2. Basic defect in HGB SCD is a type of hemoglobinopathy -globin chain defect Valine replaces glutamine at the 6th position from aminoterminal As a result HGB molecules develop sticky points Sticky points are exposed when the HGB is deoxygenated Hence, HGB molecules polymerize to form fibers / long crystals
3. Red Blood Cells from Sickle Cell Anemia Deoxygenation of SS erythrocytes leads to intracellular hemoglobin polymerization, loss of deformability and changes in cell morphology. OXY-STATE DEOXY-STATE
4. Sickle cell disease Point Mutation DNA mRNA AMINOACID C T C G A G G A G C A C G T G G U G
5. Deoxyhemoglobin S Polymer StructureA) Deoxyhemoglobin S B) Paired strands of C) Hydrophobic pocket 14-stranded polymer deoxyhemoglobin S for 6b Val (electron micrograph) (crystal structure) D) Charge and size prevent 6b Glu from binding.Dykes, Nature 1978; JMB 1979Crepeau, PNAS 1981 Wishner, JMB 1975
7. Basic defect in HGBPolymerization gives abnormal physiochemical properties to HGB - sickle hemoglobin (HbS) - that are responsible for the disease
8. PathogenesisAggregated HbS molecules assemble into long needle-like fibers within red cells, producing a distorted sickle or holly-leaf shape
9. Photomicrograph of red blood cells, showingabnormal shape characteristic of sickle cell anemia
10. PathogenesisThe major pathologic manifestations: 1. Chronic hemolysis 2. Microvascular occlusions, and 3. Tissue damageSeveral variables affect the rate and degree of sickling
11. PathogenesisSeveral variables affect the rate and degree of sickling: 1. Interaction of HbS with the other types of hemoglobin in the cell 2. Mean cell hemoglobin concentration (MCHC) 3. Intracellular pH 4. Transit time of red cells through microvascular beds
12. Mechanisms of RBC damage Severe derangement in membrane structure due to distorsion of membrane by needles of HBS crytals influx of Ca++ efflux of K+ and H2O Irreversibly sickled cells
13. Pathophysiology HgbS fibers are rigid Hgb S fibers deform RBC membranes Membrane disruption exposes transmembrane proteins and lipids that are pro-inflammatory Progressive sickling makes cells dense and inflexibleFrenette et al., Journal of Clinical Investigation 117(4): 850-858, 2007
14. Pathophysiology of sickle cell disease.
15. Sickle cell disease(peripheral blood smear)
16. Malaria and SCD
17. Distribution of malaria corresponds to occurrence of sickle cell disease
18. Sickle Cell Gene Severe Malaria
19. Who is resistant to malaria SCD or SCT ?
20. SCD usually manifests early in childhood For the first 6 months of life, infants are protected largely by elevated levels of Hb F; soon thereafter, the condition becomes evident. The following 3 prognostic factors have been identified as predictors of an adverse outcome: (1) dactylitis in infants younger than 1 year, (2) Hb level of less than 7 g/dL, and (3) leukocytosis in the absence of infection.
21. Painful Crisis The most common clinical picture during adult life is vasoocclusive crisis. The crisis begins suddenly, sometimes as a consequence of infection or temperature change, such as an air-conditioned environment during a hot summer day. However, often, no precipitating cause can be identified. Severe deep pain is present in the extremities, involving long bones. The abdomen is affected with severe pain resembling acute abdomen. The face also may be involved. Pain may be accompanied by fever, malaise, and leukocytosis. The person in crisis is in extreme discomfort. The crisis may last several hours to several days and terminate as abruptly as it began.
22. Sickle-Cell Disease: Bone Infarcts, Upper Tibiae
23. Anemia Anemia is universally present. It is chronic and hemolytic in nature and usually very well tolerated. While patients with an Hb level of 6-7 g/dL who are able to participate in the activities of daily life in a normal fashion are not uncommon, their tolerance for exercise and exertion tends to be very limited. Anemia may be complicated with megaloblastic changes secondary to folate deficiency. These result from increased RBC turnover and folate utilization. Periodic bouts of hyperhemolysis may occur.
24. Aplastic Crisis This is caused by infection with the Parvovirus B-19 (B19V). The virus infects RBC progenitors in bone marrow, resulting in cessation of erythropoiesis. Coupled with greatly shortened RBC lifespan, usually 10-20 days, a very rapid drop in Hb occurs. The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.
25. Hand-Foot Syndrome Problem occurring in infancy is hand-foot syndrome. This is a dactylitis presenting as painful swelling of the dorsum of the hand and foot. Cortical thinning and destruction of the metacarpal and metatarsal bones appear on radiographs 3-5 weeks after the swelling begins. Leukocytosis or erythema does not accompany the swelling.
26. Hand foot syndrome
27. Spleen The spleen enlarges in the latter part of the first year of life. Splenic sequestration crisis occurs due to a sudden very painful enlargement of the spleen due to pooling of large numbers of sickled cells.. The spleen undergoes repeated infarction Over time, the spleen becomes fibrotic and shrinks. This is, in fact, an autosplenectomy. Spleen is nonfunctional. Failure of opsonization cause inability to deal with infective encapsulated microorganisms, particularly Streptococcus pneumoniae.
28. Clinical intraoperative photograph showing massivesplenic infarction in a child with sickle cell anemia. Note the omental adhesions adherent to site of infarction
29. Splenic infarcts and white pulp hyperplasia (follicular lymphoid hyperplasia)
30. This photo shows the small, fibrotic residual spleen of an 11 year old child who had a history of many sickle crises and splenic sequestrations