Hematologic System

B lood, although a fluid, is one of the body's major tissues. It continuously circulates through the heart and blood vessels, carrying vital elements to every part of the body.

Blood performs several vital functions through its special components: the liquid protein (plasma) and the formed constituents (erythrocytes, leukocytes, and thrombocytes) suspended in it. Erythrocytes (red blood cells) carry oxygen to the tissues and remove carbon dioxide. Leukocytes (white blood cells) act in inflammatory and immune responses. Plasma (a clear, straw-colored fluid) carries antibodies and nutrients to tissues and carries waste away. Plasma coagulation factors and thrombocytes (platelets) control clotting.

Hematopoiesis, the process of blood formation, occurs primarily in the marrow. There primitive blood cells (stem cells) differentiate into the precursors of erythrocytes (normoblasts), leukocytes, and thrombocytes.

The average person has 5 to 6 L of circulating blood, which comprises 5% to 7% of body weight (as much as 10% in premature newborns). Blood is three to five times more viscous than water, has an arterial pH of 7.35 to 7.45, and is either bright red (arterial blood) or dark red (venous blood), depending on the degree of oxygen saturation and the hemoglobin level.

PATHOPHYSIOLOGIC MANIFESTATIONS

Bone marrow cells reproduce rapidly and have a short life span, and the storage of circulating cells in the marrow is minimal. Thus, bone marrow cells and their precursors are particularly vulnerable to physiologic changes that affect cell production. Disease can affect the structure or concentration of any hematologic cell.

Hemoglobin

The protein hemoglobin is the major component of the red blood cell. Hemoglobin consists of an iron-containing molecule (heme) bound to the protein globulin. Oxygen binds to the heme component and is transported throughout the body and released to the cells. The hemoglobin picks up carbon dioxide and hydrogen ions from the cells and delivers them to the lungs, where they are released.

A variety of mutations or abnormalities in the hemoglobin protein can cause abnormal oxygen transport.

Red blood cells

Red blood cell (RBC) disorders may be quantitative or qualitative. A deficiency of RBCs (anemia) can follow a condition that destroys or inhibits the formation of these cells. (See Erythropoiesis .)

Common factors leading to anemia include:

• drugs, toxins, ionizing radiation
• congenital or acquired defects that cause bone marrow to stop producing new RBCs cells (aplasia) and generally suppress production of all blood cells (hematopoiesis, aplastic anemia)
• metabolic abnormalities (sideroblastic anemia)
• deficiency of vitamins (vitamin B 12 deficiency, or pernicious anemia) or minerals (iron, folic acid, copper, and cobalt deficiency anemias) leading to inadequate erythropoiesis
• excessive chronic or acute blood loss (posthemorrhagic anemia)
• chronic illnesses, such as renal disease, cancer, and chronic infections
• intrinsically (sickle cell anemia) or extrinsically (hemolytic transfusion reaction) defective RBCs.

Decreased plasma volume can cause a relative excess of RBCs. The few conditions characterized by excessive production of RBCs include:

• abnormal proliferation of all bone marrow cells (polycythemia vera)
• abnormality of a single element (such as erythropoietin excess caused by hypoxemia or pulmonary disease).

Leukocytosis

Leukocytosis is an elevation in the number of white blood cells (WBCs). All types of WBCs may be increased, or only one type. (See WBC types and functions .) Leukocytosis is a normal physiologic response to infection or inflammation. Other factors, such as temperature changes, emotional disturbances, anesthesia, surgery, strenuous exercise, pregnancy, and some drugs, hormones, and toxins can also cause leukocytosis. Abnormal leukocytosis occurs in malignancies and bone marrow disorders.

Leukopenia

Leukopenia is a deficiency of WBCs ― all types or only one type. It can be caused by a number of conditions or diseases, such as human immunodeficiency virus (HIV) infection, prolonged stress, bone marrow disease or destruction, radiation or chemotherapy, lupus erythematosus, leukemia, thyroid disease, or Cushing syndrome. Because WBCs fight infection, leukopenia increases the risk of infectious illness.

Thrombocytosis

Thrombocytosis is an excess of circulating platelets to greater than 400,000/μl. Thrombocytosis may be primary or secondary.

Primary thrombocytosis

In primary thrombocytosis, the number of platelet precursor cells, called megakaryocytes, is increased and the platelet count is greater than1 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

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.

DISORDERS

Specific causes of hematologic disorders include trauma, chronic disease, surgery, malnutrition, drug, exposure to toxins or radiation, and genetic or congenital defects that disrupt production or function of blood cells.

Aplastic anemias

Aplastic or hypoplastic, anemias result from injury to or destruction of stem cells in bone marrow or the bone marrow matrix, causing pancytopenia (anemia, leukopenia, and thrombocytopenia) and bone marrow hypoplasia. Although commonly used interchangeably with other terms for bone marrow failure, aplastic anemia properly refers to pancytopenia resulting from the decreased functional capacity of a hypoplastic, fatty bone marrow.

These disorders generally produce fatal bleeding or infection, especially when they're idiopathic or caused by chloramphenicol (Chloromycetin) use or infectious hepatitis. The death rate for severe aplastic anemia is 80% to 90%.

Causes

Possible causes of aplastic anemia are:

• radiation (about half of such anemias)
• drugs (antibiotics, anticonvulsants), or toxic agents (such as benzene or chloramphenicol [Chloromycetin])
• autioimmune reactions (unconfirmed), severe disease (especially hepatitis), or preleukemic and neoplastic infiltration of bone marrow
• 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 syndrome (develops between birth and 10 years of age).

Pathophysiology

Aplastic anemia usually develops 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

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, 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).

Complications

A possible complication of aplastic anemia is:

• life-threatening hemorrhage from the mucous membranes.

Diagnosis

The following test results help diagnose aplastic anemia:

• 1 million/μl or fewer RBC of normal color and size (normochromic and normocytic).

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

• very low absolute reticulocyte count
• elevated serum iron (unless bleeding occurs), normal or slightly reduced total iron-binding capacity, 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.

Treatment

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 handwashing, etc.)
• specific antibiotics for infection (not given prophylactically because they encourage resistant strains of organisms)
• respiratory support with oxygen in addition to blood transfusions (for patients with low hemoglobin levels)
• corticosteroids to stimulate erythropoiesis; marrow-stimulating agents, such as androgens (controversial); antilymphocyte globulin (experimental); immunosuppressive agents (if the patient doesn't respond to other therapy); and colony-stimulating factors to encourage growth of specific cellular components.

Iron deficiency anemia

Iron deficiency anemia is a disorder of oxygen transport in which hemoglobin synthesis is deficient. A common disease worldwide, iron deficiency anemia affects 10% to 30% of the adult population of the United States. Iron deficiency anemia occurs most commonly in premenopausal women, infants (particularly premature or low-birth-weight infants), children, and adolescents (especially girls). The prognosis after replacement therapy is favorable.

Causes

Possible causes of iron deficiency anemia are:

• 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
• iron malabsorption, as in chronic diarrhea, partial or total gastrectomy, and malabsorption syndromes, such as celiac disease and pernicious anemia
• blood loss due to drug-induced GI bleeding (from anticoagulants, aspirin, steroids) or heavy menses, hemorrhage from trauma, peptic ulcers, cancer, or varices
• pregnancy, which diverts maternal iron to the fetus for erythropoiesis
• intravascular hemolysis-induced hemoglobinuria or paroxysmal nocturnal hemoglobinuria
• mechanical trauma to RBCs caused by a prosthetic heart valve or vena cava filters.

Pathophysiology

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 subnormal hemoglobin concentration, and, in turn, subnormal oxygen-carrying capacity of the blood.

Signs and symptoms

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:

• dyspnea on exertion, fatigue, listlessness, pallor, inability to concentrate, irritability, headache, and a susceptibility to infection due to decreased oxygen-carrying capacity of the blood caused by decreased hemoglobin levels
• increased cardiac output and tachycardia due to decreased oxygen perfusion
• coarsely ridged, spoon-shaped (koilonchyia), 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.

Complications

Possible complications include:

• infection and pneumonia
• pica, compulsive eating of nonfood materials, such as starch or dirt
• bleeding
• overdosage of oral or IM iron supplements.

Diagnosis

Blood studies (serum iron, total iron-binding capacity, 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 supplements. Characteristic blood test results include:

• low hemoglobin (males, less than 12 g/dl; females, less than 10 g/dl)
• low hematocrit (males, less than 47; females, less than 42)
• low serum iron with high binding capacity
• low serum ferritin
• low RBC count, with microcytic and hypochromic cells (in early stages, RBC count may be normal, except in infants and children)
• decreased mean corpuscular hemoglobin 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.

Treatment

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 IM administration. Considerations include:

• total-dose infusion of iron dextran (INFeD) 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 for an allergic reaction).

Pernicious anemia

Pernicious anemia, the most common type of megaloblastic anemia, is caused by malabsorption of vitamin B 12 .

If not treated, pernicious anemia is fatal. Its manifestations subside with treatment, but some neurologic deficits may be permanent.

Pathophysiology

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 B 12 absorption in the ileum. The resulting vitamin B 12 deficiency inhibits cell growth, particularly of RBCs, leading to production of few, deformed RBCs with poor oxygen-carrying capacity. It also causes neurologic damage by impairing myelin formation.

Causes

Possible causes of pernicious anemia include:

• genetic predisposition (suggested by familial incidence)
• immunologically related diseases, such as thyroiditis, myxedema, and Graves' disease (significantly higher incidence in these patients)
• partial gastrectomy (iatrogenic induction)
• older age (progressive loss of vitamin B 12 absorption).

Signs and symptoms

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
• faintly jaundiced sclera and pale to bright yellow skin due to hemolysis-induc