34 Erythropoiesis and Red Cell Turnover

Question 1

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.

Answer 1

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.

Question 2

Hepatic or renal

During fetal life, EPO production is primarily ______________.

Answer 2

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.

Question 3

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

Answer 3

Deterministic model

Question 4

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.

Answer 4

Stochastic model

Question 5

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

Answer 5

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

Question 6

A transcription factor initially identified in lymphoid cells, has been shown to regulate erythroid differentiation, especially during the switch from fetal to adult hemoglobin.

Answer 6

BCL11A

An inverse relationship exists between BCL11A and HbF expression in erythroid cells.

Question 7

Involved in actin dynamics and plays important roles in erythroblast survival and enucleation in the early and late stages of terminal erythropoiesis

Answer 7

Pleckstrin-2

Question 8

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.

Answer 8

Glucocorticoids

They play an important role during stress erythropoiesis

Question 9

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

Answer 9

Thyroid hormones

Anemia is often observed in patients with hypothyroidism

Question 10

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

Answer 10

CFU-E

Question 11

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.

Answer 11

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.

Question 12

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

Answer 12

Fibronectin

Question 13

Extrusion results in a reticulocyte and a nucleus enveloped with a thin layer of cytoplasm and the plasma membrane called

Answer 13

Pyrenocyte

Pyrenocytes are then rapidly eliminated by marrow macrophages by phosphatidylserine-dependent phagocytosis.

Question 14

The principal hormone regulating erythropoiesis is ________ , which is produced in adult life principally in the kidney

Answer 14

EPO

Half-life (T1/2) of 4–12 hours

Question 15

The transcriptional activation of the EPO gene is controlled by a specific sequence located in the 3′ flanking EPO noncoding region termed:

Answer 15

Hypoxia-responsive element (HRE)

Question 16

Interaction of EPO with its receptor EPOR results in :

Answer 16

• (1) stimulation of erythroid cell division,
• (2) erythroid differentiation by induction of erythroid-specific protein expression, and
• (3) prevention of erythroid progenitor apoptosis

Question 17

Detrimental EPO effects include:

Answer 17

A poorly understood increased cancer mortality, increased blood pressure, and thrombosis

Question 18

The response to hypoxia is controlled by transcriptional factors termed:

Answer 18

Hypoxia-inducible factors (HIFs)

Question 19

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

Answer 19

HIF-1

Question 20

Type of HIF

Has more limited tissue expression than HIF-1, but it is the principal regulator of EPO expression.

Answer 20

HIF-2

Question 21

Normal human red blood cells have a lifespan of about ________ days

Answer 21

120 days

Question 22

Physiologic changes as RBC age

Answer 22

• (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

Question 23

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.

Answer 23

miRNAs

Question 24

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.

Answer 24

Hematocrit

Question 25

Formula for hematocrit

Answer 25

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.

Question 26

When the hematocrit is greater than ___ %, almost all patients have an increase in total RCM.

Answer 26

60%

Question 27

Effective erythropoiesis is most simply estimated by determining the

Answer 27

Reticulocyte count

Question 28

Formula for Reticulocyte index

Answer 28

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

Question 29

Total erythropoiesis, which is the sum of effective and ineffective red cell production, can be estimated from a ________

Answer 29

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.

Question 30

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

Answer 30

Neocytolysis