Platelet Physiology & Investigations Flashcards
Where does platelet synthesis occur and by what mechanism?
Bone marrow
Megakaryocyte buds off peripheral cytoplasm
What is haemostasis?
Physiological mechanism to stop bleeding and maintain BV patency
Where are coagulation factors synthesised? What happens to them after synthesis?
Liver hepatocytes
Circulate in inactivated form
What is the lifespan of a PLT? What is the clinical significance of this?
7-10 days
If on antiplatelet agent, stop 7 days before elective surgery otherwise bleeding risk
Platelets have no ____
Nucleus
What initiates primary haemostasis?
Endothelial damage
What vitamin deficiency increases the risk of endothelial damage?
Vitamin C scurvy
Decreased collagen synthesis
What age group is a risk factor for endothelial damage and why?
Elderly
Increased fragility
(Why bruising is more common in elderly)
What is primary haemostasis?
Platelet plug formation
What is secondary haemostasis?
Fibrin clot formation
What are the 3 main steps of primary haemostasis?
Adhesion
Aggregation
Activation
Endothelial damage exposes ____ and _____
Collagen and Von Willebrand Factor
Endothelial damage causes the endothelium to release _____ which initiates secondary haemostasis
Tissue factor TF
What is the function of glycoprotein 1b in primary haemostasis?
Involved in platelet adhesion to collagen and VWF
In platelet adhesion in primary haemostasis, what do platelets do next?
Release granules to attract more platelets
In primary haemostasis, what granules do platelets release to attract more platelets?
ADP, thromboxane A2 and thrombin
What is the function of GPIIbIIIa and fibrinogen in primary haemostasis?
Platelet aggregation (clumping)
In platelet activation in primary haemostasis, platelets change their ____ to expose more of their phospholipid surface and ADP receptors
shape
In secondary haemostasis, platelets secretes ____ which binds to the platelet phospholipid membrane and attracts clotting factors?
Calcium
What is the function of tissue factor in secondary haemostasis?
Activates factor VII to VIIa
What are the 3 steps of secondary haemostasis?
Initiation
Amplification
Propagation
In the initiation step of secondary haemostasis, the TF/VIIa complex activates _______. It converts ____ to ____.
In the initiation step of secondary haemostasis, the TF/VIIa complex activates V/Xa. It converts II to IIa.
What are factor I, Ia, II and IIa also known as?
I fibrinogen
Ia fibrin
II prothrombin
IIa thrombin
In the propagation step of secondary haemostasis, thrombin converts _____ to _____
I to Ia
Fibrinogen to fibrin
In the amplification step of secondary haemostasis, thrombin activates _____, which also activates ______. This is referred to as the thrombin burst.
In the amplification step of secondary haemostasis, thrombin activates VIII/IXa, which also activates V/Xa. This is referred to as the thrombin burst.
Where is vitamin K absorbed? What is required for its absorption?
Upper intestine
Fat soluble
Bile salts
What is the function of vitamin K?
Activates factor II, VII, IX and X and protein C and S via carboxylation
How many factors require vitamin K to be activated?
4
Where are platelets removed?
Spleen
In fibrinolysis, ______ converts ______ to ______. It converts _____ to _______
In fibrinolysis, tPA converts PLASMINOGEN to PLASMIN. It converts FIBRIN to FIBRIN DEGRADATION PRODUCTS
What is the most clinically important fibrin degradation product? (Since it is the one that gets measured to assess fibrinolysis)
D-dimers
Protein C, protein S and anti-thrombin III are all ______
Natural anticoagulants
What is the action of anti-thrombin III?
Negative effect on:
- thrombin
- TF/VIIa
- V/Xa
- VIII/IXa
What is the action of protein C and S?
Negative effect on V/Xa and VIII/IXa
Basically stop thrombin activation and propagation
What test is a measure of primary haemostasis?
Platelet count
What test is a measure of initiation and amplification of secondary haemostasis?
Prothombin time PT initiation
Activated partial thromboplastin time APTT amplification
What is a normal platelet count?
150 - 400
What factors are tested by PT?
I, II, V, VII, X
What factors are tested by APTT?
VIII, IX, or VWD
Also XI and XII but not clinically important
What are the potential causes of a raised APTT but normal PT?
- Factor VIII problem
- Factor IX problem
- APS (interferes with test)
- VWD (decreases factor VIII)
What are the potential causes of a raised PT and APTT?
How can you differentiate the causes?
- DIC
- Cirrhosis
- Vitamin K deficiency
- DIC; low platelets, clinical history of cause eg RTA
- Cirrhosis; low platelets + low albumin, +-alcohol history
- Vitamin K deficiency; intake, absorption or vitamin K antagonist history
Where are purpura most commonly found? How are they distinguished from other rashes on exam?
Commonest on lower limb
Non-blanching
Name 5 anticoagulants
Heparin Warfarin Apixaban Rivaroxaban Dabigatran
Name 2 antiplatelets
Asprin
Clopidogrel
What is the drug mechanism of heparin?
Potentiates natural anticoagulant anti-thrombin
What is the drug mechanism of warfarin?
Vitamin K antagonist; makes protein C/S, factor II, VII, IX, X non-functional
What is the mechanism of rivaroxaban and apixaban in?
Xa inhibitor
What is the mechanism of dabigatran?
Direct thrombin inhibitor
What are the 2 forms of heparin? What routes are they given?
Unfractioned IV
LMWH SC
What routes is warfarin given?
I don’t know
What route is Xa inhibitors eg rivaroxaban and apixaban given?
PO
What route is dabigatran given?
PO
What drug class is warfarin in? What do all drugs in that class do?
Coumarins
All inhibit vit K
What effect does heparin have on APTT and PT?
Raised APTT
+- Raised PT
What are the differences between heparin and warfarin’s:
- Time to produce effect
- Therapeutic window-
- Monitoring
- Effecting secondary haemostasis
- Heparin has immediate effect, warfarin takes 1 wk
- Both have narrow therapeutic window
- Unfractioned heparin monitored by APTT, LMWH not monitored (by Xa assay if needed), warfarin monitored by INR
- Both stop secondary haemostasis
How do the half lives of unfractioned and LMWH compare, how does this effect clinical practice?
Unfractioned heparin half life 30 min
LMWH half life 1 day
If need to use anticoagulant in a patient with a high bleeding risk- use unfractioned heparin since reverse quicker
What are the side effects of heparin?
- Bleeding
- OP long term
- HITT autoimmune thrombocytopenia with thrombosis
How is heparin reversed in a severe bleed
Protamine sulfate
How is warfarin metabolised?
CYP450 enzymes
Which anticoagulant should be taken at the same time every day?
Warfarin
Warfarin has a variable response so requires different ____ in different patients
doses
What are the side effects of warfarin?
- Bruising
- Bleeding; epistaxis, haematuria, GI, ICH
- Decreased BP
Why is warfarin not used in the acute management of thrombosis?
Inhibits protein C and S so patients are prothrombotic for 1st week before anticoagulant effect kicks in
What does INR stand for? What test is it based on? What drug does it monitor?
International normalised ratio
PT
Warfarin
How is warfarin reversed if immediate reversal is needed?
Factor concentrate + IV / PO vit K
How is warfarin reversed if a patient has a mildly increased INR?
Miss a few doses
How long does vitamin K take to reverse warfarin?
6 hours
How are Xa inhibitors eg rivaroxaban and apixaban monitored?
Not monitored
Newer oral anticoagulants such as Xa inhibitors and dabigatran require no monitoring, have _____ side effects and _____ drug interactions. However, it is not possible to ______.
Newer oral anticoagulants such as Xa inhibitors and dabigatran require no monitoring, have LESS side effects and LESS drug interactions. However, it is not possible to REVERSE THEM.
What is used more commonly; Xa inhibitors eg apixaban and rivaroxaban or dabigatran?
Xa inhibitors
What are the indications for anticoagulants and how long should they be used for in these scenarios?
Single VTE = 6 months
Recurred VTE = lifelong
AF = lifelong
AF causes stasis in the ____
Left atrium
What are the indications for antiplatelets?
Arterial thrombosis
What part of haemostasis do antiplatelets act in?
Primary haemostasis; prevent platelet aggregation
What is the mechanism of aspirin?
Cyclo-oxygenase inhibitors - stop thromboxane A2 production which decreases platelet activatoin
What are the side effects of aspirin?
Bleed
PUD (due to blocking PG synthesis)
Bronchospasm (due to blocking PG synthesis)
The antiplatelet abciximab is a GP IIb/IIIa inhibitor, it is only used as an IV infusion in ______
Heart surgery
What is the mechanism of clopidogrel and prasugrel?
ADP antagonist
What is the main reason LMWH is used over unfractioned heparin?
Requires more monitoring
Atherosclerosis causes endothelial damage. Foamy _____ produce cholesterol rich plaques. _____ plaques are hyalinised or calcified and cause angina or intermittent claudication. ______ plaque rupture in ACS or stroke initiates ______.
Atherosclerosis causes endothelial damage. Foamy MACROPHAGES produce cholesterol rich plaques. STABLE plaques are hyalinised or calcified and cause angina or intermittent claudication. UNSTABLE plaque rupture in ACS or stroke initiates HAEMOSTASIS.
What hormone regulates PLT production?
Thrombopoietin
