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BLOOD ANDIMMUNOLOGY
REBECCA A. VILLANUEVA, M.D.Associate Professor, Diplomate, Fellow, PAAB
Department of Biochemistry & Nutrition
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RULE OF 2/3
2/3/ICF
2/3 INTERSTITIAL 1/3 INTRAVASCULAR
(BLOOD)
~7% BW
1/3 ICF
2/3 WATER 1/3 SOLIDS
TOTAL BODY WEIGHT
1/3 ECF
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BLOODviscous fluid with a cellular
portion and fluid portion
I. Cellular PortionplateletsWBCRBC
II. Fluid PortionPlasma
Serum without clotting factors
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Properties of Blood 7 10 % of total body weight
To = 36.5 C to 37.5 C
pH = 7.35 7.45
Osmotic pressure = 7 8 atm
Freezing point = -0.537C
Sp. Gravity = 1.035 1.075
Viscosity = 4 5 x greater than water
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Blood: Functions
I. Transport
A. Respiration
B. Nutrition
C. ExcretionD.Fluids, electrolytes,
minerals, vitamins
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Blood: Functions
II. Regulatory
A. Blood pH
B. Body Temperature
C. Body HormonesD.Body Fluids &
Electrolytes
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III. Protective
A. Infections (WBC)BacterialParasiticViralFungal
Blood: Functions
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III. Protective
B. Immune Diseases
AllergiesImmunitySelf / Non-self
C. Bleeding (Hemorrhage)
D. Excessive clotting
Blood: Functions
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PLASMAPROTEINS
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Major Fractions of Plasma Proteins
1. Fibrinogen
2. Gammaglobulin
3. Prothrombin
4. Blood grouping globulins
5. Pure Albumina. 100 mL of 25% solution = 1 unit o
blood
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Major Fractions of Plasma Proteins
small amount ofalbumin and globulin
large amount of salts
many non-proteinsubstances of low MW
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GENERALIZATIONS
Most plasma proteins aresynthesized in the liver
Plasma proteins are generallysynthesized on membrane
bound polyribosomes Almost all plasma proteins are
glycoproteins
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GENERALIZATIONS Many plasma proteins exhibit
polymorphism
Each plasma protein has acharacteristic half-life
Levels increase during acuteinflammatory states orsecondary to certain types oftissue damage
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PLASMA PROTEINS
comprise the major parts
of solids of plasma separation by Salting Out
Method
Na+ ORAmmonium Sulfate
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PLASMA PROTEINS
Plasma CHON = 7.75 g/dl (6-8)
Albumin = 4.7 5.7 gm%
Globulin = 1.3 2.5 gm%
Fibrinogen = 200 400 mg%
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ALBUMIN
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ALBUMIN
most abundant, most homogenousin electrophoresis
MW - 69,000
Ellipsoidal in shape150 Amstrom x 38 Amstrom
small & compact
Single polypeptide chain (585 a.a.)
with 17 disulfide bonds
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ALBUMIN
compact, small in size fast to travel inelectrophoresis
high solubility
reactive groups in the molecule causealbumin to combine reversibly with agreat diversity of anions and cations
responsible for most of oncotic pressureof blood
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ALBUMIN
N-terminal a.a. Asp C-terminal a.a.
Leu human,dog & rabbit Ala other species
IpH = 4.7 More phototrophic group
(Proton binding groups)
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ALBUMIN Titration studies show molecule of
albumin at ph 7.4
100 COOH groups
58 NH2 groups
16 Imidazole
19 phenolic
22 guanidine groups
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ALBUMIN
Major protein of human plasma 4.5g/dl
Produced in the Liver 12 g/day
60% of Total Plasma Protein
75 80% of Plasma Oncotic
Pressure
Initially synthesized as PRE-PRO
PROTEIN with a signal peptide
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ALBUMIN
Decreased A:G RatioLiver and Kidney Diseases
Malnutrition
Binds various LIGANDSFFA, Calcium, Steroid Hormones
Bilirubin, Tryptophan, CopperDrugs:Sulfonamides, Penicillin G
Dicumarol, Aspirin
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GLOBULIN
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GLOBULIN
Fractions:
A. Pseudoglobulin
B. Euglobulin
glob IpH=5.06 transport (LP) globIpH=5.12 transport (LP) globulin IpH=6.0 Immune system-Ab
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FIBRINOGEN
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FIBRINOGEN: Factor 1
soluble plasma glycoprotein
46 nm in length
MW: 340,000
6 polypeptide chain
(A)2: (B)2;2 A2B2;2
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FIBRINOGEN: Factor 1
end highly negatively charged(Asp & Glu residues A, B)
B - (-) tyrosine O SO4 residue Hence:
Contribute to its H2O solubility
Repulsion of termini of otherfibrinogen molecule preventingaggregation
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Diagram Of Fibrinogen
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Fibrin Polymerization
Major Protein Component
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Major Protein ComponentOf Human Plasma
Concentration
mg/100 ml
Approximate
M.W.
Other Function
Albumin 3 4.5 x 103 68,000 Osm regtransport ofFA, bilirubin
Globulin
glo 100 40 35,000 CHO Not known lipo 350
450
200,000
450,000
4070%lipid
Lipid transport
2 Glo 400900
200,000
2 glyco 200,000 CHO Unknown
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Concentrationmg/100 ml
ApproximateM.W.
Other Function
Ceruloplasmin
30 150,000 CHO Coppertransport
Prothrombin 63,000 CHO Blood clotting
Glo 6001,200
lipoprotein
350
450
3 20 M 8090%lipid
Lipid transport
Major Protein ComponentOf Human Plasma
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Concentrationmg/100 ml
Approx.M.W.
Other Function
lipo protein 350450
200,000
450,000
40 70%lipid
Lipidtransport
TransferrinPlasminogen
40 85,000
90,000
CHO Irontransport
Precursor ofFibrinolysin
Globulins 700 1,500 150 th CHO Antibody
Fibrinogen 300 340 th CHO Blood clottingfactors
Major Protein ComponentOf Human Plasma
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HAPTOGLOBIN
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HAPTOGLOBIN
Plasma glycoprotein
MW = 100,000 daltons
Alpha-phoretic mobility
Irreversibly bindsextracorpuscular Hgb in a tightnon-covalent complex (Hb-Hp)
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HAPTOGLOBIN
KidneyHb Excreted in urine orprecipitates in
tubules (iron is lost)
Hb+Hp KidneyHb-HpComplex
Catabolized By Liver Cells(Iron is Conserved)
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HAPTOGLOBIN
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CERULOPLASMIN
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CERULOPLASMIN
2-Globulin Serum Glycoprotein MW = 160,000
Carries 90% of Cu present in plasma(60% in RBC Superoxide Dismutase)
Deep blue color
Single subunit contains 6 atoms ofcopper
Displays ferroxidase activity
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Physiological functions of copper:1. Oxidation of iron
2. Erythropoiesis and Leucopoiesis
3. Bone Mineralization
4. Elastin & Collagen cross-linking
5. Oxidative phosporylation
CERULOPLASMIN
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Physiological functions of copper:
6. Catecholamine metabolism
7. Melanin formation
8. Myelin Formation
9. Glucose homeostasis
10.Antioxidant protection of cells
CERULOPLASMIN
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-1 ANTITRYPSIN(-1 Antiproteinase)
1 ANTITRYPSIN
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-1 ANTITRYPSIN(-1 Antiproteinase)
polymorphic single chain plasmaprotein (394 AA); MW 52,000
90% of-1 fraction of humanplasma
synthesized by hepatocytes andmactophages
1 ANTITRYPSIN
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principal serine proteaseinhibition (serpin or Pl) of human
plasma
inhibits trypsin, elastase andother proteases
genetic defect which leads todeficiency causes emphysema
and liver diseases
-1 ANTITRYPSIN(-1 Antiproteinase)
1 ANTITRYPSIN
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smoking
oxidizes methionine residue
inactivates -1 antitrypsinincrease proteolytic
destruction of lung tissue
emphysema
-1 ANTITRYPSIN(-1 Antiproteinase)
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HEMOSTASIS
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VASOCONSTRICTION
HEMOSTASIS
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HEMOSTASIS
PLATELET PLUG
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HEMOSTASIS
FIBRIN CLOT
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PLASMIN - FIBRINOLYSIS
HEMOSTASIS
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10x
Inactive
Enzyme A
ActiveEnzyme A
InactiveEnzyme B
ActiveEnzyme B
10x
10xInactiveEnzyme C
Active
Enzyme C
Amplification 10x
Amplification 100x
Amplification 1000x
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PLATELET
ADHESION &
ACTIVATION
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ACTION OF PLATELETS
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ACTION OF PLATELETS
SEROTONIN GROWTH
FACTOR
LIPOPROTEINS FACTOR IV
FACTOR V
20%
FACTOR XIII
(ALPHA S.U.)
ADP THROMBOXANE A2
PLATELETS
vWF
COLLAGEN
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Arachidonic Acid
Cyclooxygenase
Endoperoxidase
Thromboxanesynthetase
ThromboxaneA2
Thromboxane B2(platelets)
Prostacyclinsynthetase
Prostacyclin(PGI2)
6 Keto PGF1(endothelial
cells)
PROPERTY HEPARIN WARFARIN
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PROPERTY HEPARIN WARFARIN
STRUCTURE Large Acidic
polymer
Small lipid-
soluble mol.ROUTE Parenteral Oral
ONSET OF
ACTION
Rapid (Seconds) Slow
M.O.A. ActivatesAntithrombin III
InhibitsVitamin K
ANTIDOTE Protamine Vitamin K /Plasma
USE Acute (Days) Chronic
(Wks. Mos.)
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ANTIPLATELET DRUGS
Inhibits thromboxane synthesisby blocking cycloxygenase
Used in prophylaxis and
treatment of MI, TIA and otherthrombotic events
ASPIRIN / NSAIDS
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Inhibits ADP Formation
Prevents TIA, for patients whocant tolerate aspirin
TICLOPIDINE (Ticlide 500mg)
ANTIPLATELET DRUGS
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ANTIPLATELET DRUGS
CLOPIDOGREL (PLAVIX 75 mg)
A. Inhibits the ADP pathway
B. Both are used for people with stent
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ANTIPLATELET DRUGS
CILOSTAZOL (PLETAAL)
A. Inhibits Phosphodiesterase useespecially with people withintermittent claudication
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SERINE PROTEASE INHIBITORS
Aprotinin
* Risk of kidney failure
A A GS
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Inhibits phophodiesteraseincreasing cAMP
Used in prevention of
thrombosis in artificial heartvalves
DIPYRIDAMOLE
ANTIPLATELET DRUGS
ANTIPLATELET DRUGS
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ANTIPLATELET DRUGS
SOLUDEXINE(VESSEL DUE-F)
ANTIPLATELET DRUGS
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Mechanism unknown
Rarely Used
SULFINPYRAZONE
ANTIPLATELET DRUGS
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COAGULATION
PATHWAY
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Numerical System
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Numerical SystemFor Nomenclature of
Blood Clotting Factors
Factor I Fibrinogen
Factor II Prothrombin
Factor III Tissue FactorFactor IV Ca++
Numerical System
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Factor V Proaccelerin, labile
factor, acceleratorglobulin
Factor VII Proconvertin, serum
prothrombin conversionaccelerator (SPCA),cothromboplastin
Numerical SystemFor Nomenclature of
Blood Clotting Factors
Numerical System
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Factor VIII Antihemophilic Factor
A, Antihemophilicglobulin
Factor IX Antihemophilic Factor
B, Christmas Factor,plasma thromboplastincomponent (PTC)
u e ca SysteFor Nomenclature of
Blood Clotting Factors
Numerical System
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Factor X Stuart-Power Factor
Factor XI Plasma thromboplastinantecedent (PTA)
Factor XII Hageman Factor
Factor XIII Fibrin Stabilizing factor(FSF), Fibrinoligase
yFor Nomenclature of
Blood Clotting Factors
ZYMOGENS OF SERINE
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ZYMOGENS OF SERINEPROTEASES
Factor XIIBinds to exposed collagen at
site of vessel wall injuryactivated by HMWK &kallikrein
Factor XIActivated by Factor XIIa
ZYMOGENS OF SERINE
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ZYMOGENS OF SERINEPROTEASES
Factor IXActivated by Factor XIa in
the presence of Ca++
Factor VIIActivated by thrombin inthe presence of calcium
ZYMOGENS OF SERINE
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Factor XActivated on surface of
activated platelets by tenasecomplex (Ca++, FactorsVIIa and IXa) and by Factor
VIIa in the presence ofFactor III & IV
ZYMOGENS OF SERINEPROTEASES
ZYMOGENS OF SERINE
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Factor II
Activated on surface ofactivated platelets byprothrombinase complex
(Ca++, Factors Vaand Xa)
ZYMOGENS OF SERINEPROTEASES
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COFACTORS
Factor VIII
- Activated by thrombin- Cofactor in the activation
of Factor X by Factor IXa
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Factor V
- Activated by thrombin- Cofactor in the activation
of Prothrombin byFactor Xa
COFACTORS
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Factor III (Tissue Factor)
- Lipoprotein found on thesurfaces of extravascularcells that acts as acofactor for factor VII
COFACTORS
DiagrammaticR i f P h bi
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Representation of ProthrombinNH2
(Gla-XI)P
R
O
T
H
R
O
M
B
I
N
ArgThr
ArgIIe
COO-
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THROMBIN ACTIVATES
FACTOR VII
FACTOR V
PROTEINC
FACTOR
XIIIFACTOR
VIII
REGULATORY AND OTHER
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REGULATORY AND OTHERPROTEINS
Protein C
Activated to protein Ca bythrombinbound tothrombomodulin;
then degrades FactorsVIIIa and Va
REGULATORY AND OTHER
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Protein SAct as a cofactor of Protein C;
both has Gla residues
THROMBOMODULIN
Protein on the surface ofendothelial which then activateProtein C cells binds thrombin
REGULATORY AND OTHERPROTEINS
REGULATORY AND OTHER
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PSPC PCa
THROMBINTHROMBOMODULIN
Va
VIIIa
REGULATORY AND OTHER
PROTEINS
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FIBRIN CLOT
FORMATION OF FIBRIN CLOT
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NH3+Arg Gly
FIBRINOPEPTIDE(A OR B)
Thrombin
FORMATION OF FIBRIN CLOT
STABILIZATION OF FIBRIN CLOT
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FIBRIN-CH2-CH2-CH2-CH2-NH3+ (LYSYL) NH2-CO-CH2-CH2-
FIBRIN (GLUTAMINYL)
FIBRIN-CH2-CH2-CH2-CH2-NH-C-CH2-CH2-FIBRIN
FACTOR XIIIa(TRANSGLUTAMINASE)NH+
STABILIZATION OF FIBRIN CLOT
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FIBRINOLYSIS
DISSOLUTION OF BLOOD CLOT
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FIBRIN
CLOT TPA
FIBRIN
CLOT
PLASMINOGEN PLASMINSOLUBLE
FRAGMENTSFIBRIN
t.PA
t.PA PLASMIN
RESPECTIVE INACTIVECOMPLEXES
INHIBITORSPAI-1 PAI-2
Arg Val
DISSOLUTION OF BLOOD CLOT
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THROMBOLYTIC AGENTS
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Large human protein, MW50,000 Produced in bacteria through
recombinant DNA
Directly converts Ferin-BoundPlasminogen to Plasmin
ALTEPLASE (tPA)
THROMBOLYTIC AGENTS
THROMBOLYTIC AGENTS
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APSAC (Anisoytated Plasminogen
Streptokinase Activator Component) Prodrug (ANISOYL, Group
HYDROLYZED in VITRO)
Slow Release (Long Half Life)
Human TPA from recombinant DNA
ANISTREPLASE
THROMBOLYTIC AGENTS
THROMBOLYTIC AGENTS
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Obtained from bacterialcultures
Forms a complex with
plasminogen prior toconversion
STREPTOKINASE
THROMBOLYTIC AGENTS
THROMBOLYTIC AGENTS
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UROKINASE
Extracted from cultured humankidney cells
Directly converts plasminogen
to plasmin
THROMBOLYTIC AGENTS
PLASMINOGEN
ACTIVATION INHIBITION
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PLASMIN
VARIOUS STIMULI
BLOODPROACTIVATOR
BLOODACTIVATOR
(+) (+)
tPA, UROKINASE(+)
STREPTOKINASE
ACTIVATOR(+)
PROACTIVATOR
ANISTREPLASE
(-)
ANTIACTIVATORS
(-)
AMINOCAPROIC ACIDTRANEXAMIC ACID
Arg Val
DEGRADATION
PRODUCTS FIBRINOGEN
THROMBIN
FIBRINFIBRIN SPLITPRODUCTS
(+) (+)
ACTIVITY OF HEPARIN
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HEPARIN+
ANTITHROMBIN III
PROTAMINESULFATE
( - )
HEPARIN ANTITHROMBIN COMPLEX
THROMBIN XII a XI a X a IX a
ACTIVITY OF HEPARIN
VITAMIN K CYCLE
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VITAMIN K CYCLE
DIHYDROQUINONE / VITAMIN K(H2) + O2 + CO2
PROTEINCARBOXYLASE
VITAMIN K EPOXIDE / VITAMIN K(O) + H3O+
FACTORS II, VII, IX,X PROTEIN C / S
WARFARIN
COUMARIN
DITHIOLS (THIOREDOXIN) / X-(SH)2
PLURIPOTENT
STEM CELL
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PROERYTHROBLAST ERYTHROCYTE
MEGAKARYOCYTES THROMBOCYTES
N. MYELOCYTES PMN
PROMONOCYTES MONOCYTE
E. MYELOCYTES EOSINOPHIL
B. MYELOCYTES BASOPHIL
MYELOID
STEM CELL
B LYMPHOBLAST B CELL
PRE B CELL
T LYMPHOBLAST T CELL
PROTHYMOCYTE
LYMPHOID
STEM CELL
STEM CELL
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