The role of a low erythropoietin level in the diagnosis of JAK2 exon 12-mutated polycythemia vera Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Stephen E. Langabeer

Plasma adiponectin is a potential biomarker for organ involvement in male Fabry disease patients Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Marina Hovakimyan, Venkata Ajay Narendra Talabattula, Claudia Cozma, Christian Beetz, Arndt Rolfs, Deborah Elstein Abstract Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in GLA. It manifests in hemizygous males and in many heterozygous females. Cardiovascular and renal involvement are frequent. Adiponectin is a circulating hormone that has been linked to numerous disease conditions including heart and kidney failure. In the present pilot study, we investigated plasma adiponectin levels in a cohort of 56 individuals with a genetic diagnosis of Fabry disease. Adiponectin levels did not differ between patients and controls. However, in male patients, significantly decreased adiponectin levels were associated with cardiovascular manifestation, while increased levels were associated with renal involvement. Similar trends in female patients did not reach statistical significance. Lyso-Gb3, a metabolite with good diagnostic/screening performance, was not indicative of organ involvement. In combination, adiponectin and Lyso-Gb3 may be of value for identification and stratification of Fabry patients. A potential additional relevance for prognosis and monitoring should be addressed by future studies in larger cohorts.

Platelet function defects in patients with Gaucher disease on long term ERT- implications for evaluation at bleeding challenges Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Veroniki Komninaka, Konstantina Repa, Theodoros Marinakis, Abraham Pouliakis, Theodora Koutsouri, Dimitrios Tsokanas, Pagona Flevary, Ersi Voskaridou, Marianna Politou

Hereditary xerocytosis - spectrum and clinical manifestations of variants in the PIEZO1 gene, including co-occurrence with a novel β-globin mutation Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Karolina Maciak, Anna Adamowicz-Salach, Alicja Siwicka, Jaroslaw Poznanski, Tomasz Urasinski, Danuta Plochocka, Monika Gora, Beata Burzynska Abstract Hereditary xerocytosis (HX) is a rare, autosomal dominant congenital hemolytic anemia (CHA) characterized by erythrocyte dehydration with presentation of various degrees of hemolytic anemia. HX is often misdiagnosed as hereditary spherocytosis or other CHA. Here we report three cases of suspected HX and one case of HX associated with β-thalassemia. Sanger method was used for sequencing cDNA of the PIEZO1 gene. Variants were evaluated for potential pathogenicity by MutationTaster, PROVEAN, PolyPhen-2 and M-CAP software, and by molecular modeling. Four different variants in the PIEZO1 gene were found, including three substitutions (p.D669H, p.D1566G, p.T1732 M) and one deletion (p.745delQ). In addition, in the patient with the p.T1732 M variant we detected a 12-nucleotide deletion in the β-globin gene leading to a deletion of amino acids 62AHGK65. The joint presence of mutations in two different genes connected with erythrocytes markedly aggravated the presentation of the disease. Bioinformatic analysis and molecular modeling strongly indicated likely deleterious effects of all four PIEZO1 variants, but co-segregation analysis showed that the p.D1566G substitution is in fact non-pathogenic. Identification of causative mutations should improve the diagnosis and management of HX and provide a new insight into the molecular basis of this complex red blood cell abnormality.

Allergy and inhibitors in hemophilia - a rare complication with potential novel solutions Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Sarina Levy-Mendelovich, Tami Livnat, Assaf Arie Barg, Mona Kidon, Tami Brutman-Barazani, Gili Kenet Abstract Introduction Hemophilia is a rare bleeding disorder caused by a deficiency of the plasma coagulation factors VIII and IX (hemophilia A [HA] and hemophilia B [HB], respectively). Replacement therapy with clotting factor concentrates is the mainstay of treatment. Unlike in patients with HB, anaphylaxis in patients with HA is extremely rare. Methods A retrospective study of prospectively collected data on patients with hemophilia who experienced anaphylaxis was conducted in our center. Demographic and clinical data were collected, and laboratory workups that included thrombin generation were conducted. Results Our first patient underwent successful immune tolerance induction (ITI) following the administration of rituximab. The second patient was transitioned to emicizumab. The third patient receives recombinant activated VIIa (rFVIIa) on demand. Thrombin generation was performed following current medical management protocols for supporting hemostasis. Discussion Our case series illustrates the difficulty in managing patients with anaphylaxis to replacement therapy. In the era of novel therapies, such as emicizumab, the management of HA patients who experience anaphylaxis to replacement therapy is becoming easier and may obviate the need for ITI. Current treatment strategies for HB patients with such anaphylaxis, however, are limited to rFVIIa, and it continues to pose a challenge.

Polymorphisms in genes that affect the variation of lipid levels in a Brazilian pediatric population with sickle cell disease: rs662799 APOA5 and rs964184 ZPR1 Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Thaisa Netto Souza Valente-Frossard, Nilcemar Rodrigues Carvalho Cruz, Fernanda Oliveira Ferreira, Andre Rolim Belisario, Brisa Machado Pereira, Antônio Frederico de Freitas Gomides, Glaucia Aparecida Domingos Resende, Aline Menezes Carlos, Helio Moraes-Souza, Cibele Velloso-Rodrigues Abstract This cross-sectional study investigated associations between SNPs in metabolizing lipid genes, alpha-thalassemia and laboratory parameters in two forms of sickle cell disease (SCD), sickle cell anemia (SCA) and hemoglobin SC disease (HbSC) in a pediatric population. Among the groups SCA and HbSC was found a higher proportion of increased triglycerides (TG) in SCA. High levels of TG were significantly associated with lower hemoglobin (p = 0.006) and HDL-C (p = 0.037), higher white blood cell count (p = 0.027), LDH (p = 0.004) and bilirubins (p < 0.05) in SCD. Patients with HDL-C ≤40 mg/dL had higher markers hemolytic levels. Therapy of HU significantly influenced several hematological and biochemical parameters but not lipid fractions. Genotypes of the APOA5 rs662799 were not associated with lipid levels. The G-risk allele rs964184/ZPRI ZNF259/ZPR1 gene (GC + GG genotypes) was associated with increased levels of TG in children ≥10 years old (p = 0.045) and the atherogenic ratio TG/HDL-C (p = 0.032) in SCD. The use of HU improves levels of hemolysis and inflammation markers in SCD with high TG and, while not interfering with lipid levels, seems to overlap the effect of the G-risk allele in on them. This study reported for the first time that rs964184 SNP could be a genetic modifier of TG in SCD.

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Oyebimpe O. Adesina, Isaac C. Jenkins, Qian V. Wu, Ellen B. Fung, Radhika R. Narla, Edward W. Lipkin, Kanika Mahajan, Barbara A. Konkle, Rebecca Kruse-Jarres Abstract People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 μg/mmol during vaso-occlusive crises to 2.62 μg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

High red blood cell distribution width might predict thrombosis in essential thrombocythemia and polycythemia vera Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Ivan Krečak, Filip Krečak, Velka Gverić-Krečak

White blood cell labeling with Technetium-99m (99mTc) using red blood cell extracellular vesicles-mimetics Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Seung Hyun Son, Ji Min Oh, Prakash Gangadaran, Hyun Dong Ji, Ho Won Lee, Ramya Lakshmi Rajendran, Se Hwan Baek, Arunnehru Gopal, Senthilkumar Kalimuthu, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn Abstract Background Extracellular vesicles, have gained increasing attention for their application in drug delivery. Here, we developed a novel method for radiolabeling WBCs with 99mTc using RBC-derived extracellular vesicles -mimetics (EVMs), and monitored in vivo inflammation tracking of 99mTc-WBC using gamma camera in acute inflammation mouse model. Methods Engineered EVMs from RBCs were produced by a one-step extrusion method. RBC-EVMs were analyzed by NTA and TEM. Cells were labeled with 99mTc by using 99mTc-RBC-EVMs. Inflammation mice model was prepared and confirmed by 18F-FDG PET/CT. 99mTc-WBCs were injected in mice, and their biodistribution was analyzed by gamma camera. Finding The radiochemical purity of 99mTc-RBC-EVMs was 100%. The 99mTc-labeling did't affect the size and morphology. The 99mTc in the cytoplasm of RBC-EVMs was successfully confirmed by high angle annular dark field STEM (scanning transmission electron microscope). Cells were successfully labeled with 99mTc using 99mTc-RBC-EVMs, and the counts per minute was increased in dose- and time-dependent manners. The 18F-FDG PET/CT images confirmed establishment of acute inflammation (left mouse foot). 99mTc-WBCs showed higher uptake in the inflamed foot than non-inflamed foot. Interpretation This novel method for radiolabeling WBCs using RBC-EVMs. 99mTc labeling may be a feasible method to monitor the in vivo biodistribution of cells.

Prevalence and predictive factors of splenic sequestration crisis among 423 pediatric patients with sickle cell disease in Tunisia Publication date: February 2020 Source: Blood Cells, Molecules, and Diseases, Volume 80 Author(s): Monia Ben Khaled, Monia Ouederni, Yosra Mankai, Samia Rekaya, Ilhem Ben Fraj, Nawel Dhouib, Ridha Kouki, Fethi Mellouli, Mohamed Bejaoui Abstract This study was aimed to identify the predictors of splenic sequestration crisis (SSC) among pediatric patients with sickle cell disease (SCD). This prognosis study was carried out in the pediatric immuno-hematology unit, over 20 years (1998 to 2017), enrolling patients with SCD. The cox model was used in multivariate analysis. Among 423 patients with SCD (240 S/S phenotype, 128 S/B0, 30 S/B+, 14 S/O arab and 11 S/C), 150(35.4%) had at least one episode of SSC. The average age of patients at the first episode was 48.3 months ± 32.4(2–168). Recurrence of SSC was observed in 117 patients (78%). Spleen size ≥3 cm at baseline was the strongest predictor of SSC occurrence (HR = 7.27, CI: 4.01–13.20, p = 0.05) and recurrence (HR = 6.37, CI: 1,46–27.83, p = 0.01). Pallor revealing the disease, age at onset of symptoms <24 months and reticulocytosis ≥300,000/mm3 increased the risk of SSC. Pain crisis revealing the disease as well as neutrophilia was associated with a lower risk of SSC. In conclusion, this study confirmed the high prevalence of SSC in SCD and the high frequency of recurrence after a first episode. The SSC occurrence and recurrence were intimately linked to the presence of splenomegaly, chronic pallor revealing the disease as well as reticulocytosis.