Blood Groups (W2308y6) PDF

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LECTURE-01 BLOOD GROUPS INTRODUCTION In the olden days, when the concept of blood groups was not yet known, people found that blood transfusions would sometimes lead to severe reactions with sudden haemolysis of RBCs and death. In1900, Karl Landsteiner discovered the fundamental principles of blood groups and laid down that ABO system. He discovered that different people had different antigenic and immune properties hence blood transfusion to a person belonging to a different blood group ie.mismatching would lead to severe reactions. There are several hundred antigens normally present on the surface of the RBCs. Most of these antigens do not cause major reactions, hence are called minor blood groups (21) e.g. MNS,P,Lutheran,Kell,Lewis,Dufy,Diego.These are mainly useful for studying inheritance of genes. There are two major groups of antigens causing major mismatched blood transfusion reactions: 01) ABO system discovered by Landsteiner in 1900. 02) Rh system discovered by Landsteiner in 1940. ABO SYSTEM ANTIGEN: Any foreign invading substance which can evoke an immune response in the body. AGGLUTINOGENS:Specific Antigens(glycoproteins) present on the surface of the RBC membrane. Classification of blood groups: Depending on the presence or absence of agglutinogen on the surface of RBC membrane, blood groups are classified as follows; Agglutinogen A Blood Group A 41% Agglutinogen B Blood Group B 09% Both Agglutinogens A & B Blood Group AB 03% Absence of Agglutinogens A & B Blood Group O 47% Inheritance: They are genetically determined & appear at the 6 th week of IUL. Agglutinogens A & B are inherited as Mendelian dominant charachters and are formed in the presence of A& B genes (dominant) while Type O gene is functionless. Blood group is thus determined by the genotype of a person i.e. the genes he has received from both parents. Genotype Blood Group ^AA/*AO A ^BB/*BO B AB AB OO O ^homozygous,*heterozygous

Blood Group A is further classified as A1 and A2 (On addition of kulith extract, agglutination seen with A1) In 80% people agglutinogens are present in various secretions (gastric, salivary), hence they are called secretors. ANTIBODY:are substances formed in response to an antigen. AGGLUTININS:are specific antibodies, naturally found in the plasma ,which have the ability to bind to a specific agglutinogen e.g. AntiA, antiB. They are formed in the plasma in response to various antigens entering the body via food, inhalation, Bacteria etc. Blood group A B AB O

Agglutinogen A B A,B ---

Agglutinin AntiB AntiA --AntiA,AntiB

Q: If the AgA is present on the Red cell, why is Anti A not produced? Why is Anti B being formed in the plasma? A: AgA is present at birth and is recognized as self antigen hence antibodies AntiA are not produced in response to antigen A entering he body. However AntiB is produced in the plasma in response to various antigens entering the plasma via food,inhalation,bacteria etc. LANDSTEINER’S LAW: States that 01) if an agglutinogen is present on the RBC membrane, then the corresponding agglutinin must be absent in the plasma. 02) if an agglutinogen is absent on the RBC membrane, then the corresponding agglutinin must be present in the plasma. ABO system follows both parts of Landsteiners law. Titre of Agglutinins at different ages:

At birth conc.of agglutinins in the plasma is almost zero.2-8 months later infant starts to produce agglutinins(antiA in B,O and antiB in A,O)). Maximum titers are reached at 8-10 years of age and then they decline throughout the remaining years of life. Nature of agglutinins: They are basically immunoglobulins ,gammaglobulins.

AntiA,AntiB

IgM

Anti Rh antibodies

IgG

Cold antibodies(respond 5-20’C) Warm antibodies(body temp)

10 binding sites 2 binding sites

Though AntiA and Anti B are IgM in nature, they are active at body temp. AGGLUTINATION: When a specific agglutinogen e.g AgA comes in contact with a specific agglutinin e.g Anti A, there occurs an antigen antibody reaction in the form of agglutination. Anti A t has 10 binding sites (IgM) hence potentially 10 RBC’s having agglutinogen A can bind to it.

COMPATIBILITY BETWEEN DIFFERENT BLOOD GROUPS; Agglutination of RBC is seen in case of mismatched blood transfusion. e.g.if blood groupA(donor) is given to person of B blood group(recipient). Donor-Blood GroupA RBC-AgA Plasma-AntiB

Recipient-Blood GroupB RBC-AgB Plasma-AntiA

Agglutination can be between Donor RBC’s and Recipients plasma agglutinins or between Donor’s plasma agglutinins and recipients RBC. Donor RBC’s having AgA are agglutinated by the recipients plasma agglutinins AntiA. What happens to recipients RBC having AgB? Do they agglutinate due to donors agglunins AntiB? Ans: No Because the donors plasma is diluted in the recipients plasma hence the antibodies are diluted, hence fail to agglutinate the recipients RBC. Donor Group Recipient group A B AB O A √ × √ × B × √ √ × AB × × √ × O √ √ √ √ Can Blood Group A be given to AB? Ans: Yes. Since AB has no natural agglutinins, donor cells are safe and anti B of donor serum gets diluted in the recipients plasma. Can Blood Group A be Given to O? Ans: No Because donor cells (AgA ) get agglutinated by recipients anti- A.

Hence Blood group O is universal Donor as the donor cells do not have any agglutinogen. Exception 1)Bombay Blood Group Bombay blood group is a rare group in which O blood group is associated with hh genotype, hence an antigenic substance which is formed makes them unsuitable as donors. 2) Rh mismatch (Rh Positive) And Blood group AB is universal Recipient as it does not have any agglutinins FATE OF THESE TRANSFUSION REACTIONS Due to the process of agglutination, the cells clump together, block small blood vessels. Physical distortion of these cells make them prone for phagocytosis by WBC,s or they burst in the spleen or lungs, thereby releasing haemoglobin into the plasma. This process is called as haemolysis.Thus here there is delayed haemolysis. Hb released into the plasma is converted to bilirubin and excreted by the liver. Sometimes if the titer of antibodies is very high, activation of the complement system which releases proteolytic enzymes causes immediate haemolysis of RBC’s in the blood itself. Hb then lodges in the renal tubules and causes blockage with acute renal shutdown DETERMINATION OF BLOOD GROUPS Principle: Blood is highly diluted with normal saline. Two drops of this suspension containing erythrocytes is mixed with a drop of Antisera A & Antisera B serum respectively. Interpretation; Antisera A Antisera B Blood Group √ × A × √ B √ √ AB × × O CROSS MATCHING To be absolutely sure and to avoid reactions due to minor blood groups and other weak antigens, cross matching is done. Suspension of donor erythrocytes is mixed with recipient’s serum. Suspension of recipient’s erythrocytes is mixed with donor’s serum. In both cases if there is no agglutination, blood is perfectly compatible.

Minor blood groups :( 30)  do not cause major reactions.  mainly useful for studying inheritance of genes.  MNS,P,Lutheran,Kell,Lewis,Duffy,Diego Major Blood Groups antigens cause major mismatched blood transfusion reactions: ABO system discovered by Landsteiner in 1900 Rh system discovered by Landsteiner in 1940.

Classification of Blood Groups Agglutinogen A B Both A & B Absence of A & B

Blood Group Incidence A 41% B 09% AB 03% O 47%

Inheritance Genotype Blood Group

^AA/*AO A ^BB/*BO B AB AB OO O ^homozygous,*heterozygous Blood group A B AB O

Agglutinins Agglutinogen Agglutinin A B A,B ---

AntiB AntiA --AntiA,AntiB

Landsteiner’s Law States that : 01) if an agglutinogen is present on the RBC membrane,then then the corresponding agglutinin must be absent in the plasma. 02) if an agglutinogen is absent on the RBC membrane, then the corresponding agglutinin must be present in the plasma. ABO system follows both parts of Landsteiners law Titer of Agglutinins at different ages

Nature of agglutinins AntiA,AntiB IgM Cold antibodies (respond 5-20’C) Anti Rh IgG Warm antibodies antibodies (body temp)

10 binding sites 2 binding sites

Though AntiA and Anti B are IgM in nature, they are active at body temp. Agglutination

Mismatched blood transfusion

Donor-Blood GroupA Recipient-Blood GroupB RBCAgA RBCAgB Plasma- AntiB Plasma- AntiA Compatibility between different Blood Groups Donor Group

Recipient group A

B

AB

O

A

√

×

√

×

B

×

√

√

×

AB

×

×

√

×

O

√

√

√

√

 Blood group O is universal Donor Exceptions: 1) Bombay blood group 2) Rh+ cannot donate to Rh-ve  Blood group AB is universal Recipient Fate of these transfusion reactions  Agglutinated cells block small vessels

phagocytosis by WBC,s or they burst in the spleen or lungs leading to release of Hb  Hb is then converted to bilirubin –jaundice  if the titer of antibodies is very high, activation of the complement system  Acute haemolysis ,released Hb blocks renal tubules -renal shutdown 

Determination of blood groups Antisera A Antisera B Blood Group √ × A × √ B √ √ AB × × O Crossmatching  Suspension of donor erythrocytes is mixed with recipient’s serum.  Suspension of recipient’s erythrocytes is mixed with donor’s serum  In both cases if there is no agglutination, blood is perfectly compatible LECTURE NO-2

Rh SYSTEM

Discovered by Landsteiner & Wiener in 1940.Term Rh stands for Rhesus .Landsteiner was working with Rhesus monkeys when he found this system.

This is also another imp. group to be matched before transfusion. Most of the Indians are Rh+ve .(Japanese are Rh-ve) RH AGGLUTINOGENS: There are 6 known agglutinogens which are also called Rh factors present on the R.B.C membrane. They are C,D,E and,c,d,e.They are not detected in any other tissues other than RBC. Inheritance: Each person inherits atleast 3 of the above factors from both groups in various combinations from both parents. e.g CDE,cDe,cDE,-----Agglutinogen D is highly antigenic. Person having “D” will be called Rh+ve.irrespective of the fact whether C,E is present or not as C,E are poor agglutinogens. Cde,CdE,cde.------Ag D is absent Hence even if C,E are present, person will be labelled Rh-ve. Rh AGGLUTININS: Person who has Ag D i.e Rh+ve has no naturally occuring agglutinins in the plasma. Hence Rh sysytem follows first part of LANDSTEINERS LAW. However if a PERSON is Rh -ve and has no agglutinogen D yet has no agglutinins in his plasma. Hence Rh system fails to obey the second part of Landsteiner Law. Rh IMMUNE RESPONSE; Rh-ve blood can be given to a person who is Rh+ve as it has no agglutinins against D antigen. However if Rh+ve blood is given to a person who is Rh-ve,an immune response is seen. as the D antigen is foreign to the recipient. Hence the recipient develops immune antibodies to it. Anti Rh agglutinins develop slowly within a few hours. Maximum conc. of the antibodies is seen 2-4 months later. Hence no agglutination is seen as by the time agglutinins are formed, the donor cells are already destroyed. However, a second exposure of Rh-ve person to Rh+ve blood, severe transfusion reaction is seen due to agglutination of donor erythrocytes with the anti Rh antibodies which had been formed in the plasma previously. On multiple exposures to Rh factor, Rh-ve person gets so sensitized, that transfusion reactions can be massive similar to ABO incompatibility.

ERYTHROBLASTOSIS FETALIS: Also called Hemolytic Disease of the Newborn or Icterus Gravis neonatorum.

Cause: It is due to Rh incompatibility when the mother is Rh-ve and the fetus is Rh+ve.This is possible if the the father is Rh+ve DD/Dd. 

If the father is DD all the children are Rh+ve as D is dominant in nature.

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However if the father is Dd,and the mother dd, then there is 50% chance that the baby will be Rh negative (dd).

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Also if both parents are Rh+ve but heterozygous Dd, there is one in four chance that the baby will be Rh-ve.

Sensitization: Initially the mother gets sensitized to the fetal blood carrying Rh antigens. Fetal cells enter mother’s blood at the time of separation of placenta, when the maternal sinuses are open. These fetal cells stimulate production of antibodies in the mother. However these antibodies cannot harm the first baby as separation of placenta takes place after birth of the first baby. The first baby thus escapes from the incompatibility. In the second pregnancy, these antibodies which have been formed in the earlier pregnancy can diffuse through the placental barrier (IgG) and and cause agglutination of the fetal R.B.C’s provided the second baby is Rh+ve. In reality 3% of the second baby suffers. While in the third pregnancy, 10% babies suffer. Incidence rises with each successive pregnancy. First born baby may be affected if  Mixing of blood in abortions, any intrauterine manipulations-fetomaternal bleed.  If mother has been sensitized by previous Rh+ve blood transfusion. Hence never give Rh+ve blood to a young Rh-ve female in the reproductive age group as far as possible Clinical picture: Disease is called Hemolytic Disease of the Newborn because the newborn shows haemolysis due to maternal antibodies. Baby looks pale and anaemic.Haemolysed blood then releases Hb into the circulation which is then converted into bilirubin by macrophages. Baby then looks jaundiced. Icterus Gravis Neonatorum. Rh antibodies remain in the babies blood for 1-2 months during which more haemolyis takes place. To make up for this loss, liver and spleen enlarge to increase rate of erythropoiesis.However due to rapid rate of production, immature nucleated R.B.C enter circulation and the peripheral blood shows large nucleated R.B.C Hence called Erythroblastosis Fetalis. Unconjugated bilirubin then gets deposited in the basal ganglia and cause destruction of the neuronal cells as the blood brain barrier is not yet developed. Baby then shows

permanent damage to the motor areas and is mentally retarded. Conjugation of bilirubin does not take place as liver is not yet mature This condition is called Kernicterus. If the baby does survive above, then the last stage is of generalized edema due to damage to liver & hypoprotenemia.-Hydrops Fetalis. Treatment: Exchange Transfusion  Carried out soon after birth  400 ml of Rh-ve ,ABO compatible blood is transfused into Rh+ve baby over a period of few hours. Simultaneously Rh+ve blood is removed from the other hand. This procedure is repeated several times in the first few weeks of life.  Principle: Rh-ve blood is not agglutinated by antibodies present in the fetus and hence can tide over the period in which antibodies are circulating. Babys blood containing antibodies and bilirubin is removed hence the baby is saved from complications. After a few weeks when almost no antibodies are present,babys own marrow produces Rh+ve blood which is now safe. Prevention;  Avoid giving Rh+ve blood to a young Rh-ve female in the reproductive age group.  Single dose Injection Anti D is given to the mother within 72 hours of delivery so that these antibodies will agglutinate the fetal cells circulating in the maternal blood and they are removed before they can sensitize the mother.  Gap between two pregnancies so that antibody titers are low.  Premarital counseling. IMPORTANCE OF BLOOD GROUPS

     

Blood transfusions Rh blood typing to avoid Erythroblastosis Fetalis. Paternity Tests. Can rule out paternity not confirm it Forensic Medicine to identify criminals Anthropological studies to understand the racial differences and the evolution of blood Groups. Correlation between blood groups and disease e.g Bld grp O is prone to duodenal ulcer, Bld Grp A is prone to gastric malignancy, pernicious anemia.

BLOOD TRANSFUSION

Indications: severe anemia, hemorrhagic shock due to wounds, accidents, maternal haemorrhage. Procedure: Blood is collected from a healthy Donor. It is then stored at 40C in a bag containing ACD/CPD which act as anticoagulants and can be used within 21 days. Hazards of blood transfusion;  Due to immune transfusion reactions A) Hemolytic transfusion reaction Major mismatch leads to agglutination of Donor RBC’s. Activation of complement system leads to sudden haemolysis and release of Hb into circulation. Acute renal shutdown (causes) 1)Release of toxic substances during haemolytic reaction causes powerful renal vasoconstriction . 2)Toxic substances and the loss of RBC’s makes a person go into circulatory shock. Blood pressure falls with reduced renal blood flow and urine output. 3)Also free Hb which is not bound to haptoglobulin blocks renal tubules causing acute renal shutdown.---fatal B) Nonhaemolytic immune reaction 1) fever with chills due to allergic reaction to donors plasma or ACD bag 2) Anaphylactic reaction due to release of histamine from donors basophils 

Nonimmune transfusion reaction 1) circulatory overload and cardiac failure due to rapid transfusion 2) stored blood transfusion reaction a) ACD causes chelation of Calcium leading to tetany. b) Haemolysed RBC release K+ and increased plasma levels i.e hyperkalemia is seen especially if the blood is more than 14 days old. 3) mild thrombocytopenia because platelets and clotting factors do not survive in stored blood 4) Last but not the least,infections transmitted via blood are viral hepatitis,HIV, malaria etc.

RH AGGLUTINOGENS

6 known agglutinogens: C,D,E and,c,d,e.  Not detected in any other tissues  Inheritance: e.g CDE,cDe,cDE -----------Rh+ve Cde,CdE,cde -----------Rh-ve 

Rh AGGLUTININS Rh+ve -----------no agglutinins in plasma Rh-ve -----------no agglutinins in plasma Hence Rh system does not follow second part of Landsteiner’s law.

    

Rh IMMUNE RESPONSE Rh-ve blood can be given safely to Rh+ve person But if Rh+ve blood given to Rh-ve person Anti Rh agglutinins develop slowly in a few hours ,peak at 2-4 months Second exposure harmful as person has Anti D in his blood Repeated exposures can cause severe reaction similar to ABO incompatibility

ERYTHROBLASTOSIS FETALIS Also called Hemolytic Disease of the Newborn or Icterus Gravis neonatorum. Cause: It is due to Rh incompatibility when the mother is Rh-ve and the fetus is Rh+ve Sensitization:  Fetal cells enter mother’s blood at the time of separation of placenta  AntiRh antibodies are formed in the mother  In second pregnancy, they cross placental barrier(IgG) and agglutinate Rh+ve fetal RBC’s  First baby may affected if - If mother has been sensitized by previous Rh+ve blood transfusion - Previous abortions, any intrauterine manipulations Hence never give Rh+ve blood to a young Rh-ve female in the reproductive age group Incidence: 3% of second baby suffers, 10% of third baby and so on Clinical picture:

 Hemolytic Disease of the Newborn Fetal RBC haemolysed by maternal antibodies

 Icterus Gravis Neonatorum Hb released is converted into bilirubin- yellow

 Erythroblastosis Fetalis Increase rate of erythropoiesis,immature nucleated cells appear in circulation

 Kernicterus

Bilirubin is deposited in basal ganglia,permanent motor damage, mental retardation

 Hydrops Fetalis Damage to liver,hypoprotenemia,generalised edema

Treatment: Exchange Transfusion  Carried out soon after birth  Rh-ve ,ABO compatible blood is transfused into Rh+ve baby  Rh+ve blood is removed from the other hand  Principle: Transfused Rh-ve cells are safe in the presence of antibodies, while fetal blood containing AB are removed,later babys ow...