clinical approaches to anemia presented by : cheryl morrow md

Clinical Approaches to

Anemia Presented by: Cheryl Morrow MD

I would like to acknowlege and thank the

American Society of Hematology

for granting permission

to use their educational slides to illustrate this lecture.

You will be able to access all of the images

that I will be using by going directly to the

ASH Image Bank @

http://imagebank.hematology.org/

And type in the Slide number.

Happy Birthday, Ernest!

Anemia: Course ObjectivesAt the end of the program, the participant will be able to:

Name the common physiological responses and symptoms that occur in anemia

Name the laboratory tests that should be ordered to determine the degree of severity and type (etiology) of anemia with which a given patient is presenting.

List the likely cause(s) of anemia when provided the results of the patient’s laboratory tests for anemia

Based on an understanding of anemia etiology, name one recommended treatment option for each of the following anemia types: nutritional deficiency, CKD, blood loss anemia, autoimmune anemia, anemia due to bone marrow failure.

Anemia – So why do we care ?

• Oxygen: the most essential element of human life - critical for:• Cellular respiration, growth and repair • Vital organ function: brain, heart, lung, kidneys, liver, nervous • Quality of life: movement, communication, senses, perceptions

• Oxygen is critical but dumb ! (I’m a dumb ox) - it doesn’t know where it needs to go, how to get there, nor how many of the crew are needed to get the job done at each location.

• Hemoglobin has the esteemed jobs of both escorting and managing the entire crew of available oxygen molecules

Hemoglobin the Super Hero:

The Proper Functioning of Hemoglobin requires:

• adequate numbers (inadequate = anemia)

• healthy molecules (Sickly = Hb S, C, thalassemia)

• in a healthy environment (Sick = oxygen; CO )

Oxygen-Hemoglobin Dissociation Curve

100% ___________________________________________________________

65 35% oxygen dropped off

% Sat.

0 PaO2 mmHg 100

Right Shift: temp, pH, CO2

Left Shift: temp, pH, CO2, Hb F

• Functional definition of anemia: inadequacy of one’s hemoglobin, or the red blood cells that contain the hemoglobin, to transport and deliver adequate oxygen supplies to the tissues where it is needed.

• Technical definition of anemia:• Males: hemoglobin < 14 g/dl; hematocrit < 40 %• Females: hemoglobin < 12 g/dl; hematocrit < 37%

Sx’s of Anemia = Sx’s of Hypoxemia

o Tired, Sleeping moreo Loss of energy, weaknesso Pale skino Easy Fatigueo Tachycardia, esp. with exertiono New onset AFo Shortness of breatho Dizzinesso Headacheo Confusion, poor concentrationo Angina

Go to ASH Website and select slide 3632

The RBC indices tell us about the Red Cell Physical Characteristics, and hemoglobin content:

Index Full Name

What’s measured

Normal Range

MCV Mean Corpuscular Volume

AverageRed blood cell Size

80-100 Femtoliters

MCH Mean Corpuscular Hemoglobin

Average amount of Hb in each RBC

27-31Picograms/ cell

MCHC Mean Corpuscular HemoglobinConcentration

Hb density: Is it compactedor spread out?

32-36Grams/ deciliter

RDW Red Blood Cell Distribution Width

Variations in RBC size

11.5-14.5 %

Low make, High take, Mistake !

So let’s talk about anemia:• Anemia develops when there is an imbalance between

the production and the loss/destructrion of RBC’s.

• Anemia can also be caused by a genetic defect causing the production of faulty hemoglobin and/or RBC’s.

• Thus, the causes of anemia can be classified as either …

Low Make High Take Mistake

MCV - Based Approach to Anemia Diagnosis :

<80 80 – 100 > 100 Microcytic Normocytic Macrocytic

Ferritin & Iron Studies Reticulocyte Count Blood Smear Morphology

Low Normal High Low Normal High -- HS PMN’s* + HS PMN’s

Iron Thalassemia Anemia Anemia Acute Hemolysis Polychro- Target Vit B12Defic. Hemoglobin- Chronic Chronic Blood Chronic masia Cells DeficiencyAnem. opathy Disease Disease Loss Bld.Loss Reticulo- Liver Folate Hemo- CRP, cytosis Disease Deficiency globin ESR LDH Electro- Sidero- Bilirubin Liver B12, phoresis blastic Haptoglobin ETOH Enzymes Folate Lead poisoning anemia Direct Anti- Abuse Levels, globulin test Hypothyroid MMA, Lead Bone Marrow Schilling Level Ringed sideroblasts Melodysplasia TFT’s Test * HS PMN’s = Hypersegmented Polymorphonuclear Neutrophils

Bone MarrowRinged Sideroblasts

BMP E-po.Defic

Microcytic Anemias . . . .

“Anorexics love to ingest small” ( MCV< 70)

Case 1:

Mrs. B is a 92 year old nursing home patient who, on routine lab testing, was found to have a hemoglobin of 9.0, and a hematocrit of 28.1. The patient’s aids note that she requires more assistance with ADL’s of late. She is weaker and seems more confused.

Other Labs: WBC 6.9 (5-10)

platelet 460 (150,000-400,000)

MCV 70.5 (80-100)

MCH of 22.5 (27.0-32.0) MCHC 32.0 (32-36)

RDW was elevated at 17.8 (11.5-14.5)

What is in the differential diagnosis? What do we do next?

Ferritin (& Iron Studies) Reticulocyte Count Blood Smear Morphology

Case 1 continued:

Iron studies:

Ferritin: 8 (10-250) LOW

Serum Iron: 14 (35-150) LOW

TIBC: 254 (250-450) NORMAL

% Saturation: 6 (12-50) LOW

Condition Causes CBC/other Iron studies Treatment

Iron Deficiency

Bleeding, pregnancy

Platelets up;RDW up

Serum Fe , %Sat. ,Ferritin TIBC

Suppl. IronStop bleed

Anemia of Chronic Disease

Diseaseswith chronicinflammation

Elevated ESR& CRP; MCVis normal-low

Serum Fe , %Sat. Ferritin TIBC

TreatUnderlying disease

Beta Thalassemia Trait

hereditary IncreasedHbA2, HbF -electrophoresis

Serum Fe, %Sat.,Ferritin TIBC normal

Usually noneMis-dx’dAs Fe-defic.

Sideroblastic Anemia

Hereditary &ETOH, B6 def.Isoniazide,Zyvox, MDS

Prussian BlueStain of BMshows ringedsideroblasts

Serum Fe , %Sat. Ferritin TIBC nl

D/C causativeagent; treatwith Vit. B6 -helps 40-80%

Lead Toxicity

Lead ingestionOften from paint chips.

Basophilicstipling

D/C lead Exposure;ChelationTherapy prn

Causes of Microcytic Anemia:

Diagnosis: Iron Deficiency Anemia

Treatment: Supplemental iron; Look for occult GI bleed

Case 1 continued:

Iron studies:

Ferritin: 8 (10-250) LOW

Serum Iron: 14 (35-150) LOW

TIBC: 254 (250-450) NORMAL

% Saturation: 6 (12-50) LOW

• Go to ASH website and select slide 4045

Labs: His Hb is 8,8; Hct is 26.2; His Ferritin was WNL. His other iron studies were within normal limitis.

His peripheral blood film as follows:

Case 2.

Peter is a six year old boy who developed headaches, difficulty sleeping, stomach pain, weight loss, irritability and regression in school over the past several months.

His mother, who is a single mom, usually works until 6 at night and the patient and his ten year old sibling are left alone in their apartment in the late afternoon until Mom returns.

Iron Deficiency

Bleeding, pregnancy

Platelets up;RDW up

Lead Toxicity

Basophilicstipling

Lead Poisoning

Diagnosis:• The blue speckles seen on several RBC’s is Basophilic Stippling.• Basophilic stippling is seen in heavy metal poisoning,

particularly lead poisoning, the thalassemias; and a few other conditions.

• His blood lead level was 22 mg/dl (upper nl is 5 mg/dl for child)• Diagnosis was made: chronic lead poisoning caused by ingestion

of paint chip fragments.• Treatment: hospitalized for IV chelation therapy with DMSA and

returned to his baseline.

Case 3HPI: A 42-year-old woman was referred for mild, chronic microcytic anemia discovered 18 years before. She c/o chronic fatigue that she has learned to live with.

PE: was normal except for some generalized weakness.

Labs: Hb 9.6 g/dL, MCV 73 fL, MHC 23 pg (27-32) RDW 27% (10.5-14.5). The WBC and platelet counts were WNL.

Iron studies: ferritin 465 (10-252). Fe, % Sat are TIBC nl.

Her peripheral smear follows:

Iron Deficiency

Bleeding, pregnancy

Platelets up;RDW up

Lead Toxicity

Basophilicstipling

Ringed sideroblasts = Sideroblastic Anemia

• Peripheral Smear showed a double population of RBC’s: one normal and one extremely microcytic and hypochromic. Very unusual need a bone marrow.

• Bone marrow aspirate: 35% of erythroid cells were ringed sideroblasts: nucleated erythroblasts with granules of (Prussian-blue stained) iron in perinuclear mitochondria

• In sideroblastic anemia, the body/RBC has iron available but cannot incorporate it into hemoglobin.

Diagnosis: X-Linked Sideroblastic Anemia

Case 3:

• X-linked sideroblastic anemia was confirmed by DNA sequencing on this patient. A skewed X-chromosome inactivation ratio explained the phenotype with two cell populations. Gender preval.: 1/3 women and 2/3 men.

• Aquired Sideroblastic anemia: myelodysplastic syndrome, ETOH abuse, lead poisoning, B6 defic., drugs (Isoniazid, linezolid, etc)

• Treatment: Oral pyridoxine (B6) therapy for all types with varying effectiveness. In this real case, pyridoxine increased her Hb to 11.4; and peripheral films showed disappearance of the microcytic population.

Normocyctic Anemias . . . .

“average men hunt burgers” (MCV 80-100)

BMP E-po.Defic

• Reticulocytosis: Reticulocytes: immature RBC’s pushed out of the bone

marrow early because of anemia. They stain “blue” because of nuclear fragments. These fragments show up better on a vital stain which enables counting of reticulocytes

Polychromasia: the bluish tint of the reticulocytes on a routine Wright’s stain, provides evidence of immature RBC’s

• Example: Hemolytic disease of the newborn secondary to ABO incompatibility• Notice the polychromasia (causing an increase in MCV)• Notice the nucleated RBC

What is the Ddx ?

Case 4

A 58 year old, obese, diabetic female presents with c/o feeling exhausted. She states that over the past 1 month, she has gotten increasingly short of breath while walking from the parking lot to his office. Over the past one week, she has also experienced the sensation of her “heart pounding out of her chest” when walking back and forth to his car.

When you ask her about pain, she admits to chronic back and joint pain for which she regularly takes ibuprofen with good relief. She denies dyspepsia, diarrhea, melena and hematochezia. She is post-menopausal. Her PE is normal.

What kind of anemia does she have?

Case 4 continued:

Relevant lab work is as follows: Na 135

WBC 7.6 MCV 92 K+ 4.4

Hb 8.2 MCH 29 (27-32) Cl 106

Hct: 24.5 Serum Fe normal CO2 24

Plt: 333 Ferritin normal BUN 64

Diff: normal Creat. 3.2

RBC morphology on next page. GFR: 19

Reticulocyte count: 0.4 (0.5-2.5)

BMP E-po.Defic

• Case 4

• Answer: she has Anemia of Chronic Kidney Disease with acute on chronic renal failure secondary to NSAID use.

• Treatment: Stop NSAIDS! Treat anemia with erythropoetin. Monitor kidneys closely

Case 5

HPI: A 21-year-old African-American woman presented for routine prenatal care for her second pregnancy. Her past medical history included normocytic anemia of uncertain etiology, for which she was treated with iron, during her first pregnancy. Her physical examination was unremarkable.

Labs: hemoglobin, 9.4 g/dL; MCV 81 fl; RDW 15.3

WBC and platelet counts were WNL

Electrophoresis/chromatography for.

hemoglobinopathy were normal,

Here is her periperal blood film:.

Peripheral blood smear showed many elliptocytes, which is diagnostic of hereditary elliptocytosis (HE).

HE is caused by various gene mutations ultimately affecting the red cell cytoskeleton and membrane protein integrity Spontaneous hemolysis not mediated by Ab’s.

HE is seen in numerous ethnic groups; with incidence highest in west and central Africans.

Most patients with heterozygous HE are asymptomatic, although some may demonstrate hemolytic anemia and splenomegaly.

Other lab findings: haptoglobin, LDH, Indir. Bilirubin, direct antiglobulin test (DAT) is neg. b/c not Ab-mediated.

Treatment: Folic acid reduces hemolysis.

Hemolytic Anemia

Case 6.

HPI: A previously healthy 23 year old male

college student was noted by his buddies to

be pale, fatigued, and just not keeping up.

His mother comes to visit and notes that

he has lost 10 pounds over the past 1 month.

She wonders if he has been using drugs.

She brings him to your office for evaluation.

Lab tests reveal: WBC 11.8, Hb 8.3, Hct 26.0, MCV 96

What’s your Ddx? What questions do we need to ask him?

Case 6, continued:

Upon your ROS, he reveals that he has had

Multiple episodes of loose stool over the

Past two months. When pressed, he admits

That the stools have been maroon in color.

Additional Labs:

Na 148, K 3.2, CO2 16, BUN 32, Creat. 1.2

(BUN/Creat. Ratio 27).

WBC 11.8, Hb 8.3, Hct 26.0, MCV 96

What’s your Ddx? What do we do next to confirm the dx?

BMP E-po.Defic

Case 6, continued:

Upon your ROS, he reveals that he has had

Multiple episodes of loose stool over the

past 2-3 weeks. When pressed, he admits

That the stools have been loose and bloody.

Additional Labs:

Na 148, K 3.2, CO2 16, BUN 32, Creat. 1.2

(BUN/Creat. Ratio 27).

WBC 11.8, Hb 8.3, Hct 26.0, MCV 96

His peripheral blood film is the next slide.

What’s your Ddx? What do we do next to confirm the dx?

Case 6, continued: The blood film confirms what the indices

have told us: normocytic, normochromic

We order a reticulocyte count and it comes

back at 2.5% (normal is 0.5- 2.5 %). The

Bleed is still too acute for a great response.

Diagnosis:

You refer him to GI who scopes him and diagnoses him with new onset Crohns. He starts anti-inflammatory Meds and his symptoms subside. He has a normal bone marrow so,

when given adequate iron, and nutrients, he will replace his lost RBC’s without difficulty.

Macrocytic Anemias . . . .

“Large men routinely hunt virtually ALL food”

MCV > 100

BMP E-po.Defic

• Reticulocytosis: Reticulocytes: are immature RBC’s pushed out of the bone

marrow early because of anemia. They are larger than mature RBC’s and thus increase the MCV.

Polychromasia: the bluish tint of the reticulocytes on a routine Wright’s stain, They stain “blue” because of retained nuclear fragments. These fragments show up better on a vital stain which enables counting of reticulocytes

: provides evidence of immature RBC’s

• Example: Hemolytic disease of the newborn secondary to ABO incompatibility• Notice the polychromasia (causing an increase in MCV)• Notice the nucleated RBC

• Go to the ASH website and select slide number 3513

• Megaloblastic Anemia and Hypersegmented PMN’s

• Megaloblastic Anemia; a macrocytic anemia that results from inhibition of DNA snthesis during RBC production.

• A mismatch occurs in the maturation of nucleus and cytoplasm as the result of the lack of folic acid or B12.

• As a result, RBC’s have lacier nuclei and larger cell size;

Neutrophils become Hypersegmented,- 6 or more lobes

Peripheral films will also have giant bands

• Go to the ASH website and select slide 2869

Megaloblastic Anemia, continued:

• BM aspirate from a patient with folic acid deficiency is shown • erythroid hyperplasia with marked nuclear/cytoplasmic

dysynchrony noted at all stages of erythroid maturation; and nuclear budding.

• The Megaloblastic Anemias include:• B12 deficiency from dietary lack• B12 deficiency due to malabsorption (lack of Intrinsic Factor)

known as Pernicious Anemia. Do Schilling Test to differentiate.• Folic Acid defiency – (Pregnant women at increased risk)• To differentiate, check B12, Folic Acid and MMA levels. • With B12 deficiency, will also have neurologic symptoms.

• Pernicious Anemia • Note the macro-ovalocytes characteristic of vitamin B12

or folate deficiency states.

Case Study 7.

• A 21-year-old woman presented with severe anemia and mild splenomegaly.

• Her CBC revealed a Hb of 6.8 g/dL, hematocrit 22%, MCV 114 fL, and MCH 21.4 (27.0-32.0).

• The reticulocyte count was 3.6%.

• Her peripheral film is as follows:

Case Study 7.

• The peripheral smear (panel A) showed macrocytic target cells, polychromatophilia, macro-ovalocytes, and a few microcytes.

• In view of the target cells, liquid chromatography was performed. Hemoglobin E disease was Dx’d. It typically shows microcytic hypochromic anemia with target cells.

• Her serum B12 level was 94 ng/L (normal range, 180-640 ng/L) with normal serum and red cell folate levels.

• A diagnosis of vitamin B12 deficiency with hemoglobin E disease was made. After 2 weeks of supplementation of vitamin B12 and folate, her hemoglobin rose to 9.6 .

BMP E-po.Defic

• Macrocytic Anemias (Non-megaloblastic)

• Also occur with various organ diseases such as Hypothyroid, liver disease, and in alcoholism.

• In addition to the expected abnormal lab studies associated with each of these conditions:

Target cells are particularly associated with Liver Disease.

• For the remainder of this lecture, we’ll take a quick look at some blood films and clinical characteristics of other anemias that we do not have time to present in Case Study format.

• The first is Sickle cell disease – Note the RBC morphology on the following slides that results in the deformed cells plugging up blood vessels and causing painful ischemic attacks.

• In addition to the RBC findings of sickled cells, this image shows a nucleated RBC (arrow). Because of the marked anemia, the bone marrow pushes out immature cells.

• For the remainder of this lecture, we’ll take a a quick look at miscellaneous blood films of other anemias that we do not have time to go into today.

• The first is Sickle cell disease – Note the RBC morphology

• In addition to the RBC findings of sickled cells, this image shows a nucleated RBC (arrow).

• Pappenheimer bodies may be found in a variety of conditions including megaloblastic anemia, thalassemias, hemolytic anemias, and post-splenectomy.

Hemoglobin C Disease• Hemoglobin C crystals crystalize outside of and inside of

RBC’s causing disruption of cells and blockage of vessels..

• Both extracellular (single arrows) and intracellular crystals are noted.

RBC morphology in thalassemia • A hypochromic polychromatophilic RBC (arrow) is

shown . • The smear from a child with hemoglobin of 7.5 g/dl,

RBC of 5.9 × 106/ul and an MCV of 47 fL consistent with a diagnosis of thalassemia.

• The marked RBC microcytosis and hypochromia are evident.

• The child had received an RBC transfusion prior to smear being performed accounting for the dual population of RBCs.

• A spherocyte (arrow) is present on the smear and is of donor origin

• RBC abnormalities in S/β thalassemia • Peripheral smear from a patient with S/β +

Thalassemia is shown. The MCV in this patient was 67 femtoliters consistent with microcytosis.

• Hemoglobin analysis showed 67% hemoglobin S; 25% hemoglobin A; 2% hemoglobin F; and 6% hemoglobin A2. Sickle cell (small arrow) and target cell (large arrow) typical of this disorder are shown.

• Microangiopathic hemolytic anemia secondary to artifical aortic valve malfunction

• The smear is shown at higher magnification and demonstrates more clearly the marked schistocytosis.

BMP E-po.Defic

Microcytic Anemias . . . .

“Anorexics love to ingest small” ( MCV< 70)

Normocyctic Anemias . . . .

“average men hunt burgers” (MCV 80-100)

Macrocytic Anemias . . . .

“Large men routinely hunt virtually ALL food”

MCV > 100

THE END … and Ernest, it’s finally time for your birthday vacation !!!

clinical approaches to anemia presented by : cheryl morrow md

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