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University of Tabuk

University of Tabuk. Faculty of Applied Medical Sciences Department Of Medical Lab. Technology 3 rd Year – Level 6 – AY 1434-1435. Blood bank, MLT 309. Rh BLOOD GROUP SYSTEM. Objectives. Compare the three theories of inheritance of the Rh antigens.

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University of Tabuk

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  1. University of Tabuk Faculty of Applied Medical Sciences Department Of Medical Lab. Technology 3rd Year – Level 6 – AY 1434-1435 Blood bank, MLT 309

  2. Rh BLOOD GROUP SYSTEM

  3. Objectives • Compare the three theories of inheritance of the Rh antigens. • List the antigens and antibodies of the system using both Wiener and Fisher-Race nomenclature. • Convert haplotype from Fisher-Race nomenclature into Wiener, and vice versa. • Discuss key characteristics of antigens and antibodies in the Rh system. • Compare major characteristics of the Rh system to the ABO system. • List the three theories of the weak D antigen. • Evaluate reactions of Rh typing, using conventional reagents. • Explain the principle of the weak D test. • Discuss situations when weak D testing would be appropriate. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  4. Introduction • Rh is the most important blood group system after ABO in transfusion medicine. • One of the most complex of all RBC blood group systems with more than 50 different Rh antigens. • Discovered in 1940 after work on Rhesus monkeys. • The genes that control the system are autosomal codominant located on the short arm of chromosome 1. • Only the most clinically significant Ags will be discussed. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  5. HISTORY • Levine and Stetson (1939) described a hemolytic transfusion reaction in an obstetric patient following delivery of stillborn infant. The women required transfusion. Her husband, who had the same ABO type, was selected as her donor, after transfusion the recipient, demonstrated the classic symptoms of acute hemo]ytic transfusion reaction. • Subsequently an antibody was isolated from the mother’s serum that react both at 37°C and 20 °C with the father’s red cells. It was postulated that the fetus and the father possessed a common factor that the mother lacked. While the mother carry the fetus, she was exposed to this factor and subsequently built up an antibody that reacted against the transfused red cells from the father and resulted in hemolytic transfusion reaction. • Landsteiner and Wiener (1940) reported on an antibody by guinea pigs and rabbits when they were transfused with rhesus monkey red cells. • This antibody which agglutinated 85% of human red cells was named Rh. • The name Rh was retained for the human produced antibody. • Anti-rhesus formed by the animals was renamed anti-LW (Landsteiner and Wiener). BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  6. Antigens of Rh System • Terms “D positive” and “D negative” refer only to presence or absence of the Rh antigen D on the red blood cell. • Terms “Rh pos” and “Rhneg” are old terms, although blood products still labeled as such. • Four additional antigens: C, c, E, e. • Named by Fisher for next letters of alphabet according to precedent set by naming A and B blood groups. • Major alleles are C/c and E/e. • MANY variations and combinations of the 5 principle genes and their products, antigens, have been recognized. • The Rh antigens and corresponding antibodies account for majority of unexpected antibodies encountered. • Rh antibodies stimulated as a result of transfusion or pregnancy, they are immune. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  7. Clinical Significance • D antigen, after A and B, is the most important RBC antigen in transfusion practice. • Individuals who lack D antigen DO NOT have anti-D. • Antibody produced through exposure to D antigen through transfusion or pregnancy. • Has been reported that > 80% of D neg individuals who receive single unit of D pos blood can be expected to develop immune anti-D. • Testing for D is routinely performed so D neg will be transfused only with D neg. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  8. Nomenclature • Fisher Race : CDE Terminology • Suggested that antigens are determined by 3 pairs of genes which occupy closely linked loci. • Each gene complex carries D or its absence (d), C or c, E or e. • Each gene (except d, which is an amorph) causes production of an antigen. • The order of loci on the gene appears to be “DCE” but many authors prefer to use “CDE” to follow alphabet. • Inherited from parents in linked fashion as haplotypes • The gene d is assumed to be present when D is absent. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  9. Fisher-Race • Three loci carry the Rh genes are so closely linked that they never separate but are passed from generation to generation as a unit or gene complex. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  10. Fisher-Race • With the exception of (d); each allelic gene controls presence of respective antigen on RBC. • The gene complex DCe would cause production of the D, C and e antigens on the red cells. • If the same gene complex were on both paired chromsomes (DCe/DCe) then only D, C and e would be present on the cells. • If one chromsome carried DCe and the other was DcE this would cause D, C, c, E and e antigens to be present on red blood cells. • Each antigen except d is recognizable by testing red cells with specific antiserum. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  11. Wiener • Postulated that TWO genes, one on each chromosome pair, controls the entire express of Rh system. • Each gene produces a structure on the red cell called an agglutinogen (antigen). • Eight (8) major alleles (agglutinogens): R0, R1, R2, Rz, r, r’, r” and ry. • Each agglutinogen has 3 factors (antigens or epitopes) • The three factors are the antigens expressed on the cell. • For example the agglutinogen R0= Rh0 (D), hr’ (c), hr’ (e) • Each agglutinogen can be identified by its parts or factors that react with specific antibodies (antiserums). BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  12. Weiner’s Theory BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  13. Weiner and Fisher-Race • The two theories are the basis for the two notations currently used for the Rh system. • Immunohematologists use combinations of both systems when recording most probable genotypes. • You MUST be able to convert a Fisher-Race notation into Wiener shorthand, i.e., Dce (Fisher-Race) is written R0. • Given an individual’s phenotype you MUST determine all probable genotypes and write them in both Fisher-Race and Wiener notations. • R1r is the most common D positive genotype. • rr is the most common D negative genotype. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  14. Weiner and Fisher-Race D = R 1 ( C) Z (both C & E ) 2 ( E ) 0 (neither C or E ) D c e D C E D C D c E d = r ‘( C) y (both C & E ) ‘’ ( E ) (neither C or E ) d c e d C E d C e d cE BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  15. Comparison of Weiner and Fisher-Race BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  16. Produces D antigen on RBC r” R0 R” R’ Produces C antigen on RBC r’ Single gene at Rh locus • The main difference between the Fisher-Race and Wiener theories is that the: • Fisher-Race theory has three closely linked loci, • the Wiener theory has only one gene locus at which multiple alleles occur. • Wiener theory: BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  17. Differentiating Superscript from Subscript Superscripts (Rh1) refer to genes Subscripts (Rh1) refer to the agglutinogen (complex of antigens) For example, the Rh1 gene codes for the Rh1 agglutinogen made of D, C, e Usually, this can be written in shorthand, leaving out the “h” DCe is written as R1 BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  18. Converting Wiener into Fisher-Race or Vice Versa R  D r  no D 1 and ‘ C 2 and “ E Example: DcE  R2 r”  dcE Written in shorthand BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  19. Rosenfield • Each antigen assigned a number • Rh 1 = D • Rh 2 = C • Rh 3 = E • Rh 4 = c • Rh 5 = e • In writing the phenotype, the prefix “Rh” is followed by colon, then number (if negative, number is preceded by -) • e.g. D+, C+, E-, c+, e+ is written as Rh:1,2,-3,4,5 BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  20. Comparison of Three Systems BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  21. International Society of Blood Transfusion • Abbreviated ISBT • International organization created to standardize blood group system nomenclature. • Assigned 6 digit number for each antigen. • First 3 numbers indicate the blood group system, eg., 004 = Rh • Last 3 numbers indicates the specific antigen, eg., 004001 = D antigen. • For recording of phenotypes, the system adopts the Rosenfield approach BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  22. Genotype Frequencies • Refer to textbook. • Genotypes are listed as “presumptive” or “most probable”. • Genotypes will vary in frequency in different racial groups. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  23. Weak Expression of D Not all D positive cells react equally well with anti-D. RBCs not immediately agglutinated by anti-D must be tested for weak D. Incubate cells with anti-D at 37C, coating of D antigens will occur if present. Wash X3 add AHG AHG will bind to anti-D coating cells if present. If negative, individual is D negative (By AHG method). If positive, individual is D positive w BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  24. Three Mechanisms for Weak D Genetic Position effect Mosaic Results in differences from normal D expression Quantitative (inherited weak D or position effects) Qualitative (mosaic D; could produce Anti-D) BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  25. Weak D - Genetic Inheritance of D genes which result in lowered densities of D Antigens on RBC membranes, gene codes for less D. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  26. Weak D - Genetic RBC with normal amounts of D antigen Weak D (Du) BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  27. Position Effect C trans - position effect; The D gene is in trans to the C gene, eg., C and D are on OPPOSITE sides: Dce/dCe C and D antigen arrangement causes steric hindrance which results in weakening or suppression of D expression. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  28. Position Effect C in trans position to D: D c e / d C e Weak D C in cis position to D: D C e / d c e NOweak D BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  29. Partial D (“D mosaic”). Absence of a portion or portions of the total material that comprises the D antigen. Known as “partial D” (old term “D mosaic”). BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  30. D Mosaic/Partial D If the patient is transfused with D positive red cells, they may develop an anti-Dalloantibody to the part of the antigen (epitope) that is missing Missing portion RBC RBC BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  31. Significance of Weak D Donors Labeled as D positive Weak D substantially less immunogenic than normal D Weak D has caused severe HTR in patient with anti-D Patients If weak D due to partial D can make antibody to portion they lack. If weak D due to suppression or genetic expression theoretically could give D positive Standard practice to transfuse with D negative Weak D testing on donors by transfusion service not required. Weak D testing on patients not required except in certain situations. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  32. Rh Null Red cells have no Rh antigen sites Genotype written ---/--- The lack of antigens causes the red cell membrane to appear abnormal leading to: Stomatocytosis Hemolytic anemia 2 Rh null phenotypes: Regulator type – gene inherited, but not expressed Amorph type – RHD gene is absent, no expression of RHCE gene Complex antibodies may be produced requiring use of rare, autologous or compatible blood from siblings. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  33. Rh Antibodies Except for rare examples of anti-E and anti-Cw which may be naturally occurring, most occur from immunization due to transfusion or pregnancy. Associated with HTR and HDFN. Characteristics IgG but may have MINOR IgM component so will NOT react in saline suspended cells (IS). May be detected at 37C but most frequently detected by IAT. Enhanced by testing with enzyme treated cells. Order of immunogenicity: D > c > E > C > e Do not bind complement, extravascular destruction. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  34. Rh Antibodies Anti-E most frequently encountered antibody followed by anti-c. Anti-C rare as single antibody. Anti-e rarely encountered as only 2% of the population is antigen negative. Detectable antibody persists for many years and sometimes for life. Anti-D may react more strongly with R2R2 cells than R1R1 due to higher density of D antigen on cells. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  35. Hemolytic disease of the Newborn (HDN) • Usually related to D antigen exposure and the formation of anti-D • Usually results from D negative female and D positive male producing and offspring. • The baby will probably be D positive. • 1st pregnancy not effected, the 2nd pregnancy and on will be effected-results in still birth, severe jaundice, anemia related to HDN. • To prevent this occurrence the female is administered RH-IG. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  36. Rh factor First pregnancy • Rh factor can cause complications in some pregnancies. Placenta Rh+ antigens • Mother is exposed to Rh antigens at the birth of her Rh+ baby. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  37. Mother makes anti-Rh+ antibodies. Possible subsequent pregnancies Anti-Rh+ antibodies • During the mother’s next pregnancy, Rh antibodies can cross the placenta and endanger the fetus. BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

  38.  Thanks  BB. MLT309. 2013-2014.Lec.5.Mr. Waggas

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