rbc structure and function

THE RED BLOOD CELL:

STRUCTURE AND

FUNCTION

Blood:Ave 70 kg 5 L of bld (7% by vol)

Erythrocytes

Structurally the simplest

cell in the body

Basic function: Create

& maintain an

environment for

physical integrity &

functionality of Hgb

Erythropoiesis

(Kinetics)

Substances necessary for RBC production:

Metals (iron, cobalt,

manganese)

Vitamins (B12, B6, C,

E, folate, riboflavin,

pantothenic, thiamine)

Amino acids

Regulatory substances:

Erythropoietin

Thyroid hormones

Androgens

Erythroid hyperplasia of BM in anemia

Reduced production

Deficiency of hematinics

Iron deficiency

Folate & B12 deficiency

Dyserythropoiesis

ACD

MDS

Sideroblastic a

Marrow infiltration

Failure of production

Aplastic anemia

Pure red cell aplasia

Increased destruction

Hemolytic anemia

Intrinsic causes

Membrane defects

Enzymopathy

Hemoglobinopathy

Extrinsic causes

Immune reactions

Microangiopathic

Parasitic

Hypersplenism

Bleeding

Classification of anemia

Anemia due to failure of

production: Aplastic anemia

Causes Of Aplastic Anemia

Idiopathic (70 % or >)

Inherited:

Fanconi anemia

Familial aplastic anemia

Dyskeratosis congenita

Shwachman Diamond Syndrome

Dubowitz syndrome

Causes Of Aplastic Anemia

Acquired:

Secondary

Drugs 6 –mecaptopurine

Methotrexate

Cyclophosphamide

Chloremphenicol

Chemicals: insecticides

Toxin (benzene ,carbon tetrachloride)

Irradiation

Infection: Viral hepatitis; HIV; IM; CMV

MDS

Aplastic anemia: hypocellular bone marrow is largely devoid

of hematopoietic cells; often only fat cells, fibrous stroma,

Aplastic anemia

CAUSES

DEPRESSION OR CESSATION OF ACTIVITY OF

ALL BLOOD PRODUCING ELEMENT

DAMAGE TO STEM CELL

LEUKOPENIA

THROMBOCYTOPENIA

DECREASE IN FORMATION OF RBC

PANCYTOPENIA

REPEATED

INFECTION;

FREQUENT

SICK DAY

BLEEDING

TENDENCY AEB

ECCHYMOSIS,

PURPURA,

PETICHIAE,

BLEEDING FROM NOSE,

MOUTH,

VAGINA, RECTUM

PALLOR OF SKIN & MUCOUS

MEMBRANE, CYANOSIS

APLASTIC ANEMIA

Aplastic Anemia: Clinical Features

Anemia: pallor, easy fatigability, weakness, loss of appetite

Thrombocytopenia: petechiae, easy bruising, severe nosebleeds, bleeding into GIT & renal tract

Leukopenia: increased susceptibility to infections & oral ulcer

Hepatosplenomegaly & LAD do not occur; their presence suggest underlying leukemia

Hyperplastic gingivitis

Special features

Skin: Hyperpigmentation, café –au-lait spots, erythematous rash

Head: Microcephaly, micro-ophthalmia

Mouth: cleft lip, leukoplakia

General: small stature

Erythrocytes: Normal mature RBC

Biconcave disc

Approximatly 8 um in

dia

2.5 um thick at the

periphery

1.0 um thick at center

Contains 27- 34 pg (10-

12 g) of hgb (about

95% of dry wt of RBC)

Areas of RBC metabolism

crucial for RBC survival &

function

RBC membrane

RBC metabolic pathways

Hemoglobin structure & function

RBC MEMBRANE:

Hereditary Membrane Dse.

Hereditary Spherocytosis

Hereditary Ovalocytosis / Elliptocytosis

Hereditary Stomatocytosis

RBC MEMBRANE:

3 Major Structural Proteins

Semi-permeable bilayer of

lipids (including cholesterol)

& proteins

Deformable to pass through

microvessels & permeable

to allow H2O & electrolytes

to exchange (inc surface

area)

Major protein is spectrin Cytoskeletal Proteins: Maintain

RBC Shape, Strength, Flexibility


Autosomal Dominant -

Most Common

Autosomal Recessive -

More Severe

MC in Northern

European ancestry

A spectrin def w/

principal defect in

abnormality of ankyrin

Vertical stabilization

defect of phospholipid

bilayer spectrin -

phospholipid bilayer

separates

Portions PL bilayer

forms vesicles (lost)

decreased surface

area spherocytosis


Mutation of Ankyrin Gene

(Most Common Defect)

Abnormal Ankyrin Protein

Deficiency of Spectrin

Assembly


Defects may be in:

Actin - spectrin - band 3 complex

Spectrin - 4.1 -glycophorin complex

Connection between bilayer & spectrin

Hereditary Spherocytosis: S/S:

Waxing / waning anemia, jaundice (hemolysis

accelerated by infection)

Splenomegaly (hyperplasia secondary to

increased workload), pigmented gallstones

(hx cholecystectomy), ankle ulcers

Family hx: (AD 1: 5000 people of European

descent)

Hereditary Spherocytosis Lab Dx:

PBS: Moderate Anemia;

Spherocytes; Reticulocytes

(polychromatophilia)

Inc retic ct, inc LDH, inc B1,

inc EOFT

Normal MCH w/ an inc

MCHC

BM - Erythroid Hyperplasia

Coomb’s Test - Negative

Inc Autohemolysis Test

corrected by glucose


Tx: folate replacement, splenectomy in some

circumstances

Pearl: Parvovirus B19 infection in patients w/

hemolytic anemias in general aplastic crisis

Case

14 mon old African-

American child

presents w/ mild

anemia; Hx / PDx

obtained & when

reviewed showed these

cells

What are they?

Hereditary elliptocytosis &

Hereditary pyropoikilocytosis

Defects in horizontal

junctions:

Between a- & b-

spectrin dimers or

Between spectrin, actin

& band 4.1

RBC cytoskeleton loose

structural strength &

lateral integrity

Hereditary elliptocytosis

Autosomal dominant

Structural abnormality of spectrin or def of

RBC membrane protein 4.1

W/o anemia & usually w/o splenomegaly &

only mild hemolysis; Most patients

asymptomatic

EV hemolysis, thus splenectomy corrects

hemolysis, but not the RBC membrane defect

Hereditary elliptocytosis

PBS: large #s of elliptocytes &/or ovalocytes

# of elliptocytes does not correlate w/ severity of hemolysis

EOFT is usually normal

Reticulocytes mild inc (<5%)

Haptoglobin levels low

Hereditary pyropoikilocytosis

Rare AR

Severe hemolysis, bizarre poikilocytosis & RBC fragmentation (hallmarks)

Structural abnormality of spectrin, RBCs fragment when heated (45°C)

Normal RBCs fragment at 49°C

Case

Membrane permeability

defect in

stomatocytosis

Biochemical changes that can cause shape

change in RBC

Accumulation of cholesterol causes

increased membrane

Target cell

Acanthocyte

Decreased spectrin causes decreased

membrane

Spherocyte

Bite cell

RBC Metabolic Pathways

Essential for O2 transport & maintaining

physical characteristics of RBC

Red cell metabolic pathways

Generates 90% of energy

needs from Glucose 2

ATP molecules (energy)

90-95% of intracellular

glucose thru free-energy

diffusion

RBCs have no glycogen

Glucose (Na-K ATPase

pump & Ca-Mg ATPase

pump affected in PK Def

Case

5 y/o African-American

boy recently presented

w/ fever. Prescribed

Bactrim for presumed

otitis media. Brought

back in by mom due to

increased fatigue &

PBS showed


Metabolizes 5-10% of glucose

Protects RBC from oxidative injury

G6PD is rate-limiting enzyme

G6PD also produces NADPH (keeps glutathione reduced)

Glutathione protects via break down of H2O2 H2O + O

Most common defect is G-6PD def

G6PD Pathophysiology

Defect in HMP

G6PD def dec antioxidant GSHRBCs sensitive to oxidant stressesoxidized hgb (Heinz bodies) Macrophages of RES phagocytose bits of RBC membrane w/ underlying precipitated hgbpoikilocyte hemolysis


Actual def not due to

absence of enzyme,

but defective protein

folding protein w/

decrease half-life

later stages of RBCs

life (> 20 days),

functional levels of

enzyme decline


Mediterranean type:

Asso w/ fava bean

ingestion

More severe hemolysis

because all RBCs have

dec G6PD activity due

to dec synthesis &

stability

African American type:

Asso w/ intermittent

hemolysis since the

older RBCs have dec

levels of G6PD &

usually occurs in

response to oxidative

states (infections)

G6PD Def: Clin Dx

Jaundice in 1st 24 hrs of life (pathologic

jaundice)

X-linked common in African Americans &

Mediteraneans

Acute self-limited IV hemolytic a

Oxidative stress: infection, medication, fava

beans

G6PD Deficiency

Episodic hemolytic a

triggered by oxidant stress

(drugs, infection)

X-linked -10 – 14% males of

African descent carry an

unstable A variant of G6PD

More severe, chronic form

seen in men of

Mediterranean descent

(think fava beans in

Mediterranean pt)

G6PD Deficiency

PBS: Bite cells & blister cells

Dx: PBS, G6PD level, Heinz body prep

G6PD levels may be normal in acute setting due to selective removal of older RBCs w/ lower baseline G6PD levels

Tx: Get rid of offending oxidant stress (drug, infection)

Important drugs to know that may precipitate hemolysis: SULFA, anti-malarial drugs, dapsone, Vit K, fava beans

G6PD Deficiency

> 400 Variants

X Linked, M > F

African Americans (Males 10%)

Mediterranean Grps (inc severity)

Asymptomatic Unless Oxidative Stress

(Therapeutic Drugs, Fava Beans)

Denatured Hgb Precipitates RBCs

Removed by Spleen

G-6-PD def

> 200 M people (Mediterranean, West

African, Mid-East & SEA) due to chronic

hemolysis

Blacks often have an episodic variant in w/c

oxidant cmpds (antimalarials, sulfonamides,

or infections) cause hemolysis

Women heterozygotes (half the normal

amount of RBC) G6PD show increased

resistance to P falciparum

G-6-PD def:

Stressors of G6PD System

Antimalarials

Sulfonamides

Nitrofurans

Phenacetin

Synthetic vit K

Naphthalene (moth balls)

Fava beans

Infection

Diabetic ketoacidosis


Maintains iron in the

ferrous (Fe2) state

In the absence of the

enzyme (methgb

reductase), methgb

accumulates & it cannot

carry O2


Leubering-Rapaport

shunt

Allows RBC to regulate

O2 transport during

conditions of hypoxia or

acid-base imbalance

Permits accumulation

of 2,3-DPG essential

for maintaining normal

O2 tension

Hb-O2 Dissociation Curve

Sigmoid Shape

F8 Histidine & Porpyrin Ring

Alpha-Beta Dimer

Cooperative Binding

OxyHgb Dissociation Curve

CO2 Transportation

Breakdown of the RBC

Toward the end of 120 day life span, 1% of

RBC’s per day

Membrane becomes less flexible

Concentration of cellular hemoglobin increases

Enzyme activity (esp glycolysis) diminishes

Erthrocyte Destruction

Extravascular Hemolysis (major- 90% via RES)

Intravascular Hemolysis (minor- 5-10%)

Extravascular Hemolysis

Intravascular Hemolysis

References

Harmening, D.H., et al., Clinical hematology and fundamental of hemostasis, 3rd Ed, F.A.

Davis Company, Philadelphia, 1997.

McKenzie, S.B., et al., Text book of hematology, 2nd Ed, Williams & Wilkins, A

Waverly Company, Baltimore,1995.

rbc structure and function

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