semmelweis university€¦ · –intrinsic pathway •factor xia –factor ix - factor ixa...
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Haemostasis-1 Dr. István Léránt
Sept 7, 2015
Department of Medical Biochemistry Semmelweis University
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Haemostasis
• Physiological process which causes bleeding to stop
• Vasoconstriction
• platelet plug
• formation of a clot
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Haemostasis
• Endothelium
• Blood coagulation
• Platelets
• Liver
• Fibrinolysis
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Clot formation Fibronolysis
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Haemostasis
Disorders
• Hemophilia
• formation of unwanted blood clots
• Embolism
• heart attack
• pulmonary
• embolism
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Haemostasis
Disorders
• Atherosclerosis
• Diabetes mellitus
• Cancer
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Mortality in Hungary 2010 [%]
7
search
54
27
8 4 7
Circulatory system
Cancer
Digestive system
Respiratory system
Others
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FG
sol
FN gel
D
E
D
FDP
Water insoluble
Ext. Int.
VIIa - TF XII
CLOTFORMATION
Plasminogen-
activators
FIBRINOLYSIS
CLOT FORMATION & FIBRINOLYSIS
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FIBRINOGEN-STRUCTURE - POLYMERISATION of FIBRIN
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MM: 340.000 Da
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FIBRIN/OGEN - POLYMERSATION
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Thrombin OLIGOMER
Monomer
Polymer
FPA, FPB
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Factor XIII
Laki-Lóránd Factor
Fibrinoligase
Plasma Transglutaminase Fibrin stabilizing factor
E.C. 2.3.2.13)
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Factor XIII
Thrombin Mr = 4000 Peptide N-terminal
Arg36-Gly37 von A subunit.
Ca2+- dependent Dissociation of B subunits.
Maximal Activity Kd= 10-3 - Ca2+
Kd= 10-8 - Fibrinogen
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Carrier-subunits
Factor XIIIa Activity
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Thrombin
• Hepatocytes
• Precursor : Prothrombin in Blood
• Protease Activity
• Signal functions
• Serin-protease
• Fibrinogen = Fibrin + Fibrinopeptids
• Substrat
– Factor V + feed back
– Factor VII
– Factor VIII + feed back
– Factor XI + feed back
– Factor XIII
• Thrombin + Thrombomodulin
• Protein Ca >>> Factor Va Factor VIIIa
- feed back
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Thrombin
• Hepatocytes
• Precursor : Prothrombin in Blood
• Protease Activity
• Signal functions
• Signal
• Protease-activated Rezeptors (PAR) – Platelets
• Plateletactivation
– Smooth muscle • Proliferation
• Migrantion
– Atherosclerosis
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Protrombin
• Synthesis:
– Liver
– Vitamin K dependent
– Gla-domain
– Kringle-domain
– Catalytic-domain
• Serin-protease
• catalytic triad
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PROTHROMBIN - TRHOMBIN
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N Arg273 Thr 274 Arg323 Ser324 C
S S
N Arg Thr Arg
AC Ser C
S
S
Fragment 1-2
Gla
Gla
Factor Xa
Thrombin
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Thrombin
• Fg – Fn
• Factor XI – XIa
• Factor V – Va
• Factor VIII – VIIIa
• Factor XIII - XIIIa
• Platelet activation
• TM-PC
• Vasoconstriction
• Mitogen
• Cerebral Aneurysm – Thrombin – Stroke
• Thrombin-”cleavage site”
– Leu-Val-Pro-Arg-Gly-Ser
– Recombinant Fusion Protein
– „Purification tag”
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Eastern Brown Snake
(Pseudonaja textilis)
• Neurotoxin
• Prothrombin Activator
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MELILOTUS ALBA MEDICUS
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N
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VITAMIN K & DICOUMAROL
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g-carboxylation
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g-carboxylation of coagulation factors
CH2
CH2
C
O O
CH2
CH
C
O O
COO-
CO2
VITAMIN K(HYDROQUINONE)
Glutamate-seiteinkette
g-Karboxy-glutamate-seiteinkette
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Factor II, VII, IX, X, PROTEIN C, S, M, Z…
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VITAMIN K CYCLUS
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Coagulation factors
g-Carboxylated
coagulation
factors
Vit-KH2
Vit-K-2,3-Epoxyd
Vit-K
Vitamin K
Reductase
Vitamin K
Epoxyd-
reductase
g-Glutamyl
carboxylase
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N
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Purified Components Relative Rate of
Thrombin Generation
(1) Prothrombin, Xa, Ca++ 1 (35 days)
(2) Prothrombin, Xa, PL, Ca++ 50 (17 hours)
(3) Prothrombin, Xa, Va, Ca++ 350 (2.4 hours)
(4) Prothrombin*, Xa*, Va, PL, Ca++ <1000 (>50 min)
(5) Prothrombin, Xa, Va, PL, Ca++ 19,000 (2.5 min)
(6) Prothrombin, Xa, Va, platelets, Ca++ 300,000 (10 sec)
Prothrombin actication
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Activation of coagulation factors
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ACTIVATION OF PROTHROMBIN
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Factor VII
– ‘proconvertin’
– serum prothrombin conversion accelerator
(SPCA)
– stabiler Factor,
– Prothrombinogen
• Serine Protease
• Hepatocytes
• Vitamin K dependent
• Gla-Domain
• Tissue Factor
• MM 59000 Da
• ß-Globulin
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Signalpeptide
Propeptide
Gla-domains
EGF-domains
VII-VIIa
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Factor VII
• Activation of blood coagulation
• Damage of vascular endothelium
• Thromboplastin - Blut + Ca2+
• + Factor VII – Factor VIIa
• Factor VIIa + PL + Ca2+
• Factor X – Factor Xa
• Factor IX – Factor IXa
• Extrinsic pathway
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VIIa Xa T
VIIGla ProTGla XGla TF
IXGla
IXa
XIa
XI
XIIa
FN
FG
In vitro
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Tissue factor pathway inhibitor (TFPI)
• MM 34000-40000
• Structure
– N-Terminal – negative
charges
– Kunitz-Typ Domain
– C-Terminal + charges
– Bovine pancreas trypsin
inhibitor Homology
• TFPI + Factor Xa
• TFPI-Factor Xa Complex –
Factor VIIa
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Tissue factor pathway inhibitor (TFPI)
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VIIa Xa T
VIIGla ProTGla XGla TF
IXGla
IXa
XIa
XI
XIIa
FN
FG
TFPI ?
Xa
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Intrinsic pathway
Intrinsic way(Kontakt Aktivation)
• F XII (Hagemann Factor)
• Prekallikrein (Fletcher Factor)
• F XI (plasma thromboplastin antecedent)
• HMWK (Fritzgerald Factor)
• C1-INH
• Limited Proteolysis – -Ser-OH
– CoFactor
– Inhibitor
• Factordeficiency: – FXII
– Precallikrein
– HMWK
– F XI Bleeding
• C1-INH – Hereditary angioedema
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Factor XII
• Hageman-Factor
• 15-45 mg/l – Serinprotease
– β-Globuline
– Monomer / Bloodplasma
– MM 80 kDa.
• Hepatocytes
• Cleavage of Propeptid / Zymogen (Plasma)
• Negatively charged surface
• Collagen,
• cell fragments,
• bacterial Endotoxins
• in vitro: Glass, Kaolin,
• preactivation. – Prekallikrein - Kallikrein.
– HMWK (Fitzgerald-Factor) - Kinin
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Factor XI
• Factor XI
– Plasma Thromboplasmin Antecedent (PTA)
– Rosenthal-Factor,
• Serinproteinase.
• Liver
• Homo-Dimer (Disulfidbridges)
• MM 80 kDa.
• [Plasma] 5 mg/l
• Half life~52 hours
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Factor XI
• Factor XI is activated by
– Factor XIIa
– Thrombin activated Factor XIa
– Intrinsic Pathway
• Factor XIa
– Factor IX - Factor IXa
– Cleavage of Arg-Ala- und eine Arg-Val-Peptide bonds.
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Factor XI
• Hemofilia C
– 8 % Ashkenazi Jews
– spontaneous Bleedings,
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Bleeding tendency
F-IX F-VII
F-XIa F-XI
F-XII
K PK
F-XIIa
surface
HMWK
Factor XII
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Bleeding tendency
F-IX F-VII
F-XIa F-XI
F-XII
K PK
F-XIIa
Complement
Plasminogen
Fibrinolyse
Prorenin
Angiotensin Kininogen
Bradykinin
Plasminogen Activators
surface
HMWK
Factor XIIa
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Factor IX
• Factor IX – Christmas-Factor
• ß-Globulin
• Liver
• Factor IXa – Serinprotease
• Factor IX-Gen – X Chromosome
N
Gla EGF Katalytische Dom. EGF
TF Bindung?
Platelet binding
Tenase-Complex-Binding
Activation by
Factor XIa
Factor VIIa
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Factor IX
• Factor IXa
• Substrat: Factor X
– Ca2+
– PL
– Factor VIIIa
• Hydrolyses of an Arg-Ile bond in Factor X
N
Gla EGF Katalytische Dom. EGF
TF Binding?
Platelet aggregation
Tenase-Complex-Binding
Aktivation:
Factor XIa
Factor VIIa
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Factor IX
• Factor IX-Gen
– X Chromosome
• Deficiency of Factor IX – Hemophilia B
• Acquired deficiency of Factor IX
– Vit. K deficiency
– Lupus • Antibodies / Factor IX
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Factor VIII
• Factor VIII • anti-hemophilic factor (AHF)
• Glycoprotein
• Synthesis – Liver / Sinusoids
– Vaskulare Endothelium
• Degradation: – Liver
– Kidneys
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Factor VIII
• Factor IXa
• Substrat: Factor X
– Ca2+
– PL
– Factor VIIIa
• Hydrolysis of an Arg-Ile bondi in Factor X
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Factor X
• Thrombokinase
• Stuart-Prower-Factor
• Vitamin K
• Liver
• Alpha-Globuline
• Factor Xa
• Serin protease
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Factor X
• Activation by – Factor VIIa + TF
– Factor IXa – Complex
• Substrate – Prothrombin
• Arg-Thr
• Arg-Ile
• Inactivation of Factor Xa – Prot Z dep Protease Inhibitor
– Deficiency of Prot Z
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Thrombin
• Fg – Fn
• Factor XI – XIa
• Factor V – Va
• Factor VIII – VIIIa
• Factor XIII - XIIIa
• Platelet activation
• TM-PC
49
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Feed back mechanisms
50
XIIa
XI XIa
IXGla IXa
XGla Xa
ProTGla
VIIGla
VIIa
V
VIII
T
TF
Va
VIIIa
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THROMBIN
51
FIBRINOGEN
Factor XIII
Platelets
Cofactor V
Cofactor VIII
Factor XI
THROMBIN
PROTEIN C
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Thrombomodulin
• Thrombin-Bindins
• T+TM – „Inactivation” of Thrombin /
– Activation of Protein C/Protein S
– Negativ feed back reationts
• TAFI
– Inhibition of fibrinolysis
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THROMBIN
53
FIBRINOGEN
Factor XIII
Platelets
Cofactor V
Cofactor VIII
Factor XI
THROMBINF
PROTEIN C
ENDOTHELIAL CELLS THROMBOMODULIN
THROMBINB Cofactor Va
Cofactor VIIIa
a
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PROTEIN C AKTIVATION
54
Zeit
[aPC] TH+TM
TH
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PROTEIN C SYSTEME
55
TM
THROMBINfree THROMBINbound
V VIII
Va VIIIa
Vi VIIIi
Protein C Protein Ca
?
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aPC RESISTENCE
56
TM
THROMBINfree THROMBINbound
V VIII
Va VIIIa
Vi VIIIi
Protein C Protein Ca
?
Cofactor V – Arg 506 / Gln
Prevalence of APC-Resistence ~ 5 %
Risk for venous Thrombosis