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TAFRO syndrome is a rare systemic inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The diagnosis of TAFRO syndrome can be challenging; however, prompt diagnosis is vital because TAFRO syndrome is a progressive and life-threatening disease. We have showcased five patients with TAFRO syndrome who had similar bone marrow (BM) findings that could be considered the findings that characterize TAFRO syndrome. All patients were treated with corticosteroids and tocilizumab; three of the five patients (60 %) responded positively to the treatment. The unique BM findings observed in this study were megakaryocytes with distinct multinuclei and three-dimensional and indistinct bizarre nuclei ("dysmorphic megakaryocyte"), similar to the megakaryocyte morphology observed in myeloproliferative neoplasms (MPNs). Notably, dysmorphic megakaryocytes were observed in all five cases, whereas only two of the five patients tested positive for reticulin myelofibrosis, and three of the five patients had megakaryocytic hyperplasia, which are considered typical findings of TAFRO syndrome. Thus, the BM findings of dysmorphic megakaryocytes could help in the correct and immediate diagnosis of TAFRO syndrome., Competing Interests: Declaration of competing interest The authors declare no conflict-of-interest relevant to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Variants in the 5' UTR of ANKRD26 are a common cause of inherited thrombocytopenia (ANKRD26-RT), and are associated with sustained ANKRD26 expression, which inhibits megakaryocyte maturation and proplatelet formation. ANKRD26 expression is controlled by the binding of a RUNX1/FLI1 complex to the 5' UTR. To date, all reported ANKRD26-RD associated variants have been within the RUNX1 binding site and a 22 base pair flanking region. Here, we report a novel variant in the 5' UTR of ANKRD26, c.-107C>T. This variant is in the FLI1 binding site, and is predicted to disrupt FLI1 binding due to loss of a hydrogen bond with FLI1. Differentiated PBMCs from affected family members showed impaired megakaryocyte maturation and proplatelet formation and sustained expression of ANKRD26, and platelets from affected family members had higher ANKRD26 expression than control platelets. The variant increased activity of the ANKRD26 promotor in a reporter assay. We also provide evidence that the previously reported c.-140C>G ANKRD26 5' UTR variant is benign and not associated with thrombocytopenia. Identification of the c.-107C>T variant extends the range of the regulatory region in the 5' UTR of ANKRD26 that is associated with ANKRD26-RT., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Wilson disease (WD) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in ATP7B. Clinical manifestations primarily involve liver and nervous system lesions, with rarely observed hematologic manifestations., Case Presentation: In the present case, a patient with WD presented with thrombocytopenia, giant platelets, and Döhle-like cytoplasmic inclusions in the leukocytes. Initially, the May-Hegglin anomaly was considered; however, whole-exome sequencing did not reveal any mutation in the MYH9 gene but a heterozygous mutation was found in (C.2804 C > T, p.T935M) in the ATP7B gene. After two years, the patient developed tremors in his hands, lower limb stiffness, and foreign body sensation in the eyes. Additionally, Kayser-Fleischer rings in the corneal limbus were detected by slit-lamp examination. Copper metabolism test indicated a slight decrease in serum ceruloplasmin. Transmission electron microscopy revealed that the inclusion bodies of leukocytes were swollen mitochondria. Mass spectrometry analysis showed that the copper levels were almost 20-fold higher in the leukocytes of the patient than in those of the control group. Based on the Leipzig scoring system, a diagnosis of WD was confirmed. Zinc sulfate treatment ameliorated the patient's symptoms and enhanced platelet, serum ceruloplasmin, and albumin levels., Conclusions: In conclusion, this case represents the first documented instance of WD presenting as thrombocytopenia, giant platelets, and Döhle-like cytoplasmic inclusions in the leukocytes. Excessive cellular copper accumulation likely underlies these findings; however, understanding precise mechanisms warrants further investigation., (© 2024. The Author(s).)

The ubiquitously expressed small GTPase Ras-related protein 1B (RAP1B) acts as a molecular switch that regulates cell signaling, cytoskeletal remodeling, and cell trafficking and activates integrins in platelets and lymphocytes. The residue G12 in the P-loop is required for the RAP1B-GTPase conformational switch. Heterozygous germline RAP1B variants have been described in patients with syndromic thrombocytopenia. However, the causality and pathophysiological impact remained unexplored. We report a boy with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a heterozygous de novo single nucleotide substitution, c.35G>A (p.G12E) in RAP1B. We demonstrate that G12E and the previously described G12V and G60R were gain-of-function variants that increased RAP1B activation, talin recruitment, and integrin activation, thereby modifying late responses such as platelet activation, T cell proliferation, and migration. We show that in our patient, G12E was a somatic variant whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations. Allogeneic hematopoietic stem cell transplantation fully restored the patient's hemato-immunological phenotype. Our findings define monoallelic RAP1B gain-of-function variants as a cause for constitutive immunodeficiency and thrombocytopenia. The phenotypic spectrum ranged from isolated hematological manifestations in our patient with somatic mosaicism to complex syndromic features in patients with reported germline RAP1B variants.

A rare lymphoproliferative disorder involving thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), renal dysfunction (R), and organomegaly (O), called TAFRO syndrome, was first reported in 2010. Considered a variant of idiopathic multicentric Castleman's disease, the recent discovery and rarity of this syndrome pose challenges to diagnosis and management. Herein, we review three pediatric cases, including an infant, that illustrate the heterogeneity of TAFRO syndrome. Despite differences in presentation and treatment responses, all patients experienced excellent outcomes. This multi-institutional case series highlights the need to work toward earlier diagnosis and improved long-term management recommendations for patients with TAFRO syndrome., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Megakaryopoiesis and platelet production is a complex process that is underpotential regulation at multiple stages. Many long non-coding RNAs (lncRNAs) are distributed in hematopoietic stem cells and platelets. lncRNAs may play important roles as key epigenetic regulators in megakaryocyte differentiation and proplatelet formation. lncRNA NORAD can affect cell ploidy by sequestering PUMILIO proteins, although its direct effect on megakaryocyte differentiation and thrombopoiesis is still unknown. In this study, we demonstrate NORAD RNA is highly expressed in the cytoplasm during megakaryocyte differentiation. Interestingly, we identified for the first time that NORAD has a strong inhibitory effect on megakaryocyte differentiation and proplatelet formation from cultured megakaryocytes. DUSP6/ERK1/2 pathway is activated in response to NORAD knockdown during megakaryocytopoiesis, which is achieved by sequestering PUM2 proteins. Finally, compared with the wild-type control mice, NORAD knockout mice show a faster platelet recovery after severe thrombocytopenia induced by 6 Gy total body irradiation. These findings demonstrate lncRNA NORAD has a key role in regulating megakaryocyte differentiation and thrombopoiesis, which provides a promising molecular target for the treatment of platelet-related diseases such as severe thrombocytopenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, the role of Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO messenger RNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-sequencing analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR), a heterodimer of asialoglycoprotein receptor 1 [ASGR1] and ASGR2, physically associates with Notch1, and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Delta-like 4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation, and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. Patients present with rheumatologic manifestations and cytopenias and may have an increased predisposition to myelodysplastic syndrome (MDS) and plasma cell neoplasms. Prior studies have reported on the peripheral blood and bone marrow findings in patients with VEXAS syndrome. Due to the protean clinical presentation and lack of specificity of morphologic features (eg, vacuoles in early erythroid and granulocytic precursors), an optimal screening methodology to identify these patients in a timely fashion is desirable., Methods: To further evaluate and describe the salient diagnostic morphologic features in VEXAS syndrome, we carried out a comprehensive study of the largest single-institution cohort to date. Diagnostic and follow-up bone marrow biopsy specimens from 52 male patients with molecularly identified VEXAS syndrome underwent central review., Results: Cytopenias were common in all cases, primarily macrocytic anemia, monocytopenia, and thrombocytopenia. Bone marrow aspirate and biopsy were often hypercellular, with an increased myeloid/erythroid ratio, granulocytic hyperplasia with left shift, erythroid left shift, and megakaryocyte hyperplasia, which exhibited a range of striking morphologic findings. Distinctly vacuolated myeloid and erythroid precursors were seen in more than 95% of cases., Conclusions: Our data reveal potential novel diagnostic features, such as a high incidence of monocytopenia and distinct patterns of atypical megakaryopoiesis, that appear different from dysmegakaryopoiesis typically associated with MDS. In our experience, those findings are suggestive of VEXAS, in the appropriate clinical context., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Five pathogenic variants in the gene encoding cytochrome c (CYCS) associated with mild autosomal dominant thrombocytopenia have been reported. Previous studies of peripheral blood CD34+ or CD45+ cells from subjects with the G42S CYCS variant showed an acceleration in megakaryopoiesis compared to wild-type (WT) cells. To determine whether this result reflects a common feature of the CYCS variants, the c.145T>C mutation (Y49H variant) was introduced into the endogenous CYCS locus in K-562 cells, which undergo megakaryocytic maturation in response to treatment with a phorbol ester. The c.145T>C (Y49H) variant enhanced the megakaryocyte maturation of the K-562 cells, and this effect was seen when the cells were cultured at both 18 % and 5 % oxygen. Thus, alteration of megakaryopoiesis is common to both the G42S and Y49H CYCS variants and may contribute to the low platelet phenotype. The Y49H CYCS variant has previously been reported to impair mitochondrial respiratory chain function in vitro, however using extracellular flux analysis the c.145T>C (Y49H) variant does not alter mitochondrial bioenergetics of the K-562 cells, consistent with the lack of a phenotype characteristic of mitochondrial diseases in CYCS variant families. The Y49H variant has also been reported to enhance the ability of cytochrome c to trigger caspase activation in the intrinsic apoptosis pathway. However, as seen in peripheral blood cells from G42S CYCS variant carriers, the presence of Y49H cytochrome c in K-562 cells did not significantly change their response to an apoptotic stimulus., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hematology is a clinical specialty with strong roots in the laboratory; accordingly, the lab can help solve perplexing clinical problems. This review highlights clinical-pathological conundrums addressed during my 35-year hematology career at McMaster University. Heyde syndrome is the association between aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia where the bleeding is usually cured by aortic valve replacement; the chance reading of a neonatal study showing reversible deficiency of high-molecular-weight (HMW) multimers of von Willebrand factor (vWF) following surgical correction of congenital heart disease provided the key insight that a subtle deficiency of HMW multimers of vWF explains Heyde syndrome. The unusual immunobiology of heparin-induced thrombocytopenia (HIT)-a highly prothrombotic, antibody-mediated, anti-platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin-dependent platelet-activating antibodies-permitted identification of key clinical features that informed development of a scoring system (4Ts) to aid in HIT diagnosis. Atypical clinical presentations of HIT prompted identification of heparin-independent anti-PF4 antibodies, now recognized as the explanation for vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as VITT-like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep-vein/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT- and cancer-associated venous limb gangrene provided insight into disturbed procoagulant/anticoagulant balance; these concepts are relevant to microvascular thrombosis in critical illness (symmetrical peripheral gangrene), including a pathophysiological role for proximate "shock liver" (impaired hepatic synthesis of natural anticoagulants)., (© 2024 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Introduction: Light transmission aggregometry (LTA) is important for diagnosing platelet function disorders (PFD) and von Willebrand disease (VWD) affecting ristocetin-induced platelet aggregation (RIPA). Nonetheless, data is lacking on the utility of LTA for investigating thrombocytopenic patients and platelet rich plasma samples with low platelet counts (L-PRP). Previously, we developed a strategy for diagnostic LTA assessment of L-PRP that included: (1) acceptance of referrals/samples, regardless of thrombocytopenia severity, (2) tailored agonist selection, based on which are informative for L-PRP with mildly or severely low platelet counts, and (3) interpretation of maximal aggregation (MA) using regression-derived 95% confidence intervals, determined for diluted control L-PRP (C-L-PRP)., Methods: To further evaluate the L-PRP LTA strategy, we evaluated findings for a subsequent patient cohort., Results: Between 2008 and 2021, the L-PRP strategy was applied to 211 samples (11.7% of all LTA samples) from 192 unique patients, whose platelet counts (median [range] × 10 9 /L) for blood and L-PRP were: 105 [13-282; 89% with thrombocytopenia] and 164 [17-249], respectively. Patient-L-PRP had more abnormal MA findings than simultaneously tested C-L-PRP (p-values <0.001). Among patients with accessible electronic medical records (n = 181), L-PRP LTA uncovered significant aggregation abnormalities in 45 (24.9%), including 18/30 (60%) with <80 × 10 9  platelets/L L-PRP, and ruled out PFD, and VWD affecting RIPA, in others. The L-PRP LTA strategy helped diagnose VWD affecting RIPA, Bernard Soulier syndrome, familial platelet disorder with myeloid malignancy, suspected ITGA2B/ITGB3-related thrombocytopenia, and acquired PFD., Conclusion: Diagnostic LTA with L-PRP, using a strategy that considers thrombocytopenia severity, is feasible and informative., (© 2023 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Idiopathic multicentric Castleman disease (iMCD) is a rare haematological disorder characterized by generalized lymphadenopathy with atypical histopathological features and systemic inflammation caused by a cytokine storm involving interleukin-6 (IL-6). Three clinical subtypes are recognized: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD-TAFRO); idiopathic plasmacytic lymphadenopathy (iMCD-IPL), involving thrombocytosis and hypergammaglobulinaemia; and iMCD-not otherwise specified (iMCD-NOS), which includes patients who do not meet criteria for the other subtypes. Disease pathogenesis is poorly understood, with potential involvement of infectious, clonal and/or autoimmune mechanisms. To better characterize iMCD clinicopathology and gain mechanistic insights into iMCD, we analysed complete blood counts, other clinical laboratory values and blood smear morphology among 63 iMCD patients grouped by clinical subtype. Patients with iMCD-TAFRO had large platelets, clinical severity associated with lower platelet counts and transfusion-resistant thrombocytopenia, similar to what is observed with immune-mediated destruction of platelets in immune thrombocytopenic purpura. Conversely, elevated platelet counts in iMCD-IPL were associated with elevated IL-6 and declined following anti-IL-6 therapy. Our data suggest that autoimmune mechanisms contribute to the thrombocytopenia in at least a portion of iMCD-TAFRO patients whereas IL-6 drives thrombocytosis in iMCD-IPL, and these mechanisms likely contribute to disease pathogenesis., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Circulating plasma cells (CPCs) are frequently noted in variable frequencies in the entire spectrum of plasma cells neoplasms. With advent of high sensitivity multi-parametric flow cytometry, it is not only possible to detect CPCs present in very low numbers, but also to categorise them into circulating tumor plasma cells (CTPCs) and circulating normal plasma cells (CNPCs), based on their marker-profile. This study used multi-colour flow cytometry to evaluate the load of both CTPCs & CNPCs at the time of diagnosis and at six months' time-point of therapy, and evaluated associations of both with clinical and laboratory parameters., Methods: Twenty one newly diagnosed MM patients were enrolled. Six to nine millilitres of EDTA-anticoagulated peripheral blood sample was used for flow cytometry. A ten colour antibody panel was used for analysis of CPCs, which were categorised further into CTPCs and CNPCs. Approximately 4.8 million events were acquired for the analysis. The percentage &absolute numbers of CTPCs and CNPCs were noted and the proportion of CTPCs out of all CPCs (CTPCs + CNPCs) were also calculated for evaluating their statistical associations., Results: All 21 patients of newly diagnosed MM showed presence of CPCs (CTPCs and/or CNPCs) at the time of diagnosis. The CTPCs were detected in 76 % of the study population. The median percentage and absolute counts of CTPCs were 0.52 % and 54.9 cells /µL, respectively. CNPCs were found in 95 % and the median percentage and absolute counts of CNPCs were 0.025 % and 2.66 cells/µL. After six months of therapy, CPCs (CTPCs and/or CNPCs) were found in all nine patients evaluated for this assay. CTPCs were found 33 %, with a median of 0.075 % and CNPCs were found in 89 % with a median of 0.01 %. Our study showed that the load of CTPCs was found to be higher in patients with presence of lytic bone lesions, plasmacytoma, presence of PCs on peripheral blood film by light microscopy, presence of Chr 1p32 deletion, expression of CD56 and CD81 on CTPCs, and in patients with absence of very good partial response (VGPR). Conversely, the load of CTPCs was significantly lower in patients with concomitant amyloidosis. Also, percentage of bone marrow plasma cells exhibited a significant positive correlation with the absolute count of CTPCs. We observed that the mean percentage of CNPCs was significantly higher in female patients. The load of CNPCs was lower in patients with thrombocytopenia and with hypoalbuminemia., Conclusion: Increased burden of CTPCs was associated with presence of lytic lesions, plasmacytomas, Chr 1p32 deletion, expression of CD56 and CD81 on tumor cells and with failure to achieve very good partial response. The CNPCs were lower in patients with thrombocytopenia and with hypoalbuminemia. To best ot our knowledge, this is the first study from India on the relevance of circulating tumor plasma cells and the first study in the world to analyse the associations of circulating normal plasma cells in newly diagnosed patients of multiple myeloma. The study also highlights the utility of multi-parametric flow cytometry in identification and enumeration of circulating plasma cells., Micro Abstract: Circulating plasma cells indicates poorer outcomes in patients of multiple myeloma. Twenty one newly diagnosed multiple myeloma patients were evaluated by flow cytometry to enumerate and characterise circulating tumor plasma cells (CTPCs) and circulating normal plasma cells (CNPCs). Higher load of CTPCs correlated with known poor prognostic markers and poor response to therapy., Competing Interests: Declaration of Competing Interest Np potential conflict of interest are reported by authors., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: GATA1 is one of the master transcription factors in hematopoietic lineages development which is crucial for megakaryocytic differentiation and maturation. Previous studies have shown that distinct GATA1 variants are associated with varying severities of macrothrombocytopenia and platelet dysfunction., Objective: To determine the underlying pathological mechanisms of a novel GATA1 variant (c. 686G > A, p. G229D) in a patient with recurrent traumatic muscle hematomas., Methods: Comprehensive phenotypic analysis of the patient platelets was performed. Procoagulant platelet formation and function were detected using flow cytometry assay and thrombin generation test (TGT), respectively. The ANO6 expression was measured by qPCR and western blot. The intracellular supramaximal calcium flux was detected by Fluo-5N fluorescent assay., Results: The patient displayed mild macrothrombocytopenia with defects of platelet granules, aggregation, and integrin αIIbβ3 activation. The percentage of the procoagulant platelet formation of the patient upon the stimulation of thrombin plus collagen was lower than that of the healthy controls (40.9 % vs 49.0 % ± 5.1 %). The patient platelets exhibited a marked reduction of thrombin generation in platelet rich plasma TGT compared to the healthy controls (peak value: ∼70 % of the healthy controls; the endogenous thrombin potential: ∼40 % of the healthy controls). The expression of ANO6 and intracellular calcium flux were impaired, which together with abnormal granules of the patient platelets might contribute to defect of procoagulant platelet function., Conclusions: The G229D variant could lead to a novel platelet phenotype characterized by defective procoagulant platelet formation and function, which extended the range of GATA1 variants associated platelet disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

GATA1 is a highly conserved hematopoietic transcription factor (TF), essential for normal erythropoiesis and megakaryopoiesis, that encodes a full-length, predominant isoform and an amino (N) terminus-truncated isoform GATA1s. It is consistently expressed throughout megakaryocyte development and interacts with its target genes either independently or in association with binding partners such as FOG1 (friend of GATA1). While the N-terminus and zinc finger have classically been demonstrated to be necessary for the normal regulation of platelet-specific genes, murine models, cell-line studies, and human case reports indicate that the carboxy-terminal activation domain and zinc finger also play key roles in precisely controlling megakaryocyte growth, proliferation, and maturation. Murine models have shown that disruptions to GATA1 increase the proliferation of immature megakaryocytes with abnormal architecture and impaired terminal differentiation into platelets. In humans, germline GATA1 mutations result in variable cytopenias, including macrothrombocytopenia with abnormal platelet aggregation and excessive bleeding tendencies, while acquired GATA1s mutations in individuals with trisomy 21 (T21) result in transient abnormal myelopoiesis (TAM) and myeloid leukemia of Down syndrome (ML-DS) arising from a megakaryocyte-erythroid progenitor (MEP). Taken together, GATA1 plays a key role in regulating megakaryocyte differentiation, maturation, and proliferative capacity. As sequencing and proteomic technologies expand, additional GATA1 mutations and regulatory mechanisms contributing to human diseases of megakaryocytes and platelets are likely to be revealed., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by isolated thrombocytopenia. Its pathogenesis is complex relying in large part on destruction of platelets recognized by autoantibodies within the spleen. However, other mechanisms, such as platelet desialylation, may play a role in platelet reduction by accelerating their clearance in the liver. In their study, Mendoza and colleagues reported on platelet scintigraphy performed in 51 ITP patients, showing a response in 87.5% when the sequestration occurred in the spleen versus 45% in case of non-splenic destruction. Platelet desialylation was also measured after splenectomy and found to be higher in non-responder patients. These latter results, while requiring confirmation prior to splenectomy, support platelet desialylation may also be a potential biomarker of non-response to splenectomy. Commentary on: Mendoza et al. Study of platelet kinetics in immune thrombocytopenia to predict splenectomy response. Br J Haematol 2024;204:315-323., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Metastatic cancer presents a treatment challenge to clinicians, particularly for patients with bone marrow infiltration. For tumor staging, therapy selection, and prognosis risk stratification, the status of the bone marrow should be known for the presence or absence of metastasis. The study aimed to evaluate the hematological findings and comprehensive analysis of bone marrow in cases of nonhematological malignancies with bone marrow metastasis., Materials and Methods: This retrospective study comprised a record retrieval of the departmental archives for the past 6 years. A total of 331 patients with nonhematological malignancies were found, of whom 31.42% (104/331) showed bone marrow metastasis. An integrated clinical approach with bone marrow examination findings and immunohistochemistry whenever necessary was used to achieve a definitive diagnosis of bone marrow metastasis., Results: Among the study population, 31.42% (104/331) of patients had nonhematological malignancies that metastasized to the bone marrow. Most of the patients with bone marrow metastasis had anemia, which was found in 77.88% (81/104) of the cases. Leukoerythroblastic reaction was noted in 31.73% (33/104) of the cases, and thrombocytopenia was found in 25% (26/104) of the cases. The most common malignancy with bone marrow metastasis in adults was prostatic adenocarcinoma (28.1%) (9/32) and in pediatric cases, neuroblastoma (53.9%) (52/98)., Conclusions: It is essential to diagnose nonhematological malignancies that have metastasized to the bone marrow since this necessitates tumor staging, therapy selection, and prognosis risk stratification. To conclude, not a single hematological parameter is predictive of bone marrow metastasis; however, unexplained anemia, a leukoerythroblastic blood picture, and thrombocytopenia in peripheral blood should raise suspicion for bone marrow metastasis in cases of nonhematological malignancies., Competing Interests: None

Abstract: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose of Review: Platelet factor 4 (PF4, CXCL4), the most abundant α-granule platelet-specific chemokine, forms tetramers with an equatorial ring of high positive charge that bind to a wide range of polyanions, after which it changes conformation to expose antigenic epitopes. Antibodies directed against PF4 not only help to clear infection but can also lead to the development of thrombotic disorders such as heparin-induced thrombocytopenia (HIT) and vaccine-induced thrombocytopenia and thrombosis (VITT). This review will outline the different mechanisms through which PF4 engagement with polyanions combats infection but also contributes to the pathogenesis of inflammatory and thrombotic disease states., Recent Findings: Recent work has shown that PF4 binding to microbial polyanions may improve outcomes in infection by enhancing leukocyte-bacterial binding, tethering pathogens to neutrophil extracellular traps (NETs), decreasing the thrombotic potential of NET DNA, and modulating viral infectivity. However, PF4 binding to nucleic acids may enhance their recognition by innate immune receptors, leading to autoinflammation. Lastly, while HIT is induced by platelet activating antibodies that bind to PF4/polyanion complexes, VITT, which occurs in a small subset of patients treated with COVID-19 adenovirus vector vaccines, is characterized by prothrombotic antibodies that bind to PF4 alone., Summary: Investigating the complex interplay of PF4 and polyanions may provide insights relevant to the treatment of infectious disease while also improving our understanding of the pathogenesis of thrombotic disorders driven by anti-PF4/polyanion and anti-PF4 antibodies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706., (© 2023 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

A young man with a history of thrombocytopenia for seven years presented with splenomegaly and fever and rapidly evolved to disseminated intravascular coagulation (DIC) and hemorrhagic shock. Spontaneous rupture of the spleen was diagnosed. The critical patient underwent an emergency splenectomy. Pathological examination revealed splenic peliosis, an extremely rare disease with unknown etiology and pathogenesis. Despite the high mortality rate due to spontaneous splenic rupture with DIC, the patient was successfully treated and the details of the case are presented in this report.

Pathogenic missense variants in SLFN14, which encode an RNA endoribonuclease protein that regulates ribosomal RNA (rRNA) degradation, are known to cause inherited thrombocytopenia (TP) with impaired platelet aggregation and adenosine triphosphate secretion. Despite mild laboratory defects, the patients displayed an obvious bleeding phenotype. However, the function of SLFN14 in megakaryocyte (MK) and platelet biology remains unknown. This study aimed to model the disease in an immortalized MK cell line (imMKCL) and to characterize the platelet transcriptome in patients with the SLFN14 K219N variant. MK derived from heterozygous and homozygous SLFN14 K219N imMKCL and stem cells of blood from patients mainly presented with a defect in proplatelet formation and mitochondrial organization. SLFN14-defective platelets and mature MK showed signs of rRNA degradation; however, this was absent in undifferentiated imMKCL cells and granulocytes. Total platelet RNA was sequenced in 2 patients and 19 healthy controls. Differential gene expression analysis yielded 2999 and 2888 significantly (|log2 fold change| >1, false discovery rate <0.05) up- and downregulated genes, respectively. Remarkably, these downregulated genes were not enriched in any biological pathway, whereas upregulated genes were enriched in pathways involved in (mitochondrial) translation and transcription, with a significant upregulation of 134 ribosomal protein genes (RPGs). The upregulation of mitochondrial RPGs through increased mammalian target of rapamycin complex 1 (mTORC1) signaling in SLFN14 K219N MK seems to be a compensatory response to rRNA degradation. mTORC1 inhibition with rapamycin resulted in further enhanced rRNA degradation in SLFN14 K219N MK. Taken together, our study indicates dysregulation of mTORC1 coordinated ribosomal biogenesis is the disease mechanism for SLFN14-related TP., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Inherited platelet disorders (IPDs) are rare diseases characterized by reduced blood platelet counts and/or impaired platelet function. Recognizing IPDs is advisable but often challenging. The diagnostic tools include clinical evaluation, platelet function tests, and molecular analyses. Demonstration of a pathogenic genetic variant confirms IPDs. We established a method to assess the platelet phenotype on blood smears using immunofluorescence microscopy as a diagnostic tool for IPDs., Objectives: The aim of the present study was to validate immunofluorescence microscopy as a screening tool for IPDs in comparison with genetic screening., Methods: We performed a blinded comparison between the diagnosis made using immunofluorescence microscopy on blood smears and genetic findings in a cohort of 43 families affected with 20 different genetically confirmed IPDs. In total, 76% of the cases had inherited thrombocytopenia., Results: Immunofluorescence correctly predicted the underlying IPD in the vast majority of patients with 1 of 9 IPDs for which the typical morphologic pattern is known. Thirty of the 43 enrolled families (70%) were affected by 1 of these 9 IPDs. For the other 11 forms of IPD, we describe alterations of platelet structure in 9 disorders and normal findings in 2 disorders., Conclusion: Immunofluorescence microscopy on blood smears is an effective screening tool for 9 forms of IPD, which include the most frequent forms of inherited thrombocytopenia. Using this approach, typical changes in the phenotype may also be identified for other rare IPDs., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a rare disease characterized by the presence of multiple cutaneous lesions and bleeding from the gastrointestinal tract with thrombocytopenia. Because of the varied phenotypes and rarity of MLT, a treatment strategy has not been standardized thus far. We describe a case of infantile MLT that did not respond to treatment with propranolol, prednisolone, or vincristine. We successfully treated the patient with everolimus, an inhibitor of the mammalian target of rapamycin. Our case provides the first evidence of the effectiveness of everolimus for the treatment of MLT., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

A 35-year-old man with persistent urine abnormalities and renal dysfunction was referred to our hospital. May-Hegglin anomaly was suspected, and a renal biopsy showed focal segmental glomerulosclerosis (FSGS) with IgA deposition. Electron microscopy revealed foot process effacements and intense bleb-like morphological changes in podocytes. Nonmuscle myosin heavy chain IIA (NMMHCIIA) staining of granulocytes revealed a localized, type II pattern, and genomic DNA sequencing of MYH9 exon 40 revealed MYH9 5773delG mutation (c.5773delG [p.(Asp1925Thrfs*23)]). Podocytes were significantly stained by an antibody specific for NMMHC-IIA abnormalities associated with this mutation. Colocalization observation of vimentin and NMMHC-IIA demonstrated a diminished form of NMMHC-IIA in podocytes. Taking these observations into account, it was determined that the present case was likely associated with MYH9 disorder. Treatment was started with olmesartan, followed by methylprednisolone pulse therapy 3 times bi-monthly. Finally, the patient began hemodialysis 18 months later. This is the first known report of renal phenotype expression associated with this MYH9 mutation. FSGS can occur in association with MYH9 mutations at the 3' regions, such as exon 40. Abnormal expression or metabolism of NMMHC-IIA in podocytes might be related to the formation of FSGS lesions due to this MYH9 mutation.

The term "Castleman disease" covers a variety of entities that have very different clinical, biological, pathological and physiopathological features. In this issue, we review the characteristics of the unicentric Castleman disease, of the HHV8 associated multicentric Castleman disease and the idiopathic multicentric Castleman disease associated or not with TAFRO syndrome ("thrombocytopenia, anasarca, fever, reticulin myelofibrosis and/or renal insufficiency, organomegaly"). We detail the differential diagnostics of these entities., (Copyright © 2022. Published by Elsevier Masson SAS.)

A 71-year-old Japanese man presented with severe thrombocytopenia. A whole-body CT at presentation showed small cervical, axillary, and para-aortic lymphadenopathy, leading to suspicion of immune thrombocytopenia due to lymphoma. Biopsy was difficult to perform because of severe thrombocytopenia. Thus, he received prednisolone (PSL) therapy and his platelet count gradually recovered. Two and a half years after PSL therapy initiation, his cervical lymphadenopathy slightly progressed without other clinical symptoms. Hence, a biopsy from the left cervical lymph node was performed, and he was diagnosed with nodal peripheral T-cell lymphoma (PTCL) with T follicular helper (TFH) phenotype. Due to various complications, we continued treatment with prednisolone alone after the diagnosis of lymphoma; however, there was no further increase in lymph node enlargement and no other lymphoma-related symptoms for one and a half years after diagnosis. Although immunosuppressive therapy has been reported to produce a response in some patients with angioimmunoblastic T-cell lymphoma, our experience suggests that a similar subset may exist in patients with nodal PTCL with TFH phenotype, which has the same cellular origin. Immunosuppressive therapies may constitute an alternative treatment option even in the era of novel molecular-targeted therapies, especially for elderly patients who are ineligible for chemotherapy.

Platelets are formed from bone marrow megakaryocytes, circulate in blood for 7-10 days, and then are destroyed in the spleen and/or liver. Platelet production depends on the megakaryocyte population state in the bone marrow: number and size of the cells. The platelet turnover, i.e., the number of platelets passing through the bloodstream in a certain time, is determined by both the rate of their production and the rate of their destruction. The review considers laboratory markers, which are used to assess platelet production and turnover in the patients with hematologic and cardiovascular pathologies. These markers include some characteristics of platelets themselves: (i) content of reticulated ("young") forms in the blood detected by their staining with RNA dyes; (ii) indicators of the platelet size determined in hematology analyzers (mean volume, percentage of large forms) and in flow cytometers (light scattering level). Alterations of platelet production and turnover lead to the changes in blood plasma concentrations of such molecules as thrombopoietin (TPO, main mediator of megakaryocyte maturation and platelet formation in the bone marrow) and glycocalicin (soluble fragment of the membrane glycoprotein Ib detached from the surface of platelets during their destruction). Specific changes in the markers of platelet production and turnover have been observed in: (i) hypoproductive thrombocytopenias caused by suppression of megakaryocytes in the bone marrow; (ii) immune thrombocytopenias caused by accelerated clearance of the autoantibody-sensitized platelets; and (iii) thrombocytosis (both primary and reactive). The paper presents the data indicating that in patients with cardiovascular diseases an increased platelet turnover and changes in the corresponding markers (platelet size indexes and content of reticulated forms) are associated with the decreased efficacy of antiplatelet drugs and increased risk of thrombotic events, myocardial infarction, and unstable angina (acute coronary syndrome).

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia. Herein, we sought to identify potential immune-related therapeutic targets in ITP., Methods: The differentially expressed genes (DEGs) between ITP patients and controls in GSE43177 and PRJNA299534 were analyzed. The intersections of the two DEG groups were screened as common genes, and enrichment analysis was performed. Additionally, differential analysis of immune cell levels between ITP and controls was performed. Changes in the proportions of T follicular helper (Tfh) and follicular regulatory T (Tfr) cells in peripheral blood samples from ITP patients, ITP patients responding to therapy, and healthy controls were identified. The expression changes in B-cell lymphoma (Bcl)-6 and interleukin (IL)-21 were further evaluated., Results: A total of 76 common genes were identified, and enrichment analysis found that these genes were mainly associated with neutrophil-mediated immunity, the MAPK signaling pathway, and the FOXO signaling pathway. Furthermore, we found different levels of Tfh cells in patients with ITP and controls. The level of Tfh cells in the peripheral blood is significantly increased in ITP patients and declines after responding to therapy. The Tfr/Tfh ratio was reduced in ITP patients and increased after responding to therapy. IL-21 and Bcl-6 were more highly expressed in ITP patients than in controls., Conclusion: We identified abnormally expressed genes in ITP related to immune-related biological functions. We further identified the changes in Tfh and Tfr cells during ITP treatment. This provides a rationale for immunotherapy in ITP patients., (© 2023 S. Karger AG, Basel.)

ANKRD26 is a highly conserved gene located on chromosome 10p12.1 which has shown to play a role in normal megakaryocyte differentiation. ANKRD26 -related thrombocytopenia, or thrombocytopenia 2, is an inherited thrombocytopenia with mild bleeding diathesis resulting from point mutations the 5'UTR of the ANKRD26 gene. Point mutations in the 5'UTR region have been shown to prevent transcription factor-mediated downregulation of ANKRD26 in normal megakaryocyte differentiation. Patients with ANKRD26 -related thrombocytopenia have a predisposition to developing hematological malignancies, with acute myeloid leukemia and myelodysplastic syndrome most commonly described in the literature. We review the clinical features and biological mechanisms of ANKRD26 -related thrombocytopenia and summarize known cases in the literature.

Background: Severe fever with thrombocytopenia syndrome (SFTS), an emerging viral infectious disease, is mainly transmitted by ticks in the surrounding environment. Clinical progress and risk factors for prognosis in SFTS patients were not yet fully understood. Thus, the objective of this study was to analyze clinical progression and laboratory data related to the prognosis of South Korean SFTS patients in a single institution from 2014 to 2021. Materials and Methods: Fifty-three confirmed SFTS patients from August 2014 to September 2021 at Gyeongsang National University Hospital (GNUH) in Jinju, South Korea were enrolled. Electronic medical records of SFTS patients' demographic features, clinical data, and laboratory data were retrospectively reviewed. Risk factors for fatality were statistically analyzed by classifying enrolled patients into fatal and non-fatal groups. Results: The mean age of patients in the fatal group was significantly higher than that in the non-fatal group ( p  = 0.036). Hemorrhagic manifestations ( p  = 0.001) and multiple organ dysfunction (MOD) ( p  < 0.001) were significantly common in the fatal group. Age, hemorrhagic manifestations, and MOD were also associated with death ( p  = 0.001, p  = 0.008, and p  = 0.041, respectively), with adjusted hazard ratios (aHRs) of 1.14, 18.25, and 2.36, respectively. Onset of illness to admission was also significantly associated with death ( p  = 0.005), with aHR of 0.48. Age, interval from onset of illness to admission, hemorrhagic manifestations, and MOD were found to be variables related to the fatality of SFTS patients. Conclusion: Laboratory test results showed a significant difference between the fatal group and the non-fatal group, but they did not have a statistically significant effect on the prognosis of SFTS patients.

Severe fever with thrombocytopenia syndrome (SFTS) has been acknowledged as an emerging infectious disease that is caused by the SFTS virus (SFTSV). The main clinical features of SFTS on presentation include fever, thrombocytopenia, leukocytopenia and gastrointestinal symptoms. The mortality rate is estimated to range between 5‑30% in East Asia. However, SFTSV infection is increasing on an annual basis globally and is becoming a public health problem. The transmission cycle of SFTSV remains poorly understood, which is compounded by the pathogenesis of SFTS not being fully elucidated. Since the mechanism underlying the host immune response towards SFTSV is also unclear, there are no effective vaccines or specific therapeutic agents against SFTS, with supportive care being the only realistic option. Therefore, it is now crucial to understand all aspects of the host‑virus interaction following SFTSV infection, including the antiviral states and viral evasion mechanisms. In the present review, recent research progress into the possible host immune responses against SFTSV was summarized, which may be useful in designing novel therapeutics against SFTS.

Objective: Valproic acid (VPA) is an effective first-line anticonvulsant that is associated with several side effects including bone marrow suppression and subsequent cytopenia. However, VPA associated myelodysplasia is not a well described entity that can be seen in patients on VPA treatment., Case Report: Herein, we describe a 9-year-old female patient with a past medical history of seizure disorder who presented with 3-week history of intermittent fevers, fatigue, weakness, and multiple unexplained bruises. Complete blood count (CBC) was remarkable for marked thrombocytopenia. Trephine biopsy showed a normocellular marrow with maturing trilineage hematopoiesis and scattered atypical megakaryocytes including numerous small hypolobated forms with frequent forms showing separated nuclei. Her CBC showed normalization 7 months after VPA was stopped., Conclusions: The presence of bone marrow suppression and myelodysplasia in patients on VPA treatment should be taken into consideration as it can cause a diagnostic pitfall especially in pediatric and elderly populations. A careful review of past medical history and medications can help make the correct diagnosis., (© 2022 by the Association of Clinical Scientists, Inc.)

Introduction: GNE myopathy is an autosomal recessive distal myopathy caused by a biallelic mutation in UDP-N-acetylglucosamine 2-epomerase/N-acetylmannosamine kinase. In this study, we discuss the clinical features, pathological characteristics, genetic profiles, and atypical clinical manifestations of 22 Chinese GNE patients., Materials and Methods: Retrospective analysis was performed for GNE myopathy patients at our institute between 2005 and 2021. Histopathological analysis and gene testing were done according to standard protocols., Results: Molecular analysis revealed 14-reported and 7 novel mutations, including c.125G > A (p.P42Q), c.226G > A (p.V76I), c.970C > G (p.H324D), c.155A > G (p.D52G), c.1055G > A (p.R352H), c.1064G > A (p.G355E), and c.491 T > C (p.I164T) in GNE. D207V was the most frequent mutation showing an allele frequency of 25%. A total of 21 patients presented classic clinical manifestation, and only 1 patient had signs of proximal muscle weakness. A patient containing p.V603L and p.R160X mutations showed idiopathic thrombocytopenia and distal weakness. There were 4 female patients who experienced rapid deterioration after pregnancy., Discussion: Our study revealed 7 novel mutations in GNE, where p.D207V was shown as a potential hotspot mutation in Chinese patients. Idiopathic thrombocytopenia should be a concern in GNE myopathy patients. Twenty-seven percent of female patients experienced rapid deterioration during pregnancy or after delivery., (© 2022. Fondazione Società Italiana di Neurologia.)

Maternal floor infarction (MFI) and massive perivillous fibrin deposition (MPFD) are overlapping placental disorders of unknown etiology, associated with adverse obstetric outcome, and a significant risk of recurrence. We describe a 31-year-old mother with asymptomatic thrombocytopenia throughout pregnancy and a positive lupus anticoagulant. She delivered a normal female neonate at term, whose weight was small for gestational age, with a placenta weighing less than the 10 th percentile. Placental examination showed MPFD together with excessive subchorionic fibrinoid deposition. The placenta showed diffuse C4d deposition and an immune-mediated reaction was postulated for the pathogenesis of the placental changes. We suggest that excessive subchorionic fibrinoid deposition may be part of the morphologic spectrum of MFI/MPFD.

Idiopathic multicentric Castleman disease (iMCD) is a systemic disorder characterized by systemic inflammation and organ dysfunction associated with an increase in pro-inflammatory cytokines. Some patients with iMCD are positive for autoantibodies, although their significance and relationship with specific associated autoimmune diseases are unclear. This study retrospectively analyzed the clinicopathological features of iMCD patients focusing on autoantibodies. Among 63 iMCD patients in our database, 19 were positive for at least one autoantibody. Among the 19, we identified five with plasma cell type (PC)-iMCD lymph node histopathology and positive anti-phospholipid antibodies. These patients were likely to have thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, organomegaly (TAFRO) symptoms, and thrombotic events. The present study suggests that patients with undiagnosed or atypical autoimmune diseases, including anti-phospholipid syndrome (APS), were treated for iMCD. APS may present with thrombocytopenia or even multi-organ failure, which overlap with clinical presentations of iMCD. Due to differences in the treatment regimen and follow-up, recognition of the undiagnosed autoimmune disease process in those suspected of iMCD is essential. Our study highlights the importance of complete exclusion of differential diagnoses in patients with iMCD in their diagnostic workup.

Since thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome was first proposed in 2010, there has been considerable progress in this area, particularly regarding its association with idiopathic multicentric Castleman disease (iMCD). TAFRO syndrome is a heterogeneous category with a constellation of symptoms that can develop in the setting of infection, rheumatologic disorder, malignancy, and iMCD. Now, iMCD with TAFRO symptoms is subtyped as iMCD-TAFRO. However, confusion between TAFRO syndrome and iMCD-TAFRO remains. In this article, we discuss the current understanding and future research agenda of TAFRO syndrome and iMCD-TAFRO from the perspective of its new validated international definition.

Humans produce and remove 1011 platelets daily to maintain a steady-state platelet count. The tight regulation of platelet production and removal from the blood circulation prevents anomalies in both processes from resulting in reduced or increased platelet count, often associated with the risk of bleeding or overt thrombus formation, respectively. This review focuses on the role of glycans, also known as carbohydrates or oligosaccharides, including N- and O-glycans, proteoglycans, and glycosaminoglycans, in human and mouse platelet and megakaryocyte physiology. Based on recent clinical observations and mouse models, we focused on the pathologic aspects of glycan biosynthesis and degradation and their effects on platelet numbers and megakaryocyte function., (© 2022 by The American Society of Hematology.)

Introduction: Thrombocytopenia has been associated with some neoplastic processes, including hematologic neoplasia. There is no information regarding specific changes in platelet measurands in dogs with hematologic neoplasia compared with healthy dogs. The objectives of our study were to establish RIs, evaluate platelet measurands in dogs with hematologic neoplasia, and compare these measurands in patients with hematologic malignancies with or without thrombocytopenia., Methods: This was a retrospective study. Platelet measurands were determined using the ADVIA 120 Hematology analyzer when a CBC was performed and included the platelet count, MPV, platelet distribution width (PDW), plateletcrit (PCT), mean platelet component (MPC), platelet component distribution width (PCDW), mean platelet mass (MPM), platelet mass distribution width (PMDW), and number of large platelets. Reference intervals were determined retrospectively using data from 129 healthy dogs. Patients with hematologic neoplasia (n = 50) were identified through retrospective evaluation of medical records from the Auburn University Veterinary Teaching Hospital and separated into thrombocytopenic (n = 20) and nonthrombocytopenic groups (n = 30)., Results: Platelet count and PCT were significantly higher in older healthy dogs compared with younger dogs. Significant differences were identified when comparing healthy dogs with those with hematologic neoplasia without thrombocytopenia for PDW, PCDW, PMDW, and the number of large platelets, indicating the presence of more heterogeneous platelets. Thrombocytopenic dogs with hematologic neoplasia had significantly decreased MPCs and increased MPVs, MPMs, and PCDWs compared with nonthrombocytopenic dogs with neoplasia., Conclusions: Dogs with hematologic neoplasia had more heterogeneous platelets, whereas thrombocytopenic patients with neoplasia had more activated platelets., (© 2022 American Society for Veterinary Clinical Pathology.)

Background: Neoadjuvant chemoradiotherapy and total mesorectal excision compose the standard of care for rectal cancer in multiple guidelines. However, neoadjuvant chemoradiotherapy has not exhibited clear survival benefits but rather has led to an increase in adverse events. Conversely, neoadjuvant chemotherapy is expected to prevent adverse events caused by radiation, yet this treatment is still controversial., Objective: The purpose of this study was to evaluate the feasibility and efficacy of S-1 and oxaliplatin neoadjuvant chemotherapy together with total mesorectal excision for resectable locally advanced rectal cancer., Design: The study was a prospective, single-arm phase II trial., Settings: The study was conducted at multiple institutions., Patients: Fifty-eight patients with resectable locally advanced rectal cancer were enrolled., Intervention: Three cycles of S-1 and oxaliplatin were administered before surgery. S-1 was administered orally at 80 mg/m2 per day for 14 consecutive days, followed by a 7-day resting period. Oxaliplatin was given intravenously on the first day at a dose of 130 mg/m2 per day. The duration of 1 cycle was considered to be 21 days. Total mesorectal excision with bilateral lymph node dissection was carried out after neoadjuvant chemotherapy., Main Outcome Measures: The study was designed to detect the feasibility and efficacy of S-1 and oxaliplatin as neoadjuvant chemotherapy., Results: The completion rate of 3 courses of S-1 and oxaliplatin as neoadjuvant chemotherapy was 94.8% (55/58). The reasons for discontinuation were thrombocytopenia (3.4%) and liver injury (1.7%). The most common severe (grade ≥3) adverse effect of neoadjuvant chemotherapy was thrombocytopenia (3.4%). There were no severe adverse clinical symptoms. Consequently, R0 resection was achieved in 51 (98.1%) of 52 patients. Pathologic complete response occurred in 10 patients (19.2%)., Limitations: This was a single-arm, nonrandomized phase II study., Conclusions: The combination of S-1 and oxaliplatin neoadjuvant chemotherapy and total mesorectal excision is a feasible and promising treatment option for resectable locally advanced rectal cancer. See Video Abstract at http://links.lww.com/DCR/B555., Un Estudio Prospectivo Multicntrico Fase Ii Sobre La Factibilidad Y Eficacia De La Quimioterapia Neoadyuvante Scon Oxaliplatino Para El Cncer De Recto Localmente Avanzado: ANTECEDENTES:La quimiorradioterapia neoadyuvante y la escisión mesorrectal total constituyen el estándar de atención para el cáncer de recto en varias guías. Sin embargo, la quimiorradioterapia neoadyuvante no ha mostrado beneficios claros en la sobrevida, pero si ha creado un aumento de eventos adversos. Por otro lado, se espera que la quimioterapia neoadyuvante prevenga los eventos adversos asociados a la radiación, aunque este tratamiento sigue siendo controvertido.OBJETIVO:Evaluar la factibilidad y eficacia de la quimioterapia neoadyuvante S-1 con oxaliplatino en conjunto con la escisión mesorrectal total para el cáncer de recto localmente avanzado resecable.DISEÑO:El estudio fue un ensayo prospectivo fase II de brazo único.AMBITO:Estudio realizado en múltiples instituciones.PACIENTES:Se incluyeron 58 pacientes con cáncer de recto localmente avanzado resecable.INTERVENCIÓN:Se administraron tres ciclos de S-1 con oxaliplatino antes de la cirugía. Se administró S-1 por vía oral a 80 mg / m2 / día durante 14 días consecutivos, seguido de un período de descanso de 7 días. El oxaliplatino se administró por vía intravenosa el primer día a una dosis de 130 mg / m2 / día. Se consideró la duración de un ciclo de 21 días. Posterior a la quimioterapia neoadyuvante se realizó la excisión total mesorrectal con disección ganglionar bilateral.PRINCIPALES VARIABLES EVALUDADAS:El estudio fue diseñado para conocer la factibilidad y eficacia de S-1 con oxaliplatino como quimioterapia neoadyuvante.RESULTADOS:La tasa de conclusión con tres ciclos de S-1 con oxaliplatino como quimioterapia neoadyuvante fue del 94,8% (55/58). Los motivos de interrupción fueron trombocitopenia (3,4%) y daño hepático (1,7%). El efecto adverso grave más común (grado ≥ 3) de la quimioterapia neoadyuvante fue la trombocitopenia (3,4%). No hubo síntomas clínicos adversos graves. Como resultado, la resección R0 se logró en 51 de 52 pacientes (98,1%). Una respuesta patológica completa se obtuvo en 10 pacientes (19,2%).LIMITACIONES:Fue un estudio de fase II no aleatorizado de un solo brazo.CONCLUSIONES:La combinación de S-1 con oxaliplatino como quimioterapia neoadyuvante y escisión mesorrectal total es factible y es una opción de tratamiento prometedora para el cáncer de recto localmente avanzado resecable. Consulte Video Resumen en http://links.lww.com/DCR/B555. (Traducción-Dr Juan Antonio Villanueva-Herrero)., (Copyright © The ASCRS 2022.)

Inherited thrombocytopenia 2 (THC2) is difficult to diagnose due to the lack of specific clinical characteristics and diagnostic methods. To identify potential plasma protein biomarkers for THC2, we collected the plasma samples from a THC2 family (9 THC2 and 15 non-THC2 members), enriched the medium and low abundant proteins using Proteominer and analyzed the protein profiles using the liquid chromatography-mass spectrometry in data independent acquisition mode. Initially, we detected 784 proteins in the plasma samples of this family and identified 27 up-regulated and 36 down-regulated in the THC2 group compared to the non-THC2 group (|log 2 ratio| >1 and p -value <0.05). To improve the predictive power, top eight dysregulated proteins (B7Z2B4, LTF, HP, ERN1, IGHV1-8, A0A0X9V9C4, VH6DJ, and D3JV41) were selected by an area under the curve-based random forest process to construct a clinical model. Multivariate analysis with random forest and support vector machine showed that the prediction model provided high discrimination ability for THC2 diagnosis (AUC: 1.000 and 0.967, respectively). The potential plasma protein biomarkers will be tested in more THC2 patients and other thrombocytopenia patients to further validate their specificity and sensitivity.

Immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disorder characterized by persistent thrombocytopenia. It may be induced by different pathogenesis due to its heterogeneity, and the therapeutic effects vary on different patients. Bone marrow derived mesenchymal stem cells (BMMSCs) can modulate innate and adaptive immunity, thus resulting in a tolerant microenvironment. Functional defects and immunomodulatory disorders of BMMSCs are significant causes of ITP. Functional effects associated with the activation of the P53 pathway include decreased activity of the phosphatidylinositol 3 kinase/AKT pathway and activation of the TNFAIP3/NF-κB/SMAD7 pathway. Immune dysfunction appears to be correlated with an impaired ability of BMMSCs to induce various types of immune cells in ITP. An in-depth investigation into the pathogenesis of ITP facilitates the treatment of ITP, but larger-scale clinical trials are needed to verify the efficacy of exogenous BMMSCs in the clinical treatment of ITP.