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Chapter 19 The Blood
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The Blood The cardiovascular system consists of three components:
Heart Blood vessels
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Functions of Blood Blood transports:
oxygen & CO2 between lungs & tissues nutrients from the digestive tract metabolic wastes- from body to kidneys for elimination hormones from endocrine glands to target organs Blood regulates: body temperature pH using buffer systems Blood protects against blood loss by initiating hemostasis & coagulation against infection – antibodies, complement proteins, WBCs
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Physical Characteristics of Blood
It is viscous (thick) and more dense than water temperature slightly warmer than core body temperature (T = 38o C) slightly alkaline pH ( ) oxygenated blood bright red, poorly oxygenated blood dark red makes up 8% of body mass Blood volume: 5–6 L for males, and 4–5 L for females
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Constituents of Blood Blood is 5 liters of a specialized fluid connective tissue composed of formed elements (45%) suspended in a solution called plasma (55%) If a sample of blood is centrifuged cellular portion will precipitate out of solution and form a heavier sediment below the straw colored liquid plasma The normal RBC mass is almost 45% by volume – this is called the hematocrit (Hct)
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Constituents of Blood
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Blood Plasma Plasma is 92% water, with dissolved solutes:
Plasma proteins – produced by the liver albumin, globulins, fibrinogen Nitrogenous wastes urea, uric acid, creatinine Nutrients – glucose, fatty acids, amino acids Electrolytes sodium, potassium, calcium, chloride, bicarbonate Respiratory gases oxygen and carbon dioxide Hormones Clotting factors If plasma is allowed to coagulate it is called serum - serum is just plasma without the clotting factors- used or blood testing
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Plasma Proteins Albumin
contributes significantly to colloidal osmotic pressure of blood It also plays an important role as a carrier molecule for lipid soluble substances e.g. hormones globulins, of which there are several types: α-globulins and β- globulins are carrier proteins δ-globulins are immunoglobulins (antibodies) made by activated B lymphocytes called plasma cells Fibrinogen- clotting factor –forms the blood clot
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Formed Elements The formed elements of blood include:
Erythrocytes ( RBCs)- highest count Leukocytes( WBCs) Platelets Are continuously formed in the bone marrow 1mm3 = 1uL = mL The Hct = % females, 40-54% for males; Hemoglobin (Hgb) = g/dl
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Hematopoiesis The process by which the formed elements of blood develop is called hemopoiesis (hematopoiesis). blood cells are formed in red bone marrow from pluripotent stem cells. Red bone marrow: In adults : bones of axial skeleton, pectoral & pelvic girdles, heads of humerus & femur In newborns- all bone marrow is red Lymphoid tissues includes the thymus, spleen, tonsils, or lymph nodes.
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Hematopoiesis
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Hematopoiesis Blood cells are formed from pluripotent stem cells.
The pluripotent stem cells (hemopoietic stem cells) produce the myeloid stem cell and lymphoid stem cell myeloid stem cell gives rise to: RBCs, platelets, monocytes, neutrophils, eosinophils, and basophils lymphoid stem cell gives rise to: T lymphocytes, B lymphocytes, NK cells Regulation of hematopoiesis: Erythropoietin (EPO) regulates RBC formation Thrombopoietin regulates platelet formation Colony stimulating factors & interleukins stimulate WBC formation
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Clinical connection Bone marrow examination by bone marrow aspiration or bone marrow biopsy For diagnosis of leukemias, anemias Site: usually iliac crest of hip bone, sternum
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Red Blood Cells to the tissues of the body-
About 5 million RBCs/mm3 of blood Red blood cells are bi-concave discs- increases the cell surface area- gives them a high oxygen carrying capacity Mature RBCs don't have a nucleus or any protein making machinery -die in about 120 days. specific purpose – to carry O2 to the tissues of the body- also carry 23 % CO2 Their shape also allows them to deform and fit in small capillary beds
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RBCs and Hemoglobin Each RBC contains 280 million molecules of Hb
Hemoglobin (Hb) is a protein molecule adapted to carry O2 (and CO2 as well) A Hgb molecule consists of globin protein (2 alpha and 2 beta polypeptide chains), each embedding an iron-containing heme group Oxygen binds to the heme group ( one Hb binds 4 oxygen molecules) CO2 binds to globin proteins Red cells contain hemoglobin. A heme is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic subunit; these are known as hemoproteins.
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RBCs RBCs and CO2: Red blood cells contain the enzyme carbonic anhydrase Carbon dioxide diffuses fron tissues into RBCs It combines with water to form carbonic acid- H2CO3 which quickly dissociates into hydrogen ions and bicarbonate ions 70 % of CO2 is transported in blood as bicarbonate ions which is an important blood buffer
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RBCs Life Cycle Erythropoiesis is the part of hematopoiesis that deals with the production of RBCs. Control is by negative feedback Erythropoiesis increases when states of hypoxia (O2 deficiency)- stimulates the kidneys to release the hormone erythropoietin (EPO) EPO circulates to the red marrow and speeds up the maturation and release of immature red cells Thrombopoietin shows great promise for preventing the depletion of platelets, which are needed to help blood clot, during chemotherapy. CSFs and thrombopoietin also improve the outcome of patients who receive bone marrow transplants. Hemopoietic growth factors are also used to treat thrombocytopenia in neonates, other clotting disorders, and various types of anemia. Research on these medications is ongoing and shows a great deal of promise.
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Negative feedback regulation of Erythropoiesis
Some stimulus disrupts homeostasis by Decreasing Oxygen delivery to kid-neys (and other tissues) Receptors Kidney cells detect low oxygen level Input Increased erythropoietin secreted into blood Control center Return to homeostasis when oxygen delivery to kidneys increases to normal Proerythroblasts in red bone marrow mature more quickly into reticulocytes Output Increased erythropoietin secreted into blood Effectors Larger number of RBCs in circulation Increased oxygen delivery to tissues
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RBCs Life Cycle As cells mature in the bone marrow, they
become smaller the nucleus is lost Most organelles lost the amount of Hb increases At reticulocyte stage RBCs are sent out into the blood stream
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Reticulocytes Reticulocytes:
At this stage the RBCs are sent out into the blood stream Normally 1-2% of the RBCs in the peripheral circulation are reticulocytes The rate of erythropoiesis is measured by the number of immature RBCs (called reticulocytes or “retics”) in the peripheral circulation A low retic count (<.5%) indicates a low rate of erythropoiesis while an elevated rate (>2%) indicates a high rate of erythropoiesis
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RBC Life Cycle RBCs live only about 120 days- are destroyed mainly in spleen To maintain normal numbers, new cells must enter the circulation at 2 million/s to balance high rate of RBC destruction Ruptured RBCs are destroyed by macrophages in the spleen and liver Heme and globin are separated Globin is metabolized into amino acids- released into the circulation Iron of the heme is salvaged for re-use Heme is degraded to bilirubin
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RBC Life Cycle Key: 10 9 8 7 6 5 4 3 2 1 Key: 9 8 7 6 5 4 3 2 1 Key:
Amino acids Reused for protein synthesis Globin Circulation for about 120 days Bilirubin Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme Biliverdin 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Circulation for about 120 days Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme Biliverdin Bilirubin 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Stercobilin Bilirubin Urobilinogen Feces Small intestine Circulation for about 120 days Bacteria Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme Biliverdin 12 11 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Urine Stercobilin Bilirubin Urobilinogen Feces Small intestine Circulation for about 120 days Bacteria Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Kidney Macrophage in spleen, liver, or Ferritin Urobilin Heme Biliverdin 13 12 11 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Urine Stercobilin Bilirubin Urobilinogen Feces Large intestine Small Circulation for about 120 days Bacteria Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Kidney Macrophage in spleen, liver, or Ferritin Urobilin Heme Biliverdin 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Circulation for about 120 days Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Ferritin Heme 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Heme 3 2 1 Globin Red blood cell death and phagocytosis Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Heme 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Heme 4 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Liver Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Ferritin Heme 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Liver Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Ferritin Heme 6 5 4 3 2 1 Red blood cell death and phagocytosis Key: in blood in bile Macrophage in spleen, liver, or red bone marrow 1
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Clinical connections Anemia is a condition of insufficient RBC’s or hemoglobin (quality or quantity) It is most often the result of low iron intake, hemolysis, blood loss, or lack of production in the bone marrow Polycythemia is a condition of excess number of RBCs It occurs in response to hypoxia, shots of EPO (illegal “doping”), COPD
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Anemias Iron deficiency anemia is the most common anemia in the U.S., and affects primarily menstruating women Chronic blood loss is a cause Hemorrhagic anemia is the result of precipitous blood loss, and results in an equal decrease in Hct, Hb content, and RBC count
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Anemias Sickle-cell disease (SCD), also called sickle-cell anemia, is an autosomal recessive disorder. A genetic defect in the primary DNA sequence leads to production of a faulty Hb β chain, and RBCs that take on a rigid, sickle-shape Sickling decreases the cells' flexibility and results in a variety of complications; life expectancy is shortened
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White Blood Cells WBCs number- between 5000-10,000 cells/mm3
There are 5 different types of WBCs (WBCs) or leukocytes have nuclei and other organelles 1mm3 = 1uL = mL
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Leukocytes Leukocytes are divided into two groups depending on whether they contain conspicuous cytoplasmic granules (when stained) Granulocytes include the neutrophils, eosinophils, and basophils Agranulocytes are the monocytes and lymphocytes
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Neutrophils The most numerous WBC in normal blood (60-70% )is the neutrophil, or polymorphonucleocyte (PMN) PMNs are granulocytes lilac granules and nuclei have 2-5 lobes They are phagocytes - their principal role is to fight bacterial infections PMN phagocytizing a microbe
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Eosinophils Eosinophils are characterized by their large red granules and bilobed nuclei They are (2-4% of circulating WBCs), but their numbers increase slightly with allergic reactions & parasitic infections they have also been associated with the development of allergies
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Basophils Basophils are the granulocytes that contain large, dark blue, histamine containing granules Normally, they are the lowest number of circulating WBCs (only 0-1%), May have a role to play in the inflammatory responses
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Monocytes While monocytes are not granulocytes, they come from the same immediate precursor cell as the 3 granulocytes (the myeloid stem cell) 3-8% of the circulating WBCs Along with neutrophils, monocytes are the other major group of phagocytic cells. they are more numerous in the peripheral, tissues where they act as “fixed” phagocytes The dead cells of PMNs and monocytes make up the debris found in pus.
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Lymphocytes Approximately 20-30% of circulating WBCs are lymphocytes
increase in number in acute viral infections Most lymphocytes continually move between lymphoid tissues, lymph, and blood, spending only a few hours in blood Lymphocytes are the cornerstone of the specific immune response There are two types of lymphocytes: T cells and B cells T cells control immune responses B cells give rise to plasma cells, which produce antibodies
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Functions of Leukocytes
To get rid of pathogens the WBCs have to leave the blood stream and collect at sites of infection or injury WBCs leave the bllod vessels by the process called emigration : Rolling along the endothelium & then sticking- by complementary adhesion molecules on endothelium (selectins) and on leucocytes (integrins ) Squeeze out between endothelial cells -diapedesis Chemicals released by microbes and inflamed tissues attract phagocytes, a phenomenon called chemotaxis
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Functions of Leukocytes
Neutrophils are the first to emigrate in bacterial infections Reach by chemotaxis & engulf pathogen by phagocytosis Release strong oxidants & defensins to destroy engulfed bacteria Neutrophils are followed by monocytes- which get transformed into phagocytic tissue macrophages Lymphocytes take part in immune responses B cells- antobody mediated humoral immunity T cells – immune regulation & destruction of viral infected and cancer cells
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Emigration of neutrophils
Interstitial fluid Blood flow Emigration of neutrophils Neutrophil Endothelial cell Rolling Sticking Squeezing between endothelial cells Key: Selectins on endothelial cells Integrins on neutrophil
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Chemotaxis & phagocytosis
Diapedesis Chemotaxis & phagocytosis From Wikimedia Commons
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WBC Indices For diagnostic purposes, physicians measure the total leucocyte count A leukocytosis is any WBC count > 10,000/mm3, and usually indicate an infectious process or inflammation A leukopenia is any WBC count < 5,000/mm3, and usually indicates a severe disease (AIDS, bone marrow failure, severe malnutrition, or chemotherapy) Differential leucocyte count : percentages of each of the 5 types of WBCs
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WBC Indices Shifts in the normal percentages of circulating WBCs will often point towards a bacterial infection (elevated neutrophils) or a viral infection (elevated lymphocytes) In this peripheral blood smear a patient with lymphocytic leukemia has a WBC >150,000 and 90% of the WBCs are cancerous lymphocytes! Lymphocytic leukemia.
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Platelets Platelets (thrombocytes) are about 150, ,000 cells/mm3 , they have a short life span (5 to 9 days) Their granules contain chemicals (serotonin, Ca2+, ADP) that, once released, promote blood clotting Also release PDGF- promotes growth & healing of damaged vessels 1mm3 = 1uL = mL
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Platelets Megakaryocytes (immediate precursors of platelets) are huge cells that splinter into 2000 to 3000 fragments while still in the red bone marrow Each disc shaped fragment is a platelet Platelets leave the red bone marrow and enter the circulation
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Hemostasis Hemostasis is a sequence of responses that stops bleeding when blood vessels are damaged or ruptured Three mechanisms reduce blood loss Vascular spasm Formation of a platelet plug Blood clotting (coagulation)
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Hemostasis Platelets adhere to damaged endothelium to form a
Vascular spasm occurs as damaged blood vessels constrict- (by neural & chemical stimuli) Platelets adhere to damaged endothelium to form a platelet plug
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2.Platelet Plug Formation
1 2 3 Red blood cell Platelet Collagen fibers and damaged endothelium Liberated ADP, serotonin, and thromboxane A2 Platelet plug Platelet adhesion Platelet release reaction Platelet aggregation 1 2 Red blood cell Platelet Collagen fibers and damaged endothelium Liberated ADP, serotonin, and thromboxane A2 Platelet adhesion Platelet release reaction 1 Red blood cell Platelet Collagen fibers and damaged endothelium Platelet adhesion 2.Platelet Plug Formation
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Hemostasis Clotting (coagulation) is possible because of the presence of several clotting proteins normally dissolved in the blood in inactive state Coagulation occurs in a cascade whereby one activated clotting protein triggers the next step in the process, which triggers the next There are 2 pathways to activate the clotting cascade: extrinsic & intrinsic
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Blood clotting cascade
Tissue trauma Tissue factor (TF) Blood trauma Damaged endothelial cells expose collagen fibers (a) Extrinsic pathway (b) Intrinsic pathway Activated XII Ca2+ platelets Platelet phospholipids Activated X Activated PROTHROMBINASE V Prothrombin (II) THROMBIN Loose fibrin threads STRENGTHENED FIBRIN THREADS Activated XIII Fibrinogen (I) XIII (c) Common pathway 1 2 3 + Tissue trauma Tissue factor (TF) Blood trauma Damaged endothelial cells expose collagen fibers (a) Extrinsic pathway (b) Intrinsic pathway Activated XII Ca2+ platelets Platelet phospholipids Activated X Activated PROTHROMBINASE V Prothrombin (II) THROMBIN (c) Common pathway 1 2 + Tissue trauma Tissue factor (TF) Blood trauma Damaged endothelial cells expose collagen fibers (a) Extrinsic pathway (b) Intrinsic pathway Activated XII Ca2+ platelets Platelet phospholipids Activated X Activated PROTHROMBINASE V 1 Blood clotting cascade
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Hemostasis The extrinsic pathway has few steps, occurs within seconds, once the protein “tissue factor” (TF) or tissue thromboplastin leaks into the blood from cells The intrinsic pathway is more complex, & slower in response blood contact with collagen under endothelial cells- activates factor XII
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Hemostasis Both the extrinsic and intrinsic clotting pathways converge at a common point (pathway) where factor X becomes activated (Xa), combines with factor V to form: Prothrombin activator(prothombokinase) Prothrombin is converted into thrombin Thrombin converts soluble fibrinogen into insoluble fibrin threads,
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Hemostasis Ca2+ plays an important role throughout the clotting system
Clot retraction is the consolidation of the fibrin clot. Fibrin threads contract as platelets pull on them As the clot retracts, it pulls the edges of the damaged vessel closer together, decreasing the risk of further damage – new endothelial cells can then repair the vessel lining
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Fibrinolysis Because blood clotting involves positive feedback cycles, a clot has a tendency to enlarge, this is checked by: The fibrinolytic system - dissolves clots Vessel endothelial cells release tissue plasminogen activator ( tPA) that can activate plasminogen an inactive plasma enzyme to become plasmin, (the enzyme that actively dissolves clots)
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Intravascular Clotting
Inappropriate clotting in an unbroken blood vessel is called thrombosis; the clot itself, called a thrombus Such clots may be initiated by: endothelial injury resulting from atherosclerosis, trauma, or infection Stasis of blood- allowing clotting factors to accumulate locally and initiate the coagulation cascade
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Intravascular Clotting
A thrombus may become dislodged and be swept away in the blood blood clot transported by the bloodstream is called an embolus emboli can obstruct a blood vessel and cause ischemia to the tissue beds e.g. pulmonary embolism, stroke
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Blood Groups Red cells have antigens or agglutinogens on their surface
These antigens are: Unique to the individual Recognized as foreign if transfused into another individual Presence or absence of these antigens is used to classify blood groups Major blood group antigens are A and B antigens & Rh antigen The major blood groups are ABO & Rh blood groups
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Blood Groups In transfusion medicine the presence or absence of the
A and B red cell antigens forms the basis of the ABO blood group system Another major red cell antigen is the Rh antigen, which 85% of the population have, and comprises the other important blood grouping
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Blood Groups For reason that are not totally clear, serum contains anti-ABO antibodies of a type opposite to the ABO antigen on the red cell surface For instance, those with A antigens on their red cells have anti-B antibodies in their serum
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Blood Groups By knowing the status of the A antigen, B antigen, and Rh antigen, most of the major blood incompatibility issues can be avoided Type AB individuals are “universal recipients” because they has neither anti-A nor anti-B antibodies in their serum that would destroy transfused RBCs Type O individuals are “universal donors” because their RBCs have no antigens on the cell surface that can potentially react with the recipients serum
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Rh Incompatibility Individuals whose RBCs have the Rh antigen are said to be Rh+ while those who lack the Rh antigen are Rh- Unlike ABO blood groups, anti-Rh antibodies are not spontaneously formed in Rh– individuals If an Rh– individual is exposed to Rh+ blood, anti-Rh antibodies form( e.g. receiving Rh+ transfusion) A second exposure to Rh+ blood will result in a transfusion reaction
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Hemolytic Disease of the Newborn
Rh– mother carries a Rh+ fetus At the time of birth she gets exposed to Rh+ blood- anti RH antibodies are formed In a subsequent pregnancy, these Rh+ antibodies cross the placenta and attack the RBCs of a Rh+ baby Results in hemolyis of babys RBCs- baby is born with severe anemia Prevention- RhoGAM given to Rh– mother ( during pregnancy & at birth) RhoGAM destroys any Rh+ cells before the mother’s immune system can produce anti-Rh antibody
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Blood Typing & Cross Matching
Blood typing for ABO status is done using single drops of blood mixed with different antisera: Anti-A serum contains anti-A antibodies Anti-B serum contains anti-B antibodies Agglutination with an antisera indicates the presence of that antigen on the RBC Rh typing: a drop of blood mixed with antiserum containing anti- Rh antibodies Cross matching: RBCs of donors blood of same type mixed with recipients serum- checked for agglutination
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Transfusion Reactions
Mismatched transfusions cause transfusion reactions Donor’s cells are attacked by the recipient’s plasma antibodies causing agglutination & hemolysis : Clumped cells block small blood vessels & hemolyse Ruptured RBCs release free hemoglobin into the bloodstream Free hemoglobin can block kidneys tubules and cause acute renal failure Person can go into shock
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