2.7 Haemostasis And Thrombosis Flashcards
What is Haemostasis
Halting of blood following trauma to blood vessels
A state of equilibrium
Functions of Haemostasis
Prevention of blood loss from intact vessels
Arrest of bleeding from injured vessels
Balance model
Fibrinolytic factors, anticoagulant proteins vs. Coagulation factors, platelets
Why is the balance important
Coagulation, thrombosis, fibrinolysis
Allows stimulation of blood clotting processes following injury
Limits extent of response to prevent excessive or generalised blood clotting
Starts the process leading to the breakdown of the clot as part of the healing process
First stage o Haemostasis
Vessel constriction
Stage 2 of Haemostasis
Primary Haemostasis
Formation of unstable platelet plug
Stage 3 of Haemostasis
Secondary Haemostasis
Stabilisation of the plug with fibrin
4th stage of Haemostasis
Fibrinolysis
Brief vessel constriction
Vascular smooth muscle cells contract locally
Limits blood flow to injured vessel
Brief formation of unstable platelet plug
Platelet adhesion
Platelet aggregation
Limits blood loss and provides surface for coagulation
Brief stabilisation of the plug with fibrin
Blood coagulation
Stops blood loss
Brief vessel repair and dissolution of clot (fibrinolysis)
Cell migration/ proliferation and fibrinolysis
Restores vessel integrity
Why is it important to understand Haemostatic mechanisms
Diagnose and treat bleeding disorders
Control bleeding
Identify and treat thrombotic disorders
Monitor drugs used in treatment
What are platelets differentiated from
Megakaryocytes
How long do platelets circulate
10 days
Haemostatic 0latelet plug formation overview
Vessel constriction
Primary Haemostasis (formation of unstable platelet plug)
Secondary Haemostasis (stabilisation of plug with fibrin)
Fibrinolysis (dissolution of clot and vessel repair)
Platelet adhesion
Primary
Vwf forms a bridge for platelet to bind to via Glp1b
Or platelets bind directly to exposed collagen by Glp1a
Changes shape from discoid to rounded with spicules for platelet platelet interactions
What’s released following platelet adhesion
ADP and prostaglandins
Which components are used in binding sites between platelets in platelet aggregation
Fibrinogen and Ca2+
Glp2b/3a
How is the prostaglandins thromboxane a2 produced
From arachidonic acid in the cell membrane
Catalysed by cyclo oxygenate (cox) to cyclic endoperoxides
Thromboxane synthesise in platelets then produces TXA2
Arachidonic acid in endothelial cells
Catalysed by cox to cyclic endoperoxides
Prostacyclin synthetase then catalyses to prostacyclin PGI2 in endothelial cells
Prostacyclin function
Inhibits platelet aggregation
Aspirin and clopidogrel are
Antiplatelet drugs
Irreversibly bind to. Cox
Clopidogrel function
Irreversibly blocks ADP receptor p2y12 on platelets
Last 7-10 days due to platelet life span
Why can endothelial cells still produce prostacyclins even with aspirin
Can synthesise it’s own cox
Where are clotting factors produced
Mostly in the liver
Vwf in endothelial cells and platelets
Factor 5 in platelets
Which factors are reliant on vit k
1972 - 10, 9, 7 and 2 (prothrombin)
Initiation stage
Tissue factor binds to factor 7a
Triggers activation of 9 and 10 to a
Results in generation of small amount of thrombin (2a) from prothrombin (2)
Amplification propagation phase
Thrombin activates factor 11 and cofactors 5 and 8 to a and platelets to their activated form
11a amplifies factor 9 to 9a
Factors 9a and 8a cause amplification of conversion of 10 to 10a
10a causes a rapid burst in the generation of thrombin 2a which cleaves the soluble fibrinogen to insoluble fibrin clot
What is calcium needed for in coagulation
Binding clotting factors to the platelet surface
Direct coagulation inhibition
Antithrombin - inhibitor of thrombin and other clotting proteinases
Indirect coagulation inhibition
Inhibition of thrombin generation by pathways (e.g. protein c and s antiocoagulant oathways)
What does antithrombin bind to
Heparin
What are protein c and protein s involved in
Thrombin generation
What does antithrombin have its affect on
10a and thrombin (2a)
What does protein c have its affect on
8a
What does protein s have its affect on
5a
Therapeutic anti coagulation approaches
Reduce procoagulant factors (vit k antagonist)
Inhibit procoagulant factors (direct oral anticoagulant)
Enhance natural anticoagulant pathways (heparins and derivatives)
Anticoagulant drugs
Heparin
Warfarin
DOACs (direct oral antiocoagulant drugs)
Heparin works by
Indirectly by potentiating acting of antithrombin causing inactivation of factors 10a and 2a (thrombin)
Long chains of heparin wrap around both antithrombin and thrombin
How is heparin administered
Intravenously or subcutaneous injection
What is heparin derived from
Mixture of glycosaminylglycan chains extracted from porcine mucosa
What is warfarin derived from
Coumarin
How does warfarin work
Vit k antagonist which works by interfering with protein carboxylation (factors 1972)
Competes with vit k to stop its recycling
How is warfarin administered
Oral tablet
Why does warfarin take several days to take effect
Because it reduces synthesis of coagulation factors rather than inhibiting existing factor molecules
DOACs
Orally available drugs which directly inhibit 10a or 2a (thrombin) without antithrombin
Don’t need monitoring predictable
Why is there usually no fibrinolytic reaction
Plasminogen and tPA need to be brought together
Fibrinolysis
Plasminogen binds to the lysine residues of fibrin, activated by tissue plasminogen activator to plasminogen causing degradation of the clot
Plasmin breaks down
Fibrin (1a)
5a and 8a
What inhibits plasmin
Antiplasmin
Alpha 2 macroglobulin
Tranexamic acid in fibrinolysis
Competitive inhibitor of of plasminogen to lysine residues of fibrin
Used to treat bleeding in trauma patients surgical patients and those with inherited bleeding disorders
Haemophilia
Failure to generate fibrin to stabilise platelet plug
What is a prolonged aptt without prolonged pt seen in
Haemophilia A (factor 8 deficiency)
Haemophilia b (facto r9 deficiency)
Factor 12 deficiency(no bleeding)
What is a prolonged aptt seen in
Reduction in single or multiple clotting factors
If multiple may also be prolonged pt
Aptt
Activated partial thromboplastin time
Measure Intrinsic (and common) pathways
Performed by the contact activation of factor 12 by glass silica or kaolin
Added with phospholipid to citrated plasma followed by calcium
Time taken for mixture to clot is measured
Prothrombin time
Measures integrity of extrinsic (and common pathway)
Blood added to sodium citrate which doesn’t contain calcium to prevent clotting
Spun to produce platelet poor plasma
TF and phospholipid added to citrated plasma sample with calcium to start the reaction
Time taken for mixture to clot is recorded
What does pt estimate
Activity of factors 7,10,5 and 2 and fibrinogen
What is often used as a source of TF and phospholipid in pt
Thromboplastin
What are results of pt expressed as in the control of vit k antagonist anticoagulant therapy
INR international normalises ratio
What could loss of Haemostatic equilibrium balance result in
Bleeding
What can cause bleeding in regards to the Haemostatic balance
Reduction in platelet number or function (primary Haemostasis)
Reduction in coagulation factors (secondary haemostasis)
Increased fibrinolysis
Thrombocytopenia
Reduction in platelet number
Thrombosis describes
Formation of blood clot where you don’t need it - within an intact vessel
Virchow’s triad
Three contributory factors to pathological clotting (thrombosis)
Blood
Blood flow
Vessel wall
Changes in blood constituents is important in regard to which thrombosis
Venous thrombosis
