Browsing by Autor "Juan Carlos Valencia"

Now showing 1 - 5 of 5

Allogeneic Hematopoietic Progenitor Cell from Peripheral Whole Blood in Acute Myeloid Leukemia
(Elsevier BV, 2024) Ricardo Amaru; Reyna Mamani; Jeaneth Velarde; Mireya Carrasco; Edgar Teddy Quispe Soto; Silvia Mancilla; Juan Carlos Valencia; Daniela Patón; Ariel Amaru
Acute Myeloid Leukemia (AML) standard treatment involves initial induction therapy administrating two cycles of the 3+7 protocol (3 days anthracycline + 7 days cytarabine), and post-remission therapy of 3 cycles of high-dose cytarabine. The 5-year overall survival is 20 % (PMID: 33734442). During prolonged aplasia, infections and hemorrhages can cause treatment failure and death (PMID: 32236160). That is why transfusions of allogeneic hematopoietic progenitor cells (Allo-HPC) from whole peripheral blood to reduce the time of aplasia and complications were of interest. We studied 6 patients (3 males, 3 females) with AML (M1, M2), average age 35 years (18-60 years), who received Allo-HPC from whole peripheral blood during aplasia after each 3+7 regimen. The transfusion was performed at day 14 (day 12-16) post-regimen, when patients had neutrophils &lt;100/ul (0-100/ul). Regarding donors, one corresponded to HLA identical sibling, and 5 to haploidentical (2 fathers, 2 mothers and 1 brother), they received G-CSF 300 μg subcutaneously every 12 hours over 3 days, then 450 ml phlebotomy was performed. Phlebotomy displayed median WBC 27,310/ul, neutrophils 21,830/ul, CD34+ cells 9/ul, hemoglobin 14.8 g/dl, and platelets 218,000/ul. Thus, whole peripheral blood obtained was transfused through patients' CVC after premedication with dexamethasone 8 mg and metamizole 1 g. FISH (Y chromosome, Vysis CEP-Y DYZ1) and RT-PCR (HUMARA gene) studies were performed for chimerism analysis. Recovery of neutrophils &gt;500/ul was observed at day 9 and platelets &gt;20,000/ul at day 6. One case of cutaneous rush was observed as an adverse event. MRD after each cycle reflected 0.01% average. Three patients remain alive with follow-up of 4 years, 5 years and 1 year respectively. Two patients relapsed and died during 1year follow-up. One patient developed optic neuritis and did not receive high-dose cytarabine therapy, relapsed and died after 6 months. None of the patients presented acute or chronic GVHD. Regarding the results of chimerism, one male patient (1year follow-up) showed mixed chimera by FISH (Y=95%) and by RT-PCR (HUMARA gene), such studies were still in progress in the other two women patients. Contrasting patients who received Allo-HPC from the ones who do not, statistically differences were found in neutrophils recovery and hospital staying, the former displayed 9 + 3 days vs 14 + 4 days (p=0.008) and 19 +5 days vs 25 + 4 days (p=0.009) respectively, infections also decreased from 83% to 25%. Transfusion of Allogeneic Hematopoietic Progenitor Cell from Peripheral whole blood reduces the duration of aplasia, infections, inpatient stays, and increases survival.
Erythroid Leukemia Is Increased at High Altitude (4000 m)
(Elsevier BV, 2024) Ricardo Amaru; Maria Julieta Luna Leyza; Luis Felipe Mamani; Silvia Mancilla; Daniela Patón; Juan Carlos Valencia; Mireya Carrasco; Ariel Amaru
Acute erythroid leukemia (AEL) also known as pure erythroid leukemia (PEL) from the 2016 WHO update (PMID: 35264503; Wang, Am J Hematol. 2017; 92: 292-296) is a rare and unique subtype of acute myeloid leukemia (AML). It is characterized by immature erythroid precursors predominance with a high frequency of gains and amplifications involving EPOR/JAK2 (PMID: 35839275) and phosphorylation of ERK1/2 by inhibiting Fli-1 Promoter Activity (Min Mo, Catalysts, 2022. 13.1:84). AEL accounts for 1% of AML cases and can evolve from prior myelodysplastic syndrome or develop de novo, it is typically observed in adults with a median age ranging 66-68 years, and of dismal prognosis (&lt;6 months overall median survival) (PMID: 36323674). Its distinction attributes to erythroblastic proliferation (&gt;80%), pancytopenia, and extensive bone marrow involvement by proerythroblasts (≥30%). Common immunophenotype markers include CD105, CD34, CD71, CD36, CD235 (Wang, Am J Hematol. 2017). Moreover, it has been reported that hypoxia influences the development of erythroleukemia through various mechanisms, including promoting erythroid differentiation, inducing hemoglobin production, defining cell heterogeneity, regulating erythropoiesis, and influencing the bone marrow microenvironment (PMID: 33675821; 17255519). Regardingly, an overexpression of HIFs is related with a bad prognosis in AML (PMID: 25687039), HIF-1α is involved in cancer early stages, whereas HIF-2α in the later stages (PMID: 29753878). HIF-2a expression plays an important role in regulating proliferation in erythroleukemia cells under hypoxia (PMID: 26898802). Thus, we aimed to search for the hematologic and immunophenotypic characteristics of AEL cases among all AML diagnoses at high altitude. We retrospectively analyzed cases of AML diagnosed in Bolivia from the period of May 2019 to April 2024 considering the different altitudes 4000m (n=68), 2000m (n=62), and 400m (n=71), and gathered a comprehensive account of hematologic, bone marrow morphology, and immunophenotypic features. Among AML cases (n=201), 13 cases of AEL were identified which corresponded to 6.5 %. Interestingly, AEL cases at 4000 m accounted for 13.2 % (female 2, male 7, median age 54 years), and this was significantly higher (p=0.02) when compared to cases at 2000 m representing 3.2 % (female 1, male 1, median age 75 years) or at 400 m with 2.8 % (female 2, median age 52 years). Hematologic indices displayed mean Hb 7.3 g/dl, WBC: 11515/ul and Plt: 127154/ul. Bone marrow findings reflected &gt; 80% of prominent erythroid precursors with large irregular nuclei, dispersed chromatin, 1 to 3 elongated nucleoli, deeply basophilic cytoplasm, and an intense mitotic activity. Immunophenotypic features revealed CD34, CD71, CD105, CD36 and CD235 regarding erythroid clonality. AEL incidence is increased at high altitude, reflects intriguingly morphology and hematological characteristics. This increase may be due to the increase in HIF and Epo at high altitude, since the barometric pressure (462 mmHg) and the oxygen level in the air (14%) at high altitude are low. So, further studies elucidating the genetic mechanism involved are of interest.
History of Thrombosis at High Altitude Associates With Increased Erythropoietin
(Wiley, 2025) Ricardo Amaru; Josef T. Prchal; Mireya Carrasco; Silvia Mancilla; Teddy Quispe; Julieta Luna; Juan Carlos Valencia; Daniela Patón; Victor R. Gordeuk
In Bolivian Aymara with erythrocytosis, elevated erythropoietin strongly associates with history of thrombosis. Hypoxia and iron deficiency predict elevated erythropoietin, but they do not have a direct relationship with thrombosis history. Source: Artwork by Nadia Gordeuk.
Phenotypic Variations Related to Hypoxic Responses Among Andean Highlanders Living at Different Altitudes (400m, 4000m, 5000m)
(Elsevier BV, 2022) Ricardo Amaru; Emerson Cayo; Teddy Quispe; Juan Carlos Valencia; Daniela Patón; Luis Felipe Mamani; Julieta Luna
Introduction Adaptation to high altitude poses selective evolutionary changes involving multiple and challenging adaptive responses, and one of them deals with the low pressure of oxygen. Native Bolivian Andeans have lived at an average of 3000-5000 m for about 14,000 years, and have developed different erythroid phenotypes compared to other populations living at high altitude (PMID 30781443; PMID 25342802). Although Andeans have developed genetic adaptations related to erythropoiesis regulation (Blood, ASH 2316, 2018) they still undergone with polycythemic states, and those of clinical relevance are often Chronic Mountain Sickness erythrocytosis (CMS-E), secondary erythrocytosis (SE) and polycythemia vera (PV) (Rev Hematol Mex. 2016 Jan;17(1):8-20). Either adaptation or erythrocytosis condition entails important changes in hemoglobin, SpO2, P50 and lactate, so evaluating significant changes among Andeans living at different altitudes as well as the modifications between erythrocytosis patients and healthy highlanders became of interest. Material and method We collected venous blood samples from Bolivian native Andeans born at 4000 m (n=124) but living at 3 different altitudes (400 m, 4000 m, 5000 m), aside from Europeans (n=11) residing at 4000 m. Complete blood count, venous blood gas, and oxygen saturation studies were performed. P50 was measured by using a formula described by Lichtman. Likewise, a differential diagnosis regarding healthy inhabitants and polycythemia patients was performed. Results In healthy Andean inhabitants in different altitudes, the Hb levels increased at increasing altitude (p:0.001), meanwhile SpO2 (p:0.001) and P50 (p:0.001) decreased. No lactate variations among them were observed (Table 1). European subjects at 4000 m in relation to Andean inhabitants at the same altitude displayed higher Hb levels (p: 0.01), without variations in SpO2 and P50, but a significant increased lactate (p: 0.001) (Table 1). When comparing healthy subjects and patients with erythrocytosis (CMS-E, SE, PV) at 4000 m, the latter displayed higher Hb levels (p:0.001), decreased SpO2 (p:0.001), no variations in P50, and increased lactate in CMS-E and SE patients (p:0.01) (Table 2). Similarly, patients with erythrocytosis (CMS-E, SE) at 5000 m, related to healthy subjects at the same altitude, reflected increased Hb (p:0.001), decreased SpO2 (p:0.01), P50 without variations, and increased lactate (p:0.01) (Table 2). Conclusions Native Andeans from Bolivia born at 4000 m but living at different altitudes have variations regarding hematological phenotypes, decreased P50 shifts the hemoglobin dissociation curve to left. Patients with erythrocytosis have distinct phenotypes in relation to healthy subjects characterized by decreased saturation and increased lactate. Higher Hb levels and increased lactate in Europeans living at 4000 m probably due to the different residing time at high altitude, since native Andean inhabited high-altitude regions for many years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
Transferrin and Erythropoietin Increased Levels Correlate with Thrombosis at High Altitude
(Elsevier BV, 2023) Ricardo Amaru; Luis Felipe Mamani; Emma Mancilla; Daniela Patón; Juan Carlos Valencia; Ariel Amaru; Mireya Carrasco
Living at high altitude involves great interest because of the challenging multiple adaptive responses to a hypoxic environment. Native Bolivian Andeans have lived at an altitude of 4000 m in The Andes mountains for about 14,000 years exposed to a low atmospheric pressure (453 mmHg) and low oxygen concentration (12,7%). It was described Andeans adaptation to high altitude is mainly related to cardiovascular issues (PMID: 29100088), with a low significantly genetic selection in HIF pathway components responsible of erythropoiesis regulation (PMID: 36980912), so that they have adapted to exist with increased hemoglobin concentrations. Thus, Andeans can be prevalent to undergone hematological and thromboembolic disorders. Thrombotic events have been reported to be increased at high altitude, and this recently associated to increased transferrin (Tf) (PMID: 36040436), likewise to increased erythropoietin (Epo) (Amaru, RevMed 2022). Increased Tf were described to be induced by both iron deficiency and hypoxia via HIF (PMID: 9242677). In addition, iron deficiency was postulated to inhibit the function of prolyl hydroxylase 2 (PHD2) in the hydroxylation of HIF-2, necessary for recognition and degradation by VHL (PMID:22304911). Under normal conditions, Tf is bound to fibrinogen at a molar ratio of 4:1, leading to plasma Tf sequestration by fibrinogen and leaving little Tf free in the circulation. While at hypoxia conditions, abnormally upregulated Tf potentiates thrombin, factor XIIa and inhibits antithrombin, inducing hypercoagulability (PMID:36040436). Similarly, increased HIF1a at high altitude increases Tf promoting the transferrin gene expression, which contains HIF-1α binding sites in its enhancer region (PMID:36844187). HIF is a DNA-binding transcription factor for activating expression of Epo gene (PMID:32561149). Epo, in turn, is increased due to the hyperegulation of HIF as expected at low atmospheric pressure environments. Epo activates the hypoxia-inducible factor that leads to Epo synthesis to stimulate red blood cell production, which also increases the demand for iron to synthesize hemoglobin (PMID:21078592). This, added to a decreased iron and increased HIF 1a, gives rise to a hyperregulation of Tf. Epo has been described to have prothrombotic properties and be related to thrombotic events (PMID:10779449; Amaru, RevMed 2022). In this sense, to further observe a correlation of transferrin and erythropoietin increased levels with the risk of thrombotic events at high altitude, we studied patients with erythrocytosis, anemia and polycythemia vera. We analyzed clinical, lab tests and epidemiological data of 920 patients with Chronic Mountain Sickness erythrocytosis (CMS-e) (n=560), anemia (n=372), and Polycythemia Vera (PV) (n=20), all Bolivian Andeans born and residing at 4000 m. Considering at this altitude normal hemoglobin concentrations vary from 14-17 g/dl in women and 15-18 g/dl in men, erythrocytosis condition comprises Hb levels &gt;18 g/dl in women and &gt;19 g/dl in men (Amaru et al, Rev Hematol Mex, 2016); similarly, it embraces Hb &lt;12 g/dl for women and &lt;13 g/dl for men in anemias (PMID: 23317073). Positive JAK F617V tests were corroborated in PV patients. Iron deficiency correlation considered serum ferritin &lt;30 ug/L and MCV &lt;80 fL (Clark et al, Nutrition, 2008). Eco-doppler study records confirmed the occurrence of thrombotic events. Data analysis was performed through Excel 16.29.1 and SPSS program, Chi-squared, Fishers and Pearson tests were done. We observed significative increased Tf levels in erythrocytosis, anemia, and PV patients mainly on those presenting iron levels deficiency. Epo was highly increased in erythrocytosis patients with iron deficiency. These results correlated with the incidence of thrombotic events in erythrocytosis (CMS-e) and anemia patients with iron deficiency. Age was also relevant in both groups. (Table 1). The increase of Epo levels correlated with thrombosis in erythrocytosis and PV patients with iron deficiency (Table 1). Transferrin and Erythropoietin increased levels at high altitude correlated with thrombosis in Chronic Mountain Sickness erythrocytosis and iron deficiency anemia patients. However, Increased Tf did not correlate with thrombosis in PV patients at high altitude. Our data confirm that increased Tf and Epo have prothrombogenic properties in CMS-e, iron deficiency anemia patients at high altitude.