10. Inhibitors and Anticoagulants

Question 1

inhibitors

Answer 1

-tissue factor pathway inhibitor (TFPI) - VIIa and Xa
-antithrombin III - Xa and thrombin
-protein C and protein S : PS inactivates Va and VIIIa
action of protein s is enhanced by protein C
protein C also enhances fibrinolysis

Question 2

tissue factor pathway inhibitor TFPI

Answer 2

1st inhibitor to act
found in plasma and platelets
accumulation due to platelet activation
inhibits fact`rs VIIa and Xa

Question 3

antithrombin (III)

Answer 3

synthesised in the liver and endothelium

inactivates serine proteases, principally factor Xa and thrombin

Question 4

protein C and S

Answer 4

are vitamin K dependent proteins
made in the liver
Protein C is activated via a complex which inactivates factors Va and VIIIa
action of protein S enhanced by the action of protein C which binds protein C to the platelet surface
protein C enhances fibrinolysis by inactivating the tissue plasminogen factor (tPA) inhibitor
both protein C and S affected by warfarin, a vitamin K antagonist

Question 5

fibrinolysis `

Answer 5

when we have our stable fibrin clot and damage to blood vessel has been repaired we now need to break it down
tPA activates plasminogen to plasmin
plasmin degrades fibrin
generates soluble fragments called fibrin degradation productions (FDPs), the number of FDPs produced tells us how many clots we’re producing in our body

Question 6

fibrinolytic system see slide 36 diagram

Answer 6

tissue plasminogen factor tPA and factor XIIa both act on plasminogen activator inhibitor PAI-1 which stops conversion of plasminogen to plasmin
we use streptokinase druh to enhance the breakdown of clots. activates plasminogen to become plasmin to break down our fibrin clots, as plasmin breaks down fibrin to FDP .
streptokinase is clot buster
alpha 2 antiplasmin can also act on plasmin in the fibrinolytic pathway

Question 7

overall haemostatic response - overview

Answer 7

vascular integrity 
platelets 
blood coagulation 
fibrinolysis 
inhibitory mechanism 
there is lots of feedback and integration between the different mechanisms

Question 8

from injury

Answer 8

• tissue factor leads to blood coagulation to fibrin to stable haemostatic plug
• platelet adhesion leads to platelet aggregation which leads to primary haemostatic plug which leads to stable haemostatic plug
• vascoconstiction dueto platelet adhesion, leads to platelet aggregation anf formation of primary haemostatic plug???

Question 9

bleeding time

Answer 9

abnormal platelet function
low platelet count
normal 3-8 minutes using ivy template
- make a small incision on forearm in controlled environment
look at how long it takes for that to stop bleeding
if bleeding time is extended we either have abnormal platelet function or low platelet count

Question 10

prothrombin time (PT)

Answer 10

look back at pathways from last year
take tissue factor extract and mimic whats happening in the body. take a blood sample and add plasma containing clotting factors to tissue factor and add calcium and see how long it takes for that tissue to clot
-measure factors VII< X, V, prothrombin and fibrinogen
-normal prothrombin time is 10-14 seconds
-prolonged in liver disease, oral anticoagulant treatment (OAT) eg warfarin
-PT standardised as International Normalised Ratio INR used to monitor OAT eg warfarin
PT standardised as International Normalised Ratio INR, used to monitor OAT

Question 11

activated partial thromboplastin time (APTT)

Answer 11

measures factors VIII, IX, XI and XII but also X, V, prothrombin and fibrinogen

• normally 3 - 40 seconds
• prolonged in haemophilia, heparin therapy

Question 12

pathways

Answer 12

extrinsic system VII prothrombin time (PT),
intrinsic system XII, XI< IX, VIII advanced portal thromboplastin time APTT
both systems have factor X, V, II, fibrinogen clot
if both PT and APTT are prolonged we look at factors in the middle

Question 13

oral anticoagulants

Answer 13

act at different sites in the coagulation process for their anticoagulant effects
see slide 44

Question 14

vitamin K

Answer 14

carboxylation of vitamin K dependent proteins requires the reduced form of vitamin K , γ-glutamyl carboxylase enzyme, molecular oxygen, and carbon dioxide. Because body stores of vitamin K are low, the oxidized (inactive) form of vitamin K is recycled to the reduced (active) form by vitamin K epoxide reductase, which is inhibited by warfarin. Inhibition results in reduced hepatic synthesis of these clotting factors and reduction in their activities by 40%–50%.

Question 15

warfarin on vitamin K

Answer 15

warfarin affects th way vitamin K works, needs to act on vitamin K and prevents the vitamin K cycle, prevents the production of fully functional proteins
acts upon vitamin K process necessary for the production of fully functioning coagulation processes

Question 16

anticoagulant drugs : warfarin

Answer 16

oral anticoagulant
vitamin K antagonist - warfarin decreases vitamin K dependent Factor II, V, VII, IX and X (but to different degrees)
-monitored using INR (patient PT/mean PT, raise value to power of international sensitivity index)
INR therapeutic range 2-4, 2-3 with most conditions but 2.5-3.5 or 4 with mechanical heart valves (country dependent)
various food/drugs affect INR eg antibiotics (may ne important for some of your patients)
prescribed for eg atrial fibrillation, deep vein thrombosis, heart valv replacements

Question 17

anticoagulant drugs: heparin

Answer 17

increases the action of antithrombin (III) on thrombin and Fxa
acts immediately
low molecular weight heparin:
-high bioavailability (95%), self administered (not orally) s.c
indicated in pregnancy instead of warfarin as heparin doesn’t cross the placenta , warfarin is tetragenic
prevention - various hospital surgical procedures

Question 18

new antithrombic drugs targets (some in development)

Answer 18

theoretically any clotting factor in the enzyme cascade could be targeted
only thrombin and FXa are common toboth pathways? more effective anticoagulation targets

Question 19

FXa inhibitors

Answer 19

FXa shown to activate clotting over wider concentration than thrombin in model systems
eg rivaroxaban (Xarelto)
-NICE approval UK for growing number of conditions eg prevention of adverse outcome in patients with acute coronary sydrome

Question 20

thrombin inhibitors

Answer 20

thrombin - final effector of blood coagulation and most potent platelet agonist
direct thrombin inhibitors:
dabigatran
-only ORAL direct thrombin inhibitor
-approved for recurrent DVT
ximelagatran
-1st oral direct thrombin inhibitor
-investigated extensively a replacement for warfarin, oral. no monitoring
withdrew for marketing after reports of liver damage

Question 21

DOACs

Answer 21

direct acting oral anticoagulants, NICE guidelines
thrombin inhibitor ?
don’t need monitoring but theyre expensive

Question 22

antiplatelet agents

Answer 22

affects platelets and want to minimise bleeding
aspirin COX inhibitor
clopidogrel (ADP receptor inhibitor)
ticlopidine (ADP receptor inhibitor)
may be used in conjunction with oral anticoagulants ? effect on bleeding

Question 23

aspirin (antiplatelet)

Answer 23

one of the most widely used medicines
-irreversible inactivation of the COX enzyme (required for prostaglandin and thromboxane synthesis)
-inhibits production of thromboxane A2, which is necessary for platelet aggregation
-used long term at low dose, to prevent heart attacks, strokes and blood clots in high risk individuals
low does of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue

Question 24

ticlopidine (antiplatelet(

Answer 24

ADP receptor inhibitor
used in patients who cant tolerate aspirin and inhibits platelet aggregation
- indications(for): patients with a high risk of stroke
side effects eg known to increase neutropenia

Question 25

clopidogrel(antiplatelet)

Answer 25

drug of choice of ticlopidine
action may be related to ADP receptor on platelet membrane
indications (for)
- prevention of vascular ischemic events in patients with symptomatic atherosclerosis
- myocardial infarction
-also along with aspirin for the prevention of thrombosis after placement of intracoronary stent

Question 26

haemostasis overview

Answer 26

Vasoconstriction: blood vessels
Platelet Adhesion/ Secretion/Aggregation
Platelet plug
Blood Coagulation: initiation, amplification and propagation
Stable Fibrin clot
Inhibitors and Fibrinolysis
Lab tests / Anticoagulant drugs