Sickle cell hemoglobinopathies: Hemoglobinopathies Pathophysiology and relationship to pregnancy
SHELDON E. BAUM, D.O. Detroit, Michigan
The treatment of a patient with (sickle cell anemia) , SA hemoglobin (sickle sickle cell disease requires cell trait), SC hemoglobin (sickle cell C dis- ease) , and STH hemoglobin (sickle cell thalas- consideration of the pathophysiology semia disease). of all its various manifestations. The Varying percentages of S hemoglobin are physician must be aware of the present in the homozygous and heterozygous risks involved when pregnancy is states. In the homozygous state, the abnormal superimposed. In this article the author hemoglobin is generally in excess of 60 per reviews the pathophysiology of sickle cell cent. In the heterozygous state, type S hemo- globin constitutes usually 20 to 40 per cent of disease and its effect on reproduction. the cell hemoglobin, the remainder being nor- While fertility apparently is reduced mal. Sickle cell disease may also exist in in- in sickle cell anemia, this is not so termediate forms in conjunction with other in the other sickle cell diseases. abnormal hemoglobins. The pregnant patient with a sickle cell Adult hemoglobin (type A) is composed of alpha and beta chains of amino acids. Fetal hemoglobinopathy requires close hemoglobin (type F) , is composed of alpha supervision and exacting care during and gamma chains. At birth, F hemoglobin the pregnancy, delivery, and postpartum normally comprises 90 per cent of the blood, period. Two cases are reported. the remainder being type A hemoglobin. Usu- One involved sickle cell anemia ally by 6 to 8 months of age type A hemoglobin associated with pregnancy; delivery predominates in the normal infant, compris- ing 90 to 99 per cent of the blood. With ab- was followed by a series of grand mal normal hemoglobin, there is substitution in seizures. The other involved sickle cell the beta-amino-acid chain at the number six trait complicated at the time of position. In sickle cell hemoglobin (S hemo- pregnancy and illustrates that the globin) , valine is substituted for glutamic acid. pregnant patient with sickle cell Lysine is substituted at the same position to trait may have increased problems of result in hemoglobin C, which does not sickle.3 In sickle cell disease, there is a correlation pregnancy as well as greater problems between the seriousness and nature of clinical of sickle cell disease. symptomatology and the percentage of abnor- mal hemoglobin.2 It is generally felt that the "sickle cell prep" Sickle cell anemia is a congenital hemolytic is a good test which may be done easily to anemia which is generally fatal before the age identify sickling of erythrocytes. One must of thirty. Although the disease occurs pre- realize that this test may be positive in absence dominantly in Negroes, it has also been re- of hemoglobin S and negative in peripheral ported in persons with no Negro ancestry. 2 It blood of patients with severe disease. Thus, is characterized by the presence of an abnormal for exact identification of hemoglobin abnor- hemoglobin, type S, which is carried on auto- mality, hemoglobin electrophoresis is neces- somal intermediate chromosomes rather than sary. on X chromosomes. There are four major types The physiochemical properties of the hemo- of S hemoglobin combinations: SS hemoglobin globin in persons with the sickle cell trait are
1268/98 different from those of the hemoglobin in by obliterative vascular lesions.5 Joint and normal persons. This abnormal hemoglobin bone pain, leg cramps, and cerebral signs are crystallizes on deoxygenation and goes back frequent. Leg ulcers, cardiac hypertrophy, and into solution on oxygenation. The crystals resultant congestive heart failure are also formed within the erythrocytes distort their prominent. Hepatomegaly and splenomegaly membranes, causing the erythrocytes to as- may be seen in the early stages, but later the sume multi-pointed or "sickle," shapes. The spleen becomes smaller because of progressive degree of cellular distortion is greater and fibrosis and siderotic nodule formation. The sickling occurs more readily in persons with peripheral smear reveals sickled cells as well larger amounts of abnormal hemoglobin. Crys- as oval and target cells and occasional nu- tallization of hemoglobin within the erythro- cleated erythrocytes. The bone marrow is cyte is associated with increased viscosity of found to be hypercellular. General character- the blood. The resultant circulatory stasis then istics of hemolytic anemia are found: Jaundice predisposes to anoxia and thus exaggeration with increased bilirubin values and increase of the sickling process. Hypoxia causes injury in percentage of reticulocytes. In sickle cell to the vascular and parenchymal cells and disease, erythrocyte production is not acceler- initiates vascular occlusive processes, intra- ated until the hemoglobin falls to about 9.0 vascular coagulation, and parenchymal degen- grams/100 ml. erative changes and necrosis.5 Fertility appears to be reduced in women There is increased turnover of iron in all of with sickle cell anemia. Hendrickse and Wat- the sickle cell states, with decreased half-life son-Williams 7 stated that many of them do of the erythrocyte.6 Half-life of the erythrocyte not survive to reproductive age, especially in in patients with SS hemoglobin is 2 to 15 days, areas where intercurrent disease and dietary as compared to the normal of 120 days. Most inadequacies take many lives. Puberty may be patients with SS and SC hemoglobin have in- delayed many years in those not treated. There creased iron stores and circulating iron. In is no evidence that fertility is reduced in persons with SA and STH hemoglobin, iron hemoglobin SC disease, sickle cell thalassemia, deficiency anemia is not uncommon. Some de- sickle cell high fetal hemoglobin disease, hemo- gree of erythropoiesis is present in all forms. globin C disease, or in sickle cell trait. In patients with sickle cell trait, the S hemo- Hemoglobinopathies and pregnancy globin returns more slowly than A hemoglobin during an acute illness. For this reason, these Sickle cell trait patients may have negative sickle cell prepara- The incidence of sickle cell trait in pregnant tions during an acute illness or after acute women was 7.9 per cent in a large series re- blood loss. ported by Adams and co-workers, 5 whose as- Patients with sickle cell anemia usually sumption was that it occurs with the same have manifestations of the disease in infancy. frequency in pregnancy as in the general popu- Chronic anemia and jaundice are present lation. Carriers of the sickle cell trait usually throughout life. Generally, these persons are do not suffer from sickling phenomena and able to tolerate very low hematocrit values they ordinarily go through life unaffected. without symptoms. Often death occurs during Pregnancy in these patients neither activates childhood or in early adult life. The recurrent blood destruction nor precipitates the anemic febrile and painful illnesses ("crises") from state. The incidence of toxemia is increased in which these persons suffer are best explained these patients, but the exact cause is not