The time required for red cells to pass through the microvasculature. The normal transit times of red cells through capillary beds are too short for significant polymerization of deoxygenated HbS to occur. Hence, the tissues that are most susceptible to obstruction by sickling are those in which blood flow is normally sluggish, such as the spleen and the bone marrow. However, sickling may occur in other microvascular beds in the face of factors that retard the passage of red cells, particularly inflammation. Recall that inflammation slows blood flow by increasing the adhesion of leukocytes and red cells to endothelium and by inducing the exudation of fluid through leaky vessels (Chapter 4). In addition, sickle red cells have a greater tendency than normal red cells to adhere to endothelial cells, apparently because repeated bouts of sickling cause membrane damage that makes the red cells sticky. These factors conspire to prolong the transit times of sickle red cells, increasing the probability of clinically significant sickling.
The sickling of red cells has two major pathologic consequences: chronic moderately severe hemolytic anemia, produced by red cell membrane damage, and vascular obstructions, which result in ischemic tissue damage and pain crises (
Fig. 12.4 ). The mean life span of red cells in sickle cell anemia averages only 20 days (one-sixth of normal), and the severity of the hemolysis correlates with the fraction of irreversibly sickled cells that are present in the blood. Vasoocclusion, by contrast, does not correlate with the number of irreversibly sickled cells and instead appears to result from superimposed factors such as infection, inflammation, dehydration, and acidosis, all of which enhance the tendency of red cells to sickle within the microvasculature.
MORPHOLOGYTheanatomicalterationsinsicklecellanemiastemfrom(1)severechronichemolyticanemia,(2)increasedbreakdownofhemetobilirubin,and(3)microvascularobstructions,whichprovoketissueischemiaandinfarction.Inperipheralsmears,elongated,spindled,orboat-shapedirreversibly sickled red cells areevident(
Fig.12.3 ).Boththeanemiaandthevascularstasisleadtohypoxia-inducedfattychangesintheheart,liver,andrenaltubules.Thereisacompensatoryhyperplasia of erythroid progenitors inthemarrow.Thecellularproliferationinthemarrowoftencausesboneresorptionandsecondarynewboneformation,resultinginprominentcheekbonesandchangesintheskullresemblinga“crewcut”inradiographs.Extramedullaryhematopoiesismayappearintheliverandspleen.
Inchildrenthereismoderatesplenomegaly (splenicweightupto500g)duetoredpulpcongestioncausedbyentrapmentofsickledredcells.However,chronicsplenicerythrostasisproduceshypoxicdamageandinfarcts,whichwithtimereducethespleentoauselessnubbinoffibroustissue.Thisprocess,referredtoasautosplenectomy, iscompletebyadulthood.
Vascular congestion, thrombosis, and infarction canaffectanyorgan,includingthebones,liver,kidney,retina,brain,lung,andskin.Thebonemarrowisparticularlypronetoischemiabecauseofitssluggishbloodflowandhighrateofmetabolism.Priapism,anotherfrequentproblem,canleadtopenilefibrosisanderectiledysfunction.Aswiththeotherhemolyticanemias,hemosiderosis andpigment gallstones arecommon.