Sickle Cell Disease

 

Epidemiology and Etiology:

·         Point mutation in the 6th position of the ß-globin gene leading to an amino acid residue change

·         HbS (a2ßs2)

·         When deoxygenated, HbS undergo aggregation and polymerization (except in the presence of HbF)

·         HbS precipitation also causes oxidant damage

·         Membrane changes cause the cells to stick to each other

·         Decreased pH increases sickling by decreasing oxygen affinity

·         Sluggish and / or inflamed microvascular beds are prone to sickling (spleen and bone marrow)

·         ~8% of black Americans are heterozygous for HbS (sickle cell trait)

·         ~40% of hemoglobin is HbS

·         The remainder are normal HbA

·         Cells only sickle under severe hypoxia (generally asympomatic)

·         Homozygotes have all HbS

·         HbC is another point mutation in the ß-globin gene that has a greater tendency to form aggregates with HbS than HbA does.

·         HbSC disease is symptomatic but milder

·         Coexistence  of a-thallassemia decreases Hb concentration in the cell and the disease is milder

·         Malaria-endemic areas in Africa

·         Up to 30% of population is heterozygotes

·         Triggers:

·         Infection

·         Dehydration

·         Acidosis

·         Usually none identified

 

Common sites:

·         Infarctions:

·         Spleen

·         Bone marrow

·         Brain

·         Kidney

·         Liver

·         Retina

·         Lung

·         May produce cor pulmonale

·         Leg cutaneous (adults)

·         Penis

·         heart

 

Gross features:

·         “crew-cut” skull on X-ray

·         Prominent cheek bones

·         Splenomegaly (up to 500g in children)

·         Progressive shrinkage over time

·         Only nubbin of fibrous tissue is left by adolescence or early adulthood (autosplenectomy)

 

Histologic features:

·         Bone marrow:

·         Hyperplastic (erythroid hyperplasia)

·         Extramedullary hematopoiesis

·         Spleen:

·         Marked congestion and expansion of the red pulp

·         RBC engorgement of the cords – sickle cell morphology

·         Relativel clear sinuses

·         Thrombosis

·         Infarction

·         Fibrosis

·         Peripheral smears show irreversibly sickled cells

·          

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 

 

 

 

Molecular features:

·          

 

Other features:

·         Chronic hemolysis

·         Ischemic tissue damage due to small vessel occlusion

·         Pain crises

·         Acute chest syndrome

·         Potentially fatal cycle of worsening pulmonary and systemic hypoxemia

·         Generalized growth restriction

·         hyposthenuria

·         Sequestration crises

·         Massive sequestration of siclkled red cells

·         Rapid splenic enlargement

·         Hypovolemia

·         Shock sometimes

·         Aplastic crises

·         Acute infection of erythroblasts by parvovirus B19

·         Pigment gallstones

·         Immune deficiency

·         Increased susceptibility to encapsulated organisms (S. Pneumo, H. influenzae)

·         Septicemia and meningitis from these is most common cause of death in children with sickle cell disease

·         Reticulocytosis

·         50% survive beyond 40’s

 

References:

·         Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004.