Anemia

Question 1

Define Anemia

Answer 1

A decrease in the circulating RBC mass, with a reduction in one or more of the major RBC measurements:
• RBC count
• Hemoglobin (Hb) concentration
• Hematocrit (Hct): % RBC

Question 2

Normal ranges for Hb and Hct

Answer 2

Varies but usually Hb:Hct is 1:3

For Males:
Hb 14-18 g/dL
Hct 40-50%

For Females:
Hb 12-16 g/dL
Hct 35-45%

Anemia is defined as Hb<14 in men, <12 in women

Question 3

Populations for which the normal ranges of Hb/Hct don’t usually apply

Answer 3

Athletes
People living at high altitude
Smokers
African-Americans
Chronic disease
Older adults

Question 4

What are reticulocytes and what does the reticulocyte count tell us?

Answer 4

Immature RBCs —> mature RBCs
• spend about 3 days in bone marrow, 1 day in peripheral blood

RBC life-span ~120 days - old RBCs are primarily removed by the spleen

Reticulocyte count (“retic”) can detect abnormalities with bone marrow (should be elevated following blood loss)

Normal retic count = 0.5-2%

Question 5

Recognizing reticulocytes on a peripheral smear

Answer 5

“Lots of blue means lots of new” - polychromasia (lots of different colors)

Reticulocytes are larger than mature RBCs, lack central pallor (because not yet concave)

Question 6

Causes of anemia

Answer 6

Decreased RBC production
• Nutritional deficiencies (Iron deficiency, B12/folate deficiency), chronic disease, ineffective erythropoiesis

Increased RBC destruction
• Hemolysis (hemolytic Anemia, malaria)

Blood loss
• Menstrual, GI, trauma

Question 7

Mean Corpuscular Volume (MCV)

Answer 7

Calculated value to determine average volume (size) of RBCs

Microcytic —> MCV < 80fL
Normocytic —> MCV 80-100fL***
Macrocytic —> MCV >100fL

Question 8

Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC)

Answer 8

Reflect the amount of hemoglobin in RBCs

MCH = avg hemoglobin content
MCHC = avg hemoglobin concentration

Low MCH = hypochromic (pale on smear b/c low Hb)
High MCH = hyperchromic

MCH/MCHC usually “follow” MCV
• “Microcytic hypochromic” anemia

Question 9

Red Cell Distribution Width (RDW)

Answer 9

A measure of the variation in RBC size (normal = 11-15%
Measured by machine
“Anisocytosis” = variation in size of RBCs

Helpful in DDx

Question 10

Signs and Symptoms of Anemia

Answer 10

Fatigue/weakness
Headache
Dizziness, Dyspnea, Palpitations (due to cardiac compromise)
Pallor
Heme+ stool
Orthostatic changes
Tachycardia

Acute, abrupt onset - may have Sx with relatively mild anemia
Chronic, insidious onset - Sx may not appear until Hb <7-8 g/dL

Question 11

Three main categories of Anemia

Answer 11

Microcytic hypochromic
• Iron deficiency, thalassemia, sideroblastic anemia

Normocytic, normochromic
• Hypothyroidism, liver disease, chronic disease

Macrocytic (megaloblastic)
• Folate deficiency and vitamin B12 deficiency

Question 12

Iron Deficiency Anemia

Answer 12

Most common microcytic anemia

Major causes:
• Blood loss (most common cause of iron def in adults in resource rich countries)
• Decreased dietary intake
• Decreased iron absorption (celiac disease, bariatric surgery, H. pylori infection)

Question 13

Dx study results for iron deficiency anemia

Answer 13

Low RBC, H/H
Microcytic, hypochromic
-MCV sometimes normal in early IDA b/c we deplete our iron stores first before we take it out of circulation
Iron studies:
• Low ferritin (stored iron)
• Low serum Fe
• High TIBC (total iron binding capacity) - we have less so we have more capacity to take it up
Increased RDW (variations in cell size)
Retic count may be low or inappropriately normal

Question 14

Other clinical manifestations of iron deficiency anemia (besides blood counts etc)

Answer 14

Gloss it is, angular ceilings, koilonychia (spoon nails)
Pica (craving for ice, clay, dust)
Dysphasia (esophageal webs) - Plummer-Vinson syndrome
Restless legs syndrome

Question 15

Why is it important to identify the underlying cause of iron deficiency anemia?

Answer 15

To rule out occult malignancy

Consider referral for endoscopic and/or radio graphic testing, esp if not woman of child-bearing age

Question 16

Treatment for iron deficiency anemia

Answer 16

Treat underlying cause

Replace iron stores
• Orally: ferrous sulfate 325 mg BID-TID (must take on an acidic stomach); appropriate response = Hct 1/2 way to normal in 3 weeks, full return in 2 months; continue for 3-6 months after anemia has corrected to replenish stores
• Parenteral iron for select patients (chronic kidney disease - problem of absorption)

Blood transfusions (select patients - not recommended for iron replacement)

Question 17

Define thalassemia

Answer 17

Inherited hemoglobinopathy —> reduction in the synthesis of globin chains (alpha or beta)

Highest prevalence in parts of Africa, Asia, and the Mediterranean

Leads to ineffective erythropoiesis and hemolysis

Result: variable degrees of anemia and extramedullary hematopoiesis

Can cause bone changes, impaired growth, and iron overload

Question 18

Different types of Alpha Thalassema

Answer 18

Selection of one or more of the four alpha-globin chains

1 Deletion —> Silent carrier (aa/a-) no symptoms
2 Deletions —> Alpha-thalassemia minor (aa/- -), mild Microcytic anemia
3 Deletions —> Hemoglobin H disease (a-/- -), moderate microcytic anemia (chronic hemolytic anemia)
4 Deletions —> Hydrops fetalis (- -/- -) usually fatal in utero

Question 19

Different types of Beta-Thalassemia

Answer 19

Due to reduced or absent beta-globin chain synthesis, usually a point mutation rather than gene deletion

Thalassemia Minor (Trait)
• Dysfunction of one ß-globin chain
• Asymptomatic or mild microcytic anemia (abnormal labs but no Sx)

Thalassemia Intermedia
• Less severe phenotype than Thalassemia Major
• Non-transfusion dependent
• Chronic hemolytic anemia

Thalassemia Major
• Dysfunction of BOTH ß-globin chains
• Transfusion-dependent
• Severe hemolytic anemia
• If untreated, 85% of children will die w/in the first 5 years

Question 20

Lab evaluation for Dx of Thalassemias

Answer 20

Normal to increased RBC
MCV is strikingly low (<75 fL)
RDW is NORMAL
Retic count variably increased
Normal to increased ferritin and iron (can have overload)
Normal to decreased TIBC

***Hemoglobin Electrophoresis - helps with Dx, detects the type of hemoglobin present

Question 21

Tx of Thalassemia

Answer 21

Tailored to severity of disease

Folic acid supplementation (b/c needed for erythropoiesis in chronic hemolysis)

AVOID IRON SUPPLEMENTS!

Regular transfusion schedule if severe
May also require iron chelation therapy or splenectomy

Hematopoietic cell transplantation for severe beta thalassemia

Genetic counseling

Question 22

Sideroblastic Anemia

Answer 22

Hereditary or acquired RBC disorder

Abnormal RBC iron metabolism —> dismissed heme synthesis —> iron accumulation in cells

Question 23

Hallmark sign of sideroblastic anemia

Answer 23

Ring sideroblasts in bone marrow aspirate (blue-stained iron rings around cells)

May also see siderocytes with Pappenheimer bodies on peripheral smear (reflection of iron accumulation

Question 24

Causes of sideroblastic anemia

Answer 24

In adults, acquired is more common
Often a variant of myelodysplastic syndrome (MDS)

Other causes:
• Chronic alcoholism
• Medications
• Copper deficiency

Question 25

Diagnostic Studies for Sideroblastic Anemia

Answer 25

Bone marrow aspirate (***Ring sideroblasts) MCV - low, normal, or slightly increased (varies) Elevated RDW Normal to low retic count Normal or elevated ferritin SYSTEMIC IRON OVERLOAD (b/c increased absorption from gut) • May be indistinguishable from hereditary hemochromatosis • May lead to irreversible organ damage

Question 26

Treatment for Sideroblastic Anemia

Answer 26

``` Pt Ed and referral to hematology Treat underlying cause Discontinue offending drugs Removal of toxic agents Pyridoxine (vitamin B6) - contributes to hemoglobin synthesis Transfusion/management of iron overload ```

Question 27

Anemia of Chronic Disease (ACD)

Answer 27

Second most common cause of anemia worldwide (after iron deficiency) ``` Common chronic systemic diseases • Inflammatory diseases • Rheumatologic disorders • Malignancy • Chronic infection • Organ failure • Anemia of older adults ```

Question 28

Pathogenesis for Anemia of Chronic Disease

Answer 28

*Hepcidin-induced alterations in iron metabolism* Hepcidin = key regulator of the entry of iron into circulation (traps iron); high levels seen with inflammation —> iron trapping within macrophages and decreased gut iron absorption Inability to increase erythropoiesis (esp in older populations) Impaired EPO production (kidney disease)

Question 29

Sx and Tx for Anemia of Chronic Disease

Answer 29

Sx • Often mild anemia (Hb of 10-11 g/dL) • MCV usually normal (normocytic, normochromic) • Reticulocyte count may be low (particularly if EPO is low) • Normal or increased serum ferritin • Serum Fe and TIBC both low in the setting of inflammation Tx • Treat underlying disease • EPO may be of benefit (difficult with comorbidities)

Question 30

Causes of Macrocytic anemia

Answer 30

Reticulocytosis (hemorrhage/hemolysis) • “Lots of blue means lots of new” • Occurs when bone marrow responds as it should to blood loss Megaloblastic anemias • Defective DNA synthesis —> disordered RBC maturation, accumulation of cytoplasmic RNA, reduced cell division in BM, and larger RBCs Other causes: • Liver disease/alcoholism • Hypothyroidism • Gastric bypass surgery

Question 31

Drug induced megaloblastic anemia

Answer 31

Less common than folate/b12 deficiencies Caused by meds that interfere with purine or pyramidine metabolism • Hydroxyurea, chemotherapies, and antiretrovirals are most common

Question 32

Folate deficiency causes

Answer 32

Folate found in diet (vitamin B9) in beef liver, fresh leafy vegetables, fruits, fortified cereals, rice Don’t see as much in the US because we have fortified foods Recommended daily allowance is 400mcg in adults, 600mcg if pregnant, 500mcg if lactating 4-5 months of deprivation can result in macrocytic anemia, with same blood and bone marrow findings as in B12 deficiency

Question 33

Common causes of nutritional folate deficiency:

Answer 33

Poor nutritional intake (anorexia) Alcohol abuse Towards the end of pregnancy (body using more of it) *Anticonvulsant therapy (enzyme inhibition reduces folate absorption) Malabsorption syndromes (rare) Hemolytic anemia On dialysis (give supplements)

Question 34

Clinical manifestations of folate deficiency

Answer 34

Symptoms related to anemia **Glossitis: pain, swelling, tenderness, loss of papillae on the tongue Vague GI symptoms *Absence of neurological symptoms (as compared to B12

Question 35

Folate deficiency in pregnancy can lead to _____________

Answer 35

Neural tube defects

Question 36

Lab findings for folate deficiency

Answer 36

Low folate level Normal B12 **High homocysteine level with normal methylmalonic acid (both would be elevated in B12)

Question 37

Treatment of Folate Deficiency anemia

Answer 37

Treat underlying cause • Can usually stop supplementation once levels normalize if underlying cause is correctable Replacement therapy with folic acid (synthetic form of folate) • ***1 mg PO daily • Better absorbed with food Be sure to rule out coexisting B12 deficiency

Question 38

Vitamin B12 (cobalamin) is available only from _______________.

Answer 38

Dietary consumption of animal products

Question 39

Daily B12 requirement

Answer 39

1.0 - 2.0 µg B12 deficiency typically develops over the course of years (not acutely in a few months like folate) — body has large stores of B12

Question 40

How is B12 absorbed?

Answer 40

Vitamin B12 is bound to intrinsic factor (IF) in the stomach (IF produced by gastric parietal cells) Vitamin B12 is released from the cobalamin-IF complex in the ileum where it is absorbed

Question 41

Etiology of Vitamin B12 deficiency

Answer 41

``` Pernicious anemia • Autoimmune, ***most common cause Vegan diet Malabsorption (elderly) Gastric surgery, gastritis • Partial or complete gastrectomy prevents IF secretion and therefore B12 absorption Ileal disease or resection, bacterial overgrowth or intestinal parasites, and pancreatic insufficiency all prevent B12 absorption Medications • Metformin, H2 antagonists and PPIs ```

Question 42

Pernicious Anemia is a deficiency of _____ leading to _____________.

Answer 42

IF deficiency —> B12 malabsorption and megaloblastic anemia Autoantibodies against the gastric parietal cells impair IF secretion ``` Sx: • Typical anemia Sx • Glossitis, jaundice, splenomegaly may be present • Neurologically findings*** - decreased vibratory/position sense - ataxia - ***stocking-glove parathesias (hands and feet only) - confusion/dementia ``` Reversible if treated within six months

Question 43

Lab findings consistent with pernicious anemia

Answer 43

Macrocytosis (Increased MCV) Peripheral smear • Hypersegmented neutrophils (≥ 5 nuclear lobes) • Anisocytosis, poikilocytosis • “Macro-ovalocytes” large oval RBCs Low B12 level (+) Shilling test or antibodies to IF High methylmalonic acid AND homocysteine levels

Question 44

Treatment for Pernicious Anemia

Answer 44

Parenteral Vitamin B12 • Daily IM/SQ injections of 1000mcg for 1 week • Then weekly injections for 1 month • Then monthly injections for life Must do IM/SQ because won’t absorb PO Treat reversible causes (ie-malabsorption, diet)

Question 45

What happens if you treat pernicious anemia with folate replacement?

Answer 45

The abnormal blood findings will be corrected but if B12 is not also replaced, the patient may develop serious, possibly irreversible neurological damage —> “subacute combined degeneration of the spinal cord” ***Always test for B12 too before treating folate deficiency

Question 46

Define hemolytic anemia

Answer 46

Hemolysis = destruction of RBCs Decreased RBC survival time (normal = 120 days) RBC survival between 20-100 days can be compensated for by increased production Marrow cannot compensate for RBC survival < 20 days —> Acute Hemolytic Anemia

Question 47

Common symptoms of hemolytic anemia

Answer 47

General anemia symptoms Jaundice Gallstones (usually bilirubin stones) Dark urine (product of hemoglobin in urine)

Question 48

Lab findings for hemolytic anemia

Answer 48

Increased reticulocyte count Immature RBCs, uncleared RBCs and possibly schistocytes on peripheral smear Increased unconjugated bilirubin (why you get jaundice, gallstones) Increased lactate dehydrogenase (LDH) Decreased hemoglobin Hemoglobinuria/urine hemosiderin Decreased haptoglobin in intravascular hemolysis Direct anti globulin (Coombs) Test (DAT)

Question 49

Classification of hemolytic anemia is based on __________________.

Answer 49

Site of RBC destruction Intravascular = within the blood stream Extravascular = in the reticuloendothelial system (esp the spleen or liver) It’s possible to have components of both intravascular and extravascular hemolysis!

Question 50

Examples of causes of intravascular hemolysis

Answer 50

``` Shear stress (mechanical heart valve) Lysis from bacterial toxins (C. diff sepsis, malaria) Thrombotic microangiopathies (TTP, HUS) Red cell enzyme defects (G6PD deficiency) Paroxysmal nocturnal hemoglobinuria Paroxysmal cold hemoglobinuria Transfusion reactions Severe infection Snake bites ``` * **Foot strike hemolysis * **March hemoglobinuria (bongo drummers) * **Runners’ macrocytosis (marathoners)

Question 51

Examples of causes of extravascular hemolysis

Answer 51

``` Hereditary spherocytosis Sickle-cell anemia Thalassemias Red cell enzyme defects (G6PD deficiency - Heinz bodies) Autoimmune hemolytic anemia Liver disease/hypersplenism Certain infections Oxidant agents, IV immune globulin (IV IG) ```

Question 52

What is G6PD Deficiency?

Answer 52

X-linked recessive disorder G6PD is an enzyme essential for ensuring the normal lifespan of an RBC and is involved in the oxidizing process Deficiency of G6PD or unstable hemoglobin leads to oxidative damage and precipitation of hemoglobin Oxidative drugs and infections cause episodic hemolysis (episodic pt are usually health, no splenomegaly) Severe deficiency may cause chronic hemolysis Female carriers are rarely affected (more common with African Am./Mediterranean descent)

Question 53

Lab findings for G6PD deficiency

Answer 53

During hemolytic episodes, reticulocytes and serum indirect biliirubin are increased Peripheral smear: • Bite cells • Heinz bodies (denatured hemoglobin) G6PD levels will be low Tx - episodes are self-limited as RBCs replaced; avoid oxidative drugs

Question 54

Hereditary Spherocytosis is a ____________________ disorder characterized by ____________________.

Answer 54

Autosomal dominant disorder; mild hemolytic anemia RBCs maintain a normal MCV but a smaller surface area —> dense, globular appearance and lack central pallor RBCs are poorly deformable, get trapped in the splenic sinusoids, and are phagocytized by splenic macrophages RBC life span is reduced in patients with a spleen, and normal in pots with splenectomy

Question 55

Clinical features of hereditary spherocytosis

Answer 55

Often asymptomatic, well adapted May have mild jaundice/sclera icterus Splenomegaly Lab finding - Osmotic Fragility Test*** • RBCs demonstrate increased hemolysis on exposure to hypotonic flue due to RBC membrane defect

Question 56

Treatment for hereditary spherocytosis

Answer 56

***Splenectomy is tx of choice • Restores RBC life span to normal and removes risk of future bilirubin gallstones Splenectomy increases the risk of infections from encapsulated organisms (ie Pneumococcus) therefore administer appropriate vaccinations and delay splenectomy until adulthood if possible

Question 57

Sickle Cell Anemia is a hereditary hemoglobinopathy due to ________________

Answer 57

Autosomal recessive gene Homozygous HbSS —> sickle cell disease and Sx Heterozygous HbS/HbA —> asymptomatic carrier Occurs primarily in those of African-American descent • 8-10 % carriers, 1/500 have disease • for those with HbS/HbA, 1/4 chance their offspring will have disease Males and females equally affected RBCs become sickle shaped when deoxygenated, causing painful symptoms

Question 58

Clinical findings in sickle cell anemia

Answer 58

Usually develops in childhood (after HbF replaced) Vaso-occlusive ischemic tissue injuries —> Pain crises —> avascular osteonecrosis of the femoral and humeral heads, CVA, MI, Splenic infarcts, leg ulcers ``` Sx precipitated by: • Dehydration • Hypoxia • High altitude • Intense exercise ```

Question 59

Lab findings in sickle cell anemia

Answer 59

``` RBCs are normochromic, normocytic Thrombocytosis may be present Increased reticulocyte count (10-20%) Peripheral smear shows: • Sickled RBCs • Nucleated RBCs • Target cells • Howell-Jolly bodies*** classic sign ``` Hemoglobin electrophoresis reveals HbS in RBCs ** to confirm Dx

Question 60

Treatment for Sickle Cell Disease

Answer 60

Avoid precipitating factors RBC transfusions as needed Analgesics, fluids, and oxygen during pain crisis Vaccinations and folate supplementation Hydroxyurea (chemo) to decrease incidence of painful crises • Suppresses BM function of all cell lines though Bone marrow transplant may also help Life expectancy. = 40-50 years

Question 61

Autoimmune Hemolytic Anemia (AIHA)

Answer 61

Primary: No underlying systemic disorder Secondary: identifiable underlying systemic illness Immunologic destruction of RBCs mediated by autoantibodies directed against antigens on the patient’s RBCs Clinical manifestations depend on the type of antibody that is produced • IgM = “cold” agglutinins • IgG = “warm” agglutinins

Question 62

Major causes/associations for AIHA

Answer 62

SLE (up to 10%) and other autoimmune or connective tissue diseases Hematologists malignancies Preceding viral infection (children) Immune deficiency diseases HIV Prior blood transfusion, stem cell transplant, or solid organ transplant Drugs **Note - at risk for VTE

Question 63

Clinical findings for AIHA

Answer 63

Typical symptoms of hemolytic anemia Pallor, jaundice, splenomegaly Fevers Lymphadenopathy (look for underlying condition) Hemoglobinuria (dark urine) ***Acrocyanosis (dark purple to gray discoloration of fingertips, toes, nose when exposed to cold

Question 64

Labs for AIHA

Answer 64

Typical labs for hemolytic anemia Direct antiglobulin (Coombs) test

Question 65

Tx of AIHA

Answer 65

Depends on “warm” or “cold” disease and age • “Cold” AIHA does not need to be treated in most children (mild and self-limited) ***Corticosteroids are first line Rituximab: antibody that targets B cell lymphocytes Cytotoxic agents Splenectomy FIRST stabilize the patient and search for underlying causes

Question 66

Hemolytic Transfusion Reactions occur during or within __________ of transfusion

Answer 66

4 hours (though less severe rxn can occur up to 4 weeks later) ``` Fever Hemoglobinuria Severe hypotension Severe flank pain Pain at infusion site Chest tightness DIC (oozing from IV site) N/V/D ``` Severity correlates with the amount of blood transfused When suspected, act immediately!

Question 67

Treatment for hemolytic transfusion reaction

Answer 67

Stop the transfusion! Treat with IVF and blood pressure support Submit a transfusion reaction work up (tests donor blood for problem)

Question 68

Aplastic Anemia is ...

Answer 68

An immune injury of hematopoietic stem cells that may be life-threatening It may be total or selective for RBCs, WBCs or platelets (or all three) >50% of cases are idiopathic ``` Other causes: Drug or chemical exposure (benzene, chloramphenicol, chemo)** Viral illness (EBV, CMV, Hepatitis)** Ionizing radiation Genetic ```

Question 69

Clinical features of aplastic anemia

Answer 69

Sx related to pancytopenia • Weakness and fatigue due to progressive anemia • Recurrent infections due to neutropenia • Bleeding or hemorrhage due to thrombocytopenia

Question 70

Lab findings for aplastic anemia

Answer 70

***Pancytopenia is the hallmark (all lines down) • Anemia (and reticulocytopenia) • Leukopenia • Thrombocytopenia Bone marrow shows absence of precursors of those cells (normoblasts, granulocytes, megakaryocytes)

Question 71

Tx for aplastic anemia

Answer 71

Identify cause and if possible, treat Differentiate from other serious illness that may require different Tx: Acute leukemia, myelodysplasia, granulomatous infection involving marrow (TB) Hematology referral ***Bone marrow transplant = preferred Tx (immunosuppressive therapy if no BM transplant)