The Rh deficiency syndrome arises when all Rh factors are absent or are present in severely reduced amounts. There are two types of genetic defects that can lead to the deficiency; nevertheless, the phenotypic manifestations are the same because both lead to a decrease in the stability of the erythrocyte membrane. Thus, patients with the Rh deficiency syndrome display hemolytic anemia of varying severity.
The Rh antigen system is a complex blood group system comprised of Rh proteins, Rh glycoproteins, and other associated proteins, all of which are components of the erythrocyte membrane. The complexity of these proteins has an important role in maintaining the integrity of the erythrocyte membrane. The RhD protein represents the Rh antigen D, and the RhCE protein is responsible for the C, c, E, and e antigenicity. Both proteins are encoded on chromosome 1 and have very similar amino acid sequences and structures, but are antigenically distinct [1]. The RhAG (Rh-associated glycoprotein) has limited (about 40%) similarity to the Rh proteins and is encoded on chromosome 6. The RhD and RhCE proteins form tetrameric complexes with RhAG; the complexes are thought to interact with accessory proteins, such as light-weight (LW) glycoprotein, integrin-associated protein (CD47), glycophorin B, and others [1]. Among these proteins the Rh antigen D is the most immunogenic: therefore, the presence or absence of the Rh D antigen - the Rh positive or negative status - is routinely determined in blood donors or recipients and pregnant women. Nevertheless, for various reasons, Rh immunization may still occur in pregnancy in mothers who lack the D antigen. The reaction may cause hemolytic disease of the newborn [1].
The Rh deficiency syndrome is defined by the absence of all Rh proteins (Rhnull), or by a very substantial reduction in their amounts (Rhmod). Other proteins that are absent or considerably reduced in this condition are RhAG and many of the accessory proteins (for example glycophorin B, LW and Fy5 glycoproteins, U and Duclos antigens) [2]. The Rh deficiency syndrome is either caused by a regulatory element that is located outside the Rh locus (regulatory type deficiency), or by the presence of silent Rh genes at the Rh locus (referred to as amorph type). The genetic defects, which may be due to various mutations or deletions or the combination of both, [3] are recessive in both cases. The symptoms of the disease, i.e. signs of chronic hemolytic anemia, are also the same and are associated with the anomalies in the erythrocyte cell’s membrane structure [4]. The condition is very rare: 1 in about six million is affected [1].
Patients with the Rh deficiency syndrome show signs of compensated hemolytic anemia, the severity of which is variable, with deformities in cell shape [5], i.e. stomatocytosis and spherocytosis. The osmotic fragility of erythrocytes is increased, and their lifespan is decreased. Cation transport and Na+/K+ adenosine triphosphatase activity are increased [6], leading to dehydration of the cell [4]. Another sign of disruption of membrane structure is an abnormal phospholipid distribution [7]. Patients may present with reticulocytosis [5].
Patients with the Rh deficiency syndrome may be identified through routine testing, or because of signs of anemia. Family history may reveal consanguineous parentage [8].
Hematologic tests will show signs of mild hemolytic anemia, with somewhat low total hemoglobin, hematocrit, and mean corpuscular hemoglobin values [8]. The reticulocyte count may be higher than normal [5] [8]. The peripheral smear shows some cells with abnormal shapes i.e. stomatocytes and spherocytes. The osmotic fragility of red cells is examined by exposing them to various NaCl concentrations and following the degree of hemolysis: patients with the Rh deficiency syndrome have characteristically higher osmotic fragility than healthy individuals [5] [8]. The serum bilirubin concentration may be slightly increased because of the chronic hemolysis [5]. Monoclonal antibodies can be used to determine individual antigens within the Rh family of proteins and associated proteins. The tests will show that the Rh D, C, c, E, and e antigens, together with those for some other membrane glycoproteins are missing in cases with the Rh deficiency syndrome [8].
In patients with the Rhnull syndrome, antibodies to erythrocytes encountered through transfusion or during pregnancy may have specificities to one antigen (for example anti-C), a mixture of antigens, or all Rh antigens. These antibodies can be detected by the indirect antiglobulin test. The anti-total Rh antibody is called anti Rh29 [1] [2].