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Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
THE UNIVERSITY OF JORDAN
FACULTY OF MEDICINE
DEPARTMENT OF PATHOLOGY
HEMOLYTIC ANEMIAS
Third year medical students
First semester
2018/2019
Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
Hereditary Spherocytosis
• Intrinsic defects in the red cell membrane skeleton
• Northern Europe
• AD inheritance pattern
• Frameshift mutations
• Small spherocytes, normal Hg, (high MCHC)
• Gas exchange function is generally preserved
• Life span: 20 days
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
Clinical features
• Congestion of RBCs in the spleen causes splenomegaly and anemia
• Jaundice, pigmented gall bladder stones
• Reticulocytosis
• Family Hx of anemia or splenectomy
• Abnormal osmotic fragility test
• Treatment: splenectomy
Faculty of Medicine Dr. Tariq Aladily
Morphology
• Blood film: RBCs are round, small, hyperchromatic, no visible central pallor
• “Howell-Jolly” bodies are seen in post splenectomy. A fragment of chromosome which is detached and left in the cytoplasm after the extrusion of the nucleus, secondary to accelerated erythropoiesis. Appears as 1 or 2 eccentric dots
Faculty of Medicine Dr. Tariq Aladily
Spherocytes appear as small, round cells without the central pallor. Howell Jolly bodies are noted
Faculty of Medicine Dr. Tariq Aladily
Glucose-6-Phosphate Dehydrogenase Deficiency
• G6PD reduces nicotinamide adenine dinucleotide phosphate (NADP) to NADPH while oxidizing glucose-6-phosphate
• Present in all cells
• X-linked trait
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
Types of G6PD deficiency
• Several hundred G6PD genetic variants are known, but most are harmless
• The normal enzyme is called G6PD-B
• Only two variants, designated G6PD-A and G6PD Mediterranean, cause most of the clinically significant hemolytic anemias
• G6PD-A is present in about 10% of American blacks; G6PD Mediterranean is prevalent in the Middle East
Faculty of Medicine Dr. Tariq Aladily
Pathogenesis
• The half-life of G6PD-A is moderately reduced, whereas that of G6PD Mediterranean is functionally abnormal
• Because mature red cells do not synthesize new proteins, G6PD-A or G6PD Mediterranean enzyme activities fall quickly to levels inadequate to protect against oxidant stress as red cells age. Thus, older red cells are much more prone to hemolysis than younger ones
Faculty of Medicine Dr. Tariq Aladily
Pathogenesis
• Exposure to high levels of oxidants
• both intravascular and extravascular hemolysis
• cross-linking of globin chains, denaturation, membrane bound precipitates (Heinz bodies – supravital, crystal violet stain), membrane damage
• Splenic macrophages identify Heinz bodies and pluck them out “bite cells”
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
Causes of hemolytic crisis
Infections Drugs • antimalarials (e.g., primaquine and chloroquine),
sulfonamides, nitrofurantoins Food • fava bean (Favism) Chemicals Naphthalene, aniline dyes Unknown • chronic low-grade hemolytic anemia, neonates, absent
triggers
Faculty of Medicine Dr. Tariq Aladily
Clinical features • Normally asymptomatic • anemia develops when the enzyme level drops below 20%
of normal activity • Hemolytic crisis appear 2-3 days after exposure to oxidant • Only old RBCs hemolize, HB level drops, RBCs appear
normochromic normocytic, • Bone, muscle, joint pain • Typically, splenomegaly and GB stones are absent • G6PD-A usually is self-limited • G6PD-Mediterranian has more severe crisis, might need
blood transfusion • Recovery is associated with reticulocytosis • Dx: enzyme assay (measure conversion to NAPDH)
Faculty of Medicine Dr. Tariq Aladily
Pyrovate kinase deficiency
• AR inheritance
• PK is an enzyme in the anaerobic glycolysis pathway (main pathway in RBCs)
• PK deficiency causes decreased ATP level which is essential for cell membrane pumps
• Intracellular Na accumulates, causing swelling of RBCs and rigidity
• Spleen clears abnormal shaped RBCs
• 2,3 diphosphoglycerate (DPG) level increases inside RBCs, facilitating O2 release, ameliorating the anemia
Faculty of Medicine Dr. Tariq Aladily
Clinical
• Degree of anemia varies according to type of mutation, ranging from neonatal jaundice to anemia presenting in adulthood with jaundice, GB stones and splenomegaly
• Anemia is exacerbated by stress
• Blood film shows NN anemia, variable reticulocytosis, anisopoikelocytosis
• Diagnosis: enzyme assay
• Treatment: splenectomy
Faculty of Medicine Dr. Tariq Aladily
Paroxysmal Nocturnal Hematuria
• Acquired disease
• Some proteins are attached to cell membrane through a covalent linkage to a specialized phospholipid called glycosylphosphatidylinositol (GPI)
• In PNH, there is a mutation in the phosphatidylinositol glycan complementation group A gene (PIG-A), which synthesizes GPI
• Thus, GPI and their normally anchored proteins are absent
• Mutation occurs in hematopoietic stem cell
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
Pathogenesis
• Function of CD55 and CD59
• Consequences of deficiency: C3 convertase – alternative pathway
• Frequency of PIG-A mutation among healthy people
• Autoimmune process?
Faculty of Medicine Dr. Tariq Aladily
Clinical features
Anemia: • Acute: hemoglobinurea, nocturnal (25%), Ham
test • Chronic: no hemoglobinurea Platelets: • Thrombocytopenia, frequent thrombosis (death) Granulocytes: • Neutropenia ± • In severe cases: pancytopenia (aplastic anemia?) • 5% to 10% MDS or AML
Faculty of Medicine Dr. Tariq Aladily
Diagnosis
• Flow cytometry (detection of CD55, CD59 on WBCs and RBCs)
• LDH
• Retic count
Faculty of Medicine Dr. Tariq Aladily
Autoimmune hemolytic anemia
• A group of anemias in which an abnormal immunoglobulin is attached to RBC membrane
• Coombs test: the patient's blood is mixed with serum containing antibodies that are specific for human immunoglobulin. If the auto-antibody is present, agglutination of RBC occurs
Faculty of Medicine Dr. Tariq Aladily
Warm Antibody Type
• 70% of immunohemolytic anemias
• 50% are idiopathic (primary); the others are related to a predisposing condition or exposure to a drug.
• Most causative antibodies are of the IgG class; less commonly, IgA antibodies
• A common target is the Rh antigen on RBCs
• The red cell hemolysis is mostly extravascular. IgG-coated red cells bind to Fc receptors on phagocytes, which remove red cell membrane during "partial" phagocytosis. As in hereditary spherocytosis, the loss of membrane converts the red cells to spherocytes, which are removed in the spleen
• Moderate splenomegaly
Faculty of Medicine Dr. Tariq Aladily
Drug induced hemolytic anemia
Antigenic drugs
• large, intravenous doses of the offending drug
• Drug binds cell membrane
• occurs 1 to 2 weeks after therapy is initiated
• Penicillin, cephalosporins, anti malaria
Tolerance-breaking drugs
• Unknown mechanism
• Activates production of antibodies against Rh group
• α-methyldopa
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
Cold Agglutinin Type
• IgM antibodies
• bind red cells at low temperatures (0°-4°C), then dissociate
• Attract few amount of (C3b), recognized by macrophages
• less common than warm immunohemolytic anemia
• Acute: Self-limited, following infection by Mycoplasma pneumonia, Epstein-Barr virus, cytomegalovirus, influenza virus, and HIV
• Chronic: associated with B- cell lymphoma, severe
Faculty of Medicine Dr. Tariq Aladily
• RBC agglutination in autoimmune hemolytic anemia
Faculty of Medicine Dr. Tariq Aladily
Hemolytic Anemia Resulting from Trauma to Red Cells
• Physical damage to RBCs
• (1) Cardiac valve prosthesis
• (2) Vigorous exercise
• (3) Microangiopathic diseases:
(a) disseminated intravascular coagulation (DIC)
(b) thrombotic thrombocytopenic purpura (TTP)
(c) hemolytic-uremic syndrome (HUS), aggregates of fibrin and platelets causes damage to RBCs
• RBCs appear as fragments (schistocytes)
Faculty of Medicine Dr. Tariq Aladily
Schistocytes
Faculty of Medicine Dr. Tariq Aladily
Thalassemia
• Heterogeneous group of disorders caused by inherited mutations that decrease the synthesis of adult hemoglobin, HgA (α2β2)
• Endemic in Middle East, tropical Africa, India, Asia
• β-Thalassemia is caused by deficient synthesis of β chains, whereas α-thalassemia is caused by deficient synthesis of α chains
• The hematologic consequences of diminished synthesis of one globin chain stem not only from hemoglobin deficiency but also from a relative excess of the other globin chain, particularly in β-thalassemia
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily
β-Thalassemias
• caused by mutations that diminish the synthesis of β-globin chains (chromosome 11)
• β0 mutations, associated with absent β-globin synthesis
• β+ mutations, characterized by reduced (but detectable) β-globin synthesis
• 100 different causative mutations, mostly consisting of point mutations
Faculty of Medicine Dr. Tariq Aladily
Pathogenesis • Lower production of HgA
• RBCs: hypochromic, microcytic hypoxia
• Unpaired α chains precipitate (insoluble) in erythroid precursors and RBCs, membrane damage
• Hemolysis in BM, blood and spleen
• BM: marked erythroid hyperplasia, eroding bone and shifting oxygen and nutrients
• Ineffective erythroipoiesis extramedullary hematopoiesis
• Repeated blood transfusion + suppressed Hepcidin hemosiderosis
Faculty of Medicine Dr. Tariq Aladily
Clinical classification
• β -thal minor: loss of one β alleles, asymptomatic
• β – thal intermedia: loss of two β alleles. Patients have moderate anemia, but stable
• β – thal major: loss of two β alleles. Severe symptoms
Faculty of Medicine Dr. Tariq Aladily
α- Thalassemia
• Gene deletion • Since free β and γ chains are more soluble than free α
chains, hemolysis and ineffective erythropoiesis are less severe than in β-thalassemias
• As in β-thalassemias, the anemia occurs both from inadequate hemoglobin synthesis and the effects of excess unpaired non-α chains (β, γ, and δ)
• In newborns with α-thalassemia, excess unpaired γ-globin chains form γ4 tetramers known as hemoglobin Barts, whereas in older children and adults excess β-globin chains form β4 tetramers known as HgH, resembles β- intermedia
Faculty of Medicine Dr. Tariq Aladily
Clinical classification
• Silent carrier: a single gene deletion, patients have microcytosis but no anemia, asymptomatic
• α-Thalassemia Trait: deletion of two genes, clinically identical to β-thalassemia minor: microcytosis, minimal or no anemia, aymptomatic
• Hemoglobin H Disease: deletion of 3 genes, common in Asia, clinically resembles β-thalassemia intermedia
• Hydrops fetalis: deletion of 4 genes. Patients die in utero unless transfused
Faculty of Medicine Dr. Tariq Aladily
Diagnosis of thalassemia
• Blood film: hypochromic microcytic anemia, target cells, basophilic stippling
• Hg electrophoresis: different globin chains have different electrical charges. Hg is separated on gel and an electrical current is applied. Each type of Hg migrate a specific distance and hence can be recognized
• In β-thal, HgA2 in increased
Faculty of Medicine Dr. Tariq Aladily
Faculty of Medicine Dr. Tariq Aladily Basophilic stippling: aggregates of ribosomes, appear as
fine blue inclusions in RBCs
Faculty of Medicine Dr. Tariq Aladily
Sickle cell anemia
• AR
• Common in Africa, Middle East
• Point mutation on β gene, glutamate residue is replaced with valine (HgS)
• 1 gene: sickle cell trait (silent carrier), HgS =40%
• 2 genes: sickle cell disease, HgS =90%
• Both conditions protect against Malaria falciparum infection
Faculty of Medicine Dr. Tariq Aladily
Pathogenesis
• HgS polymerizes longitudinally upon hypoxia, acidity, dehydration
• Needle-like shape • Membrane damage • Intra + extravascular hemolysis • Capillary occlusion • HgA, HgF prevent sickling • With chronic hemolysis: BM, bone changes &
extramedullay hematopoiesis similar to thalassemia
Faculty of Medicine Dr. Tariq Aladily
Splenic changes
• Early disease: splenomegaly
• Sequestration crisis: massive entrapment of RBC in spleen, leading to hypovolemia and shock
• Advanced disease: splenic infarction (autosplenectomy)
Faculty of Medicine Dr. Tariq Aladily
Vaso-occlusive crisis
• Thrombosis, tissue infarction
• Bone and joint pain
• Skin ulcer (leg)
• Myocardial infarction
• Acute chest syndrome
• Penis (priapism)
Faculty of Medicine Dr. Tariq Aladily
Aplastic crisis
• Parvovirus B19
• Destroys erythroid cells
• Patients present with sudden, severe, worsening anemia
• Nuclei of erythroid precursors show inclusions (viral particles)
• Also complicates thalassemia
Faculty of Medicine Dr. Tariq Aladily
Diagnosis
• Blood film:
• Sickle cells, Howell Jolly bodies, target cells
• Hemoglobin electrophoresis
Faculty of Medicine Dr. Tariq Aladily
• Sickle cell anemia: numerous sickle cells and target cells
Faculty of Medicine Dr. Tariq Aladily • Crew-cut appearance of skull of X ray: secondary
to marked erythropoiesis in SSA and B-thal
Faculty of Medicine Dr. Tariq Aladily
• Aplastic crisis: pronormoblast shows nuclear inclusions
Faculty of Medicine Dr. Tariq Aladily
THE END
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