Thrombolytics; Anticoagulants; Antiplatelet Drugs Flashcards
1
Q
What is haemostasis?
A
Arrest of blood loss. Physiological response to bleeding/haemorrhage. Pathological response to damaged blood vessel.
2
Q
What can abnormalities in haemostasis lead to?
A
- haemorrhage
- thrombosis
3
Q
What are the stages in haemostasis
A
- 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)
4
Q
What is thrombosis?
A
- pathological formation of solid blood constituents within the blood vessel
- occurs in the absence of previous bleeding
5
Q
Name + describe the 3 components of Virchow’s Triad
A
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)
6
Q
What conditions can increase the coagulability of blood?
A
- pregnancy
- contraceptive pill
- leukaemia
- dehydration
7
Q
What 3 factors influence a clot formation? (hint: each of these factors can be treated by thrombolytic drugs)
A
1) platelets
2) coagulation cascade
3) fibrinolytic cascade
8
Q
Describe an arterial thrombus
A
- white
- mainly platelets surrounded by fibrin mesh
- forms embolus + detaches from site of origin (e.g. left heart/carotid artery)
9
Q
Describe a venous thrombus
A
- red
- white fibrin head
- jelly like tail composed of blood cells
- fibrin + red blood cell rich
10
Q
Where do embolus that detach from arterial thrombus usually occur?
A
brain (stroke)
11
Q
Where do embolus that detach from venous thrombus usually occur?
A
lungs (pulmonary embolus)
12
Q
Are platelets nucleated?
A
No, they are a nucleate cell fragments
13
Q
What factor influences the formation of fibrin in a clot formation?
A
thrombin (clotting factor 2a)
14
Q
What factor influences the conversion of prothrombin to thrombin?
A
- clotting factor 10a
- proteolytic cleavage of prothrombin by 10a produces thrombin
15
Q
What are the names of the 2 pathways that can form clotting factor 10a?
A
1) contact (intrinsic) pathway
2) in vivo
16
Q
What clotting factors are associated with the contact pathway?
A
clotting factors 11a + 12a
17
Q
What clotting factor is associated with the in vivo pathway?
A
clotting factor 7a
18
Q
Where are clotting factors synthesised?
A
liver (Prof Fleming’s thrombosis lecture)
19
Q
Describe the stages in platelet activation in response to endothelial damage (in the formation of a fibrin clot)
A
- 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
20
Q
The platelet membrane provides a surface allowing what to be brought together?
A
-clotting factors
21
Q
How can clotting factors attach themselves to the platelet membrane?
A
-they become carboxylated
22
Q
What charge does the platelet membrane have?
A
-negative charge
23
Q
What clotting factor facilitates prothrombin and clotting factor 10a to be brought together (to form thrombin)?
A
- clotting factor 5a
24
Q
How are clotting factors 2/7/9/10 related to their active form?
A
they are GLYCOGEN PRECURSORS of 2a/7a/9a/10a
25
What is another name for these clotting factors? (2/7/9/10)
serine proteases
26
What needs to happen to the clotting factor precursors for them to become activated?
- post-translational modification (e.g. gamma carboxylation)
27
What does the carboxylase enzyme that mediates gamma carboxylation require to work?
vitamin k in its reduced from
28
Give an alternative name for vitamin K in its reduced form
-hydroquinone
29
What is vitamin K in its oxidised form called?
-epoxide
30
What enzyme converts oxidised vitamin k to reduced vitamin k?
- vitamin k reductase
31
What does warfarin do?
- blocks vitamin K reductase
- prevents formation of hydroquinone
- prevents gamma carboxylation of clotting factors and subsequent coagulation
32
What type of drug is warfarin?
anti-coagulant
33
What are anti-coagulants used for?
- prevention of VENOUS thrombosis + embolism
| e. g. DVT/ post-op thrombosis/ artificial heart valves/ atrial fibrillation
34
What is the risk of taking anti-coagulants?
-haemorrhage
35
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
36
How is warfarin administered?
-orally
37
What is warfarin's onset of action?
2-3 days (allows time for activated clotting factors to be cleared)
38
What other anti-coagulant drug can be added to warfarin to give a more rapid effect?
-heparin
39
What is the half life of warfarin?
40 hours
40
Is the therapeutic index of warfarin low/high?
-low
| fine balance between therapeutic dose and haemorrhage-causing dose
41
The effect of warfarin must be monitored on a regular basis - what is the name given for this?
- international normalised ratio (INR)
42
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)
43
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
44
What factors can increase the risk of thrombosis (lessen warfarin action?
- physiological state (e.g. pregnancy)
| - vitamin K consumption (e.g. in certain foods)
45
What drug interactions with warfarin increase the risk of thrombosis?
- drugs that increase the hepatic metabolism of warfarin
46
If a patient overdoses on warfarin - what counteractive treatment can be given?
- vitamin K
| - increase concentration of plasma clotting factors
47
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
48
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
49
Which two clotting factors are particularly inhibited by antithrombin 3?
Factors 10a + 2a
50
Does heparin have to bind to the active site of both antithrombin 3 and factor 2a in order for 2a to be inactivated?
yes
51
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
52
What is heparin + where is it derived from?
- a naturally occurring sulphated glycosaminoglycan
- of variable molecular size
- extracted from beef lung/hig intestine
53
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
54
What serine protease(s) does low molecular weight heparin (LMWH) inhibit?
- factor 10a
| - NOT factor 2a
55
Give an example of a LMWH
- enoxaparin
| - dalteparin
56
How are LMWHs administered?
- subcutaneously
57
How is heparin administered?
- IV (immediate onset)
| - subcutaneously (1 hour onset)
58
What is an in vitro clotting test and what is it used for?
- determines the optimum dosage of heparin
| - not used for LMWH
59
What drug displays 0 order kinetics (rate of elimination not determined by concentration of drug)?
- heparin
60
What drug displays 1st order kinetics (rate of elimination is dependent on the concentration of the drug)?
- LMWH
61
How are LMWHs excreted from the body?
- via the renal system
62
Which anticoagulant drug is preferred in renal failure?
- heparin
63
What drug can be given if patient overdoses on heparin?
- protamine sulphate
64
Adverse effects of heparin/LMWH?
- haemorrhage
- osteoporosis
- hypoaldosteronism
- hypersensitivity reactions
65
Dabigatran is an example of what?
- a new orally active drug that acts as a direct inhibitor of thrombin
66
What does rivaroxaban do?
- directly inhibit factor 10a
67
What circumstances are dabigatran/rivaroxaban used in?
- patients undergoing hip/knee replacement (prevent DVT)
68
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)
69
What enzyme mediates the synthesis of thromboxane A2 (TXA2)?
- cyclooxygenase 1 (COX-1)
70
ADP/5 HT/ TXA2 act on the cell surface receptors of platelets causing expression what what receptors?
- GP 2b/3a receptors
71
What do GP 2b/3a receptors do?
- cross link platelets via fibrinogen
72
What does ADP bind to on the platelet surface?
- P2Y12 receptor
73
What drugs blocks ADP from binding to P2Y12?
- clopidogrel
74
How does P2Y12 bond to clopidogrel?
- via a disulphide bond
75
What does clopidogrel do?
- irreversibly inhibits P2Y12
76
What kind of drug is clopidogrel?
- anti-platelet drug
77
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)
78
Is aspirin first line treatment for preventing arterial thrombosis?
- yes
79
Why is clopidogrel used to treat arterial thrombosis?
- used if patient is intolerable to aspirin
80
Is clopidogrel used alongside aspirin?
- yes (has synergistic effect)
81
What does tirofiban do?
- blocks cross bridging between Gp 2b/3a receptors on platelets (prevents platelet aggregation)
- anti-platelet drug
82
Is tirofiban long/short term treatment?
- short term
83
What circumstances is tirofiban given in?
- prevents MI in patients with unstable angina
84
What other drugs are given alongside tirofiban?
- aspirin
| - heparin
85
How is tirofiban administered?
- IV
86
Once a fibrin clot is formed, how is it dissolved?
- by a process called fibrinolysis
| - fibrinolysis opposes the coagulation cascade
87
What substance converts fibrin to fibrin fragments?
- plasmin
88
How is plasmin produced?
- by converting plasminogen
89
What aids conversion of plasminogen - plasmin?
- endogenous tissue plasminogen activator (tPA)
90
Name 3 drugs which activate plasminogen?
- streptokinase
- alteplase
- duteplase
91
Streptokinase/ alteplase/ duteplase are examples of which kind of drug?
- fibrinolytics
92
What circumstances are fibrinolytics used?
- reopen occluded arteries in acute MI/stroke/ less threatening venous thrombosis or pulmonary embolism
93
How are fibrinolytics administered?
- IV
| - percutaneous coronary intervention (PCI)
94
- What other drug is given alongside fibrinolytics to make them more beneficial?
- aspirin
95
Where is streptokinase derived?
- it is a protein derived from cultures of streptococci
96
What blocks streptokinase's action (and how long after beginning treatment does this occur?)
- antibody production
| - 4 days
97
What name is given to alteplase + duteplase? (clue rt -PA)
- recombinant tissue plasminogen activator (rt - PA)
98
Are alteplase/duteplase more effective on fibrin bound plasminogen or plasma plasminogen?
- fibrin bound plasminogen
99
Are alteplast/duteplast selective?
- yes, they show selectivity for clots
100
How are alteplast/duteplast administered?
- IV infusion
101
Do alteplast/duteplast have a long/short half life?
- short
102
What is given to a patient if they overdose on fibrinolytics?
- tranexamic acid
103
What does tranexamic acid do?
- inhibits plasminogen activation
| - no conversion to plasmin
104
Name the vitamin K dependent clotting factors
- clotting factor 2/7/9/10
