Publications by authors named "Jacek Trelinski"

28 Publications

  • Page 1 of 1

Increased Oxidative Stress in Acute Myeloid Leukemia Patients after Red Blood Cell Transfusion, but Not Platelet Transfusion, Results Mainly from the Oxidative/Nitrative Protein Damage: An Exploratory Study.

J Clin Med 2021 Mar 25;10(7). Epub 2021 Mar 25.

Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.

Chronic oxidative stress (OS) can be an important factor of acute myeloid leukemia (AML) progression; however, there are no data on the extent/consequence of OS after transfusion of packed red blood cells (pRBCs) and platelet concentrates (PCs), which are commonly used in the treatment of leukemia-associated anemia and thrombocytopenia. We aimed to investigate the effects of pRBC/PC transfusion on the OS markers, i.e., thiol and carbonyl (CO) groups, 3-nitrotyrosine (3-NT), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGE), total antioxidant capacity (TAC), SOD, GST, and LDH, in the blood plasma of AML patients, before and 24 h post-transfusion. In this exploratory study, 52 patients were examined, of which 27 were transfused with pRBCs and 25 with PCs. Age-matched healthy subjects were also enrolled as controls. Our results showed the oxidation of thiols, increased 3-NT, AGE levels, and decreased TAC in AML groups versus controls. After pRBC transfusion, CO groups, AGE, and 3-NT significantly increased (by approximately 30, 23, and 35%; < 0.05, < 0.05, and < 0.01, respectively) while thiols reduced (by 18%; < 0.05). The PC transfusion resulted in the raise of TBARS and AGE (by 45%; < 0.01 and 31%; < 0.001), respectively). Other variables showed no significant post-transfusion changes. In conclusion, transfusion of both pRBCs and PCs was associated with an increased OS; however, transfusing the former may have more severe consequences, since it is associated with the irreversible oxidative/nitrative modifications of plasma proteins.
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http://dx.doi.org/10.3390/jcm10071349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037785PMC
March 2021

Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia.

Blood Adv 2020 09;4(17):4136-4146

Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom.

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.
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http://dx.doi.org/10.1182/bloodadvances.2020002003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479959PMC
September 2020

Six molecular patterns leading to hemophilia A phenotype in 18 females from Poland.

Thromb Res 2020 09 28;193:9-14. Epub 2020 May 28.

Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Poland.

Introduction: Female hemophilia is an intriguing rare disorder and few larger reports on its genetic etiology are available. While historically the diagnosis was satisfactorily reached by factor VIII activity assays, the clinical and potentially therapeutic heterogeneity of female hemophilia calls for comprehensive molecular diagnosis in each case. Currently, the genetic investigations are not a part of routine, state-funded, diagnostics in Poland, and thus molecular epidemiological data are missing.

Aim: We set out to perform a comprehensive genetic analysis of Polish females with hemophilia A.

Patients/methods: Eighteen females with hemophilia A (including 2 with severe and 5 with moderate hemophilia phenotype) consented for genetic diagnostics. To establish F8 mutations, we used next-generation sequencing of a panel of genes associated with hematological disorders, standard assays for recurrent intragenic F8 inversions and MLPA when deletions were suspected. When appropriate we also used karyotyping, genomic microarrays and X chromosome inactivation assays.

Results: While abnormally skewed X-chromosome inactivation combined with a F8 variant on the active allele was, as expected, the most common genetic etiology, a number of other genetic scenarios were unraveled. This included: misdiagnosis (molecular diagnosis of vWd), Turner syndrome, compound heterozygosity and androgen insensitivity syndrome (a phenotypical 46,XY female with a novel androgen receptor gene mutation). We report 3 novel F8 mutations.

Conclusion: Every case of female hemophilia warrants full genomic diagnostics, as this may change the diagnosis or reveal broader morbidity than a coagulation disorder (Turner syndrome, androgen insensitivity, or cardiovascular morbidity that we described previously in a SHAM syndrome carrier).
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http://dx.doi.org/10.1016/j.thromres.2020.05.041DOI Listing
September 2020

Fibrinogen Łódź: a new cause of dysfibrinogenemia associated with recurrent thromboembolic arterial events.

Pol Arch Intern Med 2019 12 9;129(12):934-935. Epub 2019 Oct 9.

John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland

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http://dx.doi.org/10.20452/pamw.15014DOI Listing
December 2019

Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: Identification of three novel fibrinogen gamma chain mutations.

Thromb Res 2019 Oct 24;182:133-140. Epub 2019 Aug 24.

John Paul II Hospital, Krakow, Poland; Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.

Introduction: Congenital fibrinogen disorders are poorly explored in Slavic populations. The aim of this study was to characterize the genetic background and clinical manifestations of fibrinogen disorders in the Polish case series.

Materials And Methods: In 27 unrelated patients (mean [SD] age, 30.4 [19.2] years, 30% men) with fibrinogen concentration (von Clauss method) < 1.8 g/L, exons and intron-exon junctions of the fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG) genes were analyzed using polymerase chain reaction (PCR) amplification followed by sequencing.

Results: At enrollment, 15 (55.6%) and 2 (7.4%) of patients experienced bleeding and thrombotic events, respectively, and the remainder were asymptomatic. The following congenital fibrinogen disorders were identified: 1A. afibrinogenemia, n = 1; 2A. severe hypofibrinogenemia, n = 2; 2B. moderate hypofibrinogenemia, n = 4; 2C. mild hypofibrinogenemia, n = 6; 3A. dysfibrinogenemia, n = 12; 3B. thrombotic related-dysfibrinogenemia, n = 1; 4C. mild hypodysfibrinogenemia, n = 1. Eight dysfibrinogenemic patients (62%) were carriers of hotspot mutations. Fifteen patients were heterozygous and one (afibrinogenemia) homozygous for known causative mutations. Three new heterozygous mutations were detected, all affecting splicing in FGG: fibrinogen Poznan II, a 177 bp deletion eliminating parts of intron 6 and exon 7 in a dysfibrinogenemic woman with recurrent bleeding; fibrinogen Zakopane, (intron 2 acceptor splice site) and fibrinogen Belchatow (intron 1 donor splice site), found in hypofibrinogenemic patients. During follow-up (median 60, interquartile range 10-60 months), bleeding episodes, mainly menorrhagia and easy bruising were reported in 15 (55.6%) patients. One thromboembolic event was observed.

Conclusion: This study of the largest cohort of Slavic patients with congenital fibrinogen disorders has enabled the identification of 3 new FGG mutations and shows a high prevalence of bleeding manifestations with recurrences.
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http://dx.doi.org/10.1016/j.thromres.2019.08.012DOI Listing
October 2019

Affecting NF-κB cell signaling pathway in chronic lymphocytic leukemia by dendrimers-based nanoparticles.

Toxicol Appl Pharmacol 2018 10 17;357:33-38. Epub 2018 Aug 17.

Department of Clinical and Laboratory Genetics, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland.

The complex genetic diversity of chronic lymphocytic leukemia (CLL) makes it difficult to determine the effective and durable therapy beneficial to patients. During the several past years' significant insights in the biology of the disease and its treatment have been made, allowing for the identification of promising novel therapeutic agents. The investigation of signaling pathways to understand the biological character of CLL together with the development of molecular profiling is key in personalized approach in therapy for this disease. As it was already proven, maltotriose (M3) modified fourth generation poly(propylene imine) dendrimers (PPI-G4) modulate BCR, TRAIL and WNT signaling pathway gene expression in CLL cells and strongly influence their survival by inducing apoptosis and inhibiting proliferation. The aim of this study was to evaluate the influence of PPI-G4-M3 dendrimers on NFκB pathway gene expression in CLL (MEC-1) cells with 60 K microarray, as it is one of the major factors in the pathogenesis of B-cell neoplasms. The findings were compared with those obtained with Fludarabine (FA) and the results indicate that PPI-G4-M3 dendrimers affect the expression of the examined genes and exert comparable effect on the CLL cells to FA. Dendrimers are one of the most potent groups of nanometer-sized macromolecules for closing the gap between the present ineffective treatment and the future effective personalized therapy due to their potential versatile biological properties.
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http://dx.doi.org/10.1016/j.taap.2018.08.007DOI Listing
October 2018

Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials.

Am J Hematol 2018 07 15;93(7):921-930. Epub 2018 May 15.

Rigel Pharmaceuticals, South San Francisco, California.

Spleen tyrosine kinase (Syk) signaling is central to phagocytosis-based, antibody-mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on-treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double-blind, placebo-controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14-24, without rescue therapy). Baseline median platelet count was 16 000/μL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as ≥1 platelet count ≥50 000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti-motility agents). Fostamatinib produced clinically-meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.
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http://dx.doi.org/10.1002/ajh.25125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055608PMC
July 2018

Blockage of Wnt/β-Catenin Signaling by Nanoparticles Reduces Survival and Proliferation of CLL Cells In Vitro-Preliminary Study.

Macromol Biosci 2017 11 1;17(11). Epub 2017 Aug 1.

Department of Clinical and Laboratory Genetics, Medical University of Lodz, Pomorska Str. 251, 92-213, Lodz, Poland.

The Wnt/β-catenin signaling pathway is shown to play a significant role in the control of the survival, proliferation, and differentiation of hematopoietic cells. Studies have confirmed that aberrant activation of canonical Wnt signaling occurs in various forms of leukemia, and is crucial for chronic lymphocytic leukemia (CLL) pathogenesis. The aim of the study is to evaluate the influence of maltotriose (M3) modified fourth generation poly(propylene imine) dendrimers (PPI-G4) on Wnt/β-catenin pathway gene expression in CLL (MEC-1) cells and to compare these findings with those obtained with fludarabine (FA). Microarray data analysis reveals seven of 19 Wnt/β-catenin pathway genes whose expression changes significantly during dendrimer and FA treatment: WNT10A, WNT6, and CDH1 among others. PPI-G4-M3 is already known to influence MEC-1 cell apoptosis and proliferation. The obtained results suggest that the reduction in cell survival under the influence of glycodendrimers and FA may be due to loss of Wnt signaling.
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http://dx.doi.org/10.1002/mabi.201700130DOI Listing
November 2017

Assessment of Selected ROTEM Parameters, Kinetics of Fibrinogen Polymerization and Plasmin Amidolytic Activity in Patients with Congenital Fibrinogen Defects.

Adv Clin Exp Med 2016 Nov-Dec;25(6):1255-1263

Department of Hemostasis, Medical University of Łódź, Poland.

Background: Congenital fibrinogen disorders (CFD) are rare fibrinogen deficiencies which may be quantitative or functional. The clinical course of hypofibrinogenemia (hypoFI) or dysfibrinogenemia (dysFI) is unpredictable and cannot be determined by the application of standard hemostasis tests.

Objectives: The main aim of this study was to assess ROTEM parameters in CFD patients.

Material And Methods: Nine patients with CFD were studied. The fibrinogen concentration was measured functionally and antigenically. EXTEM, INTEM, FIBTEM and APTEM tests were used to measure selected ROTEM parameters, including maximum clot firmness (MCF). Fibrin plasma polymerization, clot lysis and plasmin amidolytic activity were determined by spectrophotometric methods.

Results: Incorporating the antigenic, ELISA method, to the diagnostic workup allowed the initial diagnosis to be switched from hypoFI to dysFI in 3/7 patients. MCF readings (the most important parameter describing fibrin polymerization capacity) were significantly lower in patients than in controls according to all ROTEM tests. Cases with hypoFI demonstrated markedly lower readings of MCF according to all ROTEM tests than cases with dysFI. All patients demonstrated disturbances of fibrin polymerization process assessed by turbidimetry. In contrast, no marked differences were identified between studied groups in reference to plasmin amidolytic activity.

Conclusions: Our data suggests that ROTEM and fibrin plasma polymerization according to the turbidimetric method have a high sensitivity towards detection of different CFD. Although ROTEM MCF assessment may help discriminate patients with hypoor dysfibrinogenemia, this finding has to be confirmed on larger groups of patients.
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http://dx.doi.org/10.17219/acem/65781DOI Listing
June 2017

Long-lasting extreme anemia during the therapy of acute lymphoblastic leukemia in a Jehovah's Witness patient.

Transfusion 2016 Oct 7;56(10):2438-2442. Epub 2016 Jul 7.

Department of Hemostasis, Medical University of Łódź, and the, Łódź, Poland.

Background: The treatment of patients with acute leukemia, who due to their religious beliefs refuse to accept blood transfusion, is a great challenge for hematologists.

Case Report: We present a case of acute pre-T-lymphoblastic leukemia in a Jehovah's Witness who did not accept blood transfusion during chemotherapy. Standard induction and consolidation chemotherapy was used (according to the PALG ALL-6 regiment).

Results: During consolidation cycles, darbepoietin alfa, intravenous iron, and total parenteral nutrition was administered. Extreme (Hb < 5 g/dL), long-lasting (41 days) anemia was observed with the lowest Hb concentration amounting to 1.3 g/dL (lasting 7 days).

Conclusion: We believe this to be the lowest Hb value observed, particularly one that persisted for such a long period of time and resulted in the patient surviving without consequences. The patient remains in complete remission for more than 2 years after diagnosis.
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http://dx.doi.org/10.1111/trf.13703DOI Listing
October 2016

Assessment of rotation thromboelastometry parameters in patients with essential thrombocythemia at diagnosis and after hydroxyurea therapy.

Blood Coagul Fibrinolysis 2016 Mar;27(2):205-9

Department of Hematology, Medical University of Łódź, Copernicus Memorial Hospital, Łódź, Poland.

Patients with essential thrombocythemia suffer from thrombotic complications that are the main source of mortality. Due to its complex pathogenesis, no existing single laboratory method is able to identify the patients at highest risk for developing thrombosis. Twenty patients with essential thrombocythemia at diagnosis, 15 healthy volunteers and 20 patients treated with hydroxyurea were compared with regard to certain rotation thromboelastometry parameters. Clotting time (CT), clot formation time (CFT), α-angle, and maximum clot firmness (MCF) were assessed by using the INTEM, EXTEM, FIBTEM, and NATEM tests. Patients with essential thrombocythemia at diagnosis demonstrated significantly higher mean platelet count and markedly lower mean red blood count than controls. CT and CFT readings were found to be markedly lower in essential thrombocythemia patients at diagnosis than in the control group according to the EXTEM test. Patients at diagnosis had markedly lower CT values (EXTEM, FIBTEM) than patients on hydroxyurea therapy. Alpha angle values were markedly higher in essential thrombocythemia patients at diagnosis than in controls, according to the EXTEM, FIBTEM and NATEM tests. MCF readings were significantly higher in essential thrombocythemia patients at diagnosis than in controls according to EXTEM, INTEM, FIBTEM, and NATEM tests. Patients on hydroxyurea therapy had markedly lower MCF values according to EXTEM test than patients at diagnosis. Patients with essential thrombocythemia demonstrate a prothrombotic state at the time of diagnosis, which is reflected in changes by certain rotation thromboelastometry parameters. The hydroxyurea therapy induces downregulation of the prothrombotic features seen in essential thrombocythemia patients at diagnosis.
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http://dx.doi.org/10.1097/MBC.0000000000000421DOI Listing
March 2016

Effects of Rivaroxaban Therapy on ROTEM Coagulation Parameters in Patients with Venous Thromboembolism.

Adv Clin Exp Med 2015 Nov-Dec;24(6):995-1000

Department of Hematology, Medical University of Lodz, Poland.

Background: Rivaroxaban (Xarelto) does not require routine coagulation monitoring; however, in certain clinical situations (overdose, drug accumulation, urgent surgery) measurement of its plasma concentration is highly recommended. Currently, there is no single hemostasis test that shows a direct correlation between rivaroxaban plasma levels and anticoagulant efficacy.

Objectives: This study was intended to assess the value of ROTEM in determining rivaroxaban administration.

Material And Methods: Thirteen patients with venous thromboembolism and 13 healthy volunteers were compared with regard to certain ROTEM parameters and anti-FXa activity. The tests were done before the administration of 20 mg rivaroxaban (i.e. 24 h after previous administration) and 2.5 h afterwards.

Results: The study group demonstrated residual activity of rivaroxaban in plasma (20 ± 11.3 ng/mL) 24 h following the previous administration, which did not cause marked changes in clotting assays compared to controls. In the group, 2.5 h after rivaroxaban administration, prolongation of PT (PTratio 1.51 ± 0.22), APTT (APPTratio: 1.30 ± 0.14) and ROTEM CT (CTratio - EXTEM: 2.45 ± 1.06, CTratio -

Intem: 1.32 ± 0.21) were observed. The cut-off values for particular tests were created to determine if the patient had achieved desirable anticoagulant effect after rivaroxaban administration. The mean anti-FXa values were significantly lower in patients before rivaroxaban dosing than after.

Conclusions: PT demonstrated better diagnostic value than APTT in rivaroxaban administration. The ROTEM clotting time (CT) according to EXTEM may be used to determine the anticoagulation effect of rivaroxaban, but is not sensitive enough to measure the residual activity of this drug.
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http://dx.doi.org/10.17219/acem/42147DOI Listing
March 2016

Pro-Apoptotic Activity of Ruxolitinib Alone and in Combination with Hydroxyurea, Busulphan, and PI3K/mTOR Inhibitors in JAK2-Positive Human Cell Lines.

Adv Clin Exp Med 2015 Mar-Apr;24(2):195-202

Department of Hematology, Medical University of Lodz, Poland.

Background: The JAK2V617F mutation plays a crucial role in the pathogenesis of myeloproliferative neoplasms (MPNs). Inhibition of JAK2 activity by ruxolitinib (RX) results in growth inhibition and apoptosis of cells carrying the JAK2V617F mutation however the exact mechanisms regulating apoptosis have not been fully elucidated.

Objectives: This study assessed the potential cytotoxicity of RX against JAK2-positive human cell lines (SET-2 and HEL), either alone or in combination with hydroxyurea, busulphan, rapamycin or LY294002.

Material And Methods: Cell viability, the apoptosis rate (annexin-V staining), drop of mitochondrial transmembrane potential (Δψm) and caspase activation, were measured using flow cytometry. Additionally, the expression of several apoptosis-regulating proteins was evaluated.

Results: RX showed cytotoxicity against both SET-2 and HEL cell lines. The main mechanism of this action was apoptosis, with significant drop of Δψm, caspase-3 and -9 activation, and moderate activation of caspase-8 (only for SET-2 cells). Corresponding to enhanced apoptosis, the expression levels of some apoptosis-regulating proteins were changed, the most pronounced in both cell lines being up-regulation of Bax and down-regulation of Bcl-2 proteins. Additionally, up-regulation of Bak and Bad (SET-2) and down-regulation of Mcl-1 (HEL) were observed. Of the studied compounds, a combination of RX + LY294002 induced the greatest cytotoxicity in both SET-2 and HEL cell lines, and rapamycin the least.

Conclusions: This study shows that the combination of RX and a PI3K kinase inhibitor provokes a significant pro-apoptotic effect in JAK2V617F mutated cells, which may justify the beginning of clinical trials based on the combination of these drugs.
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http://dx.doi.org/10.17219/acem/32934DOI Listing
August 2015

[Correlations between ROTEM fibrinolytic activity and t-PA, PAI-1 levels in patients with newly diagnosed multiple myeloma].

Pol Merkur Lekarski 2014 May;36(215):316-9

Unlabelled: Multiple myeloma (MM) is associated with the increased risk of thrombosis. Hypofibrinolysis is among the various identified abnormalities in the hemostasis system that may cause a prothrombotic state. The aim of the study was intended to evaluate the association between certain rotational thromboelastometry (ROTEM) parameters with tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) levels and myeloma proteins in patients with MM and in controls.

Material And Methods: The study included 21 patients with MM at the time of diagnosis and 15 healthy volunteers. Maximum clot lysis (ML), clot lysis index at 30, 45 and 60 minutes (LI 30, LI 45, LI 60 respectively), t-PA and PAI-1 activity were among the parameters studied.

Results: According to the FIB TEM test, ML readings were markedly lower (1% v. 3%, p = 0.04) while LI 45, LI60 parameters were significantly higher (p = 0.01 and p = 0.04) in MM group than in controls. Also median, MCF readings (22 mm v. 16 mm, p = 0.01) and alpha-angle values (80 degrees v 74, p = 0.002) were significantly higher in MM according to the FIBTEM assay. Statistically significant higher median values of PAL-1 levels were observed in the MM group than in controls. In MM patients correlations between PAI-1 a LI 45-FIBTEM (r = - 0.65) and between t-PA a LI60- EXTEM (r = 0.45) were discovered. In MM IgG group correlation between IgG protein concentration and MCF-FIBTEM (r = 0.62) was shown.

Conclusions: Changes in ROTEM parameters and PAI-1 levels which may indicate a hypofibrinolytic state were found to occur in patients with MM at the time of diagnosis. There are correlations between t-PA, PAI-1 and some ROTEM parameters.
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May 2014

Assessment of rotation thromboelastometry (ROTEM) parameters in patients with multiple myeloma at diagnosis.

Thromb Res 2014 Apr 14;133(4):667-70. Epub 2014 Jan 14.

Department of Haematology, Copernicus Memorial Hospital, Medical University of Łódź, Poland.

Introduction: Patients with multiple myeloma (MM) have an increased risk of thromboembolic events (TEE). Due to the complex nature of the prothrombotic state in MM, no single laboratory test has been designed to identify patients with the highest risk of developing TEE. Hence, this study is intended to assess the feasibility of using global hemostasis test rotation thromboelastometry (ROTEM) in MM patients to identify the presence of changes indicating hypercoagulability.

Materials And Methods: The study included 26 patients with MM at the time of diagnosis and 20 healthy volunteers. Clotting time (CT), clot formation time (CFT), alpha angle (α), maximum clot firmness (MCF) and maximum lysis (ML) were among the most important parameters recorded during the NATEM, INTEM, EXTEM, FIBTEM and APTEM tests.

Results: For the NATEM test, CT and CFT readings were markedly lower in MM patients than in controls (524s v. 753s; p=0.0006 and 136s v. 242s; p=0.02 respectively). However, no marked differences concerning these parameters were observed in the INTEM, EXTEM, FIBTEN or APTEM tests. α-angle values were significantly higher for MM samples according to the NATEM, EXTEM, FIBTEM and APTEM tests (64° v. 48.5°, p=0.02; 77° v. 74°, p=0.02; 80° v.69.5°, p=0.00007; 77° v. 74°, p=0.01 respectively). MCF readings were significantly higher in the FIBTEM test (22mm v. 15.5mm, p=0.0003) in MM patients. Also, the NATEM test revealed a trend toward higher MCF values in MM samples (56mm v. 49.5mm, p=0.055). No marked differences were seen in the INTEM, EXTEM and APTEM tests. ML readings were markedly lower (0 % v. 4.5 %, p=0.0008) in MM samples than in controls according to the FIBTEM test. The studied clot lysis parameters did not differ markedly between analyzed groups in other tests. Marked negative correlations were noted between IgG concentration and CT (EXTEM, FIBTEM) and CFT (INTEM), as well as a significant positive correlation between IgG concentration and MCF (INTEM, FIBTEM) and α (INTEM) in MM IgG patients.

Conclusions: Our results suggest that patients with MM display changes in ROTEM tests at the time of diagnosis that may indicate a prothrombotic state.
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http://dx.doi.org/10.1016/j.thromres.2014.01.011DOI Listing
April 2014

Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil--follow-up of PALG-CLL randomized trials.

Eur J Haematol 2013 Jul 19;91(1):1-9. Epub 2013 Apr 19.

Department of Hematology, Medical University of Lodz, Lodz, Poland.

Objectives: The relationship between treatments of chronic lymphocytic leukemia (CLL) with cladribine (2-CdA) or chlorambucil and immune thrombocytopenia (IT) has not been yet determined.

Methods: The records of 777 patients in two randomized Polish Adult Leukemia Group (PALG)-CLL programs treated with these agents were retrospectively analyzed.

Results: Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence were seen between patients on chlorambucil or 2-CdA-based regiments (P = 0.33). IT developed at a median time of 0.499 yr (0.06-4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yr, 95% CI: 0.06-4.22) in relation to patients treated with 2-CdA-based regiments (0.52 yr, 95%CI: 0.34-0.69, P = 0.049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yr vs. 3.2 yr P = 0.23) but the severity of bleeding was more pronounced in the 2-CdA group. The responses to IT therapy were 35%, 54% and 75% for steroids, chemotherapy and splenectomy, respectively.

Conclusions: In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2-CdA-based regiments compared to chlorambucil regimen, the clinical course of hemorrhagic diathesis was more severe in 2-CdA group. Also, the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative relationship. The appearance of IT did not influence the median time of OS.
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http://dx.doi.org/10.1111/ejh.12112DOI Listing
July 2013

Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia.

Blood 2012 Nov 20;120(18):3670-6. Epub 2012 Aug 20.

Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland.

Rozrolimupab, a recombinant mixture of 25 fully human RhD-specific monoclonal antibodies, represents a new class of recombinant human antibody mixtures. In a phase 1 or 2 dose escalation study, RhD(+) patients (61 subjects) with primary immune thrombocytopenia received a single intravenous dose of rozrolimupab ranging from 75 to 300 μg/kg. The primary outcome was the occurrence of adverse events. The principal secondary outcome was the effect on platelet levels 7 days after the treatment. The most common adverse events were headache and pyrexia, mostly mild, and reported in 20% and 13% of the patients, respectively, without dose relationship. Rozrolimupab caused an expected transient reduction of hemoglobin concentration in the majority of the patients. At the dose of 300 μg/kg platelet responses, defined as platelet count ≥ 30 × 10(9)/L and an increase in platelet count by > 20 × 10(9)/L from baseline were observed after 72 hours and persisted for at least 7 days in 8 of 13 patients (62%). Platelet responses were observed within 24 hours in 23% of patients and lasted for a median of 14 days. Rozrolimupab was well tolerated and elicited rapid platelet responses in patients with immune thrombocytopenia and may be a useful alternative to plasma-derived products. This trial is registered at www.clinicaltrials.gov as #NCT00718692.
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http://dx.doi.org/10.1182/blood-2012-06-438804DOI Listing
November 2012

Hemostatic changes after 1 month of thalidomide and dexamethasone therapy in patients with multiple myeloma.

Med Oncol 2012 Dec 7;29(5):3574-80. Epub 2012 Jul 7.

Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, ul Ciolkowskiego 2, 93-510, Lodz, Poland.

Thromboembolic events (TEE) are a serious clinical problem in multiple myeloma (MM) patients receiving thalidomide (T). Thirty-one MM patients were tested on diagnosis and after 2 and 4 weeks of therapy with T alone, or T in combination with dexamethasone (TD). Closure time (CT) in PFA-100 and P-selectin expression were assessed, as well as plasma levels of thrombin-antithrombin complexes (TAT), D-dimer (DD), soluble thrombomodulin (sTM) and von Willebrand factor antigen (vWF:Ag), along with the activity of coagulation factor VII and factor VIII. The concentration of vascular endothelial growth factor and its type 1 and 2 receptors were also assayed. On diagnosis, significantly prolonged median CT with both used cartridges, elevated P-selectin expression, DD concentration, TAT, vWF:Ag and factor VIII and factor VII activity were seen in the patient group as compared to controls. Therapy with these regimens caused marked shortening of CT with both cartridges. Treatment with TD leads to the significant increase in CD62P expression on platelets. Median TAT value increased significantly in relation to baseline after therapy with both regimens. Factor VIII activity exceeded 150 % in all patients after 2 weeks of TD therapy and was markedly elevated compared to baseline. One month of TD therapy significantly increased sTM concentration. These results demonstrate the enhanced platelet and coagulation system activation already present in MM patients on diagnosis, which is further increased by antimyeloma therapy. These changes are more pronounced after TD therapy and may promote TEE. Tested angiogenesis marker levels are elevated already on diagnosis, do not change after therapy and have no significant impact on the coagulation system in patients with MM.
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http://dx.doi.org/10.1007/s12032-012-0290-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505549PMC
December 2012

Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy.

Med Oncol 2012 Dec 15;29(4):2388-95. Epub 2012 Mar 15.

Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, ul Ciolkowskiego 2, 93-510, Lodz, Poland.

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mechanisms can be deregulation of apoptosis, resulting in accumulation of bone marrow MKCs. In this study, we investigated the apoptotic profile, as well as the expression of apoptosis-regulating protein in MKCs and bone marrow mononuclear cells (BMMCs) in 43 patients with ET. We found significantly lower percentages of apoptotic MKCs and BMMCs, as measured by the rate of annexin-V+ and caspase-3+ (Cas-3+) cells in relation to healthy volunteers. Additionally, the expression of Bax protein in ET patients naïve to cytoreductive treatment, as well as their Bax/Bcl-2 ratio, was significantly lower than in controls (p=<0.05 and p<0.001, respectively). Patients positive for the JAK2V617F mutation had markedly higher activation of Cas-3, as well as higher Bax expression (p=0.02 and p=0.04, respectively) than JAK2V617F negative cases. There were no marked differences between patients already treated with anagrelide (ANA) or hydroxyurea (HU), although tendency toward the higher apoptosis rate was observed in the HU-treated group. In conclusion, these results demonstrate the inhibition of caspase-dependent apoptosis of both MKCs and BMMCs in untreated ET. This is associated with upregulation of Bcl-2 and downregulation of Bax proteins, predominantly in JAK2V617F negative cases. Patients treated with HU showed slightly higher pro-apoptotic Bax/Bcl-2 index than patients on ANA therapy, which may influence the better efficacy of HU therapy in ET.
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http://dx.doi.org/10.1007/s12032-012-0202-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466431PMC
December 2012

Plasma levels of angiogenic factors and circulating endothelial cells in essential thrombocythemia: correlation with cytoreductive therapy and JAK2-V617F mutational status.

Leuk Lymphoma 2010 Sep;51(9):1727-33

Department of Hematology, Medical University of Łódź, Copernicus Memorial Hospital, Łódź, Poland.

Recent studies have shown that angiogenesis plays an important role in the biology of hematological malignancies including essential thrombocythemia (ET). Using cytofluorimetric analysis, the levels of angiogenic factors, as well as the number of circulating endothelial cells (CECs), were determined in 65 patients with ET, including 33 previously untreated and 32 receiving cytoreductive therapy. Correlations between markers of angiogenesis and JAK2-V617F mutational status were also assessed. We found significantly higher levels of vascular endothelial growth factor (VEGF) and markedly decreased levels of placental growth factor in untreated patients with ET with respect to control subjects. VEGF levels were significantly increased in patients with white blood count >8.7 (x 10(9)/L) vs. <8.7 (x 10(9)/L). Furthermore, the levels of VEGF in patients on hydroxyurea (HU) therapy were markedly lower than in untreated patients. It was also demonstrated that the number of all CEC subpopulations (resting, activated, apoptotic, and circulating precursor endothelial cells) was increased in patients with ET in relation to controls, regardless of the JAK2-V617F status, and was not affected by cytoreductive treatment. In conclusion, our study highlights the possible role of angiogenesis in the pathophysiology of ET. It provides evidence that the number of CECs is elevated independently of JAK2-V617F status and is not down-regulated by HU or anagrelide therapy. Our data suggest that VEGF levels are particularly elevated in patients with high leukocytosis. Further investigation should be undertaken to determine the possible role of antiangiogenic therapy in ET.
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http://dx.doi.org/10.3109/10428194.2010.500435DOI Listing
September 2010

Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers.

Int J Hematol 2010 Jun 15;91(5):792-8. Epub 2010 May 15.

Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Ciolkowskiego 2, 93-510, Lodz, Poland.

Angiogenesis plays an important role in the biology of hematological malignancies, including essential thrombocythemia (ET) and polycythemia vera (PV). Some data suggests that it has a role in the pathogenesis of thrombosis, the major clinical problem in ET and PV. The number of different subpopulations of circulating endothelial cells (CECs), plasma levels of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor 1 and 2 (sVEGFR-1,2) and placenta growth factor (PlGF) were determined in 30 patients with ET and 16 patients with PV. Correlations between angiogenesis and JAK2-V617F mutational status, risk factors for thrombosis and coagulation activation markers were also assessed. The number of CEC subpopulations, were markedly higher in ET and PV patients, irrespective of JAK2-V617F status, when compared to the control group. The median values of activated CECs were markedly higher in PV patients with WBC >8.7 (x10(9)/l). Significantly higher VEGF plasma levels were found in ET patients and a similar trend was seen in PV patients in relation to healthy volunteers. The plasma levels of sVEGFR-1 were significantly higher, and PlGF levels markedly lower, in the ET and PV group than in controls. Our study also demonstrated markedly increased levels of D-dimer and TAT complexes in the patient groups. In conclusion, we found that angiogenesis, as measured by CEC numbers, is increased in ET and PV patients regardless of JAK2-V617F mutational status. Our results demonstrated that angiogenic cytokines interact with known thrombotic risk factors. We confirmed the coagulation activation in ET and PV patients but found no differences in levels of coagulation activation markers in relation to JAK2-V617F mutational status.
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http://dx.doi.org/10.1007/s12185-010-0596-7DOI Listing
June 2010

[Disseminated intravascular coagulation in abdominal aortic aneurysm--case report].

Pol Merkur Lekarski 2009 Aug;27(158):116-8

Medical University of Łódź, Department of Hematology, Poland.

Disseminated intravascular coagulation (DIC) constitutes a rare presentation form of aortic aneurysms. In majority of cases, DIC is asymptomatic and has chronic course, but in 0.5-4% of patients it is clinically overt. Very seldom DIC leads to diagnosis of previously unknown aortic aneurysm. The authors describe a case of 84 years old man referred to hospital due to haemorrhagic diathesis with laboratory results consistent with overt DIC. A CT scan demonstrated abdominal aortic aneurysm (AAA) as an underlying disorder. The patient was treated with fresh frozen plasma and enoxoparine. After reaching the clinical and laboratory improvement he was proposed with placing an endoluminal stent graft, but he did not agree for operation. The multidisciplinary management of this patient is presented and some issues concerning the epidemiology, treatment and coagulation assessment of AAA patients with DIC are discussed.
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August 2009

The influence of low-dose aspirin and hydroxyurea on platelet-leukocyte interactions in patients with essential thrombocythemia.

Blood Coagul Fibrinolysis 2009 Dec;20(8):646-51

Department of Hematology, Medical University of Lodz, Lodz, Poland.

Essential thrombocythemia is associated with an increased risk of thromboembolic complications. Recently, there has been a growing evidence that platelet-leukocyte interactions may contribute to pathogenesis of thrombosis in essential thrombocythemia. Low-dose aspirin (ASA) is generally recommended in the therapy of low-risk patients for thrombosis, whereas hydroxyurea in high-risk patients. The aim of the present study was to determine the effect of ASA and hydroxyurea on platelet, leukocyte functions and on formation of platelet/leukocyte conjugates in vivo in patients with essential thrombocythemia. Markers of platelet and leukocyte activation were assessed in 40 patients with essential thrombocythemia at diagnosis and in 20 controls using flow cytometry assays. In second part of the study, the tests were repeated after either ASA treatment (in 25 low-risk patients) or hydroxyurea therapy (in 15 high-risk patients). On diagnosis, significantly elevated expression of P-selectin on platelets (4.98 +/- 3.31 vs. 0.99 +/- 0.69 P < 0.001) and increased percentage of platelet-polymorphonuclear leukocyte CD11b/CD42b conjugates [10.12 (4.21-31.22) vs. 3.17 (1.43-5.99) P < 0.001] and platelet-monocyte CD11b/CD14/CD61 conjugates [36.62 (12.23-51.62) vs. 13.86 (7.14-23.51) P < 0.001] were found in essential thrombocythemia group as compared with the healthy control group. Therapy with ASA significantly reduced platelet-polymorphonuclear leukocyte [10.72 (4.21-26.97) vs. 8.12 (1.13-26.94) P < 0.05] and platelet-monocyte conjugates [38.6 (13.45-51.62) vs. 25.76 (13.52-45.02) P < 0.05]. Surprisingly, therapy with hydroxyurea was poorly effective in reduction of platelet/leukocyte conjugates. These data document an increased platelet and leukocyte activation at the time of diagnosis. This is the first report showing enhanced platelet-leukocyte aggregate formation in low-risk essential thrombocythemia patients and the efficacy of ASA in its reduction.
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http://dx.doi.org/10.1097/MBC.0b013e32832f6c5bDOI Listing
December 2009

[The assessment of platelet function in patients with essential thrombocythemia].

Pol Merkur Lekarski 2008 Jul;25(145):19-22

Department of Hematology, Medical University of Lódź, Poland.

Unlabelled: Essential thrombocythemia (ET) is associated with an increased risk of both thromboembolic and bleeding complications. Changes in platelet count and function are crucial but leukocyte activation is also suspected. The aim of the study. The study was designed to assess platelet function by optical and impedance platelet aggregometry and also PFA-100 analyser in ET patients at the time of diagnosis

Material And Methods: The tests were performed in 32 ET patients. In each patient platelet aggregation tests by optical (in platelet rich plasma) and impedance methods (in whole blood) after stimulation with ADP, collagen, epinephrine were done. The platelet function was also assessed by PFA-100 method. The control group consisted of 20 healthy volunteers.

Results: In optical platelet aggregometry different platelet function abnormalities were seen in 31 patients (97%). The most frequent was decreased aggregation (19/32) with all used agonists but especially with epinephrine. Spontaneous aggregation was observed in 10 cases and in one we observed hyperaggregation. In whole blood platelet aggregometry abnormal results concerned 23 patients (72%). The most typical (14/32) was hyperactivity of platelets (especially after ADP). In this method we noted spontaneous aggregation in patients and in 4 patients' diminished aggregation. Mixed aggregation disturbances were observed in 6 patients. The closure time in the cohort of patients was significantly prolonged with both cartridges in comparison to control group and was outside reference ranges in 25/32 patient. No significant correlation between values of platelet aggregation in platelet rich plasma and in whole blood was found. No significant differences were observed between ET patients with and without clinical symptoms of bleeding/thrombosis although closure time with both cartridges was longer in patients with bleeding.

Conclusions: In majority of ET patients different platelet function abnormalities are present. The platelet aggregation results depend on environment in which tests are performed. The PFA-100 seems to be a good method for detection of platelet defects in ET.
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July 2008

[Thrombotic thrombocytopenic purpura in pregnancy. A case report].

Ginekol Pol 2008 Jul;79(7):507-9

Katedra i Klinika Hematologii Uniwersytetu Medycznego w Łodzi.

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia, accompanied by microvascular thrombosis that causes variable degrees of tissue ischemia and infarction. About 10-20% of TTP cases are associated with the pregnancy. Preterm delivery and intrauterine fetal death are frequent pregnancy complications of TTP. The following paper presents the case of a 32-year-old woman with TTP relapse at 10 weeks of her second pregnancy. Despite regular fresh frozen plasma transfusions, intrauterine fetal death occurred at 21 weeks of gestation. Current views on TTP management during pregnancy have been presented in the article as well.
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July 2008

The influence of low molecular weight heparin on the intravascular activation of the coagulation system in patients with acute leukemia during induction chemotherapy--report of a prospective randomized study.

Leuk Lymphoma 2002 May;43(5):1021-8

Department of Hematology, Institute of Internal Medicine, Medical University of Lódź, Poland.

Unlabelled: Intravascular activation of the coagulation system can already be observed in the majority of patients with acute leukemia (AL) at the time of diagnosis. This activation can be further enhanced by chemotherapy. The study comprised of 46 patients with AL, randomly divided into two groups. Twenty-three patients received prophylactic doses of nadroparin (Fraxiparine). Thrombin-antithrombin complexes (TAT), prothrombin fragment (F1 + 2), D-dimer (DD), plasmin-antiplasmin complexes (PAP) and antithrombin III (AT III) activity were determined in all patients. The tests were performed before treatment, and on the 3rd and 8th days of chemotherapy. The TAT, F1 + 2, DD and PAP concentrations were found to be elevated in 83% of patients already at the time of diagnosis. No significant difference between either groups test results was noted when either tested before treatment or on the third day of therapy. DIC (disseminated intravascular coagulation) syndrome appeared in two patients receiving heparin prophylaxis and in three patients to whom this treatment was not administered. The concentrations of activation markers on the eighth day of chemotherapy were lower than at the beginning of treatment in most of the patients receiving nadroparin. At this time there were no laboratory signs of DIC in any of the patients receiving heparin prophylaxis.

In Conclusion: although the application of prophylactic doses of nadroparin does not prevent DIC syndrome during first days of chemotherapy, it may limit the intravascular activation of the coagulation system during later chemotherapy.
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http://dx.doi.org/10.1080/10428190290022164DOI Listing
May 2002