Published on June 26, 2014
INTRODUCTION: Hemolytic anemia is a condition in which red blood cells are destroyed and removed from the bloodstream before their normal lifespan is over.Red blood cells are disc-shaped and look like doughnuts without holes in the center. These cells carry oxygen to your body. They also remove carbon dioxide (a waste product) from your body.Red blood cells are made in the bone marrow—a sponge-like tissue inside the bones. They live for about 120 days in the bloodstream and then die.White blood cells and platelets (PLATE-lets) also are made in the bone marrow. White blood cells help fight infections. Platelets stick together to seal small cuts or breaks on blood vessel walls and stop bleeding.When blood cells die, the body's bone marrow makes more blood cells to replace them. However, in hemolytic anemia, the bone marrow can't make red blood cells fast enough to meet the body's needs.Hemolytic anemia can lead to many health problems, such as fatigue (tiredness), pain, irregular heartbeats called arrhythmias (ah-RITH-me- ahs), an enlarged heart, and heart failure. Overview Hemolytic anemia is a type of anemia. The term "anemia" usually refers to a condition in which the blood has a lower than normal number of red blood cells.Anemia also can occur if your red blood cells don't contain enough hemoglobin. Hemoglobin is an iron-rich protein that carries oxygen from the lungs to the rest of the body.Anemia has three main causes: blood loss, lack of red blood cell production, or high rates of red blood cell destruction. Hemolytic anemia is caused by high rates of red blood cell destruction. Many diseases, conditions, and factors can cause the body to destroy its red blood cells. These causes can be inherited or acquired. "Inherited" means your parents passed the gene(s) for the condition on to you. "Acquired" means you aren't born with the condition, but you develop it. Sometimes the cause of hemolytic anemia isn't known. Outlook There are many types of hemolytic anemia. Treatment and outlook depend on what type you have and how severe it is. The condition can develop suddenly or slowly. Symptoms can range from mild to severe.Hemolytic anemia often can be successfully treated or controlled. Mild hemolytic anemia may need no treatment at all. Severe hemolytic anemia requires prompt and proper treatment, or it may be fatal.Inherited forms of hemolytic anemia are lifelong conditions that may require ongoing treatment. Acquired forms of hemolytic anemia may go away if the cause of the condition is found and corrected.Normal red blood cell have a life span of 120 days.a nemias cause by accelerated red blood cell destruction are termed as hemolytic anemias.destruction can stem from either intrinsic interacorpuscular red cells defects which are usually inherited or extracorpuscular factors which are usually acquired features shared by all. Features shared by all uncomplicated hemolytic anemias include.A descreased red cell life span.A compensatory increase in erythropoiesis,The retention of the products of degraded red cells by the body.1
Types of hemolytic anemia: Intrinsic abnormalities: Hereditary Spherocytosis: ETIOLOGY: 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 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.2 PATHOGENESIS: Hereditary Spherocytosis is caused by membrane protein defects resulting in cytoskeleton instability. Spectrin deficiency leads to loss of erythrocyte surface area, which produces spherical RBCs. Spherocytic RBCs are culled rapidly from the circulation by the spleen. Patients with HS develop splenomegaly. Biochemical spectrin deficiency and the degree of spectrin deficiency are reported to correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of hemolysis. Hemolysis primarily is confined to the spleen and, therefore, is extravascular. Spectrin deficiency is the result of impaired synthesis, whereas in other instances, it is caused by quantitative or qualitative deficiencies of other proteins that integrate spectrin into the cell membrane. In the absence of these binding proteins, free spectrin is degraded, leading to spectrin deficiency.Four abnormalities in red cell membrane proteins have been identified and include (1) spectrin deficiency alone, (2) combined spectrin and ankyrin deficiency, (3) band 3 deficiency, and (4) protein 4.2 defects. Spectrin deficiency is the most common defect. Each is associated with a variety of mutations that result in different protein abnormalities and varied clinical expression. Most cases of HS are heterozygous because homozygous states are lethal.
Spectrin deficiency Mutations of alpha-spectrin are associated with recessive forms of HS, whereas mutations of beta-spectrin occur in families with autosomal dominant forms of HS.Synthesis of alpha-spectrin is 3-fold greater than that of beta-spectrin. The excess alpha chains normally are degraded. Heterozygotes for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the heterozygous state because synthesis of beta-spectrin is the rate-limiting factor. Red cell membranes isolated from individuals with autosomal recessive HS have only 40-50% of the normal amount of spectrin (relative to band protein 3), whereas red cell spectrin levels range from 60-80% of normal in the autosomal dominant form of HS. Identification of an alpha-spectrin mutation involves a point mutation at codon (969), resulting in an amino acid substitution (alanine [Ala]/aspartic acid [Asp]) at the corresponding site of alpha-spectrin in 50% of patients with severe recessive HS. Mutations involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency. The first identified point mutation leads to a defective binding of spectrin to protein 4.1. Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo proteolytic degradation. Ankyrin defects HS is described in patients with translocation of chromosome 8 or deletion of the short arm of chromosome 8 where the ankyrin gene is located, and patients with HS and deletion of chromosome 8 are shown to have a decrease in red cell ankyrin content. Ankyrin is the principal binding site for spectrin on the red cell membrane. Studies of cytoskeletal protein assembly in reticulocytes indicate that ankyrin deficiency leads to decreased incorporation of spectrin. In HS caused by ankyrin deficiency, a proportional decrease in spectrin content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with autosomal dominant HS have combined spectrin and ankyrin deficiency and the 2 proteins are diminished equally. Band 3 deficiency Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the membrane. In some people with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable. Protein 4.2 (pallidin) deficiency Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. Spherocytes, elliptocytes, or sphero- ovalocytes have characterized RBC morphology. Deficiency of protein 4.2 in HS is relatively common in Japan. One that appears to be common in the Japanese population (protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype.3
PATHOGENESIS OF HEREDITARY SPHEROCYTOSIS
MORPHOLOGY: on smears,spherocytes are dark and lack central pallor.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. Splanomagly is more common and prominent in hereditary then in any other form of hemolytic anemia.The splenic weight usually is between 500 and 1000g.The enlargement results from marked congestion of the splenic cords and increased numbers of tissue macrophages.Phagocytosed red cells are seen wihin macrophages lining the sinusoids and in particular,within the cords.In long-standing cses there is prominent systemic hemosiderosis.The other general feature of hemolytic anemias also are present,including cholelithiasis,which occurs in 40% to 50% of patients with hereditary spherocytosis.4 Clinical Features: The 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 characteristic 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 sphecrocytosis have a shortened life span,a lack of red cell production for even a few days results in a rapid worsening of the anemia.Such episodes are self-limited,but some patients need supportive blood transfusions during the period of red cell aplasia. There is no specific treatment for hereditary spherocytosis.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 suspectibility to infections,particularly in children.Partial splenectomy is gaining favour,because this approach may produce hematologic improvement while maintaining protection against sepsis.5 HEREDITARY SPHEROCYTOSIS –PHERIPHERAL BLOOD SMEAR
SICKLE CELL ANEMIA: Sickle cell disease (SCD) and its variants are genetic disorders resulting from the presence of a mutated form of hemoglobin, hemoglobin S (HbS). The most common form of SCD found in North America is homozygous HbS disease (HbSS), an autosomal recessive disorder first described by Herrick in 1910. SCD causes significant morbidity and mortality, particularly in people of African and Mediterranean ancestry (see Pathophysiology). Morbidity, frequency of crisis, degree of anemia, and the organ systems involved vary considerably from individual to individual.Approximately half the individuals with homozygous HbS disease experience vaso-occlusive crises. The frequency of crises is extremely variable. Some individuals have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or none at all. Each individual typically has a consistent pattern for crisis frequency. Many individuals with HbSS experience chronic low-level pain, mainly in bones and joints. Intermittent vaso-occlusive crises may be superimposed, or chronic low-level pain may be the only expression of the disease.Carriers of the sickle cell trait (ie, heterozygotes who carry one Hb S allele and one normal adult hemoglobin [HbA] allele) have some resistance to the often-fatal malaria caused by Plasmodium falciparum. This property explains the distribution and persistence of this gene in the population in malaria-endemic areas. ETIOLOGY: SCD originated in West Africa, where it has the highest prevalence. It is also present to a lesser extent in India and the Mediterranean region. DNA polymorphism of the beta S gene suggests that it arose from 5 separate mutations, 4 in Africa and 1 in India and the Middle East. The most common of these is an allele found in Benin in West Africa. The other haplotypes are found in Senegal and Bantu, Africa, as well as in India and the Middle East.The HbS gene, when present in homozygous form, is an undesirable mutation, so a selective advantage in the heterozygous form must account for its high prevalence and persistence. Malaria is possibly the selecting agent because a concordance exists between the prevalence of malaria and Hb S. Sickling might protect a person from malaria by either (1) accelerating sickling so that parasitized cells are removed or (2) making it more difficult for the parasite to metabolize or to enter the sickled cell. While children with sickle cell trait Hb SA seem to have a milder form of falciparum malaria, those with homozygous Hb S have a severe form that is associated with a very high mortality rate.The sickling process that prompts a crisis may be precipitated by multiple factors. Local tissue hypoxia, dehydration secondary to a viral illness, or nausea and vomiting, all of which lead to hypertonicity of the plasma, may induce sickling. Any event that can lead to acidosis, such as infection or extreme dehydration, can cause sickling. More benign factors and environmental changes, such as fatigue, exposure to cold, and psychosocial stress, can elicit the sickling process. A specific cause is often not identified.
Vaso-occlusive crises are often precipitated by the following: Cold weather (due to vasospasm) Hypoxia (flying in unpressurized aircraft)Infection Dehydration (especially from exertion or during warm weather) Acidosis Alcohol intoxication Emotional stress Pregnancy Data also suggest a role for exertional stress, particularly when compounded with heat and hypovolemia. Aplastic crises are often preceded by the following: Infection with parvovirus B19 Folic acid deficiency Ingestion of bone marrow toxins (eg, phenylbutazone) Acute chest syndrome has been linked to fat embolism and infections, pain episodes, and asthma. PATHOGENESIS: HbS arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamate in position 6 of the Hb beta chain. The resulting Hb has the physical properties of forming polymers under deoxy conditions. It also exhibits changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes.Under deoxy conditions, HbS undergoes marked decrease in solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL. It forms a gel-like substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form. A number of factors influence this equilibrium, including oxygen tension, concentration of Hb S, and the presence of other hemoglobins.Oxygen tension is a factor in that polymer formation occurs only in the deoxy state. If oxygen is present, the liquid state prevails. Concentration of Hb S is a factor in that gelation of HbS occurs at concentrations greater than 20.8 g/dL (the normal cellular Hb concentration is 30 g/dL). The presence of other hemoglobins is a factor in that normal adult hemoglobin (HbA) and fetal hemoglobin (HbF) have an inhibitory effect on gelation. MOLECULAR AND CELLULAR CHANGES IN HBS
These and other Hb interactions affect the severity of clinical syndromes. HbSS produces a more severe disease than sickle cell HbC (HbSC), HbSD, HbSO Arab, and Hb with one normal and one sickle allele (HbSA). When red blood cells (RBCs) containing homozygous HbS are exposed to deoxy conditions, the sickling process begins. A slow and gradual polymer formation ensues. Electron microscopy reveals a parallel array of filaments.Repeated and prolonged sickling involves the membrane; the RBC assumes the characteristic sickled shape. 6 PATHOPHYSIOLOGY OF SICKLE CELL DISEASE
MORPHOLOGY: The anatomic alterations in sickle cell anemia stem from The severe chronic hemolytic anemia The increased breakdown of heme to bbiliruin Microvascular obstructions,which provide tissue ischemia and infraction. In peripheral smears,elongated,spindled,or boat-shaped irreversibly sickled red cells are evident.both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in heart,liver,and renal tubules.There is a compensatory 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 skull resembling a “crewcut”in radiographs.Extramedullary hematopoiesis may appear in the liver and spleen. Vascular congestion,thrombosis and infraction can affect any organ,including the bones,liver,kidney,retina,brain,lung,and skin.7
THALASSEMIA: Majorly exist in two forms: ETIOLOGY: Common causes Genetic: Most of the alpha-thalassemia syndromes result from gene deletions Most of the beta-thalassemia syndromes result from nucleotide substitutions or deletions in genes that are otherwise intact The clinical heterogeneity of the thalassemia syndromes is a reflection of the great heterogeneity of mutations that affect the globin genes Thalassemia intermedia may be produced by a great variety of genotypes Normal hemoglobin: Adults have mainly hemoglobin A, made up of two alpha and two beta chains, together with HbA2 <2% (two alpha and two delta chains), and no HbF (two alpha and two gamma-globin chains) There are four alpha genes (located on chromosome 16) and two beta genes (on chromosome 11) At birth HbF accounts for 70-90% in normal individuals, and gamma-chain synthesis is only replaced by beta chains gradually Impairment of beta synthesis leads to the patient being asymptomatic at birth Alpha-thalassemias: The alpha-thalassemias result from mutations that cause decreased synthesis of structurally normal globin Two alpha-thalassemia phenotypes are recognized, and are referred to as follows: alpha-thalassemia 1 and alpha-thalassemia 2 (alpha+ thalassemia - low level of alpha chains) Hydrops fetalis has no alpha-globin gene (alpha0 thalassemia- no alpha chains) Hemoglobin H disease has one alpha-globin gene Alpha (α)thalassemias Beta (β) thalassemias
Beta-thalassemias: There is only one beta-globin gene, of which there are two alleles (paternal and maternal) Globin chain synthesis in the homozygous state reveals two major types of beta-thalassemia: beta+ type (suboptimal beta chains present) and beta0 type (total absence of beta chains) The beta-thalassemia syndromes are caused by mutations of the expressed beta+ allele and nonexpressed beta-0 alleles The mutations affect gene regulation or expression rather than gene deletion, and can result in decreased synthesis of structurally normal globin In individuals with beta+ thalassemia, the amount of beta-globin messenger RNA in reticulocytes and bone marrow normoblasts is decreased 3- to 10-fold In patients with homozygous beta0 thalassemia, beta-globin synthesis is absent PATHOGENESIS: The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected. Thalassemia produces a ''deficiency'' of α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin. β globin chains are encoded by a single gene on chromosome 11; α globin chains are encoded by two closely linked genes on chromosome 16. Thus in a normal person with two copies of each chromosome, there are two loci encoding the β chain, and four loci encoding the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α thalassemias. β thalassemias are common in Africans, but also in Greeks and Italians. Alpha (α) thalassemias The α thalassemias involve the genes HBA1 and HBA2, inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. α thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.
Beta (β) thalassemias Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (βo) if they prevent any formation of β chains (which is the most severe form of beta Thalassemia); they are characterized as (β+) if they allow some β chain formation to occur. In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.8 Pathogenesis Of Beta (β) thalassmias
MORPHOLOGY: A range of pathologic features are seen,depending on the specific underlying molecular lesion.on one end of the spectrum is b-thalassemia minor and a-thalassemia trait,in which the abnormalties are confined to the pheripheral blood.In smears the red cells are small (microcytic)and pale (hypochromatic),but regular in shape.Often seen are target cells ,with an increase surface area to volume ratio that allows the cytoplasm to collect in central ,dark red “puddle”.9 References: 1 http://emedicine.medscape.com/article/201066-overview http://www.nhlbi.nih.gov/health/health-topics/topics/ha/ 2Robbins basic pathology byKumar Abbas aster ch-11 hematopoietic and lymphoid systems pg:no:410 3http://emedicine.medscape.com/article/206107-overview#a0104 4Robbins basic pathology byKumar Abbas aster ch-11 hematopoietic and lymphoid systems pg:no:410 5Robbins basic pathology byKumar Abbas aster ch-11 hematopoietic and lymphoid systems pg:no:411 6http://emedicine.medscape.com/article/205926-overview#aw2aab6b2b4 7Robbins basic pathology byKumar Abbas aster ch-11 hematopoietic and lymphoid systems pg:no:412 8http://www.news-medical.net/health/Thalassemia-Pathophysiology.aspx https://www.clinicalkey.com/topics/hematology/thalassemia.html 9Robbins basic pathology byKumar Abbas aster ch-11 hematopoietic and lymphoid systems pg:no:415
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1. Mutat Res. 2009 Jul 31;668(1-2):4-10. doi: 10.1016/j.mrfmmm.2009.01.013. Epub 2009 Feb 28. Fanconi anemia and its diagnosis. Auerbach AD(1).
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