34 Erythropoiesis and Red Cell Turnover Flashcards
TRUE OR FALSE
Extramedullary hematopoiesis during adult years indicates pathologic rather than compensatory blood formation, such as is seen in patients with primary myelofibrosis wherein the stem cells have abnormal interaction with the extracellular matrix.
TRUE
Extramedullary hematopoiesis during adult years indicates pathologic rather than compensatory blood formation, such as is seen in patients with primary myelofibrosis wherein the stem cells have abnormal interaction with the extracellular matrix.
Hepatic or renal
During fetal life, EPO production is primarily ______________.
Hepatic
At birth, a gradual switch to renal production of EPO occurs.
In the adult, the kidney is responsible for approximately 85% of total production.
Hypotheses regarding commitment and differentiation of multipotential progenitors toward the erythroid lineage:
Extrinsic factors such as cytokines play an instructive role in lineage specification, by inducing the expression of lineage-specific transcription factors
Deterministic model
Hypotheses regarding commitment and differentiation of multipotential progenitors toward the erythroid lineage:
Proposes that the transcription factors encoding any specific lineage are expressed stochastically, in an autonomous, temporally regulated process, independent of extrinsic signals.
Stochastic model
Expressed during erythroid differentiation, with highest expression in colony-forming units–erythroid (CFU-Es) and pronormoblasts
Promotes erythroid differentiation by activating several erythroid-specific genes and represses transcription of Kit receptor and GATA2
GATA1 protein
Diamond-Blackfan syndrome, an inherited bone marrow failure syndrome with selective deficiency of erythroid precursors in the marrow; caused by haploinsufficiency of ribosomal protein genes
A transcription factor initially identified in lymphoid cells, has been shown to regulate erythroid differentiation, especially during the switch from fetal to adult hemoglobin.
BCL11A
An inverse relationship exists between BCL11A and HbF expression in erythroid cells.
Involved in actin dynamics and plays important roles in erythroblast survival and enucleation in the early and late stages of terminal erythropoiesis
Pleckstrin-2
Hormone that promote the self-renewal of BFU-E and prevent their differentiation to the more mature CFU-E.
Have been used to treat anemia in Diamond-Blackfan syndrome.
Glucocorticoids
They play an important role during stress erythropoiesis
Hormones that play an essential role during terminal human erythroid cell differentiation by promoting nuclear receptor coactivator 4 recruitment to chromatin regions that are in proximity to RNA polymerase II
Thyroid hormones
Anemia is often observed in patients with hypothyroidism
BFU-E or CFU-E
Has higher-level expression of EPOR and transferrin receptor density and higher EPO dependency—and form smaller colonies (50–200 cells) that mature in 3–5 days
CFU-E
TRUE OR FALSE
EPOR density declines sharply on early erythroblasts, and EPORs are absent from the more mature erythroblast forms, whereas the number of receptors for transferrin increases, reflecting the increased demands for iron for heme synthesis.
TRUE
EPOR density declines sharply on early erythroblasts, and EPORs are absent from the more mature erythroblast forms, whereas the number of receptors for transferrin increases, reflecting the increased demands for iron for heme synthesis.
Loss of _____________ receptors heralds the translocation of polychromatophilic macrocytes (reticulocytes) into blood, but some newly emerging erythrocytes remain adherent, even after release, and are temporarily sequestered by the spleen
Fibronectin
Extrusion results in a reticulocyte and a nucleus enveloped with a thin layer of cytoplasm and the plasma membrane called
Pyrenocyte
Pyrenocytes are then rapidly eliminated by marrow macrophages by phosphatidylserine-dependent phagocytosis.
The principal hormone regulating erythropoiesis is ________ , which is produced in adult life principally in the kidney
EPO
Half-life (T1/2) of 4–12 hours
The transcriptional activation of the EPO gene is controlled by a specific sequence located in the 3′ flanking EPO noncoding region termed:
Hypoxia-responsive element (HRE)
Interaction of EPO with its receptor EPOR results in :
- (1) stimulation of erythroid cell division,
- (2) erythroid differentiation by induction of erythroid-specific protein expression, and
- (3) prevention of erythroid progenitor apoptosis
Detrimental EPO effects include:
A poorly understood increased cancer mortality, increased blood pressure, and thrombosis
The response to hypoxia is controlled by transcriptional factors termed:
Hypoxia-inducible factors (HIFs)
Type of HIF
Induced in hypoxic cells and binds to a cis-acting nucleotide sequence of hypoxia-controlled gene HRE, first identified in the 3′-flanking region of the human EPO gene.
Regulates approximately 3% of all genes expressed in endothelial tissue
HIF-1
Type of HIF
Has more limited tissue expression than HIF-1, but it is the principal regulator of EPO expression.
HIF-2
Normal human red blood cells have a lifespan of about ________ days
120 days
Physiologic changes as RBC age
- (1) a decrease in the activity of enzymes;
- (2) a progressive decrease of ATP content;
- (3) a loss of lipid asymmetry with exposure of phosphatidylserine;
- (4) an accumulation of lipid peroxidation products;
- (5) a desialylation of membrane glycoprotein;
- (6) an exposure of cryptic senescent antigens and aggregation of AE-1(band 3) protein
- ; (7) a decrease in deformability caused by increased oxidative stress; and
- (8) an increase in cell surface–bound immunoglobulins and complement components
Are small 18-to-22–nucleotide noncoding RNAs that regulate gene expression by inhibiting protein translation or by destabilizing target mRNAs;
They are important regulators of hematopoiesis.
miRNAs
Packed red cell volume
The percentage of the volume of whole blood that is made up by red cells.
The simplest and most widely used test for estimating the size of RCM.
An excellent approximation of total RCM and a functional estimation of the oxygencarrying capacity and whole-blood viscosity.
Hematocrit
Formula for hematocrit
The product of the red cell count and the mean red cell volume (MCV)
Total body hematocrit is the RCM in the circulation divided by the total blood volume.
When the hematocrit is greater than ___ %, almost all patients have an increase in total RCM.
60%
Effective erythropoiesis is most simply estimated by determining the
Reticulocyte count
Formula for Reticulocyte index
Reticulocyte index = absolute reticulocyte count/correction factor (usually 2)
An average factor of 2 often is used; however, the factor depends on the degree of anemia: 1.5 in mild cases, 2.5 in moderate cases, and 3.0 in severe
Total erythropoiesis, which is the sum of effective and ineffective red cell production, can be estimated from a ________
Marrow examination
A differential count then is performed, determining the ratio between granulocytic and erythroid precursors (M:E ratio). In a normal adult, the ratio is approximately 3:1–5:1.
Hypoxia increases red cells by enhancing HIFs with subsequent EPOstimulated erythropoiesis.
Upon return to normoxia, the secondary erythrocytosis is overcorrected, as the accumulated, newly formed red cells undergo preferential destruction, a process termed
Neocytolysis
