Heme 07: Hypoproliferative Anemia Applications

Front 1

What are the categories of Hypoproliferative Anemias?

Back 1

- Impaired proliferation / differentiation of stem cells
- Impaired proliferation / maturation of erythroid precursors
- Defective hemoglobin synthesis
- BM replacement / infiltration (myelophthisic)

Front 2

What are the types of Hypoproliferative Anemias that are caused by impaired proliferation or differentiation of stem cells?

Back 2

- Aplastic anemia
- RBC aplasia

Front 3

What are the types of Hypoproliferative Anemias that are caused by impaired proliferation or maturation of erythroid precursors?

Back 3

- Megaloblastic anemia
- Anemia of renal failure
- Anemia of chronic disease
- Anemia of endocrine disorders
- Myelodysplastic syndromes

Front 4

What are the types of Hypoproliferative Anemias that are caused by defective hemoglobin synthesis?

Back 4

- Iron deficiency anemia (heme)
- Sideroblastic anemia (heme)
- Thalassemias (globin)

Front 5

What are the types of Hypoproliferative Anemias that are caused by marrow replacement / infiltration (myelophthisic)?

Back 5

- Hematopoietic tumors
- Metastatic tumors
- Granulomatous inflammation

Front 6

What are the lab findings common to all Hypoproliferative Anemias?

Back 6

- Anemia
- ↓ Reticulocyte count

Front 7

What causes of Hypoproliferative Anemia have a hypocellular BM?

Back 7

- Stem cell disorders (eg, aplastic anemia)
- Drugs / treatments (eg, chemo)

Front 8

What causes of Hypoproliferative Anemia have a hypercellular BM?

Back 8

- Marrow infiltration
- Ineffective hematopoiesis

Front 9

Case 1: 62 yo female w/ PMH of hypothyroidism presents w/ increasing fatigue and weakness and epigastric pain. Complains of nausea and loss of appetite, but no vomiting or diarrhea. Abdomen is non-tender, non-distended, and without organomegaly or masses. Limited neuro exam reveals decreased sensation to touch on bilateral lower extremities.

Which of these are relevant initial screening lab tests for this history and symptoms? Why?
- Serum glucose
- TSH
- Serum calcium
- Serum ferritin
- AST, ALT, and bilirubin

Back 9

- Serum glucose - screen for diabetes
- TSH - is her hx of hypothyroidism causing her problems
- Serum Ca2+ - hypercalcemia can cause lots of problems (stones, bones, abdominal groans, and psychiatric moans)
- AST, ALT, and bilirubin

Front 10

Case 1: 62 yo female w/ PMH of hypothyroidism presents w/ increasing fatigue and weakness and epigastric pain. Complains of nausea and loss of appetite, but no vomiting or diarrhea. Abdomen is non-tender, non-distended, and without organomegaly or masses. Limited neuro exam reveals decreased sensation to touch on bilateral lower extremities.

WBC: 2,500 / µL
Platelets: 110,000 / µL
HGB: 7.2 g/dL
HCT: 23%

What diagnosis is compatible with these CBC results?

Back 10

*Paroxysmal Nocturnal Hemoglobinuria (can cause pancytopenia)

- B, C and D affect only RBCs (would not cause pancytopenia)
- E is made up

Front 11

What disorders can cause Pancytopenia?

Back 11

- Stem cell disorders (aplastic anemia and paroxysmal nocturnal hemoglobinuria)
- Ineffective hematopoiesis (myelodysplastic syndrome and megaloblastic anemia)
- Marrow infiltration (leukemia/lymphoma, metastatic carcinoma, myelofibrosis)
- Splenic sequestration
- Drugs/tx (immunosuppressants, chemo/radiation, others)

Front 12

Case 1: 62 yo female w/ PMH of hypothyroidism presents w/ increasing fatigue and weakness and epigastric pain. Complains of nausea and loss of appetite, but no vomiting or diarrhea. Abdomen is non-tender, non-distended, and without organomegaly or masses. Limited neuro exam reveals decreased sensation to touch on bilateral lower extremities.

The WBC morphology shown is observed in the blood.

What biochemical abnormality is most directly responsible for the morphologic abnormality in this patient?

Back 12

Megaloblastic Anemia - decreased Tetrahydrofolate levels

Front 13

Case 1: 62 yo female w/ PMH of hypothyroidism presents w/ increasing fatigue and weakness and epigastric pain. Complains of nausea and loss of appetite, but no vomiting or diarrhea. Abdomen is non-tender, non-distended, and without organomegaly or masses. Limited neuro exam reveals decreased sensation to touch on bilateral lower extremities.

Which blood smear would you predict for this patient?

Back 13

C:
- Macro-ovalocytes
- Shows pronounced variation in cell size and shape
- Tear-drop cells
* Megaloblastic Anemia

Front 14

Case 1: 62 yo female w/ PMH of hypothyroidism presents w/ increasing fatigue and weakness and epigastric pain. Complains of nausea and loss of appetite, but no vomiting or diarrhea. Abdomen is non-tender, non-distended, and without organomegaly or masses. Limited neuro exam reveals decreased sensation to touch on bilateral lower extremities.

Given the CBC and blood smear abnormalities, do you need a BM evaluation for a definitive diagnosis? Why/why not?

Back 14

Serum tests are definitive; BM evaluation is not neeeded

Front 15

What are the morphologic signs of Megaloblastic Anemia in the Peripheral Blood?

Back 15

* Hypersegmented neutrophils (1st)
- Macrocytic anemia w/ oval macrocytes
- Anisopoikilocytosis (variable size and shape)

Front 16

What are the morphologic signs of Megaloblastic Anemia in the Bone Marrow?

Back 16

- Hypercellular
- Giant bands
- Nuclear to cytoplasmic dyssyncrony (megaloblastic change) in erythroids, granulocytes

Front 17

If you see this, what should you think?

Back 17

Hypersegmented neutrophil (>5 nuclear lobes)
= Megaloblastic Anemia

Front 18

Case 1: 62 yo female w/ PMH of hypothyroidism presents w/ increasing fatigue and weakness and epigastric pain. Complains of nausea and loss of appetite, but no vomiting or diarrhea. Abdomen is non-tender, non-distended, and without organomegaly or masses. Limited neuro exam reveals decreased sensation to touch on bilateral lower extremities.

A few days later, an upper GI endoscopy is performed to evaluate for epigastric pain. Gastric biopsy reveals loss of chief and parietal cells and increased chronic inflammatory cells.

What is the primary mechanism of this patient's cytopenias?

Back 18

Immune-mediated destruction of epithelial cells

(signs of Pernicious Anemia)

Front 19

What is the function of chief cells?

Back 19

Secrete acid

Front 20

What is the function of parietal cells?

Back 20

Secrete intrinsic factor

Front 21

What is the first thing to happen to Vitamin B12 upon ingestion?

Back 21

- Salivary R protein (eg, Haptocorrin) made in saliva glands is secreted
- R protein has greater affinity and binds Vitamin B12

Front 22

What happens to Vitamin B12 bound to salivary R protein?

Back 22

Complex goes to duodenum where pancreatic enzymes degrade R factor, releasing Vitamin B12

Front 23

What happens to Vitamin B12 that has been released from R factor in duodenum by pancreatic enzymes?

Back 23

Vitamin B12 binds to Intrinsic Factor

Front 24

What happens to Intrinsic Factor - Vitamin B12 complex?

Back 24

Receptors = Cubulins bind IF-Vit B12 complex to absorb Vitamin B12 in the intestine (terminal ileum)

Front 25

What causes Megaloblastic Anemia?

Back 25

- Deficiencies in Vitamin B12 and Folate
- Results in impaired DNA synthesis, leading to impaired/ineffective hematopoiesis
- Similar morphologic features in the blood and BM

Front 26

What can cause a Vitamin B12 deficiency?

Back 26

- Impaired absorption of Vitamin B12: IF deficiency, ileal resection, and pancreatic insufficiency
- Increased requirement
- Decreased intake (strict vegetarians)
- Tapeworm (Diphyllobothrium latum)

Front 27

What are the sources of Vitamin B12? How long is it stored?

Back 27

- Animal products
- Stores last for years

Front 28

What can cause impaired absorption of Vitamin B12?

Back 28

- Intrinsic factor deficiency
- Ileal resection (this is where it is absorbed)
- Pancreatic insufficiency

Front 29

What deficiency causes subacute combined degeneration (dorsal and lateral tract demyelination, parasthesias, spastic paraperesis, sensory ataxia)?

Back 29

Vitamin B12 deficiency

Front 30

What are the clinical concerns of Vitamin B12 Deficiency?

Back 30

Megaloblastic anemia
- Possibly pernicious anemia

Subacute combined degeneration
- Dorsal and lateral tract demyelination
- Parasthesias
- Spastic paraparesis
- Sensory ataxia

Front 31

Where is the spinal cord demyelinated in a Vitamin B12 Deficiency?

Back 31

Dorsal and lateral tracts

Front 32

What is the most frequent cause of Vitamin B12 Deficiency?

Back 32

Pernicious Anemia: auto-antibodies against Intrinsic Factor (IF) leads to a deficiency of Vitamin B12 (not able to absorb it)

Front 33

What is required for diagnosis of Pernicious Anemia?

Back 33

Auto-antibodies against Intrinsic Factor

Front 34

What are the lab findings in Vitamin B12 Deficiency?

Back 34

- Low Vitamin B12 levels
- Low reticulocyte count (d/t ineffective hematopoiesis)
- Auto-antibodies to IF or parietal cells (if pernicious anemia)
- Elevated methylmalonic acid (MMA)

Front 35

What are the causes of Folate deficiency?

Back 35

- Decreased intake (alcoholism, poverty)
- Increased requirements (eg, growth, pregnancy, states of high cell turnover like hemolytic anemia and leukemia)
- Defective absorption (jejunal resection or malabsorption)
- Folic acid antagonists

Front 36

What are the sources of Folate? How long is it stored?

Back 36

- Source: green veggies
- Storage: can be depleted in months

Front 37

What are the clinical presentations of Folate Deficiency?

Back 37

- Megaloblastic anemia
- Neural tube defects (300,000/year)

Front 38

What defects are caused in the fetus by a Folate Deficiency? How can this be prevented?

Back 38

Spina Bifida Occulta → Anencephaly

Folate Supplementation

Front 39

Case 1: 62 yo female w/ PMH of hypothyroidism presents w/ increasing fatigue and weakness and epigastric pain. Complains of nausea and loss of appetite, but no vomiting or diarrhea. Abdomen is non-tender, non-distended, and without organomegaly or masses. Limited neuro exam reveals decreased sensation to touch on bilateral lower extremities.

A few days later, an upper GI endoscopy is performed to evaluate for epigastric pain. Gastric biopsy reveals loss of chief and parietal cells and increased chronic inflammatory cells.

Which therapy should the physician recommend?

Back 39

Vitamin B12 supplementation

Front 40

How should you treat Megaloblastic Anemia due to Vitamin B12 Deficiency?

Back 40

- Do not treat w/ folate
- Treat with Vitamin B12 supplementation

Front 41

What are the effects of treating Megaloblastic Anemia due to Vitamin B12 Deficiency with Vitamin B12?

Back 41

- Anemia will reverse
- Neurological manifestations will not reverse

Front 42

Case 2: 30 yo, previously healthy woman with no pregnancies, presents w/ complains of fatigue. She is an avid runner and is now experiencing increased SOB w/ strenuous exercise. She is pale, in no acute distress, and otherwise unremarkable. CBC (10 years ago) was within normal limits.
HGB: 6.3 g/dL, HCT 19%, PLT 500,000/µL, MCV 61 fL.

Which blood smear would you predict for this patient?

Back 42

D - hypochromic, microcytic anemia

Front 43

Case 2: 30 yo, previously healthy woman with no pregnancies, presents w/ complains of fatigue. She is an avid runner and is now experiencing increased SOB w/ strenuous exercise. She is pale, in no acute distress, and otherwise unremarkable. CBC (10 years ago) was within normal limits.
HGB: 6.3 g/dL, HCT 19%, PLT 500,000/µL, MCV 61 fL.

Based on smear which of the following additional parameters do you predict for this patient?
a) ↑ Reticulocytes (200,000/µL)
b) Nl MCH 30 pg
c) ↑ RDW (20%)
d) ↑ RBC 6,500,000/µL
e) ↓ RBC 4,000,000/µL

Back 43

Elevated RDW
- This is increased because there is a lot of variation in size and shape

a) Would not expect a high reticulocyte count
b) Would expect a low MCH
d&e) Would expect normal RBC count

Front 44

Case 2: 30 yo, previously healthy woman with no pregnancies, presents w/ complains of fatigue. She is an avid runner and is now experiencing increased SOB w/ strenuous exercise. She is pale, in no acute distress, and otherwise unremarkable. CBC (10 years ago) was within normal limits.
HGB: 6.3 g/dL, HCT 19%, PLT 500,000/µL, MCV 61 fL.

The CBC and PB findings most likely a result of what? In a focused history, what additional history is most important to obtain for this patient?

Back 44

- Chronic blood loss (most common reason for iron deficiency in adult population)
- Most likely due to change in menstrual cycle frequency and volume

Front 45

Case 2: 30 yo, previously healthy woman with no pregnancies, presents w/ complains of fatigue. She is an avid runner and is now experiencing increased SOB w/ strenuous exercise. She is pale, in no acute distress, and otherwise unremarkable. CBC (10 years ago) was within normal limits.
HGB: 6.3 g/dL, HCT 19%, PLT 500,000/µL, MCV 61 fL.

For the severity of the lab abnormalities, the patient has relatively little symptomatology. What is the likely reason?

Back 45

Physiologic compensation over a prolonged time

Front 46

What is the definition of severe anemia? Causes?

Back 46

- <7 g/dL
- Acute blood loss (will be symptomatic)
- Nutritional deficiency (eg, iron, folate, vitamin B12, or combination)

Front 47

What are the compensatory mechanisms in anemia?

Back 47

- ↑ 2,3-DPG
- Shunting of blood from non-vital to vital areas
- ↑ Cardiac Output
- ↑ Respiratory Rate
- ↑ RBC Production
- ↑ Plasma Volume (minor compensation)

Front 48

What are the differential diagnoses for a microcytic, hypochromic anemia?

Back 48

- Iron Deficiency Anemia (most common)
- Thalassemia
- Anemia of Chronic Disease (10-20%)

Front 49

What does this slide show?

Back 49

Spherocytes

Front 50

What does this slide show?

Back 50

Sickle Cell Anemia

Front 51

What does this slide show?

Back 51

Megaloblastic Anemia (tear shaped cells, big cells)

Front 52

What does this slide show?

Back 52

Hypochromic, Microcytic Anemia
- Iron Deficiency Anemia (most common)
- Thalassemia
- Anemia of Chronic Disease (10-20%)

Front 53

What does this slide show?

Back 53

Normal

Front 54

What does this slide show?

Back 54

Fragmentation / Schistocytes

Front 55

How/where is iron stored in the body?

Back 55

- Liver, spleen, and BM
- Hemosiderin: breakdown of ferritin
- Ferritin

Front 56

What are the clinical implications of iron deficiency?

Back 56

- Iron Deficiency Anemia
- Impaired cognition, work capacity
- Immune deficiency

Front 57

What are the causes of Iron deficiency?

Back 57

- Dietary lack (eg, breast-milk fed infants)
- Impaired absorption (duodenum)
- Increased requirement (eg, pregnancy, growing child)
- Chronic blood loss (GI source if >50 yo, menstrual bleeding)

Front 58

How is heme iron absorbed?

Back 58

- Heme transporter brings heme iron into epithelial cell of duodenum
- Iron is transferred to mucosal ferritin or transported into plasma via Ferroportin 1

Front 59

How is non-heme iron absorbed?

Back 59

1) Non-heme iron converted from Fe3+ form to Fe2+ form via Reductase (Vit. C dependent)
2) Fe2+ is taken up by DMT1 (divalent metal transporter 1) into epithelial cell
3) Once inside cell it binds to Ferritin to either be stored or to continue to plasma
4) Iron can get into plasma via Ferroportin 1 (activity inhibited by Hepcidin)
5) Once in plasma immediately oxidized from Fe2+ to Fe3+ by Hephaestin
6) Once in plasma, it is bound by Plasma Transferrin which takes it to liver, etc

Front 60

What happens as Ferritin stores in liver get full of iron?

Back 60

1) Liver synthesizes Hepcidin
2) Hepcidin inhibits Ferroportin (protein responsible for bringing iron into plasma
3) Iron is trapped in intestinal epithelial cells on mucosal Ferritin
4) Epithelial cells of GI tract shed and this removes iron stored on Ferritin

Front 61

What is the receptor for Transferrin? Where is this receptor found?

Back 61

CD71 - Transferrin Receptor
- Enriched on immature RBCs and other cells that require iron

Front 62

How do you diagnose an Iron Deficiency Anemia (IDA)?

Back 62

- PB smear: microcytic, hypochromic anemia
- ↓ Serum ferritin < 30 µg/L (most sensitive assay for IDA)

Front 63

How do the serum iron, total iron binding capacity (TIBC), and % iron saturation, affect diagnosis of Iron Deficiency Anemia?

Back 63

Serum Iron:
- Many metabolic variations affect levels
* Not a sensitive to specific marker for iron deficiency

Total Iron Binding Capacity (TIBC):
- Essentially equivalent to transferrin conc.
- Normally 30% saturated
* Qualitatively the OPPOSITE of serum FERRITIN levels

% Iron Saturation:
- % = Serum Iron / TIBC
- Calculation based on these values

Front 64

How are Ferritin and Total Iron Binding Capacity (TIBC) related?

Back 64

Inverse relationship:
- As Ferritin ↓, TIBC ↑ (in order to try to scavenge for more iron)

Front 65

Case 2: 30 yo, previously healthy woman with no pregnancies, presents w/ complains of fatigue. She is an avid runner and is now experiencing increased SOB w/ strenuous exercise. She is pale, in no acute distress, and otherwise unremarkable. CBC (10 years ago) was within normal limits.
HGB: 6.3 g/dL, HCT 19%, PLT 500,000/µL, MCV 61 fL.

What does this smear show?

Back 65

Reticulocyte / polychromasia:
- Abnormally high number of red blood cells found in the bloodstream as a result of being prematurely released from the bone marrow during blood formation

Front 66

Case 2: 30 yo, previously healthy woman with no pregnancies, presents w/ complains of fatigue. She is an avid runner and is now experiencing increased SOB w/ strenuous exercise. She is pale, in no acute distress, and otherwise unremarkable. CBC (10 years ago) was within normal limits.
HGB: 6.3 g/dL, HCT 19%, PLT 500,000/µL, MCV 61 fL.

What is the minimum time interval from initiation of therapy to this observed blood smear finding?

Back 66

5-7 days

Front 67

How do you treat Iron Deficiency Anemia?

Back 67

- Decrease source of blood loss / treat underlying course (correct menstrual cycles or GI issue, etc)
- Begin therapy first with oral iron (well tolerated except sometimes constipation)
- May need parenteral or IV administration of iron (if can't tolerate oral)

Front 68

Case 3: 68 yo female w/ HTN, COPD, and rheumatoid arthritis is noted to have a low HGB and HCT on pre-op blood work. Scheduled to undergo an ortho procedure but needs medical clearance. Meds include HCTZ, albuterol, naproxen, and pantoprazole. She denies SOB or dizziness.

Iron studies show: ↓ serum iron, Nl serum ferritin, ↓ TIBC, and ↓ % Fe saturation.

Given these iron studies, what lab results are expected?

Back 68

*Low hemoglobin: d/t decrease in iron there would be a degree in heme and thus a decrease in hemoglobin

Front 69

Case 3: 68 yo female w/ HTN, COPD, and rheumatoid arthritis is noted to have a low HGB and HCT on pre-op blood work. Scheduled to undergo an ortho procedure but needs medical clearance. Meds include HCTZ, albuterol, naproxen, and pantoprazole. She denies SOB or dizziness.

Iron studies show: ↓ serum iron, Nl serum ferritin, ↓ TIBC, and ↓ % Fe saturation.

Which blood smear would you predict for this patient?

Back 69

E (normal blood smear)

80% of Anemia of Chronic Disease have normocytic, normochromic presentations. Lesser number have microcytic, hypochromic anemia.

Front 70

Case 3: 68 yo female w/ HTN, COPD, and rheumatoid arthritis is noted to have a low HGB and HCT on pre-op blood work. Scheduled to undergo an ortho procedure but needs medical clearance. Meds include HCTZ, albuterol, naproxen, and pantoprazole. She denies SOB or dizziness.

Iron studies show: ↓ serum iron, Nl serum ferritin, ↓ TIBC, and ↓ % Fe saturation.

Which therapeutic intervention is most likely to increase the hemoglobin in this patient within hours, if surgery was needed acutely?

Back 70

* RBC transfusion would boost her Hb levels enough to be able to do surgery.

- Simply giving iron would not be sufficient to increase Hb as it would just be stored by Hepcidin. Also there would still be the suppression of Epo which would not stimulate RBC formation

Front 71

Case 3: 68 yo female w/ HTN, COPD, and rheumatoid arthritis is noted to have a low HGB and HCT on pre-op blood work. Scheduled to undergo an ortho procedure but needs medical clearance. Meds include HCTZ, albuterol, naproxen, and pantoprazole. She denies SOB or dizziness.

Iron studies show: ↓ serum iron, Nl serum ferritin, ↓ TIBC, and ↓ % Fe saturation.

Which therapeutic intervention is most likely to increase the Hb in 6 months, without immediate results, provided the surgery can be delayed?

Back 71

Immunosuppressive therapy would help decrease the chronic inflammation in her underlying condition while decreasing Hepcidin which would free up the stored Fe and remove the suppression on Epo

Front 72

Case 3: 68 yo female w/ HTN, COPD, and rheumatoid arthritis is noted to have a low HGB and HCT on pre-op blood work. Scheduled to undergo an ortho procedure but needs medical clearance. Meds include HCTZ, albuterol, naproxen, and pantoprazole. She denies SOB or dizziness.

She returns 12 months after surgery and complains of frequent flare-ups of rheumatoid arthritis and fatigue. She doesn't take her arthritis medication as it upsets her stomach. She also has bright red blood in her stool and crampy abdominal pain for 2 months.

Which lab result is this patient most likely to have at this point?

Back 72

Low MCV
- This patient is chronically bleeding which leads to iron deficiency
- This would make you think of a low MCV (microcytic anemia now)
- If Fe is low, the RBCs try to maintain the Hb concentration by dividing one extra time which leads to small cells with less volume

Front 73

Case 3: 68 yo female w/ HTN, COPD, and rheumatoid arthritis is noted to have a low HGB and HCT on pre-op blood work. Scheduled to undergo an ortho procedure but needs medical clearance. Meds include HCTZ, albuterol, naproxen, and pantoprazole. She denies SOB or dizziness.

She returns 12 months after surgery and complains of frequent flare-ups of rheumatoid arthritis and fatigue. She doesn't take her arthritis medication as it upsets her stomach. She also has bright red blood in her stool and crampy abdominal pain for 2 months.

If this patient has a worsened anemia (7.6 / dL Hg) and a serum ferritin of 25 ng/dL (normal 13-150 ng/mL) what is the etiology of the worsened anemia?

Back 73

Combined iron deficiency and anemia of chronic inflammation