These articles are compiled following inspiration from a recent WMC Research post, combined with clinical patient complaints.
Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells
Review. Brzeźniakiewicz-Janus K, Rupa-Matysek J, Gil L. Stem Cell Rev Rep. 2020 Jun;16(3):472-481. doi: 10.1007/s12015-020-09971-y.
“Acquired aplastic anemia is a rare disorder presenting with bone marrow failure syndrome due to autoimmune destruction of early hematopoietic stem cells and stem cell progenitors [1, 2]. It has been shown that acquired AA may predispose to myelodysplastic syndrome and leukemia in approximately 15–16% of cases [3, 4]. … The name of the disease, aplastic anemia (AA) is misleading because it only suggests anemia whereas pancytopenia is often presented. The term ‘bone marrow failure’ is a broader concept, and the cause may not only be AA, but hypocellular myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)…
The Role of Inflammaging in Pathogenesis of Aplastic Anemia
The process of “inflammaging” refers to chronic, low-grade, sterile inflammation that develops in hematopoietic tissues with advanced age [103]. This leads in the patients to the increased activity of innate immunity and a decrease in acquired immunity. Inflammaging is a consequence of cellular turnover and chronic cellular stress in the absence of infection and is driven by pro-inflammatory mediators including TNF-α and IL-6 that are part of the senescence-associated secretory phenotype (SASP) [104]. In addition, in pathogenesis of inflammaging are involved several danger associated molecular pattern molecules (DAMPs) including extracellular ATP, oxidatively modified DNA; and aggregated proteins released from damaged cells [105]. All these DAMPs lead to activation of the Nlrp3 inflammasome, which drives the process of inflammaging in all tissues including bone marrow [106–108]. Activation of Nlrp3 inflammasome leads to release from innate immunity cells two pro-inflammatory interleukins IL-1β and IL-1 [105–108]. … IL-1β signaling decreases erythropoietin secretion in the kidney [109], IL-18 induces interferon gamma (IFN-γ) expression, which along with IL-1α synergistically inhibits erythroid colony formation [110]. This enhanced basal level of inflammaging may lead to an increased risk of clonal hematopoiesis and as a consequence spontaneous anemia…”
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Human Hematopoietic Stem, Progenitor, and Immune Cells Respond Ex Vivo to SARS-CoV-2 Spike Protein
Ropa J, Cooper S, Capitano ML, Van't Hof W, Broxmeyer HE. Stem Cell Rev Rep. 2021 Feb;17(1):253-265. doi: 10.1007/s12015-020-10056-z
“… There is little known about the effects that SARS-CoV-2 infection or exposure has on many host cell types, including primitive and mature hematopoietic cells. The hematopoietic system is responsible for giving rise to the very immune cells that defend against viral infection and is a source of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) …. We examined the expression of ACE2, to which SARS-CoV-2 Spike (S) protein binds to facilitate viral entry, in cord blood derived HSCs/HPCs and in peripheral blood derived immune cell subtypes. ACE2 is expressed in low numbers of immune cells, higher numbers of HPCs, and up to 65% of rigorously defined HSCs. We also examined effects of exposing HSCs/HPCs and immune cells to SARS-CoV-2 S protein ex vivo. HSCs and HPCs expand less effectively and have less functional colony forming capacity when grown with S protein, while peripheral blood monocytes upregulate CD14 expression and show distinct changes in size and granularity. That these effects are induced by recombinant S protein alone and not the infectious viral particle suggests that simple exposure to SARS-CoV-2 may impact HSCs/HPCs and immune cells via S protein interactions with the cells, regardless of whether they can be infected.”
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SARS-CoV-2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism
Kronstein-Wiedemann R, Stadtmüller M, Traikov S, Georgi M, Teichert M, Yosef H, Wallenborn J, Karl A, Schütze K, Wagner M, El-Armouche A, Tonn T. Stem Cell Rev Rep. 2022 Jun;18(5):1809-1821. doi: 10.1007/s12015-021-10322-8
“Background: … Severe COVID-19 disease is accompanied by reduced erythrocyte turnover, low hemoglobin levels along with increased total bilirubin and ferritin serum concentrations. Moreover, expansion of erythroid progenitors in peripheral blood together with hypoxia, anemia, and coagulopathies highly correlates with severity and mortality. We demonstrate that SARS-CoV-2 directly infects erythroid precursor cells, impairs hemoglobin homeostasis and aggravates COVID-19 disease. …
Results: RBC precursors express ACE2 receptor and CD147 at day 5 of differentiation, which makes them susceptible to SARS-CoV-2 infection. qPCR analysis of differentiated RBCs revealed increased HAMP mRNA expression levels, encoding for hepcidin, which inhibits iron uptake. COVID-19 patients showed impaired hemoglobin biosynthesis, enhanced formation of zinc-protoporphyrine IX, heme-CO2, and CO-hemoglobin as well as degradation of Fe-heme. Moreover, significant iron dysmetablolism with high serum ferritin and low serum iron and transferrin levels occurred, explaining disturbances of oxygen-binding capacity in severely ill COVID-19 patients.”
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SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small CD45- Precursors of Hematopoietic and Endothelial Cells and in Response to Virus Spike Protein Activates the Nlrp3 Inflammasome
Ratajczak MZ, Bujko K, Ciechanowicz A, Sielatycka K, Cymer M, Marlicz W, Kucia M. Stem Cell Rev Rep. 2021 Feb;17(1):266-277. doi: 10.1007/s12015-020-10010-z.
“… ACE2 is the entry receptor for SARS-CoV-2. Expression of this receptor has been described in several types of cells, including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which raises a concern that the virus may infect and damage the stem cell compartment. We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133+CD34+Lin-CD45- cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. … We demonstrate that… the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. Based on this finding, there is a possibility that human VSELs residing in adult tissues could be damaged by SARS-CoV-2, with remote effects on tissue/organ regeneration.”
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An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner
Kucia M, Ratajczak J, Bujko K, Adamiak M, Ciechanowicz A, Chumak V, Brzezniakiewicz-Janus K, Ratajczak MZ. Leukemia. 2021 Oct;35(10):3026-3029. doi: 10.1038/s41375-021-01332-z.
“Mounting evidence accumulates that hematopoietic stem/progenitor cells (HSPCs) and endothelial progenitor cells (EPCs) are damaged during severe SARS-Cov-2/COVID-19 infection [1, 2]. It has been reported that patients infected with COVID-19 frequently presented with anemia, lymphopenia, and thrombocytopenia [1–3]. This negative effect of the virus on human hematopoiesis and endothelium has been reported in infected patients and demonstrated in vitro after exposure of cells to SARS-Cov-2/COVID-19 spike protein (SP) [1, 3, 4]. It is known that virus may enter cells and, directly in case of productive infection, lead to their irreversible damage. …The interaction of viral SP [spike protein] with some of the receptors expressed on the cell surface may lead to their damage as well [1–3]. …
…Exposure to SP resulted in a significant increase in LDH level, which indicates the induction of pyroptosis in these cells. … SARS-CoV-2/COVID-19 may directly impair the viability and proliferative potential of HSPCs by hyperactivation of Nlrp3 inflammasome leading to pyroptosis. … Activation of Nlrp3 inflammasome in innate immunity cells may lead to cytokine storm and activation of the complement cascade and coagulation cascade [5].”
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Severe aplastic anemia after COVID-19 mRNA vaccination: Causality or coincidence?
Tabata S, Hosoi H, Murata S, Takeda S, Mushino T, Sonoki T. J Autoimmun. 2022 Jan;126:102782. doi: 10.1016/j.jaut.2021.102782
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SARS-CoV-2 infection associated with aplastic anemia and pure red cell aplasia
Lee NCJ, Patel B, Etra A, Bat T, Ibrahim IF, Vusirikala M, Chen M, Rosado F, Jaso JM, Young NS, Chen W. Blood Adv. 2022 Jul 12;6(13):3840-3843. doi: 10.1182/bloodadvances.2022007174
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Severe Aplastic Anemia After Receiving SARS-CoV-2 Moderna mRNA Vaccination
Sridhara S, Nair R, Stanek M. J Hematol. 2022 Feb;11(1):34-39. DOI: 10.14740/jh954
A 60-year-old male patient presented to the emergency department with complaints of easy bruising and worsening epistaxis [bloody nose] after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Moderna mRNA vaccination. He had no personal or family history of hematological conditions. He had bruises in various stages involving the upper and lower extremities…. Bone marrow biopsy confirmed very severe aplastic anemia with severely hypocellular bone marrow. His platelets continued to downtrend despite platelet transfusions and steroids. He was treated with immunosuppressive therapy with cyclosporine, anti-thymocyte globulin, eltrombopag and prednisone. The patient was discharged but was readmitted to the hospital secondary to recurrent neutropenic fever and pneumonia. He had high-grade vancomycin-resistant enterococcal infection and Clostridium difficile infection leading to septic shock and succumbing to cardiac arrest. This case demonstrates the possibility of very severe aplastic anemia following SARS-CoV-2 mRNA vaccination and clinicians need to be aware of this rare but serious side effect.
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((More souvenirs: Hospital-acquired infection with vancomycin-resistant Enterococcus faecium transmitted by electronic thermometers. Livornese et al. 1992. doi: 10.7326/0003-4819-117-2-112. /// Nosocomial acquisition of Clostridium difficile infection. McFarland et al. N Engl J Med. 1989. doi: 10.1056/NEJM198901263200402.))
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Acquired aplastic anemia following SARS-CoV-2 vaccination
Röth A, Bertram S, Schroeder T, Haverkamp T, Voigt S, Holtkamp C, Klump H, Wörmann B, Reinhardt HC, Alashkar F. Eur J Haematol. 2022 Aug;109(2):186-194. DOI: 10.1111/ejh.13788
“mRNA-based SARS-CoV-2 vaccines are routinely recommended in immune-compromised patients, including patients with AA [aplastic anemia], as these patients are at increased risk of contracting COVID-19 and developing a more severe course of disease. Between March 2021 and November 2021 relapse of AA occurred in four … out of 135 patients currently registered at our department and two de novo cases of AA in temporal context to vaccination against SARS-CoV-2, were documented. Median time after first COVID-19 vaccination and relapse of AA was 77 days. All relapsed patients were vaccinated with the mRNA-based vaccine Comirnaty®. … Our observations should prompt clinicians to take vaccine-induced relapse of AA or de novo AA after SARS-CoV-2 vaccination into account. Furthermore, careful clinical monitoring and vigilance for signs or symptoms that may indicate relapse of AA (e.g., bleeding complications) are indicated.”
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A New Immunosuppressive Therapy for Very Severe Aplastic Anemia in Children with Autoantibodies
Wang ZJ, Chen HB, Zhou F, Yu H, Wu XY, Shen YQ, Qiu YN, Jin RM. Curr Med Sci. 2022 Apr;42(2):379-386. doi: 10.1007/s11596-022-2519-2.
“At present, a number of very severe aplastic anemia (VSAA) patients cannot receive hematopoietic stem cell transplantation (HSCT) or standard immunosuppressive therapy (IST) due to the high cost of therapy, shortage of sibling donors, and lack of resources to support the HSCT. In addition, some VSAA patients with autoantibodies have no life-threatening infections or bleeding at the time of initial diagnosis. Considering the disease condition, economics and other factors, the present study designed a new and relatively mild treatment strategy: cyclosporine A plus pulsed high-dose prednisone (CsA+HDP).
… The novel CsA+HDP regimen has good therapeutic effect and safety for VSAA patients with autoantibodies, who have no serious life-threatening infections or bleeding at the time of initial diagnosis.”