r ed blood cell disorder ii by :dr abiodun mark akanmode md
TRANSCRIPT
RED BLOOD CELL DISORDER II
By :Dr Abiodun Mark Akanmode MD.
MACROCYTIC ANEMIAS. All macrocytic anemia are characterized my an MCV
value >100.
Macrocytic anemia can be further classified into megaloblastic and non megaloblastic anemia.
MEGALOBLASTIC ANEMIA. The megaloblastic anemia's are disorders caused by
impaired DNA synthesis.
They are characterized by a distinctive abnormality in the hematopoietic precursors in the bone marrow in which the maturation of the nucleus is delayed relative to that of the cytoplasm.
The underlying defect for the asynchronous maturation of the nucleus is defective DNA synthesis due to deficiency of vitamin B12 (cobalamin) and/or folic acid (folate).
MORPHOLOGY. The presence of red cells that are macrocytic and oval
is highly characteristics of magaloblastic anemia.
Because they are larger than normal and contain ample Hb, most macrocytes lack the central area of pallor.
There is also a marked variation n the size and shape of the red cells.
The neutrophils are larger than normal with their nucleus having 5 or more lobes.
ANEMIA OF VIT B12 DEFICIENCY: PERNICIOUS ANEMIA. Pernicious anemia is a specific form of megaloblastic
anemia caused by autoimmune gastritis and also a failure in production of intrinsic factor which eventually leads to vitamin B12 deff.
2 main auto antibodies are associated with pernicious anemia:
Type I: Blocks binding of Vit B12 to intrinsic factor.
Type II: Prevents the binding of the IF-B12 complex to ileal receptors.
CLINICAL FEATURES OF PERNICIOUS ANEMIA. Pernicious anemia is insidious in onset so the anemia is
often severe by the time the pt seeks help.
Diagnosis is based on:
-Moderate to severe megalobalastic anemia.-Leukopenia with hypersegmented granulocytes.-Low serum Vit B12 levels.-Elevated levels of homocysteine & methylmalonic acid in serum.-Presence of serum antibodies.
NB: Elevated homocysteine levels is a risk factor for atherosclerosis and thrombosis and its suspected that vit B12 deficiency may increase the incidence of vascular disease.
METABOLISM OF VITAMIN B12. Humans are dependant on dietary cobalamin.
Daily requirements of cobalamin is 2-3µg.
A diet of animal product includes large amt of B12 that can last several years.
B12 absorption requires IF, which is secreted by the parietal cells of the fundic mucosa.
Absorbed Vit B12 then makes its way into the liver and other rapidly dividing cells of the body in the bone marrow and GI tract.
BIOCHEMICAL FUNCTION OF B12. Only 2 reaction is humans are known to require B12.
In the first reaction Vit B12 serves as an essential cofactor in the conversion of homocysteine to methionine by methionine synthase.
The other reaction involves the isomerization of methylmalonylcoA to succinyl CoA.
CLINICAL PROBLEMS ASSOCIATED WITH VIT B12 DEFF. Tongue glossitis.
Neurologic diseases:-Peripheral neuropathy with sensorimotor defects.-Sub acute combined degeneration of the spinal cord(SACB)-Dementia from brain involvement.
The schilling’s test has been used to diagnose the cause of Vit B12 deficiency.
ANEMIA OF FOLATE DEFICIENCY. The 3 major causes of folic acid deficiency are:
-Decreased intake.-Increased requirements.-Impaired utilization.
Folic acid is generally abundant in raw foods but very sensitive to heat and are easily destroyed during cooking/frying.
Deficiency of folate is associated with impaired DNA synthesis delays nuclear maturation.
FOLIC ACID METABOLISM
Polyglutamate form is present in green vegetables and animal proteins converted to monoglutamates by intestinal conjugase in the jejunum.
Intestinal conjugase is inhibited by phenytoin.
Monoglutamate is absorbed in the jejunum (active and passive transport).
a. Monoglutamate is converted to methyltetrahydrofolate, the circulating form of folic acid.
b. Absorption of monoglutamate is also blocked by alcohol and oral contraceptives (OCPs).
c. The liver contains only a 3- to 4-month supply of folic acid.
NON-MEGALOBLASTIC MACROCYTOSIS
General differences of non-megaloblastic macrocytosis from megaloblastic macrocytic anemia's include:
a. Macrocytes are round rather than oval or egg-shaped.
b. Hypersegmented neutrophils are not present in the peripheral blood.
c. Leukocytes and platelets are quantitatively normal.
d. Glossitis and neuropathy are absent.
e. Anemia may not be present.
f. Alcohol excess is the most common cause for all types of the macrocytosis.
HEMOLYTIC ANEMIAS Hemolytic anemia's all share the following features:
Premature Rbc destruction(<120days)
Elevated erythropoietin levels and a compensatory increased erythropoesis.
Accumulation of Hb degradation products.
In majority of cases the destruction of Rbc occurs within the phagocyte i.e. Extravacular hemolysis.
Less commonly intravascular hemolysis predominates and its caused by mechanical injury, complement fixation, intracellular parasites etc.
HEMOLYTIC ANEMIA.PATHOGENESIS.
Pathogenesis of hemolytic anemia's:
Intrinsic hemolytic anemia: here there is a defect in the RBC causing the anemia e.g. hereditary spherocytosis, sickle cell anemia,G6PD etc
Extrinsic hemolytic anemia: here factors outside the RBC are responsible for the hemolysis e.g. stenotic aortic valve and immune destruction.
HEMOLYTIC ANEMIA.MECHANISMS.
The 2 major mechanisms responsible for hemolysis include:
Extravascular hemolysis. Intravascular hemolysis.
EXTRAVASCULAR HEMOLYSIS
Premature destruction of red cells within phagocytes of the spleen secondary to the following:
(RBCs are coated by IgG + C3b and macrophages have receptors for IgG and C3b)
Reduced deformability of red cells (abnormally shaped RBCs)
RBCs containing inclusions
Regardless of the cause of extravascular hemolysis, the principal features are:
“ANEMIA, SPLENOMEGALY AND JAUNDICE”
EXTRAVASCULAR HEMOLYSIS
• Maybe decrease in plasma haptoglobin
• Benefit from splenectomy
INTRAVASCULAR HEMOLYSIS
Mechanical damage Enzyme deficiency Complement mediated lysis
Hemoglobinemia, Hemoglobinuria and Hemosiderinuria.
Other features Include anemia & jaundice.
Plasma Haptoglobin is reduced, Serum LDH is elevated
HEREDITARY SPHEROCYTOSIS Intrinsic defect in membrane
RBCs become spheroid, less deformable, vulnerable to splenic sequestration and destruction (Extravascular Hemolysis)
Prevalence is highest in northern Europe (most common intracorpuscular inherited hemolytic anemia in whites)
Autosomal dominant inheritance pattern
PATHOGENESIS
• Life span of RBC ↓10 to 20 days (normal: 120 days)
• Mutations: mostly affect spectrin, ankyrin, band 3,or band 4.2
• After splenectomy - spherocytes persist, but the anemia is corrected
MORPHOLOGY
Spherocytosis
Reticulocytosis Marrow erythroid
hyperplasia Hemosiderosis Mild jaundice
Cholelithiasis (pigment stones) in 40% to 50%
Moderate splenomegaly
OSMOTIC FRAGILITY
Spherocytes are abnormally sensitive to osmotic lysis when incubated in hypotonic salt solutions
CLINICAL FEATURES
Increased MCHC
Anemia, splenomegaly and jaundice
Aplastic crises triggered by parvovirus infection
Hemolytic crises
Symptomatic Gallstones
Splenectomy treats the anemia and its complications (increases risk of sepsis)
OTHER CAUSES OF SPHEROCYTOSIS
Warm Antibody Immunohemolytic Anemias
ABO hemolytic disease of newborn
HEREDITARY ELLIPTOCYTOSIS Autosomal dominant
Mutation in spectrin/band 4.1
Intrinsic defect with extravascular hemolysis
Mild hemolytic anemia
>25% elliptocytes in peripheral blood
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
• Most common enzyme deficiency causing hemolysis
• Intrinsic defect with predominantly intravascular hemolysis and mild extravascular hemolysis
• G6PD deficiency: no symptoms until patient is exposed to an environmental factor (infection/drugs) producing oxidants
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
• G6PD gene on X chromosome, highest prevalence is in tropical Africa
• G6PD A : 10% of black males in United States (normal enzymatic activity but decreased half-life)
• G6PD Mediterranean - Hemolysis is more severe (half-life of G6PD in this variant is markedly reduced (<10% activity)
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
DRUGS : Antimalarials (Primaquine), Sulfonamides, Nitrofurantoin, Phenacetin, Dapsone, Aspirin(in large doses), and Vitamin K derivatives
FAVA beans (in persons of Mediterranean origin)
PATHOGENESIS
Infections induce phagocytes to generate oxidants (e.g. hydrogen peroxide), which are normally stopped up by GSH.
Regeneration of GSH is impaired in G6PD-deficient cells
MORPHOLOGY
Oxidized hemoglobin forms intracellular inclusions called HEINZ BODIES
Splenic phagocytes attempt to “pluck out” Heinz bodies, creating BITE CELLS
RBCs trapped in spleen and destroyed by phagocytes (Extravascular Hemolysis)
CLINICAL FEATURES
Drug-induced hemolysis develops after lag of 2/3 days
RBCs of affected males are uniformly deficient
Marrow compensates by producing new resistant RBCs
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
Intrinsic defect with intravascular hemolysis
Acquired intracorpuscular defect, X-linked
Somatic mutation in in PIG-A (impaired synthesis of GPI anchor) on MYELOID STEM CELLS
Glycosyl – Phosphatidyl – Inositol (GPI): required for fixation of CD55, CD59 and C8 binding proteins to cell surfaces (protect from complement mediated lysis)
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
PIG-A deficient precursors produce RBCs sensitive to complement-mediated lysis
All myeloid lineages are affected - Leukocytes are also deficient in protective proteins, but less sensitive to complement mediated lysis than red cells
CLINICAL FEATURES Hemoglobin containing urine on awakening ( NOCTURNAL
because fixation of complement is enhanced by decrease in blood pH during sleep due to CO2 retention)
Iron deficiency possible because of episodic hemoglobinuria
Venous thrombosis (release of aggregating agents from destroyed platelets like adenosine diphosphate)
Increased risk for developing Acute Myeloblastic Leukemia
DIAGNOSIS
Test of Choice : FLOW CYTOMETRY : ↓ CD55/CD59 expression on RBCs, WBCs and platelets
Older Diagnostic Tests: Sucrose Hemolysis Test: sucrose enhances
complement mediated lysis of RBCs Ham Acidified Serum Test: acidified serum activates
the alternative pathway causing hemolysis
TREATMENT
Corticosteroids
Targeted therapy with antibody that prevents the terminal activation of complement components. (ECULIZUMAB)
Anticoagulation to prevent thromboses
Bone marrow transplantation