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Anemia is a common complication of chronic kidney disease (CKD) that has been classically attributed to inadequate production of endogenous erythropoietin.1 Though there are many other common causes of refractory anemia in CKD like iron deficiency, vitamin B12, and folic acid deficiency, noncompliance to dialysis and erythropoietin therapy rare causes like blood loss, bone marrow failure, infections causing aplastic crisis like CMV, parvovirus B19 should be ruled out. Parvovirus has an extreme tropism for erythroid cells and is an uncommon cause of anemia in patients with CKD on maintenance dialysis (MHD) and on erythropoietin.2 Here we are reporting a rare case of refractory anemia in a patient of CKD on MHD secondary to parvovirus-related aplastic crisis. How to cite this article: Gade K, Londhe C, Pednekar S, et al. A Case of Refractory Anemia in Patient of Chronic Kidney Disease and the Challenges in its Management. J Assoc Physicians India 2023;71(10):94-95.

In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.

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BACKGROUND: Niraparib, a strong poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, contributed significantly to progression-free survival as a maintenance therapy in the platinum-sensitive period in both first-line and recurrent ovarian cancer, regardless of the BRCA mutation. Grade 3-4 anemia, which has a manageable side effect profile, especially hematological, is seen in almost 1 out of every 4 patients. To the best of our knowledge, there has been no reported case of pure red cell aplasia (PRCA) induced by niraparib treatment.
METHODS: A 65-year-old woman diagnosed with stage 3 serous carcinoma of the tuba received niraparib front-line maintenance treatment had grade 4 anemia after 3 months of niraparib treatment. She underwent bone marrow aspiration and biopsy because of refractory anemia, which needs red blood cell (RBC) transfusions despite interruption of treatment.
METHODS: The patient was treated with 1 mg/kg methyl prednisolone, after histopathological assessment was consistent with PRCA. The hemoglobin count returned to the normal range with steroid treatment.
CONCLUSIONS: In daily practice, it should be kept in mind that in the case of refractory anemia induced by niraparib, the underlying cause might be PRCA and can be improved with steroid administration.

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Objective: Short-term efficacy and safety of afatrombopag conversion therapy in patients with aplastic anemia (AA) who were previously ineffectively treated with intense immunosuppressive therapy (IST) combined with TPO receptor Agonist (TPO-RA) or who were unable to tolerate the side effects of TPO-RA. Methods: Analysis of patients with severe aplastic anemia (SAA) treated in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 2021 to December 2021 who received IST combined with TPO-RA (eltrombopag/hatrombopag) for at least 6 months, but was ineffective for at least 3 months or patients who cannot continue to use TPO-RA due to side effects, and switched from TPO-RA to avatrombopag (APAG) , and treated for at least 6 months. This study analyzed its short-term efficacy and evaluated its safety. Results: The median age was 54 (14-68) years old among the 16 patients with AA (8 male and eight female) . A total of ten patients (refractory group) who did not respond to IST combined with TPO-RA were converted to APAG median therapy for 6 (6-10) months. Only seven patients (70% ) obtained trilineage HR [four cases of complete treatment response (CTR) , one case of good treatment response (GPR) , and two cases of partial treatment response (PR) ], all of which began to take effect at 3 months of APAG treatment. There were six patients with TPO-RA intolerance, and APAG was treated for 6 (2 to 8) months. About four patients (67% ) received HR (three GPR cases and one PR case) , of which two patients received PR at 3 months and four patients received HR at 6 months of APAG treatment. No APAG-related grade 2 or more adverse events occurred during the APAG therapy, no thrombotic events occurred, no fibrologic tissue hyperplasia was found in the bone marrow pathology reexamination at 6 months of treatment, and none of the patients discontinued the drug due to adverse events. Conclusion: APAG may be a better switching treatment option for patients with AA who are refractory or are intolerant to TPO-RA.
目的： 评估阿伐曲泊帕（APAG）转换治疗在曾应用免疫抑制治疗（IST）联合TPO受体激动剂（TPO-RA）无效或TPO-RA不耐受的再生障碍性贫血（AA）患者中的近期疗效及安全性。 方法： 回顾性分析2021年1月至2021年12月中国医学科学院血液病医院（中国医学科学院血液学研究所）IST联合TPO-RA（艾曲泊帕/海曲泊帕）治疗无效或TPO-RA不耐受的16例AA患者，接受APAG转换治疗的疗效及安全性。 结果： 16例AA患者中，中位年龄54（14~68）岁，男、女各8例。IST联合TPO-RA治疗无效患者10例（难治组），转换APAG中位治疗6（6~10）个月，7例（70%）获得三系血液学反应（HR）[完全治疗反应（CR）4例、良好治疗反应（GPR）1例、部分治疗反应（PR）2例]，均在APAG治疗3个月时开始起效；TPO-RA不耐受患者6例（不耐受组），APAG中位治疗6（2~8）个月，4例（67%）获得HR（GPR 3例、PR 1例），其中APAG治疗3个月时2例获得PR，6个月时4例患者均获得HR。APAG转换治疗过程中，未发生APAG相关2级以上不良事件，无血栓事件发生，治疗6个月时复查骨髓病理未见纤维组织增生，无一例患者因不良事件停药。 结论： 对于TPO-RA难治或不耐受的AA患者，APAG可作为较好的转换治疗选择。.

Advances in genomic diagnostics hold promise for improved care of rare hematologic diseases. Here, we describe a novel targeted therapeutic approach for Ghosal hematodiaphyseal dysplasia, an autosomal recessive disease characterized by severe normocytic anemia and bone abnormalities due to loss-of-function mutations in thromboxane A synthase 1 (TBXAS1). TBXAS1 metabolizes prostaglandin H2 (PGH2), a cyclooxygenase (COX) product of arachidonic acid, into thromboxane A2. Loss-of-function mutations in TBXAS result in an increase in PGH2 availability for other PG synthases. The current treatment for Ghosal hematodiaphyseal dysplasia syndrome consists of corticosteroids. We hypothesize that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, could ameliorate the effects of TBXAS1 loss and improve hematologic function by reducing prostaglandin formation. We treated 2 patients with Ghosal hematodiaphyseal dysplasia syndrome, an adult and a child, with standard doses of NSAIDs (aspirin or ibuprofen). Both patients had rapid improvements concerning hematologic parameters and inflammatory markers without adverse events. Mass spectrometry analysis demonstrated that urinary PG metabolites were increased along with proinflammatory lipoxygenase (LOX) products 5-hydroxyeicosatetraenoic acid and leukotriene E4. Our data show that NSAIDs at standard doses surprisingly reduced both COX and LOX products, leading to the resolution of cytopenia, and should be considered for first-line treatment for Ghosal hematodiaphyseal dysplasia syndrome.

BACKGROUND: XLSA may be confused clinically with MDS-RARS, which can have patient management implications.
BACKGROUND: Sideroblastic anemia is categorized as a rare type of anemia by National Organization for Rare Disorders. Fewer than 200 cases with less than 100 unrelated probands have been described for X-linked recessive sideroblastic anemia (XLSA). XLSA is the most common type of non-syndromic congenital sideroblastic anemias (CSA), with almost 40% of all CSA cases involving mutations in the ALAS2 (δ- aminolaevulinic acid synthase) gene. Male patients (two-thirds of known cases) usually present in childhood or adolescence with symptoms of anemia, while female patients present in middle age.
METHODS: We present a case of XLSA in a male patient with symptom-onset in middle age. He initially presented with symptoms of anemia and received multiple blood transfusions over a period of 10 years. Subsequent bone marrow biopsy showed a hypercellular bone marrow with erythroid hyperplasia, increased iron and ringed sideroblasts consistent with refractory anemia with ringed sideroblasts, no abnormal karyotype in cytogenetics, and normal flow cytometry results. A liver biopsy showed hemosiderotic changes, and he was initially considered to have myelodysplastic syndrome-refractory anemia with ringed sideroblasts (MDS-RARS). Genetic testing, including SF3B1 gene mutation, revealed no findings suggestive of MDS. The patient was then started on iron chelating agents and pyridoxine with improvement in anemia and did not require any further transfusions with significant improvement in his symptoms. A hereditary anemia NGS gene sequencing and deletion/duplication panel was then done which showed pathogenic X-linked recessive hemizygous mutation involving ALAS2 gene-OMIM 301300. Response to the pyridoxine treatment, absence of SF3B1 gene mutation, and presence of ALAS2 gene mutation helped confirm the diagnosis of XLSA in our patient.
CONCLUSIONS: This case report highlights the necessity for extensive workup in patients with sideroblastic anemia, given the rarity of XLSA and similarity in its clinical symptoms to MDS-RARS, and the need for its early diagnosis. In our patient, iron overload and subsequent liver cirrhosis developed due to multiple transfusions for refractory sideroblastic anemia which was treated as MDS-RARS and could have been avoided if XLSA had been suspected earlier in the course of the disease.