Acute rhabdomyolysis in hepatitis-associated aplastic anemia patient undergoing allogeneic hematopoietic stem-cell transplantation: case report and literature review.

BACKGROUND: Hepatitis-associated aplastic anemia (HAAA) is a specific type of aplastic anemia, and hematopoietic stem-cell transplantation (HSCT) is recommended as the first-line. Acute rhabdomyolysis (AR) during hematopoietic stem-cell transplantation (HSCT) is a rare, serious complication, with only 10 cases reported in the world so far. CASE PRESENTATION: Herein, we present a case of AR developing during HLA-haploidentical HSCT in a 55-year-old man who suffered from HAAA. On day 7 after stem cell transfusion, the patient reported a muscle pull in thigh and complained of muscle swelling, pain and change in urine color. Despite the timely diagnosis (based on the levels of myoglobin and creatine kinase, and muscle MRI findings, etc.) and rapid hydration and alkalization, the situation progressed dramatically, and the patient died of multi-organ failure during the preparation for continuous renal replacement therapy (CRRT). Five days after his death, the whole-exome sequencing result confirmed that the patient had a germline missense mutation in SCN4A I 1545 V and ACTN3 R577X. CONCLUSION: AR is a rare but threatening complication during HSCT, especially in cases with kidney dysfunction. The creatine kinase level may not truly and completely reflect the severity and prognosis for cases with localized lesion. We suggest that genetic analysis should be performed for better understanding the pathological changes of AR during HSCT, especially for patients with bone marrow failure.

Healthcare costs and resource utilization in patients with severe aplastic anemia in the US.

Purpose: This study aimed to evaluate the healthcare resource utilization (HCRU) and costs for patients with severe aplastic anemia (SAA) using US claims data. Methods: This retrospective, observational database study analyzed claims data from the Truven MarketScan databases. SAA patients aged ≥2 years identified between 2014 and 2017 who were continuously enrolled for 6 months before their first SAA treatment or blood transfusion, with a ≥6-month follow-up, were included. Baseline demographics and comorbidities were evaluated. Monthly all-cause and SAA-related HCRU and direct costs in the follow-up period were analyzed and differences were presented for all patients and across age groups. Results: With an average follow-up period of 21.5 months, 939 patients were included in the study. Monthly all-cause and SAA-related HCRU [mean (SD)] were 1.65 days (2.61 days) and 0.18 days (0.70 days) for length of stay, 0.18 (0.23) and 0.01 (0.04) for hospital admissions, 0.25 (0.30) and 0.02 (0.07) for ER visits, 2.24 (1.40) and 0.46 (0.99) for office visits, and 2.90 (2.64) and 0.55 (1.31) for outpatient visits, respectively. On average, SAA patients received 0.15 (0.57) blood transfusions per month. Mean monthly all-cause direct costs were $28,280 USD ($36,127) [US dollars, mean (SD)]. Direct costs related to admissions were $11,433 USD (SD $25,040), followed by $624 USD ($1,703) for ER visits, $528 USD ($694) for office visits, $7,615 USD ($13,273) for outpatient visits, and $5,998 USD ($11,461) for pharmacy expenses. Monthly SAA-related direct costs averaged $7,884 USD (SD $16,254); of these costs, $1,608 USD ($7,774) were from admissions, $47 USD ($257) from ER visits, $127 USD ($374) from office visits, $1,462 USD ($4,994) from outpatient visits, and $4,451 USD ($10,552) from pharmacy expenses. Conclusion: SAA is associated with high economic burden, with costs comparable to blood malignancies, implying that US health plans should consider appropriately managing SAA while constraining the total healthcare costs when making formulary decisions.

Current Concepts of the Pathogenesis of Aplastic Anemia.

Abnormal activation of the immune system plays an important role in the pathogenesis of aplastic anemia (AA). Various immune cells and cytokines constitute a complex immune network, leading to bone marrow failure. The known pathogenesis is an increase of the myeloid dendritic cell (mDC)/ plasmacytoid dendritic cell (pDC) ratio, which causes the ratio of T helper (Th)1/Th2 to be skewed in favor of Th1 and eventually leads to an abnormal activation of cytotoxic T lymphocyte (CTL). The antigens that stimulate T cells in the context of AA remain unknown. In this process, regulatory T (Treg), Th17, natural killer (NK) cell, memory T cell and negative hematopoietic regulatory factors are also involved. In addition, genetic background (e.g., chromosomal abnormalities, telomere attrition, somatic cell mutations), abnormal bone marrow hematopoietic microenvironment and viral infection may also contribute to the pathogenesis of AA. This review summarizes the recent studies of the pathogenesis of AA and the current status of AA research.

Functional Capacity Change Impacts the Quality of Life of Hospitalized Patients Undergoing Hematopoietic Stem Cell Transplantation.

OBJECTIVE: The aim of the study was to compare the quality of life (QOL) of patients undergoing hematopoietic stem cell transplantation who improved their functional capacity during hospitalization (increased functional capacity group) with that of patients who maintained or decreased functional capacity during hospitalization (decreased functional capacity group). DESIGN: This observational, longitudinal study included 27 hospitalized patients undergoing hematopoietic stem cell transplantation. Patients were divided into increased functional capacity group (16 patients) and decreased functional capacity group (11 patients). Functional capacity (6-min step test), peripheral muscle strength (sit-to-stand test and handgrip strength), and QOL (European Organization for Research and Treatment of Cancer) were assessed at admission and at hospital discharge. RESULTS: Increased functional capacity patients had increased functional capacity and peripheral muscle strength of the lower and upper limbs at hospital discharge (P < 0.01, <0.01, and 0.02, respectively). The patients in the increased functional capacity group demonstrated an increase in global health and reduced symptoms at discharge (P = 0.02 and 0.03, respectively). No significant differences were observed between groups in the functional domain. CONCLUSIONS: Patients undergoing hematopoietic stem cell transplantation, who have improved functional capacity at discharge, also experience an improved QOL, with no such improvement noted among patients who have stable or reduced functional capacity. We recommend that the treatment protocol for hospitalized patients undergoing hematopoietic stem cell transplantation include an exercise program aimed at improving functional capacity.

A cohort study of immune and hematopoietic functionality changes in severe aplastic anemia patients treated with immunosuppressive therapy.

To investigate if variations in immune and hematopoietic parameters correlated with immunosuppressive therapy (IST) in severe aplastic anemia (SAA) patients.A total of 115 SAA patients who received IST were included. Their immune and hematopoietic functionality changes had been evaluated at 0, 0.5, 1, 2, and 3-year(s) IST.For SAA patients with complete remission (CR), the CD4/CD8T cell ratio continued to increase after a year of IST. The T helper (Th)1/Th2 ratio continued to decrease after 6 months of IST, as did the activated CD8 T cell percentage. The myeloid dendritic cell (mDC)/plasmacytoid dendritic cell (pDC) ratio after 3 years of IST was significantly lower compared to that of untreated patients. The mDC/pDC and Th1/Th2 ratios exhibited positive correlation. The activated CD8 T cell percentage and the number of peripheral blood neutrophils showed inverse correlation. For SAA patients with partial remission (PR), the CD4T cell percentage increased at 1-year post-IST, but the later changes were not statistically significant. The other immune indexes of patients in partial remission group and nonremission (NR) group showed no obvious recovery. For all SAA patients, the percentage of T regulatory cells in CD4 lymphocyte was higher in post-IST group compared to the pretreatment group.For SAA patients responded well to IST, increase in peripheral neutrophils and improvement in bone marrow myeloid cells were first observed followed reduction in the activated CD8 T cell percentage, Th1/Th2 ratio, CD4/CD8T ratio, along with mDC/pDC ratio, all of which negatively correlated with the hematopoietic parameters. This demonstrates that IST prompts improvements of hematopoietic functionalities of the SAA patients by regulating their immune functionalities.

A brief, but comprehensive, guide to clonal evolution in aplastic anemia.

Acquired aplastic anemia (AA) is an immune-mediated bone marrow aplasia that is strongly associated with clonal hematopoiesis upon marrow recovery. More than 70% of AA patients develop somatic mutations in their hematopoietic cells. In contrast to other conditions linked to clonal hematopoiesis, such as myelodysplastic syndrome (MDS) or clonal hematopoiesis of indeterminate potential in the elderly, the top alterations in AA are closely related to its immune pathogenesis. Nearly 40% of AA patients carry somatic mutations in the PIGA gene manifested as clonal populations of cells with the paroxysmal nocturnal hemoglobinuria phenotype, and 17% of AA patients have loss of HLA class I alleles. It is estimated that between 20% and 35% of AA patients have somatic mutations associated with hematologic malignancies, most characteristically in the ASXL1, BCOR, and BCORL1 genes. Risk factors for evolution to MDS in AA include the duration of disease, acquisition of high-risk somatic mutations, and age at AA onset. Emerging data suggest that several HLA class I alleles not only predispose to the development of AA but may also predispose to clonal evolution in AA patients. Long-term prospective studies are needed to determine the true prognostic implications of clonal hematopoiesis in AA. This article provides a brief, but comprehensive, review of our current understanding of clonal evolution in AA and concludes with 3 cases that illustrate a practical approach for integrating results of next-generation molecular studies into the clinical care of AA patients in 2018.

[Differential expression and bioinformatics analysis of microRNA in peripheral blood mononuclear cells from patients with aplastic anemia].

OBJECTIVE: To study differential expression of microRNA (miRNA) in peripheral blood mononuclear cells (PBMNC) from patients with different types of aplastic anemia (AA) and explore the role of miRNA in the pathogenesis of AA. METHODS: miRNA microarray were used to determine the differential expression profile of miRNA in PBMNC from patients with AA. Real-time quantitative polymerase china reaction (RQ-PCR) was used to verify the differential expression of miRNA. Candidate miRNA were analyzed with bioinformatics tools. RESULTS: Compared with the normal controls, 6 miRNAs were up-regulated and 10 were down-regulated in patients with severe aplastic anemia (SAA), while 24 miRNAs were up-regulated and 12 were down-regulated in patients with chronic non-severe aplastic anemia (CAA). Compared with CAA patients, 4 miRNAs were up-regulated and 11 were down-regulated in SAA patients. Compared with normal controls, 3 miRNAs were up-regulated and 4 were down-regulated in both SAA and CAA patients. As verified by RQ-PCR, expression of miR-155-5p and miR-1260b were increased in both CAA and SAA patients compared with the normal controls (P<0.01). The expression of miR-155-5p and miR-1260b of CAA patients were higher than that of SAA patients (P<0.01). Bioinformatics analysis showed that target genes of miR-155-5p and miR-1260b may be involved in regulation of cell metabolism, gene expression and transcription, TNF signaling pathway, B cell receptor signaling pathway, Fc gamma R-mediated phagocytosis and other signaling process. CONCLUSION: There are characteristic differential expression profiles of miRNA in PBMNC from CAA and SAA patients, in which miRNA-155-5p and miRNA-1260b are both up-regulated. The common target gene predicted for miRNA-155-5p and miRNA-1260b is ETS1. miRNA-155-5p and miRNA-1260b may act synergistically to inhibit the expression of ETS1 and promote differentiation of Th17, therefore play an important role in the pathogenesis of AA.

The Pathophysiology of Acquired Aplastic Anemia: Current Concepts Revisited.

Idiopathic acquired aplastic anemia is a rare, life-threatening bone marrow failure syndrome characterized by cytopenias and hypocellular bone marrow. The pathophysiology is unknown; the most favored model is of a dysregulated immune system leading to autoreactive T-cell destruction of hematopoietic stem and progenitor cells in a genetically susceptible host. The authors review the literature and propose that the major driver of acquired aplastic anemia is a combination of hematopoietic stem and progenitor cells intrinsic defects and an inappropriately activated immune response in the setting of a viral infection. Alterations in bone marrow microenvironment may also contribute to the disease process.

[Acquired aplastic anemia: recent advances in pathophysiology and treatment].

Acquired aplastic anemia (AA) is an autoimmune disease caused by T cells specific to hematopoietic stem cells (HSCs). The presence of HLA allele-lacking leukocytes due to uniparental disomy of the short arm of chromosome 6 (6pUPD) or allelic mutations strongly indicates the involvement of such cytotoxic T cells in the pathogenesis of AA. Attempts to improve treatment outcomes by intensification of immunosuppressive therapy (IST) have been unsuccessful. Eltrombopag (EPAG), a thrombopoietin receptor agonist, has recently emerged as a novel therapeutic agent for AA. EPAG directly acts on HSCs and stimulates proliferation, thereby achieving remission in approximately 40% AA patients refractory to IST. However, some cases develop chromosomal aberrations during treatment. Because somatic mutations are common in patients with AA, verifying whether EPAG induces clonal proliferation or evolution of mutant HSCs is critical.

ERCC6L2-associated inherited bone marrow failure syndrome.

BACKGROUND: ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto. METHODS: Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations. RESULTS: All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication. CONCLUSIONS: ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.

Refining the phenotype associated with biallelic DNAJC21 mutations.

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.

Aplastic Anemia and Risk of Incident Atrial Fibrillation　- A Nationwide Cohort Study.

BACKGROUND: This retrospective cohort study sought to follow up patients with aplastic anemia (AA) to evaluate their risk of developing atrial fibrillation (AF).Methods and Results:From the National Health Insurance Research Database of Taiwan, this study identified an AA cohort (n=3,921), a general population cohort (n=17,617,843) and a propensity score-matched none AA cohort (PSM non-AA cohort in brief, n=15,684) in 2000-2010. By the end of 2011, the incident AF was higher in the AA cohort than in the general population and PSM non-AA cohorts (8.94 vs. 1.14 and 6.47 per 1,000 person-years, respectively). The adjusted hazards ratio of AF for the AA cohort was 2.12 (95% confidence interval 1.46-3.08) compared with the PSM non-AA cohort, after controlling for covariates. However, after further controlling for the competing risk of death, adjusted subhazard ratio was 1.21 (95% CI 0.97-1.50). Among those who developed AF, the AA cohort had a higher mortality rate (83.7 vs. 51.1 per 100), but a lower rate of incident stroke (26.0 vs. 41.5 per 100), compared with the PSM non-AA cohort. CONCLUSIONS: Patients with AA could have an elevated risk for AF. The mortality risk increased further for those who develop AF.

Influence of genetic polymorphisms of IL23R, STAT3, IL12B, and STAT4 on the risk of aplastic anemia and the effect of immunosuppressive therapy.

Studies have suggested that IL-23/STAT3 and IL-12/STAT4 signaling pathways associate with aplastic anemia (AA) occurrence. Polymorphisms in pathway-related genes may contribute to AA risk. In the current study, we investigated the association between polymorphisms in genes of IL23R, STAT3, IL12B, and STAT4 and occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China. In the current 164 AA cases and 211 controls study, we found T allele and TT genotype of rs7574865 were more frequent in the cases than that in the controls. In the additive model, individual carrying rs7574865 T allele demonstrated a 37% (OR (95% CI) = 1.37 (1.02-1.85), Pper = 0.036) increased AA risk. In the recessive model, carrier with rs7574865 TT genotype showed a 2.08-fold increased AA risk (OR (95% CI) = 2.08 (1.14-3.70), Pper = 0.017). Additionally, we showed that G allele and GG genotype of rs11209032 were more frequent in the 88 non-severe AA cases than that in the 76 severe AA ones. Our study also found G allele and GG genotype of rs11209032, and GG-genotype of rs744166 associated with the immunosuppressive therapy outcome in AA patients. Current study results support that functional STAT4 (rs7574865), IL23R (rs11209032), and STAT3 (rs744166) variants may associate with occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China.

Nutritional support contributes to recuperation in a rat model of aplastic anemia by enhancing mitochondrial function.

OBJECTIVES: Acquired aplastic anemia (AA) is a hematopoietic stem cell disease that leads to hematopoietic disorder and peripheral blood pancytopenia. We investigated whether nutritional support is helpful to AA recovery. METHODS: We established a rat model with AA. A nutrient mixture was administered to rats with AA through different dose gavage once per day for 55 d. Animals in this study were assigned to one of five groups: normal control (NC; group includes normal rats); AA (rats with AA); high dose (AA + nutritional mixture, 2266.95 mg/kg/d); medium dose (1511.3 mg/kg/d); and low dose (1057.91 mg/kg/d). The effects of nutrition administration on general status and mitochondrial function of rats with AA were evaluated. RESULTS: The nutrient mixture with which the rats were supplemented significantly improved weight, peripheral blood parameters, and histologic parameters of rats with AA in a dose-dependent manner. Furthermore, we observed that the number of mitochondria in the liver, spleen, kidney, and brain was increased after supplementation by transmission electron microscopy analysis. Nutrient administration also improved mitochondrial DNA content, adenosine triphosphate content, and membrane potential but inhibited oxidative stress, thus, repairing the mitochondrial dysfunction of the rats with AA. CONCLUSIONS: Taken together, nutrition supplements may contribute to the improvement of mitochondrial function and play an important role in the recuperation of rats with AA.

Changes in Bi-ventricular Function After Hematopoietic Stem Cell Transplant as Assessed by Speckle Tracking Echocardiography.

Hematopoietic stem cell transplant (HSCT) is a therapeutic option for patients with sickle cell disease (SCD) and severe acquired aplastic anemia (SAA). HSCT may have beneficial effects on ventricular function in damaged myocardium. We hypothesized improvement in ventricular performance and pulmonary hypertension following HSCT with strain echocardiography in SCD and SAA. Echocardiographic strain and other standard functional data were obtained via retrospective cohort analysis of patients (n = 23) with SCD and SAA who underwent HSCT and were followed at a single center between 2000 and 2014. Left ventricular global longitudinal strain was below normal at baseline, and decreased significantly (from - 16.6 to - 11.1, P = 0.05) from pre-HSCT to the initial post-HSCT echocardiogram at 109 (SD ± 83) days. At 351 (SD ± 115) days, longitudinal strain improved significantly from initial decline (from - 11.1 to - 17.5, P = 0.009) but was comparable to baseline (P = 0.43). Other measurements of bi-ventricular function did not change significantly. Tricuspid regurgitation velocities as surrogates for pulmonary hypertension improved in the subset of patients with baseline elevated values although data points were limited. Abnormal myocardial systolic function was detected at baseline with strain imaging. HSCT was associated with initial worsening longitudinal strain values, followed by improvement to baseline levels by 1 year. Insufficient data exist on whether pulmonary hypertension improves after HSCT.

Hematopoietic development: a gap in our understanding of inherited bone marrow failure.

Inherited bone marrow failure syndromes (IBMFS) represent a heterogeneous group of multisystem disorders that typically present with cytopenia in early childhood. Efforts to understand the underlying hematopoietic stem cell (HSC) losses have generally focused on postnatal hematopoiesis. However, reflecting the role of many of the involved genes in core cellular functions and the diverse nonhematologic abnormalities seen in patients at birth, studies have begun to explore IBMFS manifestations during fetal development. Here, I consider the current evidence for fetal deficits in the HSC pool and highlight emerging concepts regarding the origins and unique pathophysiology of hematopoietic failure in IBMFS.

Bone marrow failure syndrome caused by homozygous frameshift mutation in the ERCC6L2 gene.

Inherited bone marrow failure syndromes (IBMFS) are group of disorders that lead to inadequate production of blood cells. Mutations in genes involved in telomere maintenance, DNA repair, and the cell cycle cause IBMFS. ERCC6L2 gene mutations have been associated with bone marrow failure that includes developmental delay and microcephaly. We report 2 cases of bone marrow failure with no extra-hematopoietic manifestations in patients from unrelated families with a homozygous truncating mutation in ERCC6L2. Bone marrow failure without developmental delay or microcephaly with ERCC6L2 mutation has not been previously described.

The Mechanism of Mitochondria-Mediated Pathway in the Apoptosis of Platelets in Immune-Induced Bone Marrow Failure.

Excessive platelet apoptosis is one of the pathogenic causes of immune-induced bone marrow failure (BMF). The aim of the present study was to explore the role of mitochondria-mediated pathway in the apoptosis of platelets in immune-induced BMF. An immune-induced BMF model was established in mice, which were randomly divided into three groups: normal control (CTL) group, BMF group and cyclosporine (CSA) group (n = 10 in each group). Mice were given 0.027 g/kg CSA daily in the CSA group. Platelet count (PLT), mitochondrial transmembrane potential (ΔΨm), cytochrome C (CytC), phosphatidylserine (PS), calcium ion (Ca²âº) and expression of proteins of the mitochondrial apoptotic pathway, including Bak, Bax, caspase-3, caspase-8 and caspase-9, was examined and compared. Compared with the CTL group, the BMF group had significantly a lower level of PLC and ΔΨm, but higher levels of CytC, PS, Ca²âº and higher expression levels of Bak, Bax, cleaved caspase-9 and cleaved caspase-3 (P < 0.05). CSA restored the above changes in the BMF model (P < 0.05). Further studies showed that intravenous injection of the caspase-9 inhibitor Z-LE(OMe)HD(OMe)-fluoromethylketone (FMK) into the mice could significantly inhibit apoptosis of the platelets and the effect of CSA treatment when compared to the BMF group, and exerted a better protective effect from apoptosis if the caspase-9 inhibitor was combined with the CSA treatment. These results revealed that platelet apoptosis may play an important role in the reduction of platelet of immune-induced BMF probably through the mitochondrial pathway.