How can polycythemia vera be distinguished from secondary absolute polycythemia?

Serum erythropoietin level

·        Polycythemia vera – low

·        Secondary polycythemia - high

What clinical problem do patients with polycythemia vera have?

Thromboembolic disease

Who is most often affected with polycythemia vera?

Men ages 40-60

What is the term used for primary absolute polycythemia?

Polycythemia vera

What are the causes of secondary absolute polycythemia?

1.    Chronic hypoxia

2.   Renal cell cancer with increased erythropoietin production

What are the two types of absolute polycythemia?

1.    Primary

2.   Secondary

What is absolute polycythemia?

Increase in red blood cell mass

What is relative polycythemia?

Hemoconcentration from loss of plasma water volume

What is the treatment of anemia of chronic disease?

·        Treat the chronic condition causing anemia of chronic disease

·        Erythropoietin

What is the pathophysiology of anemia of chronic disease?

Cytokines from chronic inflammation induce hepcidin production by the liver – blocks transfer of stored iron into the circulation

What are underlying diseases associated with anemia of chronic disease?

·        Chronic infections (for example osteomyelitis)

·        Chronic immune disorders (for example rheumatoid arthritis)

·        Malignancy (for example Hodgkins lymphoma)

What is the treatment of aplastic anemia?

·        Withdraw offending agent

·        Bone marrow transplant for young patients

·        Antithymocyte immunoglobulin

·        Transfusions

What is the reticulocyte count in aplastic anemia?

Low

What type of anemia does aplastic anemia cause?

Normocytic (normal MCV @ 90) and normochromic (normal MCHC)

What is found on bone marrow biopsy in aplastic anemia?

·        Absence of all cell lines

·        Bone marrow matrix is replaced with fat

How is a diagnosis of aplastic anemia made?

Bone marrow biopsy

What are the underlying causes of aplastic anemia?

1. Idiopathic: 2/3 of cases

2. Radiation therapy

3. Chemotherapy

4. Drugs

a. Dose related

b. Idiosyncratic: chloramphenicol, sulfonamides

5. Toxins (for example: benzene)

6. Viral infections

        a. AIDS

        b. Hepatitis

How is a diagnosis of folic acid deficiency made?

Low serum folic acid levels

 What is the pathophysiology of aplastic anemia?

Suppression of pluripotential stem cells causing a decreased production of all red blood cells, platelets, and all types of white blood cells

Even though vitamin B12 and folic acid deficiency both cause megaloblastic anemia, how do they differ?

Vitamin B12 deficiency causes neurologic symptoms but folic acid deficiency does not cause neurologic symptoms

What are causes of folic acid deficiency?

1. Poor dietary intake- typical with elderly &  alcoholic

2. Increased demand-pregnancy & malignancy

3. Malabsorption

        a. Sprue

        b. Drugs:

·        dilantin

·        oral contraceptives

What is the constellation of symptoms associated with pernicious anemia?

1.    Low serum B12 levels

2.   Megaloblastic anemia

3.   Antibodies against intrinsic factor

4.   Numbness, loss of proprioception, and loss of vibratory sense from demyelination of dorsal column neurologic tracts in the spine

  What are other causes of B12 deficiency?

·        Vegetarian diet

·        Resection of stomach where intrinsic factor is secreted

·        Resection of ileum where intrinsic factor-B12 is absorbed

What is pernicious anemia?

Vitamin B12 deficiency from malabsorption of B12 due to an autoimmune gastritis that leads to a lack of intrinsic factor which is normally secreted in the stomach and required to absorb vitamin B12

What are the causes of megaloblastic anemia?

·        Vitamin B12 deficiency

·        Folic acid deficiency

What type of anemia is megaloblastic anemia?

Macrocytic (high MCV – greater than 100 fl)

What are physical finding in the hands can occur in patients with iron deficiency anemia?

Spooning of the fingernails

What type of anemia does iron deficiency cause?

Microcytic (low MCV) hypochromic (low MCHC) anemia

What are causes of iron deficiency anemia?

Chronic blood loss:

·        peptic ulcer disease

·        hemorrhoids

·        menorrhagia

·        colon cancer

What is the frequency of iron deficiency anemia?

10% developed countries

25-50% developing countries

Which test identifies the presence of warm or cold reacting antibodies?

Coombs test

What clinical manifestation can occur in patients with cold reacting antibodies?

Raynauds phenomenon

What are underlying causes associated with production of cold reacting antibodies?

·        Idiopathic

·        Lymphoproliferative disorders

What are underlying causes associated with the production of warm reacting antibodies?

·        Idiopathic

·        SLE (lupus)

·        Lymphomas

·        Chronic lymphocytic leukemia (CLL)

·        Drugs

How do cold reacting antibodies cause hemolysis?

By activating complement to cause hemolysis of RBCs

How do warm reacting antibodies cause hemolysis?

Antibodies bind directly to antigens on surface of RBCs

What are the two types of antibodies in autoimmune hemolytic anemia?

1.    Warm reacting antibodies (aka warm agglutinins)

2.   Cold reacting antibodies (aka cold agglutinins)

Give two examples of alloantibodies that cause hemolytic anemia?

1.    Transfusion reaction – where recipient patient has antibodies directed against ABO group on surface of donor RBCs

2.   Rh negative mother makes IgG antibodies against Rh group that crosses the placenta and causes hemolysis of fetal RBCs

What are the histologic intracellular abnormalities seen in the red blood cells of patients with G6PD deficiency after exposure to medications that provoke hemolysis?

Intracellular inclusions in the cytoplasm called Heinz bodies consisting of clumps of oxidized hemoglobin.

What is the clinical significance of G6PD deficiency?

Patients with G6PD deficiency have no problems at all unless they receive certain medications that precipitate intravascular and extravascular hemolysis.

What percentage of African Americans have the abnormal G6PD gene?

10%

On which chromosome is the G6PD gene located?

On the X chromosome

What is the complication of repeated blood transfusions in beta-thalassemia major without also giving iron chelation therapy?

Systemic iron overload causing heart failure and liver failure.

How is beta-thalassemia major treated?

1.    Repeated blood transfusions every 3-4 weeks

2.   Iron chelation therapy to prevent systemic iron overload

3.   Bone marrow transplant in younger patients

What other clinical features accompany beta-thalassemia major?

·        Splenomegaly

·        Hepatomegaly

·        Bone changes in skull (chipmunk facies)

When does beta-thalassemia major present? Why?

At age 9 months because that is when the normal switch occurs from fetal hemoglobin to hemoglobin A

What is the pathogenesis of beta-thalassemia major?

The excess alpha chains clump together in the cytoplasm of the RBCs, which are sequestered in the spleen leading to severe anemia.

What is the genetics of a patient with beta-thalassemia major?

Homozygous for beta-thalassemia

Why is it important to make a diagnosis of beta-thalassemia minor?

For genetic counseling

How do patients with beta-thalassemia minor present?

With mild anemia

What is the genetics of a patient with beta-thalassemia minor?

The patient is heterozygous for beta-thalassemia

What determines the severity of alpha thalassemia?

The number of deleted alpha genes

What is the underlying pathology of alpha thalassemia?

Deletion of the gene that codes for the alpha peptide of the hemoglobin molecule.

Which patient populations are typically afflicted with thalassemia?

People of Mediterranean, African or Asian descent

What type of anemia is seen with thalassemia?

Microcytic hypochromic anemia

What does thalassemia entail?

Decreased or absent production of either the alpha peptides or beta peptides of the hemoglobin molecule

What are the types of thalassemia?

1.    Alpha-thalassemia

2.   Beta-thalassemia

What is the treatment of sickle cell disease?

·        Supportive care

·        Transfusions

·        Hydroxyurea: hemoglobin production is shifted to make less hemoglobin S and more fetal hemoglobin

How is a diagnosis sickle cell disease made?

Hemoglobin electropheresis

What is the prognosis of sickle cell disease?

50% of patients live beyond the 5^th decade

What age do patients with sickle cell disease typically present?

6 months old

What is aplastic crisis in sickle cell disease?

Sickle patients become infected with parvovirus which shuts down their bone marrow production of red blood cells leading to drastic fall in hemoglobin with their high RBC turnover.

What is the average lifespan of a sickle RBC?

20 days (compared to 120 days for a normal RBC)

Which organs are usually affected in sickle cell disease?

·        Bones: chronic bony pain from bone infarct

·        Spleen:

o   Eventually patients are functionally asplenic  

o   Therefore without a working spleen they are immunocompromised and at risk for pneumococcal infection

o   Receive pneumococcal vaccine and prophylactic penicillin until age 5

·        Liver

·        Kidney:

o   Inability to concentrate urine  

o   Renal failure

·        Brain: stroke

·        Lung:

o   Acute chest pain syndrome – chest pain; fever and hypoxia from sickle crisis involving the lungs

o   Long term – pulmonary hypertension

·        Skin: leg ulcers

How does cyclic sickling in sickle cell disease cause a problem?

1.    It causes hemolysis and a shorter RBC lifespan

2.   The RBCs clog up blood vessels and cause small areas of local infarct that damage various organs.

How does sickle cell disease cause problems?

The abnormal sickle peptide causes the hemoglobin to be sticky, so it clumps together and makes the RBCs sickle; the RBCs repeatedly cycle between the sickle shape and normal shape.

What is the frequency of sickle cell in the US population?

Sickle trait: 10%

Sickle cell disease: 0.1-0.2% (homozygous for the 

     sickle cell gene – both genes are sickle cell gene)

What is sickle trait?

Heterozygous for the sickle cell gene – one normal beta chain gene and one sickle chain gene

What is the pathology of sickle cell anemia?

Single amino acid substitution on the beta chain of hemoglobin – normal hemoglobin A is substituted with abnormal hemoglobin S. So each hemoglobin molecule has two alpha chains and two sickle chains (instead of the normal beta chains).

How is symptomatic hereditary spherocytosis treated?

Splenectomy

What are symptoms associated with hereditary spherocytosis?

·        Moderate anemia

·        Jaundiced

·        Splenomegaly

·        Pigmented gallstones

What is the genetic inheritance of hereditary spherocytosis?

Autosomal dominant

What is the underlying etiology of hereditary spherocytosis?

Defect in the RBC membrane that makes it shape spherical rather than the normal biconcave disc shape

What laboratory values indicate intravascular hemolytic anemia?

·        Free serum hemoglobin level – elevated since it is released from damaged RBCs

·        Hemoglobinuria (will test positive on urine dipstick of routine urinalysis as occult blood)

·        Serum haptoglobin – reduced since it binds free hemoglobin

What are causes of intravascular hemolytic anemia?

·    Mechanical trauma (for example a damaged heart valve)

·    Complement fixation (for example warm agglutinins associated with Coombs positive anemia)

·    Toxins (for example hemolytic uremic syndrome in children w/ dysentery from enteroinvasive E. coli)

What complication can occur in patients with long standing extravascular hemolysis?

Pigmented gall stones

Where does extravascular hemolysis most commonly occur?

Spleen

Is intravascular or extravascular hemolytic anemia more common?

Extravascular

What are the two categories of hemolytic anemia?

1.    Intravascular

2.   Extravascular

What abnormality is seen on physical exam and lab work in a patient with either intravascular or extravascular hemolytic anemia?

·        Jaundice

·        Elevated unconjugated bilirubin

·        Elevated urine urobilogen

What is the expected finding on bone marrow biopsy in a patient with hemolytic anemia?

Hyperactive with high red blood cell precursor cells

What is the reticulocyte count in hemolytic anemia?

Elevated as the body attempts to replace the destroyed RBCs

What is hemolytic anemia?

Anemia that results from increased destruction of red blood cells

What are differences in anemia from acute blood loss and chronic blood loss?

How is anemia with a low mean cell hemoglobin (MCH) and a low mean cell hemoglobin concentration (MCHC) referred to?

Hypochromic anemia because a low amount of hemoglobin in the RBCs decreases the red hue of the cells (for example: iron deficiency classically causes microcytic hypochromic anemia).

How is the MCV helpful?

In patients with anemia the MCV can narrow the differential diagnosis for possible causes among microcytic (small RBCs with low MCV), normocytic (normal size RBCs with normal MCV) and macrocytic (large RBCs with high MCV) types of anemia.

On a CBC what information does mean corpuscular volume (MCV) convey?

It gives the average size of each individual red blood cell in femtoliters (abbreviated fl)  (1 fl = 10 to the minus 12^th power liters).

What is the composition of fetal hemoglobin?

Two alpha chains and two gamma chains

How many oxygen (O2) molecules does each heme group bind?

How many heme groups does each peptide chain contain?

1 – Therefore, there are 4 heme groups total per hemoglobin molecule

How many peptides make up a normal hemoglobin molecule and what subtypes are they?

4 – 2 alpha chains and 2 beta chains