Publications by authors named "Christine Mannhalter"

155 Publications

Ex Vivo Improvement of a von Willebrand Disease Type 2A Phenotype Using an Allele-Specific Small Interfering RNA.

Thromb Haemost 2020 11 21;120(11):1483. Epub 2020 Oct 21.

Medical University Vienna, Vienna, Austria.

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http://dx.doi.org/10.1055/s-0040-1718412DOI Listing
November 2020

Comparison of BCR-ABL1 quantification in peripheral blood and bone marrow using an International Scale-standardized assay for assessment of deep molecular response in chronic myeloid leukemia.

Clin Chem Lab Med 2020 07;58(8):1214-1222

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

Background Monitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens. Methods We examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1IS. Results A good overall concordance of BCR-ABL1IS results was found, a systematic tendency towards higher BCR-ABL1IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1IS was assessed in the PB compared to BM aspirates. Conclusions In summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.
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http://dx.doi.org/10.1515/cclm-2019-1172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115836PMC
July 2020

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

Ann Surg 2018 11;268(5):894-902

Department of Surgery, Medical University of Vienna, Vienna, Austria.

Background: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC.

Patients And Methods: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9.

Results: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response.

Conclusion: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.
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http://dx.doi.org/10.1097/SLA.0000000000002901DOI Listing
November 2018

Phenotyping and Target Expression Profiling of CD34/CD38 and CD34/CD38 Stem- and Progenitor cells in Acute Lymphoblastic Leukemia.

Neoplasia 2018 06 15;20(6):632-642. Epub 2018 May 15.

Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Electronic address:

Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34/CD38 LSCs in patients with Ph ALL (n = 22) and Ph ALL (n = 27) by multi-color flow cytometry and qPCR. ALL LSCs expressed CD19 (B4), CD44 (Pgp-1), CD123 (IL-3RA), and CD184 (CXCR4) in all patients tested. Moreover, in various subgroups of patients, LSCs also displayed CD20 (MS4A1) (10/41 = 24%), CD22 (12/20 = 60%), CD33 (Siglec-3) (20/48 = 42%), CD52 (CAMPATH-1) (17/40 = 43%), IL-1RAP (13/29 = 45%), and/or CD135 (FLT3) (4/20 = 20%). CD25 (IL-2RA) and CD26 (DPPIV) were expressed on LSCs in Ph ALL exhibiting BCR/ABL1, whereas in Ph ALL with BCR/ABL1, LSCs variably expressed CD25 but did not express CD26. In Ph ALL, CD34/CD38 LSCs expressed IL-1RAP in 6/18 patients (33%), but did not express CD25 or CD26. Normal stem cells stained negative for CD25, CD26 and IL-1RAP, and expressed only low amounts of CD52. In xenotransplantation experiments, CD34/CD38 and CD34/CD38 cells engrafted NSG mice after 12-20 weeks, and targeting with antibodies against CD33 and CD52 resulted in reduced engraftment. Together, LSCs in Ph and Ph ALL display unique marker- and target expression profiles. In Ph ALL with BCR/ABL1, the LSC-phenotype closely resembles the marker-profile of CD34/CD38 LSCs in chronic myeloid leukemia, confirming the close biologic relationship of these neoplasms. Targeting of LSCs with specific antibodies or related immunotherapies may facilitate LSC eradication in ALL.
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http://dx.doi.org/10.1016/j.neo.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994777PMC
June 2018

Circulating cell-free DNA in plasma of colorectal cancer patients - A potential biomarker for tumor burden.

Surg Oncol 2017 Dec 7;26(4):395-401. Epub 2017 Aug 7.

Medical University of Vienna, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Austria. Electronic address:

Background: Measurement of cell-free DNA (cfDNA) in plasma - the so called liquid biopsy - is a novel method for early detection of cancer. Necrotic cancer cells release various DNA fragments that can be detected in plasma or serum. The aim of our study was to investigate the concentration of circulating ALU115, LINE79 and LINE297 fragments in plasma from venous and arterial blood of colorectal cancer (CRC) patients before, during and 5 days after surgical intervention.

Patients And Methods: Thirty patients (16 female, 14 male, median age 56 years), undergoing surgery for colorectal and appendix cancer, and 17 healthy volunteers were included in this study. Plasma samples were collected from patients and healthy individuals. Qualitative polymerase chain reaction (PCR) and quantitative real-time PCR analyses were conducted using specific primers for ALU115, LINE79 and LINE297.

Results: The concentration of ALU115 was significantly increased in plasma of CRC patients compared to the control group (p = 0.002). Interestingly, the concentration of LINE297 was significantly higher in healthy individuals than patients (p = 0.031). We did not find any difference regarding LINE79 between the two groups (p = 0.893). The total cfDNA concentration was slightly increased in plasma after the surgery (p < 0.056), however, the difference was not significant. Interestingly, no correlation was detected between the peritoneal carcinosis index (PCI) and conventional tumor markers.

Conclusion: According to our results, the concentration of ALU115 in cfDNA could be a potential biomarker for diagnosis of CRC. LINE79 or the conventional tumor markers CEA or CA19-9 do not seem useful for the detection of malignant tumors. Whether the amount of LINE297 in cfDNA represents a reliable biomarker for early diagnosis has yet to be confirmed.
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http://dx.doi.org/10.1016/j.suronc.2017.08.001DOI Listing
December 2017

Homozygous antithrombin deficiency type II causing neonatal thrombosis.

Thromb Res 2017 Oct 4;158:134-137. Epub 2017 Sep 4.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

We report four children from different families with homozygous antithrombin (AT) deficiency type II affecting the heparin binding site (p.Leu131Phe mutation). All children had severe spontaneous venous and/or arterial thromboembolic events shortly after birth. This report intends to raise awareness among clinicians about this rare but severe condition. When thrombosis occurs in an otherwise healthy newborn, a severe congenital thrombophilic disorder should be considered. In homozygous AT deficiency type II, AT activity is typically reduced but may also be in the normal range, posing a diagnostic challenge. Rapid diagnosis is important to initiate appropriate therapy. Standard anticoagulation with heparin may prove ineffective in severe AT deficiency, requiring substitution of AT concentrate and early switch to alternative anticoagulants such as vitamin K antagonists.
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http://dx.doi.org/10.1016/j.thromres.2017.08.023DOI Listing
October 2017

Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets.

Cancer Cell 2017 08;32(2):238-252.e9

Department of Neurology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; MS Center Amsterdam, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.

Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.
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http://dx.doi.org/10.1016/j.ccell.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381325PMC
August 2017

TKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of Ph+ CML.

Oncotarget 2017 Apr;8(14):23061-23072

Department of Laboratory Medicine, Medical University of Vienna, Austria.

In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions. We therefore switched from ponatinib to bosutinib. During bosutinib, platelet counts recovered. However, after 6 months, BCR-ABL1 mRNA levels increased to > 1%. Therefore, we ´switched back´ to ponatinib, and this was again followed by disappearance of BCR-ABL1 and a decrease in platelets. During the next 2 years, we applied ponatinib and bosutinib in continuous rotation-cycles and added hydroxyurea in order to suppress all sub-clones and to balance between efficacy and potential side effects following the principle of personalized medicine. With this approach the patient remained in complete molecular response and reached normal blood counts and a normal quality of life without vascular or other side effects. In conclusion, TKI rotation is a novel potent approach to suppress multiple resistant sub-clones and to balance between clinical efficacy and side effects in patients with advanced CML. Clinical trials are now warranted to show that TKI-rotation is in general safe and effective in these patients.
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http://dx.doi.org/10.18632/oncotarget.15481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410285PMC
April 2017

[New developments in molecularbiological diagnostic].

Hamostaseologie 2017 May 13;37(2):138-151. Epub 2017 Apr 13.

Christine Mannhalter, Medical University Vienna - Department of Laboratory Medicine, Währinger Gürtel 18, Wien, Österreich, Tel: 0043/1/40400-2085, Fax: 0043/1/40400-2097, E-mail:

Today, we have access to excellent and advanced molecular methods that are already widely used. This requires rules to control the quality of the methods as well as the laboratory. Both aspects will be discussed in the article. Following the isolation of nucleic acids they are used for genotyping which allows to address several questions: diagnosis of inherited diseases, inherited predispositions, forensic analyses, identification and typing of bacteria or viruses, elucidation of evolutionary aspects. Importantly, it has to be realized that the type and heterogeneity of phenotypically relevant mutations determines the method used for testing. Today, most laboratories use either PCR analyses or Sanger sequencing for diagnostic applications. However, increasingly next generation sequencing (NGS) is applied. The clinical use of NGS is still very challenging, but we can expect that the switch to regular application of this method will be coming in the very near future. The price for NGS has gone down to approx. USD 1000,- which makes the routine diagnostic use feasible. Nevertheless, several challenges have yet to be solved, such as the processing of the large data volume as well as storage of the data. Supporting data bases exist already and some will be discussed in the article. The understanding of the clinical relevance of many polymorphisms is another issue that has yet to be solved, particularly as in the context of personalized medicine polymorphisms have become increasingly important.
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http://dx.doi.org/10.5482/HAMO-17-01-0001DOI Listing
May 2017

Women with homozygous AT deficiency type II heparin-binding site (HBS) are at high risk of pregnancy loss and pregnancy complications.

Ann Hematol 2017 Jun 30;96(6):1023-1031. Epub 2017 Mar 30.

Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Data regarding outcome and therapy of pregnancies in patients with homozygous antithrombin (AT) deficiency are very rare. We conducted a retrospective, descriptive investigation with emphasis on the obstetric history of eight women with homozygous AT deficiency heparin-binding site (HBS), who had at least one pregnancy. The aim of the study was to get a better insight into the outcome and identify suitable management procedures of pregnancy in this rare disease. All patients suffered from homozygous AT deficiency caused by the mutation c.391C>T p.Leu131Phe in the AT gene (SERPINC1). The women reported in total 23 pregnancies; one pregnancy was excluded because of induced abortion. We found that only seven out of the 22 analyzed pregnancies ended with a live infant, all of them were born preterm. Among the 15 negative outcomes, seven were early pregnancy losses and eight were intrauterine fetal deaths. We found no clear association between treatment protocols and outcome. Eight pregnancies were not treated at all; all of them ended with pregnancy loss. We conclude that homozygous AT deficiency HBS, a form of severe thrombophilia, is associated with high risk of pregnancy loss and preterm delivery. Rigorous anticoagulation and/or replacement of AT during pregnancy may improve the outcome.
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http://dx.doi.org/10.1007/s00277-017-2965-2DOI Listing
June 2017

Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause.

Ann Hematol 2017 Mar 26;96(3):489-495. Epub 2016 Dec 26.

Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

In more than 50% of patients with a mild-to-moderate bleeding tendency, no underlying cause can be identified (bleeding of unknown cause, BUC). Data on parameters of fibrinolysis in BUC are scarce in the literature and reveal discrepant results. It was the aim of this study to investigate increased fibrinolysis as a possible mechanism of BUC. We included 270 patients (227 females, median age 44 years, 25-75 percentile 32-58) with BUC and 98 healthy controls (65 females, median age 47 years, 25-75percentile 39-55). Tissue plasminogen activator (tPA-) antigen and activity, plasminogen activator inhibitor type-1 (PAI-1), tPA-PAI-1 complexes, thrombin activatable fibrinolysis inhibitor (TAFI), α2-antiplasmin, and D-dimer were determined. While PAI-1 deficiency was equally frequent in patients with BUC and controls (91/270, 34%, and 33/98, 34%, p = 0.996), tPA activity levels were more often above the detection limit in patients than in controls (103/213, 48%, and 23/98, 23%, p < 0.0001). We found lower levels of tPA-PAI-1 complexes (6.86 (3.99-10.00) and 9.11 (7.17-13.12), p < 0.001) and higher activity of TAFI (18.61 (15.80-22.58) and 17.03 (14.02-20.02), p < 0.001) and α2-antiplasmin (102 (94-109) and 98 (90-106], p = 0.003) in patients compared to controls. Detectable tPA activity (OR 3.02, 95%CI 1.75-5.23, p < 0.0001), higher levels of TAFI (OR 2.57, 95%CI 1.48-4.46, p = 0.0008) and α2-antiplasmin (OR 1.03, 95%CI 1.01-1.05, p = 0.011), and lower levels of tPA-PAI-1 complexes (OR 0.90, 95%CI 0.86-0.95, p < 0.0001) were independently associated with BUC in sex-adjusted logistic regression analyses. We conclude that the fibrinolytic system can play an etiological role for bleeding in patients with BUC.
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http://dx.doi.org/10.1007/s00277-016-2893-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288436PMC
March 2017

FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors.

Blood 2016 07 23;128(2):293-6. Epub 2016 May 23.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I.

The substantial variability in pharmacokinetic parameters in hemophilia patients A poses a challenge for optimal treatment with factor VIII (FVIII) products. We investigated the effect of FVIII-specific immunoglobulin G (IgG) on FVIII half-life in a cohort of 42 adult patients with severe and moderate hemophilia A without inhibitors. Fifteen (35.7%) of 42 patients tested positive for FVIII-binding IgG with titers ≥1:20 in the initial antibody screen, 9 of these 15 patients had FVIII-specific antibodies with titers ≥1:40, mostly low-to-moderate-affinity IgG1 and IgG3, and 1 had high-affinity IgG4 and later developed low-titer FVIII inhibitors. His brother with low-to-moderate-affinity IgG1 and IgG3 also later developed low-titer FVIII inhibitors. The presence of FVIII-specific IgG subclass titer ≥1:40 antibodies was significantly associated with shorter FVIII half-life (median, 7.8 hours [interquartile range, 6.6-9.2 hours]) vs 10.4 hours [interquartile range, 8.9-13.8 hours]); the regression coefficient adjusted for log age and log von Willebrand factor (VWF) antigen was -0.32 (P = .004), accounting for 16.9% of the observed variability of FVIII half-life in our cohort. Our data indicate a significant contribution of non-neutralizing FVIII-specific IgG to FVIII half-life reduction in hemophilia A patients. Thus, screening for FVIII-specific IgG could be beneficial in tailoring FVIII prophylactic regimens.
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http://dx.doi.org/10.1182/blood-2015-10-675512DOI Listing
July 2016

Identification of CD25 as STAT5-Dependent Growth Regulator of Leukemic Stem Cells in Ph+ CML.

Clin Cancer Res 2016 Apr 25;22(8):2051-61. Epub 2015 Nov 25.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria. Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.

Purpose: In chronic myelogenous leukemia (CML), leukemic stem cells (LSC) represent a critical target of therapy. However, little is known about markers and targets expressed by LSCs. The aim of this project was to identify novel relevant markers of CML LSCs.

Experimental Design: CML LSCs were examined by flow cytometry, qPCR, and various bioassays. In addition, we examined the multipotent CD25(+)CML cell line KU812.

Results: In contrast to normal hematopoietic stem cells, CD34(+)/CD38(-)CML LSCs expressed the IL-2 receptor alpha chain, IL-2RA (CD25). STAT5 was found to induce expression of CD25 in Lin(-)/Sca-1(+)/Kit(+)stem cells in C57Bl/6 mice. Correspondingly, shRNA-induced STAT5 depletion resulted in decreased CD25 expression in KU812 cells. Moreover, the BCR/ABL1 inhibitors nilotinib and ponatinib were found to decrease STAT5 activity and CD25 expression in KU812 cells and primary CML LSCs. A CD25-targeting shRNA was found to augment proliferation of KU812 cellsin vitroand their engraftmentin vivoin NOD/SCID-IL-2Rγ(-/-)mice. In drug-screening experiments, the PI3K/mTOR blocker BEZ235 promoted the expression of STAT5 and CD25 in CML cells. Finally, we found that BEZ235 produces synergistic antineoplastic effects on CML cells when applied in combination with nilotinib or ponatinib.

Conclusions: CD25 is a novel STAT5-dependent marker of CML LSCs and may be useful for LSC detection and LSC isolation in clinical practice and basic science. Moreover, CD25 serves as a growth regulator of CML LSCs, which may have biologic and clinical implications and may pave the way for the development of new more effective LSC-eradicating treatment strategies in CML.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817228PMC
April 2016

Increased expression of transient receptor potential canonical 6 (TRPC6) in differentiating human megakaryocytes.

Cell Biol Int 2016 Feb 3;40(2):223-31. Epub 2016 Jan 3.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

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.
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http://dx.doi.org/10.1002/cbin.10558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342254PMC
February 2016

Serum-tryptase at diagnosis: a novel biomarker improving prognostication in Ph(+) CML.

Am J Cancer Res 2015 15;5(1):354-62. Epub 2014 Dec 15.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna Vienna, Austria ; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna Vienna, Austria.

Basophilia is an established prognostic variable in Ph-chromosome+ chronic myeloid leukemia (CML). However, in CML, basophils are often immature and thus escape microscopic quantification. We have previously shown that tryptase is produced and secreted by immature CML basophils. In the current study, serum samples of 79 CML patients (chronic phase=CP, n=69; accelerated/blast phase=AP/BP, n=10) treated with BCR/ABL inhibitors, were analyzed for their tryptase content. Serum-tryptase levels at diagnosis were found to correlate with basophil counts and were higher in AP/BP patients (median tryptase: 29.9 ng/mL) compared to patients with CP (11.7 ng/mL; p<0.05). In 20/69 patients with CP, progression occurred. The progression-rate was higher in patients with tryptase >15 ng/mL (31%) compared to those with normal tryptase levels (9%, p<0.05). To validate tryptase as new prognostic variable, we replaced basophils by tryptase levels in the EUTOS score. This modified EUTOS-T score was found to predict progression-free and event-free survival significantly better, with p values of 0.000064 and 0.00369, respectively, compared to the original EUTOS score (progression-free survival: p=0.019; event-free survival: p=0.156). In conclusion, our data show that the serum-tryptase level at diagnosis is a powerful prognostic biomarker in CML. Inclusion of tryptase in prognostic CML scores may improve their predictive value.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300686PMC
January 2015

Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia.

Oncotarget 2015 Feb;6(5):3071-84

Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.

Although mast cells (MC) play an important role in allergic reactions, their physiologic role remains unknown. In mice, several models of MC-deficiency have been developed. However, no comparable human model is available. We examined the in vitro- and in vivo effects of the KIT-targeting drug imatinib on growth and development of human MC. Imatinib was found to inhibit stem cell factor (SCF)-induced differentiation of MC in long-term suspension cultures (IC50: 0.01 µM). Correspondingly, long-term treatment of chronic myeloid leukemia (CML) patients with imatinib (400 mg/day) resulted in a marked decrease in MC. In patients with continuous complete molecular response during therapy, bone marrow MC decreased to less than 5% of pre-treatment values, and also serum tryptase concentrations decreased significantly (pre-treatment: 32.0 ± 11.1 ng/ml; post-therapy: 3.4 ± 1.8, p<0.01). Other myeloid lineages, known to develop independently of KIT, were not affected by imatinib-therapy. Imatinib also produced a substantial decrease in MC-development in mice. However, no clinical syndrome attributable to drug-induced MC-deficiency was recorded in our CML patients. Together, imatinib suppresses MC production in vitro and in vivo. However, drug-induced MC depletion is not accompanied by adverse clinical events, suggesting that MC are less relevant to homeostasis in healthy tissues than we assumed so far.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413638PMC
http://dx.doi.org/10.18632/oncotarget.3074DOI Listing
February 2015

The impact of uric acid on long-term mortality in patients with asymptomatic carotid atherosclerotic disease.

J Stroke Cerebrovasc Dis 2015 Feb 10;24(2):354-61. Epub 2014 Dec 10.

Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Background: Serum uric acid (SUA) has been discussed to be related to cardiovascular (CV) disease and outcome. We investigated whether levels of SUA predict long-term mortality in neurologically asymptomatic patients with carotid atherosclerotic disease.

Methods: We prospectively studied 959 consecutive patients with carotid atherosclerosis as evaluated by duplex Doppler sonography for all-cause and CV death, respectively.

Results: During a median follow-up time of 6.3 years (interquartile range [IQR], 5.4-7.1 years), 246 deaths (25.7%), including 160 CV deaths (16.7%), were recorded. Median baseline SUA levels were 5.9 mg/dL (IQR, 5.0-7.0 mg/dL). SUA was significantly associated with all-cause death and CV death. Adjusted hazard ratios (HRs) for an increase of 1 mg/dL of SUA levels were 1.12 (95% confidence interval [CI], 1.04-1.21; P = .003) and 1.20 (95% CI, 1.11-1.30; P < .001) for all-cause and CV death, respectively. Quartiles of SUA levels showed a significant association with CV mortality (log-rank P = .002). For CV death, adjusted HRs for quartiles of increasing SUA levels were 1.45 (95% CI, .87-2.43), 1.44 (95% CI, .85-2.46), and 2.26 (95% CI, 1.36-3.76; P < .01), compared with the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased levels of SUA (≥median) had an approximately 2-fold increase in risk of (CV) death, compared with patients with carotid narrowing of less than 50% and/or SUA levels less than the median (P < .001).

Conclusions: Levels of SUA represent independent predictors for CV mortality in a cohort of patients with asymptomatic carotid atherosclerosis.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.08.035DOI Listing
February 2015

Impact of variables of the P-selectin - P-selectin glycoprotein ligand-1 axis on leukocyte-platelet interactions in cardiovascular disease.

Thromb Haemost 2015 Apr 27;113(4):806-12. Epub 2014 Nov 27.

Thomas Gremmel, MD, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria, Tel.: +431 40400 4671, Fax: +431 40400 4665, E-mail:

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 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.
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http://dx.doi.org/10.1160/TH14-08-0690DOI Listing
April 2015

Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage.

Ann Hematol 2015 Feb 11;94(2):223-31. Epub 2014 Sep 11.

Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria,

Mast cell leukemia (MCL) is a rare, life-threatening malignancy defined by a substantial increase in neoplastic mast cells (MCs) in bone marrow (BM) smears, drug-resistance, and a poor prognosis. In most patients, the survival time is less than 1 year. However, exceptional cases may present with a less malignant course. We report on a 49-year-old female patient with MCL diagnosed in 2013. In February 2013, first symptoms, including flushing, headache, and diarrhea, were recorded. In addition, mild anemia was detected. The disease was characterized by a massive increase in well-granulated, mature, and often spindle-shaped MCs (80 %) in BM smears. The serum tryptase level amounted to 332 ng/mL. Like in most other MCL patients, no skin lesions were detected. However, unlike in other patients, tryptase levels remained stable, and no other signs or symptoms of MCL-induced organ damage were found. Sequencing studies revealed an isolated S476I point mutation in KIT but no mutation in codon 816. The patient received histamine receptor blockers but refused cytoreductive therapy. After 9 months, still no progression or organ damage was detected. However, progression with transformation to acute MCL occurred after 12 months. We propose that the chronic type of MCL with stable conditions, absence of organ damage, and a mature MC morphology is recognized as a distinct entity that should be distinguished from the acute variant of MCL.
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http://dx.doi.org/10.1007/s00277-014-2207-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896380PMC
February 2015

Infections and the role of plasma proteins and platelets.

Thromb Haemost 2014 Oct 11;112(4):630-1. Epub 2014 Sep 11.

Prof. Christine Mannhalter, Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria, E-mail:

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http://dx.doi.org/10.1160/TH14-09-0721DOI Listing
October 2014

Influence of proton pump inhibitors and VKORC1 mutations on CYP2C9-mediated dose requirements of vitamin K antagonist therapy: a pilot study.

Br J Haematol 2014 Nov 21;167(4):547-53. Epub 2014 Aug 21.

Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Interindividual variations in dose requirements of oral vitamin K antagonists (VKA) are attributed to several factors, including genetic variant alleles of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9), but also interaction with co-medications. In this context, proton pump inhibitor (PPI)-related alterations of VKA maintenance dose requirements have been published. The present investigation aimed to test for an interaction profile of oral VKA-therapy and PPIs in relation to the CYP2C9 genotype. Median weekly stable VKA dose requirements over 1 year were recorded in 69 patients. Patients were genotyped for CYP2C9*2, CYP2C9*3, VKORC1c.-1639G>A and VKORC1c.174-136C>T and assessed for an association with PPI use and total VKA maintenance dose requirements. PPI users with CYP2C9 genetic variations required significantly lower weekly VKA maintenance doses than those with the wild-type genotype (t-test: P = 0·02). In contrast, in subjects without PPI use, the CYP2C9 genotype had no significant influence on oral VKA dose requirements. Further, the combined CYP2C9/VKORC1 genotype was a significant predictor for VKA dose requirements [linear regression: estimate: -1·47, standard error: 0·58 (P = 0·01)]. In conclusion, in carriers of CYP2C9 gene variations, the interference with the VKA metabolism is modified by PPI co-medication and the VCKORC1 genotype. Preceding knowledge of the genetic profile and the awareness for potentially occurring severe over-anticoagulation problems under PPI co-medication could contribute to a safer and personalized VKA pharmacotherapy.
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http://dx.doi.org/10.1111/bjh.13082DOI Listing
November 2014

Biomarkers predictive of venous thromboembolism in patients with newly diagnosed high-grade gliomas.

Neuro Oncol 2014 Dec 1;16(12):1645-51. Epub 2014 Jul 1.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria (J.T., C.A., E-M.R., J.H., I.P.); Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna General Hospital, Vienna, Austria (J.T., C.A., E-M.R., C.Z., C.MAR., J.H., I.P.); Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria (C.MAN.); Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria (C.Z., C.MAR.); Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria (A.K.).

Background: High-grade gliomas (HGGs) are among the most prothrombotic of malignancies.

Methods: We performed a prospective study to investigate 11 potential biomarkers for prediction of venous thromboembolism (VTE) in newly diagnosed HGG patients who had undergone a neurosurgical intervention. In addition, we tested 2 VTE risk assessment models (RAMs). The strongest predictors of VTE, which were identified by statistical forward selection, were used for the first RAM. The parameters used for the second RAM were both predictive of VTE and available in routine clinical practice.

Results: One hundred forty-one HGG patients were included in this study, and 24 (17%) of them developed VTE during follow-up. An association with the risk of future VTE was found for the following parameters: leukocyte count, platelet count, sP-selectin, prothrombin-fragment 1 + 2, FVIII activity, and D-dimer. The first RAM included low platelet count (<25th percentile of the study population) and elevated sP-selectin (≥75th percentile). The cumulative VTE probability after 12 months was 9.7% for score 0 (n = 76), 18.9% for score 1 (n = 59), and 83.3% for score 2 (n = 6). The second RAM included low platelet count (<25th percentile), elevated leukocyte count, and elevated D-dimer (≥75th percentile). The probability of VTE was 3.3% for score 0 (n = 63), 23.0% for score 1 (n = 53), and 37.7% for score 2 (n = 22) or score 3 (n = 3).

Conclusions: We identified biomarkers suitable for assessing the VTE risk in newly diagnosed HGG patients. The application of 2 RAMs allowed identification of patients at high risk of developing VTE. We could also define patients at low risk of VTE, who would most probably not benefit from extended primary thromboprophylaxis.
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http://dx.doi.org/10.1093/neuonc/nou106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232082PMC
December 2014

Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia.

Blood 2014 Jun 28;123(25):3951-62. Epub 2014 Apr 28.

Ludwig Boltzmann Cluster Oncology, and Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;

Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although mechanisms of BCR/ABL1-induced transformation are well-defined, little is known about effector-molecules contributing to malignant expansion and the extramedullary spread of leukemic SC (LSC) in CML. We have identified the cytokine-targeting surface enzyme dipeptidylpeptidase-IV (DPPIV/CD26) as a novel, specific and pathogenetically relevant biomarker of CD34(+)/CD38(─) CML LSC. In functional assays, CD26 was identified as target enzyme disrupting the SDF-1-CXCR4-axis by cleaving SDF-1, a chemotaxin recruiting CXCR4(+) SC. CD26 was not detected on normal SC or LSC in other hematopoietic malignancies. Correspondingly, CD26(+) LSC decreased to low or undetectable levels during successful treatment with imatinib. CD26(+) CML LSC engrafted NOD-SCID-IL-2Rγ(-/-) (NSG) mice with BCR/ABL1(+) cells, whereas CD26(─) SC from the same patients produced multilineage BCR/ABL1(-) engraftment. Finally, targeting of CD26 by gliptins suppressed the expansion of BCR/ABL1(+) cells. Together, CD26 is a new biomarker and target of CML LSC. CD26 expression may explain the abnormal extramedullary spread of CML LSC, and inhibition of CD26 may revert abnormal LSC function and support curative treatment approaches in this malignancy.
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http://dx.doi.org/10.1182/blood-2013-10-536078DOI Listing
June 2014

Association between the rs342293 polymorphism and adverse cardiac events in patients undergoing percutaneous coronary intervention.

Thromb Haemost 2014 Jun 20;111(6):1060-6. Epub 2014 Mar 20.

Jolanta Siller-Matula, MD, PhD, Department of Cardiology, Medical University of Vienna, Austria, E-mail:

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.
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http://dx.doi.org/10.1160/TH13-09-0757DOI Listing
June 2014

FLAG-induced remission in a patient with acute mast cell leukemia (MCL) exhibiting t(7;10)(q22;q26) and KIT D816H.

Leuk Res Rep 2014 26;3(1):8-13. Epub 2013 Nov 26.

Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany.

Mast cell leukemia (MCL) is a life-threatening disease associated with high mortality and drug-resistance. Only few patients survive more than 12 months. We report on a 55-year-old female patient with acute MCL diagnosed in May 2012. The disease was characterized by a rapid increase in white blood cells and mast cells (MC) in the peripheral blood, and a rapid increase of serum tryptase levels. The KIT D816H mutation was detected in the blood and bone marrow (BM). Induction chemotherapy with high-dose ARA-C and fludarabine (FLAG) was administered. Unexpectedly, the patient entered a hematologic remission with almost complete disappearance of neoplastic MC and a decrease of serum tryptase levels to normal range after 2 cycles of FLAG. Consecutively, the patient was prepared for allogeneic stem cell transplantation. However, shortly after the third cycle of FLAG, tryptase levels increased again, immature MC appeared in the blood, and the patient died from cerebral bleeding. Together, this case shows that intensive chemotherapy regimens, like FLAG, may induce remission in acute MCL. However, treatment responses are short-lived and the overall outcome remains dismal in these patients. We propose to separate this acute type of MCL from more subacute or chronic variants of MCL.
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http://dx.doi.org/10.1016/j.lrr.2013.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3939382PMC
March 2014

Long-lasting complete response to imatinib in a patient with systemic mastocytosis exhibiting wild type KIT.

Am J Blood Res 2014 15;4(2):93-100. Epub 2014 Dec 15.

Ludwig Boltzmann Cluster Oncology, Medical University of Vienna Austria ; Department of Dermatology, Medical University of Vienna Austria.

Systemic mastocytosis (SM) is a hematopoietic disorder characterized by abnormal expansion of mast cells (MCs) in visceral organs. The skin is involved in most cases. In adult patients the transforming KIT mutation D816V is usually present and confers resistance against imatinib. Therefore, imatinib is not recommended for patients with KIT D816V+ SM. Nonetheless, imatinib may work in patients with SM lacking KIT D816V. However, little is known about long-term efficacy and safety of this drug in SM. We report on a 62-year-old female patient with indolent SM (ISM) who suffered from severe debilitating skin involvement despite therapy with anti-mediator-type drugs, psoralen and ultraviolet-A-radiation. Although multifocal MC infiltrates were detected in the bone marrow by immunohistochemistry, no KIT mutation was found by sequencing analysis. In 2003, treatment with imatinib (induction, 400 mg/day; maintenance, 200 mg/day) was initiated. During therapy, skin lesions and tryptase levels decreased. Treatment was well tolerated without any side effects. After 10 years, skin lesions have disappeared and the tryptase level is within normal range. This case-study confirms the long-term efficacy and safety of imatinib in patients with SM lacking activating KIT mutations. Imatinib should be considered in select cases of SM in whom MCs exhibit wild-type KIT.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351647PMC
March 2015

Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial.

J Am Coll Cardiol 2014 Feb 4;63(7):630-635. Epub 2013 Dec 4.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address:

Objectives: This study sought to examine the possible drug-drug interactions between clopidogrel and morphine.

Background: Because morphine-the recommended treatment for pain of myocardial infarction-is associated with poor clinical outcome, we hypothesized that morphine lowers the plasma levels of clopidogrel active metabolite as well as its effects on platelets.

Methods: Twenty-four healthy subjects received a loading dose of 600 mg clopidogrel together with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics was determined by liquid chromatography tandem mass spectrometry, and clopidogrel effects were measured by platelet function tests.

Results: Morphine injection delayed clopidogrel absorption (p = 0.025) and reduced the area under the curve levels of its active metabolite by 34% (p = 0.001). Morphine delayed the maximal inhibition of platelet aggregation on average by 2 h (n = 24; p < 0.001). Residual platelet aggregation was higher 1 to 4 h after morphine injection (n = 24; p < 0.005). Furthermore, morphine delayed the inhibition of platelet plug formation under high shear rates (P2Y-Innovance; n = 21; p < 0.004) and abolished the 3-fold prolongation in collagen adenosine diphosphate-induced closure times seen in extensive and rapid metabolizers (n = 16; p = 0.001).

Conclusions: Morphine delays clopidogrel absorption, decreases plasma levels of clopidogrel active metabolite, and retards and diminishes its effects, which can lead to treatment failure in susceptible individuals. (Drug/Drug Interactions of Aspirin and P2Y12-inhibitors; NCT01369186).
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http://dx.doi.org/10.1016/j.jacc.2013.10.068DOI Listing
February 2014

Prognostic value of neutrophils in patients with asymptomatic carotid artery disease.

Atherosclerosis 2013 Dec 11;231(2):274-80. Epub 2013 Oct 11.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

Background: Inflammation is associated with atherosclerotic disease. In this context, it has been shown that an increased neutrophil count is a risk factor for cardiovascular events in patients with coronary and peripheral artery disease. However, the impact of neutrophils on long-term mortality in patients with carotid atherosclerosis is not yet fully understood.

Methods: We prospectively studied 853 of 1268 consecutive patients with neurologically asymptomatic carotid stenosis for all-cause and cardiovascular death, respectively.

Results: During a median follow-up time of 6.3 years (IQR 5.8-6.7 years) a total of 203 deaths (23.8%), including 134 cardiovascular deaths (15.7%), were recorded. An increase of 1 G/L of neutrophil count indicated an increased risk for all-cause mortality of 1.20 (CI [95%] 1.10-1.31, P < 0.001) and of cardiovascular death of 1.30 (CI 1.17-1.45, P < 0.001), respectively. For the second to the fourth quartile of the neutrophil count, adjusted hazard ratios for all-cause mortality were 1.12 (CI, 0.71-1.75), 1.46 (CI, 0.96-2.21), and 1.76 (CI, 1.15-2.69; P = 0.03 for trend); and 1.41 (CI, 0.80-2.49), 1.53 (CI, 0.88-2.68), and 2.54 (CI, 1.49-4.33; P < 0.01 for trend) for cardiovascular mortality, compared to the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased neutrophil count (≥median), had a 1.9-2.4 fold increase in risk of (CV-) death, compared to patients with carotid narrowing of less than 50% and/or neutrophil count less than the median (P < 0.001). After adjusting for cardiovascular risk factors, only neutrophils, but not eosinophils, basophils, monocytes, lymphocytes, or the total leukocyte count showed a significant association with long-term mortality. No significant association was found between white blood cell subtypes with either baseline degree or progression during a 6 month follow-up of carotid stenosis.

Conclusion: The baseline neutrophil count was an independent predictor for all-cause and cardiovascular mortality in neurologically asymptomatic patients with carotid stenosis. Thus, the measurement of neutrophils could provide prognostic information on outcome in patients at risk.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.10.002DOI Listing
December 2013
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