Publications by authors named "Ansgar Weltermann"

45 Publications

Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia-A Retrospective Analysis in 337 Patients.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.

Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, = 236) and with (B, = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% ( < 0.0001), and of high colony growth (≥20/10 peripheral blood mononuclear cells) 31%, 44%, and 80% ( < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.
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http://dx.doi.org/10.3390/ijms21083025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215883PMC
April 2020

Recommendations for ibrutinib treatment in patients with atrial fibrillation and/or elevated cardiovascular risk.

Wien Klin Wochenschr 2020 Feb 14;132(3-4):97-109. Epub 2019 Aug 14.

University Clinic of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria.

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an enzyme that is essential for survival and proliferation of B‑cells by activating the B‑cell receptor signalling pathway. Ibrutinib has been shown to be highly effective in B‑cell malignancies in clinical trials and is recommended in current international guidelines as a first and/or second line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension) may complicate or be of concern for doctors and patients considering the use of this treatment. In many cases, however, it is not necessary to withhold this effective therapy. In contrast, ibrutinib treatment can be initiated or continued, if certain recommendations are followed. The possibilities of prevention, diagnosis and management of specific clinical situations are discussed in detail and recommendations are derived, which should facilitate ibrutinib use.
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http://dx.doi.org/10.1007/s00508-019-1534-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035304PMC
February 2020

The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) : A representative and useful real-life data source for further biomedical research.

Wien Klin Wochenschr 2019 Sep 18;131(17-18):410-418. Epub 2019 Jul 18.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.
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http://dx.doi.org/10.1007/s00508-019-1526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748886PMC
September 2019

Intensive consolidation with G-CSF support: Tolerability, safety, reduced hospitalization, and efficacy in acute myeloid leukemia patients ≥60 years.

Am J Hematol 2017 Oct 17;92(10):E567-E574. Epub 2017 Aug 17.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Wien, Austria.

The aim of this study was to evaluate the efficacy and feasibility of intensified consolidation therapy employing fludarabine and ARA-C in cycle 1 and intermediate-dose ARA-C (IDAC) in cycles 2 through 4, in elderly acute myeloid leukemia (AML) patients and to analyze the effects of pegfilgrastim on the duration of neutropenia, overall toxicity, and hospitalization-time during consolidation in these patients. Thirty nine elderly patients with de novo AML (median age 69.9 years) who achieved complete remission (CR) after induction-chemotherapy were analyzed. To examine the effect of pegfilgrastim on neutropenia and hospitalization, we compared cycles 2 and 4 where pegfilgrastim was given routinely from day 6 (IDAC-P) with cycle 3 where pegfilgrastim was only administered in case of severe infections and/or prolonged neutropenia. All four planned cycles were administered in 23/39 patients (59.0%); 5/39 patients (12.8%) received 3 cycles, 3/39 (7.7%) 2 cycles, and 8/39 (20.5%) one consolidation-cycle. The median duration of severe neutropenia was 7 days in cycle 2 (IDAC-P), 11.5 days in cycle 3 (IDAC), and 7.5 days in cycle 4 (IDAC-P) (P < .05). Median overall survival was 1.1 years and differed significantly between patients aged <75 and ≥75 years (P < .05). The probability to be alive after 5 years was 32%. Together, intensified consolidation can be administered in AML patients ≥60, and those who are <75 may benefit from this therapy. Routine administration of pegfilgrastim during consolidation shortens the time of neutropenia and hospitalization in these patients.
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http://dx.doi.org/10.1002/ajh.24847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115890PMC
October 2017

HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation.

Biomedicines 2017 Mar 28;5(2). Epub 2017 Mar 28.

Department of Hematology and Oncology, Medical University, 6020 Innsbruck, Austria.

Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD. Congruously, we have previously reported favorable outcomes in C1/1 recipients after ATG-based transplants in a monocentric analysis. Here, within an extended cohort, we test the hypothesis that incorporation of ATG for GVHD prophylaxis may improve survival particularly in HSCT recipients with at least one C1 KIR-ligand. Retrospectively, 775 consecutive allogeneic (excluding haploidentical) HSCTs were analyzed, including peripheral blood and bone marrow grafts for adults with hematological diseases at two Austrian HSCT centers. ATG-Fresenius/Grafalon, Thymoglobuline, and alemtuzumab were applied in 256, 87, and 7 transplants, respectively (subsequently summarized as "ATG"), while 425 HSCT were performed without ATG. Median follow-up of surviving patients is 48 months. Adjusted for age, disease-risk, HLA-match, donor and graft type, sex match, cytomegalovirus serostatus, conditioning intensity, and type of post-grafting GVHD prophylaxis, Cox regression analysis of the entire cohort ( 775) revealed a significant association of ATG with decreased non-relapse mortality (NRM) (risk ratio (RR), 0.57; 0.001), and overall mortality (RR, 0.71; 0.014). Upon stratification for HLA-C KIR-L, the greatest benefit for ATG emerged in C1/1 recipients ( 291), by reduction of non-relapse (RR, 0.34; 0.0002) and overall mortality (RR, 0.50; 0.003). Less pronounced, ATG decreased NRM (RR, 0.60; 0.036) in HLA-C group 1/2 recipients ( 364), without significantly influencing overall mortality (RR, 0.70; 0.065). After exclusion of higher-dose ATG-based transplants, serotherapy significantly improved both NRM (RR, 0.54; 0.019; 322) and overall mortality (RR, 0.60; 0.018) in C1/2 recipients as well. In both, C1/1 (RR, 1.70; 0.10) and particularly in C1/2 recipients (RR, 0.94; 0.81), there was no statistically significant impact of ATG on relapse incidence. By contrast, in C2/2 recipients ( 121), ATG neither reduced NRM (RR, 1.10; 0.82) nor overall mortality (RR, 1.50; 0.17), but increased the risk for relapse (RR, 4.38; 0.02). These retrospective findings suggest ATG may provide a survival benefit in recipients with at least one C1 group KIR-L, by reducing NRM without significantly increasing the relapse risk.
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http://dx.doi.org/10.3390/biomedicines5020013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489799PMC
March 2017

Karyotype plus NPM1 mutation status defines a group of elderly patients with AML (≥60 years) who benefit from intensive post-induction consolidation therapy.

Am J Hematol 2016 12 8;91(12):1239-1245. Epub 2016 Nov 8.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Although it is generally appreciated that a subset of elderly patients with acute myeloid leukemia (AML) may benefit from intensive consolidation, little is known about variables predicting such benefit. We analyzed 192 consecutive patients with de novo AML aged ≥60 years who were treated with intensive chemotherapy. About 115 patients (60%) achieved complete hematologic remission (CR). Among several parameters, the karyotype was the only independent variable predicting CR (P < 0.05). About 92% (105/115) of the CR-patients received up to four consolidation cycles of intermediate dose ARA-C. Median continuous CR (CCR) and disease-free survival (DFS) were 1.3 and 1.1 years, respectively. CCR, DFS, and survival at 5 years were 23%, 18%, and 15%, respectively. Only karyotype and mutated NPM1 (NPM1mut) were independent predictors of survival. NPM1mut showed a particular prognostic impact in patients with normal (CN) or non-monosomal (Mkneg) karyotype by Haemato-Oncology Foundation for Adults in the Netherlands (HOVON)-criteria, or intermediate karyotype by Southwest Oncology Group (SWOG)-criteria. The median CCR was 0.94, 1.6, 0.9, and 0.5 years for core-binding-factor, CN/Mkneg-NPM1mut, CN/Mkneg-NPM1-wild-type AML, and AML with monosomal karyotype, respectively, and the 5-year survival was 25%, 39%, 2%, and 0%, respectively (P < 0.05). Similar results (0.9, 1.5, 0.9, and 0.5 years) were obtained using modified SWOG criteria and NPM1 mutation status (P < 0.05). In summary, elderly patients with CN/Mkneg-NPM1mut or CBF AML can achieve long term CCR when treated with intensive induction and consolidation therapy whereas most elderly patients with CN/Mkneg-NPM1wt or Mkpos AML may not benefit from intensive chemotherapy. For these patients either hematopoietic-stem-cell-transplantation or alternative treatments have to be considered. Am. J. Hematol. 91:1239-1245, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24560DOI Listing
December 2016

Key Data Elements in Myeloid Leukemia.

Stud Health Technol Inform 2016 ;228:282-6

Institute of Medical Informatics, University of Muenster, Germany.

Data standards consisting of key data elements for clinical routine and trial documentation harmonize documentation within and across different health care institutions making documentation more efficient and improving scientific data analysis. This work focusses on the field of myeloid leukemia (ML), where a semantic core of common data elements (CDEs) in routine and trial documentation is established by automatic UMLS-based form analysis of existing documentation models. These CDEs (n = 227) were initially reviewed and commented by leukemia experts before they were systematically surveyed by an international voting process through seven hematologists of four countries. The total agreement score was 86%. 116 elements (51%) of these share an agreement score of 100%. This work generated CDEs with language-independent semantic codes and international clinical expert review to build a first approach towards an international data standard for ML. A first version of the CDE list is implemented in the data standard Operational Data Model and additional other data formats for reuse in different medical information systems.
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April 2017

Total body irradiation with volumetric modulated arc therapy: Dosimetric data and first clinical experience.

Radiat Oncol 2016 Mar 22;11:46. Epub 2016 Mar 22.

Department of Radiation Oncology, Krankenhaus der Barmherzigen Schwestern Linz, Seilerstätte 4, 4010, Linz, Austria.

Background: To implement total body irradiation (TBI) using volumetric modulated arc therapy (VMAT). We applied the Varian RapidArc™ software to calculate and optimize the dose distribution. Emphasis was placed on applying a homogenous dose to the PTV and on reducing the dose to the lungs.

Methods: From July 2013 to July 2014 seven patients with leukaemia were planned and treated with a VMAT-based TBI-technique with photon energy of 6 MV. The overall planning target volume (PTV), comprising the whole body, had to be split into 8 segments with a subsequent multi-isocentric planning. In a first step a dose optimization of each single segment was performed. In a second step all these elements were calculated in one overall dose-plan, considering particular constraints and weighting factors, to achieve the final total body dose distribution. The quality assurance comprised the verification of the irradiation plans via ArcCheck™ (Sun Nuclear), followed by in vivo dosimetry via dosimeters (MOSFETs) on the patient.

Results: The time requirements for treatment planning were high: contouring took 5-6 h, optimization and dose calculation 25-30 h and quality assurance 6-8 h. The couch-time per fraction was 2 h on day one, decreasing to around 1.5 h for the following fractions, including patient information, time for arc positioning, patient positioning verification, mounting of the MOSFETs and irradiation. The mean lung dose was decreased to at least 80 % of the planned total body dose and in the central parts to 50 %. In two cases we additionally pursued a dose reduction of 30 to 50 % in a pre-irradiated brain and in renal insufficiency. All high dose areas were outside the lungs and other OARs. The planned dose was in line with the measured dose via MOSFETs: in the axilla the mean difference between calculated and measured dose was 3.6 % (range 1.1-6.8 %), and for the wrist/hip-inguinal region it was 4.3 % (range 1.1-8.1 %).

Conclusion: TBI with VMAT provides the benefit of satisfactory dose distribution within the PTV, while selectively reducing the dose to the lungs and, if necessary, in other organs. Planning time, however, is extensive.
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http://dx.doi.org/10.1186/s13014-016-0625-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802832PMC
March 2016

Lapatinib-plus-pegylated liposomal doxorubicin in advanced HER2-positive breast cancer following trastuzumab: a phase II trial.

Anticancer Res 2015 Jan;35(1):517-21

3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria

Background: Trastuzumab, one important treatment option for HER2-positive metastatic breast cancer (MBC) is limited by its cardiotoxic potential. Lapatinib and pegylated liposomal doxorubicin (PLD) represent a cardiosparing alternative that can cross the blood brain barrier. This is important, because one third of breast cancer patients develop brain metastases.

Patients And Methods: We included 24 patients with HER2-positive MBC progressing under trastuzumab. They received 1,250 mg lapatinib daily until progression plus PLD (40 mg/m(2)) every 4 weeks for maximal 6 cycles. The primary end-point was the overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), 1-year PFS and 1-year OS rates.

Results: ORR was 54%. Median PFS was 5.8 and median OS 23.3 months. The one-year PFS rate was 27% and 1-year OS rate 76%.

Conclusion: Lapatinib-plus-PLD is active and safe in HER2-positive MBC, especially suitable for patients with cardiological risk or brain metastases.
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January 2015

[Consensus statement: Stroke prevention in nonvalvular atrial fibrillation in special consideration of the new direct oral anticoagulants].

Wien Klin Wochenschr 2014 Dec 3;126(23-24):792-808. Epub 2014 Oct 3.

Klin. Abt. für Hämatologie u. Hämostaseologie, Univ.-Klin. f. Innere Medizin I, MedUni Wien, Währinger Gürtel 18-20, 1090, Wien, Österreich,

The introduction of new direct oral anticoagulants has changed the treatment of nonvalvular atrial fibrillation. However, these changes are not yet fully reflected in current guidelines.This consensus statement, endorsed by six Austrian medical societies, provides guidance to current prophylactic approaches of thromboembolic events in nonvalvular atrial fibrillation on the basis of current evidence and published guidelines. Furthermore, some special subjects are treated, like changes in laboratory parameters and their interpretation under treatment with direct oral anticoagulants, treatment of bleedings, approach to operations, cardioversion and ablation, and specific neurological aspects. For a CHA2DS2-VASc-Score of ≥ 2, anticoagulation is recommended with a high level of evidence (1A). At the end of the consensus statement, recommendations for a number of specific patient subgroups can be found, in order to help treating physicians to arrive at appropriate therapeutic decisions.
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http://dx.doi.org/10.1007/s00508-014-0586-5DOI Listing
December 2014

A SAGE based approach to human glomerular endothelium: defining the transcriptome, finding a novel molecule and highlighting endothelial diversity.

BMC Genomics 2014 Aug 27;15:725. Epub 2014 Aug 27.

Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18 - 20, A-1090 Vienna, Austria.

Background: Large scale transcript analysis of human glomerular microvascular endothelial cells (HGMEC) has never been accomplished. We designed this study to define the transcriptome of HGMEC and facilitate a better characterization of these endothelial cells with unique features. Serial analysis of gene expression (SAGE) was used for its unbiased approach to quantitative acquisition of transcripts.

Results: We generated a HGMEC SAGE library consisting of 68,987 transcript tags. Then taking advantage of large public databases and advanced bioinformatics we compared the HGMEC SAGE library with a SAGE library of non-cultured ex vivo human glomeruli (44,334 tags) which contained endothelial cells. The 823 tags common to both which would have the potential to be expressed in vivo were subsequently checked against 822,008 tags from 16 non-glomerular endothelial SAGE libraries. This resulted in 268 transcript tags differentially overexpressed in HGMEC compared to non-glomerular endothelia. These tags were filtered using a set of criteria: never before shown in kidney or any type of endothelial cell, absent in all nephron regions except the glomerulus, more highly expressed than statistically expected in HGMEC. Neurogranin, a direct target of thyroid hormone action which had been thought to be brain specific and never shown in endothelial cells before, fulfilled these criteria. Its expression in glomerular endothelium in vitro and in vivo was then verified by real-time-PCR, sequencing and immunohistochemistry.

Conclusions: Our results represent an extensive molecular characterization of HGMEC beyond a mere database, underline the endothelial heterogeneity, and propose neurogranin as a potential link in the kidney-thyroid axis.
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http://dx.doi.org/10.1186/1471-2164-15-725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156628PMC
August 2014

Dabigatran: patient management in specific clinical settings.

Wien Klin Wochenschr 2014 Sep 20;126(17-18):503-8. Epub 2014 Aug 20.

Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria,

Dabigatran, a direct thrombin inhibitor, is licensed for the prevention of venous thromboembolism after knee and hip replacement, the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the treatment of acute venous thromboembolism. As dabigatran has a favourable benefit-risk profile, it is being increasingly used. Dabigatran differs from vitamin K antagonists as regards its pharmacological characteristics and its impact on certain laboratory tests, and also in the lack of a direct antagonist that can reverse dabigatran-induced anticoagulation. In emergency settings such as acute bleeding, emergency surgery, acute coronary syndrome, thrombolysis for ischaemic stroke or overdosing, specific strategies are required. A working group of experts from various disciplines has developed strategies for the management of dabigatran-treated patients in emergency settings.
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http://dx.doi.org/10.1007/s00508-014-0581-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165862PMC
September 2014

BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy.

Cancer Chemother Pharmacol 2014 Apr 14;73(4):771-8. Epub 2014 Feb 14.

Department of Medicine 1, Academic Teaching Hospital Elisabethinen Linz, Linz, Austria.

Introduction: Triple-negative breast cancer (TNBC) patients without pathological complete response (pCR) to neoadjuvant chemotherapy have an unfavourable prognosis. TNBC harbouring BRCA-1 germline mutations may be less responsive to taxanes, while sensitivity to DNA-damaging agents is retained. A similar effect was seen in tumours with epigenetic BRCA-1 silencing. Patients without pCR to neoadjuvant chemotherapy consisting of epirubicin plus docetaxel routinely received post-operative CMF at our centre. Here, we investigated the effect of adjuvant CMF in patients with or without BRCA-1 methylation or TP53 mutation.

Methods: DNA was extracted from formalin-fixed paraffin-embedded tissue. For determining BRCA-1 methylation status, quantitative methylation-specific PCR was performed. For the investigation of TP53 mutation status, DNA was PCR amplified and sequenced by Sanger sequencing.

Results: Twenty-four patients were included; BRCA-1 methylation was present in 41.7 %, while TP53 mutations were observed in 66.7 %. At a median follow-up of 27.5 months, 20 % of patients with BRCA-1 methylation had a disease-free survival (DFS) event, as compared to 64.3 % in the non-methylated group (p = 0.0472). Median DFS in the non-methylated group was 16 months and was not reached in the methylated group (n.s.). No association TP53 mutation status with clinical outcome was observed.

Conclusions: Adjuvant CMF is of limited activity in TNBC refractory to taxane-based neoadjuvant chemotherapy. In this population, BRCA-1 methylation was associated with a significant decrease in DFS events suggesting a better prognosis and potentially retained activity of DNA-damaging agents.
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http://dx.doi.org/10.1007/s00280-014-2404-1DOI Listing
April 2014

Management of dabigatran-induced bleeding: expert statement.

Wien Klin Wochenschr 2013 Nov 12;125(21-22):721-9. Epub 2013 Nov 12.

Department of Anesthesia and Intensive Care, Medical University Innsbruck, Innsbruck, Austria.

The interdisciplinary group of experts has compiled a clinical guidance for manifest dabigatran-induced haemorrhage and envisaged invasive interventions on patients under dabigatran. It recommends an escalation of treatment measures as summarized in a pocket guide (see electronic supplementary material online and insert in the print issue).
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http://dx.doi.org/10.1007/s00508-013-0430-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838590PMC
November 2013

Platelet endothelial cell adhesion molecule 1 deficiency misguides venous thrombus resolution.

Blood 2013 Nov 30;122(19):3376-84. Epub 2013 Sep 30.

Department of Internal Medicine I, Elisabethinen Hospital, Linz, Austria;

Platelet endothelial cell adhesion molecule 1 (PECAM-1) is involved in leukocyte migration and angiogenesis, which are key components of venous thrombus resolution. This study investigated the effect of PECAM-1 deficiency on thrombus resolution in FVB/n mice and the extent to which levels of soluble PECAM-1 (sPECAM-1) correlate with delayed thrombus resolution in humans after acute symptomatic deep vein thrombosis (DVT). In a mouse stagnant flow venous thrombosis model Pecam-1(-/-) thrombi were larger, persisted for longer periods of time, and displayed attenuated macrophage invasion and decreased vessel formation in the presence of increased fibrosis. In humans, higher levels of truncated plasma sPECAM-1 possibly cleaved from cell surfaces, were found in patients with delayed thrombus resolution (assessed via duplex-based thrombus scoring) relative to those whose thrombi resolved (median, 25th/75th percentile): 92.5 (87.7/103.4) ng/mL vs 71.5 (51.1/81.0) ng/mL; P < .001. Furthermore, unresolved human deep vein thrombus specimens stained positively with antibodies specific for the extracellular, but not the cytoplasmic domain of PECAM-1, consistent with accumulation of cleaved PECAM-1. Our data suggest a regulatory role of PECAM-1 in venous thrombus resolution and suggest a predictive value of sPECAM-1 for postthrombotic syndrome (PTS) after acute DVT.
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http://dx.doi.org/10.1182/blood-2013-04-499558DOI Listing
November 2013

[Periprocedual management of vitamin K antagonist's with low molecular weight heparins during invasive procedures--Consensus of experts].

Wien Klin Wochenschr 2013 Jul;125(13-14):412-20

AKH Wien, Univ.-Klinik für Innere Medizin I, Währinger Gürtel 18–20, 1090 Wien, Österreich.

Interruption of an ongoing therapy with vitamin K antagonists (VKAs) is necessary in almost all patients undergoing major surgery. The purpose of the following expert recommendations is to provide easy to use guidance for the periprocedural management of patients on VKAs based on current evidence from the literature. Management of anticoagulation during the time of interruption of VKAs is based on balancing the thromboembolic (TE) risk of underlying conditions against the bleeding risk of the surgical procedure. VKAs should be stopped 3–7days prior to surgery. Low molecular weight heparin (LMWH) is used to cover (“bridge”) the progressive pre-operative loss of anticoagulation and the slow post-operative onset of anticoagulant activity of VKAs. Patients with high risk of TE should receive a therapeutic dose of LMWH, patients with a moderate risk of TE should receive half of this dose. Patients with a low risk of TE do not need bridging therapy with LMWH. In case of an uneventful postoperative course, patients with a therapeutic pre-operative dose should be treated post-operatively with the same dose, starting on day 4 in case of major surgery and on day 2 in case of minor procedures. Patients with a half-therapeutic preoperative dose should be treated post-operatively with the same dose, starting on day 3 in case of major surgery and on day 1 in case of minor procedures. Therapy with VKAs should be re-instituted on the second post-operative day based on the preoperative dosage. Procedure-related post-operative thromboprophylaxis should be given irrespective of these recommendations on days without “bridging” anticoagulation.
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http://dx.doi.org/10.1007/s00508-013-0390-7DOI Listing
July 2013

Clinical presentation of venous thromboembolism in inflammatory bowel disease.

J Crohns Colitis 2013 Oct 3;7(9):723-9. Epub 2012 Nov 3.

Department of Internal Medicine III, Medical University Vienna, Austria.

Background And Aims: Patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE), but data on frequency, site of thrombosis and risk factors are limited. We sought to determine prevalence, incidence as well as location and clinical features of first VTE among IBD patients.

Methods: We evaluated a cohort of 2811 IBD patients for a history of symptomatic, objectively confirmed first VTE, recruited from 14 referral centers. Patients with VTE before IBD diagnosis or cancer were excluded. Incidence rates were calculated based on person-years from IBD diagnosis to first VTE or end of follow-up, respectively.

Results: 2784 patients (total observation time 24,778 person-years) were analyzed. Overall, of 157 IBD patients with a history of VTE, 142 (90.4%) had deep vein thrombosis (DVT) and/or pulmonary embolism (PE), whereas 15 (9.6%) had cerebral, portal, mesenteric, splenic or internal jugular vein thrombosis. The prevalence and incidence rate of all VTE was 5.6% and 6.3 per 1000 person years, respectively. Patients with VTE were older at IBD diagnosis than those without VTE (34.4±14.8years vs 32.1±14.4years, p=0.045), but did not differ regarding sex, underlying IBD and disease duration. 121 (77.1%) VTE were unprovoked, 122 (77.7%) occurred in outpatients and 78 (60.9%) in patients with active disease. Medication at first VTE included corticosteroids (42.3%), thiopurines (21.2%), and infliximab (0.7%).

Conclusion: VTE is frequent in IBD patients. Most of them are unprovoked and occur in outpatients. DVT and PE are most common and unusual sites of thrombosis are rare.
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http://dx.doi.org/10.1016/j.crohns.2012.10.008DOI Listing
October 2013

Tissue factor exposing microparticles in inflammatory bowel disease.

J Crohns Colitis 2013 Apr 15;7(3):222-9. Epub 2012 Jun 15.

Department of Internal Medicine III, Division of Gastroenterology and Hepatology; Medical University of Vienna, Vienna, Austria.

Background: Circulating procoagulant microparticles (MPs) are thought to be involved in the pathogenesis of venous thromboembolism in patients with inflammatory bowel disease (IBD). However, the exposure of tissue factor, the primary initiator of coagulation activation, on microparticles (TF(+)MPs) and its association with hemostasis activation has not yet been studied in IBD patients.

Methods: In this case-control study 49 IBD patients (28 Crohn's disease, 21 ulcerative colitis) and 49 sex- and age-matched, healthy controls were included. Clinical disease activity (Crohn's Disease Activity Index and Clinical Activity Index, respectively) was assessed and IBD-related data were determined by chart review. Numbers, cellular origin and procoagulant activity of TF(+)MPs in plasma were determined using flow cytometry and a chromogenic activity assay. D-dimer and high-sensitive C-reactive protein (CRP) served as markers for coagulation activation and inflammation, respectively. The primary endpoint was the number of TF(+)MPs in IBD patients compared to controls.

Results: Median number (interquartile range) of TF(+)MPs was higher in IBD patients than in controls (14.0 (11.9-22.8)×10(3)/mL vs. 11.9 (11.9-19.1)×10(3)/mL plasma, P=0.029). This finding was due to generally higher plasma levels of MPs from platelets and leukocytes in IBD patients. However, the number of TF(+)MPs was neither correlated with their procoagulant activity and D-dimer nor with disease activity and CRP.

Conclusions: Increased numbers of circulating TF(+)MPs represent a new facet of hemostatic abnormalities in IBD. However, the lack of association with activation of the coagulation system and disease activity questions their pathogenetic role for venous thromboembolism in this patient group.
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http://dx.doi.org/10.1016/j.crohns.2012.05.016DOI Listing
April 2013

[Primary immune thrombocytopenia in adults: diagnostics and treatment consensus statement of the Austrian Society of Hematology and Oncology (ÖGHO)].

Wien Klin Wochenschr 2012 Feb 3;124(3-4):111-23. Epub 2012 Mar 3.

Univ.-Klin. f. Innere Med. I, Med. Univ. Wien, Wien, Austria.

Immune Thrombocytopenia (ITP) is a rare and - in most patients - mild disease, but might be associated with severe or even life-threatening bleeding complications. The treatment of ITP has partly changed in recent years, due to new therapeutic options. International guidelines changed accordingly. This consensus statement by the Austrian Society of Hematology and Oncology (OEGHO) is not a new evaluation of the current evidence, but rather tries to discuss the available international guidelines and adapt them to the situation in Austria. The subject is primary ITP in adults only. Classification, epidemiology, clinical presentation and diagnostics of ITP, and especially the management of this disease, are discussed in detail. This includes current aspects of first, second, and third line therapies, splenectomy with its indications and contraindications, and the use of new therapeutic options like thrombopoetin receptor agonists (TRA).
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http://dx.doi.org/10.1007/s00508-012-0123-3DOI Listing
February 2012

The clinical impact of DNA methylation frequencies of JAK2 negative regulators in patients with essential thrombocythemia.

Leuk Res 2012 May 9;36(5):588-90. Epub 2012 Feb 9.

Department of Internal Medicine I, Elisabethinen Hospital, Linz, Austria.

Suppressors of cytokine signalling (SOCS) and protein tyrosine phosphatase (PTPN) proteins are negative regulators of Janus Kinase 2 (JAK2). They are thought to be involved in the molecular pathogenesis of essential thrombocythaemia (ET) particularly in patients with unmutated JAK2. In this study we compared DNA methylation of SOCS1, SOCS3 and PTPN6 in peripheral blood cells between 39 ET patients (24 JAK2 V617F mutated) and 22 healthy controls by methylation specific PCR (MSP) and analysed the clinical outcome of patients with respect to DNA methylation. In SOCS1, ET patients showed significantly less methylation (P<0.05) than healthy controls, and in SOCS3 and PTPN6 such a tendency was shown. However, there were no significant differences in the methylation frequencies between JAK2 wildtype and mutated ET patients. In addition, no correlation was detected between methylation of SOCS and PTPN and any clinical outcome parameters. Taken together, regarding the genomic regions investigated our data indicate a minor role of methylation of JAK2 negative regulators for the clinical course of ET.
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http://dx.doi.org/10.1016/j.leukres.2012.01.008DOI Listing
May 2012

Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism.

Gastroenterology 2010 Sep 12;139(3):779-87, 787.e1. Epub 2010 Jun 12.

Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background & Aims: Patients with inflammatory bowel disease (IBD) are at increased risk of a first venous thromboembolism (VTE), yet their risk of recurrent VTE is unknown. We performed a cohort study to determine the risk for recurrent VTE among patients with IBD compared with subjects without IBD.

Methods: We assessed 2811 patients with IBD for a history of VTE, recruited from outpatient clinics at 14 referral centers (June 2006-December 2008). Patients with VTE before a diagnosis of IBD or those not confirmed to have VTE, cancer, or a VTE other than deep vein thrombosis or pulmonary embolism, were excluded. Recurrence rates were compared with 1255 prospectively followed patients without IBD that had a first unprovoked VTE (not triggered by trauma, surgery, or pregnancy). The primary end point was symptomatic, objectively confirmed, recurrent VTE after discontinuation of anticoagulation therapy after a first VTE.

Results: Overall, of 116 IBD patients who had a history of first VTE, 86 were unprovoked. The probability of recurrence 5 years after discontinuation of anticoagulation therapy was higher among patients with IBD than patients without IBD (33.4%; 95% confidence interval [CI]: 21.8-45.0 vs 21.7%; 95% CI: 18.8-24.6; P = .01). After adjustment for potential confounders, IBD was an independent risk factor of recurrence (hazard ratio = 2.5; 95% CI: 1.4-4.2; P = .001).

Conclusions: Patients with IBD are at an increased risk of recurrent VTE compared to patients without IBD.
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http://dx.doi.org/10.1053/j.gastro.2010.05.026DOI Listing
September 2010

Low dose acetylsalicylic acid and shedding of microparticles in vivo in humans.

Eur J Clin Invest 2010 Jun 26;40(6):477-82. Epub 2010 Apr 26.

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

Background: Microparticles (MPs) have procoagulant properties as shown in vitro and in animal models. Their role in haemostatic system activation at the site of a vascular injury in vivo in humans has not been studied.

Material And Methods: In a prospective randomized crossover study, 13 healthy volunteers were given 100 mg acetylsalicylic acid or placebo daily for 7 days. Number and cellular origin, expression of tissue factor (TF) and phosphatidylserine on MPs, and platelet and coagulation activation markers [beta-thromboglobulin (beta-TG), prothrombin fragment f1.2 (f1.2)] were measured in venous blood and in blood from a vascular injury (shed blood) by flow cytometry and immunoassays, respectively.

Results: The number of MPs was significantly higher in shed blood than in venous blood. The majority of MPs were platelet derived. The expression of TF on MPs was low, but higher in shed blood than in venous blood. TF positive MPs were significantly higher in shed blood, which was due to an increase of MPs from platelets (PMPs). In shed blood, the number of TF expressing platelet-derived MPs correlated with beta-TG, but not with f1.2. Low dose acetylsalicylic acid did not affect shedding of PMPs, neither in venous blood nor in shed blood.

Conclusions: The release of PMPs locally at the site of platelet plug formation in humans indicates a possible role of MPs for haemostatic system activation in vivo. Low dose acetylsalicylic acid might not be strong enough to suppress shedding of PMPs in the microcirculation.
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http://dx.doi.org/10.1111/j.1365-2362.2010.02299.xDOI Listing
June 2010

Circulating tissue factor-exposing microparticles.

Thromb Res 2008 ;122 Suppl 1:S47-54

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

Upon stimulation or apoptosis, eukaryotic cells shed membrane vesicles of submicron size. These so-called microparticles (MPs) are detected and characterized based on the exposure of antigens characteristic of their respective parental cells and on the increased distribution of negatively charged phospholipids to the outer membrane layer. Among the various hypothesized functions of MPs in both health and disease, one of the most studied is their possible role in hemostasis and thrombosis. In this context, special attention is paid to tissue factor (TF) exposed on a variety of MPs. MPs may have outstanding functional because of their ability to display "active" TF due to an abundance of negatively charged phospholipids on their surface. The rapid accumulation of TF-bearing MPs (TF+MPs) in a developing thrombus as well as the increased numbers and thrombogenic activity of TF+MPs in prothrombotic disorders indicate an important role in the pathogenesis of thrombosis. Nevertheless, isolation, quantification and antigenic characterization of TF+MPs proved challenging and a lively scientific debate is ongoing with respect to a reliable method to determine the cellular source of MP in vivo. Standardization of preanalytical procedures and development of more sensitive technologies are needed to improve our current understanding of the role of circulating TF+MPs in thrombosis.
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http://dx.doi.org/10.1016/S0049-3848(08)70019-7DOI Listing
November 2008

Chemotherapy-induced thrombosis: a role for microparticles and tissue factor?

Semin Thromb Hemost 2008 Mar;34(2):199-203

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

Chemotherapy is an independent risk factor of thromboembolic events in cancer patients. Various pathogenetic mechanisms have been hypothesized in the past, but until now their individual contribution to the risk of thrombosis has been hardly investigated in clinical trials. In recent years, studies increasingly suggested an association between the prothrombotic state in cancer patients and circulating tissue factor-exposing microparticles. In this review, we discuss the roles of tissue factor and microparticles with regard to chemotherapy-induced hypercoagulability.
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http://dx.doi.org/10.1055/s-2008-1079261DOI Listing
March 2008

Genetic variation in heme oxygenase 1 (HMOX1) and the risk of recurrent venous thromboembolism.

J Vasc Surg 2008 Mar 16;47(3):566-70. Epub 2008 Jan 16.

Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.

Background/objective: Products of heme oxygenase 1 (HO1) possess antithrombotic properties, and impairment of HO1 activity may contribute to thrombus formation. Transcriptional activity of long GT-repeat alleles in HO1 gene (HMOX1) is lower as compared with short alleles. We hypothesize that these long alleles are associated with decreased HO1 anticoagulant activity and, thus, an increased risk of thrombosis..

Design/methods: In a prospective cohort study, we followed 860 patients with a first VTE, and investigated the impact of a promoter GT-dinucleotid length polymorphism in HOMX1 on the risk of recurrent venous thromboembolism (VTE).

Results: Allele groups short (S), medium (M) and long (L) of the promoter GT-dinucleotide length polymorphism were distinguished. L-alleles, but not M- or S-alleles, were found to be more frequent among patients with recurrence. Heterozygous carriers of L-alleles had a two-fold higher relative risk of recurrence [(RR 2.2 (95% CI: 1.4-3.4)] as compared to wild type, which was independent of other thrombotic risk factors. At five years, the cumulative probability of recurrence was 18% (95% CI: 15%-22%) in patients without an L-allele compared to 32% (95% CI: 19%-46%) in patients heterozygous for the L-allele (P = .001).

Conclusion: Patients with first VTE and long GT-repeat alleles in HMOX1 have an increased risk of recurrence. Genetically determined alterations in HO1 function may represent a new pathomechanism in VTE.
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http://dx.doi.org/10.1016/j.jvs.2007.09.060DOI Listing
March 2008

Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer.

Thromb Haemost 2007 Jan;97(1):119-23

Dept. of Internal Medicine I, Medical University Vienna, Austria.

The pathogenesis of hypercoagulability in cancer is not entirely understood. We hypothesized that in cancer patients circulating tissue factor-positive microparticles (TF (+) MPs) are increased and associated with hemostatic system activation. In 20 patients with advanced colorectal cancer and in 20 age- and sex-matched controls, number and cellular origin of TF (+) MPs were determined in plasma by flow cytometry. D-dimer was determined as an indicator of hemostatic system activation. Compared to controls, the median (interquartile range) number of TF (+) MPs was two-fold higher in cancer patients: 25.9 (15.4 - 42.0) x 10 (3) /ml plasma versus 13.1 (11.9 - 19.7) x 10 (3) /ml plasma, p = 0.007. This was mainly due to a higher amount of TF (+) MPs from platelets (13.4 [5.0 - 17.4] x 10 (3) /ml plasma vs. 5.8 [4.5 - 7.5] x 10 (3) /ml plasma, p = 0.017). TF (+) MPs correlated with D-dimer ( ? = 0.48, p = 0.002). High levels of TF (+) MPs in cancer patients and their correlation with D-dimer suggest that TF (+) MPs might be involved in hemostasis activation in cancer patients.
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January 2007

[Adult autoimmune thrombocytopenia: diagnosis and treatment].

Wien Klin Wochenschr 2006 May;118(9-10):255-64

Abteilung Hämatologie/Hämostaseologie, Universitätsklinik für Innere Medizin I, Medizinische Universität Wien, Wien, Austria.

The incidence of AITP is 20-30/million/year. The diagnosis is based on the finding of an isolated thrombocytopenia without other blood abnormalities and absence of a palpable spleen. Additional tests such as bone marrow examination, determination of platelet antibodies and of thrombopoetin are required only in special cases. The usual first line therapy in patients with bleeding tendency and a low platelet count is prednisolone at a dose of 1 mg/kg/day. Patients who have platelet counts of less than 20,000/microl 3-6 months after steroid therapy are candidates for splenectomy, in particular if more than 0.1 mg/kg/day prednisolone is required to keep the patient free of bleedings. Laparoscopic splenectomy has a low mortality (0.2%) and morbidity (10%). The risk of post-splenectomy overwhelming pneumococcal septicaemia can be minimized by preoperative vaccination. Older patients, who have low platelet counts after splenectomy, have a high bleeding risk. The most effective treatment options for these patients are cyclophosphamide, azathioprine and rituximab, but the choice of treatment should be carefully considered, since the risk of adverse effects may be greater than the risk of fatal bleeding.
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http://dx.doi.org/10.1007/s00508-006-0602-5DOI Listing
May 2006

Family history for venous thromboembolism and the risk for recurrence.

Am J Med 2006 Jan;119(1):50-3

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

Purpose: The relevance of a family history for venous thromboembolism with regard to the likelihood for recurrence is unknown.

Subjects And Methods: We studied 826 patients for an average of 36 months after a first unprovoked venous thromboembolism and withdrawal of oral anticoagulation. Patients with cancer, lupus anticoagulant, or deficiency of antithrombin, protein C, or protein S were excluded. The study endpoint was objective evidence of recurrent symptomatic venous thromboembolism.

Results: Recurrence for venous thromboembolism was recorded in 23 of 190 patients (12.1%) with a family history (at least one affected first-degree family member) and in 79 of 636 patients (12.4%) without familial thrombosis (relative risk for recurrence 1.0; 95% confidence interval, 0.7-1.6; P=.9). At 5 years, the likelihood for recurrence was 20% among patients with a family history for venous thromboembolism and 18% among those without a family history for venous thromboembolism (P=.9). Risk determinants for venous thromboembolism including factor V Leiden, factor II G20210A, and high factor VIII were not statistically different between the 2 groups.

Conclusion: A family history for venous thromboembolism does not segregate patients into high- or low-risk categories and is not suitable to identify patients at increased risk for recurrent venous thromboembolism.
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http://dx.doi.org/10.1016/j.amjmed.2005.04.043DOI Listing
January 2006

Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism.

Thromb Haemost 2005 Oct;94(4):787-90

Department of Internal Medicine I, Div of Hematology/Hemostasis, Medical University of Vienna, Austria.

Tissue factor pathway inhibitor (TFPI) regulates factor X activation. Low TFPI is a risk factor for a first venous thrombosis. We evaluated whether low TFPI confers an increased risk of recurrent venous thromboembolism (VTE). TFPI-free antigen was measured in 611 patients with a first spontaneous VTE, and who were prospectively followed after withdrawal of anticoagulation. The endpoint was symptomatic recurrent VTE. The relative risk (RR) of recurrence increased from 1.0 (95% CI 0.4-2.6) in patients with TFPI levels < or = 5th percentile to 2.7 (95% CI 1.0-7.4) in patients with levels < or = 2nd percentile as compared with higher levels. At five years, the probability of recurrence was 48.6% (95th CI 19.0-78.1) among patients with TFPI < or = 2nd percentile and 16.8% (95th CI 13.8-19.8) among those with higher levels (p=0.04). Compared to patients with wild type factor V and high TFPI, the RR of recurrence was 1.1 (95% CI 0.7-1.7) in patients with factor V Leiden and high TFPI, 2.3 (95% CI 0.6-9.5) in patients with wild type factor V and low TFPI and 3.5 (95% CI 0.9-14.3) in patients with factor V Leiden and low TFPI. In a multivariate analysis,the high risk of recurrence in carriers of factor V Leiden and low TFPI slightly decreased [RR 2.8 (95% CI 0.6-9.5)]. We conclude that thrombosis patients with low levels of free TFPI are at an increased risk of recurrent VTE.
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http://dx.doi.org/10.1160/TH05-06-0412DOI Listing
October 2005

Symptomatic venous thromboembolism in acute leukemia. Incidence, risk factors, and impact on prognosis.

Thromb Res 2005 ;115(1-2):59-64

Division of Haematology and Haemostasis, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

The association between malignant disorders and occurrence of venous thromboembolism is well established. Patients with cancer and venous thromboembolism have adverse prognosis. No systematic study on the incidence and prognostic impact of venous thromboembolism in acute leukemia has been performed as yet. We retrospectively evaluated the incidence of symptomatic venous thromboembolism before chemotherapy in 719 patients (371 males and 348 females, median age of 57.4 years), diagnosed with acute leukemia [534 with acute myelogenous leukemia, 185 with acute lymphoblastic leukemia]. Furthermore, the relationship of venous thromboembolism to clinical and laboratory parameters and its impact on prognosis was assessed. Fifteen patients (2.09%) had venous thromboembolism (objectively confirmed in 13 patients) in close temporal relationship to the onset of acute leukemia. The incidence of venous thromboembolism was the same in acute myelogenous and lymphoblastic leukemia. In five patients, pulmonary embolism was documented. Venous thromboembolism occurred in all subtypes of acute leukemia, but was most common in promyelocytic leukemia. All but one patient were treated with anticoagulants. No patient died from treatment-related bleedings or venous thromboembolism. Overall, survival, disease-free survival, and remission duration did not differ between the patient groups with and without venous thromboembolism. In contrast to solid tumors, venous thromboembolism before or at diagnosis of acute leukemia is not associated with poor prognosis.
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http://dx.doi.org/10.1016/j.thromres.2004.07.016DOI Listing
May 2005