Week 11 Flashcards
What is antithrombotic therapy used for
-suppress coagulation and reduce thrombin formation
-platelet activation is suppresed my anti platelet drugs
-fibrinolytics reduce existing clots that are clogging vens and arteries
the anticoags and anti platelets are preventative and used before the clotting happens
-fibrinolytics are used after clot formation
What is used to prevent thrombosis
anticoagulants and antiplatelets
What is used if open vessel is totally occluded
thrombolysis
coronary angioplasty
What is used for vasodilation
nitrates (similar to nitric oxide which is released by endothelial cells)
CCB- calcium channel blockers (blocks Ca entry into muscle cells of arteries reducing muscle contraction , more effective than nitrates but since Ca is also used by the heart you need to monitor closely when youre on this therapy)
what are the objectives of anticoagulants
-reduce morbidity
-prevents existing thrombi from getting larger
-stops the formation of new thrombi and keeps them localized
How do anticoagulants vary
mode of action
-specificity of use
-time to be effective
-how they are administered
-half life
-method of measurement
-reverse effects in the event of an overdose
what are the mode of actions of anticoagulants
deficiency of active clotting factors
-indirect inhibitors of factors
-direct inhibitors of factors
What is the most common side effect of anticoagulant therapy
uncontrolled bleeding
-fatal bleeding influenced by dose, patient, condition and age
-all anticoags should have a reversal mechanism
how do you decide which anticoagulants to use
short term vs long term
lower the risk or preventing thrombus formation
what conditions is the patient at risk for
What are the Direct Oral Anticoagulants DOAC:
Dabigatran-Direct thrombin Inhibitor
Apixaban, Rivaroxaban, Edoxaban-Direct Factor Xa Inhibitors
-Do not need antithrombin to inhibit thrombin
Direct Action by:
Prevent conversion of fibrinogen to fibrin
Or prevent activation of thrombin
When is heparin used
in hospital /surgery
bridging to Coumadin or DOACs
immediate effect
IV administration
-look at APTT when monitoring
-to check for specific Hep concentration look at FXa assay
-has a reversal protocol
-therapy for DVT, PR, and MI
targets FXa and FII
along with LMWH and fondaparinux
When are Coumadin or DOAC used
long term use at home depending on condition
-oral administration
DOACs dont need monitoring but it does effect lab tests so you need to see if they are in the pt system . they are antagonist to Thrombin or FX. Reversal protocol are just coming out
What does coumadin do
listen to lecture for this
prevents post VTE rethrombosis, recurrence of DVT
prevents ischemic stroke
targets all Vit K dependent factors
-monitor with PT/INR PTT and Xa assay
-has a reversal protocol
-known as Warfarin
Oral vitamin K antagonist
What does aspirin do
prevents acute coronary syndrome recurrence
antiplatelet inhibitor
What does rivoraxaban /Apixaban do
prevents ischemic stroke
prevents thrombosis after surgery
Oral direct anti Xa
What does dabigatran do
prevents ischemic stroke
targets thrombin FII
What is the mode of action of Coumadin
-Vitamin K antagonist
-suppresses Vitamin K reductase activity
-prevents factor carboxylation
-Vitamin K dependent factors are FII, FVII, FIX, FX and factors C & S
how was coumadin discovered
moldy sweet clover
when cows died after eating them
also used a rat poison but in different dose and form
why do we need to monitor Coumadin
listen for graph explanation
Factor FVII - vitamin K dependent factor has the shortest half life = PT monitoring we will see it prolonged upon administration (PT done 24 hours after starting therapy and checked daily until target is reached then every 4 weeks until therapy is done - 6 months)
PTT will also be prolonged eventually but its half life isnt as sensitive to dose changes like PT and FVII so its not used for coumadin therapy
Protein C has the same half life and helps to regulate coagulation during the first 3 days the pt can be at thrombotic risk if deficient so you need use Heparin to help bridge the crossover until coumadin takes effect
FII and FX have highest; 2 is highest
monitor with PT/INR
how to calculate INR
-looks at Variation in thromboplastin reagents and different instrumentation
INR (pt PT/mean of PT range) ^ISI
What is ISI
International Sensitivity Index »_space; Indicates how sensitive the reagent is to deficiencies in Vit K factors compared to the WHO reference standard reagent
We want it to be as close to 1.0 as we can
What are the side effects of coumadin therapy
affects inflammatory risk
Clotting / Hemorrhage risk
INR < 2 – still risk of Thrombosis
INR 3 – 5: no significant bleeding
INR 5 – 9: high risk for bleeding (surgery)
> 9: serious bleeding
Urticaria- skin lesions, hives
Alopecia- hair loss
Skin necrosis (initial deficiency in Protein C- bridge with heparin and wait until coumadin takes effect)
What are the pitfalls in courmadin therapy
-diet must be high in VitK (reduces INR)
monitoring must be regular
drug interference
Coumadin is metabolized with Cytochrome C50 pathway in liver so any drug who also uses this pathway can affect coumadin - metronidazole affects INR
polymorphism of enzymes
one type slows coumadin breakdown
one slows Vit K reduction making pt more sensitive to coumadin
can POCT be used as the only monitoring method
no because it doesnt always match the plasma tests
-pts should not adjust dose only DRs
-can be used to establish a trend , if there is deviation then the DR can order plasma test
why do we need to reverse the coumadin
if INR is too high - bleeding risk especially if going into surgery
takes time for carboxylation factors to be produced and then activate the Vit K dependent factors
What is the non urgent method of coumadin reversal
Just to reduce INR
-not alot of bleeding
INR 3-5= stop taking coumadin and monitor
INR >5 stop taking coumadin and get Vit K orally or through injections - monitoring
What is the urgent method of coumadin reversal
Urgent – Significant bleeding or emergency surgery required
– Stop taking coumadin and give IV Vit K + PCC
– Prothrombin Complex Concentrate is blood containing Vit K dependent factors (FII, FVII, FIX, FX) and control proteins (Protein C and Protein S)
– Note: If PCC not available, use fresh frozen plasma (also contains missing factors)
What is the mode of action for Heparin
binds -activates antithrombin to neutralize serine proteases activated by thrombin - changes the structure of antithrombin
-given intravenously - half life is 1-2H
-Dr/LAB determines therapeutic levels
antithrombin inactivates
F IIa, IXa, Xa, XIa & XIIa
What are the two types of heparin therapy
- Traditional or Unfractionated
Long molecule with variable number of chains - Low Molecular Weight (LMWH)
Shorter molecule with predetermined molecular weight
What is unfractionated heparin
UFH acts as an anticoagulant by forming a complex with antithrombin (AT)
-catalyzes the inhibition of thrombin (factor IIa), factor IXa, Xa, XIa and XIIa
-UFH + AT complex prevents fibrin formation and inhibits activation of PLTs and FV, FVIII, and FXI
What does LWWH do
- derived from UFH
-reduced inhibitory activity against FII but the same inhibitory activity on FX relative to UFH
-more predictable pharmacokinetic properties vs UFH so they can be given in fixed doses without the need for constant monitoring
How is UFH therapy monitored
by APTT but before the therapy you need a APTT baseline to make sure its not already prolonged (indication of factor deficiency, LAC)
-overdose of Hep can prolong APTT
-APTT monitored every 6 hours until dose is adjusted then every 24 hours
-PLT needs to be monitored - risk of HIT
-therapy wont work if pt has AT deficiency (heparin needs AT to work)
What is the mode of action of UFH
1)AT binds UFH, causing a conformational change in AT to activate it
2). Because UFH is long, Thrombin (FII) can also bind to UFH
3). Bridging between AT and Thrombin enhances the reaction.
4). AT-Thrombin complex will be released. This is inactive and UFH is recycled
how can UFH be reversed
protamine sulfate is catatonic and a heparin antidote
removed by the reticuloendothelial sytem
What are some therapeutic uses of UFH
-prevention of thrombosis in high risk patients
pregnancy
-limit progression thrombosis DIC
-keep IV lines open / renal dialysis
-cardiac bypass surgery / unstable angina
-Used to treat thromboembolic disease
What are some side effects of UFh
Bleeding
mild platelet dysfunction (thrombin usually activates PLTs)
Thrombocytopenia -HIT
Osteoporosis common with long-term use
Heterogeneous mixture (varies in length) therefore dosing problematic
What is LWMH
-Produced by enzymatic fractionation of UFH
-minimal effect on thrombin activity because its too short to bind FII so it binds to FX for inactivation
-given SUBCUTANEOUSLY with half life of 3-5 h
What are some differences in how LMWH act and UFH act
LMWH - has short chains
UFH - has long chains
any chain size can bind to AT and inhibit FX
but inorder to inhibit FII, the heparin molecule needs to be long enough to bind BOTH AT and Thrombin
What are the advantages of LMWH
- just as effective as UFH
-easy to adminster subcutaneous dose 1/2 a day , pts can do themselves
-easy to monitor with heparin assay (FX assay)
-safer then standard heparin because there is less risk of HIT, bleeding and inhibition of PLTs. So thrombin is still available to activate PLTs
What advanatages does LWMH have OVER ufh
-decreased heparin resistance. UFH tends to bind to non specific heparin binding proteins which leaves less heparin to activate AT but LWMH has decreased binding to those proteins
how do you monitor LWMH
not necessary in most pts- cleared by kidneys
can be useful in
renal insufficiency (creatinine >2.0 mg/dl)
obese patients with altered drug pK
major bleeding risk factors
aPTT monitoring is not useful because we would just see a prolonged APTT - no bridging so its not sensitive enough
-anti-factor Xa chromogenic assay is more appropriate but not really used
How does Monitoring (F Xa Assay) for LWMH activity work
chromogenic assay to detect LMWH
Reagent is AT & excess Xa
If LMWH is present, Hep-AT-Xa complex forms
Free Xa (that didn’t complex) + substrate = colour end products
∴ > free Xa = > the colour = < Heparin
Colour intensity of the product is INVERSELY proportional to the LMWH plasma levels
What is fondaparinux - Arixtra
synthetic drug - made of the antithrombin region of heparin
-indirect antithrombin anticoagulant - inactivates Xa by combining with AT
-subcutaneous administration
-doesnt need to be lab monitored just do a Fx assay if you do need to
-No antidote - protamine will not work
What is HIT
heparin induced thrombocytopenia
-people who are on heparin therapy can develop IgG AB to heparin platelet factor 4
-the ABs will bind to the complex on PLT surfaces which will cause a decrease in PLT count
-this leads to thrombosis because the PLT have been inactivated by the immune complex
-UFH best because it binds PLT factor 4
-thrombocytopenia is not a significant risk but complications can arise venous vs arterial thrombosis
-medical emergency - stop heparin
DUAL ACTION
What are the consequences of HIT
40% PLT decrease in 5 days = thrombocytopenia
-thrombin increases = thrombosis
-discontinue treatment
-dont use LMWH because there is cross reactivity to HIT ABs
use
Argatroban
Bivalirudin
Lepirudin
Hirudin
How does Dabigatran (Pradaxa) work
-give orally
direct thrombin inhibitor
-doenst need routine monitoring
-reduces coagulation AND fibrinolysis by binding free and clot bound thrombin
-APTT/PT can be affected but it wont be because of the drug
-Normal TT would exclude presence of Dabigatran
-Acts quick 1-3 hours can be used instead of heparin to start therapy- good bridging drug
-used for thrombosis in pts with Atrial fibrillation, Venous Thromboembolism
-not affected be diet
-can use fixed dosing
-metabolism can be affected by renal or liver disease because Dabigatran needs to be activated by digestive enzymes made there
-contradiction if PT have CrCl of <30mL/min
-to reverse use Idarucizumab (Praxbind®) - likes this better then thrombin
What the Direct Thrombin Inhibitors that are given intravenously
Argatroban
Bivalirudin
Lepirudin
All used to treat HIT
Biva and Lepi are based on hirudin which are found in leeches. Hirudin is a Potent Direct Thrombin Inhibitor
how do we monitor Hirudin
PTT prolonged
use Ecarin Clotting time
-Ecarin is from viper venom
-converts prothrombin to meizothrombin (converts fibrinogen to fibrin)
-all direct thrombin inhibitors bind meizo and generate linear dose dependent prolongation of ECT
What are the Direct F Xa Inhibitors
Apixaban (Eliquis)
Riveroxaban (Xaralto)
Edoxaban (Lixiana)
oral administration
dont need AT
synthetic
better than LWMH and Warfarin
doesnt need monitoring or dose adjustments
-2 pills daily half life of 5-11 hours
Used for prevention of:
Thrombosis in non-valvular atrial fibrillation
Venous thromboembolism
Treat HIT
what are the disadvantages of Direct F Xa Inhibitors
-no antidote yet and dialysis doesnt work
-contradiction if you have renal insuffiencies because its cleared by the kidneys
-metabolism is also affected by renal/liver disease because it needs liver cytochromes for activation
-PT/APTT/FXa assays are affected
-a standardized assay is needed for each drug
What is Andexanet Alfa (AnnexXA):
Trial Antidote -Universal Factor Xa inhibitor antidote
-Recombinant, human Factor Xa acts as a decoy and neturalizes Factor Xa inhibitors and
LMWH
-given as bolus after a 2 hour infusion
how can DOAC Affect on Lab Testing
-can affect Lupus Anticoagulant by falsely prolonging tests like dRVVT and giving false positive LAC
-are able to cause inhibitor like effect to factor assays which give them a false decrease in factor concentration
What are some Alternative Anticoagulant
Therapies
-Vasodilators
-Platelet Inhibitors-ASA (acetylsalicylic acid)
-Plasminogen activators
-(Fibrinolytic Agents:) Tissue Plasminogen
Activator (tPA), Streptokinase ,Urokinase
Direct Thrombin Inhibitor (DTI)- Hirudin
Defibrinogenating agent - Ancrod
What is ASPIRIN (Acetylsalicylic Acid): used for
Inhibition of Thromboxane A2
used for prevent of heart disease because it is a platelet inhibitor
-stops plts from aggregating when are about to form plaques to cause arterial thrombosis
-not monitored
how does ASPIRIN (Acetylsalicylic Acid work
- acetylates a platelet enzyme that produces thromboxane A2 (plt agnoist)
-stops access to arachidonic acid (plt agonist) to prevent production of A2
-acetylation is irreversible so this A2 production is shut down for the life of the platelet
how do we monitor platelet inhibitors
GOLD standard is platelet aggregation studies using arachidonic acid (AA) as the agonist
-so if PT is on aspirin and AA is added the platelets should not be able to clump- NO LIGHT TRANSMITTANCE CHANGE
PFA 100 system
2 cartridges - 1 with collagen and epinephrine while the 2nd has collagen and ADP both have apertures
-whole blood will go through the aperture and the time it takes to close the aperture by platelet formation will be measured
-if the pt is on aspirin then the time is prolonged
When is THROMBOLYTIC THERAPY used
in MI and stroke because it lyses coronary thrombi and is able to reduce mortality
-lyses hemostatic plugs increasing bleeding incidence, lowering plasma Fibrinogen which causes plasmin to break down plasminogen which causes a high rate of re occlusion
-not done in outpatient
What is Tissue Plasminogen Activator
(tPA)
-made by endothelial cells - recomb
-activates fibrin bound plasminogen to plasmin which breaks fibrin in clot
-clot buster
-limited to site of thrombus
how is Streptokinase used in thrombolytic therapy
Bacterial protein (endotoxin)
Produced by of β -hemolytic streptococci
Not used anymore bc:
Often triggers DIC
highly antigenic **
when used therapeutically can induce immune response
can cause bleeding complications
how is urokinase used in thrombolytic therapy
Made in the kidney in small amounts
Purified from urine initially
Recombinant form now available
can cause bleeding complications
