Fig. 12.5 ), a phenomenon termed ineffective erythropoiesis, and the few red cells that are produced have a shortened life span. Ineffective hematopoiesis has another untoward effect; it is associated with an inappropriate increase in the absorption of dietary iron, which without medical intervention inevitably leads to iron overload. The increased iron absorption is caused by inappropriately low hepcidin, which is a negative regulator of iron absorption (see later).
Unlike β-thalassemia, α-thalassemia is caused mainly by deletions involving one or more of the α-globin genes. The severity of the disease is proportional to the number of α-globin genes that are deleted (
Table 12.3 ). For example, loss of a single α-globin gene produces a silent-carrier state, whereas deletion of all four α-globin genes is lethal in utero because the red cells have virtually no oxygen-delivering capacity. With loss of three α-globin genes there is a relative excess of β-globin or (early in life) γ-globin chains. Excess β-globin and γ-globin chains form relatively stable β4 and γ4 tetramers known as HbH and Hb Bart, respectively, which cause less membrane damage than the free α-globin chains that are found in β-thalassemia; as a result, ineffective erythropoiesis is less pronounced in α-thalassemia. Unfortunately, both HbH and Hb Bart have an abnormally high affinity for oxygen, which renders them ineffective at delivering oxygen to the tissues.
MORPHOLOGYArangeofmorphologiesisseen,dependingonthespecificunderlyingmolecularlesion.Ononeendofthespectrumisβ-thalassemiaminorandα-thalassemiatrait,inwhichabnormalitiesareconfinedtotheperipheralblood.Insmearstheredcellsaresmall(microcytic)andpale(hypochromic),butregularinshape.Oftenseenaretarget cells, cellswithanincreasedsurfacearea-to-volumeratiothatallowsthecytoplasmtocollectinacentral,dark-red“puddle.”Ontheotherendofthespectrum,inβ-thalassemiamajorperipheralbloodsmearsshowmarkedmicrocytosis, hypochromia, poikilocytosis (variationincellshape),andanisocytosis (variationincellsize).Nucleatedredcells(normoblasts)arealsoseenthatreflecttheunderlyingerythropoieticdrive.β-Thalassemiaintermediaand http://ebooksmedicine.net
Reduced °-globin synthesis, with relative excess of ˜-globin Insoluble ˜-globin aggregateHbA
Destruction of aggregate-containing red cells in spleen
Fig. 12.5 Pathogenesis of β-thalassemia major. Note that aggregates of excess α-globin are not visible on routine blood smears. Blood transfusions constitute a double-edged sword, diminishing the anemia and its attendant complications but also adding to the systemic iron overload.
HbH disease are associated with peripheral smear findings that lie between these two extremes.