anticoagulation therapeutics Flashcards
major steps in haemostasis
vascular spasm
formation of platelet plug - platelet adhesion to damaged collagen
conversion to a clot by reinforcement with fibrin
tissue repair
ADP
serotonin
TxA2
sticky platelets
vasoconstrictor
vasoC and activates
why doesn’t the platelet plug spread along the vessel
prostacyclin - from intact endothelium inhibits platelet adhesion and aggregation
NO - from intact endothelium inhibits platelet adhesion
liver role in clotting
bile salts in bile cause gi tract to absorb vitK
fibrinolytic
fibrinolytic drug, also called thrombolytic drug, any agent that is capable of stimulating the dissolution of a blood clot (thrombus). Fibrinolytic drugs work by activating the so-called fibrinolytic pathway.
clot busters
Eminase (anistreplase)
Retavase (reteplase)
Streptase (streptokinase, kabikinase)
t-PA (class of drugs that includes Activase)
Background. Heavy menstrual bleeding (HMB) is an important physical and social problem for women. Oral treatment for HMB includes antifibrinolytic drugs which are designed to reduce bleeding how
which are designed to reduce bleeding by inhibiting clot‐dissolving enzymes in the endometrium.
what is an anticoagulant
Drug that interrupts the process involved in the formation of blood clots
called blood thinner
anticoagulants are different to antiplatelet medicines, such as aspirin and clopidogrel.
because They act on components of the clotting cascade!
how do antiplatlets work
reduce the ability of the platelets to stick together and reduces the risk of clots forming
4 ways we can quantify clotting capability
measure platlets
calculate INR ( standardised)
measure prothrombin time
measure ATPR
Platelet count = maximal strength of clot and time to stop bleeding reflected by this
prothrombin time
time to initiate coagulation (evaluates intrinsic pathway)
ATPR
measures effectiveness of reinforcing the clot (evaluates contact pathway)
what is the INR
what should your value be if taking a blood thinner
INR = Ratio of patient’s Prothrombin time to the normal population
between 2-3
prothrombin is made where
liver
precusor for thrombin
do warfarin and heparin need measuring with blood tests
yes
4 types of DOACs
rivaroxaban (Xarelto)
dabigatran (Pradaxa)
apixaban (Eliquis)
edoxaban (Lixiana)
which anticoagulant is a pentasaccharide
how does heparin work - what factors and what does it activate
heparin - encourages body natural clot lysis to break down clots that have formed acting of 10a and 2a preventing fibrin clot formation by activating antithrombin h=which is the bodys natural anticlht protein
heparin essentially brings antithrombin and factor 10 close together to speed up the reaction
difference between unfractioned and LMWH
LMWH enoxaparin binds less avidly to plasma proteins and therefore has increased bioavailability and duration of action - lower risk of osteoporosis and lower risk of HIT
when is unfractioned heparin preferred
in patients with renal impairment
LMWH stable in all types of general and orthopaedic surgery
what is fondarparinux more similar to
LMWH
what factors does heparin act on
factor 10a and 2a( thrombin)
what factor converts prothrombin to thrombin
fact 10a
what is the bodies natural anticoagulant
does heparin speed up or slow this process
what is the special role of unfracitonated heparin
antithrombin - bind to factor 10a and inhibits it.
heparin speeds up this process
unfractioned binds to antithrombin causing antithrombin to bind to both 10a and 2a means it can stop clotting in 2 places - forms a ternary complex
the other forms cannot to this
unfractionated
IV infusion Effective immediately Short half life Most likely to cause HIT APTR monitored
LMWH/fondaparinux
SC injection Effective after 1 hour Longer half life – renally excreted HIT even rarer with LMWH Doesn’t require monitoring
you can use heparin
DVT PE Acute MI VTE prophylaxis During Haemodialysis During open heart surgery (Safe to use in pregnancy)
what are contraindications and complication s
Haemorrhagic disorders Thrombocytopaenia Severe HTN Surgery / lumbar puncture Trauma Spinal or epidural anaethesia (for treatment dose) Acute bacterial endocarditis
Heparin-induced thrombocytopenia (HIT) -> autoimmune attack on platelets resulting in degradation ~ reversed on discontinuation. Counter-intuitively causes increased thrombotic events
Hypersensitivity reactions
Hyperkalaemia
how does warfarin work
acts on vit k and block 1972 and protein C and S
vitamin K is only active in it’s reduced form. Vitamin K reductase reduces Vitamin K which activates gamma-glutamyl carboxylase. Gamma glutamyl carboxylase then converts glutamic acid to Gamma-carboxy-glutamic acid which produces factor 2,7,9, 10 protein C+S.
warfarin binds to vit k reducatase enzyme in order to inactivate it
what enzyme does warfarin bind to
why do we give heparin at first too
vit k reducatase enzyme inactivating it
This means there is a decreased production in the reduced form (active form) of vitamin K. This leads to the deactivation of gamma glutamyl carboxylase which impairs the conversion of glutamic acid to gamma carboxy-glutamic acid and this suppresses the clotting factors 2, 7, 9, 10, and protein C + S.
Interestingly, 2,7,9,10 are clotting factors, but protein C + S are actually anticoagulant!! So this means initially warfarin can actually be pro-thrombotic because C+S are blocked. This is why when starting warfarin we often cover with heparin for a few days.
drugs that potentiate warfarin effects
metronidazole and co-trimazole- inhibit hepatic drug metabolism
aspirin - inhibit platelet function
cephalosporins - inhibit reduction of vit k
broad spectrum antibtiocis - dreads avaivbilty of vitamin k - gut bacteria contain it k
what drugs inhibit the effect of warfarin
rifampicin and carbamazepine - induce hepatic P450 enzymes
cholestyramine reduce warfarin absorption in the gut
when should we use warfarin
DVT
PE
AF in those at risk of embolisation
Mechanical prosthetic heart valves
Pregnancy/48hrs post partum Haemorrhagic/recent ischaemic stroke Severe renal/hepatic disease Peptic ulcer/GI bleed Severe Hypertension Recent surgery
Initially prothrombotic
Bleeding → increased risk due to interactions
Teratogenic- disordered bone development
Skin necrosis
target inr during anticoagulant therapy
when can it be allowed to be more
- 5 ( 2.0-3.0 )
- 5-3.5 - mechanical mitral heart valve
- 0.4.0 - anti phospholipid syndrome, recrurent DVT Nad or PE , first generation heart valves
81 year old male comes to you because he’s been experiencing palpitations.
You feel his pulse and he has an irregularly irregular heart rate
You explain that this can increase his risk of strokes so he will need something to ‘thin his blood’. What will you use?
won’t take warfarin either what do you give
DOAC
what do DOACs do
inhibit factor 10a - apixaban , rivaroxaban , edozaban - this is the propagation phase
in the fibrin formation phase dabigatran can inhibit factor 2a ( thrombin)
which DOac is the most bioavialbke
riavaroxaban
when should a DOAC be used
Same as warfarin
(but cannot use a DOAC if mechanical heart valve - warfarin only!!)
contraindications
Acute bleeding Coagulopathies Severe renal insufficiency Preg/breastfeeding Severe hypertension Endocarditis
complciatons
Dapbigatran- GI disturbance, diarrhoea, GI bleed risk Rivaroxaban- constipation, headaches Apixaban- lower risk of GI bleeds than others
which doac is most preferred and why
Apixaban = lowest bleeding profile so now preferred amongst physicians. dabigatran worse than warfarin! Originally didnt have reversal agents (unlike warfarin so often pts preferred warfarin) but now there are things for some of them, def for edoxaban.
what is a fibrinolytic drug
fibrinolytic drug, also called thrombolytic drug, any agent that is capable of stimulating the dissolution of a blood clot (thrombus)
most common fibrinolytic drug
altepase - recombinant tPA
how is d-dimer formed and what conditions can it detect
D-dimers are unique FSPs that are formed when cross-linked fibrin is lysed by plasmin
DVT PE Venous sinus thrombosis Aortic dissection Disseminated intravascular coagulation
antifibrinolytics example what does it do
tranezamic acid
Anti-fibrino-lytics means something that STOPS the breakdown of a clot. So the opposite of everything else we’ve been learning about. In this case, it STOPS plasminogen from converting to plasmin in order to STOP fibrinolysis (clot splitting).
what is dalteparin
- heparin –> anticoagulant
if your on an heparin infusion what range of ATPR should you have
1.5
low platelet called
thorombocytopenia
complication of taking heparin when platelets get low
HIT
