THE UNIVERSITY OF JORDAN FACULTY OF MEDICINE DEPARTMENT OF PATHOLOGY HEMOLYTIC ANEMIAS. Dr. Tariq Aladily

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1 THE UNIVERSITY OF JORDAN FACULTY OF MEDICINE DEPARTMENT OF PATHOLOGY HEMOLYTIC ANEMIAS Third year medical students First semester Faculty 2018/2019 of Medicine

2 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

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5 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

6 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

7 Spherocytes appear as small, round cells without the central pallor. Howell Jolly bodies are noted

8 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

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10 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

11 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

12 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

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14 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

15 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 Faculty has more of Medicine severe crisis, might need blood transfusion Recovery is associated with reticulocytosis Dx: enzyme assay (measure conversion to NAPDH)

16 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 Faculty shaped of Medicine RBCs 2,3 diphosphoglycerate Dr. Tariq (DPG) Aladily level increases inside RBCs, facilitating O2 release, ameliorating the anemia

17 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

18 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

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20 Pathogenesis Function of CD55 and CD59 Consequences of deficiency: C3 convertase alternative pathway Frequency of PIG-A mutation among healthy people Autoimmune process?

21 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

22 Diagnosis Flow cytometry (detection of CD55, CD59 on WBCs and RBCs) LDH Retic count

23 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 autoantibody is present, agglutination of RBC occurs

24 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 Faculty on of phagocytes, Medicine which remove red cell membrane during Dr. "partial" Tariq Aladily phagocytosis. As in hereditary spherocytosis, the loss of membrane converts the red cells to spherocytes, which are removed in the spleen Moderate splenomegaly

25 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

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27 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, Faculty following of Medicine infection by Mycoplasma pneumonia, Epstein-Barr virus, cytomegalovirus, influenza virus, and HIV Chronic: associated with B- cell lymphoma, severe

28 RBC agglutination in autoimmune hemolytic anemia

29 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)

30 Schistocytes

31 Thalassemia Heterogeneous group of disorders caused by inherited mutations that decrease the synthesis of adult hemoglobin, HgA (α 2 β 2 ) 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

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33 β-thalassemias caused by mutations that diminish the synthesis of β-globin chains (chromosome 11) β 0 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

34 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

35 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

36 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 Faculty γ 4 tetramers of Medicine known as hemoglobin Barts, whereas in older Dr. Tariq children Aladily and adults excess β- globin chains form β 4 tetramers known as HgH, resembles β- intermedia

37 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

38 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, HgA 2 in increased

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40 Basophilic stippling: aggregates of ribosomes, appear as fine blue inclusions in RBCs

41 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

42 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

43 Splenic changes Early disease: splenomegaly Sequestration crisis: massive entrapment of RBC in spleen, leading to hypovolemia and shock Advanced disease: splenic infarction (autosplenectomy)

44 Vaso-occlusive crisis Thrombosis, tissue infarction Bone and joint pain Skin ulcer (leg) Myocardial infarction Acute chest syndrome Penis (priapism)

45 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

46 Diagnosis Blood film: Sickle cells, Howell Jolly bodies, target cells Hemoglobin electrophoresis

47 Sickle cell anemia: numerous sickle cells and target cells

48 Crew-cut appearance of skull of X ray: secondary to marked erythropoiesis in SSA and B-thal

49 Aplastic crisis: pronormoblast shows nuclear inclusions

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