Haemostasis Flashcards
What is haemostasis?
The halting of blood flow following trauma to blood vessels
How is haemostasis achieved?
- Contraction of blood vessels
- Formation of unstable plate plug - primary haemostasis
- Formation of stable fibrin clot- secondary haemostasis
What is the structure of platelets?
Have no nucleus and have a discoid shape
Contain granules
Platelet plasma membrane contains glycoproteins- GP1a and GP1b
Circulate for 10 days
How are platelets formed?
Derived from myeloid stem cells
Formed in bone marrow by fragmentation of megakaryocyte cytoplasm
What happens after damage of a vessel wall?
Platelets attach to wall using GP1a to attach to GP1a receptor OR
Circulating Von Willebrand Factor (VWF) binds to damaged wall and GP1b on platelet
What 3 things can happen after platelet binds to wall?
- Platelets become activated- causes them to go from disk shape to more rounded and form spicules which helps them clump to form unstable platelet plug
- Platelets attach to wall and use arachidonic acid from membrane to form thromboxane A2 which is a vasoconstrictor
- Platelets release contents of storage granules
What happens when platelets release their ADP storage granules?
ADP works with formation of thromboxane A2 to start positive feedback loop that leads to activation and aggregation:
1. ADP binds to P2Y12 whilst thromboxane binds to thromboxane A2 receptor
2. This further activates platelets- causes GP2b/3a receptor to change shape and become capable of binding fibrinogen
Prostacyclin does the opposite of Thromboxane A2- its a vasodilator and suppresses platelet activation
What happens when platelets release their Fibrinogen storage granules?
Fibrinogen starts to bind to activate GP2b/3a which further triggers platelets:
- Platelets become linked because they’re binding fibrinogen
- These platelets form an unstable platelet plug
What happens when platelets release their VWF storage granules?
VWF circulates in the blood and helps bind to injured endothelium and promotes aggregation
Its made by endothelial cells and megakaryocytes
It’s a carrier for factor 8
Name 3 anti-clotting factors
Protein C, Protein S, anti-thromibin
What is the action of protein C?
Thrombin binds to thrombomodulin on endothelial cell surface.
This activates protein C which inactivates factor Va and VIIIa in presence of cofactor A- limits coagulation
What is the action of anti-thrombin?
Inactivates thrombin and factor 10a
What causes blood coagulation and how?
Coagulation generates thrombin- it cleaves fibrinogen to form fibrin clot. This stabalises the platelet plug (secondary haemostasis)
What is converted into an active clotting factor
an inactive zymogen/ proenzyme
What are clotting factors?
Clotting factors work on phospholipid surfaces of platelets- accelerates reaction
CA2+ ions are needed to bind clotting factors to phospholipid surfaces
Most clotting factors are made in the liver except from factor VIII and VWF which are made by endothelial cells
What are factors V and VIII
They are co-factors- not enzymes but are needed for the reaction
What factors need vitamin K?
Factors 2, 7, 9 and 10 need vit K to become activated and functional
What is the action of tissue factor?
When blood vessel is damages tissue factor is exposed
Tissue factor binds to factor 7a. This activates factor 9 and 10 which activates factor 2 (prothrombin)
Prothrombin stimulates small production of thrombin- this small amount formed is the initiation phase
Thrombin activates cofactors 5 and 8, factor 11 and platelets
Factor 11 activates factor 9 in amplification phase
Factor 9 works with factor 8 to activate even more factor 10- rapid bursts in thrombin production (propagation phase)
Thrombin cleaves fibrinogen to form insoluble fibrin clot
How is fibrinolysis achieved?
Fibrinolysis is the breakdown of a clot
Plasmin is fibrinolytic- it breaks down fibrin, fibrinogen and factors Va and VIIIa
What is plasminogen?
An inactive zymogen that circulates in blood
Tissue plasminogen activator (t-PA) and plasminogen come together on clot by binding to lysine residues on fibrin. Plasminogen is converted to plasmin which breaks down fibrin clot to form fibrin-degradation products
What are methods of thrombolytic therapy?
Give patients recombinant t-PA by IV- generates plasmin by activating plasminogen
Works better the sooner it’s given- best given within an hour of symptoms
Has a high bleeding risk
Can also be given for pulmonary embolism
What is the intrinsic pathway?
Contains things found in plasma- factors 9, 10, 11, 12 and co-factors 5 and 8
What is the extrinsic pathway?
Tissue Factor, factor 7, 10 and co-factor 5
What does prothrombin time measure?
Tests if extrinsic pathway is working
How do we measure prothrombin time?
Use a blue top bottle- contains sodium citrate which chelates calcium and stops clotting factors
Centrifuge bottle
Add TF, phospholipid and calcium
Measure how long clotting takes
What does prothrombin time show us?
If PT time is longer there may be a problem with factor 7, 10, 5, 2 or fibrinogen
Hence monitor warfarin
Convert your PT time to an international normalised ratio
What is Activated Partial Thromboplastin Time?
Test intrinsic pathway
How do you measure Activated Partial Thromboplastin Time?
Use a contact activator i.e. glass silica to activate factor 12a/12- triggers intrinsic pathway
Contact activator, phospholipid and calcium is added to citrated plasma sample
Measure time it takes to clot
What does Activated Partial Thromboplastin Time show?
APTT can be longer than normal if there’s a reduction in 1 or multiple clotting factors- also seen in haemophilia A (factor 8) and B (factor 9)
What are the 3 main causes of bleeding?
- Reduced platelets/ non functional platelets
- Too much fibrinolysis
- Reduced coagulation factors:
- Congenital- reduction in VWF is Von Willebrand disease, haemophilia A and B
- Acquired- Liver disease, anticoagulant drugs, disseminated intravascular coagulation (uncontrolled activation of coagulation)
What is Heparin?
An anti-coagulation drug
Indirectly helps anti- thrombin work better- inactivation of factor Xa and 2a
Given by IV or subcutaneously
What is Warfarin?
Anti-coagulation drug
Vitamin K antagonist- stops factors 2, 7, 9, 10 from activating
Taken orally, needs monitoring and takes several days to work
What are DOACs?
Direct oral anticoagulants
Directly inhibit thrombin/ 2a or factor 10a
What is tranexamic acid?
Antifibrinolytic drug
Binds to plasminogen, stops it binding to fibrin or being activated to plasmin
Used to treat bleeding in trauma, surgery, inherited bleeding disorders
What is thrombosis?
Formation of a blood clot in intact blood vessels. Can block of blood flow downstream and can be fatal
What are 3 factors which contribute to thrombosis?
Blood- reduced levels of anticoagulant proteins, reduced fibrinolytic activity, increased levels of clotting factors or platelets. Especially important in venous thrombi
Vessel Wall- something wrong with wall e.g. atheroma. Especially important in arterial thrombi
Blood Flow- speed of blood, how it flows, affects both venous and arterial thrombi
What are anti-platelet drugs and what are examples?
Anti-platelet drugs are used for prevention and treatment of cardiovascular and cerebrovascular disease
E.g. aspirin and clopidogrel
How does aspirin work?
Inhibits production of thromboxane A2 by irreversibly blocking the action of cyclo-oxygenase (COX) resulting in reduction of platelet aggregation
Although prostacyclin production is also inhibited by cyclo-oxygenase, endothelial cells can synthesise more COX whereas platelets cannot
Effects of aspirin lasts ~7 days until most of platelets have been replaced
How does clopidogrel work?
Irreversibly blocks the ADP receptor, P2Y12 on the platelet cell membrane.
Effects last ~7 days until new platelets have been produced
