Transcript Fyziologie krve

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