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Blood groups and Hemostasis Dpt. Of Normal, Pathological and Clinical Physiology Blood groups blood transfusion often resulted in agglutination and hemolysis, often led to death (renal shock) antibodies in the plasma of one blood react with antigens on the surface of the red cells of another blood more than 30 commonly occurring antigens hundreds of rare antigens two particular groups of antigens: AB0 and Rh systems are immunogenic enough to cause hemagglutination AB0 system - history Landsteiner Jánský actual nomenclature A II A B III B C I 0 --- IV AB AB0 system four groups: A, B, AB, 0 two (3) agglutinogens = antigens on the surface of RBC two agglutinins = antibodies present in the plasma agglutinogens = glycoprotein, oligosaccharides having different carbohydrate at their endings A – N-acetylgalactosamin B – galactose H – fucosotransferasa AB0 agglutinogens determined by two genes, one on each of two paired chromosomes 0 is functionless gene; O = “ohne” A gene determines A group; B gene determines B group codominancy: blood type A: genotype AA, A0 blood type B: genotype BB, B0 + Hh or HH blood type AB: genotype AB blood type 0: genotype 00 (or hh “Bombay” + either AA, AO, BB, BO, or AB) AB0 agglutinogens antigen H forms the antigen-carrying molecule subtypes of A antigen A1…A6, different immunogenity detectable in 4weeks old embryo during labor, 20-30% of the immunogenity in adult (> 18 years) AB0 agglutinins antibodies present in the plasma γ-globulins, IgG and IgM molecules (pentamers, not diffusing trough the placenta) not present immediately after birth produced in 2-8 months after birth by plasma cells (specialized B-cells, stimulated by similar oligosaccharides often expressed in the nature – food, intestinal bacterias) highest titer around at 10 years of age antibodies against the AB0type not present in the blood group A antibodies anti-B group B antibodies anti-A group AB no antibodies group 0 antibodies anti-A and anti-B Frequencies of the different blood types differ according to geographic and time locations group A: Atlantic population and Eskimos (60%) group B: east-south Asia, India (40%) group 0: America's Indians (100%) the Czech Rep.: A-42 %, 0-32 %, B-18 %, AB-8 % white people: A-47 %, 0-41 %, B-9 %, AB-3 % universal donor, universal acceptor - antigens autotransfusion Rh system II Landsteiner 1940 C, D, E antigens (D is most immunogenic) 85 % white people Rh+, 99 % Asians Rh+, African black 100 % Rh+ clinical importance: 1. blood transfusion 2. pregnancy: mother Rh negative and fetus Rh positive, antibodies diffuse trough the placenta (erythroblastosis fetalis, new-born hemolysis, kernicterus, jaundice) in both cases the exposition to the antigen is needed first (sensitization), because anti-Rh antibodies are NOT normally produced – Rh antigen is not often present in the nature Other systems MNSs: very low immunogens, normally no natural antibodies in blood occur, Landsteiner 1927 P system: Landsteiner, low immunogens ( 80% people); subtypes Kell, Duffy, Kidd, Lutheran, Diego Hemostasis three mechanisms: 1. vascular spasm 2. formation of a platelet plug 3. blood coagulation Vasoconstriction neural: nervous reflexes induces by activation of pain fibers, local myogenic spasm humoral: thromboxan A2 and serotonin and other substances produced by activated platelets vasoconstriction itself stops the bleeding in vessels as large as a. radialis (under ideal circumstances / i.e. crushed, not cut) lasts for minutes or even hours Platelets do not have nuclei, oval discs 2-4 mm, half-life 4-8 days megakaryocytes (1000-5000 platelets) 150 – 300.000 per 1 microliter platelets cytoplasm contains: 1. 2. 3. 4. 5. actin and myosin and thrombosthenin (platelet contraction) vesicles containing Ca2+ , serotonin, ADP enzymes that synthesize prostaglandins a-granules: PDGF, coagulating factors, von Willebrandt factor (adhesion) lysozomy platelets membrane contains large amount of phospholipids platelets function 1. adhesion, collagen: vonWillebrandt Factor released from endothel 2. activation: swelling, irregular forms, pseudopods, release of serotonin, vWF, tromboxan A2, ADP activation of other platletes 3. aggregation: stimulated by trombin, tromboxan A2, vWF, fibrinogen platelet plug (loose, then fibrin threads form an unyielding plug) closing the minute ruptures (small vessels, many times per day, petechiae) Thrombopoetin produced by the liver, little in kidney receptors in plasma membrane of stem cells and megakaryocytes and platelets (regulation) constant production, regulation by the number of platelets / the more platelets the more T bound to them less T act on stem cells and megakaryocytes liver diseases bleeding (together with lower production of clotting factors) clotting pathways intrinsic pathway extrinsic pathway common the sense is to form fibrin monomers and then polymers = fibrin fibers (threads) within few seconds (and pesence of Ca2+) fibrin is formed by activated thrombin all activators of prothrombin are called trombokinases (tissue and plasmatic trk) clotting factors - proenzymes I fibrinogen VIII AHF A II prothrombin* IX Christmas (AHF B)* III tissue thromboplastin X Stuart-Prower* IV calcium XI AHF C V XII Hageman proaccelerin VII proconvertin* * vitamin K dependent XIII fibrin-stabilizing clotting pathway – common X Xa: activated either by intrisic or extrinsic pathway +V II IIa: protrombin, trombin XIII XIIIa stabilization I Ia: fibrinogen fibrin I fibrinogen II prothrombin* III tissue thromboplastin IV calcium V proaccelerin VII proconvertin* VIII AHF A IX Christmas (AHF B)* X Stuart-Prower* XI AHF C XII Hageman XIII fibrinstabilizing clotting pathway – intrinsic submucosis, phospholipids released from platelets I XII XIIa: catalyzed by kalikrein a kininogen, II activated by negative charges (glass, III collagen) IV XI XIa: activated by XIIa V VII IX IXa: activated by XIa +VIII X Xa 1 – 6 minutes fibrinogen prothrombin* tissue thromboplastin calcium proaccelerin proconvertin* VIII AH A IX Christmas (AH B)* X Stuart-Prower* XI AH C XII Hageman XIII fibrinstabilizing clotting pathway – extrinsic tissue, lipoproteins VII VIIa: activated by tissue factor III (thromboplastin) which is released from damaged tissues X Xa: activated by VIIa 10 seconds, explosive (VIIa activates IX of intrinsic pathway as well) I fibrinogen II prothrombin* III tissue thromboplastin IV calcium V proaccelerin VII proconvertin* VIII AHF A IX Christmas (AHF B)* X Stuart-Prower* XI AHF C XII Hageman XIII fibrinstabilizing anticlotting mechanisms endothelial smoothness, glycocalyx (mucopolysaccharide repelling the factors) and thrombomodulin (protein binding thrombin) fibrin itself remove thrombin from the blood catching of activated factors by liver consumption of activated factors antithrombin III: proteases inhibitor, its binding is facilitated by heparin no activation of IX, X, XI, XII heparin – polysaccharide released from mast cells and basophils fibrinolysis thrombomodulin (endotelial wall) catalyzes activation of protein C by thrombin activated protein C (APC) 1. 2. 3. inactivates VIII inactivates V activates tissue plasminogen activator (TPA) TPA catalyzes activation of plasminogen to form plasmin, plasmin causes lysis of the clot alteplase (recombinant), streptokinase, urokinase anticoagulants heparin (+ antithrombin III) citrate, oxalate (bind Ca2+) coumarin, warfarin (inhibition of vitamin K) excessive bleeding failure of blood clotting (coagulopathy) – hematoms, joint bleeding platelets failure thrombocytopathy – petechiae vessels defects – petechiae innate coagulopathy abnormality or deficiency of one of the clotting factors hemophilia A, classic h. – – – – defect of VIII (3 subunits, defect of the clotting factor) transmitted genetically, X chromosome, males hemophilic arthropathy, muscle bleeding in legs 1 z 10000 born males von Willebrandt disease: defect of VIII, all subunits impaired (vW factor, antigen factor and clotting factor) hemophilia B: defect of IX other disorders when impaired factors I, II, V, VII, X, XIII deficiency of XI almost without any clinical signs acquired coagulopthies liver diseases (cirrhosis) – deficiency of all factors heparin deficiency of vitamin K DIC – sepsis, leukemia, AB0 incompatibility defects of platelets trombocytopenia: aplasia (radiation), hypovitaminosis B12, sequestration trombocytopathy: acetylsalicylic acid (inhibition of COX suppresses synthesis of thromboxan A2 and secretion of ADP Defekty cév von Willebrandtova choroba: defekt endotelu, chybí vWF porucha adheze, nedostatek VIII (vWF je jeho přenašeč) skorbut vrozené defekty pojiva: Rendu-Osler, HenochSchönlein