H e m a t o lo g y E d u c a t io n - European Hematology Association

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T.M. Hackeng Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University Maastricht, the Netherlands Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:349-354 Thrombosis Tissue factor pathway inhibitor Blood coagulation Blood coagulation proceeds through a tightly regulated cascade system that is triggered by a small stimulus causing activation of a coagulation zymogen into an active enzyme by selective peptide bond cleavages. Subsequently, the activated enzyme with its designated cofactor will activate the next coagulation factor, which again assembles with a cofactor and activates the following coagulation factor and so on, until by sequential amplification at each step, a burst of thrombin is generated. The initiation event occurs when tissue factor comes into contact with blood. Traces of activated factor VII (FVIIa) in blood plasma bind to tissue factor generating the extrinsic tenase complex (TF/FVIIa), which subsequently activates zymogens factor X (FX) and IX (FIX). FXa and its cofactor FVa then form the prothrombinase complex (FVa/FXa) that is the central prothrombin converting complex of the blood coagulation (Figure 1). The initial thrombin generation by prothrombinase, however, is not enough to polymerize fibrinogen effectively but governs major positive feedback reactions through activation of platelets and factors XI, VIII, and V. The activation of FXI and FVIII by thrombin together with FIX activation by FXIa and extrinsic tenase marks the propagation of coagulation, leading to additional prothrombinase and thrombin formation sufficient to generate a fibrin clot (Figure 1). Natural anticoagulants: restoring the balance Procoagulant responses are limited to the site of injury by the presence of several A B S T R A C T The tissue factor pathway inhibitor (TFPI) pathway represents an essential negative regulatory mechanism on thrombin generation in plasma. TFPI is a multimodular Kunitz-type inhibitor that first needs to interact with activated factor X before inhibiting the complex of tissue factor and factor VIIa, the physiological activator complex of blood coagulation. More recently, it has become clear that vitamin K-dependent protein S acts as a cofactor for TFPI in stimulating the initial interaction with factor Xa. TFPI and protein S form a complex in plasma, which likely stabilizes TFPI, and as a result, protein S and TFPI covariate in plasma in health and disease. As TFPI and protein S are constitutively active in plasma, an effective anticoagulant barrier against procoagulant activity is provided. Both protein S and TFPI deficiencies are associated with an increased risk for venous thrombosis, and part of the thrombotic risk associated with protein S deficiency might well be explained by accompanying low levels of TFPI. inhibitors and negative feedback systems. Inhibition of active coagulation enzymes by the serine protease inhibitors (serpins) antithrombin (AT), 1 heparin cofactor II, 2 and α 1-antitrypsin (α 1AT) 3 eliminates free enzymes from plasma, preventing downstream activation of coagulation (Figure 1). In addition, the tissue factor pathway inhibitor (TFPI) regulates the initiation of coagulation by inhibiting both factor Xa (FXa) and the phospholipid-bound complex of tissue factor and factor VIIa (TF-FVIIa). 4 Lastly, traces of thrombin bound to endothelial cell receptor thrombomodulin loose their procoagulant properties and can activate (endothelial cell protein C receptor-bound) protein C. Subsequently, APC will inactivate cofactors FVIIIa 5 and FVa 6 of blood coagulation with the help of its non-enzymatic cofactor protein S, 7 shutting down the intrinsic tenase complex and the prothrombinase complex, calling a halt to thrombin generation, and restoring the haemostatic balance. 8–10 Tissue factor pathway inhibitor TFPI TFPI is a 276 amino acid glycoprotein from the family of Kunitz-type inhibitors. It consists of a negatively charged N-terminus, three consecutive Kunitz-domains, and a positively charged C-terminal tail (Figure 2). 11 TFPI contains several N-linked and O-linked carbohydrate chains, which add approximately 10 kDa to the average amino acid backbone mass of 31,932 Da. TFPI is mainly synthesized in endothelial cells, 12 and each of its structural elements have separate functions in the mechanism of anticoagulant action of TFPI. It was reported that Ser2 in the positively-charged Nterminus is involved in phosphorylation of TFPI, 13 that the first Kunitz-domain binds to Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 349 |
16 th Congress of the European Hematology Association | 350 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) Figure 1. Blood coagulation and its regulation. Initiation: Clotting is initiated by a tissue factor exposed to plasma that subsequently recruits factor VIIa (VIIa) from the circulation. The TF/FVIIa complex activates factor X (Xa) and factor IX (IXa). Xa and factor Va form the prothrombinase complex that generates the first traces of thrombin. Propagation: A small amount of thrombin is not yet sufficient to generate fibrin but instead offers a positive feedback by activation of platelets, factors XI (XIa); more V (Va), and VIII (VIIIa). XIa generates more IXa that together with VIIIa, form the intrinsic tenase. The intrinsic tenase IXa/VIIIa generates more Xa, which together with Va, form more prothrombinase, resulting in a burst of thrombin generation and a subsequent fibrin clot. Termination: As soon as traces of Xa are generated, extrinsic initiator TF/VIIa is shut down by a TFPI/Xa/protein S-dependent process. As a result, clotting now becomes dependent on the propagation loop. Inhibition: Downstream enzyme activity is inhibited by protease inhibitors to prevent systemic coagulation activation. Degradation: Thrombin/thrombomodulin (TM) activates protein C that proteolytically inactivates Va and VIIIa in a protein S-dependent manner, restoring the hemostatic balance. Figure 2. Primary structure of tissue factor pathway inhibitor (TFPI). TFPI is a 276-amino acid glycoprotein. Charged amino acids are indicated in black, P1 residues in red, cysteines in disulfide bonds in grey. Grey diamonds indicate N-linked glycosylation sites; grey circles indicate O-linked glycosylation sites. Backbone arrows and grey boxed numbers indicate the exon map. Adapted from Girard et al. Nature 1989, 338, 518-20.
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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Table 2. The effect of HLA mismatch
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References 1. Petersdorf EW, Malkki
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neutrophil and platelet recovery an
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Figure 2. One Year-Overall Survival
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infused on day 21. No serious adver
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W, et al. Effect of graft source on
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TRM was higher for patients who rec
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following a myeloablative preparati
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effect. Surprisingly, none of the p
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nancies. Bone Marrow Transplant. 20
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J.G. Gilles Center for Molecular an
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14C12 was humanized by grafting VH
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Table 1. VWD Classification. VWD Su
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Figure 1. Missense mutations found
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associated with an increased bleedi
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49. Brown SA, Eldridge A, Collins P
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leed. These issues are especially i
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estored function. 43,44 A phase I t
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years’ experience of prophylactic
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J.A. Burger Department of Leukemia,
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chemotaxis, migration across vascul
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Regulatory T cells (T reg), identif
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16. Burger JA, Ghia P, Rosenwald A,
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TE, Nowakowski GS, et al. CD49d exp
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andomized trial demonstrating impro
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Conclusions Chemoimmunotherapy has
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with multiple comorbidities (≥ 2)
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Table 2. Treatment recommendation f
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34. Ferrajoli A. The combination of
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to be the source of additional gene
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potential to prevent LSCs from acce
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ABL1 confirms that eradication of d
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65. Fiskus W, Pranpat M, Balasis M,
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alive after 10 years. 11 Hence, CCy
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Any discussion about the definition
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H. Kantarjian J. Cortes Leukemia De
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59%; the CCyR rate was 44%. Among p
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ern era of BCR-ABL1 tyrosine kinase
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the hematopoietic system, 10 nor in
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over the period of 6 weeks, demonst
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Data on clonal changes in the blood
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2006 Feb 1;107(3):924-30. 41. Liang
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demonstrated that changes in osteob
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“Mafia” transgenic mice in whic
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ization. In WASP deficiency, lympho
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Currently the epistatic relationshi
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R. Küppers Institute of Cell Biolo
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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prognosis HL, whilst those with res
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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ity and mortality associated with t
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to azathioprine, and is particularl
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stemming from antibodies against PE
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L. Pasqualucci Institute for Cancer
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cation of molecularly distinct subg
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of cases) 46 and amplifications of
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gene alterations in B cell lymphoma
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W. Wilson National Cancer Institute
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clear distinction among the lymphom
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Treatment strategies in germinal ce
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in ABC DLBCL (Hernandez et al., 201
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DLBCL that mostly occurs in young p
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phoma. J Clin Oncol. 2005;23:5347-5
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Table 1. Diffuse Large B cell Lymph
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sion/relapse are similar to those i
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intensive therapy with curative int
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A. Karsan Genome Sciences Centre an
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Balanced translocations In contrast
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some arm 5q have also been implicat
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(H3K27) methyltransferase, and is a
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38. Starczynowski DT, Morin R, McPh
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G. Garcia-Manero Department of Leuk
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trial evaluating different doses an
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acid. 62 The second was a large mul
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Borthakur G, et al. Cause of death
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P. Krishnamurthy 1 G.J. Mufti 1,2 1
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etween 1995 and 2005. 11 Five hundr
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London, United Kingdom, June 9-12,
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attainment of FDC post DLI. Interes
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myelodysplastic syndromes is associ
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ubiquitous chaperone that promotes
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was thought that they are linked to
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pathologic induction of miR-28 in M
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STATs. Second, levels of HP1 alpha
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72. Irandoust MI, Aarts LH, Roovers
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A.M. Vannucchi Section of Hematolog
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2,559 patients with a diagnosis of
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tant use of aspirin should be caref
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sions at this regard. Based on thes
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in bcr-abl-negative myeloproliferat
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Table 1. Prognostic scoring systems
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Figure 1. Current inhibitors of JAK
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Table 4. A risk-based approach to d
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the flexibility to be adjusted as t
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A. Vacca 1 D. Ribatti 2 1 Departmen
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neovessel building together with MM
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Mevastatin, a specific inhibitor of
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egression of tumor vessels, and app
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diagnosis does not require genetic
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Genetics prognostic tools should be
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sone induction improves outcome of
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Table 1. Conventional chemotherapy
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Novel agents given as consolidation
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dence of peripheral neuropathy, gas
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31. Barlogie B, Tricot G, Anaissie
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Table 1. Major differences between
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first line therapy have shown survi
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Page 312 and 313: Table 1. Clinical signs of possible
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Page 320 and 321: U. Nowak-Göttl 1 R. Junker 1 A. Kr
Page 322 and 323: Based on the data obtained from the
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Page 326 and 327: Table 1. Characteristic features of
Page 328 and 329: Table 2. Mutational spectrum of CDA
Page 330 and 331: megarakaryoblastic leukemia (AMKL)
Page 332 and 333: R.E. Ware Professor and Vice-Chairm
Page 334 and 335: protein, cytokines, and soluble adh
Page 336 and 337: example, improving blood viscosity
Page 338 and 339: 92(9):1266-7. 36. Bensinger TA, Gil
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Page 342 and 343: port have also been used. 5 Combina
Page 344 and 345: Wingard JR, Young J-AH, Boeckh MJ.
Page 346 and 347: K. Rezvani 1 J. Barrett 2 1 Haemato
Page 348 and 349: include the childhood infectious il
Page 350 and 351: Summary Patients undergoing hematop
Page 352 and 353: Table 1. Key issues. In a retrospec
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Page 362 and 363: Figure 4. Regulation of coagulation
Page 364 and 365: T. Baglin Department of Haematology
Page 366 and 367: Figure 1. Illustration of alternati
Page 368 and 369: compared with 3.5% in patients with
Page 370 and 371: 49. Hron G, Kollars M, Binder BR, E
Page 372 and 373: Women receiving vitamin K antagonis
Page 374 and 375: molecular weight heparin as prophyl
Page 376 and 377: eral morbidity and mortality. 17-21
Page 378 and 379: the HOD construct. Furthermore, the
Page 380 and 381: Goals of future murine studies incl
Page 382 and 383: F. Noizat-Pirenne C. Tournamille Et
Page 384 and 385: phenotype. 26 In 2010, we investiga
Page 386 and 387: ody has been involved in DHTR. 37 T
Page 388 and 389: antigen. Cases can be encountered d
Page 390 and 391: S.R. Sloan Harvard Medical School &
Page 392 and 393: We also analyzed patient databases
Page 394 and 395: Index of authors Altman J. 27 Bacig
Page 396 and 397: Cornelissen J. Affiliations to disc
Page 398 and 399: GlaxoSmithKline (Research Support;
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