E-ISSN: 1308-5263
Turkish Journal of Hematology - Turk J Hematol: 36 (4)
Volume: 36  Issue: 4 - 2019
FULL TEXT
1. Turkish Journal of Hematology (Volume: 36 Issue: 4, 2019)

Pages I - II

REVIEW
2. Diagnostic Testing for Differential Diagnosis in Thrombotic Microangiopathies
Gina Zini, Raimondo De Cristofar
doi: 10.4274/tjh.galenos.2019.2019.0165  Pages 222 - 229
Thrombotic microangiopathies (TMAs) are multiple disease entities with different etiopathogeneses, characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytosis, variable symptoms including fever, and multi-organ failure such as mild renal impairment and neurological deficits. The two paradigms of TMAs are represented on one hand by acquired thrombotic thrombocytopenic purpura (TTP) and on the other by hemolytic uremic syndrome (HUS). The differential diagnosis between these two paradigmatic forms of TMA is based on the presence of either frank renal failure in HUS or a severe deficiency (<10%) of the zincprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in TTP. ADAMTS13 is an enzyme involved in the proteolytic processing of von Willebrand factor (vWF), and its deficiency results in formation of highmolecular-weight vWF-rich microthrombi in the environment of the microvasculature. The presence of these ultra-large vWF multimers in the microcirculation can recruit platelets, promoting multi-organ ischemic lesions. The presence of ADAMTS13 activity at >10% could rule out the presence of a TTP form. However, it is often difficult to differentiate either a TTP or HUS clinical scenario presenting with typical symptoms of TMA. There are in fact several additional diagnoses that should be considered in patients with ADAMTS13 activity of >10%. Widespread inflammation with endothelial damage and adverse reactions to drugs play a central role in the pathogenesis of several forms of TMA, and in these cases, the differential diagnosis should be directed at the underlying disease. Hence, a correct etiologic diagnosis of TMA should involve a critical illness, cancer-associated TMA, drug-induced TMA, and hematopoietic transplant-associated TMA. A complete assessment of all the possible etiologies for TMA symptoms, including acquired or congenital TTP, will allow for a more accurate diagnosis and application of a more appropriate treatment.

RESEARCH ARTICLE
3. A Multi-Center Study on the Efficacy of Eltrombopag in Management of Refractory Chronic Immune Thrombocytopenia: A Real-Life Experience
Demet Çekdemir, Serkan Güvenç, Füsun Özdemirkıran, Ali Eser, Tayfur Toptaş, Vildan Özkocaman, Handan Haydaroğlu Şahin, Esra Ermiş Turak, Ramazan Esen, Melda Cömert, Sevil Sadri, Müzeyyen Aslaner, Bahar Uncu Ulu, Abdullah Karakuş, Derya Selim Batut, İnci Alacacıoğlu, Demet Aydın, Atakan Tekinalp, Sinem Namdaroğlu, Funda Ceran
doi: 10.4274/tjh.galenos.2019.2018.0307  Pages 230 - 237
Objective: The aim of the present study was to evaluate the efficacy and safety of eltrombopag, an oral thrombopoietin receptor agonist, in patients with chronic immune thrombocytopenia (ITP).
Materials and Methods: A total of 285 chronic ITP patients (187 women, 65.6%; 98 men, 34.4%) followed in 55 centers were enrolled in this retrospective cohort. Response to treatment was assessed according to platelet count (/mm3) and defined as complete (platelet count of >100,000/mm3), partial (30,000-100,000/mm3 or doubling of platelet count after treatment), or unresponsive (<30,000/mm3). Clinical findings, descriptive features, response to treatment, and side effects were recorded. Correlations between descriptive, clinical, and hematological parameters were analyzed.
Results: The median age at diagnosis was 43.9±20.6 (range: 3-95) years and the duration of follow-up was 18.0±6.4 (range: 6-28.2) months. Overall response rate was 86.7% (n=247). Complete and partial responses were observed in 182 (63.8%) and 65 (22.8%) patients, respectively. Thirty-eight patients (13.4%) did not respond to eltrombopag treatment. For patients above 60 years old (n=68), overall response rate was 89.7% (n=61), and for those above 80 years old (n=12), overall response rate was 83% (n=10). Considering thrombocyte count before treatment, eltrombopag significantly increased platelet count at the 1st, 2nd, 3rd, 4th, and 8th weeks of treatment. As the time required for partial or complete response increased, response to treatment was significantly reduced. The time to reach the maximum platelet levels after treatment was quite variable (1-202 weeks). Notably, the higher the maximum platelet count after eltrombopag treatment, the more likely that side effects would occur. The most common side effects were headache (21.6%), weakness (13.7%), hepatotoxicity (11.8%), and thrombosis (5.9%).
Conclusion: Results of the current study imply that eltrombopag is an effective therapeutic option even in elderly patients with chronic ITP. However, patients must be closely monitored for response and side effects during treatment. Since both response and side effects may be variable throughout the follow-up period, patients should be evaluated dynamically, especially in terms of thrombotic risk factors.

4. Certain Killer Immunoglobulin-Like Receptor (KIR)/KIR HLA Class I Ligand Genotypes Influence Natural Killer Antitumor Activity in Myelogenous Leukemia but Not in Acute Lymphoblastic Leukemia: A Case Control Leukemia Association Study
Viktoria Varbanova, Snejina Mihaylova, Elissaveta Naumova, Anastasiya Petrova Mihaylova
doi: 10.4274/tjh.galenos.2019.2019.0079  Pages 238 - 246
Objective: Natural killers (NK) cell function is mainly controlled by the expression of killer immunoglobulin-like receptors (KIRs) and their ligation with the corresponding ligands. The objective of this study was to investigate the putative association of KIRs, HLA class I ligands, and KIR/ligand combinations with rates of development of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML).
Materials and Methods: The KIR/HLA I genotypes of 82 patients with leukemia (ALL, n=52; AML, n=17; and CML, n=13) were determined by PCR-SSP method and compared with genotypes of healthy controls (n=126).
Results: KIR genotype frequency differed significantly between myelogenous leukemia patients and healthy controls for KIR2DL5A (17.6% vs. 47.7%, p=0.02), KIR3DS1 (17.6% vs. 47.6%, p=0.02), and KIR2DS4*001 (36.6% vs. 20.2%, p=0.017). The incidence of homozygous HLA-BBw4 (31.0% vs. 12.5%, p=0.042) and HLABw4Thr80 Thr80 (13.0% vs. 1.2%, p=0.01) was significantly elevated in myeloid leukemia patients compared to healthy controls. KIR/HLA class I ligand profile KIR3DS1(+)/L (-) was decreased and KIR3DL2(+)/ HLA-A3/11(-) was increased among myeloid leukemia cases compared to controls.
Conclusion: These data suggest that the activity of NK cells as determined by inherited KIR/HLA class I ligand polymorphisms influences the susceptibility to myelogenous leukemia, but not to lymphoblastic leukemia. Additionally, the KIR genotype characterized by the absence of the inhibitory KIR2DL2 and the activating KIR2DS2 and KIR2DS3 (ID2) was found at a lower frequency in patients compared to controls, which confirmed the need for complex analysis based on all possible KIR/HLA class I ligand polymorphism combinations.

5. Stress-Induced Premature Senescence Promotes Proliferation by Activating the SENEX and p16INK4a/Retinoblastoma (Rb) Pathway in Diffuse Large B-Cell Lymphoma
Jiyu Wang, Zhitao Wang, Huiping Wang, Zhixiang Wanyan, Ying Pan, Fengfeng Zhu, Qianshan Tao, Zhimin Zhai
doi: 10.4274/tjh.galenos.2019.2019.0117  Pages 247 - 254
Objective: Cellular senescence has been thought to be an important barrier to tumor formation. Recent studies have shown that stressinduced premature senescence (SIPS) can promote partial tumor invasion, but how SIPS affects diffuse large B-cell lymphoma (DLBCL) remains inconclusive. This study aimed to address that issue.
Materials and Methods: The immunophenotype of the LY8 cell line was measured with flow cytometry. SIPS induced by tert-butyl hydroperoxide (tBHP) was detected by senescence β-galactosidase staining. Cell proliferation was analyzed with CCK8 and expression levels of ARHGAP18 (SENEX gene-encoding protein), p16/p21, and
Rb/pRb were measured with western blot. LY8 cells were transfected with SENEX-SiRNA/NC and verified by western blot.
Results: Our results suggested that the immunophenotype of the LY8 cell line is CD19-, CD20-, and CD10-positive and the immunoglobulin light chain is the kappa type. The cellular senescence model of DLBCL could be successfully induced by 30 µM tBHP. ARHGAP18, p21, p16, and Rb protein levels were significantly increased but the level of pRb expression was decreased in the SIPS group compared with other groups. Meanwhile, the proliferation rate was increased in the SIPS group more than other tBHP groups. Furthermore, the expressions of p21 and p16 were significantly decreased in the SENEX-SiRNA group compared with the negative control group.
Conclusion: SIPS formation activates ARHGAP18 and the p16/Rb pathway and promotes DLBCL cell proliferation. Furthermore, SENEX activates the p16 pathway in DLBCL. SIPS promotes proliferation by activating SENEX and the p16/Rb pathway in DLBCL. SENEX-related SIPS may serve as an important target for relapsed/refractory DLBCL therapy.

6. Differentiation Potential and Tumorigenic Risk of Rat Bone Marrow Stem Cells Are Affected By Long-Term In Vitro Expansion
Erdal Karaöz, Filiz Tepeköy
doi: 10.4274/tjh.galenos.2019.2019.0100  Pages 255 - 265
Objective: Mesenchymal stem cells (MSCs) have the capacity for extensive expansion and adipogenic, osteogenic, chondrogenic, myogenic, and neural differentiation in vitro. The aim of our study was to determine stemness, differentiation potential, telomerase activity, and ultrastructural characteristics of long-term cultured rat bone marrow (rBM)-MSCs.
Materials and Methods: rBM-MSCs from passages 3, 50, and 100 (P3, P50, and P100) were evaluated through immunocytochemistry, reverse transcription-polymerase chain reaction, telomerase activity assays, and electron microscopy.
Results: A dramatic reduction in the levels of myogenic markers actin and myogenin was detected in P100. Osteogenic markers Coll1, osteonectin (Sparc), and osteocalcin as well as neural marker c-Fos and chondrogenic marker Coll2 were significantly reduced in P100 compared to P3 and P50. Osteogenic marker bone morphogenic protein-2 (BMP2) and adipogenic marker peroxisome proliferatoractivated receptor gamma (Pparγ) expression was reduced in late passages. The expression of stemness factor Rex-1 was lower in P100, whereas Oct4 expression was decreased in P50 compared to P3 and P100. Increased telomerase activity was observed in longterm cultured cells, signifying tumorigenic risk. Electron microscopic evaluations revealed ultrastructural changes such as smaller number of organelles and increased amount of autophagic vacuoles in the cytoplasm in long-term cultured rBM-MSCs.
Conclusion: This study suggests that long-term culture of rBMMSCs leads to changes in differentiation potential and increased tumorigenic risk.

7. Hepatitis B Reactivation Rate and Fate Among Multiple Myeloma Patients Receiving Regimens Containing Lenalidomide and/or Bortezomib
Pınar Ataca Atilla, Merih Yalçıner, Erden Atilla, Ramazan İdilman, Meral Beksaç
doi: 10.4274/tjh.galenos.2019.2019.0103  Pages 266 - 273
Objective: Reactivation of the hepatitis B virus (HBV) refers to an increase in HBV replication in a patient with inactive or resolved HBV. In this retrospective study, our aim is to present and compare HBV reactivation in multiple myeloma (MM) patients who received lenalidomide and/or bortezomib at any time during treatment, evaluate the factors associated with reactivation, and demonstrate the outcome of patients.
Materials and Methods: We evaluated 178 MM patients who received lenalidomide (n=102) and/or bortezomib (n=174) during their treatment schedules. The HBsAg, anti-HBc, anti-HBs, HBeAg, and anti-HBe were detected by chemiluminescence by ARCHITECT lab analyzers using commercially available kits (Abbott, USA). HBV-DNA titers were determined by quantitative PCR. The results were evaluated by IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA).
Results: HBV reactivation was diagnosed in 6 patients (3%) after bortezomib and in 8 patients (8%) after bortezomib and lenalidomide. Three of the patients in each group had HBsAg+, HBeAg+, AntiHBeAg-, AntiHBc-, and AntiHBS+ status, whereas 5 patients in the bortezomib- and lenalidomide-treated group and 3 patients in the bortezomib-treated group had HBsAg-, HBeAg-, AntiHBeAg-, AntiHBc-, and AntiHBS+ status prior to treatment. There were no statistical differences observed between HBV reactivation in the bortezomib-treated or bortezomib- and lenalidomide-treated groups in terms of age at diagnosis, sex, International Staging System subtype, frequency of extramedullary disease, dialysis requirement, or receiving of autologous stem cell transplantation. In patients who received antiviral prophylaxis, a higher incidence of HBV reactivation was detected in HBsAg-positive patients compared to HBsAg-negative patients (4/4, 100% vs. 2/7, 29%; p=0.045). The 3-year and 5-year overall survival rates were similar in patients with or without HBV reactivation (83% vs. 84%, 73% vs. 74%, p=0.84).
Conclusion: Close follow-up is recommended for not only HBsAgpositive but also HBsAg-negative patients.

BRIEF REPORT
8. Fertility in Patients with Thalassemia and Outcome of Pregnancies: A Turkish Experience
Burcu Akıncı, Akkız Şahin Yaşar, Nihal Özdemir Karadaş, Zuhal Önder Siviş, Hamiyet Hekimci Özdemir, Deniz Yılmaz Karapınar, Can Balkan, Kaan Kavaklı, Yeşim Aydınok
doi: 10.4274/tjh.galenos.2019.2019.0025  Pages 274 - 277
Objective: In recent years, the rates of marriage and pregnancy are increasing in patients with thalassemia major. The aim of the present study was to investigate the fertility rate of thalassemic patients and the course of pregnancies in terms of mother and infant health. Materials and Methods: In this observational study patients with major hemoglobinopathy were evaluated regarding marital status, the need for assisted reproductive techniques, fertility rate, iron status, and pregnancy complications. Results: Seventeen female patients gave birth to 21 healthy infants. About one-third of the patients needed assisted reproductive techniques. Thalassemia major patients showed increased serum ferritin levels from 1203±1206 µg/L at baseline to 1880±1174 µg/L at the end of pregnancy. All babies are still alive and healthy. Conclusion: Pregnancy in patients with thalassemia can be safe for the mother and newborn with close monitoring and a multidisciplinary approach.

IMAGES IN HEMATOLOGY
9. Gingival Leukemic Infiltration in Chronic Lymphocytic Leukemia
Karima Kacem, Sami Zriba, Myriam Saadi, Raoudha Doghri
doi: 10.4274/tjh.galenos.2019.2018.0358  Pages 278 - 279
Abstract |Full Text PDF

10. Auer Rod-Like Inclusions in B-Cell Prolymphocytic Leukemia
Yantian Zhao, Juan Lv
doi: 10.4274/tjh.galenos.2018.2018.0192  Pages 280 - 281
Abstract |Full Text PDF

LETTER TO EDITOR
11. An Update of the Definition of Transfusion-Related Acute Lung Injury
Alexander P.j. Vlaar, Steve Kleinman
doi: 10.4274/tjh.galenos.2019.2019.0279  Pages 282 - 283
Abstract |Full Text PDF

12. Overwhelming Asplenic Sepsis due to Babesiosis
Chakra P. Chaulagain
doi: 10.4274/tjh.galenos.2019.2019.0080  Pages 284 - 285
Abstract |Full Text PDF

13. Isolated Mediastinal Myeloid Sarcoma after NPM1-Positive Pediatric Acute Myeloid Leukemi
Özlem Tüfekçi, Şebnem Yılmaz, Melek Erdem, Birsen Baysal, Hale Ören
doi: 10.4274/tjh.galenos.2019.2018.0434  Pages 285 - 286
Abstract |Full Text PDF

14. Acute B Lymphoblastic Leukemia Developing in Patients with Multiple Myeloma: Presentation of Two Cases
Jiang Mei, Li Na, Ji Dexiang, Li Fei, Zhang Zhanglin
doi: 10.4274/tjh.galenos.2019.2019.0018  Pages 287 - 289
Abstract |Full Text PDF

15. ALK+ Anaplastic Large Cell Lymphoma of Null Cell Phenotype with Leukemic Transformation and Leukemoid Reaction
Shih-Sung Chuang, Yen-Chuan Hsieh, Hung-Chang Wu
doi: 10.4274/tjh.galenos.2019.2019.0021  Pages 289 - 290
Abstract |Full Text PDF

16. Thirty-Two Case Reports of Synchronous Hematological Malignancy and Solid Tumor
Sha Liu, Xudong Wei, Yuanyuan Xiong, Ruihua Mi, Qingsong Yin
doi: 10.4274/tjh.galenos.2019.2019.0071  Pages 291 - 294
Abstract |Full Text PDF

17. Successful Outcome of a Case of Acute Myeloid Leukemia with t(8;21)/AML-ETO Following Langerhans Cell Histiocytosis
Guangqiang Meng, Jingshi Wang, Jian Cheng Huang, Yini Wang, Na Wei, Zhao Wang
doi: 10.4274/tjh.galenos.2019.2019.0126  Pages 294 - 296
Abstract |Full Text PDF

18. Breast Implant-Associated Anaplastic Large-Cell Lymphoma: A Case Report
Hakan Kalyon, Erman Öztürk, Sıtkı Tuzlalı, Olga Meltem Akay, Burhan Ferhanoğlu
doi: 10.4274/tjh.galenos.2019.2019.0162  Pages 296 - 299
Abstract |Full Text PDF

19. A Rare Cause of Cyanosis Since Birth: Hb M-Iwate
Birgül Mutlu, Ebru Yılmaz Keskin, Ana Catarina Oliveira, Luis Relvas, Celeste Bento
doi: 10.4274/tjh.galenos.2019.2019.0123  Pages 299 - 301
Abstract |Full Text PDF

20. Hodgkin Lymphoma, Tuberculosis, and Atypical Radiologic Image
Sora Yasri, Viroj Wiwanitkit
doi: 10.4274/tjh.galenos.2019.2019.0291  Pages 301 - 302
Abstract |Full Text PDF

21. Reply from the Authors

Page 302
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22. Author Index

Pages E1 - E3
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23. Subject Index

Pages E4 - E13
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24. Advisory Board of This Issue

Page E14
Abstract |Full Text PDF