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Figure 1. Missense mutations found in index cases with normal and abnormal multimer patterns. The mutations listed are placed at their specific position in the VWF protein. This figure is largely based on the results of the MCMDM-1VWD study, with some additions and deletions due to new insights. 19 was 39 IU/dL. 19 Impaired secretion and increased intracellular retention of synthesized VWF protein seems to be the major mechanism involved in patients with missense mutations. We have expressed 14 mutations found in the MCMDM-1VWD study to evaluate their contribution to the phenotype observed in the patients. We have established that seven mutants, located throughout the VWF gene, contribute to the phenotype on the basis of increased intracellular retention and impaired secretion of VWF compared with wt-VWF, while four mutants are probably causative mutations based on the mild reduction of secreted VWF. 25 Patients with mutations G160W, N166I, or M771I showed a normal VWF propeptide (pp)/VWF:Ag ratio and normal multimer structure. However the VWFpp levels were below the normal range. Reduced levels of VWFpp and VWF:Ag with normal multimer structure suggest that these mutations are responsible for reduced synthesis, rather than increased intracellular retention. 29 Several mutations that were expressed are involved in the loss or gain of a cysteine residue. Four out of five (C2257S, C2304Y, G2441C, and C2477Y) caused marked intracellular retention and loss of HMW multimers in combination with faster migration of multimeric bands. Upon cotransfection with wt-VWF, the defect was largely restored. Tjernberg et al. 30 have described similar results for another mutation (C2362F) involving cysteine residues, located in the same region. Although cysteines in these regions are not directly involved in the dimer- ization and multimerization process of VWF, the mutations do result in slightly abnormal multimer patterns. This is probably due to the fact that the unpaired cysteines lead to changes in the three-dimensional structure. 26,31 Impaired secretion of VWF may also be due to a defect in the WPB formation. Indeed Michaux et al. showed that three type 1 VWD mutations had a delay in the formation of WPB and showed a reduction in the length and number of WPB. 32 Accelerated clearance London, United Kingdom, June 9-12, 2011 Another mechanism that could explain the low VWF plasma levels in type 1 VWD is increased clearance of VWF. Some clearly causative mutations show significantly reduced VWF levels upon expression; however, in cotransfections with wt-VWF, the expression seems normal. This led to the hypothesis that mutations may be involved in faster clearance of the protein. The first report on increased clearance described the rapid disappearance of VWF upon DDAVP infusion in seven patients carrying the combined M740I/R1205H mutations (Type Vicenza). 33 Haberichter et al. 29 identified seven patients with reduced VWF survival predicted by a markedly increased VWFpp/VWF:Ag ratio. In all these seven patients, mutations were identified that have been previously reported with reduced VWF survival, including R1205H, C1130G/F/R, and W1144G. The Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 79 |
16 th Congress of the European Hematology Association majority of the cases with decreased VWF survival is characterized by significantly reduced steady-state VWF:Ag levels, usually below 30 IU/dl. 34,35 The half-life of VWF:Ag is also markedly reduced after DDAVP infusion. The possible contribution of ADAMTS13 proteolysis to the rapid clearance has been postulated. Indeed one mutation, the Y1584C, seems to be linked with increased susceptibility of VWF to ADAMTS13 proteolysis. 36 But detailed analysis of mutations C1130F and C1149R revealed that increased clearance in these cases was not due to increased proteolysis by ADAMTS13. 34 Sialic acid residues on the VWF glycans are known to promote ADAMTS13-mediated proteolysis and also seem to play a role in the clearance of the protein. Asialo-VWF is cleared more rapidly than sialylated VWF in animal models. 37 The Ashwell receptor, an asialoglycoprotein receptor on hepatocytes, is able to bind asialo-VWF 7 , thereby removing it from the circulation. Recent data suggest that the receptor might also be able to bind sialylated glycoproteins, 38 but whether this is the case for VWF remains unknown. The VWFpp/VWF:Ag ratio measured in healthy blood group O subjects indicate that they have a faster VWF clearance than non-O subjects. 39 This suggests that changes in carbohydrate structure of VWF may affect clearance and therefore VWF levels. For the clinical practice, increased clearance might be an important phenotype to be considered. Insight into the survival of VWF after DDAVP infusion is relevant for the treatment of type 1 VWD patients. If the half-life of endogenous circulating VWF after DDAVP treatment is too short, it might be preferable to treat the patient with a VWF concentrate instead of DDAVP infusion. Factors outside the VWF gene The lack of finding a mutation in approximately 35– 40% of the IC in the multicenter studies indicates that also other (environmental) factors outside the VWF gene could influence VWF levels in patients diagnosed with VWD type 1. Also the variability of responses to DDAVP treatment between patients with the same mutation suggests that other factors contribute to the VWF levels. 40 This notion is also reflected in the 2006 VWD classification that no longer restricts the diagnosis VWD to mutations in the VWF gene. 13 Blood groups It has been shown that 66% of the variation in VWF levels is genetically determined and that the ABO blood group locus accounts for 30% of that variation. 41 VWF is one of the few plasma proteins that contain the ABO blood group sugars. The ABH antigens are only attached to the N-linked oligosaccharide chains of VWF. Almost 30 years ago, it was recognized that the ABO blood groups are associated with VWF plasma levels, 42 and this has been confirmed in several other studies. 43 Individuals with blood group O have approximately 25% lower VWF plasma levels compared with non-O individuals. Furthermore, blood group O is overrepresented among VWD type 1 patients. The mechanisms how ABO blood groups are responsible for VWF levels remain unknown. A direct mechanism seems likely as individuals with the Bombay blood group phenotype, who lack expression of the ABH antigens, even have lower plasma levels than individuals with blood group O. 44 Furthermore, the VWF levels correlate with the amounts of A and B antigens present on the VWF molecule. 45,46 The ABH antigens may have an effect on biosynthesis, secretion, clearance of VWF, or a combination thereof. The ABH antigens on VWF do not seem to play a role in synthesis and secretion as the plasma propeptide levels are independent of the ABO blood group. 47 Platelet VWF levels are independent of ABO blood group, which is probably explained by the fact that platelet VWF does not express the ABH antigens. 48 Another study showed that the rise in VWF level after DDAVP treatment appears to be similar between patients with type 1 VWD with different blood groups, suggesting that secretion efficiency is not affected by the blood group antigens. 49 Nossent et al. 47 estimated that the half-life of VWF in controls with blood group O is almost 2 hours shorter compared with non-O blood group controls, and it was shown that in healthy individuals, the VWF half-life after DDAVP administration was shorter in blood group O individuals. 39 Furthermore, the ratio between propeptide and mature VWF, which are released in an equimolar ratio, is increased in individuals that have blood group O compared with non-O individuals. 35,47 These observations suggest that the ABH antigens on VWF determine its clearance rate, where blood group O-VWF might be cleared faster compared with non-O VWF. However, this supposition is not yet challenged in a direct comparison, nor have the molecular mechanisms been elucidated. One VWF mutation seems to be linked with the ABO blood group. In the UK study, the Y1584C mutation was found together with blood group O in 95% of the VWD cases, 21 and in another study, 11 out of the 12 IC had blood group O, 50 a higher proportion than the overall 77% prevalence of group O reported among type 1 VWD. 51 Age In preterm neonates, the VWF levels are moderately low, but at birth, the levels rise above adult norms. Stress in the neonate during the delivery might be the cause of this rise, since it is known that stress or exercise can induce significant release of VWF. 52 Several other reports have shown that with age, the VWF levels slowly increase, with a rate of approximately 10 IU/dl per decade. 51,53 This increase during life has an influence on the diagnosis in relation to age. Diagnosis of VWD at a young age might be questioned later in life. Genetic modifiers Several studies have shown that locus heterogeneity may play a role in the severity of the VWD type 1 phenotype. Among type 1 VWD patients, the frequency of the integrin a 2b 1 807C allele, which is associated with low receptor density, was found significantly higher than in the normal population. 54 Low density of the integrin a 2b 1 might result in less efficient binding of platelets to collagen and may explain the variability between bleeding symptoms in patients with the same VWF levels. Indeed Kunicki et al. 55 found that this haplotype was | 80 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
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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
Page 38 and 39: ing FLT3-ITD, wild-type NPM1, or bo
Page 40 and 41: ciated with gene activation, via th
Page 42 and 43: leukemia with inv(16) and t(8;21):
Page 44 and 45: 99. Parsons DW, Jones S, Zhang X, e
Page 46 and 47: abnormalities, some of which are al
Page 48 and 49: file. 27,31 Thus, the double gene-m
Page 50 and 51: karyotype represents a distinct gen
Page 52 and 53: Table 1. Meta-analysis of 23 random
Page 54 and 55: A recent study by the Center for In
Page 56 and 57: Patients with HLA-matched related o
Page 58 and 59: After allogeneic HSCT, an autologou
Page 60 and 61: A. Bacigalupo Ospedale San Martino,
Page 62 and 63: Table 2. The effect of HLA mismatch
Page 64 and 65: References 1. Petersdorf EW, Malkki
Page 66 and 67: neutrophil and platelet recovery an
Page 68 and 69: Figure 2. One Year-Overall Survival
Page 70 and 71: infused on day 21. No serious adver
Page 72 and 73: W, et al. Effect of graft source on
Page 74 and 75: TRM was higher for patients who rec
Page 76 and 77: following a myeloablative preparati
Page 78 and 79: effect. Surprisingly, none of the p
Page 80 and 81: nancies. Bone Marrow Transplant. 20
Page 82 and 83: J.G. Gilles Center for Molecular an
Page 84 and 85: 14C12 was humanized by grafting VH
Page 86 and 87: Table 1. VWD Classification. VWD Su
Page 90 and 91: associated with an increased bleedi
Page 92 and 93: 49. Brown SA, Eldridge A, Collins P
Page 94 and 95: leed. These issues are especially i
Page 96 and 97: estored function. 43,44 A phase I t
Page 98 and 99: years’ experience of prophylactic
Page 100 and 101: J.A. Burger Department of Leukemia,
Page 102 and 103: chemotaxis, migration across vascul
Page 104 and 105: Regulatory T cells (T reg), identif
Page 106 and 107: 16. Burger JA, Ghia P, Rosenwald A,
Page 108 and 109: TE, Nowakowski GS, et al. CD49d exp
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Page 112 and 113: Conclusions Chemoimmunotherapy has
Page 114 and 115: with multiple comorbidities (≥ 2)
Page 116 and 117: ment was finished in all 100 patien
Page 118 and 119: Table 2. Treatment recommendation f
Page 120 and 121: 34. Ferrajoli A. The combination of
Page 122 and 123: to be the source of additional gene
Page 124 and 125: potential to prevent LSCs from acce
Page 126 and 127: ABL1 confirms that eradication of d
Page 128 and 129: 65. Fiskus W, Pranpat M, Balasis M,
Page 130 and 131: alive after 10 years. 11 Hence, CCy
Page 132 and 133: each arm). A minimal change in myel
Page 134 and 135: Any discussion about the definition
Page 136 and 137: 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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68. Coetzee T, Fujita N, Dupree J,
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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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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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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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transplantation, 7,91 and generally
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methylation characterizes juvenile
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Table 1. Clinical signs of possible
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Table 4. Distribution of CSF involv
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ently results in a less than 5% cum
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90. German-Austrian-Swiss ALL-BFM S
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U. Nowak-Göttl 1 R. Junker 1 A. Kr
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Based on the data obtained from the
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59. Male C, Chait P, Ginsberg JS, e
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Table 1. Characteristic features of
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Table 2. Mutational spectrum of CDA
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megarakaryoblastic leukemia (AMKL)
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R.E. Ware Professor and Vice-Chairm
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protein, cytokines, and soluble adh
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example, improving blood viscosity
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92(9):1266-7. 36. Bensinger TA, Gil
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London, United Kingdom, June 9-12,
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port have also been used. 5 Combina
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Wingard JR, Young J-AH, Boeckh MJ.
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K. Rezvani 1 J. Barrett 2 1 Haemato
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include the childhood infectious il
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Summary Patients undergoing hematop
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Table 1. Key issues. In a retrospec
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invasive method to assess iron over
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stitution but even with optimal sub
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T.M. Hackeng Department of Biochemi
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and inhibits FVIIa, and that the se
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Figure 4. Regulation of coagulation
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T. Baglin Department of Haematology
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Figure 1. Illustration of alternati
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compared with 3.5% in patients with
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49. Hron G, Kollars M, Binder BR, E
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Women receiving vitamin K antagonis
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molecular weight heparin as prophyl
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eral morbidity and mortality. 17-21
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the HOD construct. Furthermore, the
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Goals of future murine studies incl
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F. Noizat-Pirenne C. Tournamille Et
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phenotype. 26 In 2010, we investiga
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ody has been involved in DHTR. 37 T
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antigen. Cases can be encountered d
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S.R. Sloan Harvard Medical School &
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We also analyzed patient databases
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Index of authors Altman J. 27 Bacig
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Cornelissen J. Affiliations to disc
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GlaxoSmithKline (Research Support;
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