Anemia

Question 1

Anemias General

Sxs, PE, Diagnostic evaluation

Answer 1

Symptoms of Anemia-mainly determined by severity, duration, and rapidity of onset of anemia

• Fatigue
• Dyspnea
• Palpitation, Tachycardia
• Dizziness, Lightheadedness, Faintness
• HA
• Angina
• Pica

Physical Exam
• pallor
• jaundice
• tachycardia
• tachypnea
• edema
• lymphadenopathy
• hepatosplenomegaly
• ecchymoses
• petechiae
• stool occult blood

Diagnostic evaluation
• Severity-mild= Hgb 10-12, moderate 8-10, severe
• RBC size, Hgb content

 Microcytic, normocytic, macrocytic from MCV
 Hypo or normochromic from MCH and MCHC
 RDW if high indicates more variation in size

• Abnormalities in other cells
• REVIEW the peripheral blood smear!
• Reticulocyte count-retics are young RBC just released that can be stained (RNA). The value helps evaluate the marrow’s ability to respond to anemia. Should be 1-2%. Note that it should be corrected for level of anemia= % retics X pt hct or hgb/normal hct or hgb
• Other tests done if looking for something in particular-iron studies, B12/folate, EPO, hemolysis, bone marrow biopsy

Question 2

Iron Deficiency Anemia

Answer 2

Microcytic
MC anemia in the world

Iron loss exceeds iron absorption
 Increased requirements during pregnancy, adolescence
 Loss from GI, menstrual bleeding, chronic NSAID or ASA use
 Rarely loss from urinary or respiratory tracts

Total body stores are large in males small in females

Diagnosis-
 microcytic, hypochromic
 Low serum iron, increased TIBC, low transferrin saturation, low ferritin stores
 No compensatory reticulocytosis
 Low/absent marrow iron stores

Treatment-iron orally, sometimes parenterally

Should respond with reticulocyte increase in 3-5 days and reach max in 8-10. Hgb increases after 1 week and should be normal by 6 weeks. Microcytosis may take months to resolve.

Question 3

Anemia of Chronic Disease

Answer 3

Microcytic

• Cytokines produced by inflammation process prevents the normal release and utilization of storage iron.
• Diagnosis-you must have a chronic illness! Most often causes mild to moderate anemia. Usually normochromic/normocytic, but may be slightly micro and resemble iron def. Low serum iron, low TIBC, normal/low transferring saturation, normal or increased ferritin.
• Treatment-treat underlying disease process, consider EPO if more severe. Iron therapy not effective.

Question 4

Comparison of Iron Studies

Answer 4

Iron deficiency anemia Anemia of chronic disease
Serum Iron ↓ ↓/N
Transferrin Saturation ↓ ↓/N
Total Iron Binding Capacity (TIBC) ↑ ** ↓/N**
Ferritin *↓↓ * ↑↑

Question 5

Vitamin B12 Deficiency

Answer 5

macrocytic

• Most common cause is malabsorption-

 Gastric-pernicious anemic (loss of intrinsic factor), or gastrectomy
 Ileal-crohns, sprue, surgical resection
 Competing organisms-bacterial overgrowth (blind loop) or fish tapeworm

• Note that your body stores enough for 2-3 years so diet is not usually the problem!
• Diagnosis-macrocytic anemia, hypersegmented PMN’s, megaloblastic changes in marrow erythroid precursors, smooth red tongue, Neurogenic abnormalities-decreased or absent position/vibration sense in legs sue to demyelination of posterolateral columns, if these are short term usually reversible. Low serum B12 level
• Treatment- IM B12 monthly or oral daily. If pt does not improve rapidly after B12 injection, might be folate def instead. Most labs will not let you order B12 level without folate level.

Question 6

Folate Deficiency Anemia

Answer 6

Macrocytic

• Poor dietary intake, increased requirements (preg, hemolytic anemia), malabsorption (Crohns, sprue). Body stores are small.
• Diagnosis-same blood picture as B12 however neurological abnormalities are uncommon, signs of malnutrition and liver dz are often present. Low serum folate is corrected fast, while the RBC folate level stays low longer.
• Treatment-normal diet, oral folic acid

Question 7

Hemoglobin Genetics, Development and Molecular Structure

Answer 7

Beta chains from chromosome 11
Alpha from chromosome 16

Hemoglobins

• Hgb F - present in utero, alpha₂ gamma₂
• Hgb A - adult hgb, alpha₂ beta₂
• Hgb A2 - functionally identicle to hgb A, 2.5% of adult hgb, alpha₂ delta₂
• Hgb Bart’s - abnl hgb gamma₄ (tetramer of gamma)
• Hgb H - abnl hgb - beta₄

Question 8

Hemoglobin Defects

General

Answer 8

**Heme Synthesis **

• Porphyrias - issues with porphyn ring or heme

Globin Chain Synthesis

• Thalassemias - decreased globin chain production (quantative)
• Hemoglobinopathies - amino acid substitution (qualitative)
  
  • Hundreds of variants
  • Hb S MC in US

Question 9

Why did disorders of Hgb develop?

Answer 9

Common in subsaharan Africa, Middle East, Mediterranean, and Southeast Asia –> areas where malaria is common

Question 10

Thalassemia

Pathophysiology

Answer 10

1. Decreased production of either alpha or beta globins
2. Imbalance between alpha and beta globins
3. Globins in excess ppt and damage the RBC membrane
4. **Ineffective erythropoieisis **
5. Anemia, bone marrow expansion, extramedullary hematopoiesis, increased intestinal absorption

Question 11

Thalassemia

Classification

Answer 11

Classified by…

Genetic Defect

• Alpha or Beta-Thalassemia

**Clinical Severity **

• minor: mild anemia, asymptomatic trait state
• intermedia: moderate anemia, intermittent transfusion
• major: severe anemia, transfusion anemia

Question 12

Thalassemias

Typical mutations

Answer 12

Alpha thalassemia - deletions

Beta thalassemia - point mutations

Question 13

Alpha Thalassemia

Types of

Answer 13

MC in SE Asian descent

The severity of anemia depends on the amount of nl hgb:

• Silent carrier: alpha + thal: (-a/–): no hematologic abnlities
• Thal minor: (a-/a- or –/aa) - mild hypochormic anemia
• Hgb H Disease (intermedia) - (a-/–). Results in some chain imbalance, but is compatible with survival. Variable anemia
• Hydrops fetalis (aka alpha zero thal) - (–/–) No alpha chains are produced. Affected infants have very high levles of hgb Barts (gamma4). Most affected infants are stillborn (unless transfused in utero) with signs of gross intrauterine hypoxia)

Question 14

Beta Thalassemias

Types and complications of

Answer 14

Severity of anemia is dependent on mutations:

• Minor: (ß0/ß or ß+/ß) - asymptomatic - mild disease
• Intermedia (ß+/ß+ or ß+/ß0) - moderate - moderately severe

ß thal major (Cooley anemia):

• severe clinical course beginning around 4-6 months when the switch from Hgb F to Hgb A occurs
• complications: *splenomegaly, jaundice, bone changes (causing osteopenia and pathologic fxs), facial changes, microcytic anemia, iron overload *

Question 15

Thalassemia

Treatment

Answer 15

Patients with mild disease should not receive iron because of risks for iron overload

Red Cell Transfusions: usually q2-4 weeks

Folic acid supplementation: diety intake is usually adequate

Chelation is often necessary after one year of transfusion therapy: Deferoxamine. Otherwise hemosiderosis, heart failure, cirrhosis, and endocrinopathies can occur

Splenectomy: should be fully immunized adn preferably >5y.o. Generally wait until transfusion requirements increase

Bone marrow transplant

Hydroxyurea - only works if nl alpha globin and goal is to make more Hgb F

Question 16

Thalassemia Labs

Answer 16

Want to obtain hematocrit, hemoglobin electrophoresis, reticulocyte count adn peripheral smear

Serum iron and ferritin are normal or elevated

Thal is generally more microcytic than iron deficiency

Diagnosis is confirmed, and differentiates which kind of thalessemia by hemoglobin electrophoresis

Question 17

Sickle Cell Disease

Answer 17

MC qualitative hemoglobinopathy. Single amino acid substition in the beta globin chain. Mutant hemoglobin is insoluble when deoxygenated and polymerized within RBC’s causing loss of deformability and sickle shape. Causes microvascular occlusion and pain.

Diagnosis:

• Chronic hemolytic anemia is present (Hct 20-30%)
• Characteristic sickle cells on blood smear
• Reticulocytosis
• The definitive test used to diagnose is hemoglobin electrophoresis

Supportive care during crisis - precipitated by infection, dehydration, hypoxia

• IV narcotics, hydration, supplemental O2

Other Treatment

• prn transfusion if stroke or acute chest syndrome present
• pneumococcal vaccination and prompt tx for any infection due to decreased splenic function
• PO hydroxyurea- increases levels of Hgb F and prevents complications
• Bone marrow therapy if extensive complications

Question 18

General Characteristics of Hemolytic Anemias and Classification

Answer 18

Hemolytic anemias are characterized by episodic or continuous RBC destruction

Characterized by intrinsic RBC defects or extracellular causes

**Intrinsic: **

• Membrane: hereditary spherocytosis or elliptocytosis
• Enzymomes: G6PD deficiency, pyruvate kinase (PK)
• methemoglobinemia
• Hemoglobin: sickle cell

**Extrinsic **

• autoimmune and lymphoproliferative disease
• TTP
• HUS (hemolytic uremia syndrome)
• DIC
• valvular hemolysis
• burns
• hypersplenism

Question 19

Hemolytic Anemias

Clinical features

Answer 19

• pallor
• anemia
• icterus, jaundice
• splenomegaly
• dark urine
• increased retic count
• potentially can have gallstones

Question 20

Tests for Hemolytic Anemias

Answer 20

• CBC-look at all cell lines
• Reticulocyte count- elevated and gives you a good idea of level of hemolysis/compensation
• Peripheral smear-must have!
• Direct Antiglobulin (DAT)/ Coombs Test-positive test supports immune hemolysis, false positives can occur in up to 15% of hospitalized patients.
• Bilirubin: indirect bilirubin elevated
• LDH: elevated- Serum LDH elevation is a criterion for hemolysis. LDH is not specific because it is ubiquitous and can be released in many situations.

Question 21

Intrinsic Causes

Answer 21

Membrane:

• hereditary spherocytosis or elliptocytosis - check osmotic fragility

Enzymomes: G6PD deficiency, pyruvate kinase (PK)

Hemoglobin:

• Thalassemias - globin chains
• sickle cell - hemoglobinopathy
• methemoglobinemia: Fe 3+ which binds oxygen more tightly, leading to poor oxygen delivery to tissues

Question 22

Hereditary Spherocytosis

Answer 22

Familial hemolytic disorder characterized by round (sphereocytic) red blood cells with fragile cell membranes.

• 1:5000 people in the US. #1 hereditary hemolytic anemia affecting people of Northern European descent.
• Generally autosomal dominant but about 30% of cases are spontaneous mutations.

Diagnosis can generally be made by complete blood count

o Anemia
o MCV normal or decreased
o MCHC (>35) increased in combination with RDW (>14) increased
o Spherocytes seen on smear,
o Reticulocyte count increased
o Bilirubin increased (indirect suggests hemolysis)
o Definitive test is osmotic fragility which should be done at one year of age or later. Test shows increased fragility of red blood cells

Question 23

G6PD Deficiency

Answer 23

Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is the most common disease-producing enzymopathy in humans. Inherited as an X-linked disorder. Affects 400 million people worldwide. It is thought to provide protection against malaria. G6PD deficiency results in oxidation of Hgb to methemoglobin that then forms precipitants known as Heinz bodies. Certain drugs cause more oxidative stress: quinine, sulfonamides, ASA, nitrofurantoin, fava beans.

• History:
Most patients are asymptomatic. Some patients present with or report a history of neonatal jaundice, possibly requiring exchange transfusion. A history of infection or drug-induced hemolysis is also common. Gallstones may be a prominent feature. Splenomegaly may be present due to filtration of damaged red blood cells.

• Physical Exam:
Jaundice and splenomegaly may during a G6PD def. crisis.

• Laboratory findings:
Acute hemolysis from G6PD deficiency is associated with the formation of Heinz bodies, which consist of denatured hemoglobin

• Medical Care:
Identification and discontinuation of the precipitating agent is critical. Affected individuals are treated with oxygen and bed rest, which may afford symptomatic relief. Typically crises are self limited.

Question 24

Extrinsic Causes

Answer 24

Immune Mediated Hemolytic Anemia

• Warm Ab vs. Cold Ab AIHA
• Drug Induced
• ABO or Rh incompatability
• Treatment-treat secondary causes, transfuse, corticosteroids, splenectomy, other immune suppressive drugs
• Only transfuse when cardiac or cerebral function is threatened. A small amount of blood can improve the patient. Observe pt carefully-acute intravascular hemolysis can occur with no evidence of blood incompatibility.

Mechanical Destruction

• Microangiopathic Hemolytic Anemia (MAHA) - DIC, TTP, HUS, HELLP - schistocytes
• Burns
• Hypersplenism
• Valvular Hemolysis

Complement Mediated

• Paroxysmal Nocturnal Hemoglobinuria

Question 25

Aplastic Anemia

Answer 25

• Bone marrow failure syndrome characterized by pancytopenia and bone marrow hypocellularity
• Exact etiology remains unknown
Diagnosis usually straightforward based on combination of:

o Pancytopenia
o Empty bone marrow
o Lack of other symptoms (patients look well)

Answer 26

• Stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic bone marrow
• Most prominent feature of this disease is an elevated absolute red blood cell mass because of uncontrolled red blood cell production.
• Relatively rare, occurring in 0.6-1.6 persons per million.
• Peak incidence age 50-70 years and 60% of patients are male

• Symptoms are often insidious in onset, and they are often related to blood hyperviscosity secondary to a marked increase in the cellular elements of blood, which impairs microcirculation.

o Headache, dizziness, vertigo, tinnitus, visual disturbances, angina pectoris, or intermittent claudication.
o Bleeding complications (1%) include epistaxis, gum bleeding, ecchymoses, and gastrointestinal (GI) bleeding.
o Pruritus results from increased histamine levels released from increased basophils and mast cells and can be exacerbated by a warm bath or shower. This occurs in up to 40% of patients with polycythemia vera (PV).

• Physical findings in those with polycythemia vera are due to manifestations of the myeloproliferative process and excess of the cellular elements of blood.

o Splenomegaly – Present in 75% of patients at the time of diagnosis
o Hepatomegaly – Present in approximately 30% of patients
o Plethora or a ruddy complexion is characteristic and results from the marked increase in total red blood cell mass. This manifests in the face, palms, nailbeds, mucosa, and conjunctiva.
o Hypertension is common
• Testing
o CBC shows elevated red blood cell mass, elevated Hct with normal morphology, elevated platelets, elevated WBC with basophilia.
o Bone marrow studies are not absolutely necessary to establish the diagnosis but often needed to role out other causes.

• Treatment

o Phlebotomy has been the mainstay of therapy. The object is to remove excess cellular elements, mainly red blood cells, to improve the circulation of blood by lowering the blood viscosity
o Hydroxyurea-myelosuppressive agent
o Anagrelide-prevents platelet aggregation and inhibits megakaryocyte maturation, thereby decreasing platelet counts
o ASA-prevent platelet aggregation and decreases risk of thrombosis.

Question 27

Hemochromatosis

Answer 27

• Intestinal iron absorption inappropriately large leading to increase in plasma iron and increased transferrin saturation.
• Excess iron deposits in parenchymal cells of heart, liver, pancreas and endocrine organs causing dysfunction.
• Familial genetic iron storage disorder
o 1/200 caucasians are homozygous-clinically significant phenotype
o Men are affected more often than women, with an estimated ratio of 1.8:1

• Signs/Symptoms

o Asymptomatic in early stages
o Fatigue, weakness, loss of libido, impotence, abdominal pain, arthritis
o Diabetes due to endocrine dysfunction
o Hepatomegaly>95% of cases-due to iron deposition and cirrhosis
o Skin may appear metallic or bronze
o Cardiomegaly with arrhythmias, congestive heart failure or heart block can occur

• Laboratory testing

o Increased plasma iron (>200 mcg/dL), increased transferrin saturation (70-100%)
o Increased serum ferritin, normal or low TIBC, increased liver iron.
o Diagnosis can be confidently based on genetic testing for the C282Y mutation. Liver biopsy is no longer essential for diagnosis in many cases

• Management

o Phlebotomy to decrease body iron
o Chelating agents if unable to control with phlebotomy
o Family genetic testing
o Manage complications
o Dietary restrictions-NO iron supplementation, no ETOH to protect liver. No vitamin C supplementation as increases iron absorption
o Raw or improperly cooked shellfish sometimes is contaminated with V vulnificus and can cause sepsis in patients with hemochromatosis due to iron rich environment required for growth of these bacteria.