haemostasis Flashcards
Where and how are platelets formed?
Bone marrow by fragmentation of megakaryocytic cytoplasm from myeloid stem cells
Describe the Vasoconstriction stage of Primary Haemostasis
Nitric Oxide and prostacyclin concentrations are less than endothelin concentration
So vasoconstriction occurs reducing the amount of blood being lost
Outline the process of Platelet Adhesion during Primary Haemostasis
VWF binds to collagen on the endothelium at site of injury and then GPIb receptor on the platelet binds to VWF.
OR platelets stick to collage via the GPIa receptor.
what do alpha granules contain
what do beta granules contain
VWF, fibrinogen
serotonin, Ca2+, ADP
How does the Activation and Degranulation of platelets occur in Primary Haemostasis?
what does ADP do
Platelet and GPIb receptor changes shape so that it can bind properly to endothelium
The alpha and dense granules of platelets are released
The ADP in dense granules is what activates the GPIIb/IIIa receptors to bind to the fibrinogen
its also a platelet activator resulting in further platelet recruitment
How is Thromboxane A2 synthesis stimulated?
Platelets are stimulated to produce the prostaglandin thromboxane A2 from arachidonic acid that is derived from the cell membrane (also is a vasoconstrictor)
Final step of platelet aggregation?
Platelet releases Prostaglandin Thromboxane A2 and ADP
Resulting in Positive feedback for more recruitment activation and aggregation as the platelet changes shape and many will bind to a single fibrinogen
Creating the platelet plug
what three things occur after platelet adhesion
Change in shape of platelet, can grab onto more platelets
release of granules
release thromboxane A2
What does Prostacyclin do?
vasodilator released from the endothelial cells and suppresses platelet activation, preventing inappropriate platelet aggregation by elevating cyclic-AMP levels
How does Aspirin inhibit the activation of platelets?
How does the anti-platelet drug Clopidogrel work?
Inhibits the production of thromboxane A2 by irreversibly blocking the action of cyclo-oxygenase (COX) resulting in a reduction in platelet aggregation
Irreversibly blocking ADP receptor (P2Y12) on the platelet cell membrane
function of fibrin
To reinforce the platelet plug at the site of injury and make it stronger
- Describe what happens during the extrinsic and intrinsic pathways of Secondary Haemostasis
what does Xa lead to the activation of
Extrinsic pathway:
TF binds to factor VIIa and calcium to activates factor X to Xa
factor Xa, Va and calcium bind to activate factor II (prothrombin) to IIa (thrombin)
Intrinsic pathway
Factor XII encounter phosphate ions and changes from XII to XIa to XI
XI with calcium activates IX to IXa
IXa binds with VIIIa and calcium to activate X to Xa
prothrombin to thrombin
What three co factors does thrombin activate in Secondary Haemostasis (amplification stage)
A small amount of thrombin mediates activation of co-factors V & VII and IX
What is the purpose of thrombin?
what does factor 13 do
convert fibrinogen to fibrin
activate factors 5,8 , 9
activate platelet
proteolytically cleave factor 13 to 13a
combines with calcium ion
cross link protein chains together
Outline the Propagation stage of Secondary Haemostasis
Factor XI converts more IX to IXa
With factor VIIIa, IXa will amplify conversion of factor X→Xa
Leading to a rapid burst in thrombin generation, which cleaves circulating fibrinogen to form insoluble clot
- What is the function of Proteins C & S?
what does antithrombin inhibit
Protein C is activated when thrombin binds to thrombomodulin on endothelial cell surface
Activated protein C in the presence of protein S will inactivate factors Va and VIIIa
Thrombin and factor 10
- How do Antithrombin and Heparin promote anticoagulation?
Thrombin and factor Xa inactivated by circulating inhibitor, antithrombin
Heparin enhances the binding capabilities of antithrombin to Factor II (prothrombin)
Inactivation of thrombin requires larger chains of heparin to wrap around both antithrombin and thrombin
- How does Warfarin work as an anticoagulant?
- How do direct oral coagulants work?
It is a Vitamin K antagonist working by interfering with protein carboxylation
Therefore reduces synthesis of functional factors II, VII, IX and X by the liver
Directly inhibit thrombin and factor Xa without involvement of antithrombin
- What is meant by a zymogen?
- What is the function of the Fibrinolytic system?
- What is plasminogen?
A proenzyme = an enzyme that generates another enzyme
To remove clot after vasculature is repaired The inactive zymogen form of plasmin
What does Plasmin do
Outline briefly the fibrinolytic system?
Digests Fibrin into Fibrin Degradation Products - breaks down clot
Digests Fibrinogen into Fibrinogen Degradation Products
Digests V & VII
Digests II & XII to prevent clot formation
t-PA (tissue plasminogen activator) and plasminogen bind to lysine residues on fibrin activate plasminogen to plasmin so fibrin is broken down
What is plasmin inhibited by
antiplasmin
alpha 2 macrogloblin
- How does tranexamic acid work as an antifibrinolytic drug?
It is a synthetic derivative of lysine that works by binding to plasminogen
In doing so it prevent plasminogen from binding to the lysine residues of fibrin (competitive inhibition) Prevents activation of plasminogen to plasmin, which would otherwise result in fibrinolysis
What is thrombosis?
What 3 changes in blood could increase a person’s risk of venuous thrombosis?
Formation of clot within intact blood vessel which usually obstructs blood flow
Reduced anticoagulant factors Increased coagulant factors Reduced fibrinolytic activity
- Which coagulation pathway do the aPTT and PT monitor respectively?
- What is used as the source of TF and phospholipid in PTs?
- The reduction in activity of which factors may prolong a PT?
aPTT - intrinsic
PT - extrinsic Recombinant thromboplastin Factor VII, X, V, II or fibrinogen
- What is Virchow’s Triad?
3 contributory factors to a pathological clotting or thrombosis
Blood - dominant in venuous thrombosis Vessel wall - dominant in arterial thrombosis Blood flow - complex, contributes to both arterial and venuous thrombosis
What two types of thrombolytic therapy are there and what is used in each?
encouraging clot lysis
recombinant t-PA- generate plasmin to lyse clots
given to patients presenting with ischaemic stroke or pulmonary emboli
preventing clot lysis
tranexamic acid
binds to plasminogen preventing plasminogen binding to lysine residues of fibrin
treat inherited bleeding disorders and bleeding in trauma
How is PT measurement carried out
blood collected in bottle containing sodium (chelates calcium so blood doesn’t clot in bottle
sample is spun to get platelet poor plasma
source of TF, Phospholipid and calcium is added
time taken for blood to clot is recorded
How is APTT measurement carried out?
use contact activation of factor 12 by surface such as glass or using a contact activator such as silica or kaolin
contact activator and phospholipid is added to citrated plasma sample followed by calcium
time taken to clot is recorded
What do patients with isolated prolonged APTT ( and normal PT) present with
haemophilia A (factor 8 deficiency) Haemophilia B (factor 9 deficiency) factor 11 deficiency or factor 12 deficiency but this does not present with bleeding
why is the balance between coagulant and anticoagulant proteins important
allows for simulation of blood clotting
limit the extent of clotting at tissue injury site
starts the process of healing via fibrinolysis
