anticoags, antiplatelets, fibrinolytics Flashcards
anticoagulant basic definition
prevent clot formation or extension of existing clot
have no effect after clot is formed
antiplatelet/antithrombotic basic definition
reduce PLT aggregation on the surface of the PLT
thrombolytics/fibrinolytics
converts endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed blood clots
what are the four major intrinsic anticoagulant mechanisms/pathways
fibrinolysis
tissue factor plasminogen inhibitor
protein C system
serine protease inhibitors
what is the main source of anticoagulation factors
the capillary endothelium
in what ways do we prevent blood coagulation outside the bodyo
siliconized containers
citrate ion (eats calcium)
heparin or CPB in artificial kidney disease
Tissue factor plasminogen inhibitor
a polypeptide produced by endothelial cells that acts as a natural inhibitor of the the extrinsic pathway by inhibiting the TF-VIIa complex
what are the 4 key elements of the Protein C pathway
Protein C
thrombomodulin
endothelial protein C receptor
protein S
what is protein C
an enzyme with potent anticoagulant, fibrinolytic, and anti-inflammatory properties that is activated by thrombin to form activated protein C (APC) and acts by inhibiting activated factors V and VIII (with protein S and phospholipids acting as cofactors)
what is thrombomodulin
a transmembrane receptor on the endothelial cells that prevents the formation of the clot in the undamaged endothelium by binding to the thrombin
what is endothelial protein C receptor
a transmembrane receptor that helps in the activation of protein C
what is protein S
a vitamin K dependent glycoprotein, synthesized in the endothelial cells and hepatocytes
unbound form acts as a cofactor to APC in the inactivation of factor Va and VIIIa
bound form acts as an inhibitor of the complement system and is up-regulated in the inflammatory states which reduce the protein S levels, resulting in a pro-coagulant state
SERPIN
formerly known as antithrombin III and is the MAIN INHIBITOR OF THROMBIN
binds and inactivates thrombin, IIa, IXa, Xa, XIa, and XIIa
enzymatic activity is enhanced in the presence of heparin
synthesized in the liver and the plasma half life is 2.5-3.8 days
SERPIN/AT3 deficiency
hereditary is 1 in 2,000-5,000
acquired (d/t prolonged heparin infusions >4-5days) shows decreased plasma AT activity by 50-60% of normal
citrate ion and anticoagulation
citrate deionizes calcium because it is negatively charged and it binds to the positively charged calcium to cause an un-ionized calcium compound
citrate ion is removed by the lier and polymerized into glucose or metabolized
**if there is liver damage or massive transfusion, the citrate ion might not be removed quickly enough and this can greatly depress the level of calcium ion in the blood
what are the 5 types of anticoagulants listed on her slide
vitamin K antagonist unfractionated heparin low molecular weight heparin and fondaprinux direct thrombin inhibitors direct oral anticoagulants
coumadin/warfarin is what type of anticoagulant
vitamin K antagonist
mechanism of action of coumadin
inhibits vitamin K which results in hemostatically defective vitamin K dependent coagulation proteins (II, VII, IX, and X)
this is caused by competing with vitamin K for reactive sites in the enzymatic processes for formation of prothrombin and the other clotting factors, thereby blocking the action of vitamin k
platelet activity is not altered
which are the vitamin K dependent clotting factors
II, VII, IX, X
coumadin PK
rapidly and completely absorbed
97% protein bound
long elimination half time (24-36h) after PO
crosses placenta and is teratogenic so NO TO PREGNANT MOMS
metabolized into inactive metabolites that are conjugated and excreted in bile and urine
dosing of coumadin
2.5-10mg orally, dose varies
onset 3-4 days
single dose duration 2-4 days
effects seen on INR for 8-12 hours d/t depletion of factor VII, but full clinical effects are not appreciated for several days
how do you measure coumadin anticoagulation?
PT/INR
what is your INR goal for a patient taking coumadin with A-fib, VTE, PE, tissue heart valve, or VTE prophylaxis?
2-3
what is your INR goal in a patient with a mechanical heart valve, prevention of recurrent MI, history of VTE with INR 2-3
2.5-3.5
coumadin management before surgery
CHECK PT/INR
minor surgery: d/c 1-5 days preop for PT 20% within baseline and restart 1-7 days post op
immediate surgery (24-48h) or active bleeding: give vitamin K
emergency: give FFP or 4-factor concentrate (Kcentra)
what is the dose of vit K for coumadin reversal
2.5-20mg orally or 1-5mg IV at a rate of 1mg/min
PT to normal range within 4-24 hours
what is heparin and where does it come from
a naturally occurring polypeptide that inhibits coagulation
it is released endogenously by mast cells and basophils and used widely as an anticoagulation drug
where does unfractionated heparin come from
derived from porcine intestine or bovine lung and is a mix of sulfated glycosaminioglycans that produce an anticoagulant effect by binding to and enhancing the naturally occurring effects of antithrombin
**more predictable than LMWH
how does unfractionated heparin work
it binds to antithrombin and enhances the ability of antithrombin to inactive thrombin, Xa, XII, XI, and IX by 1000X
accelerates the normally occurring antithrombin-induced neutralization of activated clotting factors
long story short, decreased thrombin = decreased fibrin = decreased clotting
unfractionated heparin prepartions
large molecular weight
only1/3 of what is administered binds to antithrombin to cause effect
1 unit of activity is the amount of heparin that maintains fluidity of 1 ml of citrated plasma for 1 hour after recalcification
must contain at least 120 UPS units/ml
unfractionated heparin PK
poorly lipid soluble because it is large
cannot cross lipid barriers or placenta - safe for OB
circulates bound to plasma proteins which occurs instantly
action is 1.5-4 hours
decrease in body temp prolongs half time
what are the dose-response relationships for heparin?
100u/kg IV elimination half time = 56 minutes
400u/kg IV elimination half time = 152 minutes
aPTT on heparin
should be 1.5 to 2.5 time longer than pre-drug(25-35s normal)
when to draw ACT on heparin
baseline
3-5 minutes post admin
30min-1hr intervals post admin
what are the three labs for monitoring unfractionated heparin
aPTT
ACT
HEPTEM
what are the clinical uses of heparin
SQ VTE and PE prophylaxis
warfarin bridge
vascular or non-CPB cases with goal ACT >200-300sec
interventional aneurysm clipping/coiling with goal ACT>250sec
CPB/ECMO with goal ACT>400-480sec (inadequate <180)
how would you dose unfractionated heparin for thromboembolism prophylaxis
5,000u SQ every 8-12 hours
unfractionated heparin dosing for treatment of thromboembolism
5,000u SQ followed by continuous gtt for goal PTT 1.5-2.5X control
unfractionated heparin dosing for CPB/ECMO
400u/kg IV
unfractionated heparin dosing for vascular interventions
100-150u/kg
heparin side effects
hemorrhage/hematomas HIT allergic reaction hypotension with large doses altered protein binding chronic exposure can progress to reduction of antithrombin activity
incidence of intraspinal hematoma
0.1 per 100,000 patients per year
more likely to occur in anticoagulated or thrombocytopenic patients, those with neoplastic disease, liver disease, or alcoholism
IV heparin and neuraxial anesthesia
1 hour delay between needle placement and heparin administration
catheter should be removed for 1 hour before heparin administration and 2-4 hours after last dose
monitor PTT or ACT
heparin induced thrombocytopenia
heparin dependent antibodies that aggregate platelets and leads to consumption which produces thrombocytopenia
mild/type I HIT
30-40% of heparin treated patients
non immune mediated
plt count <100,000 cells/mm3
typically presents in 3-15 days after initiation of therapy
severe/type II HIT
0.5-6% of heparin treated patients
immune mediated
plt count <50,000 cell/mm3
present 6-10 days after initiation of therapy
how do you confirm HIT in patients with low platelet counts that you suspect this disease
lab tests for presence of antibodies
antithrombin deficiency and heparin
patients with this will have resistance to heparin because heparin binds to AT
this occurs in up to 22% of patients undergoing cardiac surgery
common in patients who receive intermittent or continuous heparin therapy
estrogen also decreases heparin’s ability to bind to AT
you can treat this by restoring normal values with 2-4u FFP in adults or antithrombin concentrate
what is the reversal for heparin
protamine or FFP
what is the dose of protamine?
1-1.5mg for each 100u of heparin administered
low molecular weight heparins
derived from standard commercial grade unfractionated heparins by chemical depolymerization to yield fragments approximately 1/3 the size of heparin
the depolymerization results in changes to the anticoagulant profile, PK, and effects on platelet function
differences in LMWH to unfractionated heparin (there are 4)
anti-activated factor X to anti-activated factor II activity:
- LMWH: 4:1-2:1
- unfract: 1:1
molecular weight:
- LMWH: 4,000-5,000 Daltons
- unfract: 30,000 Daltons
protein binding:
- LMWH: less strong
- unfract: strongly
elimination half life/dosing:
- LMWH: 24h/once daily
- unfract: 2-3h/8-12h(BID-TID)
lovenox
binds to and accelerates antithrombin and inhibits factor Xa and factor IIa
= decreased thrombin activity and prevention of fibrin clot formation
used for DVT prophylaxis
dose of lovenox dvt prophylaxis
30mg SQ every 12h
advantages of using a LMWH like lovenox
reduced dosing frequency lack of need for monitoring more predictable PK fewer effects on platelet function reduced risk for HIT
disadvantages of using a LMWH like lovenox
more expensive
surgery must be delayed for 12h after last dose
protamine only neutralizes about 65% of anti-factor X activity, so a more complete reversal requires FFP
direct oral anticoagulants are used for
alternatives to warfarin
treatment of VTE
prevention of embolic stroke
prophylaxis in patients undergoing surgery
what are the DOACs approved in most countries
direct thrombin inhibitor (IIa) - dabigatran
direct factor Xa inhibitor - rivaroxaban, apixaban, edoxaban
advantages of DOACs
rapid onset with peak effect in 2-4h
predictable PK/PD
minimal drug interactions
no required routine lab monitoring
dabigatran (pradaxa)
direct thrombin (IIa) inhibitor
metabolized via renal elimination
half life is 12 hours unless reduced renal function
monitor via coagulation assay
reverse with idarucizumab (praxbind)
what is included in a coagulation assay
dilute thrombin time (more reliable and precise)
aPTT (normal does not mean no residual anticoag effects)
ROTEM (might correlate but less specific than dilute thrombin time)
idarucizumab - praxbind
this is an antidote for pradaxa aka dabigatran
binds to dabigatran with 350X more affinity than thrombin
half life is 45 minutes
factor Xa inhibitors name them
rivaroxaban (xarelto)
apixaban (eliquis)
edoxaban (savaysa)
metabolism of direct factor xa inhibitors
hepatic
monitoring for direct factor Xa inhibitors
coagulation assay - anti-xa (not widely available)
ROTEM is not sensitive
PT can be a helpful indicator of rivaroxaban only
general management of DOAC-treated patients undergoing surgery
minimal bleeding risk procedures are likely to undergo with no DOAC interruptions
low bleeding risk procedures - stop DOAC for 24h prior to elective surgery
high bleeding risk procedures - stop DOAC for 48h prior to elective surgery
what is the reversal for dabigatran
idarucizumab
what is the reversal for apixaban and rivaroxaban?
andexanet alfa
what is the reversal for vitamin K antagonists
PCC - prothrombin compex concentrates
what are the antiplatelet agents
cox inhibitors
P2Y12 receptor antagonists
GP IIb/IIIa inhibitors
antiplatelets
suppress platelet function (aka inhibit platelet aggregation) for the prevention of thrombosis
when is antiplatelet therapy indicated
for patients at risk for CVA, MI, or other vascular thrombosis complications
asprin
inhibits platelet aggregation by inhibiting thromboxane A2 synthesis by interfering with cox and the subsequent release of ADP by platelets and their aggregation
effects are irreversible and last the life of the platelet (8-12 days)
what is the dose of aspirin
81-325mg
how does aspirin work
cox is rendered non-functional because the acetyl group of ASA causes acetylation of cox which is the enzyme that converts arachidonic acid to thromboxane
NSAIDs
ketorolac, naprosyn, ibuprofen
same MOA as aspirin but they reversibly depress thromboxane A2
so effects are only 24-48h and are often held prior to surgery
how to manage ASA in periop period
primary prophylaxis: ASA should be continued in periop period for up to and including day of procedure, but could be held for a few days at discretion of surgeon
- think patients with hyperlipidemia but no established CV disease
secondary prophylaxis: ASA should be continued in periop period for up to and including day of procedure, and should not be stopped unless there has been an explicit discussion with their cardiac/vascular physician to establish cardiac risk vs bleeding risk
- think patients with a-fib, previous MI, stent
HOLD ASA for intracranial, middle ear, posterior eye, or intramedullary spine surgery, possibly in prostate surgery and DOCUMENT decision
P2Y12 receptor antagonist MOA
inhibitors of platelet activation and aggregation through the irreversible binding of its active metabolite to the to the P2Y12 class of ADP receptors on platelets
clopidrogel
aka plavix
P2Y12 receptor antagonist
this is a pro-drug and must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation for the life of the platelet
ticagrelor
aka brillinta
P2Y12 receptor antagonist
does not need hepatic activation and might work better for pateints with genetic variants
better mortality rates in treating patients with ACS
how long must you hold P2Y12 inhibitors?
7 days prior to elective surgery
if your patient is having emergency surgery and they are on a P2Y12 inhibitor, what could you do?
platelet transfusion
indications for P2Y12 antagonists
secondary prevention of MI, CVA coronary artery stenting ACS PAD PCI
PCI and stent placement
PCI causes endothelial and medial damage that heals by neointimal formation usually within 2-6 weeks with BMS
DES - this healing is delayed which can cause risk for platelet aggregation and thrombus formation, so they are usually anticoagulated for up to a year
elective surgery should be delayed by at least 6-12 months following DES placement
if you see a patient taking aspirin and plavix what should you think
ASA and P2Y12 antagonists act synergistically so they are going to be a high bleed risk
over 10% or ACS in periop period is associated with what
preop cessation of ASA
how long are patients with stents at a high risk of thrombotic events?
the first 3 months after insertion
platelet GP IIa/IIIb antagonists MOA
act at the corresponding fibrinogen receptor that is important for platelet aggregation to block fibrinogen which is the final common pathway of platelet aggregation
when are GP IIa/IIIb antagonists used
ACS, angioplasty failures, stent thrombosis
what are the GP IIa/IIIb antagonists
abciximab (reopro)
tirofiban (aggrastat)
eptifibatide (integrilin)
how to monitor GP IIa/IIIb antagonists
ACTs (maintained between 200-400sec)
platelet counts - d/c if thrombocytopenia (<100,000 cells/mm3) develops
how do you reverse the effects of GP IIa/IIIa antagonists?
platelet transfusions
what are the herbal anticoagulants
garlic gingko ginseng black cohosh fish oil feverfew
garlic
inhibits platelet aggregation - d/c for seven days
gingko
inhibits platelet activating factor - d/c for 36h
ginseng
inhibits platelet aggrevation and lowers blood glucose
check PT/PTT/glucose
d/c for 24h but preferably 7 days
black cohosh
claims to be useful for menopausal symptoms
contains small amounts of anti-inflammatory compounds including salicylic acid
fish oil
claims to prevent/treat atherosclerotic CV disease (800-1500mg/day)
also used to treat triglycerides (>4g/day)
dose-dependent bleeding risk with >3g/day
feverfew
claims to prevent migraines
increases the risk of bleeding because it individually inhibits platelet aggregation
has additive effects with other antiplatelet drugs and additive effects with warfarin
plasminogen
a serum protein that is absorbed into the clot as it forms
it is cleaved into plasmin which breaks down the fibrin and fibrinogen of a clot
activated by t-PA and urokinase-type-PA
which thrombolytics are fibrin specific and which are non-fibrin specific
fibrin specific: alteplase, reteplase, tenecteplase
non-fibrin specific: streptokinase
thrombolytics
possess inherent fibrinolytic effects or enhances the body’s fibrinolytic system by converting the endogenous pro-enzyme plasminogen to the fibrinolytic enzyme plasmin
they are more capable of dissolving newly formed clots which are platelet rich and have weaker fibrinogen bonds
why do we use thrombolytics
to restore circulation through a previously occluded vessel
- STEMI
- acute ischemic stroke
- acute massive PE
when are thrombolytics contraindicated
trauma, severe HTN, active bleeding, pregnancy
what is the most common risk of thrombolytics
hemorrhage or bleeding
what is the window from event time to giving a thrombolytic
6 hours
alteplase (recombinant tissue plasminogen activator)
a fibrin-specific thrombolytic drug synthesized by endothelial cells
limited to use int he first 3-6h of ischemic stroke
can be administered systemically or directly into embolism
t1/2 5 minutes - usually administered as a bolus and then infusion
streptokinase
protein produced by beta-hemolytic streptococci
it is not an enzyme
it non-covalently bonds to plasminogen and converts it to a plasminogen activator complex that acts on other plasminogen molecules to generate plasmin
it is the lease expensive of the thrombolytics
but since it is made from bacteria, antibodies may form and you could have allergic reaction
what are the thrombolytic therapy adverse effects
bleeding
re-thrombosis so administer with other anticoagulants that are longer acting
what does the efficacy of thrombolytic therapy depend upon
age of clot
older clots have more crosslinking and are more compacted so they are more difficult to dissolve
