Hematology: Anemia

PA 670
 Objectives
Describe the epidemiology, etiology, and pathophysiology of anemia

Describe the clinical presentation and differential diagnosis of anemia

Describe the diagnostic work up and patient management of anemia

Describe the treatment and prevention of anemia

Compare and contrast iron deficiency anemia and anemia of chronic disease (including
presentation, work-up, diagnosis, and treatment)

Differentiate the most common cause of iron deficiency anemia in men versus premenopausal
women

Compare and contrast Vitamin B12 deficiency and Folic Acid deficiency (including presentation,
work-up, diagnosis, and treatment)
 Pathophysiology
Hypo vs Hyperproliferative Erythropoesis
Hypoproliferative Erythropoesis: Poor production
Hyperproliferative Erythropoesis: increased destruction (hemolysis)
Reticulocyte Counts very helpful
Pumped out by BM in response to hemolysis
Take 2 days to mature into RBCs
Absolute retic count > 100 X 109/L is generally suggestive of hemolysis
May be reported as a %
>3% suggests hemolysis
Other lab abnormalities seen in hemolysis
Elevated bili, LDH
Low haptoglobin
Can see hemolytic lab values and low retic count in conditions with
ineffective erythropoiesis (B12 def, myelodysplasia, etc)
 Classification by
pathophysiology
RBC production RBC destruction
Iron deficiency: not enough Acute blood loss
heme
Thalessemia: not enough Hemolysis
globin
Intrinsic
Anemia of chronic disease: not Extrinsic
enough EPO, problem with BM
Megaloblastic anemia: DNA Infection: Clostridium
synthesis lesion perfringens, malaria
Leukemia: hematopeitic stem
cell lesion Hypersplenism
 Micro vs Macro
Microcytosis Macrocytosis
Fe Deficiency B12 deficiency
Thalassemias Folate Deficiency
Hemoglobinopathies Reticulocytosis
Lead toxicity Alcohol
Inflammation (chronic Liver Disease
disease) Hypothyroidism
Myelodysplasia
Aplastic Anemia
Pure red cell aplasia
Myeloma
Cytotoxic drugs
Pregnancy
Hypoxia
Hemochromatosis
Idiopathic
 Classification
Microcytic Macrocytic (megaloblastic)
Iron deficiency Vitamin B12 deficiency
Thalassemia Folate deficiency
Anemia of chronic disease
Macrocytic (nonmegaloblastic)
Lead toxicity
Liver disease
Hemoglobinopathies
Bone marrow failure

Normocytic
Kidney disease
Microcytic
Iron Deficiency
Anemia of Chronic disease
Thalassemias
Sideroblastic
 Iron deficiency
Serum ferritin < 20 ng/ml or < 30 Hemodialysis/Intravascular hemolysis
ng/ml if also anemic
Poor Absorption
Iron storage protein Gastric surgery
Celiac Disease
Most iron is stored in ferritin Crohns Disease
Due to bleeding until proven Zinc Deficiency
otherwise MCC
Increased Fe Needs
MCC of anemia worldwide Pregnancy
Lactation
Women: menstrual blood loss (50ml Growth Spurts (children/adolescents)
is normal)
Hemolysis
Adults: chronic blood loss - MCC Prosthetic valves
GI* ulcers, crohns
Chronic ASA use Chronic hemoglobinuria
GYN* menorrhagia
Frequent blood donation
 Pathophysiology

Iron deficiency

Chronic
Blood loss* Poor absorption Hemolysis
Hemoglobinuria

Celiac, Prosthetic
GI, GYN, Drugs
Zinc deficiency valves
 Iron Deficiency
Signs/Symptoms: Ferrous sulfate (FeSO4)
Fatigue, irritability 325mg TID (provides 180mg iron daily, 10mg
Poor concentration absorbed)
Pica craving none food items (ice, detergent, dirt) Give with Vitamin C (ascorbic acid) on empty stomach
Koilonychia- spoon shaped nails - enhances absorption
Glossitis Give with Colace Constipation common!
Angular stomatitis
Dysphagia Oral supplementation
(Plummer-Vinson syndrome: dysphagia + Should return to baseline after 2 months
esophageal webs + atrophic glossitis + Fe
deficiency) Continue for 3-6 months to replenish iron stores
Impaired psychomotor development in children Longer therapy if poor absorption or chronic blood
Restless leg syndrome loss

Laboratory Findings Parental supplementation

Low MCV Intolerance to oral iron, GI disease, chronic
hemodialysis
High RDW (narrow RDW suggests thalassemia) Failure to respond red flag!
Thrombocytosis Male: EGD and/or colonoscopy
Peripheral smear findings Female:
Normal or no menses EGD/Colonoscopy
Microcytosis, anisocytosis, poikilocytosis, target
cells, no basophilic stippling (usually with lead Menorrhagia GYN evaluation
poisoning) When to refer:
Low Ferritin ( < 20 is diagnostic**) Not responding to oral therapy
Additional Tests: Bone marrow biopsy and aspirate to Suspected diagnosis cannot be confirmed
assess iron stores

Tx:
 Anemia of Chronic Disease
Anemia resulting from chronic underlying condition chronic inflammation,
reduced response or production of Epo, organ failure, elderly
Pathophysiology: serum Fe is consequence of:
Hepcidin produced by liver in infectious/inflamm states inhibits macrophage iron release
ferritin (ferritin is an acute phase reactant, sequesters iron in storage)
EPO is inhibited by cytokines

Lab Findings:
Mild/moderate normochromic/microcytic anemia
Mild/moderate bc of compensation
Normal or low reticulocyte count (bc no hemolysis)
Serum Fe may be low
Ferritin will be normal or increased (vs IDA where Ferritin is low)
(TIBC)
Treatment:
Address the condition
Transfuse
Epo CKD (ie pts on hemodialysis)
Hbg <10, to maintain between 10-12
 Thalassemias

Hereditary, reduced number of globin chains

Classification: Alpha-thalassemia, beta-thalassemia

trait : +lab findings, - clinical
intermedia: moderate clinical impact, occas transfusion
major: life threating, transfusion dependent

Lab findings:
Hypochromic, microcytic anemia due to defective Hbg
Low Hct, Low MCV, normal or elevated RBC count

Treatment varies from:

No treatment, to folic acid, to regular transfusions
 -thalassemia -thalassemia - thalassemia -thalassemia
trait Thalassemia
minor intermedia major

Who Southeast Mediterranean Mediterranean Mediterranean

Asian, China decent decent decent

Anemia Mild anemia Modest anemia Modest anemia Severe anemia

Labs Hct: 28-40% Hct: 28-40%* Hct: 17-33%* HCT: <10%*

MCV: 60-75fL MCV: 55-75fL MCV: 55-75fL Smear: bizarre
RBC: nl/ RBC: nl/ RBC: nl/
Smear: abn Smear: Smear: SICK!
abn/basophilic abn/basophilic
stippling stip

Retic ct Normal Normal Elevated

Transfusion None None Occasional Dependent

 Thalassemia

Variable cells
Anisocytosis- variable size
>10% abnormal shape
 Sideroblastic anemia
Decreased hgb synthesis due to inablilty to synthesize heme
occure bc individuals cannot incorporate Fe
Fe is needed for BM to make heme

Congenital
Acquired: meds, lead poisoning, alcohol
Increased serum Fe
Moderate anemia,
MCV
serum Fe and transferrin saturation

Dx by bone marrow exam

Fe stores and
ringed sideroblasts (Fe in mitochondria (in pic)
Macrocytic
Vitamin B12
Folic Acid
 Vitamin B12 Deficiency
B12 Absorption Deficient Diet: Vegan (B12 present in all
animal products
Stomach: Lack of stomach acid
Acid releases B12 from food R-protein Lack of Intrinsic Factor (pernicious anemia
binds to the B12 MCC)
Intrinsic Factor produced by stomach Pancreatic insufficiency
Tapeworm infection (usurps available B12)
In the Duodenum: Intestinal malabsorption (crohns)
Nitrous Oxide exposure
B12 released from R-protein and bound to
Intrinsic Factor Meds: H2RA, PPI, nucleic acid synthesis
ETOH
Terminal Ileum: site of B12
absorption* Clinical Findings:
Slow onset of moderate to severe anemia
B12 Biochemistry
Mucosal changes (glossitis, stomatitis)
B12 is a cofactor for two processes & key for GI complaints (anorexia, diarrhea)
DNA synthesis Neurologic (peripheral paresthesias
Helps convert homocysteine to methionine balance dementia)
Helps convert methylmalonyl CoA to succinyl Spinal Cord demylination & degeneration:
CoA Ataxia, weakness,
vibration/sensory/proprioception deficits,
tendon reflexes, abnormal babinski
Hyperhomocysteinemia
 Lab Findings
CBC:
Moderate- severe anemia
MCV elevated: 110-140 fL (or could
be normal)
Pancytopenia (severe)
Peripheral Smear is megaloblastic
RBC appear as macro-ovalocytes
hypersegmented neutrophils*
Retic count: reduced
Vitamin B12: < 170 pg/mL (>210 pg/mL is
normal)
Symptomatic patients <100 pg/mL
If B12 level is low or normal
Check homocysteine and
methylmalonic acid levels
High methylmalonic acid and
homocysteine = true B12
deficiency
OR if both are normal can rule out
B12 deficiency
Falsely low B12:
Folate deficiency, myeloma,
megadose of Vitamin C
Falsely normal B12:
Hepatic disease, autoimmune
disease
 Treatment

IM or SQ 100 mcg of vitamin B12 per dose

Daily x 1 week
Weekly x 1 month
Monthly for life
(Deficiency will recur if patient d/c therapy)

Oral or sublingual methylcobalamin (1mg/d) once

deficiency is corrected, is alternative to IM/SQ
 Folic Acid Deficiency
Less likely to be deficient Lab findings:
Absorbed in duodenum and jejunum Megaloblastic anemia (same as in
Stores of 5-10mg in liver, enough to Vitamin B12 def)
supply requirements for 2-3 months. RBC folic acid level <150 mg/mL is
diagnostic
MCC: inadequate dietary intake (alcoholics,
anorexia nervosa) Treatment:
Once daily oral folic acid 1 mg
Other causes: drugs that interfere with
absorption (methotrexate, phenytoin, Pearl: know Vitamin B12 status!
Bactrim, sulfasalazine)
Replacing folate in B12 def will correct the
anemia but the neuro sx will worsen
Increase need in: pregnancy, hemolytic
anemia and exfoliative skin diseases Deficiency in preg NTD
SSx:
Similar to Vitamin B12 deficiency
Isolated folic acid def not associated
with neurologic abnormalities
 Hemolytic Anemias
Hereditary Spherocytosis
G6PD Deficiency
Sickle Cell Anemia & Related Syndromes
Autoimmune Hemolytic Anemia
Aplastic Anemia
 Hemolytic Anemias
Reduced red blood cell survival (episodic/continual)

Bone marrow can increase production up to 8 fold,

Hemolytic anemia only present when it can no longer keep up
Very short RBC survival
Impaired bone marrow

Intrinsic (RBC defect) or Extrinsic (outside cause)

Labs: retic count, indirect bilirubin, LD

 Hereditary Spherocytosis
Intrinsic

Autosomal dominant with variable severity

Disorder of RBC membrane does not have normal biconcave shape of RBCs
Cells are less deformable, decreased surface area and unable to pass through small
passageways (byproducts taken to spleen for degredation)
Premature destruction and hemolysis
Results in chronic hemolysis with jaundice and pigment gallstones

Complications: Aplastic crisis possible

Dx: Increased MCHC (only disorder with this finding)

Tx:
Folic acid,
splenectomy (eliminate site of hemolysis) cannot do this in small children, needs to be at
least 6yo
 Paroxysmal Nocturnal
Hemoglobinuria
Extrinsic Labs: consistent with hemolytic anemia of
variable severity:
Episodic hemoglobinuria low hgb,
high LDH,
Rare, acquired clonal hematopoietic stem high bili,
cell disorder low haptoglobin,
Gene defect resulting in deficiency in the high retics
cell membrane resulting in RBC being
sensitive to lysis by complement Can be mild to severe Refer all cases to
Hematology
SSx:
reddish brown urine in am (1/3 of pts) Tx:
esophageal spasm, Allogeneic bone marrow transplantation is
male erectile dysfunction, the only cure
renal damage,
mesenteric and hepatic vein thrombosis
Thrombosis common primary cause of
morbidity and mortality
 Glucose-6-phosphate
dehydrogenase deficiency
Episodic hemolysis in response to oxidative stress
caused by drugs/infection that forces hgb to
denature and form Heinz bodies (denatured Hgb Labs:
precipitates)
Reticulocytosis,
increased bilirubin,
Heinz bodies damage RBC membranes and are
removed by the spleen bite cells schistocytes
blister cells,
X-Linked recessive disorder, 400 million people Heinz bodies
world wide
MC in African, Asian, Mediterranean descent Tx:
MC in males Self-limiting, new RBCs replace older ones, avoid known
oxidative drugs/foods

SSx: episodic back or abdominal pain, sx of anemia,

jaundice, splenomegaly, hemolytic crisis, neonatal G6PD deficiency protects against
jaundice malaria
Sources of oxidative stress: infection (MCC), fava
beans, medications (sulfa drugs, antimalarials)
 Sickle Cell Anemia
Intrinsic vaso-occlusive crisis:
Sickled-cells start getting stuck
Chronic hemolytic anemia due to abnormal Ischemia, severe pain, necrosis, organ damage or
hemoglobin failure
aplastic crisis:
Autosomal dominant; Hemoglobin S is major
triggered by parvovirus B19- directly affects
hemoglobin seen on electrophoresis; rate of production of RBCs
sickling is influenced by concentration of hgb S
sequestration crisis:
4.4 million people have the disease, vasoocclusion in spleen spleenomegaly & rapid
Hgb +/- fatal
43 million people have the trait world wide.
Splenic infarction (functional asplenia)
Most cases in sub-Saharan Africa
hemolytic crisis:
Jaundice, gallstones, pneumococcal meningitis
Factors that cause sickling: dehydration,
acidosis, hypoxemia acute chest syndrome:
At least 2 sx: CP, fever, pulmonary infiltrates,
hypoexmia
Very sick & can be fatal 25%
 Sickle Cell Anemia
Labs:
Reticulocytosis,
Nucleated RBCs,
Howell-Jolly bodies smooth single, large
round inclusions remnants of nuclea
chromatin (clusters of DNA)
Presence signifies damaged or absent
spleen (healthy spleen would filter this
out)
target cells,
elevated indirect bilirubin

Tx:
Acute Attack: hydration, analgesics, blood
transfusions
Cure with stem cell transplant before onset of
end-organ damage (children)
Autoimmune Hemolytic Anemia
IgG antibodies bind to rbc membrane Dx:
recognized by macrophages RBC Coombs test + (direct antiglobulin test)
membrane destroyed spherocytosis Reticulocytosis,
spherocytosis,
cases are idiopathic (MCC)
nucleated rbcs,
Autoimmune SLE
increased indirect bilirubin,
Malignancy CLL
increased LDH,
Cold agglutinins reduced haptoglobin

May be rapid and life threatening Tx:

prednisone,
SSx:
splenectomy for those with more severe
Jaundice and splenomegaly, acrocyanosis disease,
+\- immunosuppressants
Autoimmune Hemolytic Anemia
 Aplastic Anemia
Bone marrow failure from
suppression of or injury to the
hematopoietic stem cell
Causes: exposure to drugs,
chemicals, radiation, immune
disease, virus, bacteria
SSx
Pancytopenia (all cell lines)
Weakness, fatigue, neutropenia,
thrombocytopenia
Pallor, purpura (bc no platelets),
petechiae
Definitive Dx:
bone marrow biopsy (not always
necessary if you can find
underlying cause but up to 50%
are idiopathic)
Treatment depends on severity
Supportive if mild:
rbc transfusions, platelet
transfusions, antibiotics
Severe if neutrophils <500, plt
< 20,000, reticulocytes < 1%,
bone marrow cellularity <20%:
Bone marrow transplant in
children or immunosuppressant
with transfusion and antibiotics in
adults
Aplastic Anemia
 Neutropenia
Absolute Neutrophil Count = <1500, severe if <500
Mild if ANC 1000-1500/microL
Mod if ANC 500-1000/microL
Severe if ANC below 500/microL

Vulnerable to infections by bacteria and fungi

MCC is chemotherapy

Complications: septicemia, cellulitis, pneumonia, fever

Tx the cause, antibiotics if bacterial

 Blood Transfusion
Risks to discuss with patients Fever/allergic rxns MC, HIV is very rare