10- Haemeostasis And Thrombosis Flashcards
What is primary and secondary haemostasis
1: formation of unstable platelet plug
2: stabilisation of plug with fibrin
Then dissolution of clog and vessel repair
Describe the 2 mechanisms of platelet adhesion
Collagen in damaged endothelial layer is exposed
The collagen is recognised in TWO ways:
Von Willebrand Factor binds to the collagen and attracts platelets - the platelets bind to the Glycoprotein 1b Receptor (GlpIb) on the Von Willebrand Factor
OR
Glycoprotein 1a Receptor (*lp1a) on the platelets directly binds to the collagen
in the subendothelial layer
What happens when platelets are activated by either mechanism
When activated, the platelets will release ADP and PROSTAGLANDINS
(Thromboxane in particular)
• Prostaglandins activate other platelets so the platelets aggregate - the glycoproteins IIa and IIIb receptors become available which the fibrinogen can bind to
In the blood coagulation cascade, a protease called thrombin gets generated which can also directly activate the platelets so that they aggregate
How does platelet structure change during activation
Certain phospholipids which are usually inside the platelet come to the outside
• This is important because it is those phospholipids that bind to the coagulation factors
• The platelet presents new or activated proteins on their surface (e.g. GlpIIb and IIIa - this becomes an active conformation so it can react with the FIBRINOGEN)
Platelet changes shape
Where are clotting factors synthesised
Liver
Most of these factors are made in the LIVER
• Endothelial Cells
Von Willebrand factor is made in high concentration in the endothelium
• Megakaryocytes (–> Platelets)
Factor V is synthesised in the megakaryocyte
Describe the intrinsic clotting cascade
Factor xii-> xii a
Xi -> xia
Ix -> Ixa
X -> xa
Describe the extrinsic clotting cascade
When a vessel is damaged, the blood comes into contact with TISSUE FACTOR
• Tissue factor is a membrane protein which isn’t normally found in the blood - smooth muscle cells contain tissue factor
• Tissue factor is a potent initiator of the clotting cascade
• Tissue factor binds to Factor 7 converting it to Factor 7a which then converts Factor 10 to Factor 10a
Describe the common clotting cascade
10a converts prothrombin to thrombin
• Thrombin can further activate the platelet - it forms a fibrin clot
• Factor 5a helps Factor 10a convert prothrombin to thrombin faster
• Factor 5a is generated from Factor 5 by trace amounts of thrombin
• Thrombin converts fibrinogen (soluble) to fibrin forming a FIBRIN CLOT
• The fibrin clot is insoluble
• The clot can be crosslinked by Factor 13a - crosslinking is covalently
crosslinking the fibrin clot so that it is stabilised and can’t be broken down by the shear forces
• Tissue factor can also activate Factor 9 to Factor 9a when tissue factor binds to Factor 7
What are some defects in primary haemostasis
Collagen - Vessel Wall
• Steroid therapy makes the collagen and vessel wall weak
• Ageing also weakens the vessel wall Von Willebrand Factor
• Von Willebrand Disease - genetic deficiency in Von Willebrand Factor
Platelets
• Aspirin and other drugs can affect platelet activity
• Thrombocytopenia is a relative decrease in the number of platelets
in the blood
What are some features of primary haemostasis
Immediate • Easy Bruising • Nosebleeds (prolonged: >20 mins) • Gum bleeding (prolonged) • Menorrhagia (anaemia) • Bleeding after trauma/surgery • Petechiae (specific for thrombocytopenia)
What are some defects of secondary haemostasis
Haemophilia: Factor 8 or Factor 9 (hereditary due to genetic defect) Liver Disease (acquired - most coagulation factors are made in the liver) Drugs (warfarin - inhibits synthesis of coagulation factors)
Dilution (results from volume replacement)
Consumption (disseminated intravascular coagulation - acquired)
What are some features of secondary haemostasis
Often delayed (after primary haemostasis)
• Prolonged
• Deeper: joints and muscles
• Do not tend to get excessive bleeding from small cuts (because primary
haemostasis is ok)
• Small vessels are generally ok
• Nosebleeds are rare
• Bleeding after trauma/surgery
• Bleeding after intramuscular injections
What are 2 coagulation inhibition mechanisms
Direct Inhibition.
e.g. Antithrombin (sometimes known as antithrombin III), which
is an inhibitor of thrombin and other clotting proteinases
(ii) Indirect inhibition.
e.g. Inhibition of thrombin generation by the protein C
anticoagulant pathway
What is heparin
Heparin
accelerates the
action of
antithrombin
Name 4 things that cause inhibition of coagulation to fail
Antithrombin deficiency
Protein C deficiency
3. Protein S deficiency
4. Factor V Leiden
