anti coagulants Flashcards
what is a haemostatic plug formed from
aggregated platelets within a fibrin mesh
how does body respond to ruptured blood vessels
vasoconstriction + formation of haemostatic plug
what does thrombomodulin do
thromobomodulin on endothelial cells reversibly binds thrombin
when bound thrombin no longer activates fibrin formation, however it does activate protein C
protein C inhibits coagulation factors 5a and 7a and stimulates fibrinolysis
what factors prevent spontaneous coagulation
thrombomodulin, antithrombin 3 and heparin cofactor 2
what does antithrombin 2
an alpha 2 globulin
neutralises serine proteases: factors: 2a, 9a, 10a, 11a and 12a
what does heparin cofactor 2 do
inhibits factor 2a (thrombin)
what are the 2 pathways of the blood coagulation cascade and how are they caused
intrinsic pathway: surface contact
extrinsic pathway: tissue damage, may also be activated by factor 12a
describe intrinsic pathway of blood coagulation cascade
surface contact causes factor 12 to convert to 12a
12 a causes factor 11 to go to 11a
11a causes factor 9 to go to 9a
9a converts 8 to 8a and platelet factor 3
9a also converts 10 to 10a
10a converts 2 to 2a
2a converts 13 to 13a which along with calcium converts fibrin to inslouble fibrin
2a also converts fibrinogen into fibrin
2 a also acts on platelets
how does extrinsic pathway of blood coagulation cascade happen
tissue damage leads to formation of tissue factor
tissue factor along with 7a causes 10 to convert to 10 a which then follows intrinsic pathway
tissue damage also gives rise to platelet factor 3 (platelets also give rise to platelet factor 3)
what are targets of drugs of haemostasis
fibrin formation, platelet adhesion and activation and fibrin removal/fibrinolysis
what agents promote blood coagulation
vitamin k; acts as cofactor for the g-carboxylation of glutamic acid residues on N terminals of precursor glycoproteins, this process yields zymogens (inactive precursors of active factors), zymogens: factors 2,7,9 and 10
vitamin k difficiency is normally acquired through liver disease or excessive use of oral anticoagulants
factor 8 is used for treatment of type A haemophilia
factor 9 is used for treatment of type B haemophillia
which agents decrease blood coagulation
injectable anticoagulants : heparin
oral anticoagulants: warfarin
direct thrombin inhibitors: dabigatran
where is heparin found endogenously
in mast cells and plasma
what does heparin do
inactivates thrombin (factor 2a) and factors 9a-12a
anticoagulant effect due to pentasaccharide sequence that promotes action of antithrombin 3
it does this by combining with antithrombin 3 and accelerates its action
antithrombin 3 is physiological inhibitor of these factors
high molecular weight comes from bovine sources, not commonly used
low molecular weight is depolymersied and is synthetic
what happens with prolonged use of heparin
prolonged use can deplete stores of antithrombin 3 and diminish effects of heparin
how is heparin administered, how long is it active
it is not active orally, given via IV injection
active for 2-4 hours
when is heparin given
low dose is given subcutaneously peri-operatively to reduce risk of deep venous thrombosis and pulmonary embolism
how is dose of heparin calculated
since it binds plasma proteins; determined by bioassay and biological standardisation; dose is controlled by measuring partial thromboplastin time
what are other injectable anticoagulants that do not involve antithrombin 3
thrombin inhibitors: such as lepirudin, useful for patients who develop immune response to heparin
ancrod: acts on fibrinogen to produce unstable fibrin fibrils leading to depletion of fibrinogen
how does warfarin act
interferes with reduction of viatmin K, prevents vitamin K from acting as cofactor in gamma carboxylation of glutamate residues at N terminal ends of factors 2,7,9 and 10
if these residues are not carboxylated they are non functional and so inactive
what is adverse affect of warfarin
excessive bleeding, counteracted with increasing vitamin k intake but it takes some time to produce active factors
describe warfarin pharmacokinetics
administered orally, half life is 40 hours, drug is only effective when existing pool of factors is depleted which takes 12-16 hours
maximum effect at 36-48 hours
duration of action is 4-5 days
rate of exhaustion of active coagulation factors is increased when metabolic is increased
dose does not need to be monitored continuously
what benefits do direct thrombin inhibitors have
actions are more predictable than warfarin
easier to use because actions are more predictable so lab monitoring is not necessary
reacts with less other drugs than warfarind
however does not seem to have better protective efficacy (e.g against strokes) than warfarin
what are drug interactions with oral anticoagulants (warfarin)
response of oral anticoagulants is decreased by:
prior administration of drugs which cause induction of liver microsomal e.g barbiturates
oral contraceptives
response to oral anticoagulatns is increased by:
drugs which displace plasma protein binding of the anticoagulant e.g aspirin
agents which impair platelet aggregation e.g aspirin
what is thrombosis
pathological formation of haemostatic plug, factors that contribute to likelihood are ;
injury to vessel wall, altered blood flow, altered coagulability of blood
what are white clots
aggregated platelets
what causes platelet activation and what causes platelet aggregation
platelets are either activated by thrombin or adhesion to thrombogenic surface
platelet activation:
arachidonic acid generation leads to cyclic endoperoxidase which causes synthesis of TXA2
TXA2 causes expression of glycoprotein 1ib/3a receptors which leads to platelet linkage by fibrinogen binding to glycoprotein receptors
what are the most commonly used drugs in atherosclerotic disease
aspirin: irreversible COX2 inhibitor
ADP (P2Y12) inhibitors: clopidogrel
in acute coronary syndrome low molecular weight heparins are used
what is the fibrinolytic cascade
initiated by coagulation cascade
results in formation of plasmin from plasminogen which digests fibrin by tissue plasminogen activators such as streptokinase
drugs may work to promote formation of plasmin
what is a red clot
the fibrin mesh
