Hematologic Disorders
ANEMIA
Anemia is a condition associated with lower than normal levels of erythrocytes in the blood. There are several types of anemia, including aplastic, iron deficiency, and pernicious.
Causes
Aplastic Anemia
Congenital or acquired
Autoimmune reactions or other severe disease (hepatitis)
Drugs, radiation, and toxic agents
Iron Deficiency Anemia
Inadequate iron intake or iron malabsorption
Blood loss
Pregnancy, which diverts maternal iron to fetus
Intravascular hemolysis-induced hemoglobinuria or paroxysmal nocturnal hemoglobinuria
Trauma by prosthetic heart valve or vena cava filters
Pernicious Anemia
Vitamin B12 deficiency due to lack of intrinsic factor in stomach lining
Genetic predisposition and age over 60
Immunologically related disorder
Partial gastrectomy
Pathophysiology
Aplastic anemia usually develops when damaged or destroyed stem cells inhibit blood cell production. Less commonly, damage to bone marrow microvasculature creates an unfavorable environment for cell growth and maturation.
Iron deficiency anemia occurs when the supply of iron is inadequate for optimal formation of red blood cells (RBCs); the result is microcytic (smaller-sized) cells with pale color (hypochromic) on staining. Body stores of iron, including plasma iron, become depleted, and the concentration of serum transferrin, which binds with and transports iron, decreases. Insufficient iron stores lead to a depleted RBC mass with low hemoglobin (Hb) concentration and impaired oxygen-carrying capacity.
Decreased production of hydrochloric acid in the stomach and a deficiency of intrinsic factor characterize pernicious anemia. The resulting vitamin B12 deficiency inhibits cell growth, leading to the production of scant, deformed, macrocytic (larger-sized) RBCs having poor oxygen-carrying capacity.
COMPLICATIONS
Aplastic Anemia
Life-threatening hemorrhage
Major infection
Iron Deficiency Anemia
Infection and pneumonia
Pica and lead poisoning in children
Bleeding
Hemochromatosis (from overreplacement of iron)
Pernicious Anemia
Psychotic behavior
Neurologic disability
Signs and Symptoms
Although fatigue, weakness, pallor, and tachycardia, chest pain, and shortness of breath may occur in individuals with all types of anemia, the following signs and symptoms have been more closely associated with one of the types of anemia.
Aplastic Anemia
Progressive weakness, fatigue, and altered level of consciousness
Ecchymosis, pallor, petechiae, and hemorrhage from the mucous membranes or into the retina (may result in visual disturbances)
Fever, oral and rectal ulcers, and sore throat
Bibasilar crackles and tachycardia
Iron Deficiency Anemia
Spoon-shaped, brittle nails
Unusual craving for nonnutritious items (for example, dirt, ice, or chalk)
Uncomfortable tingling or crawling feeling in the legs
Burning or smooth tongue, with sores at the corners of the mouth
Pernicious Anemia
Weakness, numbness, and tingling of extremities in areas that would be covered by socks or gloves
Gingival bleeding and tongue inflammation
Disturbed position sense, lack of coordination, impaired fine finger movement, and altered vision, taste, and hearing
Irritability, poor memory, headache, depression, delirium, and ataxia; changes may have occurred before treatment
Diagnostic Test Results
Aplastic Anemia
Laboratory studies show 1 million/mm3 or fewer RBCs of normal color and size with a very low absolute reticulocyte count, elevated serum iron level, normal or slightly reduced total iron-binding capacity, and decreased platelet, neutrophil, and lymphocyte counts.
Bone marrow biopsy may show severely hypocellular or aplastic marrow and depression of RBCs and precursors.
 PERIPHERAL BLOOD SMEAR IN APLASTIC ANEMIA |
 PERIPHERAL BLOOD SMEAR IN IRON DEFICIENCY ANEMIA |
Iron Deficiency Anemia
Laboratory analysis reveals low hematocrit, low Hb, low serum ferritin and serum iron with high iron-binding capacity (TIBC), low RBC count with microcytic (low MCV) and hypochromic cells (low MCHC) due to decreased mean corpuscular Hb., and depleted or absent iron stores.
Bone marrow studies show hyperplasia of precursor cells.
Pernicious Anemia
Laboratory analysis shows low hematocrit (Hct), low Hb, low RBC count, mean corpuscular volume (MCV) greater than 120 mm3, and serum vitamin B12 less than 0.1 µg/mL.
Schilling test evaluates excretion of radiolabeled vitamin B12.
Gastric analysis shows the absence of free hydrochloric acid after histamine or pentagastrin injection.
Bone marrow aspiration shows erythroid hyperplasia with increased megaloblasts but few normally developing RBCs.
Antibody testing reveals intrinsic factor antibodies and antiparietal cell antibodies.
Treatment
Aplastic Anemia
Blood or platelet transfusion
Bone marrow transplantation
Measures to prevent infection and antibiotics
Respiratory support with oxygen
Corticosteroids, marrow-stimulating agents, immunosuppressive agents, and colony-stimulating factors
Iron Deficiency Anemia
Oral or parenteral iron
Blood transfusions in cases of severe anemia
SICKLE CELL ANEMIA
Acongenital hemolytic anemia that occurs primarily, but not exclusively, in blacks, sickle cell anemia results from a defective hemoglobin molecule (Hb S) that causes RBCs to become sickle-shaped. Such cells clog capillaries and impair circulation, resulting in chronic ill health (fatigue, dyspnea on exertion, swollen joints), periodic crises, long-term complications, and early death.
If both parents are carriers of sickle cell trait (or another hemoglobinopathy), each child has a 25% chance of developing sickle cell anemia. Approximately 1 out of every 500 blacks has sickle cell anemia. The defective Hb S-producing gene may have persisted because, in areas where malaria is endemic, the heterozygous sickle cell trait provides resistance to malaria and is actually beneficial.
AGE ALERT
Half of patients with sickle cell anemia once died by their early 20s; few lived to middle age. Earlier diagnosis and more effective treatment have improved the prognosis of sickle cell anemia. Most patients now survive well into adulthood.Causes
Homozygous inheritance of the gene that produces Hb S
Heterozygous inheritance of this gene results in sickle cell trait, which is usually asymptomatic
Pathophysiology
Hb S becomes insoluble whenever hypoxia occurs. As a result, these RBCs become rigid and elongated, forming a crescent or sickle shape. Such sickling can produce hemolysis (cell destruction). In addition, these altered cells make blood more viscous and tend to accumulate in smaller blood vessels and capillaries. The result is loss of normal circulation, swelling, tissue infarctions, and pain. Furthermore, the blockage causes anoxic changes that lead to further sickling and obstruction. Each patient with sickle cell anemia has a different hypoxic threshold and particular factors that trigger a sickle cell crisis. Illness, exposure to cold, stress, acidotic states, or a pathophysiologic process that pulls water out of the sickle cells precipitates a crisis in most patients. The blockages then cause anoxic changes that lead to further sickling and obstruction.
COMPLICATIONS
Chronic obstructive pulmonary disease
Heart failure and heart murmurs
Splenic infarction and splenomegaly (splenic sequestration)
Retinopathy
Nephropathy
Major organ infarction
Stroke
Acute chest syndrome
Pulmonary infarctions, which may result in cor pulmonale
Ischemic leg ulcers (especially around the ankles)
Increased susceptibility to infection
Iron overload from recurrent blood transfusions
Signs and Symptoms
Tachycardia, cardiomegaly, and systolic and diastolic murmurs
Chronic fatigue and unexplained dyspnea or dyspnea on exertion
Joint pain
Delayed growth
Irritability in children
Occlusive or Infarctive Crises
Severe abdominal, thoracic, muscular, or bone pain
Worsening jaundice, dark urine
Aplastic Crisis
Pallor
Lethargy, sleepiness, and coma
Dyspnea
Markedly decreased bone marrow activity and RBC hemolysis
Diagnostic Test Results
Electrophoresis shows Hb S.
Stained peripheral blood smear shows the presence of sickled cells.
Laboratory studies show low RBC count, elevated white blood cell (WBC) and platelet counts, decreased erythrocyte sedimentation rate, increased serum iron levels, decreased RBC survival, and reticulocytosis.
Lateral chest X-ray shows “Lincoln log” deformity in the vertebrae of many adults and some adolescents.
Treatment
Prophylactic penicillin before age 4 months
Oral hydroxyurea to reduce the number of painful crises
Packed RBC transfusions for severe anemia
Sedation
Analgesics
Oxygen
Oral or I.V. fluids
Folic acid supplements
Antibiotics
Infectious disease prevention, through immunizations, proper food preparation, and frequent handwashing
Bone marrow-stem cell transplant
 PERIPHERAL BLOOD SMEAR IN SICKLE CELL ANEMIA |
 SICKLE CELL CRISIS |
THALASSEMIA
Thalassemia, a group of hereditary hemolytic anemias, is characterized by defective synthesis in the polypeptide chains of the protein component of Hb. RBC synthesis is also impaired.
Thalassemias are most common in people of Mediterranean ancestry (especially Italian and Greek, who develop the form called beta-thalassemia). People whose ancestors originated in Africa, southern China, southeast Asia, and India develop the form called alpha-thalassemia, which reflects deletion of one or more of four Hb genes. Prognosis varies with the number of deleted genes.
In beta-thalassemia, the most common form of this disorder, synthesis of the beta-polypeptide chain is defective. It occurs in three clinical forms: major, intermedia, and minor. The severity of the resulting anemia depends on whether the patient is homozygous or heterozygous for the thalassemic trait. The prognosis varies:
thalassemia major — patients seldom survive to adulthood
thalassemia intermedia — children develop normally into adulthood; puberty usually delayed
thalassemia minor — normal life span.
Causes
Beta-Thalassemia
Thalassemia major or intermedia — homozygous inheritance of a partially dominant autosomal gene
Thalassemia minor — heterozygous inheritance of the same gene
Alpha-Thalassemia
Deletion of one or more of four genes
Pathophysiology
In beta-thalassemia, total or partial deficiency of beta-polypeptide chain production impairs Hb synthesis and results in continual production of fetal Hb beyond the neonatal period. Normally, immunoglobulin synthesis switches from gamma- to beta-polypeptides at the time of birth. This conversion doesn’t happen in thalassemic infants. Their RBCs are hypochromic and microcytic. In alpha-thalassemia, a much reduced quantity of alpha-globin chains is produced.
COMPLICATIONS
Pathologic fractures and bone deformities
Cardiac arrhythmias and heart failure
Iron overload from multiple blood transfusion
Growth and developmental delays in children
Infections
Splenomegaly
Signs and Symptoms
Thalassemia Major
At birth — no symptoms
Infants ages 3 to 6 months — pallor; yellow skin and sclera
Infants ages 6 to 12 months — severe anemia, bone abnormalities, failure to thrive, and life-threatening complications
Splenomegaly or hepatomegaly, with abdominal enlargement; frequent infections; bleeding tendencies (especially nosebleeds); anorexia
Small body, large head (characteristic features); possible mental retardation
Facial features similar to Down syndrome in infants, due to thickened bone at the base of the nose from bone marrow hyperactivity
Thalassemia Intermedia
Some degree of anemia, jaundice, and splenomegaly
Signs of hemosiderosis, such as hemoptysis, iron deficiency anemia, or paroxysmal nocturnal hemoglobinemia — due to increased intestinal absorption of iron
Thalassemia Minor
Usually produces no symptoms
Mild anemia, often overlooked
Alpha-Thalassemia Syndromes
Reflect the number of gene deletions present
Range from asymptomatic to incompatible with life
Diagnostic Test Results
Laboratory analysis reveals low RBC and Hb level, microcytosis, and high reticulocyte count; elevated bilirubin and urinary and fecal urobilinogen levels; and low serum folate level.
Peripheral blood smear shows target cells; microcytes; pale, nucleated RBCs; and marked anisocytosis.
Skull and long bone X-rays show thinning and widening of the marrow space due to overactive bone marrow, granular appearance of bones of skull and vertebrae, areas of osteoporosis in long bones, and deformed (rectangular or biconvex) phalanges.
Quantitative Hb studies (hemoglobin electrophoresis) reveal significantly increased fetal Hb level and slightly increased Hb A2 level.
Family studies of DNA analysis may be conducted to evaluate carrier status and confirm mutations in the alpha- or beta-globin-producing genes.
Thalassemia Intermedia
Peripheral blood smear shows hypochromic, microcytic RBCs (less severe than in thalassemia major).
Thalassemia Minor
Peripheral blood smear shows hypochromic, microcytic RBCs.
Quantitative Hb studies (hemoglobin electrophoresis) reveal significantly increased Hb A2 level and moderately increased fetal Hb level.
Treatment
Iron supplements contraindicated in all forms of thalassemia
Beta-Thalassemia Major: Essentially Supportive
Prompt treatment with appropriate antibiotics for infections
Folic acid supplements
Transfusions of packed RBCs to increase Hb levels (used judiciously to minimize iron overload)
Splenectomy and bone marrow transplantation (effectiveness hasn’t been confirmed)
Beta-Thalassemia Intermedia and Thalassemia Minor
No treatment
Alpha-Thalassemia
Blood transfusions
In utero transfusion for hydrops fetalis
 PERIPHERAL BLOOD SMEAR IN THALASSEMIA MAJOR |
POLYCYTHEMIA VERA
Polycythemia vera is a chronic disorder characterized by increased RBC mass, erythrocytosis, leukocytosis, thrombocytosis, elevated Hb level, and low or normal plasma volume. This disease is also known as primary polycythemia, erythremia, or polycythemia rubra vera. It occurs most commonly among Jewish males of European descent.
AGE ALERT
Polycythemia vera usually occurs between ages 40 and 60; it seldom affects children.Prognosis depends on age at diagnosis, treatment, and complications. In untreated polycythemia, mortality is high and associated with thrombosis, hyperviscosity, or expanded blood volume. Additionally, myeloid metaplasia (ectopic hematopoiesis in the liver and spleen) with myelofibrosis (fibrous tissue in bone marrow) and acute leukemia may develop.
Causes
Unknown, but probably related to a clonal stem cell defect. Nearly all patients have a mutation on the JAK2 gene, which results in altered signal within the Janus kinase pathway.
Pathophysiology
In polycythemia vera, uncontrolled and rapid cellular reproduction and maturation cause proliferation or hyperplasia of all bone marrow cells (panmyelosis). Increased RBC mass makes the blood abnormally viscous and inhibits blood flow through the microcirculation. Diminished blood flow and thrombocytosis set the stage for intravascular thrombosis.
