Current concepts of the coagulation system€¦ · Blood Coagulation Activates platelets crosslinks...
Transcript of Current concepts of the coagulation system€¦ · Blood Coagulation Activates platelets crosslinks...
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Björn DahlbäckLund University
University Hospital, Wallenberg Laboratory Malmö, Sweden
Advanced Course in Thrombosis & Hemostasis
Cascais, PortugalMarch 13-16, 2014
Current concepts of the coagulation system
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The human body(Vascular system)
GI-tract
Liver
Heart
Lung
Spleen
Carotic artery
Aortic arch
Kidney
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PRIMARY HEMOSTASIS
BLOOD COAGULATION
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Vessel wall damageactivation of primary hemostasis and blood coagulation
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Scanning electron microscopy of plateletsShape change associated with activation
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Platelet adhesion to subendothelium
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PRIMARY HEMOSTASISPLATELET FUNCTIONS
ADHESION (TO SUBENDOTHELIUM)GPIb-V-IX – von Willebrand faktorn (VWF)GPIa-IIa, GPVI – collagen
AGGREGATION (PLATELET-PLATELET)GPIIbIIIa (IIb3) – fibrinogen, fibronectin,
thrombospondin,VWF
RELEASE OF PLATELET GRANULESdense granules – Ca2+, ADP, serotonin, polyphosphate-granules – coagulation factors, VWF, PF4, P-selectin
Thromboxane A2 (TXA2), Platelet Activating Factor (PAF)
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Platelet adhesion - role of von Willebrand’s factor
Abrams and Plow in Hematology, Churchill Livingstone
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Platelet aggregationreceptor fibrinogen/VWF interaction
FibrinogenVWF
Modified from McEver in Platelets, Elsevier
Activated platelet Activated platelet
IIb3 IIb3
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Jackson SP et al J Thromb Haemost 2009, suppl 1, 17-20
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Jackson SP et al J Thromb Haemost 2009, suppl 1, 17-20
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Pathogenesis of idiopathic TTP caused by ADAMTS13 deficiency.
Sadler J E Blood 2008;112:11-18
©2008 by American Society of Hematology
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Jackson, Nature Med 2011,17;1423
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B-PLATELETS
PLATELET FUNCTIONSPlatelet aggregation
PRIMARY HEMOSTASIS - ANALYSESANAMNESIS
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Vessel wall damageactivation of primary hemostasis and blood coagulation
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TFTF TF
Activation of Blood CoagulationTissue factor (TF) exposed at sites of vascular injury
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TF
FVIIa
FVIIa
FVIIa binds to Tissue Factor
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VIIa IX/XXa
IXaTF
TF-FVIIa complex activates FIX and FX
Rapid turnover
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Activation and Propagation of Coagulation
Modified from Dahlbäck, Blood 2008
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Enzyme-cofactor complex on negatively charged phospholipids
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Blood coagulation is localized to surfaces
Extra vascular cell Activated platelets
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Vitamin K-dependent Coagulation factors
ProcoagulantFactor VIIFactor IXFactor X
Prothrombin
AnticoagulantProtein CProtein S
Vitamin K needed for the formation of GLAGLA=-carboxyglutamic acid residue
YY YY YY YBinds to phospholipid membrane
Gla domain
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Gla domain needed for binding to phospholipid surface
FVII, FIX, FX and PT are vitamin K-dependent contain -carboxy glutamic acid residues
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Factor V
A1 A2 B A3 C1 C2
FactorV
A1 A3
A2 B
C1 C2
FactorVIII
A1 A2 B A3 C1C2
FactorV
A1 A3
A2 B
C1 C2
Factor V and Factor VIIItwo similar proteins
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Activation of factor V by thrombin or factor Xa
FVa
R709 R1018 R1545
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Prothrombinase complex
Autin et al, Proteins 2006
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Factor VIII - von Willebrand factor complex
Activation by thrombin
Factor VIIIa
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Principles of Blood Coagulation Amplification
Modified from Dahlbäck, Blood 2008
1, multiple linked enzymatic reactions2, enzyme-cofactor complexes3, surface localization4, feed-back activation5, coagulation factor concentrations increasing in pathway
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Explosive thrombin generation after initial lag phase
Lag phase
peak
inhibition
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Fibrinogen cleavage by thrombin results in fibrin polymerisation
Thrombin cleaves fibrinogen andfibrinopeptides are released
fibrin polymerisation
erythrocyte trapped in fibrin clot
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Fibrinolytic System Degrades the Fibrin Clot
Crosslinked fibrin
D-dimers
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Blood Coagulation
Activates platelets crosslinks fibrin
”contact phase”XII XIIa
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Renne et al, Blood 2012,120;4296
Contact Phase System
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Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation
Morrissey et al, Blood 2012, 19;5972
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Intrinsic pathway of blood coagulationAPTT (activated partial thromboplastin time)
Contact phase
Phospholipid surface
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FIBRIN
PROTROMBIN
FXa
FVa
FIXa
FVIIIa
FX FX
FIX
FXIa
FVIIa - TFFVIII
FVIIa - TF
FIX
FXITROMBIN
TROMBIN
TROMBIN
FV
TROMBIN
FIBRINOGEN
KONTAKTFAS
EXTRINSIC
FOSFOLIPIDYTA
INR=International Normalized Ratio
Patient plasmaControl plasma
1 is normal
Prothrombin complex analysisTesting FVII, FX, and PT
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Activation and Propagation of Coagulation
Modified from Dahlbäck, Blood 2008
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Thank you!
Advanced Course in Thrombosis & Hemostasis
Cascais, PortugalMarch 13-16, 2014
Current concepts of the coagulation system