Blood Pathology Flashcards
Hematopoietic and lymphoid disorders are based on whether they affect what three things
most common red cell disorders are those that lead to what?
White cell disorders are most often associated with what?
Hemostatic derangements may result in what?
Give one example of how the pro- duction, function, and destruction of red cells, white cells, and components of the hemostatic system are closely linked, and pathogenic derangements primarily affecting one cell type or component of the system often lead to alterations in others. (Remember what gapoend whrn B cells
Make autoantibodes against components of red cell membrane )
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. Give an example (remember ehat happens in a patient diagnosed w lymphoma by lymph node biopsy)
red cells, white cells, or the hemostatic 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, as a result of malignant transformation.
Hemostatic derange- ments may result in hemorrhagic diatheses (bleeding disor- ders).
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.
. Hence, a patient who is diagnosed with lymphoma by lymph node biopsy also may be found to have neoplastic lymphocytes in their bone marrow and blood. The malig- nant lymphoid cells in the marrow may suppress hemato- poiesis, giving rise to low blood cell counts (cytopenias), and the further seeding of tumor cells to the liver and spleen may lead to organomegaly. Thus, in both benign and malignant hematolymphoid disorders, a single under- lying abnormality can result in diverse systemic manifesta- tions.
Disorders of rbcs can result jn whivh two diseases?
What is anemia? What is hemoglobin
What are the three causes if anemia?
With the exception of anemia caused by what,decrease in tissue oxygen tension that accompanies anemia triggers what compensatory mechanism?
In well
Noirished persons eho become anemic cuz of acute boeeding or increased rbc destruction (hemolysis), the
compensatory response can do what?
Anemias caused by decreased rbc production are associated with what?
Anemias can also be vlassified on the basis of what? What specific features of the RBcs provide etiologic clues? How are these features judged subjectively?
What is mean cell volume? Mean cell hemoglobin,mean cell hemoglobin concentration,red cell distribution width,reticulocyte count? Depending on the ddx what other five blood tests may be performed to evaluate anemia and state their functions in evaluating anemia? In Isolated anemia which tests suffice to establish the cause? When anemia occurs w thrombocytopenia and or granulocytooenia,its more likely to be associated w what disease? In this cause ehat exam is used?
Clinical consequences of anemia are determined by ehat? If the onset is slow,how is 02 carrying capapcity deficit partially compensated for?
These compensations are less effective in which people and effective jn ehich people? Which three signs are common to all forms of anemia?
Hemolytic anemias are associated w what four diseases? Anemias that stem from ineffective hematopoiesis are associated w what ? Which can lead to what? If this is left untreated, severe congenital anemias can result in what?
Disorders of red cells can result in anemia or, less com- monly, polycythemia (an increase in red cells also known as erythrocytosis).
Anemia is defined as a reduction in the oxygen-transporting capacity of blood(the hb) which usually stems from a decrease in the red cell mass to subnormal levels.(hemoglobin, also spelled haemoglobin, iron-containing protein in the blood of many animals—in the red blood cells (erythrocytes) of vertebrates—that transports oxygen to the tissues. Hemoglobin forms an unstable reversible bond with oxygen)
Anemia can result from bleeding, increased red cell destruc- tion, or decreased red cell production.
With the exception of anemias caused by chronic renal failure or chronic inflammation (described later), the decrease in tissue oxygen tension that accompanies anemia triggers increased production of the growth factor erythro- poietin from specialized cells in the kidney. This in turn drives a compensatory hyperplasia of erythroid precursors in the bone marrow and, in severe anemias, 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 five- to eight-fold. 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, anemias caused by decreased red cell production (are generative anemias) are associated with subnormal reticulocyte counts (reticulocytopenia).
Anemias also can be classified on the basis of red cell morphology, which often points to particular causes. Spe- cific features that provide etiologic clues include the size, color and shape of the red cells. These features are judged subjectively by visual inspection of peripheral smears and also are expressed quantitatively using the following indices:
• Meancellvolume(MCV):theaveragevolumeperredcell, expressed in femtoliters (cubic microns)
• Mean cell hemoglobin (MCH): the average mass of hemo- globin 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
• Redcelldistributionwidth(RDW):thecoefficientofvaria- tion of red cell volume
Red cell indices are directly measured or automatically calculated by specialized instruments in clinical laborato- ries.
The same instruments also determine the reticulocyte count, a simple measure that distinguishes between hemo- lytic and aregenerative anemias. Depending on the dif- ferential diagnosis, a number of other blood tests also may be performed to evaluate anemia, including (1) iron indices (serum iron, serum iron-binding capacity, transferrin satu- ration, and serum ferritin concentrations), which help dis- tinguish among anemias caused by iron deficiency, chronic disease, and thalassemia; (2) plasma unconjugated bilirubin, haptoglobin, and lactate dehydrogenase levels, which are abnor- mal in hemolytic anemias; (3) serum and red cell folate and vitamin B12 concentrations, which are low in megaloblastic anemias; (4) hemoglobin electrophoresis, which is used to detect abnormal hemoglobins; and (5) the Coombs test, which is used to detect antibodies or complement on red cells in suspected cases of immunohemolytic 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.
the clinical consequences of anemia are determined by its severity, rapidity of onset, and underlying pathogenic mechanism. If the onset is slow, the deficit in O2-carrying capacity is partially compensated for by adaptations such as increases in plasma volume, cardiac output, respiratory rate, and levels of red cell 2,3- diphosphoglycerate, a glycolytic pathway intermediate that enhances the release of O2 from hemoglobin.
These 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.
Anemias caused by the premature destruction of red cells (hemolytic anemias) are associated with hyperbilirubinemia, jaundice, and pigment gallstones, all related to increases in the turnover of hemoglobin. Anemias that stem from ineffective hematopoiesis (the premature death of erythroid progenitors in the marrow) are 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, severe congenital anemias such as β-thalassemia major inevi- tably result in growth retardation, skeletal abnormalities, and cachexia.
What are the classifications of anemia according to the underlying mechanism and give two diseases or things that cause those mechanisms
Blood Loss:
Acute: trauma
Chronic: gastrointestinal tract lesions, gynecologic disturbances
2.Increased Destruction (Hemolytic Anemias):
a. Intrinsic (Intracorpuscular) Abnormalities
Hereditary
Membrane abnormalities
Membrane skeleton proteins: spherocytosis, elliptocytosis Membrane lipids: abetalipoproteinemia
Enzyme deficiencies
Enzymes of hexose monophosphate shunt: glucose-6-phosphate
dehydrogenase, glutathione synthetase Glycolytic enzymes: pyruvate kinase, hexokinase
Disorders of hemoglobin synthesis
Structurally abnormal globin synthesis (hemoglobinopathies): sickle
cell anemia, unstable hemoglobins
Deficient globin synthesis: thalassemia syndromes
Acquired
Membrane defect: paroxysmal nocturnal hemoglobinuria
b. Extrinsic (Extracorpuscular) Abnormalities
Antibody-mediated
Isohemagglutinins: transfusion reactions, immune hydrops (Rh disease
of the newborn)
Autoantibodies: idiopathic (primary), drug-associated, systemic lupus
erythematosus Mechanical trauma to red cells
Microangiopathic hemolytic anemias: thrombotic thrombocytopenic purpura, disseminated intravascular coagulation
Defective cardiac valves Infections: malaria
- Impaired Red Cell Production:
Disturbed proliferation and differentiation of stem cells: aplastic anemia, pure red cell aplasia
Disturbed proliferation and maturation of erythroblasts Defective DNA synthesis: deficiency or impaired utilization of
vitamin B12 and folic acid (megaloblastic anemias) Anemia of renal failure (erythropoietin deficiency) Anemia of chronic disease (iron sequestration, relative
erythropoietin deficiency) Anemia of endocrine disorders
Defective hemoglobin synthesis
Deficient heme synthesis: iron deficiency, sideroblastic anemias Deficient globin synthesis: thalassemias
Marrow replacement: primary hematopoietic neoplasms (acute leukemia, myelodysplastic syndromes)
Marrow infiltration (myelophthisic anemia): metastatic neoplasms, granulomatous disease
What are the adult reference ranges(dtate the unit ,for male and female) for Hb, rbc count ,reticulocyte count,mean cell volume, mean cell Hb ,mean cell Hb concentration,red cEll distribution width
Hemoglobin (Hb) : g/dL ,13.2–16.7(male), 11.9–15.0 (female)
Hematocrit (Hct): %,38–48(male), 35-44(female)
Red cell count :× 10 raised to the power 6/μL, 4.2–5.6 (male),3.8–5.0(female)
Reticulocyte count :% ,0.5–1.5 (male),0.5–1.5(female)
Mean cell volume (MCV): fL ,81–97 (male) ,81–97(female)
Mean cell Hb (MCH) :pg ,28–34(male) ,28–34(female)
Mean cell Hb concentration (MCHC): g/dL, 33–35 (male),33–35(female)
Red cell distribution width (RDW) :11.5–14.8 (male)
Summary(state the causes of anemia, under morphology (what is microcytic,macrocytic,normocytic but eith abnormal shapes and give two diseases that cause those morphologies ),what are the acute and chronic manifestations of anemia
What is Poikilocytosis
What is hemoglobinemia
With acute blood loss exceeding 20 percent of blood volume, what is yhe immediate threat? If the patient survives from the threat,what happens . What is the morphology of rbcs in anemia due to acute blood loss
Recovery from blood loss anemia is enhanced by what? With chronic blood loss what hapoens to iron stores? Iron is important for what and its deficiency leads to what ? Normal RbCs have a life span of how many days? What is hemolytic anemia? It can stem from which two defects? Features shared by all uncomplicated hemolytic anemias include what three things?
Hemolytic anemias are associated with what two things? In severe hemolytic anemia what may appear in the liver,spleen and lymph nodes? Destruction of rbcs can occur in which two places? What causes intravascukar hemolysis? What three things does this kind of hemolysis lead to? Conversion of heme to bilirubin cab result in what two things? Massive intravsvukar hemolysis sometimes leads to what?
What is haptoglobin and what does it cause? Extravascular hemolysis takes place where? What si the function of the liver and spleen with regards to rbcs? What causes splenic sequestration and phagocytosis
Extra vascular hemolysis is not associated w hemoglobinemia and hemoglobinuria but kften rodouces what? What happens to haptoglobin in this type of hemolysis . In most forms of chronic extravasvulr hemolysis what results in splenomegaly
Pathology of Anemias Causes • Blood loss (hemorrhage) • Increased red cell destruction (hemolysis) • Decreased red cell production
Morphology
• Microcytic (iron deficiency, thalassemia) : small size of RBCs in affected patient compared to RBCs in normal patient
• Macrocytic (folate or vitamin B deficiency 12)- rbcs are bigger in affected patient that normal
• Normocytic but with abnormal shapes (hereditary sphero- cytosis, sickle cell disease): It means you have normal-sized red blood cells, but you have a low number of them.
Clinical Manifestations
• Acute: shortness of breath, organ failure, shock
• Chronic
Pallor, fatigue, lassitude
With hemolysis: jaundice and gallstones
With ineffective erythropoiesis: iron overload, heart and
endocrine failure
If severe and congenital: growth retardation, bone deformities due to reactive marrow hyperplasia
Poikilocytosis is the term for abnormally shaped red blood cells in the blood.
Increased hemoglobin
With acute blood loss exceeding 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 normo- cytic 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.
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.
Normal red cells have a life span of about 120 days. Anemias caused by accelerated red cell destruction are termed hemolytic anemias. Destruction can stem from either intrinsic (intracorpuscular) red cell defects, which are usually inherited, or extrinsic (extracorpuscular) factors, which are usually acquired.
Features shared by all uncomplicated hemolytic anemias include (1) a decreased red cell life span, (2) a compensa- tory increase in erythropoiesis, and (3) the retention of the products of degraded red cells (including iron) by the body.
Because the recovered iron is efficiently recycled, red cell regeneration may almost keep pace with the hemolysis.
Consequently, hemolytic anemias are associated with erythroid hyperplasia in the marrow and increased numbers of reticulo- cytes in the peripheral blood. In severe hemolytic anemias, extramedullary hematopoiesis may appear in the liver, spleen, and lymph nodes.
Destruction of red cells can occur within the vascular compartment (intravascular hemolysis) or within tissue mac- rophages (extravascular hemolysis).
Intravascular hemolysis can result from mechanical forces (e.g., turbulence created by a defective heart valve) or biochemical or physical agents that damage the red cell membrane (e.g., fixation of complement, exposure to clostridial toxins, or heat). Regardless of cause, intravascular hemolysis leads to hemoglobinemia, hemoglobinuria, and hemosiderinuria. The conversion of heme to bilirubin can result in unconju- gated hyperbilirubinemia and jaundice. Massive intravas- cular hemolysis sometimes leads to acute tubular necrosis.
Haptoglobin, a circulating protein that binds and clears free hemoglobin, is completely depleted from the plasma, which also usually contains high levels of lactate dehydrogenase (LDH) as a consequence of its release from hemolyzed red cells.
Extravascular hemolysis, the more common mode of red cell destruction, primarily takes place within the spleen and liver. These organs contain large numbers of macro- phages, the principal cells responsible for the removal of damaged or immunologically targeted red cells from the. circulation. Because extreme alterations of shape are neces- sary for red cells to navigate the splenic sinusoids, any reduction in red cell deformability makes this passage dif- ficult and leads to splenic sequestration and phagocytosis. Extravascular hemolysis is not associated with hemoglobinemia and hemoglobinuria, but often produces jaundice and, if long-standing, leads to the formation of bilirubin-rich gallstones (pigment stones). Haptoglobin is decreased, as some hemoglobin invariably escapes from macrophages into the plasma, and LDH levels also are elevated. In most forms of chronic extravascular hemolysis there is a reactive hyperplasia of mononuclear phagocytes that results in splenomegaly.
What is hereditary spherocytosis
How is it transmitted
What is the morphology of this disease
(On smears how do these spherocytes look like ? Excessive red cell destruction and resultant anemia in this disease lead to what? Increased red cell production is marked by? What sign is more common and prominent in hereditary spherocytosis than in any other form of hemolytic anemia and what causes this sign? In long standing cases what sign is seen? Name one other general feature of hemolytic anemia
This disorder stems from inherited (intrinsic) defects in the red cell membrane that lead to the formation of sphero- cytes, nondeformable cells that are highly vulnerable to sequestration and destruction in the spleen. Hereditary spherocytosis is usually transmitted as an autosomal domi- nant trait; a more severe, autosomal recessive form of the disease affects a small minority of patients.
On smears, spherocytes are dark red and lack central pallor (Fig. 11–2). The excessive red cell destruction and resultant anemia lead to a compensatory hyperplasia of red cell progenitors in the marrow and an increase in red cell production marked by reticulocytosis. Splenomegaly is more common and prominent in hereditary spherocytosis than in any other form of hemolytic anemia.
The splenic weight usually is between 500 and 1000 g. The enlargement results from marked congestion of the splenic cords and increased numbers of tissue macrophages. Phagocytosed red cells are seen within macrophages lining the sinusoids and, in particular, within the cords.
In long-standing cases there is prominent systemic hemosiderosis. The other general fea- tures of hemolytic anemias also are present, including cho- lelithiasis, which occurs in 40% to 50% of patients with hereditary spherocytosis
What is the pathogenesis of hereditary spherocytosis
What is the major skeleton protein
What do the mutations in this disease frequently involve
What is a shared feature of pathogenic mutations? How do the cells become spherical ? What organ plays a major role in destruction of spherocytes?
The floppy discoid shape of normal red cells allows considerable latitude for shape changes. By contrast, spherocytes have limited deform- ability and are sequestered in the splenic cords, where they are destroyed by the plentiful resident macrophages. The critical role of the spleen is illustrated by the beneficial effect of splenectomy; although the red cell defect and spherocytes persist, the anemia is corrected
True or false
Hereditary spherocytosis is caused by abnormalities in the membrane skeleton, a network of proteins that underlies lipid bilayer of the red cell The major membrane skeleton protein is spectrin, a long, flexible het- erodimer that self-associates at one end and binds short actin filaments at its other end. These contacts create a two- dimensional meshwork that is linked to the overlying mem- brane through ankyrin and band 4.2 to the intrinsic membrane protein called band 3, and through band 4.1 to glycophorin.
The mutations in hereditary spherocytosis most frequently involve ankyrin, band 3, and spectrin, but mutations in other components of the skeleton have also been described.
A shared feature of the pathogenic mutations is that they weaken the vertical interactions between the membrane skeleton and the intrinsic membrane proteins. This defect somehow destabilizes the lipid bilayer of the red cells, which shed membrane vesicles into the cir- culation as they age. Little cytoplasm is lost in the process and as a result the surface area to volume ratio decreases progressively over time until the cells become spherical (Fig. 11–1).
The spleen plays a major role in the destruction of sphe- rocytes. Red cells must undergo extreme degrees of defor- mation to pass through the splenic cords..
What are the characteristic clinical features of hereditary spherocytosis
Most commonly what is the severity of the anemia?
Why do red cells in hereditary spherocytosis have increased osmotic fragility ? And when do they have this increased osmotic fragility? This characteristic (increased osmotic fragility ) can help establish the diagnosis true or false
Hereditary spherocytosis is often stable but may be punctuated by which crises? The most severe crises are triggered by what? What will result in rapid worsening of anemia in hereditary spherocytosis?
Such episodes are self-limited, but some patients need supportive blood transfusions during the period of red cell aplasia. True or false? What treatment is there for patients w hereditary spherocytosis?
What are hemoglobinopathies?
What is sickle cell anemia?
Normal hemoglobins are tetraners composed of what? How is HbS produced?
On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2). True or false
in all homozygotes all HbA is replaced by what? In heterozygotes how much of HbA is replaced?
Incidence
Sickle cell anemia is the most common familial hemolytic anemia in the world. In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a small but significant protective effect of HbS against Plasmodium falciparum malaria. In the United States, approximately 8% of blacks are heterozygous for HbS, and about 1 in 600 have sickle cell anemia. True or false
Clinical Features
The characteristic clinical features are anemia, splenomegaly, and jaundice. The anemia is highly variable in severity, ranging from subclinical to profound; most commonly it is of moderate degree. Because of their spherical shape, red cells in hereditary spherocytosis have increased osmotic fragility when placed in hypotonic salt solutions, a character- istic that can help establish the diagnosis.
The clinical course often is stable but may be punctuated by aplastic crises. The most severe crises are triggered by parvovirus B19, which infects and destroys erythroblasts in the bone marrow. Because red cells in hereditary sphe- rocytosis have a shortened life span, a lack of red cell pro- duction for even a few days results in a rapid worsening of the anemia.
There is no specific treatment for hereditary spherocy- tosis. Splenectomy provides relief for symptomatic patients by removing the major site of red cell destruction. The benefits of splenectomy must be weighed against the risk of increased susceptibility to infections, particularly in chil- dren. Partial splenectomy is gaining favor, because this approach may produce hematologic improvement while maintaining protection against sepsis.
The hemoglobinopathies are a group of hereditary disor- ders caused by inherited mutations that lead to structural abnormalities in hemoglobin.
Sickle cell anemia, the proto- typical (and most prevalent) hemoglobinopathy, stems from a mutation in the β-globin gene that creates sickle hemoglobin (HbS).
Normal hemoglobins are tetramers composed of two pairs of similar chains. HbS is produced by the substitution of valine for glutamic acid at the sixth amino acid residue of β-globin. In homozygotes, all HbA is replaced by HbS, whereas in heterozygotes, only about half is replaced.
True
What is the pathogenesis of Sickle cell anemia
What are the three factors that influence
The two major consequences that arise from the sickling of red cells
On deoxygenation, HbS molecules form long polymers by means of intermolecular contacts that involve the abnormal valine residue at position 6. These polymers distort the red cell, which assumes an elongated crescentic, or sickle, shape (Fig. 11–3). The sickling of red cells initially is reversible upon reoxygenation. However, the distortion of the membrane that is 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. Over time, this cumu- lative damage creates irreversibly sickled cells, which are rapidly hemolyzed.
Many variables influence the sickling of red cells in vivo. The three most important factors are
• The presence of hemoglobins other than HbS. In
heterozygotes approximately 40% of Hb is HbS and the remainder is HbA, which interacts only weakly with deox- ygenated HbS. Because the presence of HbA greatly retards the polymerization of HbS, the red cells of het- erozygotes have little tendency to sickle in vivo. Such persons are said to have sickle cell trait. HbC, another mutant β-globin, has a lysine residue instead of the normal glutamic acid residue at position 6. About 2.3% of Ameri- can blacks are heterozygous carriers of HbC; as a result, about 1 in 1250 newborns are compound heterozygotes for HbC and HbS. Because HbC has a greater tendency to aggregate with HbS than does HbA, HbS/HbC com- pound heterozygotes have a symptomatic sickling disorder called HbSC disease. HbF interacts weakly with HbS, so 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.
• The intracellular concentration of HbS. The poly- merization 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. The relatively low concentration of HbS also contributes to the absence of sickling in heterozygotes with sickle cell trait.
• The transit time for red cells through the micro- vasculature. The normal transit times of red cells through capillaries are too short for significant polymeriza- tion of deoxygenated HbS to occur. Hence, sickling in microvascular beds is confined to areas of the body in which blood flow is sluggish. This is the normal situation
in the spleen and the bone marrow, two tissues promi- nently affected by sickle cell disease. Sickling also can be triggered in other microvascular beds by acquired factors that retard the passage of red cells. As described previ- ously, inflammation slows the flow of blood by increasing the adhesion of leukocytes and red cells to endothelium and by inducing the exudation of fluid through leaky vessels. In addition, sickle red cells have a greater tendency than normal red cells to adhere to endothelial cells, appar- ently because repeated bouts of sickling causes mem- brane damage that make them sticky. These factors conspire to prolong the transit times of sickle red cells, increasing the probability of clinically significant sickling.
Two major consequences arise from the sickling of red cells .
First, the red cell membrane damage and dehydration caused by repeated episodes of sickling produce a chronic hemolytic anemia. The mean life span of red cells in sickle cell anemia is only 20 days (one sixth of normal). Second, red cell sickling produces widespread microvascular obstructions, which result in ischemic tissue damage and pain crises. Vaso-occlusion does not cor- relate with the number of irreversibly sickled cells and there- fore appears to result from factors such as infection, inflammation, dehydration, and acidosis that enhance the sickling of reversibly sickled cells.
What is the morphology of sickle cell anemia(anatomic alterations in sickle cell anemia stem from what three things ? What kind of red cells are seen in peripheral smears? What changes do the anatomic alterations cause in the heart,liver and renal tubules? What causes the prominent cheekbones and changes in skull that resemble a crewcut in radiographs? Extramedullary hematopoiesis may appear in which organs? In children why is there moderate splenomegaly in sickle cell anemia? What is autosplenomegaly? Why is the bone marrow prone to ischemia? Priapism can lead to what two diseases? Vascular congestion,thrombosis and infarction can affect any organ. Including which 7 organs ?
MORPHOLOGY
The anatomic alterations in sickle cell anemia stem from (1) the severe chronic hemolytic anemia, (2) the increased breakdown of heme to bilirubin, and (3) microvascular obstructions, which provoke tissue ischemia and infarction. In peripheral smears, elongated, spindled, or boat-shaped irreversibly sickled red cells are evident (Fig. 11–3).
Both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in the heart, liver, and renal tubules. There is a com- pensatory hyperplasia of erythroid progenitors in the marrow. The cellular proliferation in the marrow often causes bone resorption and secondary new bone formation, resulting in prominent cheekbones and changes in the skull resembling a “crewcut” in radiographs. Extramedullary hematopoiesis may appear in the liver and spleen.
In children there is moderate splenomegaly (splenic weight up to 500 g) due to red pulp congestion caused by entrapment of sickled red cells. However, the chronic splenic erythrostasis produces hypoxic damage and infarcts, which over time reduce the spleen to a useless nubbin of fibrous tissue. This process, referred to as autosplenectomy, is complete by adulthood.
Vascular congestion, thrombosis, and infarction can affect any organ, including the bones, liver, kidney, retina, brain, lung, and skin. The bone marrow is particularly prone to ischemia because of its sluggish blood flow and high rate of metabolism. Priapism, another frequent problem, can lead to penile fibrosis and erectile dysfunction. As with the other hemolytic anemias, hemosiderosis and gallstones are common
What is the clinical course of sickle cell anemia (homozygous SCD is usually asymptomatic until when and why? How severe is Anemia in homozygous SCD? Most patients w this SCD have hematocrits of what values? Chronic hemolysis is associated w what two things? What are the most serious crises that can occur in SCD? Which site is commonly involved in vaso-occlusion
? What is a feared complication of SCD? How can it be triggered? How does it occur? WhT other major complication can occur in SCD? What is aplastic crisis? How is it triggered? Patients w SCD are prone to what? And why?
I’m adults what’s the basis for hyposplenism? In earlier childhood phase of splenic enlargement, what interferes w bacterial sequestration and killing? What does this mean for kids w enlarged spleens? SCD patients are predisposed to what type of salmonella infection? In homozygous SCD what is seen in routine perioheral blood smears? How can. Sickling be induced in vitro? How is the diagnosis confirmed? How is prenatal diagnosis of sickle cell anemia performed? What treatment is important to prevent pneumococcal infections ? When will sickle cell trait show symptoms
What therapy reduces pain crises and in which four ways can it work?
Clinical Course
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 18% to 30% (normal range, 36% to 48%). The chronic hemolysis is associated with hyperbilirubine- mia and compensatory reticulocytosis. From its onset, the disease runs an unremitting course punctuated by sudden crises. The most serious of these are the vaso-occlusive, or pain, crises. The vaso-occlusion in these episodes can involve many sites but occurs most commonly in the bone marrow, where it often progresses to infarction.
A feared complication is the acute chest syndrome, which can be triggered by pulmonary infections or fat emboli from infarcted marrow. The blood flow in the inflamed, ischemic lung becomes sluggish and “spleenlike,” leading to sickling within hypoxemic pulmonary beds. This exac- erbates the underlying pulmonary dysfunction, creating a vicious circle of worsening pulmonary and systemic hypox- emia, sickling, and vaso-occlusion. Another major compli- cation is stroke, which sometimes occurs in the setting of the acute chest syndrome. Although virtually any organ can be damaged by ischemic injury, the acute chest syndrome and stroke are the two leading causes of ischemia-related death.
A second 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, while severe, is self-limited.
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 seques- tration and killing; hence, even children with enlarged spleens are at risk for 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.
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 is highly variable. As a result of improvements in supportive care, an increasing number of patients are surviving into adulthood and producing offspring. Of particular importance is prophylactic treat- ment with penicillin to prevent pneumococcal infections. Approximately 50% of patients survive beyond the fifth decade. By contrast, sickle cell trait causes symptoms rarely and only under extreme conditions, such as after vigorous exertion at high altitudes.
A mainstay of therapy is hydroxyurea, a “gentle” inhibi- tor of DNA synthesis. Hydroxyurea reduces pain crises and lessens the anemia through several beneficial intracor- puscular and extracorpuscular effects, including (1) an increase in red cell levels of HbF; (2) an anti-inflammatory effect due to the inhibition of white cell production; (3) an increase in red cell size, which lowers the mean cell hemo- globin concentration; and (4) its metabolism to NO, a potent vasodilator and inhibitor of platelet aggregation. Encouraging results also have been obtained with alloge- neic bone marrow transplantation, which has the potential to be curative.
What is Thalassemia
What is the result of Thalassemia?
Mutations that cause thalassemia are particularly common among whixh populations
As with HbS, it is hypothesized that globin mutations asso- ciated with thalassemia are protective against falciparum malaria. True or false
What are the clinical features of the types of beta thalassemia and the types of alpha thalassemia
The thalassemias are inherited disorders caused by muta- tions that decrease the synthesis of α- or β-globin chains. As a result, there is a deficiency of Hb and additional red cell changes due to the relative excess of the unaffected globin chain. The mutations that cause thalassemia are par- ticularly common among populations in Mediterranean, African, and Asian regions in which malaria is endemic.
β-Thalassemia major:severe anemia,regular blood transfusion required
β-Thalassemia intermedia: Severe anemia, but regular blood transfusions not required
β-Thalassemia minor: Asymptomatic with mild or absent anemia; red cell abnormalities seen
α-Thalassemias
Silent carrier: Asymptomatic; no red cell abnormality (Mainly due to gene deletions)
α-Thalassemia trait: Asymptomatic, like β-thalassemia minor
HbH disease: Severe; resembles β-thalassemia intermedia
Hydrops fetalis: Lethal in utero without transfusions
What mutations underlie thalassemias
Adult hemoglobin is a tetramer composed of which chains? What are these chains encoded by? What do the clinical features depend on? Mutations Associated with beta thalassemia fall in two categories . Name them
Persons inheriting one abnor- mal allele have β-thalassemia minor (also known as β-thalassemia trait), which is asymptomatic or mildly symptomatic. So which people have beta thalassemia major . What is B thalassemia intermedia? State one difference between alpha and beta thalassemia?
The mutations responsible for beta thalassemia disrupt beta globin in synthesis in what ways?
What mechanisms contribute to anemia in beta thalassemia?
What is Ineffective erythropoiesis ? What is the effect of this ?
Alpha thalassemia is caused by what? The severity of the disease is proportional to what? Give an example of this. What is HbH and Hb Bart? How are they formed and what two things do they cause?
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 genes, which lie in tandem on chromosome 11, while the β chains are encoded by a single β-globin gene located on chromo- some 16. The clinical features vary widely depending on the specific combination of mutated alleles that are inherited by the patient (Table 11–3), as described next.
β-Thalassemia
The 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 revealed more than 100 different causative mutations, a majority con- sisting of single-base changes. Most people inheriting any two β0 and β+ alleles have β-thalassemia major; occasionally, persons inheriting two β+ alleles have a milder disease termed β-thalassemia intermedia. In contrast with α-thalassemias (described later), gene deletions rarely underlie β-thalassemias .
The mutations responsible for β-thalassemia disrupt β-globin synthesis in several different ways (Fig. 11–5):
• Mutations leading to aberrant RNA splicing are
the most common cause of β-thalassemia. Some of these mutations disrupt the normal RNA splice junc- tions; as a result, no mature mRNA is made and there is a complete failure of β-globin production, creating β0. Other mutations create new splice junctions in abnormal positions—within an intron, for example. Because the normal splice sites are intact, both normal and abnormal splicing occurs, and some normal β-globin mRNA is made. These alleles are designated β+.
• Some mutations lie within the β-globin promoter and lower the rate of β-globin gene transcription. Because some normal β-globin is synthesized, these are β+ alleles.
• Other mutations involve the coding regions of the β- globin gene, usually with severe consequences. For example, some single-nucleotide changes create termina- tion (“stop”) codons that interrupt the translation of
5 ́
3 ́
β-globin mRNA and completely prevent the synthesis of
β-globin.
Two mechanisms contribute to the anemia in
β-thalassemia. The reduced synthesis of β-globin leads to inadequate HbA formation and results in the production of poorly hemoglobinized red cells that are pale (hypochro- mic) and small in size (microcytic). Even more important is the imbalance in β-globin and α-globin chain syn- thesis, as this creates an excess of unpaired α chains that aggregate into insoluble precipitates, which bind and severely damage the membranes of both red cells and erythroid pre- cursors. A high fraction of the damaged erythroid precursors die by apoptosis (Fig. 11–6), a phenomenon termed ineffec- tive erythropoiesis, and the few red cells that are produced have a shortened life span due to extravascular hemoly- sis. 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 levels of hepcidin, which is a negative regulator of iron absorption .
α-Thalassemia
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 missing .
For example, the loss of a single α-globin gene produces a silent- carrier state, whereas the 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.
What is the morphology of thalassemia ( in Beta thalassemia minor and alpha thalassemia trait,where are the abnormalities confined to? In smears, how do the rbcs appear? What are target cells? In beta thalassemia major, peripheral blood smears show what?
Beta thalassemia intermedia and HbH disease are associated w what kind of peripheral smear findings ? Ineffective erythropoiesis and hemolysis result in what? What does this result in? Extramedullary hematopoiesis and hyperplasia of mononuclear phagocytes result in? The ineffective erythropoietic precursors cause what effect? If steps are not taken to prevent iron overload what can develops? HbH disease and β-thalassemia intermedia are also associated w what three signs?
A range of pathologic features are seen, depending on the specific underlying molecular lesion. On one end of the spec- trum is β-thalassemia minor and α-thalassemia trait, in which the abnormalities are confined to the peripheral blood. In smears the red cells are small (microcytic) and pale (hypo- chromic), but regular in shape. Often seen are target cells, cells with an increased surface area-to-volume ratio that allows the cytoplasm to collect in a central, dark-red “puddle.” On the other end of the spectrum, in β-thalassemia major, peripheral blood smears show marked microcytosis, hypochromia, poikilocytosis (variation in cell size), and anisocytosis (variation in cell shape). Nucleated red cells (normoblasts) are also seen that reflect the underlying eryth- ropoietic drive. β-Thalassemia intermedia and HbH disease are associated with peripheral smear findings that lie between these two extremes. he anatomic changes in β-thalassemia major are similar in kind to those seen in other hemolytic anemias but profound in degree. The 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 remi- niscent of that seen in cancer patients. Unless steps are taken to prevent iron overload, over the span of years severe hemosiderosis develops (Fig. 11–6). HbH disease and β-thalassemia intermedia are also associated with spleno- megaly, erythroid hyperplasia, and growth retardation related to anemia, but these are less severe than in β-thalassemia major.
β-Thalassemia minor and α-thalassemia trait (caused by dele- tion of two α-globin genes) are often asymptomatic. What kind of anemia is usually present? Which other type of anemia is associated w the red cell
appearance seen in beta thalassemia minor and alpha thalassemia trait
When does beta thalassemia major manifest? Affected kids suffer from what? How are they sustained?what is the long term effect of this way to sustain them? When this long term effect occurs,how should patients be treated? HbH disease (caused by deletion of three α-globin genes) and β-thalassemia intermedia are not as severe as β-thalassemia major. Why? How is beta thalassemia major diagnosed on Hb electrophoresis ?
Prenatal diagnosis of β-thalassemia is challenging due to the diversity of causative mutations, 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 molecu- lar diagnostics. The diagnosis of β-thalassemia minor is made by Hb electrophoresis, which typically reveals 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. True or false
Clinical Course
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 labora- tory tests (described later).
β-Thalassemia major manifests postnatally as HbF synthe- sis diminishes. Affected children suffer from growth retar- dation that commences in infancy. They are sustained by repeated 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 over- load 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 chela- tors, cardiac dysfunction from secondary hemochromatosis inevitably develops and often is fatal in the second or third decade of life. When feasible, bone marrow transplantation at an early age is the treatment of choice. HbH disease (caused by deletion of three α-globin genes) and β-thalassemia intermedia are not as severe as β-thalassemia major, since the imbalance in α- and β-globin chain synthe- sis 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.
The diagnosis of β-thalassemia major can be strongly suspected on clinical grounds. Hb electrophoresis shows pro- found reduction or absence of HbA and increased levels of HbF. The HbA2 level may be normal or increased. Similar but less profound changes are noted in patients affected by β-thalassemia intermedia.
What inactivates oxidants that red cells are exposed?
What happens when synthesis of this thing that does the inactivation is affected? How are older red cells more sensitive to oxidant stress?
Episodes of hemolysis are triggered by what? What causes intravascular hemolysis in G6PD deficiency ? What creates bite cells? What is extra vascular hemolysis?
When will G6PD deficiency produce symptoms? Name four drugs that’ll cause G6PD deficiency to produce symptoms?
Clinical Features
Drug-induced hemolysis is acute and of variable severity. Typically, patients develop hemolysis after a lag of 2 or 3 days. Since 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 6) 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. Since the marrow compensates for the anemia by producing new resistant red cells, 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. True or false
Red cells are constantly exposed to both endogenous and exogenous oxidants, which are normally inactivated by reduced glutathione (GSH). Abnormalities affecting the enzymes responsible for the synthesis of GSH leave red cells vulnerable to oxidative injury and lead to hemolytic anemias. By far the most common of these anemias is that caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency. The G6PD gene is on the X chromosome. Because red cells do not synthesize proteins, older G6PD A− red cells become progressively deficient in enzyme activity and the reduced form of glutathione. This in turn renders older red cells more sensitive to oxidant stress.
G6PD deficiency produces no symptoms until the patient is exposed to an environmental factor (most commonly infectious agents or drugs) that produces oxidants. The drugs incriminated include antimalarials (e.g., primaquine), sulfonamides, nitrofurantoin, phenacetin, aspirin (in large doses), and vitamin K derivatives. More commonly, episodes of hemolysis are triggered by infections, which induce phagocytes to generate oxidants as part of the normal host response. These oxidants, such as hydrogen peroxide, are normally sopped up by GSH, which is converted to oxi- dized glutathione 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, which have sulfhydryl groups that are susceptible to oxida- tion. Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions called Heinz bodies, which can damage the cell membrane sufficiently to cause intravas- cular hemolysis. Other, less severely damaged cells lose their deformability and suffer further injury when splenic phago- cytes attempt to “pluck out” the Heinz bodies, creating so-called bite cells .Such cells become trapped upon recirculation to the spleen and are destroyed by phago- cytes (extravascular hemolysis).
What is Paroxysmal nocturnal hemoglobinuria (PNH)
How does it occur?
In Immunohemolytic Anemias
Some individuals develop antibodies that recognize deter- minants on red cell membranes and cause hemolytic anemia. Where do these antibodies come from? Immunohemolytic anemias are uncommon and classified on the basis of what two things? Diagnosis of this anemia depends on detection of what?
This is done with the direct Coombs antiglobulin test, in which the patient’s red cells are incubated with antibodies against human immunoglobulin or complement. In a posi- tive 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 true or false
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare dis- order worthy of mention because it is the only hemolytic anemia that results from an acquired somatic mutation in myeloid stem cells
PATHOGENESIS
PNH stems from acquired mutations in gene PIGA, which is required for the synthesis of phosphatidylinositol glycan (PIG), a membrane anchor that is a component of many proteins. Without the “PIG-tail,” these proteins cannot be expressed on the cell surface. The affected proteins include several that limit the activation of complement. As a result, PIGA-deficient precursors give rise to red cells that are inordinately sensitive to complement-mediated lysis. Leukocytes are also deficient in these protective pro- teins, but nucleated cells are generally less sensitive to com- plement than are red cells, and as a result the red cells take the brunt of the attack. The paroxysmal nocturnal hemolysis that gives the disorder its name occurs because the fixation of complement is enhanced by the slight decrease in blood pH that accompanies sleep (owing to CO2 retention). However, most patients present less dramatically with anemia due to chronic low-level hemolysis. Another complication that is often serious and sometimes fatal is venous throm- bosis.
These antibodies may arise spontaneously or be induced by exogenous agents such as drugs or chemicals. Immunohemolytic anemias are uncommon and classified on the basis of (1) the nature of the antibody and (2) the presence of predisposing conditions (summarized in Table 11–4).
The diagnosis of immunohemolytic anemias depends on the detection of antibodies and/or complement on red cells.
.
Warm Antibody Immunohemolytic Anemias are caused by what? What are the three causes of it? The hemolysis usually results from what? How are the red cells transformed into spherocytes in this kind of anemia? What is the mechanism of hemolysis induced by drugs such as alpha methyldopa and penicillin?
How are cold antibody immunohemolytic anemias caused? Why is hemolysis extra vascular in this type of immunohemolytic anemia?
Binding of pentavalent IgM also cross-links red cells and causes them to clump (agglutinate). Sludging of blood in capillaries due to agglutination often produces Raynaud phenom- enon in the extremities of affected individuals. Cold agglu- tinins 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 agglu- tinin hemolytic anemia occur in association with certain B cell neoplasms or as an idiopathic condition. True or false
Warm antibody immunohemolytic anemias are caused by immunoglobulin G (IgG) or, rarely, IgA antibodies that are active at 37°C. More than 60% of cases are idiopathic (primary), while another 25% are secondary to an underly- ing disease affecting the immune system (e.g., systemic lupus erythematosus) or are induced by drugs. The hemo- lysis usually results from the opsonization of red cells by the autoantibodies, which leads to erythrophagocytosis in the spleen and elsewhere. In addition, incomplete consump- tion (“nibbling”) of antibody-coated red cells by macro- phages removes membrane. With loss of cell membrane the red cells are transformed into spherocytes, which are rapidly destroyed in the spleen, as described earlier for hereditary spherocytosis. The clinical severity of immunohemolytic anemias is quite variable. Most patients have chronic mild anemia with moderate splenomegaly and require no treatment.
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 immu- nogenicity of native epitopes and thereby circumvents T cell tolerance (Chapter 4). Other drugs such as penicillin act as haptens, inducing an antibody response by binding covalently to red cell membrane proteins. Sometimes anti- bodies recognize a drug in the circulation and form immune complexes that are deposited on red cell membranes. Here they may fix complement or act as opsonins, either of which can lead to hemolysis.
Cold antibody immunohemolytic anemias usually are 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 well, the latter steps of the complement fixation 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, the hemolysis is extravascular.
Mechanical hemolysis is sometimes produced by what? Microangiopathic hemolytic anemia is observed where? Name conditions that Microangiopathic hemolytic anemia occurs in . What are the morphologic alterations in the schistocytes in hemolytic anemias due to mechanical trauma of red blood cells?
Hemolytic Anemias Resulting from Mechanical Trauma to Red Cells
Abnormal mechanical forces result in red cell hemolysis in a variety of circumstances. More significant mechanical hemolysis is sometimes produced by defective cardiac valve prostheses (the blender effect), which can create sufficiently turbulent blood flow to shear red cells. 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 intravas- cular 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, hemolytic uremic syndrome, and disseminated cancer. The morphologic alterations in the injured red cells (schistocytes) are striking and quite characteristic; “burr cells,” “helmet cells,” and “triangle cells” may be seen (Fig. 11–8). While microangio- pathic hemolysis is not usually in and of itself a major clinical problem, it often points to a serious underlying condition.
Name the organisms that cause Malaria as a cause of hemolytic anemia that is due to mechanical trauma to red cells . How is it transmitted? What is the pathogenesis of malaria?
The distinctive clinical and anatomic features of malaria are related to four the factors ,name them
Fatal falciparum malaria often involves which part of the body and what’s the name of the complication? Normally, red cells bear nega- tively charged surfaces that interact poorly with endothe- lial cells. What happens when these red cells are infected w P falciparum? How do the cerebral vessels become engorged and occluded in kids who are infected w P falciparum? What three things can occur in cerebral malaria?
Fortunately, falciparum malaria usually pursues a chronic course, which may be punctuated at any time by blackwater fever. The trigger is obscure for this uncommon complication, which is associated with massive intravascular hemolysis, hemo- globinemia, hemoglobinuria, and jaundice. True or false
It is caused by one of four types of protozoa. Of these, the most important is Plasmo- dium falciparum, which causes tertian malaria (falciparum malaria), a serious disorder with a high fatality rate. The other three species of Plasmodium that infect humans— Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale—cause relatively benign disease. All forms are trans- mitted by the bite of female Anopheles mosquitoes, and humans are the only natural reservoir.
The life cycle of plasmodia is complex. 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 reproduc- tion to produce more merozoites or give rise to gameto- cytes capable of infecting the next hungry mosquito. During their asexual reproduction in red cells, each of the four forms of malaria develops into trophozoites with a somewhat distinctive appearance. Thus, the species of malaria that is responsible for an infection can be identified in appropriately stained thick smears of peripheral blood. The asexual phase is completed when the trophozo- ites give rise to new merozoites, which escape by lysing the red cells.
Clinical Features
The distinctive clinical and anatomic features of malaria are related to the following factors:
• Showers of new merozoites are released from the red cells at intervals of approximately 48 hours for P. vivax, P. ovale, and P. falciparum and 72 hours for P. malariae. The episodic shaking, chills, and fever coincide with this release.
• The parasites destroy large numbers of infected red cells, thereby causing a hemolytic anemia.
• A characteristic brown malarial pigment derived from hemoglobin called hematin is released from the rup- tured red cells and produces discoloration of the spleen, liver, lymph nodes, and bone marrow.
• Activation of defense mechanisms in the host leads to a marked hyperplasia of mononuclear phagocytes, producing massive splenomegaly and occasional hepatomegaly.
Fatal falciparum malaria often involves the brain, a complication known as cerebral malaria. Normally, red cells bear nega- tively charged surfaces that interact poorly with endothe- lial cells. Infection of red cells with P. falciparum induces the appearance of positively charged surface knobs con- taining parasite-encoded proteins, which bind to adhesion molecules expressed on activated endothelium. Several endothelial cell adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), have been proposed 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. Cerebral malaria is rapidly progressive; convulsions, coma, and death usually occur within days to weeks.
