Thrombolytics; Anticoagulants; Antiplatelet Drugs Flashcards
What is haemostasis?
Arrest of blood loss. Physiological response to bleeding/haemorrhage. Pathological response to damaged blood vessel.
What can abnormalities in haemostasis lead to?
- haemorrhage
- thrombosis
What are the stages in haemostasis
- local vasoconstriction (loss of blood supply)
- adhesion + activation of platelets at site of injury (platelet plug) (primary haemostasis)
- formation of fibrin clot (blood coagulation) (secondary haemostasis)
What is thrombosis?
- pathological formation of solid blood constituents within the blood vessel
- occurs in the absence of previous bleeding
Name + describe the 3 components of Virchow’s Triad
1) injury to blood vessel wall (loss of surface/inflammation)
2) abnormal blood flow (stasis/turbulence)
3) increased coagulability of the blood (formed by platelets/coagulation proteins that increase blood viscosity)
What conditions can increase the coagulability of blood?
- pregnancy
- contraceptive pill
- leukaemia
- dehydration
What 3 factors influence a clot formation? (hint: each of these factors can be treated by thrombolytic drugs)
1) platelets
2) coagulation cascade
3) fibrinolytic cascade
Describe an arterial thrombus
- white
- mainly platelets surrounded by fibrin mesh
- forms embolus + detaches from site of origin (e.g. left heart/carotid artery)
Describe a venous thrombus
- red
- white fibrin head
- jelly like tail composed of blood cells
- fibrin + red blood cell rich
Where do embolus that detach from arterial thrombus usually occur?
brain (stroke)
Where do embolus that detach from venous thrombus usually occur?
lungs (pulmonary embolus)
Are platelets nucleated?
No, they are a nucleate cell fragments
What factor influences the formation of fibrin in a clot formation?
thrombin (clotting factor 2a)
What factor influences the conversion of prothrombin to thrombin?
- clotting factor 10a
- proteolytic cleavage of prothrombin by 10a produces thrombin
What are the names of the 2 pathways that can form clotting factor 10a?
1) contact (intrinsic) pathway
2) in vivo
What clotting factors are associated with the contact pathway?
clotting factors 11a + 12a
What clotting factor is associated with the in vivo pathway?
clotting factor 7a
Where are clotting factors synthesised?
liver (Prof Fleming’s thrombosis lecture)
Describe the stages in platelet activation in response to endothelial damage (in the formation of a fibrin clot)
- platelets adhere to damaged site
- aggregation of platelets
- secretion of preformed mediators from platelet granules (e.g. ADP/5-HT/coagulation factors)
- synthesis of other mediators (e.g. TXA2)
- further aggregation
The platelet membrane provides a surface allowing what to be brought together?
-clotting factors
How can clotting factors attach themselves to the platelet membrane?
-they become carboxylated
What charge does the platelet membrane have?
-negative charge
What clotting factor facilitates prothrombin and clotting factor 10a to be brought together (to form thrombin)?
- clotting factor 5a
How are clotting factors 2/7/9/10 related to their active form?
they are GLYCOGEN PRECURSORS of 2a/7a/9a/10a
What is another name for these clotting factors? (2/7/9/10)
serine proteases
What needs to happen to the clotting factor precursors for them to become activated?
- post-translational modification (e.g. gamma carboxylation)
What does the carboxylase enzyme that mediates gamma carboxylation require to work?
vitamin k in its reduced from
Give an alternative name for vitamin K in its reduced form
-hydroquinone
What is vitamin K in its oxidised form called?
-epoxide
What enzyme converts oxidised vitamin k to reduced vitamin k?
- vitamin k reductase
What does warfarin do?
- blocks vitamin K reductase
- prevents formation of hydroquinone
- prevents gamma carboxylation of clotting factors and subsequent coagulation
What type of drug is warfarin?
anti-coagulant
What are anti-coagulants used for?
- prevention of VENOUS thrombosis + embolism
e. g. DVT/ post-op thrombosis/ artificial heart valves/ atrial fibrillation
What is the risk of taking anti-coagulants?
-haemorrhage
Does warfarin block vitamin k reductase in vivo or in vitro? (or in both?)
- warfarin blocks vit k reductase in vivo only.
- this is because vitamin k is needed for warfarin to work - outwith the body on exogenous surfaces there is no vit k
How is warfarin administered?
-orally
What is warfarin’s onset of action?
2-3 days (allows time for activated clotting factors to be cleared)
What other anti-coagulant drug can be added to warfarin to give a more rapid effect?
-heparin
What is the half life of warfarin?
40 hours
Is the therapeutic index of warfarin low/high?
-low
fine balance between therapeutic dose and haemorrhage-causing dose
The effect of warfarin must be monitored on a regular basis - what is the name given for this?
- international normalised ratio (INR)
What factors can increase the risk of haemorrhage (if patient is given warfarin)?
- liver disease (decreases clotting factors - as they are synthesised in liver)
- high metabolic rate (high clearance of clotting factors)
What drug interactions with warfarin increase the risk of haemorrhage?
- drugs that inhibit platelet function (NSAIDS/aspirin)
- drugs that inhibit hepatic metabolism of warfarin
- drugs that decrease availability of vitamin K
What factors can increase the risk of thrombosis (lessen warfarin action?
- physiological state (e.g. pregnancy)
- vitamin K consumption (e.g. in certain foods)
What drug interactions with warfarin increase the risk of thrombosis?
- drugs that increase the hepatic metabolism of warfarin
If a patient overdoses on warfarin - what counteractive treatment can be given?
- vitamin K
- increase concentration of plasma clotting factors
What is antithrombin 3?
- important inhibitor of coagulation that neutralises all protease factors in the coagulation cascade (clotting factors 2/7/9/10) by binding to their active site
What is heparin’s role in relation to antithrombin 3?
- heparin binds to antithrombin 3
- this increases antithrombin 3’s affinity for serene proteases (clotting factors)
- greatly increases rate of inactivation
Which two clotting factors are particularly inhibited by antithrombin 3?
Factors 10a + 2a
Does heparin have to bind to the active site of both antithrombin 3 and factor 2a in order for 2a to be inactivated?
yes
Does heparin have to bind to the active site of both antithrombin 3 and factor 10a in order for 10a to be inactivated?
no, heparin only has to bind to antithrombin 3 in order for 10a to be inactivated
What is heparin + where is it derived from?
- a naturally occurring sulphated glycosaminoglycan
- of variable molecular size
- extracted from beef lung/hig intestine
What are the dosage units for heparin?
- dosage is specified in units of activity instead of mass
- this is because preparations of heparin have variable potency
What serine protease(s) does low molecular weight heparin (LMWH) inhibit?
- factor 10a
- NOT factor 2a
Give an example of a LMWH
- enoxaparin
- dalteparin
How are LMWHs administered?
- subcutaneously
How is heparin administered?
- IV (immediate onset)
- subcutaneously (1 hour onset)
What is an in vitro clotting test and what is it used for?
- determines the optimum dosage of heparin
- not used for LMWH
What drug displays 0 order kinetics (rate of elimination not determined by concentration of drug)?
- heparin
What drug displays 1st order kinetics (rate of elimination is dependent on the concentration of the drug)?
- LMWH
How are LMWHs excreted from the body?
- via the renal system
Which anticoagulant drug is preferred in renal failure?
- heparin
What drug can be given if patient overdoses on heparin?
- protamine sulphate
Adverse effects of heparin/LMWH?
- haemorrhage
- osteoporosis
- hypoaldosteronism
- hypersensitivity reactions
Dabigatran is an example of what?
- a new orally active drug that acts as a direct inhibitor of thrombin
What does rivaroxaban do?
- directly inhibit factor 10a
What circumstances are dabigatran/rivaroxaban used in?
- patients undergoing hip/knee replacement (prevent DVT)
Upon endothelial damage, platelet aggregation is driven by platelet-derived substances - name these.
- adenosine diphosphate (ADP)
- 5 - hydroxytryptamine (5-HT)
- coagulation factors (excreted from platelet granules)
What enzyme mediates the synthesis of thromboxane A2 (TXA2)?
- cyclooxygenase 1 (COX-1)
ADP/5 HT/ TXA2 act on the cell surface receptors of platelets causing expression what what receptors?
- GP 2b/3a receptors
What do GP 2b/3a receptors do?
- cross link platelets via fibrinogen
What does ADP bind to on the platelet surface?
- P2Y12 receptor
What drugs blocks ADP from binding to P2Y12?
- clopidogrel
How does P2Y12 bond to clopidogrel?
- via a disulphide bond
What does clopidogrel do?
- irreversibly inhibits P2Y12
What kind of drug is clopidogrel?
- anti-platelet drug
What does aspirin (another anti-platelet drug) do?
- irreversibly blocks COX1 (in platelets/endothelial cells)
- prevents synthesis of TXA2
- prevents COX1 from converting arachidonic acid into cyclic-endoperoxidase (in the synthesis of TXA2)
Is aspirin first line treatment for preventing arterial thrombosis?
- yes
Why is clopidogrel used to treat arterial thrombosis?
- used if patient is intolerable to aspirin
Is clopidogrel used alongside aspirin?
- yes (has synergistic effect)
What does tirofiban do?
- blocks cross bridging between Gp 2b/3a receptors on platelets (prevents platelet aggregation)
- anti-platelet drug
Is tirofiban long/short term treatment?
- short term
What circumstances is tirofiban given in?
- prevents MI in patients with unstable angina
What other drugs are given alongside tirofiban?
- aspirin
- heparin
How is tirofiban administered?
- IV
Once a fibrin clot is formed, how is it dissolved?
- by a process called fibrinolysis
- fibrinolysis opposes the coagulation cascade
What substance converts fibrin to fibrin fragments?
- plasmin
How is plasmin produced?
- by converting plasminogen
What aids conversion of plasminogen - plasmin?
- endogenous tissue plasminogen activator (tPA)
Name 3 drugs which activate plasminogen?
- streptokinase
- alteplase
- duteplase
Streptokinase/ alteplase/ duteplase are examples of which kind of drug?
- fibrinolytics
What circumstances are fibrinolytics used?
- reopen occluded arteries in acute MI/stroke/ less threatening venous thrombosis or pulmonary embolism
How are fibrinolytics administered?
- IV
- percutaneous coronary intervention (PCI)
- What other drug is given alongside fibrinolytics to make them more beneficial?
- aspirin
Where is streptokinase derived?
- it is a protein derived from cultures of streptococci
What blocks streptokinase’s action (and how long after beginning treatment does this occur?)
- antibody production
- 4 days
What name is given to alteplase + duteplase? (clue rt -PA)
- recombinant tissue plasminogen activator (rt - PA)
Are alteplase/duteplase more effective on fibrin bound plasminogen or plasma plasminogen?
- fibrin bound plasminogen
Are alteplast/duteplast selective?
- yes, they show selectivity for clots
How are alteplast/duteplast administered?
- IV infusion
Do alteplast/duteplast have a long/short half life?
- short
What is given to a patient if they overdose on fibrinolytics?
- tranexamic acid
What does tranexamic acid do?
- inhibits plasminogen activation
- no conversion to plasmin
Name the vitamin K dependent clotting factors
- clotting factor 2/7/9/10
