Approach to Anemia Rafi Ahmed, MD - PowerPoint Presentation

Slide1

Approach to Anemia

Rafi Ahmed, MD

Hematology and Oncology Fellow

4-10-14

Slide2

Overview

Not a diagnosis, but a sign of disease

Warrants an investigation

Definition: Reduction in oxygen carrying capacity of blood due to decreased erythrocyte mass

Women:

Hgb <

11.6-12.3

g/dL

Men:

Hgb < 13

-14.2 g/dL

Slide3

Causes of Anemia

G

eneral categories

Blood Loss

Redistribution (enlarged spleen

)

Decreased erythrocyte production

Increased destruction

Slide4

Anemic Patient Algorithm

Slide5

Evaluation

History and Physical

Any history or evidence of blood loss: GI/GU?

CBC with differential

Peripheral Blood Smear

Reticulocyte count

Reflection of marrow’s response to anemia

Bone Marrow Biopsy

Ancillary tests

Slide6

CBC with differential

WHITE BLOOD CELL COUNT 5.0

RED CELL COUNT 2.85 (L)

HEMOGLOBIN 9.3 (L)

HEMATOCRIT 27.0 (L)

MCV 94.6

MCH 32.5

MCHC 34.3

RDW 23.7 (H)

MPV 7.4

PLATELET COUNT 92 (L)

PLATELET ESTIMATE, SMEAR DECR

NEUTROPHILS % AUTO 96.6

LYMPHOCYTES % AUTO 2.0

MONOCYTES % AUTO 1.4

EOSINOPHIL % AUTO 0

BASOPHILS % AUTO 0

NEUTROPHIL ABS AUTO 4.80

LYMPHOCYTE ABS AUTO 0.1 (L)

MONOCYTES ABS AUTO 0.1

EOSINOPHIL ABS AUTO 0

BASOPHILS ABS AUTO 0

ANISOCYTOSIS MK (Abnl)

POIKILOCYTOSIS MOD

POLYCHROMASIA SL

OVALOCYTES SL

LEFT SHIFT NOT PRESENT

TEAR DROPS SL

TOXIC GRANULATION PRESENT

Slide7

Peripheral Blood Smear

Slide8

Reticulocyte Count

EPO stimulates RBC production

Retic Count is

r

eflection of marrow’s response to anemia

I

mmature RBCs with ribosomal RNA

Usually 1% of total circulating RBCs (last one day)

High reticulocyte count reflects adequate marrow response to anemia

Inappropriately low indicates underproduction anemia

Reported as percentage of total erythrocytes

Artificially increased because decrease in total erythrocytes

THUS, must

be corrected for degree of anemia

Retic Index: %

retic x (Hct/45)x0.5Retic <2%: production/maturation defectRetic >3%: survival defect

Slide9

Bone Marrow Biopsy

Slide10

Algorithm for Anemic Patient

Figure 5, page 17

Slide11

Low or Normal Reticulocyte Count

Evaluate Peripheral Blood Smear

Look at Red Cell Indices

MCV: mean corpuscular volume

Microcytic: MCV <80

Macrocytic: MCV >

100

Normocytic

: MCV 80-100

Slide12

Microcytic Anemia

MCV<80

“

Find Those Small Cells”

F

: Fe Deficiency

Anemia

T

: Thalassemia’s

S:

S

ideroblastic anemia

Bone

marrow produces ringed sideroblasts rather

than healthy RBCS (genetic, MDS, poisoning)

C: Chronic Disease (also can be normocytic)

Slide13

Clinical Case

55 year old male presents to your office with for initiation of care after losing his insurance 5 years ago. He reports increasing fatigue for the past few years. Exam

with a Pale appearance

Labs

:

CBC: WBC 6.0 / Hgb 9.8 / Plt 550K

MCV 78 / Retic 1.5%

Slide14

Indices: Fe 25 / TIBC 450 / Ferritin 32

Slide15

Microcytic Anemia: Iron Deficiency

Iron Deficiency –most common cause of anemia worldwide

Most total body iron stored in erythrocytes

Storage & Supply:

Men – 50mg/kg total

Women – 40mg/kg total

Compartments:

60-80% Hemoglobin

10-15%

Storage

Modulated by hepcidin: inhibits iron absorption by causing proteolysis of iron transport protein: ferroportin

In iron deficient states, hepcidin level depressed so allows increase absorption through ferroportin

Slide16

Figure 6 Hepcidin

Need more info

Slide17

Diagnosis

Physical Exam

Pallor (conjunctiva), glossitis, stomatitis

Pica: obsessive consumption of clay or starch

Pagophagia: ICE!!!!

Koilomychosis: spoon shaped nails

Blue sclerae

Gold Standard: Bone Marrow Biopsy

Slide18

Iron Deficiency Anemia Labs

Peripheral Smear: Microcytic, Hypochromic

Serum

Iron : Low

circulating iron bound to transferrin

Total Iron Binding Capacity (TIBC):

High

Indirectly measures transferrin by determining total amount of iron the blood can bind

Transferrin Saturation: Low

Serum Iron/TIBC

Ferritin:

Low

Iron stored within cell in protein complexes

Good indicator or iron stores in equilibrium conditions

Acute phase reactant, can be elevated in inflammation/chronic disease

Soluble Transferrin Receptor Concentration: Elevated

Elevated in iron deficiency and normal in ACD

Slide19

Iron Deficient Anemia

Causes

Blood loss

Hemolysis

Gastric Bypass

Malabsorption

Menstruation

GI loss must be presumed cause until proven otherwise

Therapy

Orally: FeSO4 325mg

TID with +/- ascorbic acid

Parenteral Iron if concern for Malabsorption

Slide20

Clinical Case

23 yo Asian female presents to your office to establish care. Only history is having anemia due to iron deficiency. Has been

iron therapy for years

. No family history of anemia. Exam unremarkable.

Labs:

CBC: WBC 10.5 / Hgb 11.2 / Plt 325k

MCV 65 / Retic - 0.9%

Ferritin 290

Slide21

Thalassemia

Hemoglobin is tetrameric molecule

Two alpha globin chains and two beta globin chains linked to heme (complex of ferrous iron and protoporphyrin)

Thalassemic syndromes results from defects in synthesis of alpha or beta chains

Leads to ineffective erythropoiesis

Decreased production of hemoglobin tetramers-> less RBCs

Unbalanced globin chains-> hemolysis

Slide22

THALASSEMIA SYNDROMES

α

2

β

2

=

HbA: Predominant >97.5%

α

2

γ

2

= Hb F

α

2

δ

2

= HbA

2

α

Thal = ↓ synthesis of

α

chains

β

Thal = ↓ synthesis of

β

chains

DISORDERED CHAIN SYNTHESIS

α

Thal

β

Thal

↑

β

chains ↑

α

chains

Slide23

α

Thalassemia

Chromosome 16 contains 2 copes of

α

-gene at two different loci

Thus 4

α

genes

Clinical manifestations correlate with alpha genes affected

More loci affected, worse the symptoms

Seen in African, Mediterranean, SE Asian

Slide24

α

THAL

Normal

α

Thal

minima

silent carrier

Asymptomatic

or

α

Thal

MINOR

α

Thal-1

Asymptomatic, MCV low, little to no anemia

α

Thal

intermedia

Hemoglobin H disease

β

4

= Hb H (left shift curve)

Unpaired Beta Chains form tetramers forming inclusions in peripheral cells

-Hemolytic

anemia

α

Thal MAJOR

HYDROPS Fetalis

γ

4

= Hb

BARTS (too high oxygen affinity so no delivery)

Hb Barts

Hb H

Death in utero

Slide25

β

Thalassemia

Range of mutations within

β

globin locus of chromosome 11

Three categories

Minor

Major

Intermedia

Seen in Mediterranean, Middle Eastern, Asians

Slide26

β

Thalassemia

β

Thal minima

β

Thal

MINOR

: Heterozygotes Mild to No anemia, usually asymptomatic, usually elevated HbA2 and increased HbF

Hemolytic anemia

↑

α

2

γ

2

(Hb F)

↑

α

2

δ

2

(Hb A

2

)

β

THAL

INTERMEDIA:

Homozygous but not with full clinical severity (range from asymptomatic to transfusion dependent): minor defects in B globin, alpha thal co-inheritance, decreased precipitation of insoluble tetramers

or

B

o

B

o

B

o

B

+

B

+

B

+

B

s

B

s

B

o

or

or

B

o

or

B

+

B

s

Β

THAL

MAJOR

Highly insoluble alpha globin precipitates which are toxic and leads to severe anemia & hemolysis

{

B

+

s = subtle defect

+ = some production

o = no production

Slide27

Know the following

Thalassemia's often misdiagnosed as iron deficiency anemia

Rule out iron deficiency

Microcytosis then can be evaluated by electrophoresis

Normal in alpha thalassemia

HbA2 increased in Beta thalassemia

Slide28

Clinical Case

76 yo female admitted for pneumonia

PMHx: RA, HTN, CAD

Admit CBC:

CBC: WBC 14k / Hgb 10.2 / Plt 120k

MCV 89 / Retic 1.2%

Serum Fe 30 / TIBC 100

Ferritin 250

Slide29

Anemia of Chronic Disease

Impaired iron utilization

Inflammatory State

Macrophages produce IL-6

Induces hepcidin production by liver

Inhibits iron absorption from GI tract

Decreases release of iron from macrophages

Causes: rheumatoid, infectious, neoplastic

Slide30

Anemia of Chronic Disease

Peripheral

Smear:

Normocytic

,

Normochromic

Serum Iron : Low

circulating iron bound to transferrin

Total Iron Binding Capacity (TIBC):

Low

Indirectly measures transferrin by determining total amount of iron the blood can bind

Transferrin

Saturation:

Low/Normal

Serum Iron/TIBC

Ferritin: High/High NormalIron stored within cell in protein complexes

Good indicator or iron stores in equilibrium conditions

Acute phase reactant, can be

elevated

in inflammation/chronic disease

Soluble

Transferrin Receptor Concentration:

Normal

Slide31

Slide32

Clinical Case

63 yo Caucasian man presents with fatigue, wt loss, and decreased appetite. He is a recovering alcoholic. Other history is unremarkable. Exam shows an obese man with spider angiomata, with decreased proprioception in the toes.

Labs:

CBC: WBC 3.2 / Hgb 8.5 / Plt 65k

MCV 104 / Retic 1.2%

Slide33

What is this?

Slide34

Macrocytic Anemia: MCV> 100

“FAT RBC, MD”

F: Folate deficiency

A: Alcohol use

T: Hypothyroid

R: Reticulocytosis (increased)

B: B12 Deficiency

C: Cirrhosis (Liver Disease)

M: Myelodysplasia (MDS)

D: Drugs (AZT, phenytoin, hydroxyurea)

Slide35

B12/Folate Deficiency

Infective Erythropoiesis

Defective DNA synthesis

Unable to form thymidine

Clinical:

Infertility

Neurologic Deficits – B12

only

Slide36

B12/ Folate Deficiency

B12 necessary for DNA synthesis

Binds to Intrinsic Factor and absorbed in Terminal

Ileum-

> transcobalamin

Due to

Malabsorption

Pernicious Anemia (Lacks Intrinsic Factor)

Inflammatory

Bowel Disease

Pancreatic

Insufficiency,

bacterial overgrowth

Rare decrease intake in Vegans

Folate Deficiency

Found in green leafy vegetablesDue to decrease intakeETOH abuseDrugs – Dilantin, Bactrim, MTXTreat by repletion of deficiencies

Slide37

MMA elevated in B12 only

Homocysteine elevated in B12 and Folate deficiency

Slide38

Pernicious Anemia

Most common cause of B12 malabsorption

Decreased secretion of intrinsic factor

Positive family hx in 30%

Associated

with other autoimmune diseases

Schilling Test for diagnosis

Ant parietal

cell IgG

antibody

Anti-IF antibody

Slide39

Normocytic Anemia MCV 80-100

Low to Normal Retic Count

Aplasia

Marrow Infiltration

Renal Disease

Anemia of Chronic Disease

High Retic Count (Exclude Bleeding)

Schistocytes: Microangiopathy

Spherocytes: Warm antibodies or heriditary spherocytosis

Sickle Cells: Sickle Cell Disease

Bite Cells: G6PD deficiency

Target Cells: Thalassemias

Inclusions: Malaria

Slide40

Normocytic Anemia

Increased red blood cell loss or destruction

Decreased red blood cell production

Overexpansion of plasma volume

Pregnancy

Over hydration

Slide41

Normocytic Anemia

Is there increased destruction or decreased production?

Check Reticulocyte Count

Is there evidence of:

- renal failure anemia of renal failure

- endocrine failure anemia of endocrine failure

- chronic inflammation anemia of chronic disease

Normal or decreased

If not, then consider a 1

o

marrow

problem

Bone marrow investigation

Slide42

What is this?

Slide43

Uremia

Echinocytes

Anemia of kidney disease

Minor increases in serum creatinine may have reduced EPO levels

Target Hb 11-12 g/dL for patients on HD

Slide44

What is this?

Slide45

Bone Marrow Biopsy: Multiple Myeloma

Slide46

Normocytic Anemia

Is there increased destruction or decreased production?

Check Reticulocyte Count

Increased

Is there evidence of hemolysis?

Hemolytic anemia

yes

Bleed

no

Evidence of RBC

DESTRUCTION

Indirect bilirubin level

LDH elevation

Slide47

Hemolytic Anemias:

INTRINSIC (to the red cell)

HEMOGLOBIN

ENZYME

Hereditary spherocytosis

Hereditary elliptocytosis

other

Sickle cell

Thalassemia

Unstable hemoglobins

G6PD

↓

Pyruvate kinase ↓

Other

ACQUIRED

PNH

Paroxysmal

Nocturnal

Hemoglobinuria

abnormality

abnormality

MEMBRANE

abnormality

Slide48

IMMUNE

: IgG +/- C’ – Coombs test

Autoimmune: Autoimmune disease / Lymphoproliferative ds

Alloimmune: ABO transfusion reaction

INFECTIOUS

: Mycoplasma pneumoniae (IgM)

LYMPHOPROLIFERATIVE DISEASE

: IgM – Lymphoma, Cold agglutinin ds

IgG – Lymphoma

DRUGS

:

IDIOPATHIC

MECHANICAL

: Fragmentation

March hemoglobinuria

Other

AgAb Complex

Hapten

autoimmune

Pen..Ab against pen, sits on membrane with penicillin

quinine + ab

Vasculitis

Severe hypertension

DIC; HUS

Abnormal heart valve

Hemolytic Anemias:

Extrinsic

(to the red cell)

Slide49

Hemolytic Anemia : Also grouped as extravascular/intravascular

Extravascular

RBC are outside vascular space, in reticuloendothelial system (spleen)

Engulfed by macrophages

Intravascular

RBCs lysed in blood vessels

Due to non-immune phenomenon DIC, TTP/HUS, HELLP, heart valves

Labs

Haptoglobin: Low in Hemolysis (Both intravascular and extravascular)

Binds to hemoglobin and then engulfed by macrophages

Urine Hemosiderin: High in intravascular

Iron lost more in urine with intravascular hemolysis

LDH: High in Both

Coombs Test: Ab or complement mediated hemolysis (Extravascular)

Slide50

Slide51

Clinical Case

48 yo white female presents to the ED with c/o severe fatigue, SOB, yellow eyes, dark urine. She denies fever, chills, sweats, or CP. She does c/o palp. She also c/o severe joint pains for many years, she thinks it is arthritis.

On exam she is ill appearing, tachycardia, and hypotensive. She has conjunctival pallor, no skin lesions. Guiac neg stool. Remainder was unremarkable.

Slide52

What is this?

Slide53

Cold agglutininsIgM antibodies that react with polysaccharide antigens on the RBC surface only at temperatures below core temperature of the body.

Warm agglutinins

IgG antibodies that generally react with protein antigens on the RBC surface at body temperature.. They seldom directly agglutinate the RBCs.

Auto antibodies

Slide54

Slide55

Autoimmune

Hemolytic Anemia

Antibodies react with RBC membrane proteins

Stimulate macrophages and cells in spleen and reticuloendothelial system to gradually snip portions of cell membrane

Thus causing spherocytosis

Detect using the Coombs Test for IgG

For IgM antibodies to C3

Common in CLL and lymphoma, SLE, EBV infection

Slide56

AIHA

Treat underlying disorder

Blood product support (give least incompatible blood products)

Steroids: Prednisone 1-2mg/kg qd

Splenectomy: 50% pts respond

IVIG

Plasma Exchange

Cytotoxic Agents: Cytoxan & Imuran

Slide57

What are these?

Slide58

Schistocytes!

Microangiopathic Hemolytic Anemia

Slide59

Microangiopathic Hemolytic Anemia

Diagnosis:

Jaundice

Hemolytic Anemia: Coomb

’

s Neg

Peripheral Smear: SCHISTOCYTES

DIC

HELLP syndrome (pregnancy)

Vasculitis

TTP – pentad

Ultra-large multimers of vWF accumulate due to lack of ADAMST13

MAHA, thrombocytopenia, fever, renal insufficiency, CNS event

Emergent plasma exchange

Slide60

What is this?

Slide61

Hereditary Spherocytosis

Hereditary Spherocytosis and Elliptocytosis

Autosomal dominant

Loss of Membrane flexibility and associated with chronic hemolysis

Test with osmotic fragility test

Complications include

Cholelithiasis

Splenomegaly

Slide62

What is this?

Slide63

G6PD deficiency

X linked G6PD gene

Variable deficiencies in the reduced state of glutathione

Protective mechanism against oxidative stress

Infections, meds (dapsone, sulfa, antimalarial)

Hemolysis can be mild to massive

“Bite Cells”

Heinz Bodies (denatures hemoglobin chunks)

Slide64

What is this?

Slide65

Sick Cell Syndrome

Mutation in Beta globulin where valine substituted for glutamine

Both Beta chains affected, sickle cell anemia

Deoxygenated Hemoglobin S stiffens RBC membrane and prevents passing through small vessels

Slide66

Lame Joke of the Day