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VTE, 💡antithrombotics include antiplatelets, anticoagulants,…
VTE
1. VTE Basics
Virchow's Triad (3)
hyper coagulable state, endothelial injury, circulatory stasis
risk factors to getting a clot
abnormal blood vessels: disruption of a plaque, injury, change in tissue
abnormal blood flow: blood flows through veins at a low pressure, so there can be risk of it stopping completely (stasis) and forming a clot; caused by not moving around, HF, AF
abnormal blood: overactive clotting factors, high estrogen, cancer
Definition of VTE
DVT
clot in deep veins (legs, arms, cerebral)
PE
blockage of a lung artery by a clot that has traveled from somewhere else in the body like legs or pelvis
VTE: blood clot in the vein that may or may not embolize
Red vs White Clot (arterial vs venous)
white clot happens in arteries and is called "atherosclerotic", it is caused by platelets so it needs antiplatelet tx
presents as: ACS or atherosclerotic stroke
red clot happens in veins and is called "thrombus", it is caused by RBC being trapped within the walls due to fibrin; it needs anticoagulant for tx
presents as: VTE, or cardioembolic stroke
arteries vs veins
arteries have high flow and pressure and have thick walls; carry oxygenated blood
veins have low flow and pressure and have thinner walls; carry Deoxygenated blood
complications of VTE
DVT ➡️ PE, recurrence, post-clot syndrome, pain in limbs
PE ➡️ death, recurrence, pulmonary HTN, right ventricle failure
clotting cascade
thrombin (aka Clotting factor #2) is the last one involved, and it has the longest half life (takes 5-6 days to prevent clotting); clotting factor #7 has the shortest half life of 6 hours
when giving warfarin, we want coagulation factor to be 30-40%
4. Treatment Options
(antithrombotic agents)
warfarin
(stabilizes clot)
INR
standardized Prothrombin Time
measures how long it takes for blood to clot
higher number = takes longer to clot (higher risk of bleeding)
we want it to be between 2-3 for pts on warfarin (ie blood takes 2-3x longer to clot)
initiation/maintenance
initiation (3-4 weeks)
for the first 5 days, bc warfarin has a delayed effect before it kicks in, need to also be using a parenteral anticoagulant like LMWH until INR is at least 2.0 twice in a row
for the first month of therapy, if pt is at high risk of clotting, can use LMWH with warfarin
you're trying to see which dose best fits each pt specifically (can range from 0.5mg to 38mg a day); pt has to go 2-3x a week for INR testing
start with 5mg for 2 days, then test INR on day 3 and day 6 to see which adjustments need to be done
BUT REMEMBER: warfarin takes 5-6 days to actually kick in, so you might not need to make such a big dose adjustment just yet, because the full effects of warfarin may not have hit yet
take average of the doses given (eg. 5mg + 5mg + 2mg + 2mg / 4) to see which dose to change to
⚠️ might be on exam: if you start a pt on 5mg and their INR goes from 1.0 to 1.8 in just 2 days, you actually want to lower the dose bc if you keep them at 5mg for any longer, their INR will spike up past 3.0 and that can be dangerous. so you will reduce to 2mg then reassess INR 2 days later, and if the INR only went from 1.8-2.1, you can increase dose of warfarin to 3mg and reassess after another 4 days
maintenance (clotting factors are at steady state, and INR is stable)
trying to consistently achieve target INR for each specific pt
know that the response of warfarin is NOT linear, meaning if you double the dose, you will not see a doubling in the INR
it is common for pts to take different doses on different days (eg. pt takes 5mg on Monday, but 4mg on Tuesday)
if INR is too low ➡️ give up to 2x the daily dose, and consider increasing weekly dose
if INR is too high ➡️ hold warfarin that day and consider decreasing weekly dose
if INR is > 5 ➡️ hold warfarin for 1-2 doses, consider Vitamin K
if INR is > 10 ➡️ hold warfarin, give Vitamin K higher dose and reassess INR
if INR is stable, extend by 1 week intervals (max of 6 week intervals to go for testing)
mechanism
works on clotting factors produced by the liver, not found in circulation like the DOACs do, which is why it acts slowly; bc clotting factor #2 has such a long half life, warfarin takes a long time to kick in, bc it is dependant on that clotting factor
inhibits recycling of Vitamin K from oxidized to reduced; half lives of clotting factors are more important than half life of warfarin in this case
proteins C and S are the body's natural anticoagulants; but they have a shorter half life than clotting factor #2 (thrombin), so when we initiate warfarin which relies on thrombin (long half live, remember), we are getting rid of proteins C and S BEFORE warfarin can actually kick in, therefore inducing a hyper-clotting state at the beginning of therapy
indirectly impacts clotting factors; delayed
thrombolytics
role in
massive
PE
injectable anticoagulants
(stabilize clot)
UFH (unfractioned heparin)
acts on 10a and 2a; it is larger than LMWH and has a longer chain
given IV; short half life; unpredictable bioavailability;
NEEDS MONITORING
of aPTT or anti-10a; given bolus, then IV infusion
Fondaparinux
very long half life; same as LMWH for the rest of the stuff
7.5mg q24h if pt weighs 50-100kg
LMWH (low molecular weight heparins)
enoxaparin 1mg/kg q12H, dalteparin 100 units/kg q12h, tinzaparin 175 units/kg q24h
act on clotting factor 10a
SC; peak at 2-3 hours; short half life; similar duration in body as DOACs; predictable dosing;
renally eliminated
; dosing is based on weight;
c/I: CrCl <30
act quickly, but indirectly as they need a cofactor
they act on clotting factors in the circulation, but need antithrombin to bind to before they can enact their effects, therefore they are not directly acting
antidotes
Andexanet Alfa
for the rest of the DOACs; acts on Factor 10a; used to reverse major bleeding (but then causes risk of clotting)
Vitamin K
warfarin antidote; only oral or IV
idarucizumab (dabigatran antidote)
Direct Oral Anticoagulants (DOACs)
(stabilize clot)
rivaroxaban
most bioavailable; d/I with 3A4 AND P-gp; high doses taken with food; acts on #10
tx of acute VTE: 15mg BID F3W, then 20mg qd;
3M-lifelong
(10mg is fine too, instead of 20)
prophylaxis of VTE post surgery
: 10mg qd (without food)
stroke/MI prevention: 2.5mg BID with ASA
edoxaban
acts on #10; half of it is renally cleared; shortest onset of action
tx of acute VTE: first give injection anticoagulant for 5-10 days, then switch to edoxaban 60mg qd if CrCl >50 (adjust dose based on kidney function, weight,
any d/I with P-gp
);
for 3M-lifelong
apixaban
least renally cleared; d/I with 3A4 AND P-gp; acts on clotting factor #10
tx of acute VTE: 10mg BID F7D, then 5mg BID;
3M-lifelong
(can taper to 2.5mg BID)
dabigatran (more fyi tbh)
not really used a lot because it's mainly renally eliminated and is only 6% bioavailable. has the longest half life too. only DOAC that acts on clotting factor #2
indications and dosing
tx of VTE: injection anticoagulant for 5-10 days then switch to dabigatran 150mg BID or 110mg BID if pt is old;
3 months or lifelong
A-Fib 150mg BID or 110mg BID if you're old
; for life
act directly on clotting factors quickly
to tx acute VTE, and that is what we want (warfarin acts too slowly and indirectly)
antiplatelets
(stabilize clot)
ASA, ticlopidine, clopidogrel, dipyridamole, prasugrel, ticagrelor
ASA decreases recurrent VTE by 33% (DOACs decrease by 80%, so they're preferred over ASA)
fibrinolytics
(break down the clot)
streptokinase, alteplase, tenecteplase, reteplase
7. Monitoring and Management
Anti-Xa levels for LMWH
used for DOACs (minus dabigatran) to measure anticoagulant effect
HIT (Type I vs II)
type 1
"heparin induced thrombocytopenia"; non-immune mediated, happens early on then goes away
type 2
immunologic response; severe reaction that happens later on (days 5-14); requires limb amputation in severe cases; platelet count falls 40-50% from baseline;
monitor for clotting, skin necrosis, systemic reactions and presence of HIT antibodies
immediately stop the LMWH, use vitamin K if warfarin is currently being used, initiate an alternative like a DOAC or fondaparinux; send pt to ER
monitoring DOACs (when needed)
no routine monitoring; just annual CBC and SCr (sooner if pt has renal impairment)
no target ranges for DOACs; perform DOAC level testing if there's bleeding/clotting event or a drug interaction that cannot be avoided
INR for warfarin
quick test that gives results right away; not good for DOACs
factors impacting INR
changes to medications (especially ones that impact 2C9)
changes to lifestyle, like Vitamin K intake, alcohol consumption and changes to exercise routine
changes to health
acute changes like fever, flu, major diarrhea makes INR go up
chronic changes, like heart failure or hypothyroidism (need more warfarin)
duration and follow-up strategies
make sure pt gets up and is active again after starting anticoagulant therapy; we don't want them to stay sitting
for DVT: monitor leg swelling, color, pain, tenderness
for PE: monitor stabbing pain, SOB, right heart pressure, activity limitations
acute VTE: 3-6 months of anticoagulants if pt has no c/I
then reassess if they need secondary prevention
6. Special Populations and Contraindications
pregnancy and breastfeeding
warfarin is teratogenic
avoid DOACs
drug interactions (CYP 3A4, P-gp)
drugs that inhibit 3A4/P-gp (aka increase DOAC levels)
"-azoles" (AVOID USE, except fluconazole); ritonavir, cobicistat, dronedarone, glecaprevier/pibrentsivir
if pt has to take "Paxlovid" which contains Ritonavir, they should completely stop rivaroxaban and switch to another DOAC at a low dose;
^
if they are high clot risk, switch to LMWH for the course of the Paxlovid, until it is over
if they are low clot risk: hold DOAC, switch to ASA for the time being
^
clot within the past 6 months
inducers of 3A4/P-gp (aka decrease DOAC levels)
rifampin, carbamazepine, phenytoin, phenobarbital, SSRI/SNRI, St. John's Wort
SSRI/SNRI are ok to use because benefit outweighs harm of bleeding
renal/hepatic dysfunction
use UFH if CrCl <20, use tinzaparin if 20-30, use any LMWH if >30
avoid DOACs in severe
hepatic
impairment
avoid use of dabigatran if CrCl <30, apixaban if <25, riva and edoxa if <15
COVID + VTE risk
higher VTE rates during the pandemic in hospitalized pts in ICU (think, if someone is in bed all day, their blood stops moving and that puts you at risk of a clot)
cancer-associated thrombosis
extend therapy past 3 months
2. Clinical Presentation and Diagnosis
Signs and Sx of PE
SOB, hypoxemia, tachycardia, sudden cough, chest pain that worsens with breathing, tiredness, more vascular resistance in the lungs, fainting, confusion, unstable body
Severity Classifications of PE
sub-massive
no hypotension; right ventricle of the heart is starting to fail, high troponin and BNP
non-massive
stable, no need for hospital admission
massive
unstable, in shock; admitted to hospital
Signs and Symptoms of DVT
Distal DVT (legs)
anything below the knee, smaller veins, smaller clots; likely to get bigger and travel up the leg
superficial vein thrombosis (SVT)
can happen in the legs, but in the superficial veins, not deep ones, so risk of PE is low, and urgency is not that high
presents as red, warm, inflamed tender area
use anticoagulation
if they also have VTE or a 3cm clot next to the SFJ, to prevent PE
usually treated with pre NSAIDs or compression stockings
proximal DVT (legs)
majority of DVTs; anything above knee, larger veins, larger clots; more likely to travel up to lungs
pain, tenderness in area, swelling far from the clot, discolouration, joint pain, warm,
nonspecific sx/signs = we NEED testing to confirm DVT
diagnostic tools
D-dimer blood test
used for low-intermediate likelihood of the diagnosis being VTE
above threshold ➡️ do a compression US to confirm VTE
below threshold ➡️ not VTE ❌
Compression Ultrasonography
done right away if high likelihood of VTE, or if D-dimer was high; useful for PROXIMAL DVT
Wells Criteria (DVT and PE)
DVT
low = 0 ✅
intermediate = 1-2 ⚠️
high = 3+ 🚩
active cancer (1), paralysis (1), bedridden or has had surgery (1), local tenderness (1), entire leg swollen (1), calf swelling 3+cm (1), superficial veins (1)
PE
low = 1-2
intermediate = 2-6
high = 7+
hx of PE or DVT (1.5), HR >100 (1.5), recent surgery (1.5), clinical signs of DVT (3), cancer (1)
if intermediate or high, an OAC should be initiated while waiting for tests
V/Q, CT angiography
for PE diagnosis
CT angiography has risk of cancer bc of radiation so be careful when using
5. Choosing + Dosing Therapy
dose adjustments
weight
age
renal
duration of therapy
(if pt needs to be on AC for longer than 3 months)
provoked VTE
major or minor risk factor? continuing risk factor (eg. cancer?)
provoked by major risk (prolonged surgery) ➡️ do not extend therapy
minor risk factor (eg. estrogen therapy) ➡️ recommend ongoing therapy, but can also stop after 3 months if you want (based on judgement)
if pt has a second VTE episode, they will need lifelong AC therapy
unprovoked VTE
no identifiable cause
recommend ASA lifelong to prevent future clot, it's better than nothing
can lead to
post-thrombotic syndrome
which looks like. a super thick vein in the legs (not as painful as first DVT episode); but it does progressively get worse (unlike DVT, which stays the same the whole time)
elevate the leg at a level above the heart to pull fluid out of the tissues
can recommend compression stockings
after the first month of their episode
which are super tight at the ankle and get looser at the top
will NOT prevent recurrent DVT
parenteral bridging
dabigatran
edoxaban
warfarin
summary table: DOAC dosing in VTE
3. Goals + Phases of Treatment
Goals:
reduce sx of clot
recurrence
prevent PE death
thrombolytic therapy
for PE
is reserved for pts at greatest risk of dying (bc harm of bleeding outweighs benefit of tx, so ONLY if they're going to actually die can we consider giving them thrombolytic therapy)
prevent long term complications of DVT/PE
treatment phases
long term (7-21 days to 3-6 months)
goal
: let the clot heal
warfarin (INR of 2-3) OR DOACs
extended (secondary prevention, can be lifelong)
goal
: prevent future clots
warfarin (less common now) OR DOACs (low doses sometimes)
initial (0-7 days)
injection anticoagulant + warfarin/
dabigatran/edoxaban OR riva high dose OR apix high dose
goal
: stabilize the clot from growing or moving
💡antithrombotics include antiplatelets, anticoagulants, fibrinolytics
NOTE: the doses listed for DOACs are specific to VTE, so for A-Fib, stroke, or anything else, the dosing might differ
NOTE: know that edoxaban and dabigatran interact with the P-gp mechanism, and rivaroxaban and apixaban interact with 3A4 AND P-gp
VTE prophylaxis should be considered in hospitalized, bed-ridden pts with no c/i!
use low dose DOAC/LMWH (usually will see tinzaparin; DOACs are only for hip/knee surgery prophylaxis)