. Geissler

    No preview · Article · Oct 2013 · Onkologie
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    ABSTRACT: Background: Chronic eosinophilic leukemia (CEL) is a myeloproliferative neoplasm characterized by expansion of neoplastic eosinophils, tissue infiltration, and organ damage. In a subset of these patients, the FIP1L1/PDGFRA (F/P) oncoprotein is detectable. F/P exhibits constitutive tyrosine kinase activity and activates a number of signaling pathways. So far, however, little is known about the role of F/P-dependent proteins in the pathogenesis of CEL. Methods: A screen for F/P-dependent cytokines was performed in growth factor-dependent human cell lines lentivirally transduced with F/P. Signal transduction pathways were characterized in Ba/F3 cells with doxycycline-inducible expression of F/P and in EOL-1 cells. Cytokine expression was confirmed in patients' material by immunohistochemistry, immunofluorescence, and confocal microscopy. Gene expression analysis, proliferation assays, and chemotaxis assays were used to elucidate paracrine interactions between neoplastic eosinophils and stromal cells. Results: We show that F/P upregulates expression of oncostatin M (OSM) in various cell line models in a STAT5-dependent manner. Correspondingly, neoplastic eosinophils in the bone marrow were found to overexpress OSM. OSM derived from F/P + cells stimulated proliferation of stromal cells. Moreover, OSM-containing supernatants from F/P + cells were found to upregulate production of stromal cell-derived factor-1 (SDF-1)/CXCL12 in human fibroblasts. SDF-1, in turn, induced migration of EOL-1 cells in a dose-dependent manner. Conclusions: We have identified a F/P-driven paracrine interaction between neoplastic eosinophils and stromal cells that may contribute to tissue fibrosis and accumulation of neoplastic eosinophils in CEL.
    No preview · Article · Apr 2013 · Allergy
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    ABSTRACT: Data on the long-term survival following venous thromboembolism (VTE) are rare,and the influence of thrombophilia has not been evaluated thus far. Our aim was to assess thrombophilia-parameters as predictors for long-term survival of patients with VTE. Overall, 1,905 out-patients (99 with antithrombin-, protein C or protein S deficiency, 517 with factor V Leiden, 381 with elevated factor VIII and 160 with elevated homocysteine levels, of these 202 had a combination and 961 had none of these risk factors) were included in the study between September 1, 1994 and December 31, 2007. Retrospective survival analysis showed that a total of 78 patients (4.1 %) had died during the analysis period, among those four of definite or possible pulmonary embolism and four of bleeding. In multivariable analysis including age and sex an association with increased mortality was found for hyperhomocysteinemia (hazard ratio 2.0 (1.1.-3.5)) whereas this was not the case for all other investigated parameters. We conclude that the classical hereditary thrombophilia risk factors did not have an impact on the long-term survival of patients with a history of VTE. Thus our study supports the current concept that thrombophilia should not be a determinant for decision on long term anticoagulation. However, hyperhomocysteinaemia, known as a risk factor for recurrent VTE and arterial disease, might impact survival.
    No preview · Article · Nov 2012 · Thrombosis and Haemostasis
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    ABSTRACT: P-selectin variant 715Pro is associated with lower concentrations of plasma P-selectin and reduced risk for thrombosis. We examined the influence of 715Pro on P-selectin synthesis, post-translational processing, surface expression and function using HEK293 cells, which do not express endogenous P-selectin. Mass spectrometry revealed that HEK293 cells produced recombinant P-selectin which has a glycosylation pattern comparable to platelet P-selectin. Compared to wild-type transfectants, 715Pro transfectants have ~50% less terminally glycosylated P-selectin and accumulate more immature P-selectin in Golgi. Following Brefeldin A treatment, the majority of 715Pro P-selectin is not modified by Golgi enzymes, while wild-type P-selectin undergoes complete modification. Flow cytometry revealed that 715Pro transfectants have ~20% less P-selectin on the cell surface compared to wild-type transfectants. Secretion of P-selectin by 715Pro transfectants was about 38% lower compared to wild-type transfectants. Binding of HL-60 cells to 715Pro transfectants was ~29% lower than to wild-type transfectants. This observation was confirmed by the presence of fewer platelet-monocyte aggregates (PMA) in the blood of healthy individuals and patients with angiographically proven atherosclerosis, carrying 715Pro P-selectin compared to individuals with wild-type P-selectin. We conclude that the 715Pro variant impairs terminal glycosylation of P-selectin in Golgi, leading to reduced amounts of mature P-selectin and subsequently less surface expression and secretion of P-selectin. The reduced surface expression of 715Pro P-selectin contributes to inefficient adhesion to HL-60 cells or monocytes.
    No preview · Article · Sep 2012 · Thrombosis and Haemostasis
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    ABSTRACT: In chronic myeloid leukaemia (CML), clonal evolution with resistance to tyrosine kinase inhibitors (TKIs) is often triggered by BCR/ABL1 mutations. However, in the context of the complex pro-oncogenic signalling networks which ultimately lead to clonal expansion and disease progression, the exact contribution of BCR/ABL1 mutants remains uncertain. Recent data indicate that detection of BCR/ABL1 mutant subclones does not permit prediction of their expansion dynamics and their potential to become drivers of resistant disease. To determine the patterns of clonal evolution and the distinct proliferation kinetics of individual BCR/ABL1 mutants during treatment, we employed ligase-dependent polymerase chain reaction (LD-PCR) analysis for quantitative surveillance of CML subclones with various tyrosine kinase domain (TKD) mutations including M244V, L248V, G250E, E255K, T315I, F317L-A/G, M351T and F359V. Inadequate treatment responses were observed in 27 of 100 patients investigated and 16 were found to bear one or more BCR/ABL1 TKD mutations in separate subclones. Rapid subclone expansion upon onset or switch of TKI treatment was common and sometimes preceded corresponding changes in BCR/ABL1 transcript levels. Mutant subclones were found to respond differentially and sometimes unexpectedly to various treatment modalities. Decline and persistent depletion of specific mutation-bearing subclones in response to treatment could be documented by LD-PCR surveillance. The observations show that quantitative monitoring of mutant BCR/ABL1 subclones by LD-PCR is a powerful tool for detection of clonal evolution, subclone-expansion and subclone-depletion and can contribute to optimised management of patients with CML.
    No preview · Article · Sep 2011 · European journal of cancer (Oxford, England: 1990)
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    ABSTRACT: Venous thromboembolism (VTE) is a life-threatening complication in cancer patients. Identification of risk factors has been in focus in the past years. Functional single nucleotide polymorphisms (SNP) of coagulation factors known to influence the concentration or function may be considered to influence the risk of VTE in cancer patients. We evaluated the influence of fibrinogen plasma levels, the -455G>A SNP in the fibrinogen beta gene and the Val34Leu (163G>T) SNP in the factor XIII A-subunit (FXIII-A) gene on the risk of VTE. In 1,079 tumour patients recruited for the prospective Vienna Cancer and Thrombosis Study (CATS) fibrinogen levels were determined by the Clauss method. The FXIII-A Val34Leu and the fibrinogen -455G>A SNPs were tested by allele-specific PCR. The median follow-up time was 604 days, 83 thrombotic events occurred. The median fibrinogen level was 381 mg/dl (25th-75th percentile: 312 to 467). In a multivariable Cox model adjusted to chemotherapy, surgery, radiotherapy, age and sex, neither the fibrinogen concentration (hazard ratio [HR] =1.05, confidence interval [CI] 0.839-1.310 p=0.68), nor the -455G>A SNP (HR=0.77, 95%CI 0.491-1.197; p=0.24), nor the Val34Leu SNP (HR=0.99, 95%CI 0.646-1.542 p=0.99) were associated with occurrence of VTE. The fibrinogen concentration was not significantly different among the fibrinogen -455G or A genotype carriers (p = 0.33). Disseminated intravascular coagulation was observed in only five patients, none of these developed VTE. In conclusion, fibrinogen plasma levels, the fibrinogen -455G>A and the FXIII-A Val34Leu polymorphisms were not associated with VTE in our study.
    No preview · Article · Sep 2011 · Thrombosis and Haemostasis
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    Full-text · Dataset · Jun 2011
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    ABSTRACT: Overexpression of plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor tyrosine kinase activity and thus favours insulin resistance and atherosclerotic vascular disease. Recent findings indicate that the minor variant K121Q in the PC-1 gene confers an increased risk for early myocardial infarction independent of other established risk factors. We hypothesized that genetic variants in PC-1 may also influence the risk for cerebrovascular disease. Aim: Therefore, we assessed the association of the PC-1 K121Q variant in the coding region and a polymorphism (G2906C) in the 3' untranslated region of the PC-1 gene with the risk of stroke. Patients: We analyzed 1014 patients with a history of ischaemic stroke from the Vienna stroke registry and 1001 control individuals without vascular disease. Results, conclusion: Genotype frequencies of both genetic variants were similar in patients and controls in the total study population. By multivariate analysis, no interactions were observed between the PC-1 genotype and established vascular risk factors. However, the PC-1 2906C allele was significantly more frequent in patients who suffered from stroke before the age of 40 years. In these patients the risk for ischaemic stroke was increased four-fold.
    No preview · Article · Jun 2011 · Hamostaseologie
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    Full-text · Conference Paper · Jun 2011
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    ABSTRACT: Acute myocardial infarction at a young age is associated with high morbidity and long-term mortality. The NADPH oxidase system as a main source of reactive oxygen species in vascular cells has been implicated in development and progression of coronary artery disease (CAD). In our study, we investigated the effect of polymorphisms in the p22-PHOX (CYBA) gene on CAD in young patients (≤ 40 years). We prospectively recruited 302 subjects into our multi-centre case control study, including 102 young myocardial infarction patients (≤ 40 years) from two high-volume cardiac catheterisation hospitals and frequency-matched them on age, gender, and center to 200 hospital controls in an approximate 2:1 ratio per case patient. The homozygote c.-930A>G promoter polymorphism was significantly more prevalent in the controls than in the infarction patients. In the adjusted logistic regression analysis, we detected a protective effect of the c.-930A>G promoter polymorphism against premature myocardial infarction. Using a log-additive/per-allele model, we detected an unadjusted odds ratio (OR) of 0.63 (95% confidence interval [CI] 0.45-0.9, p-value 0.011). In the adjusted model the association was more pronounced with an OR of 0.5 (95% CI 0.3-0.81, p-value 0.005). The C242T polymorphism and the 640A>G polymorphism did not differ significantly between the study groups. Furthermore we could not detect a significant effect for these polymorphisms in the logistic regression analysis. The present study suggests a protective association between the c.-930A>G promoter polymorphism in the p22-PHOX (CYBA) gene and the development of myocardial infarction in young individuals (≤ 40 years).
    No preview · Article · Dec 2010 · Thrombosis and Haemostasis

Publication Stats

5k Citations
878.23 Total Impact Points


  • 1985-2015
    • Medical University of Vienna
      • • Institute for Social Medicine
      • • Clinical Department of Medical and Chemical Laboratory Diagnostics
      • • Department for Molecular Biology
      Wien, Vienna, Austria
  • 1984-2011
    • University of Vienna
      • • Department of Internal Medicine III
      • • Clinic for Internal Medicine I
      • • Institute of Social Medicine
      • • Division of Molecular Systems Biology
      Wien, Vienna, Austria
  • 1996-2005
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 2004
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany