Pathology_Robbins

Pathology_Robbins. Deficiencies of Factor VIII–von Willebrand Factor Complex Complications of Transfusion Disorders of the Spleen and Thymus The hematopoietic and lymphoid systems are affected by a wide spectrum of diseases. One useful way to organize these disorders is based on whether they primarily affect red cells, white cells, or the coagulation system, which includes platelets and clotting factors. The most common red cell disorders are those that lead to anemia, a state of red cell deficiency. White cell disorders, by contrast, are most often associated with excessive proliferation resulting from malignant transformation. Derangements in blood coagulation may result in hemorrhagic diatheses (bleeding disorders). Finally, splenomegaly, a feature of numerous diseases, is discussed at the end of the chapter, as are tumors of the thymus.


Pathology_Robbins

Pathology_Robbins. Although these divisions are useful, in reality the production, function, and destruction of red cells, white cells, and components of the hemostatic system are closely linked, and derangements primarily affecting one cell type or component of the system often lead to alterations in others. For example, in certain conditions B cells make autoantibodies against components of the red cell membrane. The opsonized red cells are recognized and destroyed by phagocytes in the spleen, which becomes enlarged. The increased red cell destruction causes anemia, which in turn drives a compensatory hyperplasia of red cell progenitors in the bone marrow.


Pathology_Robbins

Pathology_Robbins. Other levels of interplay and complexity stem from the anatomically dispersed nature of the hematolymphoid system and the capacity of both normal and malignant white cells to “traffic” between various compartments. Hence, a patient who is diagnosed with lymphoma by lymph node biopsy also may be found to have neoplastic lymphoid cells in the bone marrow and blood. The malignant clone of lymphoid cells in the marrow may suppress hematopoiesis, giving rise to low blood cell counts (cytopenias), and the dissemination of tumor cells to the liver and spleen may lead to organomegaly. Thus, in both benign and malignant hematolymphoid disorders, a single underlying abnormality can result in diverse systemic manifestations. Keeping these complexities in mind, we will use the time-honored classification of hematolymphoid disorders based on predominant involvement of red cells, white cells, and the hemostatic system. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Disorders of red cells can result in anemia or, less commonly, polycythemia (an increase in red cells also known as erythrocytosis). Anemia is defined as a reduction in the oxygen-transporting capacity of blood, resulting from a decrease in the red cell mass to subnormal levels. Anemia can stem from bleeding, increased red cell destruction, or decreased red cell production. These mech anisms serve as one basis for classifying anemia (Table 12.1 ). In some entities overlap occurs, for example in thalassemia, wherebothreducedredcellproductionandearlydestruction contribute to anemia. With the exception of anemia caused by chronic renal failure or chronic inflammation (described Table 12.1 Classification of Anemia According to Underlying Mechanism Acute:traumaChronic:gastrointestinaltractlesions,gynecologicdisturbances MembraneabnormalitiesMembraneskeletonproteins:spherocytosis,elliptocytosisMembranelipids:abetalipoproteinemia


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Deficienthemesynthesis:irondeficiency,sideroblasticanemiasDeficientglobinsynthesis:thalassemiasMarrowreplacement:primaryhematopoieticneoplasms(acuteleukemia,myelodysplasticsyndromes)Marrowinfiltration(myelophthisicanemia):metastaticneoplasms,granulomatousdisease later), the decrease in tissue oxygen tension that accompanies anemia triggers increased production of the growth factor erythropoietin from specialized cells in the kidney. This in turn drives a compensatory hyperplasia of erythroid precursors in the bone marrow and, in severe anemia, the appearance of extramedullary hematopoiesis within the secondary hematopoietic organs (the liver, spleen, and lymph nodes). In well-nourished persons who become anemic because of acute bleeding or increased red cell destruction (hemolysis), the compensatory response can increase the production of red cells fivefold to eightfold. The rise in marrow output is signaled by the appearance of increased numbers of newly formed red cells


Pathology_Robbins

Pathology_Robbins. the compensatory response can increase the production of red cells fivefold to eightfold. The rise in marrow output is signaled by the appearance of increased numbers of newly formed red cells (reticulocytes) in the peripheral blood. By contrast, anemia caused by decreased red cell production (aregenerative anemia) is associated with subnormal reticulocyte counts (reticulocytopenia).


Pathology_Robbins

Pathology_Robbins. Anemia also can be classified on the basis of red cell morphology, which often points to particular causes. Features that provide etiologic clues include the size, color, and shape of the red cells. These are judged subjectively by visual inspection of peripheral smears and also are expressed quantitatively using the following indices: Mean cell volume (MCV): the average volume per red cell, expressed in femtoliters (cubic microns) Mean cell hemoglobin (MCH): the average mass of hemoglobin per red cell, expressed in picograms Mean cell hemoglobin concentration (MCHC): the average concentration of hemoglobin in a given volume of packed red cells, expressed in grams per deciliter Red cell distribution width (RDW): the coefficient of variation of red cell volume


Pathology_Robbins

Pathology_Robbins. Red cell distribution width (RDW): the coefficient of variation of red cell volume Red cell indices are directly measured or automatically calculated by specialized instruments in clinical laboratories. The same instruments also determine the reticulocyte count, a simple measure that distinguishes between hemolytic and aregenerative anemia. Adult reference ranges for these tests are shown in


Pathology_Robbins

Pathology_Robbins. Table 12.2 . Depending on the differential diagnosis, a number of other blood tests also may be performed to evaluate anemia, including (1) serum iron indices (iron levels, iron-binding capacity, transferrin saturation, and ferritin concentrations), which help distinguish among microcytic anemia caused by iron deficiency, chronic inflammation, and thalassemia; (2) plasma unconjugated bilirubin, haptoglobin, and lactate dehydrogenase levels, which are abnormal in hemolytic anemia; (3) serum and red cell folate and vitamin B12 concentrations, which are low in megaloblastic anemia; (4) hemoglobin electrophoresis, which is used to detect abnormal hemoglobin; and (5) the Coombs test, which is used to detect antibodies or complement bound to red cells in suspected cases of antibody-mediated hemolytic anemia. In isolated anemia, tests performed on the peripheral blood usually suffice to establish the cause. By contrast, when anemia occurs along with thrombocytopenia and/or granulocytopenia,


Pathology_Robbins

Pathology_Robbins. anemia. In isolated anemia, tests performed on the peripheral blood usually suffice to establish the cause. By contrast, when anemia occurs along with thrombocytopenia and/or granulocytopenia, it is much more likely to be associated with marrow aplasia or infiltration; in such instances a marrow examination usually is warranted.


Pathology_Robbins

Pathology_Robbins. As discussed later, the clinical consequences of anemia are determined by its severity, rapidity of onset, and underlying http://ebooksmedicine.net Table 12.2 Adult Reference Ranges for Red Blood Cells Hemoglobin(Hb)g/dL13.2–16.711.9–15.0 11.5–14.8 aReferencerangesvaryamonglaboratories.Thereferencerangesforthelaboratoryprovidingtheresultshouldalwaysbeusedininterpretingalaboratorytest.


Pathology_Robbins

Pathology_Robbins. pathogenic mechanism. If the onset is slow, the deficit in O2carrying capacity is compensated for by increases in cardiac output, respiratory rate, and red cell 2,3-diphosphoglycerate (DPG), a glycolytic pathway intermediate that enhances the release of O2 from hemoglobin. These adaptive changes mitigate the effects of mild to moderate anemia in otherwise healthy persons but are less effective in those with compromised pulmonary or cardiac function. Pallor, fatigue, and lassitude are common to all forms of anemia. Anemia caused by the premature destruction of red cells (hemolytic anemia) is associated with hyperbilirubinemia, jaundice, and pigment gallstones (if hemolysis is chronic), all related to increases in the turnover of hemoglobin. Anemia that stems from ineffective hematopoiesis (the premature death of marrow erythroid progenitors) is associated with inappropriate increases in iron absorption from the gut, which can lead to iron overload (secondary hemochromatosis) with


Pathology_Robbins

Pathology_Robbins. (the premature death of marrow erythroid progenitors) is associated with inappropriate increases in iron absorption from the gut, which can lead to iron overload (secondary hemochromatosis) with consequent damage to endocrine organs and the heart. If left untreated, a severe congenital anemia such as β-thalassemia major inevitably results in growth retardation, skeletal abnormalities, and cachexia.


Pathology_Robbins

Pathology_Robbins. Microcytic(irondeficiency,thalassemia) Normocyticbutwithabnormalshapes(hereditaryspherocytosis,sicklecelldisease) Acute: shortnessofbreath,organfailure,shock Pallor,fatigue,lassitude Withhemolysis:jaundiceandgallstones Withineffectiveerythropoiesis:ironoverload,heartandendocrinefailure Ifsevereandcongenital:growthretardation,bonedeformitiesduetoreactivemarrowhyperplasia ANEMIAOFBLOODLOSS:HEMORRHAGE


Pathology_Robbins

Pathology_Robbins. Withineffectiveerythropoiesis:ironoverload,heartandendocrinefailure Ifsevereandcongenital:growthretardation,bonedeformitiesduetoreactivemarrowhyperplasia ANEMIAOFBLOODLOSS:HEMORRHAGE Anemia of blood loss can be divided into anemia caused by acute bleeding (hemorrhage) and anemia caused by chronic blood loss (described later). The effects of acute bleeding are mainly due to the loss of intravascular volume, which if massive can lead to cardiovascular collapse, shock, and death. If blood loss exceeds 20% of blood volume, the immediate threat is hypovolemic shock rather than anemia. If the patient survives, hemodilution begins at once and achieves its full effect within 2 to 3 days; only then is the full extent of the red cell loss revealed. The anemia is normocytic and normochromic. Recovery from blood loss anemia is enhanced by a compensatory rise in the erythropoietin level, which stimulates increased red cell production and reticulocytosis within a period of 5 to 7 days.


Pathology_Robbins

Pathology_Robbins. With chronic blood loss, iron stores are gradually depleted. Iron is essential for hemoglobin synthesis and erythropoiesis, and its deficiency leads to a chronic anemia of underproduction. Iron deficiency anemia can occur in other clinical settings as well; it is described later along with other forms of anemia caused by decreased red cell production.


Pathology_Robbins

Pathology_Robbins. Hemolytic anemias are a diverse group of disorders that have as a common feature accelerated red cell destruction (hemolysis). By definition, the red cell life span is shortened to less than its normal 120 days, often markedly so. Regardless of cause, low tissue O2 levels trigger increased erythropoietin release from the kidney, which in turn stimulates the growth of erythroid elements and increased release of reticulocytes from the bone marrow. Thus, erythroid hyperplasia and reticulocytosis are hallmarks of all hemolytic anemias. In severe hemolytic anemias, the erythropoietic drive may be so pronounced that extramedullary hematopoiesis appears in the liver, spleen, and lymph nodes. There are several ways to organize hemolytic anemias. One approach groups them according to whether the pathogenic red cell defect is intrinsic (intracorpuscular) or extrinsic (extracorpuscular) (see


Pathology_Robbins

Pathology_Robbins. Table 12.1 ). A second more clinically useful approach groups hemolytic anemias according to whether hemolysis is primarily extravascular or intravascular. Extravascular hemolysis is caused by defects that increase the destruction of red cells by phagocytes, particularly in the spleen. The spleen contains large numbers of macrophages, the principal cell responsible for the removal of damaged or antibody-coated red cells from the circulation. Because extreme alterations of shape are necessary for red cells to navigate the splenic sinusoids, any reduction in red cell deformability makes this passage difficult, and red cells that become “stuck” are recognized and phagocytosed by resident splenic macrophages. As described later in the chapter, diminished deformability is a major cause of red cell destruction in several hemolytic anemias. Findings that are relatively specific for extravascular hemolysis http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 12.1 Pathogenesis of hereditary spherocytosis. (Left panel) Normal organization of the major red cell membrane skeleton proteins. Mutations in α-spectrin, β-spectrin, ankyrin, band 4.2, and band 3 that weaken the association of the membrane skeleton with the overlying plasma membrane cause red cells to shed membrane vesicles and transform into spherocytes (right panel). The nondeformable spherocytes are trapped in the splenic cords and phagocytosed by macrophages. GP, Glycophorin. (as compared to intravascular hemolysis) include the following: Hyperbilirubinemia and jaundice, stemming from degradation of hemoglobin in macrophages Varying degrees of splenomegaly due to “work hyperplasia” of phagocytes in the spleen If long-standing, formation of bilirubin-rich gallstones (pigment stones) and an increased risk of cholelithiasis


Pathology_Robbins

Pathology_Robbins. If long-standing, formation of bilirubin-rich gallstones (pigment stones) and an increased risk of cholelithiasis Intravascular hemolysis, by contrast, is characterized by injuries so severe that red cells literally burst within the circulation. Intravascular hemolysis may result from mechanical forces (e.g., turbulence created by a defective heart valve) or biochemical or physical agents that severely damage the red cell membrane (e.g., fixation of complement, or exposure to clostridial toxins or heat). Findings that distinguish intravascular hemolysis from extravascular hemolysis include the presence of the following: Hemoglobinemia, hemoglobinuria, and hemosiderinuria. Hemoglobin released into the circulation is small enough to pass into the urinary space. Here, it is partially resorbed by renal tubular cells and processed into hemosiderin, which is then lost in the urine when renal tubular cells are sloughed.


Pathology_Robbins

Pathology_Robbins. Loss of iron, which may lead to iron deficiency if hemolysis is persistent. By contrast, iron recycling by phagocytes is very efficient, and so iron deficiency is not a feature of extravascular hemolytic anemias. A final feature of both intravascular and extravascular hemolysis is decreased serum levels of haptoglobin, a plasma protein that binds free hemoglobin and is then removed from the circulation. Apparently macrophages “regurgitate” sufficient hemoglobin during consumption of red cells to cause haptoglobin levels to fall, even when hemolysis is entirely extravascular. We now turn to some of the common hemolytic anemias.


Pathology_Robbins

Pathology_Robbins. We now turn to some of the common hemolytic anemias. This disorder stems from inherited (intrinsic) defects in the red cell membrane that lead to the formation of spherocytes, nondeformable cells that are highly vulnerable to sequestration and destruction in the spleen. Hereditary spherocytosis is usually transmitted as an autosomal dominant trait; a more severe, autosomal recessive form of the disease affects a small minority of patients. Hereditary spherocytosis is caused by inherited defects in the membrane skeleton, a network of proteins that stabilizes the lipid bilayer of the red cell ( Fig. 12.1 ). The major membrane skeleton protein is spectrin, a long, flexible heterodimer that self-associates at one end and binds short actin filaments at its other end. These contacts create a two-dimensional meshwork that is connected to the transmembrane proteins band 3 and glycophorin via the linker proteins ankyrin, band 4.2, and band 4.1.


Pathology_Robbins

Pathology_Robbins. Mutations that cause hereditary spherocytosis most frequently involve ankyrin, band 3, or spectrin. The common feature of the pathogenic mutations is that they weaken vertical interactions between the membrane skeleton and intrinsic red cell membrane proteins. This defect destabilizes the lipid bilayer of red cells, which shed membrane vesicles into the circulation as they age. Little cytoplasm is lost in the process and as a result the surface area-tovolume ratio decreases progressively with time until the cells become spherical ( Fig. 12.1


Pathology_Robbins

Pathology_Robbins. Fig. 12.1 The critical role of the spleen in hereditary spherocytosis is illustrated by the beneficial effect of splenectomy; although the red cell defect and spherocytes persist, the anemia is corrected. Red cells must undergo extreme degrees of deformation to pass through the splenic cords. The floppy discoid shape of normal red cells allows considerable latitude for shape changes. By contrast, spherocytes have limited deformability and are sequestered in the splenic cords, where they are destroyed by the plentiful resident macrophages. On smears, spherocytes are dark red and lack central pallor


Pathology_Robbins

Pathology_Robbins. On smears, spherocytes are dark red and lack central pallor Fig. 12.2 ). The excessive red cell destruction and resultant genitors in the marrow and an increase in red cell production markedbyreticulocytosis.Splenomegaly ismorecommonandprominentinhereditaryspherocytosisthaninanyotherformofhemolyticanemia.Thesplenicweightusuallyisbetween500and1000g.Theenlargementresultsfrommarkedcongestionofthespleniccordsandincreasesinthenumbersofmacrophages.Phagocytosedredcellsareseenwithinmacrophagesliningthesinusoidsand,inparticular,withinthecords.Theothergeneralfeaturesofhemolyticanemiaalsoarepresent,includingcholelithiasis, whichoccursin40%to50%ofpatientswithhereditaryspherocytosis.


Pathology_Robbins

Pathology_Robbins. Fig. 12.2 Hereditaryspherocytosis—peripheralbloodsmear.Notetheanisocytosisandseveralhyperchromicspherocytes.Howell-Jollybodies(smallnuclearremnants)arealsopresentintheredcellsofthisasplenicpatient.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School,Dallas,Texas.) Clinical Features. The characteristic features are anemia, splenomegaly, and jaundice. The anemia is variable in severity, ranging from subclinical to profound; most commonly it is moderate in degree. Because of their spherical shape, red cells in hereditary spherocytosis show increased osmotic fragility when placed in hypotonic salt solutions, a characteristic that can help establish the diagnosis.


Pathology_Robbins

Pathology_Robbins. The course is generally stable but may be punctuated by aplastic crises, the most severe of which are triggered by parvovirus B19 infection. This virus has a marked tropism for erythroblasts, which undergo apoptosis during viral replication. Until the immune response controls the infection (usually in 10–14 days), the marrow may be virtually devoid of red cell progenitors. Because of the shortened life span of red cells in hereditary spherocytosis, a lack of red cell production, even for a few days, results in rapid worsening of the anemia. Blood transfusions may be needed to support patients until the infection is cleared.


Pathology_Robbins

Pathology_Robbins. There is no specific treatment. Splenectomy improves the anemia by removing the major site of red cell destruction. The benefits of splenectomy must be weighed against the increased risk of serious bacterial infections, particularly in children. Partial splenectomy is gaining favor in children because this approach produces hematologic improvement while maintaining protection against sepsis. The downside is that because the partially resected spleen eventually regains its size, many patients will need a second resection. The hope is that this can be delayed until adulthood, when the risk of serious infection is lower.


Pathology_Robbins

Pathology_Robbins. The hope is that this can be delayed until adulthood, when the risk of serious infection is lower. Hemoglobinopathies are a group of hereditary disorders caused by inherited mutations that lead to structural abnormalities in hemoglobin. Sickle cell anemia, the prototypic hemoglobinopathy, is caused by a mutation in β-globin that creates sickle hemoglobin (HbS). Numerous other hemoglobinopathies have been described, but these are infrequent and beyond the scope of this discussion. Sickle cell anemia is the most common familial hemolytic anemia. In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a protective effect against Plasmodium falciparum malaria. In the United States, approximately 8% of blacks are heterozygous HbS carriers and about 1 in 600 have sickle cell anemia.


Pathology_Robbins

Pathology_Robbins. Sickle cell anemia is caused by a single amino acid substitution in β-globin that results in a tendency for deoxygenated HbS to self-associate into polymers. Normal hemoglobins are tetramers composed of two pairs of similar chains. On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2). In patients with sickle cell anemia, HbA is completely replaced by HbS, whereas in heterozygous carriers, only about half is replaced. HbS differs from HbA by having a valine residue instead of a glutamate residue at the 6th amino acid position in β-globin. On deoxygenation HbS molecules undergo a conformational change that allows polymers to form via intermolecular contacts involving the abnormal valine residue. These polymers distort the red cell, which assumes an elongated crescentic, or sickle, shape ( Fig. 12.3


Pathology_Robbins

Pathology_Robbins. Fig. 12.3 The sickling of red cells initially is reversible on reoxygenation. However, membrane distortion produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water and also damages the membrane skeleton. With time, this cumulative damage creates irreversibly sickled cells that rapidly undergo hemolysis.


Pathology_Robbins

Pathology_Robbins. Three factors are particularly important in determining whether clinically significant polymerization of HbS occurs in patients: • The intracellular levels of hemoglobins other than HbS. In heterozygotes approximately 40% of Hb is HbS and the remainder is HbA, which interacts only weakly with deoxygenated HbS. Because HbA greatly retards HbS polymerization, the red cells of HbS heterozygotes have little tendency to sickle in vivo. Such persons are said to have sickle cell trait. Similarly, because fetal hemoglobin (HbF) interacts weakly with HbS, newborns with sickle cell anemia do not manifest the disease until HbF falls to adult levels, generally around the age of 5 to 6 months. Hemoglobin C (HbC), another mutant β-globin, has a lysine residue instead of the normal glutamic acid residue at position 6. About 2.3% of American blacks are heterozygous carriers of HbC and about 1 in 1250 newborns are compound HbC/HbS heterozygotes. HbC has a greater tendency to aggregate with HbS than


Pathology_Robbins

Pathology_Robbins. at position 6. About 2.3% of American blacks are heterozygous carriers of HbC and about 1 in 1250 newborns are compound HbC/HbS heterozygotes. HbC has a greater tendency to aggregate with HbS than does HbA, and as a result HbS/HbC compound heterozygotes have a symptomatic sickling disorder called HbSC disease.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 12.3 Sicklecellanemia—peripheralbloodsmear.(A)Lowmagnificationshowssicklecells,anisocytosis,poikilocytosis,andtargetcells.(B)Highermagnificationshowsanirreversiblysickledcellinthecenter.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) The intracellular concentration of HbS. The polymerization of deoxygenated HbS is strongly concentration-dependent. Thus, red cell dehydration, which increases the Hb concentration, facilitates sickling. Conversely, the coexistence of α-thalassemia (described later), which decreases the Hb concentration, reduces sickling.


Pathology_Robbins

Pathology_Robbins. The time required for red cells to pass through the microvasculature. The normal transit times of red cells through capillary beds are too short for significant polymerization of deoxygenated HbS to occur. Hence, the tissues that are most susceptible to obstruction by sickling are those in which blood flow is normally sluggish, such as the spleen and the bone marrow. However, sickling may occur in other microvascular beds in the face of factors that retard the passage of red cells, particularly inflammation. Recall that inflammation slows blood flow by increasing the adhesion of leukocytes and red cells to endothelium and by inducing the exudation of fluid through leaky vessels (Chapter 4). In addition, sickle red cells have a greater tendency than normal red cells to adhere to endothelial cells, apparently because repeated bouts of sickling cause membrane damage that makes the red cells sticky. These factors conspire to prolong the transit times of sickle red cells, increasing the


Pathology_Robbins

Pathology_Robbins. cells, apparently because repeated bouts of sickling cause membrane damage that makes the red cells sticky. These factors conspire to prolong the transit times of sickle red cells, increasing the probability of clinically significant sickling.


Pathology_Robbins

Pathology_Robbins. The sickling of red cells has two major pathologic consequences: chronic moderately severe hemolytic anemia, produced by red cell membrane damage, and vascular obstructions, which result in ischemic tissue damage and pain crises ( Fig. 12.4 ). The mean life span of red cells in sickle cell anemia averages only 20 days (one-sixth of normal), and the severity of the hemolysis correlates with the fraction of irreversibly sickled cells that are present in the blood. Vasoocclusion, by contrast, does not correlate with the number of irreversibly sickled cells and instead appears to result from superimposed factors such as infection, inflammation, dehydration, and acidosis, all of which enhance the tendency of red cells to sickle within the microvasculature.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Inchildrenthereismoderatesplenomegaly (splenicweightupto500g)duetoredpulpcongestioncausedbyentrapmentofsickledredcells.However,chronicsplenicerythrostasisproduceshypoxicdamageandinfarcts,whichwithtimereducethespleentoauselessnubbinoffibroustissue.Thisprocess,referredtoasautosplenectomy, iscompletebyadulthood. Vascular congestion, thrombosis, and infarction canaffectanyorgan,includingthebones,liver,kidney,retina,brain,lung,andskin.Thebonemarrowisparticularlypronetoischemiabecauseofitssluggishbloodflowandhighrateofmetabolism.Priapism,anotherfrequentproblem,canleadtopenilefibrosisanderectiledysfunction.Aswiththeotherhemolyticanemias,hemosiderosis andpigment gallstones arecommon.


Pathology_Robbins

Pathology_Robbins. Clinical Features. From its onset, the disease runs an unremitting course punctuated by sudden crises. Homozygous sickle cell disease usually is asymptomatic until 6 months of age when the shift from HbF to HbS is complete. The anemia is moderate to severe; most patients have hematocrits of 18% to 30% (normal range, 38%–48%). The http://ebooksmedicine.net Oxygenation Additional cycles of deoxygenation Ca2+ K+, H2O Irreversibly sickled cell Cell with dehydration and membrane damage Extensive membrane damage Deoxygenation, prolonged transit times Reversibly Fig. 12.4 Pathophysiologyofsicklecelldisease. chronic hemolysis is associated with hyperbilirubinemia and compensatory reticulocytosis. Much more serious are vasoocclusive crises, which are characteristically associated with pain and often lead to tissue damage and significant morbidity and mortality. Among the most common and serious of these vasoocclusive crises are the following:


Pathology_Robbins

Pathology_Robbins. Hand-foot syndrome, resulting from infarction of bones in the hands and feet, is the most common presenting symptom in young children. Acute chest syndrome, in which sluggish blood flow in inflamed lung (e.g., an area of pneumonia) leads to sickling within hypoxemic pulmonary beds. This exacerbates pulmonary dysfunction, creating a vicious circle of worsening pulmonary and systemic hypoxemia, sickling, and vasoocclusion. Acute chest syndrome may also be triggered by fat emboli emanating from infarcted bone. Stroke, which sometimes occurs in the setting of the acute chest syndrome. Stroke and the acute chest syndrome are the two leading causes of ischemia-related death. Proliferative retinopathy, a consequence of vasoocclusions in the eye that can lead to loss of visual acuity and blindness.


Pathology_Robbins

Pathology_Robbins. Proliferative retinopathy, a consequence of vasoocclusions in the eye that can lead to loss of visual acuity and blindness. Another acute event, aplastic crisis, is caused by a sudden decrease in red cell production. As in hereditary spherocytosis, this usually is triggered by the infection of erythroblasts by parvovirus B19 and, although severe, is self-limited.


Pathology_Robbins

Pathology_Robbins. In addition to these crises, patients with sickle cell disease are prone to infections. Both children and adults with sickle cell disease are functionally asplenic, making them susceptible to infections caused by encapsulated bacteria, such as pneumococci. In adults the basis for “hyposplenism” is autoinfarction. In the earlier childhood phase of splenic enlargement, congestion caused by trapped sickled red cells apparently interferes with bacterial sequestration and killing; hence, even children with enlarged spleens are at risk for the development of fatal septicemia. Patients with sickle cell disease also are predisposed to Salmonella osteomyelitis, possibly in part because of poorly understood acquired defects in complement function.


Pathology_Robbins

Pathology_Robbins. In homozygous sickle cell disease, irreversibly sickled red cells are seen in routine peripheral blood smears. In sickle cell trait, sickling can be induced in vitro by exposing cells to marked hypoxia. The diagnosis is confirmed by electrophoretic demonstration of HbS. Prenatal diagnosis of sickle cell anemia can be performed by analyzing fetal DNA obtained by amniocentesis or biopsy of chorionic villi. The clinical course of sickle cell disease is highly variable. As a result of improvements in supportive care, an increasing number of patients are surviving into adulthood. Approximately 50% of patients now survive beyond the fifth decade. Of particular importance is prophylactic treatment with penicillin to prevent pneumococcal infections, especially in children younger than age 5.


Pathology_Robbins

Pathology_Robbins. A mainstay of therapy is hydroxyurea, a “gentle” inhibitor of DNA synthesis. Hydroxyurea reduces pain crises and lessens the anemia through several effects, including (1) an increase in levels of HbF; (2) an anti-inflammatory effect because of the inhibition of white cell production; (3) an increase in red cell size, which lowers the intracellular hemoglobin concentration; and (4) its metabolism to NO, a potent vasodilator and inhibitor of platelet aggregation. Encouraging results also have been obtained with allogeneic bone marrow transplantation, which is potentially curative.


Pathology_Robbins

Pathology_Robbins. Thalassemias are inherited disorders caused by mutations in globin genes that decrease the synthesis of α-or β-globin. Decreased synthesis of one globin results not only in a deficiency of Hb, but also in red cell damage that is caused by precipitates formed from excess unpaired “normal” globin chains. The mutations that cause thalassemia are particularly common in Mediterranean, African, and Asian regions in which malaria is endemic. As with HbS, it is hypothesized that globin mutations associated with thalassemia protect against falciparum malaria. A diverse collection of α-globin and β-globin mutations underlies the thalassemias, which are autosomal codominant conditions. As described previously, adult hemoglobin, or HbA, is a tetramer composed of two α chains and two β chains. The α chains are encoded by two α-globin http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Table 12.3 Clinical and Genetic Classification of Thalassemias genes lying in tandem on chromosome 16, whereas the β chains are encoded by a single β-globin gene located on chromosome 11. The clinical features vary widely depending on the specific combination of mutated alleles that are inherited by the patient ( Table 12.3), as described next.


Pathology_Robbins

Pathology_Robbins. Table 12.3), as described next. Mutations associated with β-thalassemia fall into two categories: (1) β0, in which no β-globin chains are produced; and (2) β+ , in which there is reduced (but detectable) β-globin synthesis. Sequencing of β-thalassemia genes has shown more than 100 different causative mutations, a majority consisting of single-base changes. Persons inheriting one abnormal allele have β-thalassemia minor (also known as β-thalassemia trait), which is asymptomatic or mildly symptomatic. Most people inheriting any two β0 and β+ alleles have β-thalassemia major; occasionally, persons inheriting at least one β+ allele have a milder disease termed β-thalassemia intermedia. In contrast with α-thalassemia (described later), gene deletions rarely underlie β-thalassemia ( Table 12.3


Pathology_Robbins

Pathology_Robbins. Table 12.3 The mutations responsible for β-thalassemia are diverse and disrupt β-globin synthesis in several different ways. The most common mutations lead to abnormal RNA splicing, whereas others fall in the β-globin gene promoter or coding regions. The specific nature of the mutation determines whether the outcome is a β+ or β0 allele. Defective synthesis of β-globin in β-thalassemia contributes to anemia through two mechanisms: (1) inadequate HbA formation, resulting in small (microcytic), poorly hemoglobinized (hypochromic) red cells; and (2) by allowing the accumulation of unpaired α-globin chains, which form toxic precipitates that severely damage the membranes of red cells and erythroid precursors. A high fraction of erythroid precursors are so badly damaged that they die by apoptosis (


Pathology_Robbins

Pathology_Robbins. Fig. 12.5 ), a phenomenon termed ineffective erythropoiesis, and the few red cells that are produced have a shortened life span. Ineffective hematopoiesis has another untoward effect; it is associated with an inappropriate increase in the absorption of dietary iron, which without medical intervention inevitably leads to iron overload. The increased iron absorption is caused by inappropriately low hepcidin, which is a negative regulator of iron absorption (see later). Unlike β-thalassemia, α-thalassemia is caused mainly by deletions involving one or more of the α-globin genes. The severity of the disease is proportional to the number of α-globin genes that are deleted (


Pathology_Robbins

Pathology_Robbins. Table 12.3 ). For example, loss of a single α-globin gene produces a silent-carrier state, whereas deletion of all four α-globin genes is lethal in utero because the red cells have virtually no oxygen-delivering capacity. With loss of three α-globin genes there is a relative excess of β-globin or (early in life) γ-globin chains. Excess β-globin and γ-globin chains form relatively stable β4 and γ4 tetramers known as HbH and Hb Bart, respectively, which cause less membrane damage than the free α-globin chains that are found in β-thalassemia; as a result, ineffective erythropoiesis is less pronounced in α-thalassemia. Unfortunately, both HbH and Hb Bart have an abnormally high affinity for oxygen, which renders them ineffective at delivering oxygen to the tissues.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYArangeofmorphologiesisseen,dependingonthespecificunderlyingmolecularlesion.Ononeendofthespectrumisβ-thalassemiaminorandα-thalassemiatrait,inwhichabnormalitiesareconfinedtotheperipheralblood.Insmearstheredcellsaresmall(microcytic)andpale(hypochromic),butregularinshape.Oftenseenaretarget cells, cellswithanincreasedsurfacearea-to-volumeratiothatallowsthecytoplasmtocollectinacentral,dark-red“puddle.”Ontheotherendofthespectrum,inβ-thalassemiamajorperipheralbloodsmearsshowmarkedmicrocytosis, hypochromia, poikilocytosis (variationincellshape),andanisocytosis (variationincellsize).Nucleatedredcells(normoblasts)arealsoseenthatreflecttheunderlyingerythropoieticdrive.β-Thalassemiaintermediaand http://ebooksmedicine.net Reduced °-globin synthesis, with relative excess of ˜-globin Insoluble ˜-globin aggregateHbA Destruction of aggregate-containing red cells in spleen


Pathology_Robbins

Pathology_Robbins. Reduced °-globin synthesis, with relative excess of ˜-globin Insoluble ˜-globin aggregateHbA Destruction of aggregate-containing red cells in spleen Fig. 12.5 Pathogenesis of β-thalassemia major. Note that aggregates of excess α-globin are not visible on routine blood smears. Blood transfusions constitute a double-edged sword, diminishing the anemia and its attendant complications but also adding to the systemic iron overload. HbH disease are associated with peripheral smear findings that lie between these two extremes.


Pathology_Robbins

Pathology_Robbins. The anatomic changes in β-thalassemia major are similar in kind to those seen in other hemolytic anemias but are profound in degree. Ineffective erythropoiesis and hemolysis result in a striking hyperplasia of erythroid progenitors, with a shift toward early forms. The expanded erythropoietic marrow may completely fill the intramedullary space of the skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities. Extramedullary hematopoiesis and hyperplasia of mononuclear phagocytes result in prominent splenomegaly, hepatomegaly, and lymphadenopathy. The ineffective erythropoietic precursors consume nutrients and produce growth retardation and a degree of cachexia reminiscent of that seen in cancer patients. Unless steps are taken to prevent iron overload, during the span of years severe hemosiderosis develops (Fig. 12.5


Pathology_Robbins

Pathology_Robbins. develops (Fig. 12.5 ). HbH disease and β-thalassemia intermedia are also associated with splenomegaly, erythroid hyperplasia, and growth retardation related to anemia, but these are less severe than in β-thalassemia major.


Pathology_Robbins

Pathology_Robbins. Clinical Features. β-Thalassemia trait and α-thalassemia trait are typically asymptomatic. There is usually only a mild microcytic hypochromic anemia; generally, these patients have a normal life expectancy. Iron deficiency anemia is associated with a similar red cell appearance and must be excluded by appropriate laboratory tests (described later).


Pathology_Robbins

Pathology_Robbins. β-Thalassemia major manifests postnatally as HbF synthesis diminishes. Affected children suffer from growth retardation that commences in infancy. They are sustained by blood transfusions, which improve the anemia and reduce the skeletal deformities associated with excessive erythropoiesis. With transfusions alone, survival into the second or third decade is possible, but systemic iron overload gradually develops owing to inappropriate uptake of iron from the gut and the iron load in transfused red cells. Unless patients are treated aggressively with iron chelators, cardiac dysfunction from secondary hemochromatosis inevitably develops and often is fatal in the second or third decade of life. When feasible, hematopoietic stem cell transplantation at an early age is the treatment of choice. HbH disease and β-thalassemia intermedia are not as severe as β-thalassemia major, because the imbalance in α-and β-globin chain synthesis is not as great and hematopoiesis is more effective. Anemia


Pathology_Robbins

Pathology_Robbins. HbH disease and β-thalassemia intermedia are not as severe as β-thalassemia major, because the imbalance in α-and β-globin chain synthesis is not as great and hematopoiesis is more effective. Anemia is of moderate severity and patients usually do not require transfusions. Thus, the iron overload that is so common in β-thalassemia major is rarely seen.


Pathology_Robbins

Pathology_Robbins. The diagnosis of β-thalassemia major can be strongly suspected on clinical grounds. Hb electrophoresis shows a profound reduction or absence of HbA and increased levels of HbF. The HbA2 level may be normal or increased. Similar but less severe changes are noted in patients affected by β-thalassemia intermedia. Prenatal diagnosis of β-thalassemia is challenging, but can be made in specialized centers by DNA analysis. In fact, thalassemia was the first disease diagnosed by DNA-based tests, opening the way for the field of molecular diagnostics. The diagnosis of β-thalassemia minor is made by Hb electrophoresis, which typically shows a reduced level of HbA (α2β2) and an increased level of HbA2 (α2δ2). HbH disease can be diagnosed by detection of β4 tetramers by electrophoresis.


Pathology_Robbins

Pathology_Robbins. Red cells are constantly exposed to both endogenous and exogenous oxidants, which are normally inactivated by reduced glutathione (GSH). Abnormalities affecting enzymes responsible for the synthesis of GSH leave red cells vulnerable to oxidative injury and hemolysis. By far the most common of these conditions is glucose-6-phosphate dehydrogenase (G6PD) deficiency. The G6PD gene is on the X chromosome. More than 400 G6PD variants have been identified, but only a few are associated with disease. One is G6PD A− , which is carried by approximately 10% of black males in the United States. G6PD A− has a normal enzymatic activity but a decreased half-life. Because red cells do not synthesize proteins, older G6PD A− red cells become progressively deficient in enzyme activity and GSH. This in turn renders older red cells more sensitive to oxidant damage.


Pathology_Robbins

Pathology_Robbins. G6PD deficiency is associated with transient episodes of intravascular hemolysis caused by exposure to an environmental factor (usually infectious agents or drugs) that produces oxidant stress. Incriminated drugs include antimalarials (e.g., primaquine), sulfonamides, nitrofurantoin, phenacetin, aspirin (in large doses), and vitamin K derivatives. More commonly episodes of hemolysis are triggered by infection, which induce phagocytes to generate oxidants as part of the host response. These oxidants, such as hydrogen peroxide, are normally sopped up by GSH, which is converted to oxidized GSH in the process. Because regeneration of GSH is impaired in G6PD-deficient cells, oxidants are free to “attack” other red cell components including globin chains. Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions called Heinz bodies, which can damage the red cell membrane so severely that intravascular hemolysis results. Other cells with lesser damage lose their


Pathology_Robbins

Pathology_Robbins. precipitates, forming intracellular inclusions called Heinz bodies, which can damage the red cell membrane so severely that intravascular hemolysis results. Other cells with lesser damage lose their deformability and suffer further injury when splenic phagocytes attempt to “pluck out” the Heinz bodies, creating bite cells (


Pathology_Robbins

Pathology_Robbins. Fig. 12.6 ). Such cells become trapped on recirculation to the spleen and are destroyed by phagocytes (extravascular hemolysis). Fig. 12.6 Glucose-6-phosphatedehydrogenasedeficiencyafteroxidantdrugexposure—peripheralbloodsmear.(Inset)Redcellswithprecipitatesofdenaturedglobin(Heinzbodies)shownbysupravitalstaining.Asthesplenicmacrophagespluckouttheseinclusions,“bitecells”similartotheoneinthissmearareproduced.(Courtesy of Dr. Robert W. McKenna, Depart-ment of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)


Pathology_Robbins

Pathology_Robbins. Clinical Features. Hemolysis typically develops 2 or 3 days after drug exposure and is of variable severity. Because G6PD is X-linked, the red cells of affected males are uniformly deficient and vulnerable to oxidant injury. By contrast, random inactivation of one X chromosome in heterozygous females (Chapter 7) creates two populations of red cells, one normal and the other G6PD-deficient. Most carrier females are unaffected except for those with a large proportion of deficient red cells (a chance situation known as unfavorable lyonization). In the case of the G6PD A− variant, it is mainly older red cells that are susceptible to lysis. Because the marrow compensates for the anemia by increasing its production of new red cells with adequate levels of G6PD, the hemolysis abates even if the drug exposure continues. In other variants such as G6PD Mediterranean, found mainly in the Middle East, the enzyme deficiency and the hemolysis that occur on exposure to oxidants are more severe.


Pathology_Robbins

Pathology_Robbins. Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia that stems from acquired mutations in PIGA, a gene required for the synthesis of phosphatidylinositol glycan (PIG), which serves as a membrane anchor for many proteins. Because PIGA is X-linked, normal cells have only one active PIGA gene, a mutation of which is sufficient to cause PIGA deficiency. The pathogenic mutations in PNH occur in an early hematopoietic progenitor that is capable of giving rise to red cells, leukocytes, and platelets. Progeny of the PIGA-mutated clone lack the ability to make “PIG-tailed” proteins, including several that limit the activity of complement; as a result, red cells derived from PIGA-deficient precursors are inordinately sensitive to lysis by the complement C5b-C9 membrane attack complex. Leukocytes share the same deficiency but are less sensitive to complement than are red cells, and so red cells take the brunt of the attack. The nocturnal hemolysis that gives PNH its name occurs


Pathology_Robbins

Pathology_Robbins. Leukocytes share the same deficiency but are less sensitive to complement than are red cells, and so red cells take the brunt of the attack. The nocturnal hemolysis that gives PNH its name occurs because complement fixation is enhanced by the decrease in blood pH that accompanies sleep (owing to CO2 retention). However, most patients present less dramatically with anemia and iron deficiency resulting from chronic intravascular hemolysis.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The most feared complication of PNH is thrombosis, which often occurs within abdominal vessels such as the portal vein and the hepatic vein. The prothrombotic state also is somehow related to excessive complement activity, as Eculizimab, an antibody that binds C5 and inhibits the assembly of the C5b–C9 membrane attack complex, greatly lessens the incidence of thrombosis as well as the degree of intravascular hemolysis. Eculizimab has no effect on early stages of complement fixation, and treated patients continue to have varying degrees of extravascular hemolysis because of the deposition of C3b on red cell surfaces. Loss of C5b-C9 activity in patients receiving Eculizimab poses a risk for Neisseria infections, particularly meningococcal sepsis; thus, all treated patients must be vaccinated against N. meningococcus.


Pathology_Robbins

Pathology_Robbins. N. meningococcus. Immunohemolytic anemia is caused by antibodies that bind to determinants on red cell membranes. These antibodies may arise spontaneously or be induced by exogenous agents such as drugs or chemicals. Immunohemolytic anemia is uncommon and is classified based on (1) the nature of the antibody and (2) the presence of predisposing conditions (summarized in Table 12.4 The diagnosis depends on the detection of antibodies and/or complement on red cells. This is done with the direct Coombs test, in which the patient’s red cells are incubated with antibodies against human immunoglobulin or complement. In a positive test result, these antibodies cause the patient’s red cells to clump (agglutinate). The indirect Coombs test, which assesses the ability of the patient’s serum to agglutinate test red cells bearing defined surface determinants, can then be used to characterize the target of the antibody.


Pathology_Robbins

Pathology_Robbins. In this entity, hemolysis results from the binding of high-affinity autoantibodies to red cells, which are then removed from the circulation by phagocytes in the Table 12.4 Classification of Immunohemolytic Anemias Secondary:Bcellneoplasms(e.g.,chroniclymphocyticleukemia),autoimmunedisorders(e.g.,systemiclupuserythematosus),drugs(e.g.,α-methyldopa,penicillin,quinidine) Acute: Mycoplasma infection,infectiousmononucleosis


Pathology_Robbins

Pathology_Robbins. Acute: Mycoplasma infection,infectiousmononucleosis Chronic:idiopathic,Bcelllymphoidneoplasms(e.g.,lymphoplasmacyticlymphoma) spleen and elsewhere. In addition to frank erythrophagocytosis, incomplete consumption (“nibbling”) of antibody-coated red cells by macrophages removes membrane and transforms red cells into spherocytes, which are rapidly destroyed in the spleen, just as in hereditary spherocytosis (described earlier). Warm antibody immunohemolytic anemia is caused by immunoglobulin G (IgG) or (rarely) IgA antibodies that are active at 37°C. More than 60% of cases are idiopathic (primary), whereas another 25% are secondary to an underlying immunologic disorder (e.g., systemic lupus erythematosus) or are induced by drugs. The clinical severity is variable, but most patients have chronic mild anemia and moderate splenomegaly and require no treatment.


Pathology_Robbins

Pathology_Robbins. The mechanisms of hemolysis induced by drugs are varied and in some instances poorly understood. Drugs such as α-methyldopa induce autoantibodies against intrinsic red cell constituents, in particular Rh blood group antigens. Presumably, the drug somehow alters the immunogenicity of native epitopes and thereby circumvents T cell tolerance (Chapter 5). Other drugs such as penicillin act as haptens, which induce an antibody response by binding covalently to red cell membrane proteins. Sometimes antibodies recognize a drug in the circulation and form immune complexes that are deposited on red cells. Here they may fix complement or act as opsonins, either of which can lead to hemolysis.


Pathology_Robbins

Pathology_Robbins. Cold antibody immunohemolytic anemia usually is caused by low-affinity IgM antibodies that bind to red cell membranes only at temperatures below 30°C, such as occur in distal parts of the body (e.g., ears, hands, and toes) in cold weather. Although bound IgM fixes complement, the latter steps of the complement cascade occur inefficiently at temperatures lower than 37°C. As a result, most cells with bound IgM pick up some C3b but are not lysed intravascularly. When these cells travel to warmer areas, the weakly bound IgM antibody is released, but the coating of C3b remains. Because C3b is an opsonin (Chapter 2), the cells are phagocytosed by macrophages, mainly in the spleen and liver; hence, in most cases the hemolysis is mainly extravascular. Binding of pentavalent IgM also crosslinks red cells and causes them to clump (agglutinate). Sludging of blood in capillaries because of agglutination often produces Raynaud phenomenon in the extremities of affected individuals. Cold agglutinins


Pathology_Robbins

Pathology_Robbins. cells and causes them to clump (agglutinate). Sludging of blood in capillaries because of agglutination often produces Raynaud phenomenon in the extremities of affected individuals. Cold agglutinins sometimes also appear transiently during recovery from pneumonia caused by Mycoplasma spp. and infectious mononucleosis, producing a mild anemia of little clinical importance. More important, chronic forms of cold agglutinin hemolytic anemia occur in association with certain B cell neoplasms or as an idiopathic condition.


Pathology_Robbins

Pathology_Robbins. Hemolysis of red cells due to their exposure to abnormal mechanical forces occurs in two major settings. Clinically significant traumatic hemolysis is sometimes produced by defective cardiac valve prostheses, which may create sufficiently turbulent blood flow to shear red cells (the blender effect). More commonly, it occurs incidentally during an activity involving repeated physical pounding of one or more body parts (e.g., marathon racing, karate chopping, bongo drumming). Microangiopathic hemolytic anemia is observed in pathologic states in which small vessels become partially obstructed or narrowed by lesions that predispose passing red cells to mechanical damage. The most frequent of these conditions is disseminated intra-vascular coagulation (DIC) (see later), in which vessels are narrowed by the intravascular deposition of fibrin. Other causes of microangiopathic hemolytic anemia include malignant hypertension, systemic lupus erythematosus, thrombotic thrombocytopenic purpura


Pathology_Robbins

Pathology_Robbins. narrowed by the intravascular deposition of fibrin. Other causes of microangiopathic hemolytic anemia include malignant hypertension, systemic lupus erythematosus, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated cancer. Mechanical fragmentation of red cells (schistocytosis) leads to the appearance of characteristic “burr cells,” “helmet cells,” and “triangle cells” in peripheral blood smears (


Pathology_Robbins

Pathology_Robbins. Fig. 12.7 ). Although microangiopathic hemolysis is not usually a major clinical problem in and of itself, it often points to a serious underlying condition. http://ebooksmedicine.net Fig. 12.7 Microangiopathichemolyticanemia—peripheralbloodsmear.Thisspecimenfromapatientwithhemolyticuremicsyndromecontainsseveralfragmentedredcells.(Courtesy of Dr.Robert W. McKenna,Department of Pathol-ogy,University of Texas Southwestern Medical School,Dallas,Texas.)


Pathology_Robbins

Pathology_Robbins. It is estimated that malaria affects 500 million and kills more than 1 million people per year, making it one of the most serious afflictions of humans. Malaria is endemic in Asia and Africa, but with widespread jet travel cases are now seen all over the world. It is caused by one of five types of protozoa. Of these, the most important is Plasmodium falciparum, which causes tertian malaria (falciparum malaria), a disorder with a high fatality rate. The other four species of Plasmodium that infect humans—Plasmodium malariae, Plasmodium vivax, Plasmodium knowlesi, and Plasmodium ovale—cause relatively benign disease. All forms are transmitted by the bite of female Anopheles mosquitoes, and humans are the only natural reservoir. The life cycle of plasmodia is complex (


Pathology_Robbins

Pathology_Robbins. The life cycle of plasmodia is complex ( Fig. 12.8 ). As mosquitoes feed on human blood, sporozoites are introduced from the saliva and within a few minutes infect liver cells. Here the parasites multiply rapidly to form a schizont containing thousands of merozoites. After a period of days to several weeks that varies with the Plasmodium species, the infected hepatocytes release the merozoites, which quickly infect red cells. Intraerythrocytic parasites either continue asexual reproduction to produce more merozoites or give rise to gametocytes capable of infecting the next hungry mosquito. During their asexual reproduction in red cells, each of the four forms of malaria develops into trophozoites. The asexual phase is completed when the trophozoites give rise to new merozoites, which escape by lysing the red cells.


Pathology_Robbins

Pathology_Robbins. Fatal falciparum malaria often involves the small vessels of the brain, a complication known as cerebral malaria. Normally, red cells bear negatively charged surfaces that interact poorly with endothelial cells. Infection of red cells with P. falciparum induces the appearance of positively charged surface knobs containing parasite-encoded proteins, which bind to adhesion molecules expressed on activated endothelium. Several endothelial cell adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), appear to mediate this interaction, which leads to the trapping of red cells in postcapillary venules. In an unfortunate minority of patients, mainly children, this process involves cerebral vessels, which become engorged and occluded. Fig. 12.8 LifecycleofPlasmodium falciparum. ICAM-1, Intercellularadhesionmolecule-1;RBC, redbloodcell.(Drawn by Dr. Jeffrey Joseph, Department of Pathology, Beth Israel Deaconess Hospital, Boston, Massachusetts.) http://ebooksmedicine.net


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Showers of new merozoites are released from the red cells at intervals of approximately 24 hours for P. knowlesi, 48 hours for P. vivax, P. ovale, and P. falciparum, and 72 hours for P. malariae. Episodic shaking, chills, and fever coincide with this release. Hemolytic anemia of varying severity is a constant feature. Cerebral malaria associated with P. falciparum is rapidly progressive; convulsions, coma, and death usually occur within days to weeks. Fortunately, falciparum malaria more often pursues a chronic course that may be punctuated at any time by blackwater fever. The trigger is obscure for this uncommon complication, which is associated with massive intravascular hemolysis, hemoglobinemia, hemoglobinuria, and jaundice.


Pathology_Robbins

Pathology_Robbins. With appropriate chemotherapy, the prognosis for patients with most forms of malaria is good; however, falciparum malaria is becoming more difficult to treat due to the emergence of drug-resistant strains. Because of the potentially serious consequences of the disease, early diagnosis and treatment are important. The ultimate solution is an effective vaccine, which is long sought but still elusive. Autosomaldominantdisordercausedbymutationsthataffecttheredcellmembraneskeleton,leadingtolossofmembraneandeventualconversionofredcellstospherocytes,whicharephagocytosedandremovedinthespleen Manifestedbyanemia,splenomegaly Blockageofvesselsbysickledcellscausespaincrisesandtissueinfarction,particularlyofthemarrowandspleen •Autosomalcodominantdisorderscausedbymutationsinαorβ-globinthatreducehemoglobinsynthesis,resultinginamicrocytic,hypochromicanemia.Inβ-thalassemia,unpairedα-globinchainsformaggregatesthatdamageredcellprecursorsandfurtherimpairerythropoiesis.


Pathology_Robbins

Pathology_Robbins. •X-linkeddisordercausedbymutationsthatdestabilizeG6PD,makingredcellssusceptibletooxidantdamage Anemias of diminished erythropoiesis include those caused by an inadequate dietary supply of nutrients, particularly iron, folic acid, and vitamin B12. Other anemias of this type are associated with bone marrow failure (aplastic anemia), systemic inflammation (anemia of chronic inflammation), or bone marrow infiltration by tumor or inflammatory cells (myelophthisic anemia). In this section, some common examples of anemias of these types are discussed individually.


Pathology_Robbins

Pathology_Robbins. Deficiency of iron is the most common nutritional deficiency in the world and results in clinical signs and symptoms that are mostly related to anemia. About 10% of people living in developed countries and 25% to 50% of those in developing countries are anemic, and in both settings the most frequent cause is iron deficiency. The factors responsible for iron deficiency differ in various populations and are best understood in the context of normal iron metabolism.


Pathology_Robbins

Pathology_Robbins. The normal total body iron mass is about 2.5 g for women and 3.5 g for men. Approximately 80% of functional body iron is present in hemoglobin, with the remainder located in myoglobin and iron-containing enzymes (e.g., catalase, cytochromes). The iron storage pool, consisting of hemosiderin and ferritin-bound iron in the liver, spleen, bone marrow, and skeletal muscle, contains on average 15% to 20% of total body iron. Because serum ferritin is largely derived from this storage pool, the serum ferritin level is a good measure of iron stores. Assessment of bone marrow iron is another reliable but more invasive method for estimating iron stores. Iron is transported in the plasma bound to the protein transferrin. In normal persons, transferrin is about 33% saturated with iron, yielding serum iron levels that average 120 µg/dL in men and 100 µg/dL in women. Thus, the normal total iron-binding capacity of serum is 300 to 350 µg/dL. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In keeping with the high prevalence of iron deficiency, evolutionary pressures have yielded metabolic pathways that are strongly biased toward iron retention. Iron is lost at a rate of 1 to 2 mg/day through the shedding of mucosal and skin epithelial cells, and this loss must be balanced by the absorption of dietary iron, which is tightly regulated (described later). The normal daily Western diet contains 10 to 20 mg of iron. Most is found in heme within meat and poultry, with the remainder present as inorganic iron in vegetables. About 20% of heme and 1% to 2% of nonheme iron are absorbable; hence, the average Western diet contains sufficient iron to balance fixed daily losses. Regulation of iron absorption occurs within the duodenum ( Fig. 12.9 ). After reduction by ferric reductase, ferrous


Pathology_Robbins

Pathology_Robbins. Regulation of iron absorption occurs within the duodenum ( Fig. 12.9 ). After reduction by ferric reductase, ferrous Fig. 12.9 Regulationofironabsorption.Duodenalepithelialcelluptakeofhemeandnonhemeirondiscussedinthetextisdepicted.Whenthestoragesitesofthebodyarerepletewithironanderythropoieticactivityisnormal,plasmahepcidinbalancesironuptakeandlosstomaintainironhemeostasisbydown-regulatingferroportinandlimitingironuptake(middlepanel).Hepcidinrisesinthesettingofsystemicinflammationorwhenironlevelsarehigh,decreasingironuptakeandincreasingironlossbythesheddingofduodenocytes(rightpanel),anditfallsinthesettingoflowplasmaironorprimaryhemochromatosis,resultinginincreasedironuptake(leftpanel)withreducedshedding.DMT1, Divalentmetaltransporter-1.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net iron (Fe2+) is transported across the apical membrane by divalent metal transporter-1 (DMT1). A second transporter, ferroportin, then moves iron from the cytoplasm to the plasma across the basolateral membrane. The newly absorbed iron is next oxidized by hephaestin and ceruloplasmin to ferric iron (Fe3+), the form of iron that binds to transferrin. Both DMT1 and ferroportin are widely distributed in the body and are involved in iron transport in other tissues as well. As depicted in Fig. 12.9 (middle panel), part of the iron that enters enterocytes is delivered to transferrin by ferroportin, whereas the remainder is incorporated into cytoplasmic ferritin and is lost through the exfoliation of mucosal cells.


Pathology_Robbins

Pathology_Robbins. The fraction of iron that is absorbed is regulated by hepcidin, a small peptide that is synthesized and secreted from the liver in an iron-dependent fashion. In general, high iron levels in the plasma enhance hepcidin production, whereas low iron levels suppress it. However, hepcidin production also is sensitive to inflammation and to factors released from erythroblasts in the bone marrow. Specifically, hepcidin levels rise in the face of systemic inflammation because of the direct effects of inflammatory mediators such as IL-6 on hepatocytes, and in the setting of ineffective hematopoiesis, which is marked by increased numbers of erythroblasts in the bone marrow. Hepcidin circulates to the duodenum, where it binds ferroportin and induces its internalization and degradation. Thus, when hepcidin concentrations are elevated (


Pathology_Robbins

Pathology_Robbins. Fig. 12.9 , right panel), such as when serum iron levels are high or there is systemic inflammation, ferroportin levels fall and more iron is incorporated into cytoplasmic ferritin and is lost by excretion. Conversely, when hepcidin levels are low ( Fig. 12.9 , left panel), such as when there is iron deficiency, ineffective hematopoiesis, or the genetic defects that lead to primary hemochromatosis (Chapter 16), the basolateral transport of iron is increased. In iron deficiency, the suppression of hepcidin is beneficial as it serves to help to correct the deficiency, but inappropriately low levels of hepcidin, as in primary hemochromatosis, eventually lead to systemic iron overload. Iron deficiency arises in a variety of settings:


Pathology_Robbins

Pathology_Robbins. Iron deficiency arises in a variety of settings: Chronic blood loss is the most important cause of iron deficiency anemia in the Western world. The most common sources of bleeding are the gastrointestinal tract (e.g., peptic ulcers, colon cancer, hemorrhoids) and the female genital tract (e.g., menorrhagia, metrorrhagia, endometrial cancer). In the developing world, low intake and poor bioavailability because of predominantly vegetarian diets are the most common causes of iron deficiency. In the United States, low dietary intake is an infrequent culprit but is sometimes culpable in infants fed exclusively milk, in the impoverished, in the elderly, and in teenagers subsisting predominantly on junk food. Increased demands not met by normal dietary intake occur worldwide during pregnancy and infancy. Malabsorption can occur with celiac disease or after gastrectomy (Chapter 15).


Pathology_Robbins

Pathology_Robbins. Increased demands not met by normal dietary intake occur worldwide during pregnancy and infancy. Malabsorption can occur with celiac disease or after gastrectomy (Chapter 15). Fig. 12.10 Irondeficiencyanemia—peripheralbloodsmear.Notetheincreasedcentralpallorofmostoftheredcells.Scattered,fullyhemoglo-binizedcells,fromarecentbloodtransfusion,standoutincontrast.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas South-western Medical School, Dallas,Texas.) Regardless of the cause, iron deficiency develops insidiously. Iron stores are depleted first, marked by a decline in serum ferritin and the absence of stainable iron in the bone marrow. These changes are followed by a decrease in serum iron and a rise in the serum transferrin. Ultimately, the capacity to synthesize hemoglobin, myoglobin, and other iron-containing proteins is diminished, leading to microcytic anemia, impaired work and cognitive performance, and even reduced immunocompetence.


Pathology_Robbins

Pathology_Robbins. Clinical Features. In most instances iron deficiency anemia is mild and asymptomatic. Nonspecific manifestations, such as weakness, listlessness, and pallor, may be present in severe cases. With long-standing anemia, abnormalities of the fingernails, including thinning, flattening, and “spooning,” may appear. A curious but characteristic neurobehavioral complication is pica, the compunction to consume nonfoodstuffs such as dirt or clay. In peripheral smears, red cells are microcytic and hypo-chromic ( Fig. 12.10 ). Diagnostic criteria include anemia, hypochromic and microcytic red cell indices, low serum ferritin and iron levels, low transferrin saturation, increased total iron-binding capacity, and, ultimately, response to iron therapy. For unclear reasons, the platelet count often is elevated. Erythropoietin levels are elevated, but the marrow response is blunted by the iron deficiency; thus, marrow cellularity usually is only slightly increased.


Pathology_Robbins

Pathology_Robbins. Persons often die with iron deficiency anemia, but virtually never of it. An important point is that in well-nourished persons, microcytic hypochromic anemia is not a disease but rather a symptom of some underlying disorder. Often referred to as the anemia of chronic disease, anemia associated with chronic inflammation is the most common form of anemia in hospitalized patients. It superficially resembles the anemia of iron deficiency but arises instead from the suppression of erythropoiesis by systemic inflammation. It occurs in a variety of disorders associated with sustained inflammation: • Chronic microbial infections, such as osteomyelitis, bacterial endocarditis, and lung abscess http://ebooksmedicine.net Chronic immune disorders, such as rheumatoid arthritis and regional enteritis Neoplasms, such as Hodgkin lymphoma and carcinomas of the lung and breast


Pathology_Robbins

Pathology_Robbins. Chronic immune disorders, such as rheumatoid arthritis and regional enteritis Neoplasms, such as Hodgkin lymphoma and carcinomas of the lung and breast The anemia of chronic inflammation stems from high levels of plasma hepcidin, which blocks the transfer of iron to erythroid precursors by downregulating ferroportin in macrophages. The elevated hepcidin levels are caused by proinflammatory cytokines such as IL-6, which increase hepatic hepcidin synthesis. In addition, chronic inflammation blunts erythropoietin synthesis by the kidney, lowering red cell production by the marrow. The functional advantages of these adaptations in the face of systemic inflammation are unclear; they may serve to inhibit the growth of iron-dependent microorganisms or to augment certain aspects of host immunity.


Pathology_Robbins

Pathology_Robbins. Clinical Features. As in anemia of iron deficiency, the serum iron levels usually are low in the anemia of chronic disease, and the red cells may be slightly hypochromic and microcytic. Unlike iron deficiency anemia, however, storage iron in the bone marrow and serum ferritin are increased and the total iron-binding capacity is reduced. Administration of erythropoietin and iron can improve the anemia, but only effective treatment of the underlying condition is curative. The two principal causes of megaloblastic anemia are folate deficiency and vitamin B12 deficiency. Both vitamins are required for DNA synthesis and the effects of their deficiency on hematopoiesis are essentially identical. However, the causes and consequences of folate and vitamin B12 deficiency differ in important ways. We will first review some of the common features and then touch on those that are specific to folate and vitamin B12 deficiency.


Pathology_Robbins

Pathology_Robbins. Megaloblastic anemia stems from metabolic defects that lead to inadequate biosynthesis of thymidine, one of the building blocks of DNA. As we will discuss, folate and vitamin B12 are both essential factors for the synthesis of thymidylate, which is required for DNA replication. Thymidine deficiency causes abnormalities in rapidly dividing cells throughout the body, but the hematopoietic marrow is most severely affected. Because the synthesis of RNA and cytoplasmic elements proceeds at a normal rate and thus outpaces that of the nucleus, the hematopoietic precursors show nuclear-cytoplasmic asynchrony (described later). This maturational derangement contributes to the anemia in several ways. Many red cell progenitors are so defective in DNA synthesis that they undergo apoptosis in the marrow (ineffective hematopoiesis). Others mature into red cells but do so after fewer cell divisions, further diminishing the output of red cells. Granulocyte and platelet precursors also are affected


Pathology_Robbins

Pathology_Robbins. (ineffective hematopoiesis). Others mature into red cells but do so after fewer cell divisions, further diminishing the output of red cells. Granulocyte and platelet precursors also are affected (although not as severely) and most patients present with pancytopenia (anemia, thrombocytopenia, and granulocytopenia).


Pathology_Robbins

Pathology_Robbins. Fig. 12.11 Megaloblasticanemia.Aperipheralbloodsmearshowsahyper-segmentedneutrophilwithasix-lobednucleus.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) MORPHOLOGYCertainmorphologicfeaturesarecommontoallformsofmegaloblasticanemia.Thebonemarrowismarkedlyhypercellularandcontainsnumerousmegaloblasticerythroidprogenitors.Megaloblasts arelargerthannormalerythroidprogenitors(normoblasts)andhavedelicate,finelyreticulatednuclearchromatin(indicativeofnuclearimmaturity).Asmegaloblastsdifferentiateandacquirehemoglobin,thenucleusretainsitsfinelydistributedchromatinandfailstoundergothechromatinclumpingtypicalofnormoblasts,aclassicexampleofnuclear-cytoplasmicasynchrony.Thegranulocyticprecursorsalsodemonstratenuclear-cytoplasmicasynchrony,yieldinggiant metamyelocytes. Megakaryocytesmayalsobeabnormallylargeandhavebizarremultilobednuclei.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Folate deficiency is usually the result of inadequate dietary intake, sometimes complicated by increased metabolic demands. Although folate is present in nearly all foods, it is destroyed by 10 to 15 minutes of cooking, and as a result folate stores are marginal in a surprising number of healthy persons. The risk of overt folate deficiency is highest in those with a poor diet (the economically deprived, the indigent, and the elderly) or those with increased metabolic needs (pregnant women and patients with chronic hemolytic anemias, such as sickle cell disease). http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Deficiency may also stem from problems with absorption or metabolism. Food folates are predominantly in polyglutamate form and must be split into monoglutamates for absorption, a conversion that is inhibited by acidic foods and substances found in beans and other legumes. Some drugs, such as phenytoin (dilantin), also interfere with folate absorption, whereas others, such as methotrexate, inhibit folate metabolism. Malabsorptive disorders, such as celiac disease and tropical sprue, that affect the upper third of the small intestine where folate is absorbed, may also impair folate uptake.


Pathology_Robbins

Pathology_Robbins. The metabolism and functions of folate are complex. Here it is sufficient to note that its conversion within cells from dihydrofolate to tetrahydrofolate by dihydrofolate reductase is particularly important. Tetrahydrofolate acts as an acceptor and donor of one-carbon units in several reactions that are required for the synthesis of deoxythymidine monophosphate (dTMP). If intracellular stores of folate fall, insufficient dTMP is synthesized and DNA replication is blocked, leading to megaloblastic anemia.


Pathology_Robbins

Pathology_Robbins. Clinical Features. The onset of the anemia of folate deficiency is insidious, being associated with nonspecific symptoms such as weakness and easy fatigability. The clinical picture may be complicated by the coexistent deficiency of other vitamins, especially in alcoholics. Because the cells lining the gastrointestinal tract, like the hematopoietic system, turn over rapidly, symptoms referable to the alimentary tract, such as sore tongue, are common. Unlike in vitamin B12 deficiency (described later), neurologic abnormalities do not occur. The diagnosis of a megaloblastic anemia is readily made from the examination of smears of peripheral blood and bone marrow. The anemia of folate deficiency is best distinguished from that of vitamin B12 deficiency by measuring serum and red cell folate and vitamin B12 levels.


Pathology_Robbins

Pathology_Robbins. Vitamin B12 is widely present in foods, is resistant to cooking and boiling, and is even synthesized by gut flora. Thus, unlike folate, vitamin B12 deficiency is virtually never caused by inadequate intake except in vegetarians who scrupulously avoid milk and eggs. Instead, deficiencies typically arise from some abnormality that interferes with vitamin B12 absorption, a complex process involving the following steps: 1. Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary protein called haptocorrin. 2. On entering the duodenum, haptocorrin–B12 complexes are processed by pancreatic proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal cells of the gastric fundic mucosa. 3. The intrinsic factor–B12 complexes pass to the distal ileum and attach to cubilin, a receptor for intrinsic factor, and are taken up into enterocytes. 4.


Pathology_Robbins

Pathology_Robbins. 3. The intrinsic factor–B12 complexes pass to the distal ileum and attach to cubilin, a receptor for intrinsic factor, and are taken up into enterocytes. 4. The absorbed vitamin B12 is transferred across the basolateral membranes of enterocytes to plasma transcobalamin, which delivers vitamin B12 to the liver and other cells of the body. After absorption, the body handles vitamin B12 very efficiently. It is stored in the liver, which normally contains reserves sufficient to support bodily needs for 5 to 20 years. Because of these large liver stores, clinical presentations of vitamin B12 deficiency typically follow years of unrecognized malabsorption.


Pathology_Robbins

Pathology_Robbins. The most frequent cause vitamin B12 deficiency is pernicious anemia, which is believed to result from an autoimmune attack on the gastric mucosa that suppresses the production of intrinsic factor. Histologically, there is a chronic atrophic gastritis marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells, and megaloblastic changes in mucosal cells similar to those found in erythroid precursors. The serum of most affected patients contains several types of autoantibodies that block the binding of vitamin B12 to intrinsic factor or prevent binding of the intrinsic factor–vitamin B12 complex to cubilin. Autoantibodies are of diagnostic use, but they are not thought to be the primary cause of the gastric pathology; rather, it seems that an autoreactive T cell response initiates gastric mucosal injury and triggers the formation of autoantibodies. When the mass of intrinsic factor-secreting cells falls below a threshold (and reserves of stored vitamin B12


Pathology_Robbins

Pathology_Robbins. response initiates gastric mucosal injury and triggers the formation of autoantibodies. When the mass of intrinsic factor-secreting cells falls below a threshold (and reserves of stored vitamin B12 are depleted), anemia develops.


Pathology_Robbins

Pathology_Robbins. Other causes of vitamin B12 malabsorption include gastrectomy (leading to loss of intrinsic factor–producing cells), ileal resection (resulting in loss of intrinsic factor–B12 complex–absorbing cells), and disorders that disrupt the function of the distal ileum (such as Crohn disease, tropical sprue, and Whipple disease). Particularly in older persons, gastric atrophy and achlorhydria may interfere with the production of acid and pepsin, which are needed to release the vitamin B12 from its bound form in food. The metabolic defects responsible for the anemia of vitamin B12 deficiency are intertwined with folate metabolism. Vitamin B12 is required for recycling tetrahydrofolate, which, as described previously, is the form of folate that is needed for DNA synthesis. In keeping with this relationship, the anemia of vitamin B12 deficiency is reversed with the administration of folate.


Pathology_Robbins

Pathology_Robbins. By contrast, folate administration does not prevent and may in fact worsen certain neurologic symptoms that are specific to vitamin B12 deficiency. The main neurologic lesions associated with vitamin B12 deficiency are demyelination of the posterior and lateral columns of the spinal cord, sometimes beginning in the peripheral nerves. In time, axonal degeneration may supervene. The severity of the neurologic manifestations is not related to the degree of anemia. Indeed, neurologic disease may occur in the absence of overt megaloblastic anemia.


Pathology_Robbins

Pathology_Robbins. Clinical Features. The manifestations of vitamin B12 deficiency are nonspecific. As with all anemias, findings include pallor, easy fatigability, and, in severe cases, dyspnea and even congestive heart failure. The increased destruction of erythroid progenitors because of ineffective erythropoiesis may give rise to mild jaundice, and megaloblastic changes in the oropharyngeal epithelium may produce a beefy red tongue. The spinal cord disease begins with symmetric numbness, tingling, and burning in the feet or hands, followed by unsteadiness of gait and loss of position sense, particularly in the toes. Although the anemia responds dramatically to parenteral vitamin B12, the neurologic manifestations often fail to resolve. As discussed in Chapter 15, patients with pernicious anemia have an increased risk for the development of gastric carcinoma. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Findings supporting the diagnosis of vitamin B12 deficiency are (1) low serum vitamin B12 levels, (2) normal or elevated serum folate levels, (3) moderate to severe macrocytic anemia, (4) leukopenia with hypersegmented granulocytes, and (5) a dramatic reticulocytic response (within 2 to 3 days) to parenteral administration of vitamin B12. Pernicious anemia is associated with all of these findings plus the presence of serum antibodies to intrinsic factor. Aplastic anemia is a disorder in which multipotent myeloid stem cells are suppressed, leading to bone marrow failure and pancytopenia. The marrow often is virtually devoid of recognizable hematopoietic elements. It must be distinguished from pure red cell aplasia, in which only erythroid progenitors are affected and anemia is the only manifestation.


Pathology_Robbins

Pathology_Robbins. The pathogenesis of aplastic anemia is not fully understood, but two major etiologies have been invoked: an extrinsic, immune-mediated suppression of marrow progenitors, and an intrinsic abnormality of stem cells. Experimental studies have focused on a model in which activated T cells suppress hematopoietic stem cells. It is hypothesized that stem cells are first antigenically altered by exposure to drugs, infectious agents, or other unidentified environmental insults. This provokes a cellular immune response, during which activated TH1 cells produce cytokines such as interferon-γ (IFN-γ) and TNF that suppress and kill hematopoietic progenitors. This scenario is supported by experience with immunosuppressive therapy directed against T cells, which restores hematopoiesis in 60% to 70% of patients.


Pathology_Robbins

Pathology_Robbins. Alternatively, the notion that aplastic anemia results from an intrinsic stem cell abnormality is supported by observations showing that from 5% to 10% of patients have inherited defects in telomerase, which, as mentioned earlier, is needed for the maintenance and stability of chromosomes. It is hypothesized that the defect in telomerase leads to premature senescence of hematopoietic stem cells. Of further interest, the bone marrow cells in an additional 50% of cases have unusually short telomeres, possibly stemming from as-yet undiscovered defects in telomerase or excessive replication of hematopoietic stem cells. These two mechanisms are not mutually exclusive, because genetically altered stem cells (e.g., those with abnormal telomeres) also might express “neoantigens” that serve as targets for a T cell attack.


Pathology_Robbins

Pathology_Robbins. Clinical Features. Aplastic anemia affects persons of all ages and both sexes. The slowly progressive anemia causes the insidious development of weakness, pallor, and dyspnea. Thrombocytopenia often manifests with petechiae and ecchymoses. Neutropenia may set the stage for serious infections. It is important to separate aplastic anemia from anemia caused by marrow infiltration (myelophthisic anemia), “aleukemic leukemia,” and granulomatous diseases, which may have similar clinical presentations but are easily distinguished by examination of the bone marrow. Aplastic anemia does not cause splenomegaly; if present, another diagnosis should be sought.


Pathology_Robbins

Pathology_Robbins. The prognosis is unpredictable. Withdrawal of an inciting drug sometimes leads to remission, but this is the exception. Hematopoietic stem cell transplantation often is curative, particularly in nontransfused patients younger than 40 years of age. Transfusion sensitizes patients to alloantigens, producing a high rate of engraftment failure; thus, it must be minimized in persons eligible for transplantation. Successful transplantation requires “conditioning” with immunosuppressive radiation or chemotherapy, reinforcing the notion that autoimmunity has an important role in the disease. As mentioned earlier, patients who are poor transplantation candidates often benefit from immunosuppressive therapy.


Pathology_Robbins

Pathology_Robbins. Myelophthisic anemia is caused by extensive infiltration of the marrow by tumors or other lesions. It most commonly is associated with metastatic breast, lung, or prostate cancer. Other tumors, advanced tuberculosis, lipid storage disorders, and osteosclerosis may produce a similar clinical picture. The principal manifestations include anemia and thrombocytopenia; in general, the white cell series is less affected. Characteristically misshapen red cells, some resembling teardrops, are seen in the peripheral blood. Immature granulocytic and erythrocytic precursors also may be present (leukoerythroblastosis) along with mild leukocytosis. Treatment is directed at the underlying condition.


Pathology_Robbins

Pathology_Robbins. ANEMIAOFDIMINISHEDERYTHROPOIESISunsteadiness of gait and loss of position sense, particularly in the toes. Although the anemia responds dramatically to unsteadiness of gait and loss of position sense, particularly in the toes. Although the anemia responds dramatically to •Causedbychronicbleedingorinadequateironintake;resultsininsufficienthemoglobinsynthesisandhypochromic,microcyticredcells Anemia of Chronic Inflammation •Causedbyinflammatorycytokines,whichincreasehepcidinlevelsandtherebysequesterironinmacrophages,andalsosuppresserythropoietinproduction Resultsinenlargedabnormalhematopoieticprecursors(megaloblasts),ineffectivehematopoiesis,macrocyticanemia,and(inmostcases)pancytopenia http://ebooksmedicine.net •Causedbybonemarrowfailure(hypocellularity)resultingfromdiversecauses,includingexposurestotoxinsandradiation,idiosyncraticreactionstodrugsandviruses,andinheriteddefectsintelomeraseandDNArepair


Pathology_Robbins

Pathology_Robbins. Polycythemia, or erythrocytosis, denotes an increase in red cells per unit volume of peripheral blood. It may be absolute (defined as an increase in total red cell mass) or relative. Relative polycythemia results from dehydration, such as occurs with water deprivation, prolonged vomiting, diarrhea, or the excessive use of diuretics. Absolute polycythemia is described as primary when the increased Table 12.5 Pathophysiologic Classification of Polycythemia Abnormalproliferationofmyeloidstemcells,normalorlowerythropoietinlevels(polycythemiavera);inheritedactivatingmutationsintheerythropoietinreceptor(rare) Adaptive: Lungdisease,high-altitudeliving,cyanoticheartdisease Paraneoplastic: Erythropoietin-secretingtumors(e.g.,renalcellcarcinoma,hepatomacellularcarcinoma,cerebellarhemangioblastoma)


Pathology_Robbins

Pathology_Robbins. Adaptive: Lungdisease,high-altitudeliving,cyanoticheartdisease Paraneoplastic: Erythropoietin-secretingtumors(e.g.,renalcellcarcinoma,hepatomacellularcarcinoma,cerebellarhemangioblastoma) Surreptitious: Enduranceathletes red cell mass results from an autonomous proliferation of erythroid progenitors, and secondary when the excessive proliferation stems from elevated levels of erythropoietin. Primary polycythemia (polycythemia vera) is a clonal myeloid neoplasm considered later in this chapter. The increases in erythropoietin that cause secondary forms of absolute polycythemia include a variety of causes ( Table 12.5


Pathology_Robbins

Pathology_Robbins. Table 12.5 Disorders of white cells include deficiencies (leukopenias) and proliferations, which may be reactive or neoplastic. Reactive proliferation in response to a primary, often microbial, disease is common. Neoplastic disorders, although less common, are more ominous: They cause approximately 9% of all cancer deaths in adults and a staggering 40% in children younger than 15 years of age. Presented next are brief descriptions of some nonneoplastic conditions, followed by more detailed considerations of the malignant proliferations of white cells. Leukopenia results most commonly from a decrease in granulocytes, the most numerous circulating white cells. Lymphopenia is much less common; it is associated with rare congenital immunodeficiency diseases, advanced human immunodeficiency virus (HIV) infection, and treatment with high doses of corticosteroids. Only the more common leukopenias of granulocytes are discussed here.


Pathology_Robbins

Pathology_Robbins. A reduction in the number of granulocytes in blood is known as neutropenia or, when severe, agranulocytosis. Neutropenic persons are susceptible to severe, potentially fatal bacterial and fungal infections. The risk of infection rises sharply as the neutrophil count falls below 500 cells/µL. The mechanisms underlying neutropenia can be divided into two broad categories: Decreased granulocyte production. Clinically important reductions in granulopoiesis are most often caused by marrow hypoplasia (as occurs transiently with cancer chemotherapy and chronically with aplastic anemia) or extensive replacement of the marrow by tumor (such as with leukemia). Alternatively, neutrophil production may be suppressed while other blood lineages are unaffected. This is most often caused by certain drugs or by neoplastic proliferations of cytotoxic T cells and natural killer (NK) cells (so-called “large granular lymphocytic leukemia”).


Pathology_Robbins

Pathology_Robbins. Increased granulocyte destruction. This can be encountered with immune-mediated injury (triggered in some cases by drugs) or in overwhelming bacterial, fungal, or rickettsial infections resulting from increased peripheral use. Splenomegaly also can lead to the sequestration and accelerated removal of neutrophils. MORPHOLOGYThealterationsinthebonemarrowdependontheunderlyingcause.Compensatorymarrowhypercellularityisseenwhenthereisexcessiveneutrophildestructionorineffectivegranulopoiesis,suchasoccursinmegaloblasticanemia.Drugsthatselectivelysuppressgranulocytopoiesisareassociatedwithdecreasednumbersofgranulocyticprecursorsandpreservationoferythroidelementsandmegakaryocytes,whilemyelotoxicchemotherapydrugsreducethenumberofelementsfromalllineages. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Clinical Features. Infections constitute the major problem. They commonly take the form of ulcerating, necrotizing lesions of the gingiva, floor of the mouth, buccal mucosa, pharynx, or other sites within the oral cavity (agranulocytic angina). Owing to the lack of leukocytes, such lesions often contain large masses or sheets of microorganisms. In addition to local inflammation, systemic symptoms usually are present consisting of malaise, chills, and fever. Because of the danger of sepsis, patients are started on broad-spectrum antibiotics covering both bacterial and fungal infections at the first sign of infection. Depending on the clinical context, patients also may be treated with granulocyte colony-stimulating factor (G-CSF), a growth factor that speeds recovery of neutrophil counts.


Pathology_Robbins

Pathology_Robbins. An increase in the number of white cells in the blood is common in a variety of inflammatory states caused by microbial and nonmicrobial stimuli. Leukocytoses are relatively nonspecific and are classified according to the particu lar white cell series that is affected (Table 12.6). As discussed later, in some cases reactive leukocytosis may mimic leukemia. Such “leukemoid reactions” must be distinguished Table 12.6 Causes of Leukocytosis Acutebacterialinfections(especiallythosecausedbypyogenicorganisms);sterileinflammationcausedby,e.g.,tissuenecrosis(myocardialinfarction,burns) Allergicdisorderssuchasasthma,hayfever,allergicskindiseases(e.g.,pemphigus,dermatitisherpetiformis);parasiticinfestations;drugreactions;certainmalignancies(e.g.,Hodgkinlymphomaandsomenon-Hodgkinlymphomas);collagen-vasculardisordersandsomevasculitides;atheroembolicdisease(transient) Rare,oftenindicativeofamyeloproliferativeneoplasm(e.g.,chronicmyeloidleukemia)


Pathology_Robbins

Pathology_Robbins. Rare,oftenindicativeofamyeloproliferativeneoplasm(e.g.,chronicmyeloidleukemia) Chronicinfections(e.g.,tuberculosis),bacterialendocarditis,rickettsiosis,andmalaria;collagenvasculardiseases(e.g.,systemiclupuserythematosus);andinflammatoryboweldiseases(e.g.,ulcerativecolitis) Accompaniesmonocytosisinmanydisordersassociatedwithchronicimmunologicstimulation(e.g.,tuberculosis,brucellosis);viralinfections(e.g.,hepatitisA,cytomegalovirus,Epstein-Barrvirus);Bordetella pertussis infection from true white cell malignancies. Infectious mononucleosis merits separate consideration because it gives rise to a distinctive syndrome associated with lymphocytosis.


Pathology_Robbins

Pathology_Robbins. Infectious mononucleosis is an acute, self-limited disease of adolescents and young adults that is caused by Epstein-Barr virus (EBV), a member of the herpesvirus family. The infection is characterized by (1) fever, sore throat, and generalized lymphadenitis and (2) a lymphocytosis of activated, CD8+ T cells. Of note, cytomegalovirus infection induces a similar syndrome that can be differentiated only by serologic methods.


Pathology_Robbins

Pathology_Robbins. EBV is ubiquitous in all human populations. In the developing world, EBV infection in early childhood is nearly universal. Even though infected children mount an immune response (described later), most remain asymptomatic and more than half continue to shed virus, usually for life. By contrast, in developed countries with better standards of hygiene, infection typically is delayed until adolescence or young adulthood and symptomatic infection is much more common. For unclear reasons, only about 20% of healthy seropositive persons in developed countries shed the virus, and only about 50% of those exposed to the virus acquire the infection.


Pathology_Robbins

Pathology_Robbins. Transmission to a seronegative “kissing cousin” usually involves direct oral contact. It is hypothesized that the virus initially infects oropharyngeal epithelial cells and then spreads to underlying lymphoid tissue (tonsils and adenoids), where mature B cells are infected. The infection of B cells takes one of two forms. In a minority of cells, the infection is lytic, leading to viral replication and release of virions. More commonly, the infection is nonproductive and the virus persists in latent form as an extrachromosomal episome.


Pathology_Robbins

Pathology_Robbins. B cells that are latently infected with EBV become “activated” and proliferate as a result of the action of several viral proteins (Chapter 6). These cells disseminate in the circulation and secrete antibodies with unusual specificities, including the antibodies that recognize sheep red cells that are detected in diagnostic tests for mononucleosis. During acute infections, EBV is shed in the saliva; it is not known whether the source of these virions is oropharyngeal epithelial cells or B cells.


Pathology_Robbins

Pathology_Robbins. The host T cell response controls the proliferation of EBV-infected B cells and the spread of the virus. Early in the course of the infection, IgM antibodies are formed against viral capsid antigens. Later the serologic response shifts to IgG antibodies, which persist for life. More important in the control of the EBV-positive B cell proliferation are cytotoxic CD8+ T cells. Virus-specific CD8+ T cells appear in the circulation as atypical lymphocytes, a finding that is characteristic of mononucleosis. In otherwise healthy persons, the fully developed humoral and cellular responses to EBV act as brakes on viral shedding. In most cases, however, a small number of latently infected EBV-positive B cells escape the immune response and persist for the life of the patient. As described later, impaired T cell immunity places patients at high risk for EBV-driven B cell proliferations. http://ebooksmedicine.net


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Clinical Features. Infectious mononucleosis classically manifests with fever, sore throat, and lymphadenitis, but atypical presentations are not unusual. Sometimes there is little or no fever and only fatigue and lymphadenopathy exist, raising the specter of lymphoma; fever of unknown origin, unassociated with lymphadenopathy or other localized findings; hepatitis that is difficult to differentiate from one of the hepatotropic viral syndromes (Chapter 16); or a febrile rash resembling rubella. Ultimately, the diagnosis depends on the following, in increasing order of specificity: (1) the presence of atypical lymphocytes in the peripheral blood; (2) a positive heterophil reaction (Monospot test); and (3) a rising titer of antibodies specific for EBV antigens. In most patients, mononucleosis resolves within 4 to 6 weeks, but sometimes the fatigue lasts longer. Occasionally, one or more complications supervene. Perhaps the most common of these is hepatic dysfunction, associated with


Pathology_Robbins

Pathology_Robbins. resolves within 4 to 6 weeks, but sometimes the fatigue lasts longer. Occasionally, one or more complications supervene. Perhaps the most common of these is hepatic dysfunction, associated with jaundice, elevated liver enzyme levels, disturbed appetite, and, rarely, even liver failure. Other complications involve the nervous system, kidneys, bone marrow, lungs, eyes, heart, and spleen (including fatal splenic rupture).