Anemia

      I.                  I.            Overview

A.    A.    Definition.

1.       Normal hematocrit (HCT) = 36% to 48%, hemoglobin (Hb) = 12 to 16 g/dl. Anemia is defined as a low HCT and Hb.

2.     Changes in intravascular volume can be reflected in the hematocrit. Fluid overload leads to hemodilution and a lower HCT, whereas volume contraction can yield a spuriously elevated HCT even in the face of anemia.

B.     B.     Signs and symptoms of anemia.

1.       Symptoms. Dyspnea on exertion, palpitations, angina pectoris, light-headedness, syncope, anorexia, tinnitus.

2.     Signs. Pallor of mucous membranes and skin, mild tachycardia, peripheral edema, systolic ejection murmurs from increased flow though not sensitive or specific.

C.     C.     History. Obtain history including presence of jaundice or gallstones (hemolysis), history of blood loss, alcohol abuse, diarrhea, other chronic disease, drugs. etc.

D.    D.    Laboratory evaluation.

1.       All anemic patients should have the following labs:

a.      a.      Differential CBC.

b.     b.     Platelet count.

c.      c.      Mean corpuscular volume (MCV). In hemolysis, elevated MCV reflects reticulocytosis.

d.      d.      Serum ferritin (estimate of Fe stores).

e.      e.      Reticulocyte count.

§         The reticulocyte count is expressed as a percentage of total cells counted and must be corrected to a total number of reticulocytes per microliter. This is done by multiplying the red blood cell count by the percentage of reticulocytes. Normal is 50 to 100,000 reticulocytes per microliter.

§         Reticulocyte counts that are normal or low (in the face of anemia) are suggestive of the inability of the bone marrow to respond to anemia (marrow failure).

§         Reticulocyte counts that are increased are indicative of acute blood loss or hemolysis with a marrow that is able to respond.

§         If reticulocyte count is low or normal reflecting the inability of the marrow to respond to anemia ("marrow failure"), the MCV is helpful in diagnosing anemia. The MCV is either normocytic at 80 to 100 femtoliters, microcytic <80 fl, or macrocytic >100 fl.

§         Consider serum haptoglobin, serum free hemoglobin to evaluate for hemolysis.

 Normal Bone Marrow

 Normal Peripheral Smear

RBC Precursors in the Bone Marrow

 II.             II.            Microcytosis and Unresponsive Marrow

Low or normal reticulocyte count and anemia.

A.     .        Iron deficiency anemia generally has microcytic MCV but may occasionally be normocytic.

1.       Causes. Increased iron requirements (during infancy, adolescence, pregnancy, etc.), inadequate iron intake, decreased iron absorption (gastrectomy, achlorhydria, chronic diarrhea), blood loss from menses or GI tract.

2.     Exam. Skin and conjunctivae may show pallor; nails may be dry and brittle with ridges; cardiovascular exam may reveal tachycardia and flow murmur. Stomatitis or glossitis may be present. However, physical signs and symptoms are not sensitive enough to rule in or out the diagnosis of anemia.

3.     Lab tests.

a.      0.     CBC will show microcytic, hypochromic cells.

b.     1.       Low serum ferritin (overall best test for outpatients). Serum ferritin elevated by fever, cancer, other inflammatory processes and is therefore a poor predictor of iron deficiency anemia in hospitalized patients.

c.      2.     Increased TIBC with transferrin saturation <15%.

d.      3.     Low serum iron.

e.      4.     Bone marrow biopsy specimen will show decreased iron stores.

f.      5.     Must differentiate from the thalassemias and anemia of chronic disease.

4.     Other work-up. All adults with iron deficiency anemia should be evaluated for upper and lower GI bleeding. If a source is found in the upper GI tract, there is little chance of there being a second lower GI source. However, use clinical judgment when deciding whether to work up both upper and lower GI.

5.     Treatment. Ferrous sulfate 325 mg PO TID. Enteric-coated and timed-release products are poorly absorbed. Better absorbed if administered between meals on an empty stomach, but less GI upset if taken with meals. Vitamin C will increase absorption. Calcium and magnesium may impair Fe absorption. Iron may impair absorption of thyroxin. Treat for 6 months to replace body stores. Iron is very toxic and should be kept away from children.

6.     If marrow does not respond to iron, consider another superimposed cause of anemia such as inflammation, vitamin B12 or folate deficiency, continued bleeding, etc.

 Microcytic Anemia

 Microcytic Anemia

B.     A.    Anemia of chronic disease. Microcytic in 30% of cases. See IIIB later in this section for details.

C.     B.     Thalassemias.

1.       Hemoglobin made up of paired alpha and beta chains. Thalassemia caused by a defect in the synthesis of either alpha or beta chains. Normally have 4 genes to produce alpha chains but only 2 to produce beta chains.

2.     Alpha-thalassemia. Caused by decreased synthesis of alpha subchain of Hb. Since normally have 4 copies, generally a mild disease.

a.      0.     Silent carrier state. One of the four genes is deleted. No hematologic abnormalities.

b.     1.       Alpha-thalassemia trait. Two of four genes are deleted. RBCs are microcytic, hypochromic. No significant anemia. Hemoglobin shows a decrease in Hb A₂.

c.      2.     Beta-thalassemia minor. Caused by decreased synthesis of beta chains. One of two genes not present (heterozygous).

§         Presentation. Symptoms of anemia, splenomegaly, icterus. Cells are microcytic. Examination of peripheral smear shows target cells, cigar-shaped cells, and basophilic stippling.

§          Diagnosis. Hb electrophoresis shows increased Hb A₂, usually >4% and possibly an increase of hemoglobin F. May occur with a normal Hb A, however.

§          Treatment. None. Genetic counseling is necessary.

3.     Beta-thalassemia major (Cooley's anemia).

a.      0.     Both genes for beta-chain synthesis defective or missing.

b.     1.       Presentation. Manifestations begin at approximately 4 to 6 months of life. Usually present with severe anemia (HCT less than 20%). There is pronounced wasting, jaundice, slow growth and development, and delayed onset of secondary sex features. The patient will have skeletal abnormalities secondary to bone marrow expansion.

c.      2.     Diagnosis. Hb electrophoresis shows large amounts of Hb F, variable amounts of Hb A, and increased Hb A₂. Nucleated RBCs.

d.      3.     Treatment. Transfusion, splenectomy, deferoxamine, folic acid supplementation. Watch for development of hemochromatosis.

4.     4.     Prognosis. Many die before puberty secondary to hemochromatosis.


Basophilic Stippling

D.    C.     Sideroblastic anemia.

1.       Causes. Anemia and ineffective erythropoiesis.

a.      0.     Hereditary. Likely X-linked recessive.

b.     1.       Acquired. Drugs and toxins (alcohol, lead, INH, chloramphenicol), neoplasia and inflammation (rheumatoid arthritis, carcinoma, lymphoma, leukemia), malnutrition (folate deficiency), idiopathic. May also represent a myelodysplastic syndrome with deletion of either chromosome 5 or chromosome 7.

2.     Lab tests. CBC may show normochromic or hypochromic cells; anisocytosis and poikilocytosis are pronounced. Sideroblasts may or may not be present. Iron studies will show increased serum iron, increased ferritin, increased transferrin saturation, decreased TIBC. LDH may be elevated. If appropriate, determine if there is chromosomal abnormality.

3.     Clinically. May have anemia or hemochromatosis.

4.     Treatment.

a.      0.     Withdraw offending agent, especially alcohol.

b.     1.       Pyridoxine 200 mg QD x 2 to 3 months with or without folate. May work.

c.      2.     Androgens may be of benefit.

 

III.            III.            Normocytosis and Unresponsive Marrow

Low or normal reticulocyte count and anemia.

A.     .        Iron deficiency. Generally there is microcytosis but may be normal (see above).

B.     A.    Anemia of chronic disease.

1.       Causes. Chronic infections (subacute bacterial endocarditis, osteomyelitis, AIDS), chronic inflammatory disorders (RA, SLE, sarcoidosis, renal failure), neoplasms, hypothyroidism, liver disease, alcoholism, CHF, diabetes though some authors do not include diseases associated with liver, kidney, and endocrine systems in this classification.

2.     Multifactorial causes. Decreased RBC life-span, unresponsive bone marrow, inability to mobilize iron stores.

3.     Lab tests. Hemoglobin generally between 9 and 11 mg/dl. Cells may be normocytic or microcytic. Serum ferritin
usually increased but may be normal. TIBC and serum iron will be decreased.

4.     Treatment. Treat underlying disease. Transfuse only as needed for symptoms. Erythropoietin may be used as well. Start with 100 to 150 U/kg SQ 3 x per week and increase to 300 U/kg SQ 3 x per week if no response in 3 weeks. If no response by 12 weeks, the patient isn't going to respond, and erythropoietin should be discontinued. Reduce dose when HCT reaches 36% and hold dose if HCT = 40.

C.     B.     Primary marrow disorders.

1.       Include congenital aplastic anemia, acquired aplastic anemia, and marrow depression from drugs and toxins (antineoplastic agents, immunosuppressive drugs, ionizing radiation, benzene, chloramphenicol, antithyroid agents, oral hypoglycemics, TMP/SMX, etc.), infections including hepatitis, mononucleosis, graft versus host disease, lupus, HIV.

2.     Clinical manifestations. Weakness and fatigue from anemia, bleeding from thrombocytopenia, infection from leukopenia.

3.     Aplastic anemia.

a.      0.     In aplastic anemia, course may be mild or severe though predicting the course based on marrow cellularity etc. is imprecise. 70% mortality by 1 year with "severe" disease.

b.     1.       Diagnosis. CBC may show pancytopenia with normochromic-normocytic anemia. Reticulocyte count will be very low. Serum iron will be elevated with normal TIBC. Bone marrow will be hypocellular.

c.      2.     Therapy. Requires hematology consultation.

 
Aplastic Bone Marrow

 IV.             IV.            Macrocytosis with Unresponsive Marrow

Low or normal reticulocyte count and anemia.

A.     .        Causes.

1.       Vitamin B₁₂ deficiency (malabsorption from pernicious anemia, gastrectomy, Crohn's disease, celiac sprue). Strict vegetarians are at high risk but not a problem in Ovo-Lacto vegetarians. In the elderly, achlorhydria and lack of intrinsic factor may decrease vitamin B₁₂ absorption.

2.     Folic acid deficiency (usually caused by poor intake in alcoholics, indigent; or increased demand in pregnancy).

3.     Drugs (including methotrexate, trimethoprim, pentamidine, AZT, hydroxyurea, alkylating agents, chloramphenicol).

4.     Alcohol also causes macrocytosis independent of nutritional effects.

5.     Arsenic.

6.     Endocrine including hypothyroidism.

B.     A.    Clinical presentation.

1.       Vitamin B₁₂ deficiency.

a.      0.     Symptoms of anemia. Gastrointestinal symptoms (glossitis, taste bud atrophy, anorexia, weight loss, diarrhea). Neurologic symptoms including numbness, paresthesias, weakness, ataxia, sphincter dysfunction, positive Babinski sign (toe upgoing).

b.     1.       Signs include those of anemia (pallor, tachycardia, etc.) and neurologic signs of hypereflexia or hyporeflexia, positive Romberg sign, impaired positional and vibratory sensation, depressed mentation, hallucinations, and personality changes. Neurologic disease may occur with normal hematocrit.

c.      2.     Some would suggest periodic screening of those >55 years of age, since can have symptoms of deficiency before have hematologic changes. If use 258 pmol/L as cutoff, 40.5% may be deficient.

2.     Folate deficiency. Signs and symptoms are the same as in vitamin B₁₂ deficiency, except that the patient is more likely to be malnourished. Neurologic abnormalities are generally absent as is glossitis.

C.     B.     Diagnosis. Elevated MCV, low reticulocyte count. However, many have normal indices because of coexistent thalassemia or iron deficiency, etc. Low vitamin B₁₂ or RBC folate levels respectively (check both vitamin B₁₂ and folate!). Serum folate level varies with meals and is an unreliable indicator of base state. Thrombocytopenia (50%) and leukopenia are late findings. Smear shows anisocytosis, poikilocytosis, basophilic stippling, hypersegmentation of neutrophils. Once the diagnosis of vitamin B₁₂ deficiency is made, a Schilling test can identify the pathophysiologic characteristics.

D.    C.     Therapy.

1.       Vitamin B₁₂ deficiency. IM cyanocobalamin 1000 µg per week for 6 weeks and then 1000 µg IM every month for life.

2.     Folate deficiency. One milligram of folic acid PO QD is sufficient.

3.     Blood transfusions are usually not required.

4.     Empiric therapy before a diagnosis is established can be dangerous. A patient deficient in vitamin B₁₂ may have a hematologic response to folic acid but an exacerbation of neurologic symptoms.

5.     Esophageal, stomach, and colorectal tumors have a higher incidence in those with pernicious anemia. They also have a higher rate of hypothyroidism; so screen these patients.

  Macrocytic Anemia

Macrocytic Anemia

     V.                 V.            Anemia with Increased Red Blood Cell Production

A.     .        Usually acute anemias primarily associated with blood loss or hemolysis. May be caused by prolonged running or marching as well as microangiopathic changes as with HUS/TTP or artificial valves.

B.     A.    Hemolytic Anemia.

1.       Presentation. Patients usually present with classic signs of anemia. See section IB for symptoms. Hemolytic crisis, which is rare, presents with fever, chills, tachycardia, tachypnea, backache, hemoglobinuria. Can progress to renal failure from hemoglobinuria. In addition to the causes below, consider malaria, ehrlichiosis, etc.

2.     Lab tests.

a.      0.     Often normochromic-normocytic but may be macrocytic.

b.     1.       Generally have an elevated indirect bilirubin with normal direct bilirubin.

c.      2.     Haptoglobin is decreased; serum LDH is increased; hemosiderinuria and hemoglobinuria may be present.

d.      3.     Serum free hemoglobin may be increased.

e.      4.     Coombs' tests. Direct Coombs' test measures antibody that is attached to RBCs (antibody directly on RBC). Indirect Coombs' tests for circulating anti-RBC antibodies in serum. Example: In Rh disease, mother has positive indirect Coombs (circulating anti-D antibody). Rh-positive child has positive direct Coombs because mother's antibodies are coating cells (tested after birth).

3.     Hemolytic anemia secondary to acquired hemolytic disorders.

a.      0.     Warm-antibody induced hemolytic anemia. Antibodies most active at temperature of 37° C. About 70% of those with antibody-related hemolytic disease have warm antibodies.

§          May be primary (60%) or secondary (40%) to underlying disease affecting the immune system (such as CLL, non-Hodgkins lymphoma, SLE, myeloma, HIV, ulcerative colitis). Commonly occurs with drugs (penicillin, alpha-methyldopa, INH, sulfonamides).

§         Usually have positive direct Coombs' test, generally an IgG antibody.

§         Often severe with Hb of 7.0 or less; can be fatal.

§          May have enlarged spleen, liver, jaundice.

§          No therapy required if disease is mild. With significant hemolysis, prednisone at dose of 1 to
1.5 mg/kg/day, transfusions, splenectomy (50% to 75% response; may relapse), and cytotoxic agents (cyclophosphamide 50 to 150 mg/day or azathioprine 50 to 200 mg/day) have been used with some success as have androgens. Hematology consultation is recommended.

b.     1.       Cold-antibody induced hemolytic anemia. Represent about 15% of those with antibody-related hemolysis. Generally get agglutination of cells followed by hemolysis.

§           These IgM antibodies agglutinate RBCs at temperature <37° C (most reactive <30° C). Seen with Mycoplasma pneumoniae, infectious mononucleosis, and lymphoid neoplasms.

§          May note cold-related symptoms such as acrocyanosis, which gets better on warming.

§         Maintain patient in warm environment. Chlorambucil is the most common agent used. If related to infectious process, generally resolve spontaneously in weeks.

c.      2.     Trauma in the circulation.

§         Abnormalities of the vessel wall: seen in malignant hypertension, eclampsia, TTP, valve prostheses, and microvascular thrombi.

§         Diagnosis. Fragmented and nucleated RBCs. See appropriate book section on underlying disease.

§          Therapy. Directed toward underlying illness.

d.      3.     Red blood cell defects. Hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis can cause a hemolytic anemia.

C.                 4.     Paroxysmal nocturnal hemoglobinuria


Spherocytosis


Spleen with Spherocytosis

 Howell Jolly Bodies


Helmet Cells

 

Cause	Reticulocyte Number
Bone Marrow Failure	Low or Normal
Hemolysis or Acute Blood Loss	High

Microcytic Anemia

Macrocytic Anemias

Anemia due to Decreased RBC Production

 

Hemolytic Anemia

Inflammation
Elevated ESR!

Sickle cell disease

Sickle cell disease is an inherited disorder of the red blood cells. Normal red blood cells contain only normal hemoglobin and are shaped like Biconcave discs. These cells are very flexible and move easily through small blood vessels.

But in sickle cell disease, the red blood cells contain sickle hemoglobin, which causes them to change to a curved shape (sickle shape) after oxygen is released. Sickled cells become stuck and form plugs in small blood vessels. This blockage of blood flow can damage the tissue. Because there are blood vessels in all parts of the body, damage can occur anywhere in the body.

The most common types of sickle cell disease are:

Sickle cell anemia

Sickle Cell Trait

Hemoglobin SC disease

Sickle beta-thalassemia

How are babies affected?

Babies with sickle cell disease may have:

o        Anemia (a low number of red blood cells). People with anemia may tire easily.

o        Aplastic crisis. Babies with sickle cell disease may stop making red blood cells for a short time. Signs include paleness, less activity than normal, fast breathing, and fast heartbeat.

o        Hand-and-foot syndrome. (Dactylitis) Babies with sickle cell disease may have pain and swelling in their hands or feet.

o        Painful episodes / crisis (mostly in the arms, hands, legs, feet, or abdomen). This happens when sickle cells plug blood vessels and block the flow of blood.

o        Severe infections. The child with sickle cell anemia is at great risk for serious infections -- such as sepsis, meningitis, and pneumonia. The risk of infection is increased because the spleen does not function normally.

o        Splenic sequestration crisis. The spleen is the organ that filters blood. In children with sickle cell disease, the spleen can enlarge rapidly from trapped red blood cells. This condition is called splenic sequestration crisis and can be life-threatening.

o        Stroke. This happens when blood vessels in the brain are blocked by sickled red blood cells. Signs include seizure, weakness of the arms and legs, speech problems, and loss of consciousness.

Epidemiology

In the United States, most people who have sickle cell disease are African Americans. About 1 in 375 African-American children has sickle cell disease. Hispanic Americans from the Caribbean, Central America, and parts of South America also may have the disease. Sickle cell disease is also found in individuals from Turkey, Greece, Italy, the Middle East, or East India.

Genetics

All forms of sickle cell disease are inherited. Children inherit genes for the disease from their parents.

When both parents have sickle cell trait, for each pregnancy, the chances are: 1 in 4 that the baby will have only normal hemoglobin. 2 in 4 that the baby will have both normal and sickle hemoglobin (sickle cell trait). 1 in 4 that the baby will have only sickle hemoglobin (sickle cell anemia).

Treatment  

By 2 months of age, your baby should start taking penicillin by mouth twice each day. It is very important to give the medicine exactly as the doctor tells you. This will help prevent life-threatening infections. Penicillin should be continued until at least 5 years of age.  

Also, by 2 months of age, immunization against H. influenzae and pneumococcus – encapsulated bacteria.

Call Orders

Fever (over 101.5 degrees), must be seen right away.

o        Tachypnea

o        Coughs frequently

o        Hypersthesia

o        Fatigue

o        Weakness

o        Emesis

o        Anorexia

o        Diarrhea

o        Decreased Urine Output

o        Abdominal pain or swelling

o        Swollen hands or feet

o        Pale blue or grey lips or skin

Good Nutrition and plenty of liquids when ill is very important. Consider multivitamins.

Environmental Control: Make sure the baby does not become overheated or chilly. Cold baths or cold air can slow the baby's blood flow and cause problems.
 
Sickle Cell Anemia

 
Sickle Cell Anemia

Hemoglobin SC

IRON DEFICIENCY

DEFINITION:

A disorder characterized by iron deficiency resulting in a microcytic, hypochromic anemia.

EPIDEMIOLOGY:

• incidence: most common hematologic disease of infancy & childhood
• age of onset:
• 9-24 months of age (inadequate dietary iron)
• risk factors:
• see below

PATHOGENESIS:

1. Etiology of Iron Deficiency Anemia

·  1. Deficient Intake of Iron

• cow's milk

·  2. Impaired Absorption of Iron

• Inflammatory Bowel Disease
• Malabsorption Syndrome
• postgastrectomy
• severe prolonged diarrhea

·  3. Increased Iron Demand

·  1. Growth States

• low birth weight, prematurity, twins
• adolescence
• pregnancy

·  2. Cyanotic Congenital Heart Disease

·  4. Increased Blood Loss

·  1. Perinatal

·  2. Postnatal

·  1. GI Losses

• hemangioma, Meckel diverticulum, peptic ulcer, polyp, whole cow's milk

2. Sequence of Changes in Iron Deficiency

• depletion of storage iron
• both ferritin and hemosiderin act as iron storage compon-ents with serum ferritin providing a relatively accurate estimate of body iron stores
• decreased hemosiderin content in the liver & bone marrow
• decreased serum ferritin to 1-35 ug/L
• decreased serum iron and elevated transferrin (TIBC)
• at this point the pool of storage iron is unable to main-tain the serum iron
• the lack of iron stimulates the transcription of the transferrin protein
• total iron binding capacity (TIBC) is an indirect measure-ment of transferrin
• elevated levels of free erythrocyte protoporphyrins (FEP)
• FEP's are heme precursors which accumulate in iron de-ficiency
• RBC structure affected
• microcytic, hypochromic, poikilocytosis
• decreased activity of intracellular enzymes containing iron
• catalase, cytochromes (c, P-450), peroxidase

3. Dietary-based Iron Deficiency

• daily elemental iron is needed for the first 15 years of life to increase the total body iron from 0.5 grams (newborn) to 5.0 grams (adult); to do so 0.8-1.5 mg of elemental iron is needed daily (since only 10% of elemental iron is absorbed from the diet through the jejunum, the daily elemental iron re-quirement is 8-15 mg daily)
• 1. Cow's Milk Iron Deficiency Anemia
• as hemoglobin levels fall during the first 2-3 months of life, a considerable amount of iron is reclaimed and stored; thus dietary based iron deficiency anemia is very unusual before 4 months of age but becomes common from
• 9-24 months of age
• as the iron content of cow's milk is 0.75 mg/L, at least 10 liters of cow's milk would have to be consumed daily to met the recommended daily iron requirement - thus, infants whose diet consists primarily of cow's milk are at risk for developing iron deficiency anemia - instead of only absorbing 10% of iron, breast-fed babies absorb 49% of the iron from the breast milk

CLINICAL FEATURES:

1. Anemia

·  1. Hb >70 g/L

• pallor

·  2. Hb <70 g/L

• anorexia - splenomegaly (in 10-15% of patients)
• irritability - systolic murmer
• pica - tachycardia

INVESTIGATIONS:

1. Serum

·  1. CBC

• hypochromic, microcytic anemia
• reticulocytes normal or slightly elevated

·  2. Smear

• anisocytosis and poikilocytosis

·  3. Iron Studies

• decreased serum ferritin
• decreased serum iron
• elevated transferrin (TIBC)

2. Bone Marrow

• hypercellular with erythroid hyperplasia
• micronormoblastic maturation
• decreased hemosiderin on iron staining
• normal myeloid lineage

MANAGEMENT:

·  I. APPROACH

·  1. Diagnosis

·  2. Education

·  3. Goals of Therapy

·  4. Management Strategies

·  1. Supportive

·  2. Diet

·  3. Iron Supplementation

·  4. RBC Transfusion

1. Diagnosis

·  1. Laboratory

• microcytic, hypochromic anemia
• low serum ferritin and iron
• elevated transferrin

·  2. Therapy

• therapeutic response to iron supplementation

2. Education

• definition, epidemiology, pathogenesis, role of diet, treatment options

3. Goals of Therapy

• to return the hemoglobin to physiological levels

4. Management Strategies

·  1. Supportive

• correct any causes of chronic blood loss
• correct underlying disorders, i.e., Malabsorption

·  2. Diet

• decrease intake of cow's milk
• use iron-fortified formulas and cereals

·  3. Iron Supplementation

• 6 mg/kg/day of elemental iron po tid
• treat for 4-6 weeks after the hemoglobin has normalized
• should see a subjective improvement in the patient (decreased irritability and increased appetite) within 24 hours of initiating therapy with reticulocytosis peaking at 5-7 days and a return to normal Hb levels between 4-30 days; it may take 1-3 months to replete the body's iron stores
• iron supplements
• ferrous sulfate - 20% elemental iron
• ferrous gluconate - 10-12% "

·  4. PRBC Transfusion

• indicated for severe symptomatic anemia
• 2-3 cc/kg of PR
  BC's +/- lasix

SIDEROBLASTIC

DEFINITION:

A heterogeneous group of disorders characterized by the ab normal utilization of iron resulting in a microcytic anemia.

EPIDEMIOLOGY:

• incidence: ?
• age of onset:
• childhood
• risk factors:
• see below

PATHOGENESIS:

1. Classification of Sideroblastic Anemias

1. Hereditary

·  1. X-linked

·  2. Autosomal Recessive

2. Acquired

·  1. Idiopathic

·  2. Secondary

·  1. Drugs

• alcohol, chloramphenicol, cytotoxic drugs (aza-thioprine, nitrogen mustard), isoniazid, lead

·  2. Diseases

·  1. Hematologic

• hemolytic anemia, leukemia, megalobastic anemia

·  2. Inflammatory

• autoimmune disorders, polyarteritis nodosa, rheumatoid arthritis

·  3. Neoplastic

• Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma

2. Pathogenesis

• in Sideroblastic Anemia, there appears to be an inadequate or abnormal utilization of intracellular iron for hemoglobin synthesis despite adequate or increased amounts of iron within the mitochondria of RBC precursors

CLINICAL FEATURES:

1. Anemia

• mild to severe
• tends to be mild during childhood becoming more severe and refractory to treatment in adulthood
• complications
• 1. Extramedullary Hematopoiesis
• hepatosplenomegaly (hepatomegaly)
• 2. Hemosiderosis
• 1. Cardiomyopathy
• arrhythmias, congestive heart failure, recurrent pericarditis
• 2. Gastrointestinal
• hepatic fibrosis and cirrhosis
• 3. Endocrinopathies
• diabetes mellitus; secondary hypopituitarism, hypoparathyroidism, hypothyroidism
• 4. Cutaneous
• darkening of the skin due to iron-stimulated melanin production

INVESTIGATIONS:

1. Serum

1. CBC

• hypochromic, microcytic anemia

2. Smear

• marked anisocytosis and poikilocytosis

3. Iron Studies

• elevated serum ferritin
• elevated serum iron
• decreased (or normal) transferrin (TIBC)

2. Bone Marrow

• erythroid hyperplasia
• course hemosiderin granules (containing iron), form a peri-nuclear ring within the normoblasts and these cells are called "ringed sideroblasts" - increased in the bone marrow of patients with Sideroblstic Anemia

MANAGEMENT:

1. Supportive

• treat underlying disorder if a secondary etiology
• usually do not respond to iron therapy
• PRBC transfusions if anemia severe

2. Medical

1. Pyridoxine (Vitamin B6)

• 200-500 mg/day

some cases are partially responsive

CHRONIC DISEASE

DEFINITION:

Normocytic and normochronic anemia associated with a wide variety of chronic disorders.

EPIDEMIOLOGY:

• incidence: 2nd most common form of anemia worldwide
• age of onset:
• any
• risk factors:
• see below

PATHOGENESIS:

1. Chronic Diseases

1. Infections

• bronchiectasis - osteomyelitis
• lung abscess - TB

2. Inflammatory Diseases

• Rheumatic Fever, SLE
• Rheumatoid Arthritis, Ulcerative Colitis
• Sarcoidosis, vasculitic syndromes

3. Neoplasms

• hematologic - Hodgkin's Disease, Non-Hodgkin's Lymphoma
• solid tumors - neuroblastoma, Wilms' Tumor

2. Pathogenesis

• chronic disease
• hyperactive reticuloendothelial system
• increased RBC hemolysis
• defective iron reutilization where the reticular cells tenaciously retain iron from senescent RBC's (concomittant reticuloendothelial siderosis)
• hypoactivity of bone marrow with relative inadequate production of erythropoietin

CLINICAL FEATURES:

1. Anemia

• mild to moderate
• develops slowly over months

2. Underlying Disorders

• signs and symptoms of underlying disorders

INVESTIGATIONS:

1. Serum

• Hb: normocytic, normochromic, mean = 60-90 g/L
• normal or decreased reticulocytes
• decreased serum iron and TIBC (elevated transferrin)
• increased free erythrocyte protoporphyrin (FEP)
• increased copper, WBC, ESR

2. Bone Marrow

• normal cellularity and RBC precursors
• decreased number of bone marrow sideroblasts
• increased hemosiderin level

MANAGEMENT:

·  1. Supportive

• treat underlying disorder and anemia resolves unless associated with an iron deficiency anemia
• iron therapy has no role (except if concomittant iron deficiency anemia)

PRBC transfusions have only a temporary effect and are rarely indicated

APLASTIC ANEMIA

DEFINITION:

A group of disorders characterized by peripheral blood pancytopenia secondary to an acquired decrease in bone marrow function.

EPIDEMIOLOGY:

• incidence: 2-6/million
• age of onset:
• any
• risk factors:
• see below
• M = F

PATHOGENESIS:

1. Risk Factors

·  1. Idiopathic

·  2. Secondary

·  1. Drugs/Chemicals

·  1. Regular

• benzene, cytotoxic (busulphan, cyclophosphamide, 6-mercaptopurine, methotrexate, nitrogen mustard)

·  2. Idiosyncratic

• anticonvulsants, antibiotics (chloramphenicol,sulfonamides, tetracycline), antirheumatoids (NSAID, gold), quinacrine, cimetidine

·  2. Infections (Viruses)

• EBV (mono)
• hepatitis (C > A & B)
• HIV
• parvovirus

·  3. Immune Diseases

• eosinophilic fascilitis
• hypoimmunoglobulinemia

·  4. Others

• paroxysmal nocturnal hemaglobinuria, preleukemia, pregnancy, thymoma, radiation

2. Pathogenesis

• exposure to risk factor -> damage to progenitor cells (GM-CFU, E-CFU, E-BFU, GEMM-CFU) +/- more mature progeny
• risk factors produce stem cell failure by affecting the stem cells directly or indirectly via the microenvironment thus interfering with hematopoiesis

3. Prognostic Factors

• of severe aplastic anemia:
• WBC less than 5
• PLT less than 20,000
• reticulocytes less than 1%
• hypocellular bone marrow
• 67% mortality within 6 months of onset
• major cause of death - infection > bleeding

CLINICAL FEATURES:

1. Thrombocytopenia

1. Bleeding

• usually the first clinical manifestation
• petechiae, ecchymoses, epistaxis, bleeding from mucous membranes

2. Anemia

• pallor, fatigue, tachycardia

3. Neutropenia

• increased susceptability to bacterial infections - Pseudomonas, Klebsiella, E. coli, S. aureus, S. epi., Streptococcus
• oral ulcerations, febrile neutropenia

4. Complications

• leukemia
• paroxysmal nocturnal hemoglobinuria

INVESTIGATIONS:

1. Serum

• Hb: macrocytic/normocytic, increased HbF, low reticulocytes
• increased RBC i antigen, erythropoietin
• thrombocytopenia
• neutropenia

2. Bone Marrow

• scanty, fatty, hypocellular
• predominance of lymphocytes, plasma cells, reticulum cells, mast cells
• decreased number of progenitor stem cells of erythroid and granulocytic series
• giant pronormoblasts (parvovirus replicates only in human erythroid progenitor cells)

MANAGEMENT:

1. Supportive

• remove offending agent
• avoid bleeding:
• soft toothbrush, avoid trauma, amicar
• pipercillin/tobramycin for febrile neutropenia

2. Transfusions

·  1. PRBC

• filtered, washed, target >80 g/L
• watch for hemosiderosis with chronic transfusions and treat with iron chelators when ferritin >500 ng/cc

·  2. Platelets

• filtered, irradiated
• indicated if bleeding or platelet <20,000

3. Bone Marrow Transplantation

• treatment of choice in refractory severe cases
• acts to replace stem cells

4. Experimental Therapies

• anti-thymocyte globulin, anti-lymphocyte globulin
• high-dose dexamethasone
• cyclosporine
• hematopoietic growth factors (GM-CSF)

DIAMOND-BLACKFAN SYNDROME

DEFINITION:

A disorder characterized by a congenital deficiency in RBC precursors resulting in anemia.

EPIDEMIOLOGY:

• incidence: rare (400 cases worldwide)
• age of onset:
• median: 2 months (M); 3 months (F)
• risk factors:
• most cases sporadic - i.e., new mutation
• familial in 10% of cases - autosomal recessive
• autosomal dominant
• M > F (1.1:1)

PATHOGENESIS:

1. Background

• considered to be one of at least 3 disorders where there is a congenital deficiency in erythroid precursors
• other congenital single cytopenias:
• AASE Syndrome
• Congenital Dyserythropoietic Anemia

2. Genetic Defect

• genetic defect -> defective erythroid stem cells -> decreased or absent BFU-E and CFU-E in bone marrow
• there may be a defect of the erythropoietin receptors on erythroid stem cells

CLINICAL FEATURES:

1. Anemia

• 10% of patients are severely anemia at birth while 90% are severely anemic by 12 months of age
• pallor, lethargic, irritable, heart failure, death

2. Dysmorphic Features

1. Facial (13%)

• micro- or macrocephaly, micrognathia, macroglossia, wide fontanelle
• tow coloured hair, snub nose, wide set eyes, thick upper lip

2. Upper Limbs (10%)

• flattened thenar eminences +/- weak radial pulses
• abnormal thumbs - absent, bifid, subluxed, supernumerary, triphalangeal

3. Ocular (7%)

• blue sclerae, cataracts, epicanthal folds, glaucoma, hypertelorism, microphthalmos, strabismus

4. Renal (4%)

• absent, duplicated, or horseshoe kidneys

5. Others

• short stature, short or webbed neck

3. Complications

1. Hemosiderosis

• due to multiple transfusions (>100)
• hepatosplenomegaly (hepatomegaly)
• leukopenia, thrombocytopenia
• short stature
• delayed puberty
• diabetes mellitus
• death in 2nd decade due to ischemic and siderotic myo-cardial disease -> CHF

2. Neoplasms

• leukemia - ALL, AML
• thymomas

INVESTIGATIONS:

1. Serum

• Hb: macrocytic, normochromic, low reticulocytes
• high erythropoietin (also in urine)
• fetal characteristics of erythrocytes
• presence of fetal membrane antigen i
• increased HbF
• macrocytosis
• elevated serum iron, ferritin, folic acid, vit B12, RBC adenosine deaminase activity (ADA)
• negative direct Coombs
• smear - macrocytes, anisocytosis, tear drops
• WBC - normal or slightly decreased
• PLT - normal or slightly increased

2. Bone Marrow

• normocellular with selective deficiency of RBC precursors:
• low number of BFU-E and CFU-E
• myeloid-erythroid ratio (10-200:1)
• erythroid hypoplasia or total aplasia (in 90% of cases)
• few pronormoblasts
• iron accumulation (after multiple transfusions)

MANAGEMENT:

1. Corticosteroids

1. Prednisone

• treatment of choice
• 2 mg/kg/d po tid or qid initially and then may increase to
• 4-6 mg/kg/d
• reticulocytosis in 1-2 weeks
• normal Hb to normal levels by 4-6 wks
• gradually taper then alternate day therapy
• variable patterns of response - steroid nonresponders, high-dose responders, and failures may make up 50% of cases
• side effects: growth retardation, osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes, fluid retention, gastric ulcers, cataracts, glaucoma

2. RBC Transfusions

• indication: steroid-resistant patients (10% of cases)
• every 3-6 weeks
• side effects: transfusion reactions, AIDS, hepatitis, alloantibody formation, hemosiderosis (treat with iron chelating agent - subcutaneous desferrioxamine)

3. Bone Marrow Transplantation

• experimental for steroid-nonresponders

4. Prognosis

• 15-20% spontaneous remission rate
• steroid treatment improves survival with good quality of life
• median survival age: 31 yrs (including non-responders)

FANCONI ANEMIA

DEFINITION:

A chromosomal breakage disorder characterized by familial aplastic anemia, various congenital anomalies, and a characteristic chromosomal response to clastogenic stress.

EPIDEMIOLOGY:

• incidence: ?
• age of onset:
• 90% of males diagnosed by age 12 years; mean of 7.9 years
• 90% of females diagnosed by age 14 years; mean of 8.8 years
• risk factors:
• familial - autosomal recessive
• chrom.#: ?20q13.2-q13.3
• gene: ?
• M > F (1.3:1)

PATHOGENESIS:

1. Background

• considered to be a "chromosomal breakage syndrome"
• one of at least 4 disorders associated with a high frequency of chromosomal defects with an increased risk of lymphoreticular (leukemia) and other malignancies - other syndromes:
• Ataxia-Telangiectasia
• Bloom Syndrome
• Xeroderma Pigmentosum
• most common of the heritable aplastic anemias
• there is an International Fanconi Anemia Registry

2. Genetic Defect

• genetic defect -> in utero disruption of hematopoiesis and malformation of specific body areas between 25-34 days of gestation
• hematopoietic defect evident at progenitor cell level
• bone marrow - decreased GM-CFU, E-CFU, E-BFU
• blood - " E-BFU

3. Chromosomal Abnormalities

• chromosomal breaks, gaps, and rearrangements
• high frequency of clastogenic-induced chromosomal breaks
• endoreduplication, exchanges, triradials or quadriradials
• involve homologous and nonhomologous chromosomes
• number of sister chromatid exchanges per cell is lower than normal
• because of the high variation in the number and frequency of clinical abnormalities, (25% of affected patients are structurally normal and phenotypic expression is modified by genetic and environmental factors) the diagnosis must be confirmed cytogenetically
• prenatal diagnosis - amniotic fluid cells when treated with di-epoxybutane may demonstrate a higher than normal incidence of chromosomal abnormalities

CLINICAL FEATURES:

1. Haematological Manifestations

1. Pancytopenia

• anemia
• develops early to middle childhood
• pallor
• fatigue
• thrombocytopenia
• bleeding usually first manifestation and progressive
• easy bruising
• leukopenia
• recurrent infections

2. Congenital Anomalies (67% of cases)

1. Craniofacial

• broad nasal bridge
• epicanthal folds
• micrognathia
• microcephaly

2. Musculoskeletal

• small for gestational age
• congenital dislocation of the hip
• short stature
• radii - hypoplasia or aplasia (if radii affected, thumb too)
• thumb - hypoplasia, aplasia, and/or supernumerary

3. Cutaneous

• cafe-au-lait spots
• hyperpigmentation - on trunk, neck, intertriginous areas
• hypopigmented spots

4. Genitourinary

• absent kidney
• cryptorchidism
• duplication of kidney or collecting system
• horseshoe kidney
• primary testicular failure +/- small penis & testes
• renal ectopia

5. Neurological

• hyperreflexia
• mental retardation

6. Ocular

• microophthalmia
• strabismus

7. Neoplasms (in 20% of cases)

• lymphoreticular tumors
• leukemias - acute nonlymphocytic leukemia
• AML (in 5-10% of cases)
• hepatic
• hepatocellular carcinoma
• hepatomas
• adenomas
• others
• squamous cells carcinoma
• GI tumors
• gynecologic tumors

INVESTIGATIONS:

1. Serum

• Hb: macrocytic (MCV = 95-105 fL), HbF (5-15%), low reticulocytes
• pancytopenia
• smear: anisocytosis, poikilocytosis
• elevated serum erythropoietin levels
• growth hormone deficiency

2. Bone Marrow

• hypocellular with increased fatty tissue
• prominent reticulum, plasma and mast cells
• low erythroid and granulocytic precursors
• pancytopenia

3. Chromosome Breakage Analysis

• of blood lymphocytes, amniotic cells, or chorionic villus cells
• metaphase preparations exposed to clastogenic stress
• exposure to difunctional alkylating agents such as mito-mycin C or diepoxybutane induces a higher than normal rate of chromosomal abnormalities (10-70% compared to <10% in normals)
• spontaneous chromosomal breakage rate also higher than normal
• needed for diagnosis

4. Imaging Studies

1. Renal Ultrasound

• congenital renal anomalies

2. Skeletal X-rays

• upper limbs and hands

MANAGEMENT:

1. Supportive

• transfusions of PRBC, platelets, antibiotics
• treatment of aplastic anemia
• avoid drugs and chemicals which can cause aplastic anemia
• splenectomy is not indicated

2. Steroid Therapy

1. Androgens +/- Corticosteriods

• oxymetholone most frequently used androgen +/- prednisone
• increases Hb (1-2 months), WBC counts, then platelet counts (up to 6-12 months)
• 50% response rate
• may relapse if steroids discontinued
• may increase survival rate
• SE: obstructive liver disease, peliosis hepatis (hemor-rhagic cysts of the liver), liver tumors, refractory to androgen therapy, masculinization

3. Bone Marrow Transplantation

• to prevent/cure aplastic anemia and/or leukemia
• chemotherapy and/or radiation may accelerate appearance of secondary malignancies

4. Others

• immunotherapy - methylprednisolone, cyclosporin A
• lithium

hematopoitic growth factors

THALASSEMIA - BETA

DEFINITION:

A diverse group of microcytic hemolytic anemias characterized by the absence or decreased synthesis of the beta globin chain of hemoglobin.

EPIDEMIOLOGY:

• incidence: ?
• age of onset:
• 2-4 years (Thal. Intermedia); 1st year of life (Thal. Major)
• risk factors:
• familial - autosomal recessive
• chrom.#: 11p15.5
• gene: beta-globin chain
• certain ethnic groups:
• Mediterranean, Near and Middle Eastern, Southeast Asia
• type of mutation is usually specific to a given ethnic group
• gene frequences range from 5-20%

PATHOGENESIS:

1. Background

·  1. Normal Adult Hemoglobin (Hb)

Hb Chains %

A a2b2 95.5

A2 a2d2 2.5

F a2g2 <2.0

·  2. Embryogenesis

• beta chain production is activated as early as the 8th week of gestation with the switch to adult hemoglobin completed between 3-4 months of age (thus Thal. Major will not present until after the 3-4 month of life)

2. Genetic Defect

• genetic defect -> abnormal or no synthesis of the beta-globin chain -> bone marrow fails to produce adequate RBC's and increased hemolysis of circulating RBC's -> anemia -> medullary hematopoiesis (bone marrow expansion with typical Beta-Thal. facies) and extramedullary hematopoiesis (hepatosplenomegaly, lymphadenopathy)
• at least 91 point mutations and several deletional mutations have been identified within and around the beta-globin chain gene all affecting the expression of the beta-globin chain gene resulting in defects in activation, initiation, transcription, processing, splicing, cleavage, translation, and/or termination
• types of expression:
• 1. Beta+ - reduced beta-globin chain synthesis
• 2. Betao - no beta-globin chain synthesis

3. Types of Beta Thalassemia

·  1. Heterozygous States

·  1. Thal. Minima - silent beta-globin chain defect

·  2. Thal. Minor - one normal beta-globin chain gene and one beta-thalassemia gene

·  2. Homozygous States

·  1. Thal. Intermedia - 2 beta-thalassemia genes (later-onset)

·  2. Thal. Major - 2 beta-thalassemia genes (early-onset)

CLINICAL FEATURES:

1. Heterozygote States

1. Thalassemia Minima

• asymptomatic

2. Thalassemia Minor

• majority asymptomatic and not anemic
• women may become severely anemia during pregnancy
• complications (in a minority):
• bone changes
• cholelithiasis
• leg ulcers
• splenomegaly

2. Homozygous States

1. Thalassemia Intermedia

• 2-10% of Beta Thalassemics
• symptomatic by 2-4 years of age (but CBC may show anemia during the first year of life)
• moderate anemia
• complications:
• hepatosplenomegaly
• growth failure
• jaundice
• thalassemic facies

2. Thalassemia Major

• also called Cooley anemia, Mediterranean anemia, or von Jaksch anemia
• symptomatic by 12 months of age (often as early as 3 months)
• severe anemia
• complications:
• 1. Craniofacial Features
• onset within the first 6 months of life
• represents medullary hematopoiesis
• mandibular prominence - prominent malar
• maxillary overbite eminences
• depressed nasal bridge - frontal bossing
• 2. Extramedullary Hematopoiesis
• hepatomegaly/hepatosplenomegaly
• peripheral lymphadenopathy
• 3. Iron Overload (Hemosiderosis)
• elevated GI absorption of iron due to chronic anemia results in:
• hepatic fibrosis & cirrhosis (by age 5 years)
• darkening of skin (iron-stimulated melanin production)
• sideroblastic cardiomyopathy (arrhythmias, congestive heart failure, recurrent pericarditis)
• endocrinopathies (diabetes mellitus, secondary hypopituitarism, hypoparathyroidism, hypothyroidism)
• 4. Others
• recurrent infections, overwhelming infections, septicemia
• failure to thrive, growth retardation

INVESTIGATIONS:

1. CBC

• normal Hb in the Heterozygote Forms
• Hb > 70 g/L in Thal. Intermedia
• Hb < 70 g/L in Thal. Major

2. Blood Smear (RBC Morphology)

• normal in Thal. Minima
• microcytic hypochromic in all other forms
• anisocytosis, poikilocytosis, target cells, ovalcytes, basophilic stippling, polychromasia, macrocytes, nucleated RBC's, precipitated alpha chain inclusions

3. Hemoglobin Electrophoresis

• diagnostic
• pattern depends on the degree of beta-globin chain synthesis impairment and presence of other globin-chain defects
• 1. Thalassemia Minima
• elevated alpha/beta globin chain ratio
• 2. Thalassemia Minor
• decreased HbA
• elevated HbA2 > 3.5% (normally 2.5%)
• elevated HbF > 2.0 (normally < 2%)
• 3. Homozygote States
• 1. Beta+
• decreased HbA
• low, normal, or high HbA2
• HbF is 10-90% of total hemoglobin
• 2. Betao
• absent HbA
• elevated HbA2 and HbF (HbF may be 100% at birth)

4. Serum

• normal or low serum iron
• normal transferrin (TIBC)
• normal or elevated transaminases, bilirubin,
• decreased haptoglobin, hemopexin

5. Imaging Studies

·  1. Skeletal X-Rays (Thal. Major)

• "hair-on-end" pattern in the skull
• thinning of the long bone cortices

MANAGEMENT:

I. APPROACH

·  1. Diagnosis

·  2. Education

·  3. Treatment Options

·  4. Goals of Therapy

·  5. Management Strategies

·  1. Transfusion Therapy

·  2. Chelation Therapy

·  3. Splenectomy

·  4. Bone Marrow Transplantation

1. Diagnosis

·  1. Clinical - hemolytic microcytic hypochronic anemia

·  2. Laboratory - Hb electrophoresis, molecular characterization

2. Education

• definition, epidemiology, diagnostic criteria, prognosis, treatment options

3. Treatment Options

·  1. No Treatment

• Heterozygote States

·  2. Treatment

• Homozygote States

4. Goals of Therapy

• to maintain a "physiologic" Hb level
• prevent iron accumulation and promote iron excretion

5. Management Strategies

1. Transfusion Therapy

• 6-8 cc/kg of PRBC's every 2-3 weeks
• yearly requirement of <200 cc/kg/year of PRBC's
• q2-3w interval decreases the yearly iron load by 20%
• side effects:
• urticaria, fever (use WBC-poor or washed PRBC's)
• hepatitis B (immunize against Hepititis B)
• hypersplenism, hemosiderosis

2. Desferrioxamine (Chelation) Therapy

• 20-60 mg/kg subcutaneously over 8 hours for a minimum of 5 days/week
• goal is to achieve an iron balance in growing children and a negative iron balance in older or symptomatic patients
• ascorbic acid supplementation to keep ascorbic acid levels normal (when iron chelation is optimal)
• initiated between 4-5 years of age when serum ferritin is greater than 1000 ng/cc and transferrin is >50% saturated
• Desferrioxamine toxicity:
• local irritation - erythema, pruritis
• neurotoxicity
• visual impairment (cataracts, impaired colour vision, poor dark adaptation)
• hearing impairment (high frequency sensorineuronal hearing loss)

3. Splenectomy

• indicated for hypersplenism:
• due to regular transfusion therapy
• occurs between 6-8 year of age
• when PRBC requirements exceed 200-250 cc/kg/yr
• risks:
• post-splenectomy sepsis due to encapsulated organisms (S. pneumoniae, H. flu, N. meningitidis); risk is greater in those under 5 years of age
• vaccinate against pneumococcus and H. flu prior to splenectomy
• Penicillin (250 mg po bid) prophylaxis post splenectomy
• aggressive infection control

4. Bone Marrow Transplantation

• used since 1982
• risks:

mortality, chronic graft vs host disease

APLASTIC CRISIS

DEFINITION:

A transient cessation of erythropoiesis resulting in the acute onset of anemia in a patient with chronic hemolytic anemia.

EPIDEMIOLOGY:

• incidence: ?
• age of onset:
• 90% occur before age 15 with peak between 5-19 years of age
• risk factors:
• human parvovirus B19 (B19)
• any chronic hemolytic anemia:

·  1. Intrinsic RBC Disorders

• Structural Defects
• Enzyme Defects
• Hemoglobin Defects (Hemoglobinopathies, Thalassemias)

·  2. Extrinsic RBC Disorders

• Immune
• Non-Immune

PATHOGENESIS:

1. History

• aplastic crisis was first described in 1948 by Owren
• B19, a small single-stranded DNA virus, was discovered in 1975
• the link of B19 to aplastic crisis was first made in 1981 by Pattison et al.

2. Epidemiology of B19

• B19 is associated with Fifth Disease, acute arthritis, hydrops fetalis, chronic bone marrow failure in immunocompromised patients
• response to B19 infection in patients with chronic hemolyticanemia:
• aplastic anemia
• nonspecific illness
• asymptomatic seroconversion
• aplastic crises due to B19 tend to peak every 2-3 years
• rate of secondary transmission to susceptible household members is 50% via respiratory secretions

3. Background

• in any chronic hemolytic anemia, individuals must maintain an increased rate of erythropoiesis to maintain the hemoglobin concentration (aplastic crises best characterized in sickle cells anemias)
• B19 can lead to a bone marrow hypoplasia by disrupting erythropoiesis and thus precipitate an aplastic crisis
• B19 is associated with about 90% of aplastic crises in patients with underlying hemolytic disorders (10% have other causes)

4. Pathogenesis

• B19 infection of the bone marrow where the host cells (of erythropoiesis) are actively dividing in patients with chronic hemolytic anemia
• B19 infection results in the specific inhibition of erythroid colony formation (no effect of other cells lines)
• lytically infects and subsequently kills the erythroid precursors
• production of IgM and IgG directed towards B19 results in:
• normoblasts and erythroid hyperplasia in the bone marrow
• reticulocytes to peripheral blood
• increased concentration of hemoglobin
• recurrence is rare due to the acquisition of lifelong B19 immunity after the first infection

CLINICAL FEATURES:

1. Prodrome

• viral-like illness in a patient with an underlying hemolytic disorder

2. Symptoms (%)

• fever (80-100%)
• abdominal pain, diarrhea, nausea/vomiting (40-80%)
• malaise (40-80%)
• headache, myalgia, arthralgia (15-45%)
• URTI complaints - cough, rhinorrhea, sore throat (0-40%)
• rash (0-23%)
• conjunctivitis, eye pain, photophobia (0-15%)

3. Aplastic Crisis

1. Anemia

• pallor
• anorexia
• irritability
• pica
• splenomegaly
• systolic murmer
• tachycardia
• episode lasts for 3-6 days

INVESTIGATIONS:

1. Serum

1. CBC

• profound anemia (Hb < 20-30 g/L)
• reticulocytes <1%
• occasionally lymphocytosis, eosinophilia, neutropenia, and thrombocytopenia

2. Serology

• B19 IgM appears within 1-3 days of presentation and lasts for 1-2 months (indicative of acute infection)
• B19 IgG appears within a few days of infection and persists indefinitely (indicative of immunity)

2. Bone Marrow

• aplasia or hypoplasia of the erythroid series with other cell lineages being normal
• giant pronormoblasts

MANAGEMENT:

1. Diagnosis

·  1. History - acute anemia in a patient with chronic hemolytic anemia

·  2. Laboratory

• anemia with low reticulocytes
• aplasia or hypoplasia of the erythroid series

2. Education

• diagnosis, definition, epidemiology, prognosis, treatment options

3. Treatment Options

1. No Treatment

• asymptomatic, self-limiting disorder

2. Treatment

• symptomatic - cardiopulmonary disease, congestive heart failure

4. Goals of Therapy

• to support the patient until the bone marrow can recover

5. Management Strategies

1. Supportive

• observe and await for peripheral blood reticulocytosis
• if hospitalized, put patient in strict respiratory and contact isolation

2. RBC Transfusions

• 10-15 cc/kg PRBC IV:
• should increase the hematocrit by 10%
• give slowly over 3-4 hours if symptomatic +/- lasix
• may require multiple transfusions

3. Experimental

gamma globulin IV

TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD

DEFINITION:

A disorder characterized by an acquired anemia in a previously healthy child.

EPIDEMIOLOGY:

• incidence: ? (>400 cases reported)
• more common than Diamond-Blackfan Anemia
• age of onset:
• 90% >1 year of age (only 10% >3 years)
• mean age: 26 months (M) and 29 months (F)
• risk factors:
• see etiologic agents below
• M > F (1.4:1)

PATHOGENESIS:

1. Risk Factors:

·  1. Idiopathic

·  2. Secondary

·  1. Infectious

·  1. Bacterial

·  2. Viral

• gastrointestinal or respiratory
• anemia presents 0-4 months after infection
• viral illness prodrome in >50% of cases

·  2. Drugs

• aspirin
• chloramphenicol
• dilantin
• piperazine
• sulfonamides
• valproic acid

2. Proposed Pathogenesis

• exposure to etiologic agent -> humoral or cellular autoimmune response -> transient immune suppression of erythropoiesis -> depressed BFU-E and/or CFU-E -> decreased erythroid progenitors
• autoimmune responses:
• humoral - antibodies to BFU-E and/or CFU-E
• cellular - inhibitory mononuclear cells
• etiologic agents may also directly affect BFU-E and/or CFU-E, i.e., viruses

CLINICAL FEATURES:

1. Anemia

• pallor, lethargy, tachycardia
• gradual onset
• complications: seizures, transient ischemic attacks

2. Others

• no congenital anomalies
• normal height and weight for age

INVESTIGATIONS:

1. Serum

• Hb: normocytic, normochromic (mean = 58 g/L), normal HbF, low reticulocytes (< 0.5%)
• normal WBC (neutropenia in only 25%), platelet, haptoglobin, i antigen, serum iron and TIBC, ferritin, osmotic fragility, RBC adensoine deaminase
• elevated erythropoietin
• recovery stage: elevated HbF, i antigen, macrocytosis

2. Bone Marrow

• transient erythroblastopenia in an otherwise normal bone marrow
• maturational arrest of erythroblasts
• myeloid/erythroid ratio ranges from 5-100:1
• recovery stage: "stress erythropoiesis"

MANAGEMENT:

1. Current Recommendations

• observe
• transfuse only if cardiovascular compromise
• no role for prednisone, anabolic steroids, or other immunosuppressive therapies
• most patients well within 1-2 months of diagnosis