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Blood groups and Hemostasis
Dpt. Of Normal, Pathological and Clinical Physiology
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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
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AB0 system - history
Landsteiner Jánský actual nomenclature
A II A
B III B
C I 0
--- IV AB
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AB0 system
four groups: A, B, AB, 0two (3) agglutinogens = antigens on the surface of RBCtwo agglutinins = antibodies present in the plasmaagglutinogens = glycoprotein, oligosaccharides having different carbohydrate at their endingsA – N-acetylgalactosaminB – galactoseH – fucosotransferasa
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AB0 agglutinogens
determined by two genes, one on each of two paired chromosomes0 is functionless gene; O = “ohne”A gene determines A group; B gene determines B groupcodominancy:blood type A: genotype AA, A0blood type B: genotype BB, B0blood type AB: genotype ABblood type 0: genotype 00 (or hh “Bombay” + either AA, AO, BB, BO,
or AB)
+ Hh or HH
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AB0 agglutinogens
antigen H forms the antigen-carrying moleculesubtypes of A antigen A1…A6, different immunogenitydetectable in 4weeks old embryoduring labor, 20-30% of the immunogenity in adult (> 18 years)
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AB0 agglutininsantibodies present in the plasmaγ-globulins, IgG and IgM molecules (pentamers, not diffusing trough the placenta)
not present immediately after birthproduced 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 ageantibodies against the AB0type not present in the bloodgroup A antibodies anti-Bgroup B antibodies anti-Agroup AB no antibodiesgroup 0 antibodies anti-A and anti-B
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Frequencies of the different blood types
differ according to geographic and time locationsgroup 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 - antigensautotransfusion
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Rh system II
Landsteiner 1940C, 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
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Other systems
MNSs: very low immunogens, normally no natural antibodies in blood occur, Landsteiner 1927P system: Landsteiner, low immunogens ( 80% people); subtypesKell, Duffy, Kidd, Lutheran, Diego
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Hemostasis
three mechanisms:
1. vascular spasm2. formation of a platelet plug3. blood coagulation
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Vasoconstriction
neural: nervous reflexes induces by activation of pain fibers, local myogenic spasmhumoral: thromboxan A2 and serotonin and other substances produced by activated plateletsvasoconstriction 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
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Plateletsdo not have nuclei, oval discs 2-4 m, half-life 4-8 daysmegakaryocytes (1000-5000 platelets)150 – 300.000 per 1 microliterplatelets cytoplasm contains:
1. actin and myosin and thrombosthenin (platelet contraction)2. vesicles containing Ca2+ , serotonin, ADP3. enzymes that synthesize prostaglandins4. -granules: PDGF, coagulating factors, von Willebrandt factor
(adhesion)5. lysozomyplatelets membrane contains large amount of phospholipids
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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)
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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)
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clotting pathways
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)
intrinsic pathway extrinsic pathway
common
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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 proaccelerin XII Hageman
VII proconvertin* XIII fibrin-stabilizing
* vitamin K dependent
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clotting pathway – common
X Xa: activated either by intrisic or extrinsic pathway
II IIa: protrombin, trombin
XIII XIIIa I Ia: fibrinogenfibrin
+V
stabilization
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 fibrin-stabilizing
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I fibrinogen
II prothrombin*
III tissue thromboplastin
IV calcium
V proaccelerin
VII proconvertin*
VIII AH A
IX Christmas (AH B)*
X Stuart-Prower*
XI AH C
XII Hageman
XIII fibrin-stabilizing
XII XIIa: catalyzed by kalikrein a kininogen, activated by negative charges (glass, collagen)
XI XIa: activated by XIIa
IX IXa: activated by XIa
X Xa1 – 6 minutes
+VIII
clotting pathway – intrinsicsubmucosis, phospholipids released from platelets
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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 fibrin-stabilizing
clotting pathway – extrinsictissue, 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)
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anticlotting mechanisms
endothelial smoothness, glycocalyx (mucopolysaccharide repelling the factors) and thrombomodulin (protein binding thrombin)
fibrin itself remove thrombin from the bloodcatching of activated factors by liverconsumption of activated factorsantithrombin III: proteases inhibitor, its binding is facilitated by heparin
no activation of IX, X, XI, XIIheparin – polysaccharide released from mast cells and basophils
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fibrinolysis
thrombomodulin (endotelial wall) catalyzes activation of protein C by thrombinactivated protein C (APC)
1. inactivates VIII2. inactivates V3. activates tissue plasminogen activator (TPA)
TPA catalyzes activation of plasminogen to form plasmin, plasmin causes lysis of the clotalteplase (recombinant), streptokinase, urokinase
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anticoagulants
heparin (+ antithrombin III)citrate, oxalate (bind Ca2+)coumarin, warfarin (inhibition of vitamin K)
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excessive bleeding
failure of blood clotting (coagulopathy)– hematoms, joint bleeding
platelets failure thrombocytopathy– petechiae
vessels defects– petechiae
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innate coagulopathy
abnormality or deficiency of one of the clotting factorshemophilia 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 IXother disorders when impaired factors I, II, V, VII, X, XIIIdeficiency of XI almost without any clinical signs
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acquired coagulopthies
liver diseases (cirrhosis) – deficiency of all factorsheparindeficiency of vitamin KDIC– sepsis, leukemia, AB0 incompatibility
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defects of platelets
trombocytopenia: aplasia (radiation), hypovitaminosis B12, sequestration
trombocytopathy: acetylsalicylic acid (inhibition of COX suppresses synthesis of thromboxan A2 and secretion of ADP
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Defekty cév
von Willebrandtova choroba: defekt endotelu, chybí vWF porucha adheze, nedostatek VIII (vWF je jeho přenašeč)skorbutvrozené defekty pojiva: Rendu-Osler, Henoch-Schönlein