In primary thrombocytosis, the number of platelet precursor cells, called megakaryocytes, is increased and the platelet count is more than 1 million/µl. The condition may result from an intrinsic abnormality of platelet function and increased platelet mass. It may accompany polycythemia vera or chronic granulocytic leukemia. In the presence of thrombocytosis, both hemorrhage and thrombosis may occur. This paradox occurs because accelerated clotting results in a generalized activation of prothrombin and a consequent excess of thrombin clots in the microcirculation. This process consumes exorbitant amounts of coagulation factors and thereby increases the risk of hemorrhage.

Secondary thrombocytosis is a result of an underlying cause, such as stress, exercise, hemorrhage, or hemolytic anemia. Stress and exercise release stored platelets from the spleen. Hemorrhage or hemolytic anemia signal the bone marrow to produce more megakaryocytes.

Thrombocytosis may also occur after a splenectomy. Because the spleen is the primary site of platelet storage and destruction, platelet count may rise after its removal until the bone marrow begins producing fewer platelets.

♦ Autoimmune reactions (unconfirmed), preleukemic and neoplastic infiltration of bone marrow, or severe disease (especially hepatitis)

♦ Congenital (idiopathic anemias); two identified forms of aplastic anemia are congenital: hypoplastic or Blackfan-Diamond, anemia (develops between ages 2 and 3 months) and Fanconi’s syndrome (develops between birth and age 10)

♦ Drugs (antibiotics, anticonvulsants) or toxic agents (such as benzene or chloramphenicol)

♦ Radiation (about half of such anemias)

Aplastic anemias usually develop when damaged or destroyed stem cells inhibit blood cell production. Less commonly, they develop when damaged bone marrow microvasculature creates an unfavorable environment for cell growth and maturation.

Signs and symptoms of aplastic anemia vary with the severity of pancytopenia but develop insidiously in many cases. They may include:

♦ progressive weakness and fatigue, shortness of breath, bibasilar crackles, headache, pallor, and ultimately tachycardia and heart failure due to hypoxia and increased venous return

♦ ecchymosis, petechiae, and hemorrhage, especially from the mucous membranes (nose, gums, rectum, vagina) or into the retina or central nervous system due to thrombocytopenia

♦ infection (fever, oral and rectal ulcers, sore throat) without characteristic inflammation due to neutropenia (neutrophil deficiency).

A possible complication of aplastic anemia is life-threatening hemorrhage from the mucous membranes.

The following test results help diagnose aplastic anemia:

♦ 1 million/µl or fewer red blood cells (RBCs) of normal color and size (normochromic and normocytic).

RBCs may be macrocytic (larger than normal) and anisocytotic (excessive variation in size), with:

♦ a low absolute reticulocyte count

♦ an elevated serum iron level (unless bleeding occurs), a normal or slightly reduced total ironbinding capacity, the presence of hemosiderin (a derivative of hemoglobin), and microscopically visible tissue iron storage

♦ decreased platelet, neutrophil, and lymphocyte counts

♦ abnormal coagulation test results (bleeding time) reflecting decreased platelet count

♦ “dry tap” (no cells) from bone marrow aspiration at several sites

♦ biopsy showing severely hypocellular or aplastic marrow, with varied amounts of fat, fibrous tissue, or gelatinous replacement; absence of tagged iron (because iron is deposited in the liver rather than bone marrow) and megakaryocytes (platelet precursors); and depression of RBCs and precursors (erythroid elements).

Differential diagnosis must rule out paroxysmal nocturnal hemoglobinuria and other diseases in which pancytopenia is common.

Effective treatment must eliminate an identifiable cause and provide vigorous supportive measures, including:

♦ packed RBC or platelet transfusion; experimental histocompatibility locus antigen-matched leukocyte transfusions

♦ bone marrow transplantation (treatment of choice for anemia due to severe aplasia and for patients who need constant RBC transfusions)

♦ for patients with leukopenia, special measures to prevent infection (avoidance of exposure to communicable diseases, diligent hand washing)

♦ a specific antibiotic for infection (not given prophylactically because antibiotics encourage resistant strains of organisms)

♦ respiratory support with oxygen in addition to blood transfusions (for patients with a low hemoglobin level)

♦ a corticosteroid to stimulate erythropoiesis; a marrow-stimulating agent, such as an androgen (controversial); antilymphocyte globulin; an immunosuppressant (if the patient doesn’t respond to other therapy); and a colony-stimulating factor to encourage growth of specific cellular components.

♦ If the platelet count is low (less than 20,000/µl), prevent bleeding by avoiding I.M. injections, suggesting the use of an electric razor and a soft toothbrush, humidifying oxygen to prevent drying of mucous membranes, avoiding enemas and rectal temperatures, and promoting regular bowel movements through the use of a stool softener and a proper diet to prevent constipation. Also, apply pressure to venipuncture sites until bleeding stops. Detect bleeding early by checking for blood in urine and stool and assessing skin for petechiae.

♦ Take safety precautions to prevent falls that could lead to prolonged bleeding or hemorrhage.

♦ Help prevent infection by washing your hands thoroughly before entering the patient’s room, by making sure the patient is receiving a nutritious diet (high in vitamins and proteins) to improve his resistance, and by encouraging meticulous mouth and perianal care.

♦ Watch for life-threatening hemorrhage, infection, adverse reactions to drug therapy, or blood transfusion reaction. Make sure routine throat, urine, nose, rectal, and blood cultures are done regularly and correctly to check for infection. Teach the patient to recognize signs of infection, and tell him to report them immediately.

♦ If the patient has a low hemoglobin level, which causes fatigue, schedule frequent rest periods. Administer oxygen therapy as needed. If blood transfusions are necessary, assess for a transfusion reaction by checking the patient’s temperature and watching for the development of other signs and symptoms, such as rash, hives, itching, back pain, restlessness, and shaking chills.

♦ Reassure and support the patient and family by explaining the disease and its treatment, particularly if the patient has recurring acute episodes. Explain the purpose of all prescribed drugs and their adverse effects, including which ones he should report promptly. Encourage the patient who doesn’t require hospitalization to continue his normal lifestyle, with appropriate restrictions (such as regular rest periods), until remission occurs.

♦ To prevent aplastic anemia, monitor blood studies carefully in any patient receiving a drug that could cause anemia.

♦ Support efforts to educate the public about the hazards of toxic agents. Tell parents to keep toxic agents out of the reach of children. Encourage people who work with radiation to wear protective clothing and a radiation-detecting badge and to observe plant safety precautions. Those who work with benzene (solvent) should know that 10 parts per million is the highest safe environmental level and that a delayed reaction to benzene may develop.

♦ Alcohol abuse (alcohol may suppress metabolic effects of folate)

♦ Bacteria competing for available folic acid

♦ Excessive cooking, which can destroy much of the folic acid in foods

♦ Impaired absorption (due to intestinal dysfunction from bowel resection and such disorders as celiac disease, tropical sprue, and regional jejunitis)

♦ Increased folic acid requirements during pregnancy, during rapid growth in infancy (common because of recent increase in survival of premature infants), during childhood and adolescence (because of general use of folatepoor cow’s milk), and in patients with neoplastic diseases and some skin diseases (chronic exfoliative dermatitis)

♦ Limited capacity to store folic acid (in infants)

♦ Poor diet (common in alcoholics, elderly people living alone, and infants, especially those with infections or diarrhea)

♦ Prolonged drug therapy (with anticonvulsants or estrogens, including hormonal contraceptives)

Folic acid (pteroylglutamic acid, folacin) is found in most body tissues, where it acts as a coenzyme in metabolic processes involving one carbon transfer. It’s essential for formation and maturation of red blood cells (RBCs) and for synthesis of deoxyribonucleic acid. Although its body stores are relatively small (about 70 mg), this vitamin is plentiful in most well-balanced diets.

Even so, because folic acid is water-soluble and heat-labile, it’s easily destroyed by cooking. Also, about 20% of folic acid taken in through diet is excreted unabsorbed. Insufficient daily folic acid intake (less than 50 mcg/day) usually induces folic acid deficiency within 4 months, as the body stores in the liver are depleted. This deficiency inhibits cell growth, particularly of RBCs, leading to production of few, deformed RBCs. These enlarged red cells characteristic of the megaloblastic anemias have a shortened life span of weeks rather than months.

Folic acid deficiency anemia gradually produces clinical features characteristic of other megaloblastic anemias, without the neurologic manifestations:

♦ progressive fatigue

♦ shortness of breath

♦ palpitations

♦ weakness

♦ glossitis

♦ nausea

♦ anorexia

♦ headache

♦ fainting

♦ irritability

♦ forgetfulness

♦ pallor

♦ slight jaundice.

Folic acid deficiency anemia doesn’t cause neurologic impairment unless it’s associated with vitamin B₁₂ deficiency, as in pernicious anemia.

Folic acid deficiency anemia produces no complications.

The Schilling test and a therapeutic trial of vitamin B₁₂ injections help distinguish folic acid deficiency anemia from pernicious anemia. Significant findings include macrocytosis, decreased reticulocyte count, structurally abnormal platelets, and a serum folate level less than 4 mg/ml.

♦ Primarily, a folic acid supplement (given orally or parenterally to patients who are severely ill, have malabsorption, or are unable to take oral medication) and elimination of contributing causes

♦ A well-balanced diet

If the patient has a combined vitamin B₁₂ and folate deficiency, folic acid replenishment alone may aggravate neurologic dysfunction.

♦ Teach the patient to meet daily folic acid requirements by including a food from each food group in every meal. If the patient has a severe deficiency, explain that diet only reinforces folic acid supplementation and isn’t therapeutic by itself. Urge compliance with the prescribed course of therapy. Advise the patient not to stop taking the supplements when he begins to feel better.

♦ Encourage the avoidance of alcohol, nonherbal teas, antacids, and phosphates, which impair the absorption of B vitamins and iron.

♦ If the patient has glossitis, emphasize the importance of good oral hygiene. Suggest regular
use of mild or diluted mouthwash and a soft toothbrush.

♦ Watch fluid and electrolyte balance, particularly in the patient who has severe diarrhea and is receiving parenteral fluid replacement therapy.

♦ Because anemia causes severe fatigue, schedule regular rest periods until the patient is able to resume normal activity.

♦ To prevent folic acid deficiency anemia, emphasize the importance of a well-balanced diet high in folic acid. Identify patients who are alcoholic and have poor dietary habits, and try to arrange for appropriate counseling. Tell female patients who aren’t breast-feeding to use commercially prepared formulas. (See Preventing folic acid deficiency anemia.)

♦ Blood loss due to drug-induced GI bleeding (from an anticoagulant, aspirin, or a steroid) or heavy menses, cancer, hemorrhage from trauma, a peptic ulcer, increased frequency of laboratory blood samples (in chronically ill patients), sequestration (in patients on dialysis), or varices

♦ Inadequate dietary intake of iron (less than 1 to 2 mg/day), as in prolonged nonsupplemented breast-feeding or bottle-feeding of infants or during periods of stress, such as rapid growth, in children and adolescents

♦ Intravascular hemolysis-induced hemoglobinuria or paroxysmal nocturnal hemoglobinuria

♦ Iron malabsorption, as in chronic diarrhea, partial or total gastrectomy, and malabsorption syndromes, such as celiac disease and pernicious anemia

♦ Mechanical trauma to red blood cells (RBCs) caused by a prosthetic heart valve or vena cava filters

♦ Pregnancy, which diverts maternal iron to the fetus for erythropoiesis

Iron deficiency anemia occurs when the supply of iron is inadequate for optimal formation of RBCs, resulting in smaller (microcytic) cells with less 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 a subnormal hemoglobin level and, in turn, subnormal oxygen-carrying capacity of the blood.

Because iron deficiency anemia progresses gradually, many patients exhibit only symptoms of an underlying condition. They tend not to seek medical treatment until anemia is severe.

At advanced stages, signs and symptoms include:

♦ exertional dyspnea, fatigue, listlessness, pallor, inability to concentrate, irritability, headache, palpitations, and a susceptibility to infection due to decreased oxygen-carrying capacity of the blood caused by a decreased hemoglobin level

♦ increased cardiac output and tachycardia due to decreased oxygen perfusion

♦ coarsely ridged, spoon-shaped (koilonychia), brittle, and thin nails due to decreased capillary circulation

♦ sore, red, and burning tongue due to papillae atrophy

♦ sore, dry skin in the corners of the mouth due to epithelial changes.

♦ Infection and pneumonia

♦ Pica, compulsive eating of nonfood materials, such as soil, clay, ice, or starch

♦ Bleeding

♦ Overdose of an oral or I.M. iron supplement

Blood studies (serum iron, total iron-binding capacity, and ferritin levels) and iron stores in bone marrow may confirm iron deficiency anemia. However, the results of these tests can be misleading because of complicating factors, such as infection, pneumonia, blood transfusion, or iron supplementation. Characteristic blood test results include:

♦ a low hemoglobin level (males, less than 12 g/dl; females, less than 10 g/dl)

♦ low hematocrit (males, less than 47%; females, less than 42%)

♦ a low serum iron level with high binding capacity

♦ a low serum ferritin level

♦ a low RBC count, with microcytic and hypochromic cells (in early stages, RBC count may be normal, except in infants and children)

♦ a decreased mean corpuscular hemoglobin level in severe anemia

♦ depleted or absent iron stores (by specific staining) and hyperplasia of normal precursor cells (by bone marrow studies).

Diagnosis must also include exclusion of other causes of anemia, such as thalassemia minor, cancer, and chronic inflammatory, hepatic, or renal disease.

The first priority of treatment is to determine the underlying cause of anemia. Only then can iron replacement therapy begin. Possible treatments are:

♦ oral preparation of iron (treatment of choice) or a combination of iron and ascorbic acid (enhances iron absorption)

♦ parenteral iron (for patient noncompliant with oral dose, needing more iron than can be given orally, with malabsorption preventing adequate iron absorption, or for a maximum rate of hemoglobin regeneration).

Because total-dose I.V. infusion of supplemental iron is painless and requires fewer injections, it’s usually preferred to I.M. administration. Considerations include:

♦ total-dose infusion of iron dextran in normal saline solution given over 1 to 8 hours (pregnant patients and geriatric patients with severe anemia)

♦ I.V. test dose of 0.5 ml given first (to minimize the risk of an allergic reaction).

♦ Monitor the patient’s compliance with the prescribed iron supplement therapy. Advise the patient not to stop therapy even if he feels better because replacement of iron stores takes time.

♦ Tell the patient he may take iron supplements with a meal to decrease gastric irritation. Advise him to avoid milk, milk products, and antacids because they interfere with iron absorption; however, vitamin C can increase absorption.

♦ Warn the patient that iron supplements may result in dark green or black stools and can cause constipation.

♦ Instruct the patient to drink liquid supplemental iron through a straw to prevent staining his teeth.

♦ Tell the patient to report reactions, such as nausea, vomiting, diarrhea, constipation, fever, or severe stomach pain, which may require a dosage adjustment.

♦ If the patient receives I.V. iron, monitor the infusion rate carefully, and observe for an allergic reaction. Stop the infusion and begin supportive treatment immediately if the patient shows signs of an adverse reaction. Also, watch for dizziness and headache and for thrombophlebitis around the I.V. site.

♦ Use the Z-track injection method when administering iron I.M. to prevent skin discoloration, scarring, and irritating iron deposits in the skin.

♦ Because an iron deficiency may recur, advise regular checkups and blood studies. (See Preventing iron deficiency anemia, page 414.)

♦ Genetic predisposition (suggested by familial incidence)

♦ Immunologically related diseases, such as Graves’ disease, myxedema, and thyroiditis (significantly higher incidence in these patients)

♦ Older age (progressive loss of vitamin B₁₂ absorption)

♦ Partial gastrectomy (iatrogenic induction)

Elderly patients commonly have a dietary deficiency of vitamin B₁₂ in addition to or instead of poor absorption.

Pernicious anemia is characterized by decreased production of hydrochloric acid in the stomach and a deficiency of intrinsic factor, which is normally secreted by the parietal cells of the gastric mucosa and is essential for vitamin B₁₂ absorption in the ileum. The resulting vitamin B₁₂ deficiency inhibits cell growth, particularly of red blood cells (RBCs), leading to production of few, deformed RBCs with poor oxygen-carrying capacity. It also causes neurologic damage by impairing myelin formation.

Characteristically, pernicious anemia has an insidious onset but eventually causes an unmistakable triad of symptoms:

♦ weakness due to tissue hypoxia

♦ sore tongue due to atrophy of the papillae

♦ numbness and tingling in the extremities as a result of interference with impulse transmission from demyelination.

Other common manifestations include:

♦ pale appearance of lips and gums due to hypoxemia

♦ faintly jaundiced sclera and pale to bright yellow skin due to hemolysis-induced hyperbilirubinemia

♦ high susceptibility to infection, especially of the genitourinary tract.

Pernicious anemia may also have GI, neurologic, and cardiovascular effects.

GI signs and symptoms include:

♦ nausea, vomiting, anorexia, weight loss, flatulence, diarrhea, and constipation from disturbed digestion due to gastric mucosal atrophy and decreased hydrochloric acid production

♦ gingival bleeding and tongue inflammation (may hinder eating and intensify anorexia).

Neurologic signs and symptoms are related to impaired myelin formation and subsequent interference with neuron transmission and may include:

♦ neuritis; weakness in the extremities