Cause:Genetic, autosomal. Homozygote = thalassemia major, Cooley's anemia. Heterozygote = thalassemia minor or thalassemia trait
Pathophys:
ß-Hemoglobin chain synthesis blocked in homozygote so they are unable to make Hgb A (
2ß2) but can make Hgb A2 and Hgb F. Heterozygote has some decreased ß-chain synthesis
/ß-Thalassemia interaction: in ß-thal, ß/ = 0.5, but can be >0.5 toward 1 if concomitant -thalassemia gene as well, since this decreases inclusion production and thus intramedullary ineffective rbc production, leaving only a hypochromic, microcytic pattern (Nejm 1972;286:586)
Caucasians, esp Mediterraneans, eg, Greeks and Italians, up to 60% gene prevalence in some villages. Blacks, 1% of US black population carries. Southeast Asians, 2-10% gene prevalence (Found Blood Res 10/86). Sustained by partial malaria resistance in heterozygotes
Sx:
Thal major: onset age 3-6 mo when Hgb A replaces Hgb F
Thal minor: asx unless precipitants (Nejm 1974;290:939)
Si:
Thal major: skull bossing (marrow proliferation)
Thal minor: splenomegaly
Thal major: hemochromatosis/siderosis w transfusions leading to diabetes, insulin resistance (Nejm 1988;318:809), and hypopituitarism with impaired puberty and 2° amenorrhea; prevented with Fe-binding rx begun before age 10 yr (Nejm 1990;323:713); r/o thal trait plus Hgb E, which looks like thal homozygote, HEMOGLOBIN E is present in 40% of Southeast Asians (Found Blood Res 10/86); B12; folate deficiency
Thal minor: sickle/thal disease (1/4 as common as SS disease). Fe deficiency decreases chain production, which in turn worsens the disease (Nejm 1985;313:1402). B12, folate deficiency. Most commonly presents as a mild microcytic anemia so r/o other causes (Iron Deficiency Anemia)
Lab:
Amniotic fluid:To detect affected fetus, DNA probes works 85% of time, no false pos or neg (Nejm 1983;309:384; 1983;308:1054)
Chem:In thal major, iron and % saturation both increased; bilirubin, urine, and stool urobilinogen all increased
Path:Liver bx to monitor iron load (Nejm 2000;343:327)
Hem:In both, MCV <79 m3, rbc stippling (RNA and mitochondria); siderocytes (hemosiderin-laden) in peripheral blood; targets; rbc "ghosts"; teardrops if spleen still in, vacuoles if not (Nejm 1972;286:589)
Hgb electrophoresis: in thal minor, Hgb A2 ( 2
2) persists at 
2 × normal %; >3.5% is diagnostic (Nejm 1973;288:351). In thal major, no significant Hgb A; Hgb F may persist
Xray:Skull films show "hair-on-end" evidence of marrow space increase
Rx:
Prevention (Nejm 2002;347:1162) in high-risk populations w PCR analysis of chorionic villus sampling, abortion, and genetic counselling
of thal major: splenectomy and transfusions to keep Hgb >10 and thus diminish bone fragility (Nejm 1972;286:586); marrow transplant, 25% mortality (Nejm 1990;322:417), but only ~6% if transplanted early in course before liver damage (Nejm 1993;329:840); 5-azacytidine iv over 4 d q 1 mo increases Hgb F (Nejm 1993;329:845) as does hydroxyurea and butyrate iv qd (Nejm 1993;328:81)
of Fe overload: AVOID FE RX; tetracycline po to decrease gi absorption (Nejm 1979;300:5); deferoxamine sc with pump hs decreases diabetes, late liver and heart disease (Nejm 1994;331:567, 574), but can cause dose-dependent deafness and blindness (Nejm 1985;313:869); or possibly deferiprone po (Nejm 1998;339:417; 1995;332:918), but not effective and adverse effects: agranulocytosis, hepatic fibrosis