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Red Blood Cells and Bleeding Disorders

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Subject: Pathology Topic: RBC s and Bleeding Disorders Lecturer: Dr. Cagampan Date of Lecture: August 9, 2011 Transcriptionist: Mopster and Pinay Editor: Mopster and Pinay Pages: 15 Bloodlines

Above: From pluripotent cells arise the WBC and RBC and lymphoid series. Note that some cells will arise from the same mother cell. Anemias y Reduction below normal limits of the total circulating red cell mass y Reduced oxygen transport capacity of the blood y Reduction below normal in the volume of packed red cell as measured by hematocrit or hemoglobin concentration y IOW, the patient will appear pale and weak from lack of oxygen. Classification of Anemia According to Underlying Mechanism y Blood loss y Increased rate of destruction (hemolytic anemias) y Impaired red cell production Anemia of Blood Loss Acute blood loss (microcytic, hypochromatic RBC s may not be evident) y Reflect loss of blood volume may lead to shock, death y Hemodilution shift of water from interstitial fluid compartment into intravascular space y Erythropoietin production reticulocytosis (Immature RBC containing remnants of nuclei seen only in special stain. Bigger than usual RBC. Polychromatophilic bluish red hue) reaching 10 15% y Reticulocyte count normally 0.5 1.5% Chronic blood loss (microcytic, hypochromic RBC s are more evident in chronic blood loss) y GIT bleeding: gastric ulcer, hematemesis, hemorrhoids o Striking reticulocytosis may not be seen. y Gynecologic causes 1

SY 2011-2012

Increased Rate of Destruction (Hemolytic Anemia) y Intrinsic (intracorpuscular) abnormalities of red cells o Hereditary Red cell membrane disorders Disorders of membrane cytoskeleton: spherocytosis, elliptocytosis Disorders of lipid synthesis: selective increase in membrane lecithin Red cell enzme deficiencies Glycolytic enzymes: pyruvate kinase deficiency, hexokinase deficiency Enzymes of hexose monophosphate shunt: G6PD, glutathione synthetase Disorders of hemoglobin synthesis Deficient globin synthesis: thalassemia syndromes Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia, unstable hemoglobin o Acquired Membrane defect: paroxysmal nocturnal hemoglobinuria y Extrinsic (extracorpuscular) abnormalities o Antibody mediated Isohemagglutinins: transfusion reactions, erythroblastosis fetalis Autoantibodies: idiopathic (primary), drug associated, SLE, malignant neoplasm, mycoplasmal infections o Mechanical trauma to red cells Microangiopathic hemolytic anemia: thrombotic thrombocytopenic purpura, DIC Cardiac traumatic hemolytic anemia Infections: malaria Chemical injury: lead poisoning Sequestration in mononuclear phagocyte system: hypersplenism Impaired Red Cell Production y Disturbance of proliferation and differentiation of stem cells: aplastic anemia, pure red cell aplasia, anemia of renal failure, anemia of endocrine disorders y Disturbance of proliferation and maturation of erythroblasts: o Defective DNA synthesis: deficiency or impaired use of vitamin B12 and folic acid (megaloblastic anemia) o Defective hemoglobin synthesis Deficient heme synthesis: iron deficiency Deficient globin synthesis: thalassemias

Unknown or multiple mechanisms: sideroblastic anemia, anemia of chronic infections, myelophthisic anemia due to marrow infiltration

Hemolytic Anemia y Premature destruction of red cells and a shortened red cell life span below the normal 120 days y Elevated erythropoietin levels and a compensatory increase in erythropoiesis y Markedly increased erythropoiesis with associated reticulocytosis y Accumulation of hemoglobin degradation products released by red cell breakdown derived from hemoglobin (e.g., bilirubin) y Pigment stone formation as a result of hemoglobin degradation. y Tend to produce extravascular hemolysis although, on occasion, intravascular hemolysis may occur. y Tend to be autosomal dominant y Rare in the Philippines, except Thalassemia. y Intravascular hemolysis (causes): o Mechanical injury: e.g., prosthetic cardiac valves, thrombi o Complement fixation to red cells: e.g., mismatched transfusion o Toxic injury: e.g., malaria y Manifestations of intravascular hemolysis: o Anemia o Hemoglobinemia o Hemoglobinuria o Jaundice: a small percentage of gall stones are of hemoglobin origin o Hemosiderinuria Extravascular hemolysis o Occurs in mononuclear phagocytes of spleen o Predisposing factors: Red blood cell membrane injury Reduced deformability opsonization o Sequestration of deformed or foreign red blood cells followed by opsonization phagocytosis as red cells navigate sinusoids o These sequestered RBC s are rendered palatable to macrophages due to hypoxia and ATP depletion. o Clinical features Anemia Splenomegaly Jaundice Morphology of hemolytic anemias o Normoblastic hyperplasia in marrow o Reticulocytosis in peripheral blood o Pigment gallstones o Hemosiderosis o Jaundice, anemia




Below: Defective RBC s sequestered outside are then phagocytized.

Below: How primary membrane defect leads to phagocytosis on a chemical basis. This pathophysiology is common to most hemolytic anemia and needs to be known by heart.

Hereditary Spherocytosis y Intrinsic defect in RBC membrane ankyrin deficiency and other (usually spectrin) skeletal membrane components y RBC spheroidal, less deformable, vulnerable to splenic sequestration and destruction y Ankyrin deficiency associated with reduced stability and loss of membrane fragments as cells traverse circulation y Inherited disorder, in Northern Europe y Autosomal dominant y Morphology: o Spheroidal RBC (normal is biconcave disc) o No central pallor noted o Moderate splenomegaly due to marked congestion of the cords of Billroth o Erythrophagocytes in the splenic cords o Features of hemolytic anemia y Clinical course: treatment is splenomegaly o Chronic hemolytic anemia mild to moderate o Aplastic crisis parvovirus infection o Hemolytic crisis o Diagnosis: Osmotic Fragility Test Below: Cell membrane defect leads to formation of spherocytes, which are sequestered and rendered palatable to macrophages.

Below (next 2 photos): Note round shape of RBC s and absence of central pallor.

G6PD Deficiency y X linked y One of the tests for newborn screening y Impaired or deficient enzyme function which reduce ability of red cells to fight against oxidative injuries y Abnormalities in Hexose Monophosphate Shunt pathway or glutathione metabolism y Need reduced glutathione to protect RBC against oxidants y Oxidant stress: o Drugs: antimalarials, sulfonamides, etc o Infection: viral hepatitis, TF, pneumonia o Fava bean ingestion



Pathogenesis: Oxidative stress results in the oxidation of globin chains which causes the globin chains to denature and precipitate to form Heinz Bodies. Heinz bodies render the RBC palatable to phagocytes. Sometimes, the Heinz bodies are so abundant, that intravascular hemolysis can occur. Extravascular and intravascular hemolysis can occur.

Below: Not the Bite Cell in the center of the larger picture. In the smaller picture in the upper left corner, note the presence of Heinz Bodies under special stain.

Infarction in bone, brain, kidney, liver, and retina o Leg ulcer, cor pulmonale o Pigment gallstones y Clinical course: o Severe anemia: reticulocytosis o Vasoocclusive complications: acute chest syndrome o Chronic hyperbilirubinemia: gallstones o Increased susceptibility to infection septicemia and meningitis o CNS hypoxia: seizures, stroke o Aplastic crisis: triggered by parvovirus infection o Sequestration crisis o Priapism: thrombi lead congestion of blood vessels which can lead to persistent, painful erection. y Diagnosis o PBS, metabisulfite-induced sickling o Hemoglobin electrophoresis o Fetal DNA by chorionic biopsy of amniocentesis Below: Single point mutation leads to sickle cell formation which leads to hemolysis in the spleen and infract in the tissues. o

Sickle Cell Anemia y Structurally abnormal hemoglobin y Substitution of valine for glutamic acid at the 6th position of globin chain y American blacks: o Heterozygote: 40% HgbS o Homozygote: 100% HgbS y Under deoxygenation, the RBC will sickle. y At first the sickling is reversible until such time that the RBC can no longer change its shape and is sequestered and phagocytized. y Infarction: sickle cells have the unique feature of having increased adhesion to each other. This what causes them to aggregate and form thrombi which can lead to infarct. y Morphology: o Hyperplastic marrow lead to resorption of bone o Extramedullary hematopoiesis o Sickle red cells o Initial splenomegaly erythrocytosis thrombosis and infarction scarring autosplenectomy

Below: Sickle cell admixed with anisocytosis, hypochromia, poikylocytosis

Below: Spleen shrunken down to 3 cm.


Below: Severe congestion because of trapping of the RBC s

Clinical course: o Growth retardation o Death at early age of homozygous patient o Manifestation depends on severity o Prone to infection Below: Typical facie of patient with thalassemia. Prominent cheekbones are a result of increased blood production by the facial bones in order to compensate for RBC loss. y

Thalassemia y type seen in the Philippines o There are 2 genetic loci for the chain, thus there are 4 alleles. There are 4 types of thalassemia, each type coinciding to a loss a allele. Type 1: Loss or mutation of single allele. Minimal symptomatology because the other 3 chains are present. Type 2: 2 alleles affected. Mild anemia. Type 3: 3 alleles affected. Leads to Hemoglobin H. Type 4: 4 alleles affected. Hydrops fetalis. No chance of survival. y Patients with mild forms of the disease are usually asymptomatic and are noticed to have anemia when a CBC is ordered. They are then given iron, which does not improve the anemia. The astute doctor may suspect

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