RBC Disorders

RBC Structure+Function

structure

• non-nucleated+bioconcave disk

• larger surface area for O2 diffusion

• flexible membrane→pass through capillaries

men→48% of blood concentration
women→42% of blood concentration

function

transport oxygen to tissues

Hemoglobin (HGB)

function
attaches on to oxygen→transports oxygen to tissues

95-98% O2 binding

increases by 1g/dL q2-3 weeks (rate depends on iron present)

increasing age→decreasing amount of progenitor cells→decline after middle-age

structure
-globin unit (protein)
+
-heme unit (surrounds iron atom)

each unit carries 2 oxygen molecules/unit→4 oxygen molecules total

adult hemoglobin (HbA): 2 alpha chains+2 beta chains

infant hemoglobin (HbF): 2 alpha chains+ 2 gamma chains
higher affinity than HbA

Hematopoeisis

PP: production of blood cells
continues throughout life+increases→replace aged/destroyed RBC from infxn

E:
fetus
liver
spleen

after birth
bone marrow

blood cell creator cells
protenitor cell
hematopoietic
pluripotent stem cell (HSC)

Erythropoeisis (General)

PP: production of RBCs

E:
up to 5 y/o: bones

adults:
vertebrae
sternum
ribs
pelvis

CM:
steps

1. pluripotent stem cells

2. proertyhroblasts

3. erythroblasts (precursor to RBC)

4. normoblasts

5. nucleus condenses+reabsorbed

6. reticulocytes

7. erythrocytes/RBCs

8. hemoglobin synthesis stops

Erythropoiesis Regulation

time from stem cell developing to reticulocyte formation→1 week

reticulocyte to erythrocyte maturation→24-48 hrs→remain in bone marrow x 24 hrs→released into circulation

1% of RBCs

total amount of RBCs in healthy body remains constant

steps

1. hypoxia

2. kidneys increase production of erythropoeitin (EPO)

3. bone marrow binds to EPO receptors on proerythroblasts

4. increases production of RBCs

Erythropoiesis Nutritional Requirements

vitamin B12
vitamin B15
folate
niacin
vitamin C
vitamin E
proteins
minerals

lacking→slows down production→anemia

Red Cell Destruction

RBC lifespan→120 days/4 months
-removed from circulation by spleen
-rate of destruction=rate of production (1%/day)

aging→increased changes→more fragile
-metabolic enzyme+ATP activity decrease
-membrane lipids decrease+more fragile→self destruct in narrow spaces

E: phagocytes
-spleen
-liver
-bone marrow
-lymph nodes

CM:

• phagocytes ingest+destroy defective RBCs

• iron+amino acids salvaged+reused

• heme converted into bilirubin→attaches to plasma proteins for transport

• removed from blood by liver→excreted by bile

excessive RBC destruction→increased bilirubin production→unconjugated bilirubin accumulation→jaundice

Erythropoiesis+Iron Cycle

25 mg iron needed for erythropoeisis
-1-2mg→dietary
-remaining amount→recycled erythrocytes

iron use percentage
67%→bound to heme+myoglobin
30%→stored in macrophages+liver
3%→urine/sweat/bile

recycled iron
bind to transferrin

stored as:
-ferritin
-hemosiderin

Blood Composition

plasma→55%

• 91%→water

• 7%→proteins

• 2%:
  -ions
  -nutrients
  -waste products
  -gases
  maintains acid-base balance

albumin: regulates movement of water/solutes
maintains oncotic pressure

fibrinogen→clotting

forced elements→45%

RBCs (measured by hematocrit)

buffy coat

• WBCs

• platelets

Normal RBC Values+Indices

mean corpuscular volume (MCV)→size/volume of RBCs

• normocytic→normal size

• macrocytic→big→high MCV

• microcytic→small→low MCV

mean corpuscular hemoglobin concentration (MCHC)→concentration of hemoglobin in cell→color of the cell

• normochromic→normal color

• hypochromic→pale→low MCHC

mean cell hemoglobin→mass of red cell (least useful for anemia dx)

Anisocytosis

abnormal variation in cell size

low anisocytosis→low RDW→normal

high anisocytosis→high RDW→PP

Pokilocytosis

abnormal variation in cell shape

• flat

• elongated

• teardrop

• crescent

• sickle→sickle cell dx

• etc.

Complete Blood Count (CBC)

components

• RBC

• WBC

• platelets

CBC with diff→measures WBCs

• neutrophils

• lymphocytes

• monocytes

• eosinophils

• basophils

left shift
bone marrow prematurely releases WBC into bloodstream→increased # of WBCs (“bands”)→infxn

Anemia (General)

PP: decreased # of RBC/hemoglobin/both→decreased tissue oxygenation
not considered a dx

E: excessive RBC loss (bleed/hemorrhage)
inadequate RBC production (bone marrow failure)
increased RBC destruction (hemolysis)
defective RBCs

CM: pallor of skin/mucous membranes/conjunctiva/nail beds
tachycardia
palpitations
accelerated erythropoiesis→diffuse bone
accelerated erythropoiesis→sternal tenderness
fatigue
weakness
dyspnea
angina
headache
lightheadedness
dim vision

Blood Loss Anemia

PP: excessive loss of RBCs→hypoxia of tissues+cells→stimulates erythropoietin→proliferation of erythroid stem cells→reticulocyte production
-acute→loss of intravascular volume
-chronic→blood loss>replacement capacity by bone marrow

E: bleeding
trauma
GI hemorrhage
GI dissection
DIC
splenic rupture
SAH

chronic
GI bleeding
menstrual disorders

CM:

acute
10-15%→vascular instability→circulatory shock+collapse
hypotension
decreased organ perfusion
orthrostatic hypotension
tachycardia
under 40%→hypovolemic shock

chronic
slow blood loss
asx until 50%+ red cell mass lost/hemoglobin under 8g/dL

DX:
CBC: normocytic
normochromic

TX:
acute
stop bleeding
volume replacement
blood transfusion
iron supplements
return to baseline→6-8 weeks

C: MI
CVA
organ damage/failure
death

P: chronic→iron deficiency anemia (IDA)

Hemolytic Anemia

PP: premature+accelerated destruction of RBCs before replaced
RBC destruction
retention of iron+other products of hemoglobin destruction
increase in erythropoiesis

E:
intravascular
mechanical trauma
toxic trauma
complement fixation→jaundice

extravascular
cells less deformable→macrophage sequestration+phagocytosis→jaundice
age-related changes in RBC surgace→more rigid+less able to change shape

congenital
intrinsic defects in erythrocytes+cell membrane
-G6PD deficiency
-thalassemia
-sickle cell anemia
-increased shear stress in narrow vessels

acquired
immunologic
allergic
erythrocyte antigens→autoantibodies produced→RBC destruction

CM: jaundice→hemolytic anemia
reticulocytosis
hemoglobinuria
hemosiderinuria
congenital→splenomegaly

DX:
CBC:
normocytic
normochromic

hemolysis labs:
reticulolysis→over 2%
peripheral smear→schistocytes
haptoglobin under 30
increased indirect bilirubin 2/2 heme breakdown
increased LDH

Hereditary Spherocytosis

PP: loss of lipid bilayer in RBC→spherical/circular RBC shape→stuck in splenic fenestration→lyse

E: inherited molecular defect in proteins of RBC membrane
hemolytic anemia
1/2000
northeast europe

CM: hemolytic anemia
jaundice
splenomegaly
bilirubin gallstones

DX:
CBC: normocytic anemia

labs: hemolysis
high MCHC→hyperchromic cells
peripheral smear→spherocytes
osmotic fragility test

TX: blood transfusion
splenectomy

C: aplastic crisis (parvovirus b19)

G6PD Deficiency

PP: G6PD enzyme deficiency→RBC more vulnerable to oxidants→direct oxidization of hemoglobin into methemoglobin→can’t transport O2→hemoglobin denaturing→heinz bodies

RF: X linked recessive
africa
mediterranea

E: primaquine
sulfonamides
ASA (aspirin)
nitrofurantonin
hepatitis A
hepatitis B
typhoid
pneumonia
fava beans
peanuts
peas
artificial food dyes

CM: asx
or (2-3 days after triggering)
hemoglobinemia
hemoglobinuria
jaundice
weakness/malaise
abdominal+lumbar pain

DX:
CBC: between episodes→normal
episodes:
hemolysis
peripheral smear:
bite cells
bizarre poikilocytes

Quantitative UV spectrophotometric assay (gold standard)
rapid spot test for G6PD

TX: avoid offending agents
blood transfusion PRN
non-severe→folic acid supplements

Autoimmune Hemolytic Anemia

PP: immune system recognizes RBCs as foreign bodies→produce antibody→binds to RBC surface antigens→cell destruction+phagocytosis

E: idiopathic (50%)
SLE
lymphomas
chronic lymphocytic leukemia
PCN
fludarabine
ceftriaxone
zosyn

CM:
triad:
abrupt+dramatic onset
splenomegaly
jaundice

DX:
CBC→normocytic anemia

direct coombs test (DCT)→confirmation

TX:
1st line→prednisone+rituximab
2nd line: azathioprine
cyclophosphamides
cyclosporines
splenectomy
stem cell transplant
no blood-threatening anemia→no transfusion

Sickle Cell Disease vs Trait

recessive inheritance pattern of hemoglobin S gene (HbS)
need 2 copies of gene to show trait

disease→homozygous/2 HbS genes→expresses sickle cell

trait→heterozygous/1 HbS gene→sickle cell carrier

Sickle Cell Anemia

PP: physical stress/low O2 tension→RBCs turn into sickle shape→get stuck in capillaries→tissue ischemia+pain→end-organ damage

no stress/high O2 tension→RBCs return to normal shape

chronic→RBC permanently in sickle cell shape

RF: hypoxia
dehydration
acidosis
extreme termperatures
menses

E: point mutation in beta chain of Hb molecule (changes 6th amino acid from glutamic acid to valine)→abnormal structure of HbS gene
sickle cell disease
1 y/o as HgB F decreases

CM:
disease (homozygous)
severe hemolytic anemia
hyperbilirubinemia→jaundice

vaso-occlusive crisis:
-acute pain
-fever
-tachycardia
-anxiety
x hrs-2 weeks

DX:
all newborns screened in US
CBC:
normocytic anemia
hemolysis

peripheral smear: sickled cells 5-50%

hematocrit→significant reticulocytosis15-30%

hemoglobin electrophoresis→confirmation
-over 50%+→HgB S

TX: no full tx→palliative tx

NP:
avoid RFs
IV fluids
rest
pain control oxygen
tx complications
blood transfusion
peds→bone marrow transplant
prophylactic exchange transfusions

MX:
hydroxyurea ± l-glutamine daily
folic acid daily
under 5 y/o→low-dose penicillin prophx
recurrent pneumococcal infxns→low-dose penicillin prophx

C:
cholelithiasis
splenomegaly
chronic lower extremity ulcers
encapsulated organism infxn
avascular necrosis
priapism (painful erection)

P: 40-50 y/o

Alpha Thalassemia

PP: decreased synthesis of alpha globin chains of HbA→decreased production of affected chain+continued production of unaffected globin chain

RF: China
southeast asia
black people

E: heterozygous→mild
homozygous→severe
microcytic anemia
hypochromic anemia
hemolytic anemia

CM:
sx produced by alpha globin gene deletions

1 deletion→silent carrier
asx

2 deletions→thalassemia minor
mild hemolytic anemic

3 deletions→hemoglobin H dx
chronic moderate hemolytic anemia
-accumulation of unstable beta chains
-beta chains more soluble→less toxic to RBCs

4 deletions→hydrops fatalis
most severe
only in infants
incompatible with life→death
electrophoresis→only hemoglobin B present

DX:

CBC:
MCV→60-70
marked anemia
chronic hemolysis

iron+ferritin studies→normal

peripheral smear:
target cells

Beta Thalassemia (Cooley/Mediterranean Anemia)

PP: alpha chains denatured→heinz bodies→DNA synthesis impaired→damage RBC membrane

E: deficient synthesis of beta chain

CM:
sx produced by alpha globin gene deletions

1 deletion→beta thalassemia minor
don’t develop severe dx

2 deletions→beta thalassemia major
ineffective hematopoiesis+hemolysis→erythropoietin secretion+hyperplasia in bone marrow

DX:
minor
CBC:
hypochromic
microcytic
no hemolysis

major (cooley’s anemia)
severe anemia→frequent transfusions
hemosiderosis
stunted growth
thinning cortical bone→fx
splenomegaly
hepatomegaly

formation of new bone:
-maxilla bone
-frontal bone

both
CBC:
MCV→60-70
marked anemia
chronic hemolysis

iron+ferritin studies→normal

peripheral smear:
target cells

TX (major):
regular blood transfusions
iron chelation tx
stem cell transplant→cure

C (major):
iron overload→cardiac+hepatic+endocrine dx→death

Iron Deficiency Anemia

PP: loss of iron→decreased hemoglobin synthesis→RBC breakdown for more iron usage→anemia
2-4mL/day

E:
3rd world countries→diet deficiency
-men→7-10mg
-women→7-20mg
10-15% iron ingested
eating dxs

1st world countries→chronic blood loss
-childbearing-age women
-menstrual bleeding

men/postmenstrual women
h pylori
GI bleeding
peptic ulcer
hemorrhoids
esophageal varices
cirrhosis
cancer
celiac dx
chronic diarrhea
increased requirements
surgery

CM:
pica (eating non-food stuff)
koilonychia (curved nails)
glossitis (smooth tongue)
angular stomatitis
fatigue
palpitations
dyspnea
angina
tachycardia

DX:

CBC:
microcytic
hypochronic
poikilocytosis
-decreased reticulocytes (under 1%)
-low iron (under 30ng)
-low ferritin (under 30)

peripheral smear:
poikilocytosis
anisocytosis

RDW→high

TIBC→elevated

TX:
NP:
tx underlying cause
workup for occult blood loss

TX:
ferrous sulfate PO QOD x 2-6 months
ferrous fumarate PO QOD x 2-6 months
parenteral iron

Megaloblastic Anemia

PP: impaired DNA synthesis→large RBCs→slow maturing nuclei+normal maturing cytoplasm→die prematurely→anemia
RNA synthesis→normal
nuclear-cytoplasmic asynchrony→megaloblastic changes in bone marrow

E: vitamin B12 deficiency
folic acid deficiency
m/c→inadequate absorption
-lack of intrinsic factor→pernicious anemia
-bacterial overgrowth
-parasites
-GI surgery
-nitrous oxide
-etc.

inadequate intake
rare
vegan/vegetarian diet

decreased utilization
enzyme deficiencies
transport protein abnormality

CM:
mild jaundice
glossitis
confusion
dementia neuropsych changes
neuro changes→irreversible
-symmetric paresthesia of fingers/feet
-decreased position+vibratory sense
-abnormal gait
-spastic ataxia

DX:

CBC→macrocytic+normochromic

peripheral smear:
MCV→over 100+ (110-140)
more notes→continue writing here

TX:
PO vitamin B12
SL vitamin B12

neuro
IM vitamin B12
deep SC vitamin B12

GI sx
parenteral B12 monthly x until issue revolved

Vitamin B12 Pathogenesis (Normal Production)

1. vitamin B12 released form animal protein

2. goes to stomach

3. binds to intrinsic factor
   -protects vitamin B12 from digestion by intestinal enzymes
   -secreted by gastric parietal cells

4. goes to ileum

5. binds to epithelial cells

6. separates from epithelial cells

7. transported into circulation

Pernicious Anemia

PP: autoimmune disorder
autoantibodies destroy gastric parietal cells or their produced intrinsic factor (IF)→lack of IF→IF deficiency→impaired DNA synthesis (megaloblastic anemia)+demyelination of nerves→neuro sx

E: atrophic gastritis
lack of intrinsic factor

TX: parenteral B12 weekly x 4 weeks→monthly x indefinitely

Folic Acid Deficiency Anemia

PP: lack of folic acid→megaloblastic anemia

E:
m/c→folic acid diet deficiency→not enough raw greens+flour+grain
-50-200mcg/day
alcohol
celiac dx
neoplastic dx
methotrexate
pregnancy→neural tube defects

CM: no neuro sx

DX:
CBC→megaloblastic+macrocytic+anemia

folic acid level→under 150 ng/mL
serum B12→normal
methylmalonic acid (MMA)→normal
homocysteine→elevated

TX: folic acid PO daily x 4 months
childbearing-age women+dating/married→0.4mg/day

P: tx correction→2-3 months

Folic Acid Pathogenesis

folates

• coenzymes

• needed for thymine+purine synthesis
  -thymine deficiency→decreases rapid cellular division

• needed for homocysteine→methionine conversion

• absorbed from small intestine→stored in liver
  -poor storage→deficiency develops x weeks-months

E:
green/leafy vegetables→lost in cooking
flour
grain
cereal

Aplastic Anemia

PP: hematopoeisis failure/bone marrow aplasia→pancytopenia→reduced RBC+WBC+platelets→bone marrow can’t replace RBCs→anemia
uncertain pathogenesis

E: idiopathic (75%)
high-dose radiation
chemotherapy
alkylating agents
antimetabolites
arsenicals
benzene
chloramphenicol
viral hepattis
CMV
epstein-barr
HIV
herpes zoster
fanconi anemia
telomerase defects
paroxysmal nocturnal hemoglonbinuria (PNH)

CM: hypocellular bone marrow→replaced with fat
petechiae
purpura
epistaxis
bleeding gums

severe
hypoxemia
pallor
fever
dyspnea
sx of bleeding

slow onset
weakness
fatigue

DX:
CBC→normocytic+normochromic

peripheral smear→pancytopenia
reticulocytopenia (under 1)

bone marrow biopsy→hypocellular+fatty+no fibrous/cancerous cells

TX: hematology referral required

mild-moderate
supportive tx
growth factors
transfusions

severe
under 40→allogenic stem cell transplant
over 40→immunosuppression+equine antithymocyte globulin (TAG)+cyclosporine+methylprednisone

P: rapid progression→50%
bleeding infxn→highest risk of death
over 40 tx→60-70% pt tx

Anemia of Chronic Disease

PP: decreased erythrocyte lifespan→production of erythropoietin+impaired iron utilization due to chronic dx states/inflammation→ineffective bone marrow erythroid progenitor response to erythropoietin→decreased iron metabolism+iron sequestration by macrophages→failure to increase erythropoiesis→anemia

E: chronic activation→cytokine activation

DX:
CBC→normocytic+normochromic→microcytic+hypochromic
decreased reticulocytes

MCV→normal

ferritin→normal/decreased

TX:
severe/affecting quality of life (QOL)
Hgb under 8→PRBC transfusion
Hgb under 10+renal insufficiency→parenteral recombinant erythropoietin (EPO)

Sideroblastic Anemia

PP: impaired ability to incorporate iron into protoporyphyrin 9→decreased hemoglobin synthesis→anemia despite normal iron levels

E: x-linked mutations
autosomal mutations
myelodysplastic syndrome (MDS)
alcoholism
lead poisoning
copper deficiency
isoniazid
chloramphenicol

DX:
CBC:
congenital→microcytic
acquired→macrocytic
RDW→increase

serum iron→increase
ferritin→increase
transferrin→increase

peripheral smear:
dimorphic RBCs
ringed sideroblasts

bone marrow aspiration:
shows erythroid hyperplasia
prussian blue stain→ringed sideroblasts

TX: stop causative agents
blood transfusions PRN
pyroxidine daily

iron overload:
chelation
phlebotomy

Hemochromatosis

PP: iron metabolism disorder→abnormal iron build in organs→organ toxicity

primary/hereditary (HH)
mutation of gene→increased expression of iron transport protein→increased iron absorption in intestine→iron overload→end-organ damage
-HFE (regulates hepcidin→regulates iron in adults)
-HJV
-TFR2
-SLC40A1
-HAMP

secondary
blood transfusion→RBC injury→heme releases iron→iron accumulates in liver/heart/skin/body
-inefficient erythropoiesis anemias
-dietary overload
-repeat blood transfusions
-repeat iron injections

RF: men
northern europe

E: autosomal recessive
1/200-500 people

CM:
hereditary→asx (75%)
fatigue
impotency
arthralgia
hepatomegaly
skin pigmentation change→bronzing
arthritis

DX:
serum iron→increased
transferrin→increased
ferritin→increased

hemoglobin→normal/high

HFE→molecular genetic testing

TX:
ferritin under 50→phlebotomy
avoid iron in diet
avoid alcohol
family genetic testing
hepatocellular carcinoma screening

C: liver cirrhosis
hepatocellular carcinoma
CHF
arrhythmias
DM
hypogonadism
thyroid dysfxn

Polycythemia Vera (General)

abnormally high RBC+hemoglobin+hematocrit concentrations

men→over 54%+
women→over 47%+

relative→loss of plasma volume
-RBCs stay the same

absolute→increased RBC mass
-primary
-secondary

Absolute Primary Polycythemia Vera

PP: pluripotent bone marrow cells→increased total RBC mass+WBC count+platelet count

E: erythrocytosis

CM: abdominal pain
HTN
angina
headache
dizziness
decreased concentration
vision loss
hearing loss
heat/water→itching
finger+toe pain

PE: splenomegaly
red hands/feet/face/ears
raynaud phenomenon
buerger dx
venous stasis changes

DX:
CBC: normocytic+normochromic→anisocytosis

peripheral smear:
increased erythrocytes
increased total blood volume→confirmation

Hgb concentration→14-28 g/dL
hematocrit→over 60%+
JAK2 mutation→confirmation

TX: phlebotomy

C: increased viscosity→hyper-coagulable state→vessel thrombosis+occlusion
thrombocythemia→increased bleeding risk→hemorrhage
hematocrit over 50%+→cardiac dysfxn+vascular obstruction
hematocrit over 60%+→hypoxia
acute leukemia

Absolute Secondary Polycythemia Vera

PP: physiologic increase in erythropoietin

E: more common than primary
hypoxia response
erythropoietin secreting neoplasms
kidney dx/hydronephrosis/renal cysts→blood flow obstruction→increased erythropoietin

TX: relieve hypoxia