Haemostasis Flashcards
What is Haemostasis?
the specific, regulated cessastion of bleeding in response to a vascular injury to stop bleeding and allow vessel repair to occur
Explain the vascular response to bleeding
Vasoconstriction to reduce blood flow and therefore bleeding
What is primary haemostasis?
What is its funciton?
- platelet adhesion
- platelet aggregation that forms an
- unstable white plug
–> limits blood loss + provides surface for coagulation
What is secondary haemostasis?
What is its function?
To stabalise cloth formed in primary haemostasis
- activated coagulation factors
- fibrin mesh
- —> stops blood loss
Explain the structure and function of the vasculature wall in haemostasis
Vascular wall endothelium is anti-coagulant
- e.g. thrombomodulin etc.
The sub-endothelium is pro thrombotic and procuagulant basement membrane
- Elastin, Collagen, TF (on vascular SM cell, fibroblasts)
Explain the role of the vascular response to injury
- st step in Haemostasis–> vasoconstriction
- most important in small vessels
- local response to injury
- to reduce blood flow
What are platelets?
What is a normal platelet count?
- small
- anuclear cells
- lifespan about 10 days
- very responsive because of many receptors that can interact with outside stiummuli
- normal count: 150-350 x 109/L
What is a alpha-granule in a platelet?
granule in platelet containing
- growth factor
- fibrinogen
- VWF
–> released when activated
What is a dense granule in a platelet?
contains
- ADP
- ATP
- Serotonin
- Ca2+ and get released when activated
What are the role of the platelet membrane in haemostasis
In inactivated state: normal membrane
When Activated: negatve charge from phospholipids turns outside and makes surface very attractive for anti-coagulants
How does the platelet shape changes in platelet activation?
Cytoskeleton changes:
conversion from a passive to an interactive cell
Explain the Recruitement of platelets to the site of injury
Vessel Injury exposes collagen
VWF binds to collagen–> changes conformation that exposes binding sites on VWF for platelets
Platelets adhere to now exposed VWF via Gp1b
platelets can also adhere to collagen but only when low blood flow, it is VWF dependant
How do platelets get activated
Different stimmuli lad to activation
- Collagen
- Thrombin
- ADP
- Thromboxane
- each other via alpah2bß3
What happens when platelets get activated ?
Relase granule
- change of membrane –> negative charge
- release of thromboxane
- release of ADP
- more
What are the Thrombocytopaenia levels when do certain characteristics occur?
Normal range 10-300 109 /l
<10 spontaneous bleeding common
<40 spontaneous bleeding
<100 no spontaneous bleeding but bleeding in trauma
Where are coagulation factors synthesised?
- The liver – most plasma haemostatic proteins
- Endothelial cells – VWF, TM, TFPI
- Megakaryocytes – VWF, FV
What are zymogen hormones in haemostasis?
Precursors to serine proteases
What is the role of serine proteases in haemostasis?
Cleaving someting and activating it by this
–> factors have a serine protease domain at activated site
What is a Gla domain?
Where is it present
Domain that give clotting factors the ability to interact with phospholipid surfaces
on
- VII
- X
- Prothrombin
- IX
- Protein C
- Protein S
Where is Tissue factor present?
What is its role in haemostasis ?
Factor III–> binds complex with VII to set of extrinsic pathway–>
- normally located at extravascular sites
- i.e not usually exposed to the blood (VSMC, fibroblasts etc…)
- TF expressed higher in certain organs
- (i.e. lungs, brain, heart, testis, uterus, and placenta)
- TF in these locations provide further haemostatic protection in these organs.
- (i.e. lungs, brain, heart, testis, uterus, and placenta)
Where is Coagulation factor VII synthesised?
What is its funciton?
Circulates inactively in plasma –> Has to get activated
- has Gla domain
- Serine protease domain
very small amount of active factor VII citculates 1%
What is the role of vitamine K in blood coagulation?
Important in Gla domain formation:
It does post-translational modification of proteins that give rise to calcium binding site
–> calcium changes conformation, can now interact with negative phospholipid membranes
What is the mechanism of action of Warfarin?
Vit.K carboxylase antagonist
–> deminishes function of a number of clotting facotrs by impairing interaction with phospholipid membrane with Gla domain
Explain the coagulation cascase
What is Haemophilia A?
Lack of clotting factor VIII
What is Haemophilia B?
Lack of clotting factor IX
How is Haemophilia inherited?
X-chromosomal recessive
What is the role of TFPI (tissue factor pathway inhibitor) in haemostasis?
Inhibits coagulation at site of activation
–> binds to factor Xa which then binds to complex III+VII –> inactivation of all 3 proteins
Explain the role of protein C in haemostasisi
Cleave factor V and VIII –> inhibits them
Explain the formation of protein C in haemostasis
Thrombin binds to Thrombomodulin on tissues
–> Thrombomodulin modulates thrombrin to cleave Protein C to activate it –> shots down coagulation at edges of blood coagulation (because thrombomodulin is present at intact endothelial surface
What is the role of Antithrombin
serine protease inhibitor (not just inactivated thrombine)
• AT inactivates many activated coagulation serine proteases (FXa, thrombin, FIXa, FXIa)
What is the site of action of heparine
Enhances the activity of Antithrombin to make it more effective to inhibit Thrombin + FX
Explain the process of fibrinolysis
Done by Plasmin –> degrades fibrin fibres
Plasmin is activated from precursor form plasminogen by tissue plasminogen activator (tpa)
Explain the clinical use and mechanism of action of tPA
tissue Plasminogen activator
–> turns plaminogen into plasmin
Plasmin degrades fibrin and lyses blood cloths
This can be used in thrombotic infarctions e.g. stroke, MI etc.
What is the drug group and of heparin and warfarin.
When would you give it to a patient?
Thea are anticoagulatns
Manily used for someone at risk of venous thrombosis
Which type of drugs would you perscribe to someone at risk of venous thrombosis?
Hepatin, warfarin, directly acting anticoagulatns
–> Anticoagulants (over anti-platelet agents)
Explain the mechanism of action of Aspirin and its clinical use
It is an anti-platelet agent –> irreversibly blocks COX1+2 leading to
- reduced production of TxA2 –> less thrombocyte aggregation (Cox1)
- reduced prostacyclin –> anti fever+analgesic effect
Used in arterial thrombosis
Which type of drug (and which specific drug) would you perscribe someone at risk of arterial thrombosis?
Anti-platelet agent (Thrombozytenaggregationshemmer)
–> Asperin
What are the tests available to test coagulation?
- Coagulation
- PT time ( measures the number of seconds it takes for a clot to form in your sample of blood after reagents are added
- APPT test
- Platelet funciton test
- d-dimer test –> fibrin degradation product (how much clotting is happening in individual in the past)
What is the role of Protein S in Coagulation?
It is a co-factor of Protein C –> anti-thrombotic effects
What factors get activated by the TF (VIII)/ VII complex?
Factor X
- Directly
- Indirectly via Factor IX activation (one cross-link between intrinsiv + extrinsic pathway)
What clotting factors are activated by thrombin?
- Aim: Activation of Fibrinogen to Fibrin (for clot stabilisation)
But also makes positive feedback loop by activation of
1. V and VIII (two important co-factors - increase activity of Factor X (V) and Factor IX (VIII) 5-fold)
2. Activation of Factor XI –> Factor XI activates Factor IX
What is the role of Factor XIII in coagilation?
Needed for cross-linking of fibrin clots and stablelisation of clots
What pathways are defined as the extrinsic, intrinsic and common pathway in coagulation?
What does the Prothrombin time test?
What is added during the test?
Time it takes to produce fibrin polymers after adding thromboplastin (tissues factor and phospholipids) and calcium (NR 12-14s)
Asesses the extrinsic and commmon pathway –> VII, X, V and II
What does the Activated partial thromboplasin time test?
What is added to the reagent?
Time it takes to produce fibrin polymers after adding phospholipids (calcium, partial thromboplastin)
Asesses the intrinsic + common pathway:
II, V, X, IX, XI, XII
Partial thromboplastin does not activate the extrinsic pathway, but replaces platelet phospholipids in the steps where it is required to activate the intrinsic patthway
What does the INR measure?
Derived from PT, but calculated by comparing the laboratory-specific PT to a standardized PT
–> Therefore asesses extrinsic and common pathway
What is TT? What does it measure?
Thrombin time –> measures the Common pathway
Time it takes to produce fibrin polymers after adding thrombin
