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
The human body(Vascular system)
GI-tract
Liver
Heart
Lung
Spleen
Carotic artery
Aortic arch
Kidney
PRIMARY HEMOSTASIS
BLOOD COAGULATION
Vessel wall damageactivation of primary hemostasis and blood coagulation
Scanning electron microscopy of plateletsShape change associated with activation
Platelet adhesion to subendothelium
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)
Platelet adhesion - role of von Willebrand’s factor
Abrams and Plow in Hematology, Churchill Livingstone
Platelet aggregationreceptor fibrinogen/VWF interaction
FibrinogenVWF
Modified from McEver in Platelets, Elsevier
Activated platelet Activated platelet
IIb3 IIb3
Jackson SP et al J Thromb Haemost 2009, suppl 1, 17-20
Jackson SP et al J Thromb Haemost 2009, suppl 1, 17-20
Pathogenesis of idiopathic TTP caused by ADAMTS13 deficiency.
Sadler J E Blood 2008;112:11-18
©2008 by American Society of Hematology
Jackson, Nature Med 2011,17;1423
B-PLATELETS
PLATELET FUNCTIONSPlatelet aggregation
PRIMARY HEMOSTASIS - ANALYSESANAMNESIS
Vessel wall damageactivation of primary hemostasis and blood coagulation
TFTF TF
Activation of Blood CoagulationTissue factor (TF) exposed at sites of vascular injury
TF
FVIIa
FVIIa
FVIIa binds to Tissue Factor
VIIa IX/XXa
IXaTF
TF-FVIIa complex activates FIX and FX
Rapid turnover
Activation and Propagation of Coagulation
Modified from Dahlbäck, Blood 2008
Enzyme-cofactor complex on negatively charged phospholipids
Blood coagulation is localized to surfaces
Extra vascular cell Activated platelets
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
Gla domain needed for binding to phospholipid surface
FVII, FIX, FX and PT are vitamin K-dependent contain -carboxy glutamic acid residues
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
Activation of factor V by thrombin or factor Xa
FVa
R709 R1018 R1545
Prothrombinase complex
Autin et al, Proteins 2006
Factor VIII - von Willebrand factor complex
Activation by thrombin
Factor VIIIa
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
Explosive thrombin generation after initial lag phase
Lag phase
peak
inhibition
Fibrinogen cleavage by thrombin results in fibrin polymerisation
Thrombin cleaves fibrinogen andfibrinopeptides are released
fibrin polymerisation
erythrocyte trapped in fibrin clot
Fibrinolytic System Degrades the Fibrin Clot
Crosslinked fibrin
D-dimers
Blood Coagulation
Activates platelets crosslinks fibrin
”contact phase”XII XIIa
Renne et al, Blood 2012,120;4296
Contact Phase System
Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation
Morrissey et al, Blood 2012, 19;5972
Intrinsic pathway of blood coagulationAPTT (activated partial thromboplastin time)
Contact phase
Phospholipid surface
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
Activation and Propagation of Coagulation
Modified from Dahlbäck, Blood 2008
Thank you!
Advanced Course in Thrombosis & Hemostasis
Cascais, PortugalMarch 13-16, 2014
Current concepts of the coagulation system
