Chapter 9 The Hematopoietic and Lymphoid Systems
One should note that overhydration due to fluid retention may expand plasma volume, and fluid loss may contract plasma volume. These conditions are called hemodilution and hemoconcentration, respectively. Hemodilution should not be confused with anemia.
|Anisocytosis||Variation in RBC size||Nonspecific|
|Poikilocytosis||Variation in RBC shape||Nonspecific|
|Target cells||Targetlike appearance||Thalassemia, hemoglobinopathies|
|Sickle cells||Bipolar (sickle) or hollyleaf||Sickle cell anemia RBCs|
|Schistocytes||RBC fragments||Microangiopathic hemolytic anemia|
|Teardrops||Tennis racket RBCs||Myelofibrosis, severe anemias|
|Spherocytes||Spherical RBCs with dense hemoglobin content||Hereditary spherocytosis, alcoholism|
|Bite cells||Smooth semicircle taken from one edge||G6PD deficiency|
The reticulocyte is a stage of RBC maturation, normally present in both the marrow and the blood. Under normal conditions, the peripheral blood contains less than 1.5% reticulocytes, but in some anemic patients, their number may be increased. Reticulocyte count is used to assess the capacity of the bone marrow to increase RBC production in response to increased demand. On the basis of the reticulocyte count, anemias may be classified as hypoproliferative, normoproliferative, and hyperproliferative.
No. Most of the tissue changes caused by anemia are nonspecific. These findings include consequences of prolonged mild ischemia and hypoxia, such as fatty change of liver and heart cells. Prolonged and severe anemia leads to a loss of neurons in the brain, but such a loss cannot be readily recognized in routine histologic sections.
Massive blood loss may result in shock and even death. If the person survives, the blood volume is rapidly restored by entry of water from the interstitial spaces into the circulation. This redistribution of water results in hemodilution, which lowers the hematocrit. The RBC counts performed at this point will usually show anemia, which is typically normocytic and normochromic. Thrombocytosis and leukocytosis may be found in peripheral blood because of mobilization of these cells from the marginal pools. Reactive reticulocytosis occurs a few days later. It is mediated by erythropoietin released from the kidneys in response to low oxygen tension in the blood depleted of RBCs. Reticulocytosis will reach its peak 7 to 10 days after hemorrhage and may be as high as 10% to 15% (i.e., 10 times higher than normal).
Chronic blood loss causes a loss of iron, but significant anemia occurs only when the rate of loss exceeds the regenerative capacity of the bone marrow or when iron reserves are markedly depleted. Anemia of chronic blood loss is common in menstruating women, who lose approximately 70 mL of blood during every menstruation. Frequent pregnancies and childbirth are other important causes of anemia. Gastrointestinal diseases are the most common cause of iron-deficiency anemia in men. Nevertheless, in all patients with iron-deficiency anemia, testing of stools and the urine for occult blood loss should be performed.
In both forms of hemolysis, there is anemia and jaundice. Hemoglobinemia and hemoglobinuria occur only in intravascular hemolysis. Hypertrophy of the mononuclear phagocyte system and consequent splenomegaly are seen only in extravascular hemolysis.
All forms of hemolytic anemia are accompanied by premature destruction of erythrocytes. The resulting anemia and lowered oxygen saturation of blood stimulate increased production of erythropoietin in the kidneys, which leads to an increase in the number of normoblasts in the bone marrow and prominent reticulocytosis in the peripheral blood.
17 What is the difference between anemia caused by extrinsic factors (extracorpuscular defects) and anemia caused by intrinsic factors (intracorpuscular defects)?
Hereditary spherocytosis (HS) is caused by several inherited defects in the red cell membrane skeleton that render the RBCs spheroid (round) and less deformable during their passage through the splenic sinusoids. Spherical RBCs are thus more prone to splenic sequestration and destruction, which lead to intracorpuscular hemolysis.
The normal membrane cytoskeleton of RBCs is composed of several proteins, the most important of which are α and β spectrin, ankyrin, actin, and proteins known as band 4.1 and band 3 (Fig. 9-2). Together these proteins maintain the normal biconcave shape of RBCs. The mutation of ankyrin gene is the most common defect in autosomal dominant HS, and the mutations of gene encoding protein band 3 account for 20% of cases. Genes encoding other cytoskeletal proteins are less often mutated.
The prevalence of HS is as high as 1 in 5000 in Caucasians of northern European origin. The autosomal dominant pattern of inheritance accounts for 75% of these cases. The autosomal recessive form of the disease is less common, but it is much more severe than the autosomal dominant form.
Exposure of RBCs to drugs or toxins that generate oxygen radicals is counteracted by reduced glutathione. To form this antioxidant, the cells must increase the breakdown of glucose through the hexose-monophosphate shunt. G6PD is an enzyme that plays a crucial role in this metabolic pathway and is essential for maintaining the glutathione in its active form. Erythrocytes deficient in G6PD are less resistant to oxidant injury, and consequently any exposure to oxidants will cause hemolysis.
Sickle cell anemia is a hereditary hemoglobinopathy caused by mutation of the b-globin gene. This mutation affects hemoglobin A (HbA), transforming it into an abnormal hemoglobin S (HbS). Aggregation and polymerization of the HbS molecules, initiated by deoxygenation, leads to the formation of HbS fibers and resultant distortion of the red cells by sickling. Initially, sickling is a reversible phenomenon, but with repeated episodes of sickling and unsickling, membrane damage ensues, and the cells become irreversibly deformed.
Sickle cell anemia is most common in Africa, but it is also encountered in Mediterranean countries and India. In some areas of Africa, as many as 40% of inhabitants are heterozygotes for HbS. The prevalence of heterozygosity among African Americans is 10%. One in 650 of these people is monozygous and has clinical signs of sickle cell anemia. Approximately 50,000 people have sickle cell anemia in the United States.
The mutation that causes either sickle cell disease or sickle cell trait is a point mutation in the gene that leads to substitution of a valine for glutamic acid at the sixth position of the β-globin chain of hemoglobin:
29 Why do dehydration and anoxia (e.g., high altitude) potentiate sickling of RBCs in sickle cell anemia?
The precipitation of HbS fibers has deleterious effects on the red cell membrane in irreversibly sickled cells but also in normal-appearing cells. With membrane injury, the RBCs have difficulty maintaining normal intracellular volume, and consequently intracellular hemoglobin concentration increases (MCHC is higher), with a higher concentration of the HbS within the cell. Dehydration removes the water from RBCs, bringing HbS molecules even closer to each other, thus greatly facilitating sickling.
Hypoxia, as occurs at high altitudes, increases the amount of deoxygenated HbS. Because deoxygenated HbS molecules aggregate and polymerize many times more readily than oxygenated HbS, it is obvious that hypoxia will promote sickling. Similarly, a decrease in pH lowers the affinity of hemoglobin for oxygen and therefore increases the amount of deoxygenated HbS, which will increase sickling.
Irreversibly sickled cells have rigid and nondeformable membranes and have difficulty negotiating the splenic sinusoids. They become sequestered in the spleen, where they are destroyed by the mononuclear phagocytes. The spleen may become enlarged early in the disease (up to 500 g in children). There is a marked congestion of the red pulp due to the trapped sickled red cells. This erythrostasis leads to thrombosis and infarction in the spleen or at least to marked tissue hypoxia. Continued scarring causes progressive shrinkage of the spleen, resulting in autosplenectomy by adolescence or early adulthood, when only a small nubbin of fibrous tissue may be left.
The bone marrow in these patients is hyperplastic because of the compensatory expansion of normoblasts. The resorption of bone with secondary new bone formation sometimes develops as a consequence of the expansion of bone marrow. These changes on the calvaria produce the x-ray appearance of a crew cut.
33 Discuss the most common bacteria causing infection, death, or both in children with sickle cell anemia
Septicemia and meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae are the most common causes of severe infection or death in these children. Salmonella species are a common cause of osteomyelitis.
Thalassemia is a group of disorders caused by a lack of or decreased synthesis of structurally normal hemoglobin chains. This disease is classified according to the type of chains that are missing. If the α chains are missing, it is called α-thalassemia; if the β chains are missing, it is called β-thalassemia. Low intracellular hemoglobin (hypochromia), as well as the relative excess of the other chain, accounts for the morphologic and functional disturbances seen in these diseases.
A quantitatively defective synthesis of β-globin chains is found in all β-thalassemias. The synthesis of α chains is unimpaired, leading to an excess of α chains. Free α chains tend to aggregate into insoluble inclusions within erythrocytes and their precursors, leading to:
40 What is the difference between the three clinical types of β-thalassemia (thalassemia major, intermedia, and minor)?
α-Thalassemias are disorders caused by reduced synthesis (α⨥-thalassemias) or absent synthesis (α0-thalassemias) of α-globin chains. Because there are four α-globin genes (two on each member of the chromosome pair), there are many variations. The anemia stems both from lack of adequate hemoglobin and from the effects of excess unpaired non-α chains.
This is the only example of hemolytic anemia in which there is an acquired defect in the cell membrane. In PNH, the gene that is essential for the synthesis of the glycosyl-phosphatidyl-inositol (GPI) anchor is mutated. The absence of several GPI-linked membrane proteins renders blood cells unusually sensitive to lysis by endogenous complement. The somatic mutation affects pluripotent stem cells, and, accordingly, all their descendants (including platelets and granulocytes) are more sensitive to lysis by complement.
PNH affects young people, and the average age of onset is 20 to 25 years. Patients with PNH present with intravascular hemolysis, which (despite its name) is paroxysmal and nocturnal in only 25% of cases. Hemosiderinuria with loss of iron leads to iron deficiency. Patients may also suffer from multiple episodes of venous thrombosis involving the hepatic, portal, or cerebral veins. These episodes are fatal in 50% of cases. The disease can evolve into aplastic anemia or acute leukemia. Steroid treatment may stabilize the disease in more than 50% of cases, but many patients still die within 10 years of onset.
The Coombs antiglobulin test is the major tool for diagnosing this disease. It relies on the capacity of the antibodies prepared in animals against human globulins to agglutinate red cells if these globulins are present on red cell surfaces. The temperature dependence of the autoantibody also helps to specify the type of the antibody.
Megaloblastic anemias are characterized by impaired DNA synthesis and distinctive morphologic changes of affected RBC precursors and their descendants in the blood and bone marrow. It is a disease of older age, most commonly diagnosed in the fifth to eighth decade of life. Two main types are:
Humans are totally dependent on dietary animal products for their vitamin B12 requirement. Absorption of vitamin B12 requires intrinsic factor (IF), which is secreted by the parietal cells of the stomach along with hydrochloric acid. The vitamin is released from its protein-bound form by action of pepsin and then binds to salivary vitamin B12–binding proteins called cobalophilins, or R-binders. R–vitamin B12 complexes are broken down by pancreatic proteases in the duodenum. The released vitamin B12 then attaches to IF and goes to the ileum, where it adheres to IF-specific receptors on the ileal cells. Vitamin B12 enters the mucosal cells, which pass it on to transcobalamin II, a plasma transport protein.
Pernicious anemia is believed to result from immunologically mediated, possibly autoimmune, destruction of gastric mucosa. The resultant chronic atrophic gastritis is marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells, and nuclear changes in the mucosal cells similar to those found in the erythroid precursors. It is suspected that an autoreactive T cell response initiates gastric mucosal injury, which then triggers the formation of autoantibodies. These antibodies cause further injury to the epithelium, and after the mass of IF-secreting cells is significantly depleted (together with reserves of stored vitamin B12), anemia develops. Two processes aggravate anemia: