Haemostasis 1 Flashcards
(26 cards)
functions of haemostasis
prevention of blood loss from intact vessels
arrest of bleeding from injured
The Plug Formation Injury
local vasoconstriction Primary Haemostasis formation of an instable platelet plug stabilisation of platelet plug with fibrin Secondary Haemostasis dissolution of clot and vessel repair.
describe primary haemostasis
Primary Haemostasis
- Endothelial cell damage which exposes sub-endothelial structures (such as collagen).
- One of either:
a. Exposed collagen binds to Von Williebrand Factor (VWF) which captures platelets using the Glycoprotein 1b receptor (Glp1b).
b. Platelets bind DIRECTLY to exposed collagen by the Glycoprotein 1a receptor (Glp1a). - With activated receptors, the platelet activates and releases ADP and prostaglandins (e.g. thromboxane A2).
- The hormones cause platelet aggregation by use of fibrinogen which bind to each other using Glycoprotein 2b/3a
- (In the blood coagulation cascade, a protease called thrombin is generated which cleaves a receptor on platelets which causes activation/aggregation).
define coagulation
the process by which blood is converted from a liquid to a solid state
- causes the formation of a fibrin mesh
- secondary haemostasis
purpose of intact blood vessel
intact vasculature separates blood from collagen and tissue factors using endothelium to prevent abnormal clotting
define vWF
von Willebrand factor is plasma protein secreted by endothelium cells and platelets
giant adhesive plasma protein
has many binding sites for platelets, collagen and factor VIII, usually assembled to multimers and raled up in blood to hide binding sites
define platelets
fragments of megakaryotypes no nucleus granular
GP1ba complex
GP1a-11a + GPV1
ADP
PG12 receptors
GP1ba complex: binding site for VWF
GP1a-11a + GPV1: bind to collagen
ADP: P2Y, P2Y12
PG12 receptors: thromboxane
activated platelet display
Activated platelets display:
Change in shape,
change in membrane composition (exposed phospholipids)
present new or activated proteins on their surface (i.e. Glp2b/3a).
why do two methods of activation exist in primary homeostatic
Two methods of activation exist due to varying flows of blood. I.E. in small blood vessels, there is high shear stress which may favour the VWF mechanism.
platelet half life
approx. 10 days
what does primary haemostasis require
- collagen
- platelets
- von Willebrand factor
site of synthesis of clotting factors, fibrinolytic factors and inhibitors
- liver
- endothelial cells (VIII and VWF)
- Megakaryocytes (to platelets) (VWF +/- FV)
most synthesis is in the liver
The Intrinsic Pathway to Coagulation
The Intrinsic Pathway to Coagulation - Proteases Read the picture. Note the ‘a’ is the activator enzyme.
§ Involves the activation of a ZYMOGEN – a precursor of a protease enzyme, this is the non-a factor.
§ F8a (FVIIIa) is a co-factor and NOT a protease.
o F8 exists on the platelet membrane as a phospholipid.
§ F8 is then converted to an active form in the intrinsic pathway which mediates thrombin formation.
The Extrinsic Pathway to Coagulation
The Extrinsic Pathway to Coagulation – Tissue Factor
§ Tissue factors are not normally found in blood; it is found inside SMCs but it is a potent initiator of clotting.
§ Tissue Factor activates F7 (VII) à F7a (VIIa) which mediates activation of:
o F9a from F9.
o F10a from F10 (into the common pathway).
The Common Pathway to Coagulation
The Common Pathway to Coagulation
§ Factor 10a mediates prothrombin to thrombin which further activates platelet.
§ Thrombin activates:
o F5 to create a positive feedback activation of thrombin.
o F13 to mediate cross-linked fibrin formation.
§ The cross-linked fibrin is more resistant to shear stresses.
what is the main driver of blood coagulation
Factor XII is not required to drive coagulation. Instead, TISSUE FACTOR is the main driver of the blood coagulation cascade and is known as the physiological initiator of the coagulation cascade. F12 (XII) is however important in laboratory testing.
Summary points
- what do zymogens do
- what do cofactors do
SUMMARY POINTS
§ There are ZYMOGENS that are converted to PROTEASES.
§ There are CO-FACTORS which need to be activated and exist on the surfaces of platelets (green boxes).
§ The trigger to initiate coagulation in vivo is TISSUE FACTOR.
§ The trigger to initiate coagulation in vitro is F12 (FXII).
what is activated by thrombin
factor XIII (cross links fibrin and inhibits fibrinolysis) and TAF1- inhibitor of fibrinolysis
deficiency of coagulation factors causes
bleeding disorders
define haemostasis
fibrin clot stabilising
it’s an amplification system
zymogens converted to proteinase cofactors which need to be activated
surfaces made of activated platelets- localise and accelerate the reactions
trigger to initiate coagulation in vivo in tissue factor
although FXII can be activated to FXIIa, this is mainly an in vitro reaction, useful for some diagnostic tests
Types of Coagulation Inhibition
Types of Coagulation Inhibition
- Direct Inhibition.
a. E.G. Antithrombin – inhibits thrombin. - Indirect Inhibition.
a. E.G. Reduction of thrombin generation by the protein C anticoagulant pathway.
Direct Inhibition
Direct Inhibition
§ ALL of the active proteinases can be inhibited by antithrombin.
§ Heparin ACCELERATES the action of antithrombin.
o So heparin is used for immediate anticoagulation in venous thrombosis and PE. F8 and F5 are activated by TRACE amounts of Thrombin and become COFACTORS that bind to the surface of platelets.
Indirect Inhibition – Protein C Pathway
Indirect Inhibition – Protein C Pathway The COFACTORS (F8 and F5) are the targets of protein C.
- Coagulation activates thrombin.
- Thrombin binds to the endothelium proteins and forms thrombomodulin.
- Protein C is activated (with protein S from the inactive zymogen PC).
- The activated protein C and S inactivate the cofactors. A deficiency in one of the inhibitory proteins means you cannot control coagulation by the indirect inhibitory pathway.
