Lecture 10 RBCs Diseases PDF

Pathophysiology PHMU 534 Lecture 10 RBCs Disorders I Dr. Radwa Sabry 1  Competencies Domain 1: Fundamental Knowledge 1-1- Competency Key Elements 1-1-1 Demonstrate understanding of the pa...

Pathophysiology PHMU 534 Lecture 10 RBCs Disorders I Dr. Radwa Sabry 1  Competencies Domain 1: Fundamental Knowledge 1-1- Competency Key Elements 1-1-1 Demonstrate understanding of the pathophysiological mechanisms of different diseases. 1-1-2 Utilize the proper medical terms in pharmacy practice. 1-1-3 Integrate knowledge from fundamental sciences to relate the mechanisms of disease to their clinical manifestations and possible complications. 1-1-4 Utilize scientific literature, and collect and interpret information to enhance professional decision. Domain 2: Professional and Ethical Practice 2-1- Competency Key Elements 2-1-1 Recognize the role of physicians as members of the health care professional team and perform responsibilities in compliance with the professional structure. Domain 3: Pharmaceutical Care 3-1- Competency Key Elements 3-1-1 Apply the principles of body function and basis of genomics in health and disease states to manage different diseases. 3-1-2 Relate etiology, epidemiology, pathophysiology, laboratory diagnosis, and clinical features of diseases to understand their pharmacotherapeutic approaches. Domain 4: Personal Practice 4-1- Competency Key Elements 4-1-1 Demonstrate responsibility for team performance and peer evaluation of other team members, and express time management skills. 4-1-2 Retrieve and critically analyze information and work autonomously and effectively in a team. 4-2- Competency Key Elements 4-2-1 Demonstrate effective communication skills verbally, non-verbally, and in writing with professional health care team, patients, and communities. 4-2-2 Use contemporary technologies and media to demonstrate effective presentation skills. 4-3- Competency Key Elements 4-3-1 Practice independent learning needed for continuous professional development. 2  Outline Overview Anemia of blood loss: hemorrhage Lec 10 Hemolytic anemias 1. Hereditary spherocytosis 2. Sickle cell anemia 3. Thalassemia 4. Glucose-6-phosphate dehydrogenase deficiency 5. Immunohemolytic anemia Lec 11 Anemia of diminished erythropoiesis 1. Iron deficiency anemia 2. Aplastic anemia 3  Causes of Anemia Increased RBCs destruction (Hemolytic Anemia) Intrinsic (Intracorpuscular) Extrinsic (Extracorpuscular) Anemia Low RBCs count or Low Hb or Both Decreased RBCs production Bleeding Inadequate supply (Iron deficiency) Chronic: GIT lesions, gynecologic disturbances Disturbed proliferation and maturation of erythroblasts Marrow replacement and infiltration 4  RBCs reference ranges Unit Men Women Hemoglobin (Hb) g/dL 13.2-16.7 11.9-15.0 Hematocrit (Hct) The ratio of the volume of RBCs to the total volume of blood % 38-48 35-44 Red cell count x106/µL 4.2-5.6 3.8-5.0 Reticulocyte count % 0.5-1.5 Mean cell volume (MCV) fL 81-97 Average volume of RBC Mean cell Hb (MCH) Pg 28-34 Average mass of Hb per RBC Mean cell Hb concentration (MCHC) g/dL 33-35 Average Hb concentration in each RBC Red cell distribution width (RDW) % 11.5-14.8 % Variation of RBC volume/size Reference ranges vary among laboratories. The reference ranges for the laboratory providing the results should always be used. 5  Morphology Size: 6 - 9 μm, MCV: 80 - 97 fL Size: 6 - 9 μm, MCV: 80 - 97 fL Normal erythrocyte Normocytic normochromic Peripheral smears (Hemolytic Anemia …) Size: < 6 μm, MCV: 9μm, MCV: >100 fL Microcytic hypochromic Macrocytic anemia (iron deficiency, thalassemia) (Folate or vitamin B12 deficiency) 6  Anemia of blood loss Acute blood loss: If exceeding 20% of blood volume, the immediate threat is hypovolemic shock rather than anemia. The RBCs are normocytic and normochromic Rise in the erythropoietin level Chronic blood loss (Anemia): Iron stores are gradually depleted Iron deficiency anemia The anemia is microcytic and hypochromic 7  Hemolytic anemias Intrinsic Abnormalities Extrinsic Abnormalities (Intracorpuscular) (Extracorpuscular) Membrane Skeleton proteins Abnormal globin synthesis Hereditary Spherocytosis Sickle cell anemia Enzyme deficiency Deficient globin synthesis Antibody mediated Glucose-6-phosphate dehydrogenase Thalassemia Immuno-hemolytic anemia 8  Hemolytic anemias Features shared by hemolytic anemias: A decreased RBC life span  premature destruction. Erythroid hyperplasia in the bone marrow  trying to compensate  Reticulocytosis. In severe hemolytic anemias, extramedullary hematopoiesis ( hematopoiesis outside the bone marrow) may appear in the liver, spleen, and lymph nodes. Because the pathways for the excretion of excess iron are limited, this often causes iron to accumulate, giving rise to systemic hemosiderosis or, in very severe cases, secondary hemochromatosis. 9  Hemolytic anemias Blood Vessels RBCs Hemolysis Liver Spleen Intravascular Extravascular  Mechanical forces (turbulence by a defective heart valve)  Any reduction in RBC deformability  Biochemical (exposure to toxins)  Jaundice  Jaundice  Hyperbilirubinemia (unconj.)  Hyperbilirubinemia (unconj.)  Haptoglobin decrease  Haptoglobin decrease (if severe) Hemosiderinuria Bilirubin-rich gallstones Hemoglobinemia No Hemoglobinemia Hemoglobinuria No Hemoglobinuria LDH increase Splenomegaly 10 Hereditary Spherocytosis Pathogenesis Morphology Clinical features Treatment 11  Hereditary Spherocytosis Pathogenesis: The horizontal spectrin connected to vertical transmembrane protein band 3, via linker protein Anjyrinstabilize the membrane and are responsible for the normal biconcave shape, strength, and flexibility of the red cell. 12  Hereditary Spherocytosis Pathogenesis: The mutations mostly involve ankyrin, band 3, and spectrin. RBCs have reduced membrane stability and consequently lose membrane fragments after their release into the periphery, while retaining most of their volume. Spherocytes become less deformable, and vulnerable to splenic sequestration and destruction by Macrophages. It is transmitted most commonly as an autosomal dominant. Approximately 25% of patients have a more severe autosomal recessive form. 13  Hereditary Spherocytosis Morphology RBCs lack the central zone of pallor because of their spheroidal shape. Spherocytosis is not diagnostic; it is seen in other conditions, such as immune hemolytic anemias, in which there is a loss of cell membrane relative to cell volume 14  Hereditary Spherocytosis Clinical Features  Anemia: most commonly of moderate degree  Splenomegaly: is greater and more common in HS than in any other form of hemolytic anemia.  Jaundice  Aplastic Crises: o The clinical course often is stable but may be punctuated due to infection and destruction of erythroblasts in the bone marrow by parvovirus B19. o Worsening of anemia + disappear of reticulocytosis o Such episodes are self-limited, but some patients need supportive blood transfusions during the period of red cell aplasia.  RBCs have increased osmotic fragility when placed in hypotonic salt solutions. 15  Hereditary Spherocytosis Treatment There is no specific treatment for hereditary spherocytosis. Splenectomy provides relief for symptomatic patients. The benefits of splenectomy must be weighed against the risk of increased susceptibility to infections, particularly in children. Partial splenectomy is gaining favor, because this approach may produce hematologic improvement while maintaining protection against sepsis. 16 Sickle cell Anemia Pathogenesis Consequences Morphology Clinical features Factors affecting sickling 17  Sickle cell anemia Epidemiology Sickle cell anemia is the most common familial hemolytic anemia in the world. In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a small but significant protective effect of HbS against Plasmodium falciparum malaria. In the US, approximately 8% of blacks are heterozygous for HbS, and about 1 in 600 have sickle cell anemia. 18  Sickle cell anemia Normal Hemoglobin: Normal hemoglobin is a tetramer composed of two pairs of similar chains. On average, the normal adult red cell contains: 96% HbA (α2β2) 3% HbA2 (α2δ2) 1% fetal Hb (HbF, α2γ2) 19  Sickle cell anemia Pathogenesis HbS is produced by the substitution of valine for glutamic acid at the sixth amino acid residue of β-globin. In homozygotes, all HbA is replaced by HbS, whereas in heterozygotes, only about half is replaced. 20  Sickle cell anemia Pathogenesis Point Mutation Deoxygenation 21  Sickle cell anemia Pathogenesis On deoxygenation, HbS molecules form long polymers by means of intermolecular contacts that involve the abnormal valine residue at position 6. These polymers distort the red cell, forming elongated crescentic, or sickle, shape. The distortion of the membrane that is produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water (dehydration) and also damages the membrane skeleton. The sickling of red cells initially is reversible upon reoxygenation. Over time, this cumulative damage creates irreversibly sickled cells, which are rapidly hemolyzed. 22  Sickle cell anemia Consequences 23  Sickle cell anemia Consequences Chronic hemolytic anemia: RBC membrane damage and dehydration are caused by repeated episodes of sickling The mean life span of red cells in sickle cell anemia is only 20 days There is a compensatory hyperplasia of erythroid progenitors in the bone marrow. As with the other hemolytic anemias, hemosiderosis and gallstones are common. Microvascular obstructions: Reversibly sickled RBCs; lose their deformability so they get stuck in small capillaries Microvascular occlusion  Resulting in ischemic tissue damage and pain crises commonly in the bone marrow (sluggish blood flow), where it often progresses to infarction. Vaso-occlusion is enhanced by infection, inflammation, and dehydration that enhance the sickling of RBCs. Infarction and autosplenectomy, is complete by adulthood. 24  Sickle cell anemia Sickle cell anemia—peripheral blood smear. A, Low magnification shows sickle cells B, Higher magnification shows an irreversibly sickled cell in the center. 25  Sickle cell anemia Clinical Features  The vaso-occlusion in these episodes can involve many sites but occurs most commonly in the bone marrow (BM), where it often progresses to infarction.  Acute chest syndrome, which can be triggered by pulmonary infections or fat emboli/BM embolism from infarcted bone marrow.  The acute chest syndrome and stroke are the two leading causes of ischemia-related death.  Aplastic crisis, is caused by a sudden decrease in red cell production, usually is triggered by the infection of erythroblasts by parvovirus B19 and, while severe, it is self-limited. 26  Sickle cell anemia Clinical Features  Both children and adults with sickle cell disease are functionally asplenic, making them susceptible to infections  In adults the basis for “hyposplenism” is autoinfarction.  Even children with enlarged spleens (Splenomegaly) are at risk for development of fatal septicemia.  The diagnosis is confirmed by electrophoretic demonstration of HbS. 27  Sickle cell anemia Factors that influence RBCs sickling 1. The presence of hemoglobins other than HbS: Sickle cell trait: in heterozygotes 40% of Hb is HbS and the remainder is HbA. RBCs have little tendency to sickle in vivo (manifested under extreme conditions, such as after vigorous exertion at high altitudes). sickling can be induced in vitro by exposing cells to hypoxia. HbF: newborns with sickle cell anemia do not manifest the disease until HbF falls to adult levels, generally around the age of 5 to 6 months. 28  Sickle cell anemia Factors that influence RBCs sickling 2. The intracellular concentration of HbS: RBC dehydration facilitates sickling as it increases HbS concentration. Coexistence of α-thalassemia (decreased Hb concentration) reduces sickling. 3. The transit time for RBCs through the microvasculature: Sickling in microvascular beds more prominent in areas of the body in which blood flow is sluggish (spleen and bone marrow) Inflammation slows the flow of blood. 29  References Robbins Basic Pathology, 10th edition, by Vinay Kumar, Abul K. Abbas and Jon C. Aster. Elsevier, ISBN: 9780323353175, 2018. ROBBINS Basic Pathology 9th Edition 30 Thank you 31