Anticoagulants, antiplatelets, and thrombolytics Flashcards
Anticoagulants work by
prevent clot formation or extension of existing clot (DON’T BREAK DOWN CLOTS)
Antiplatelet agents work by
reducing PLT aggregation on the surface of the PLT
Thrombolytics work by
converting endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed blood clots
List the major counter-regulatory pathways for anticoagulants:
fibrinolysis, tissue factor plasminogen inhibitor, protein C system, serine protease inhibitors (SERPINs)
Prevention of blood coagulation outside of the body includes
siliconized containers (stored donated blood), heparin in CPB or artificial kidney machines, citrate ion
Random blood clotting is normally prevented by
the presence of endogenous anticoagulation factors- the capillary endothelium is the main source of anticoagulation factors
Tissue factor plasminogen inhibitor is a
polypeptide produced by endothelial cells. it acts as a natural inhibitor of the extrinsic pathway by inhibiting TF-VIIa complex
Coagulation propagation is inhibited by the
Protein C pathway that primarily consists of four key elements
The four key elements of the Protein C pathway includes
Protein C, thrombomodulin, endothelial protein C receptor, and protein S
Protein S is a
vitamin K-dependent glycoprotein
it functions as a cofactor to APC in the inactivation of FVa and FVIIIa
Endothelial protein C receptor is
another transmembrane receptors that helps in the activation of Protein C
Protein C is an
enzyme with potent anticoagulation, profibrinolytic, and anti-inflammatory properties. it is activated by thrombin to form activated protein C and acts by inhibiting activated factors V and VIII
Thrombomodulin is a
transmembrane receptor on the endothelial cells, it prevents the formation of the clot in the undamaged endothelium by binding to the thrombin
SERPIN or antithrombin is (alt. name and inhibitor of?)
known as AT III and is the main inhibitor of thrombin
Antithrombin binds and inactivates
thrombin, factor IIa, IXa, Xa, XIa, and XIIa
The enzymatic activity of AT is enhanced in
the presence of heparin
Patients can have an antithrombin deficiency as a result of
hereditary AT deficiency or acquired deficiency d/t prolonged heparin infusions
Antithrombin mainly inhibits
Xa and IIa but also inhibits VIIa, IXa, XIa, and XIIa
Citrate ion works by
negatively charged citrate ion combines with positively charged calcium in the blood to cause an un-ionized calcium compound
After injection, the citrate ion is
removed by liver and is polymerized into glucose or metabolized
Any substance that ____ ___ _____ _____ will prevent coagulation
deionizes the blood calcium
If there is liver damage or massive transfusion, the citrate ion
may not be removed quickly enough, and this can greatly depress the level of calcium ion in the blood
Anticoagulants include
vitamin K antagonists, unfractionated heparin, low molecular weight heparin and fondaparinux, direct thrombin inhibitors, and direct oral anticoagulants
Coumadin is considered a
vitamin K antagonist
Warfarin works by
inhibiting vitamin K which results in the hemostatically defective vitamin-K dependent coagulation proteins (II, VII, IX, and X)
Warfarin works on the following coagulation proteins:
II, VII, IX, and X
When warfarin is administered, platelet activity is
not altered
Coumadin is not suitable to use in
parturients because it crosses the placenta and is severely teratogenic
Coumadin has a (elimination half time)
long elimination half-time of 24-36 hours after PO administration
Coumadin is effective in preventing
thromboembolisms
The onset of action of coumadin and the duration of a single dose is
3-4 days
duration: 2-4 days
Coumadin levels are measured by
PT/INR
effects are see on INR in 8-12 hours d/t depletion of factor VIII
INR goals of 2-3 for coumadin are for
afib, tx of VTE, PE, prevention of VTE in high risk surgery, and tissue heart valves
INR goals of 2.5-3.5 for coumadin are for
mechanical heart valve, prevention of recurrent MI, history of VTE with INR 2-3
Coumadin management before surgery includes
checking the PT/INR
For minor surgery, coumadin is
discontinued 1-5 days preop for PT 20% within baseline and reinstituted the regimen 1-7 days postop
For immediate surgery (24-48 hours) or active bleeding,
vitamin K should be given to reverse coumadin
For emergency surgery in patients on coumadin,
FFP or 4 factor concentrate (Kcentra) can be used to reverse
Heparin is a naturally occurring
polysaccharide that inhibits coagulation
Heparin is released
endogenously by mast cells and basophils and used widely as an anticoagulation drug
Unfractionated heparin works by
enhancing the naturally occurring antithrombin
Unfractionated heparin binds to
antithrombin (III)
enhances 1,000 times the ability of antithrombin to inactivate a number of coagulation enzymes (thrombin IIa, factors Xa, XII, XI, and IX)
Neutralized thrombin prevents
the conversion of fibrinogen to fibrin
Unfractionated heparin must contain at least
120 UPS units/mL
The USP defines 1 unit of activity as the amount of heparin that
maintains the fluidity of 1 mL of citrated plasma for 1 hour after re-calcification
Unfractionated heparin does (placenta)
not cross the placenta and is safe in obstetrics)
The action of heparin lasts about
1.5-4 hours
Injected heparin is destroyed by
an enzyme in the blood (heparinase)
Unfractionated heparin cannot
cross lipid barriers in significant amounts
Monitoring heparin can be done through
monitoring aPTT, ACT (baseline, 3-5 minutes post admin, 30 min to 1 hour intervals post admin), Heptem
Clinical uses of heparin include
SQ VTE and PE prophylaxis- ERAS cases, orthopedic cases, post-MI, hemodialysis
Warfarin “bridge”
Vascular or non-CPB cases vary ACT >200-300 seconds
Interventional aneurysm clipping/coiling >250 seconds
CPB–ACT >400-480 seconds
The unfractionated heparin dosing in CPB includes
400 units/kg IV TBW
Heparin side effects include
hemorrhage/hematomas, thrombocytopenia (HIT), allergic reaction, hypotension with large doses, altered protein binding, chronic exposure can progress to reduction of antithrombin activity
Intraspinal hematoma is more likely to occur in
anticoagulated or thrombocytopenic patients, patients 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 1 hour before heparin administration and 2-4 hours after last heparin dose
monitor PTT or ACT
Allergic reactions with heparin:
heparin is obtained from animal tissues & thus caution should be used in patients with a preexisting history of allergy
fever, urticaria, hemodynamic changes
Heparin induced thrombocytopenia is caused by
heparin dependent antibodies that aggregate platelets and leads to consumption which produces thrombocytopenia
Mild or type 1 HIT is
non-immune mediated
platelet count <100,000 cells
typically presents 3-15 days after initiation of therapy
Severe or type II HIT is
low incidence <6%
immune mediated
Platelet count <50,000
typically presents 6-10 days after initiation of therapy
Heparin reversal is
protamine
1-1.5 mg for each 100 units of heparin administered
When heparin resistance is secondary to an antithrombin deficiency, treatment is to restore normal values through
2-4 units FFP in adults
or antithrombin concentrate
Patients with ______will have a resistance to heparin
antithrombin deficiency
No antithrombin=
nothing for heparin to bind to
The decrease in antithrombin may paradoxically
increase the thrombotic tendency
Estrogen containing contraceptives also
decrease antithrombin’s ability to inhibit Xa
Low molecular weight heparin is derived from
unfractionated heparin
Comparison of LMWH to unfractionated heparin:
LMWH: inhibits factor X more than unfractionated, smaller molecular weight, less protein binding, 1x daily dosing
Enoxaparin works by
binding to and accelerating antithrombin
inhibits factors Xa and IIa
Factor Xa catalyzes the conversion of
prothrombin to thrombin so enoxaprin’s inhibition of this process results in decreased thrombin activity and prevention of fibrin clot formation
Advantages to low molecular weight heparin include
reduced dosing frequency and the lack of need for monitoring, more predictable pharmacokinetic response, fever effects on platelet function, reduced risk for HIT
Disadvantages to LMWH:
more expensive, surgery delayed for 12 hours after the last dose, protamine only neutralizes 65% of anti-factor X activity of LMWH- requires a more complete reversal of LMWH with FFP
Direct oral anticoagulants are an alternative to warfarin
for tx of VTE, prevention of embolic stroke and prophylaxis in patients undergoing surgery
Direct oral anticoagulants include
direct thrombin IIa inhibitor-dabigatran
direct factor Xa inhibitor- rivaroxaban, apixaban, and edoxaban
Advantages to direct oral anticoagulants include
rapid onset with peak effect in 2-4 hours, predictable pharmacodynamics, minimal drug interactions, no required routine lab monitoring
Dabigatran is a
direct thrombin IIa inhibitor
Dabigatran is the only direct thrombin inhibitor that is
metabolized via renal elimination
Reversal of direct thrombin inhibitor includes
idarucizumab (praxbind)- specific antidote for dabigatran
half-life is 45 minutes
Monitoring for dabigatran includes
coagulation assay:
dilute thrombin time (more reliable and precise measurement)
aPTT
ROTEM (less specific than thrombin time)
Direct factor Xa inhibitors include
rivaroxaban (Xarelto)
apixaban (eliquis)
edoxaban (savaysa)
all metabolized hepatic metabolism
Monitoring of direct factor Xa inhibitors includes
coagulation assay- anti Xa
ROTEM is not sensitive
PT can be a helpful indicator for rivaroxaban only
For patients requiring minimal bleeding risk procedures, they are likely safe to undergo with
no DOAC interruptions (cataracts, skin biopsies, minor dental procedures)
Low bleeding risk procedures are recommended to (in regards to DOACs)
stop DOCAs for 24 hour hours prior to elective surgery (hernia repair)
High bleeding risk procedures are recommended to
interrupt DOAC therapy 48 hours prior to elective surgery
cardiac, intracranial, etc.
Longer interruption of DOACs is necessary for
dabigatran and impaired renal function
_____ can be given to reverse dabigatran
Idarucizumab
_____ can be given to reverse apixaban, betrixaban, edoxaban, rivaroxaban, and heparins
andexanet alfa
______ can be given to reverse vitamin K antagonists
prothrombin complex concentrates
Antiplatelet agents include
cyclooxygenase inhibitors: aspirin, NSAIDs
P2Y12 receptor antagonists
glycoprotein IIB/IIIA inhibitors
Antiplatelets work by
suppressing platelet function (inhibit platelet aggregation) for the prevention of thrombosis
Antiplatelet therapy is indicated for
patients at risk for CVAs, MI, or other vascular thrombosis complications
Aspirin exerts an
antithrombotic effect by inhibiting platelet aggregation
Aspirin inhibits
thromboxane A2 synthesis by interfering with the activity of cyclooxygenase 1 and 2 enzymes and the subsequent release of ADP by platelets and their aggregations
Aspirins effects are
irreversible and last for the life of the platelet (8-12 days)
_______ is the rate-limiting enzyme in the conversion of arachidonic acid to thromboxane A2
cyclooxygenase
NSAIDs include
ketorolac, naprosyn, and ibuprofen
NSAIDS mechanism of action
have the same MOA as aspirin (nonselective COX inhibitors) but they reversibly depress thromboxane A2 production by platelets
NSAIDS (day of)
are more temporary (24-48 hours) and are often held prior to surgery
Anticoagulants work by
delaying or preventing clotting and they have no affect after the clot is formed
Thrombolytics possess inherent
fibrinolytic effects
Antithrombotic drugs influence the
formation of clots by inhibiting platelet activity
Adverse effects of thrombolytics include
bleeding
re-thrombosis- anticoagulants such as heparin are usually co-administered and continued after thrombolytic therapy
older clots are more difficult to dissolve
Streptokinase is a
protein produced by beta-hemolytic streptococci
Streptokinase works by
noncovalently binding to plasminogen and converting it to a plasminogen activator complex that acts on other plasminogen molecules to generate plasmin
Streptokinase adverse effect
as a bacterial product it may stimulate antibody production and subsequent allergic reactions
Alteplase is a
fibrin-specific thrombolytic drug synthesized by endothelial cells
Alteplase is limited to use
in the first 3-6 hours of ischemic stroke
Alteplase can be administered
systemically or directly into embolism (place of invasive lines before administration)
Thrombolytics work by
converting plasminogen to the active form, plasmin
plasmin breaks down fibrin
Thrombolytics are used to
restore circulation through a previously occluded vessel such as in STEMI, acute ischemic stroke, acute massive PE
thrombolytics are contraindicated in
trauma, severe HTN, acute bleeding, and pregnancy
Thrombolytics include
urokinase, streptokinase, alteplase
The most common risk of thrombolytics is
hemorrhage or bleeding
Thrombolytics are more capable of
dissolving newly formed clots (platelet rich and weaker fibrinogen bonds)
Thrombolytics possess inherent
fibrinolytic effects or enhances the body’s fibrinolytic system by converting endogenous pro-enzyme plasminogen to the fibrinolytic enzyme plasmin
Thrombolytic classes include:
fibrin-specific agents: alteplase, reteplase, tenecteplase
non-fibrin specific agents- streptokinase
Plasminogen is a
serum protein that is absorbed into the clot at its formation
Plasminogen is cleaved into
plasmin which breaks down fibrin and fibrinogen
TPA and urokinase type plasminogen activators are released from the capillary endothelium
Garlic works by
inhibiting platelet aggregation and should be discontinued for 7 days
Ginkgo works by
inhibiting platelet activating factor and should be discontinued for 36 hours
Ginseng works by
inhibiting platelet aggregation and lowers blood glucose; check PT/PTT/glucose & d/c for 24 hours (preferably 7 days)
Black cohosh
claims to be useful for menopausal symptoms and contains small amounts of anti-inflammatory compounds including salicylic acid
Fish oil
claims to prevent/treat atherosclerotic CV disease; dose dependent bleeding risk increases with dose >3 g/day
Feverfew:
claims to prevent migraines; increases the risk of bleeding because it individually inhibits platelet aggregation, has additive effects with other antiplatelet agents
Primary prophylaxis of ASA:
hyperlipidemia in the absence of established CV disease- should be continued in the preop period up to and including the day of the procedure
may be held for a few days at the discretion of the surgeon or procedural physician
Secondary prophylaxis of ASA (afib, previous MI, stent):
should be continued in the preoperative period up to and including the day of the procedure
stopping ASA in these patients needs an explicit discussion
Holding ASA in specific circumstances:
intracranial, middle ear, posterior eye or intramedullarly spine surgery; possibly in prostate surgery
Clopidogrel (Plavix) and ticagrelor (brilinta) are
inhibitors of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets
P2Y12 receptor antagonists must be (regarding day of surgery)
discontinued 7 days prior to elective surgery
Clopidogrel 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
Indications for P2Y12 receptor antagonists include
secondary prevention of MI, CVA; coronary artery stenting, acute coronary syndrome, peripheral artery disease
As a general approach, elective surgical procedures should be delayed for at least
6 weeks and ideally 6 months after DES placement
Withdrawal of ASA in patients with CAD is associated with
increase in death/MI
ASA and P2Y12 receptor antagonists act
synergistically
Platelet glycoprotein IIb/IIIa antagonists act at
the corresponding fibrinogen receptor that is important for platelet aggregation
Platelet glycoprotein IIb/IIIa antagonists are utilized in
ACS, angioplasty failures, and stent thromboses
Platelet glycoprotein IIb/IIIa antagonists include
abciximab, tirofiban, and eptifibatide (integrilin)
Platelet glycoprotein IIb/IIIa blocks
fibrinogen which is the final common pathway of platelet aggregation
The effects of platelet glycoprotein IIb/IIIa can be reversed with
platelet transfusions
Platelet inhibitor glycoprotein IIb/IIIa antagonists monitoring can be done with
ACTs and reversible with the clearance of the drug
ACT is maintained between 200 and 400 seconds
_____ should be monitoring with platelet inhibitor glycoprotein IIb/IIIa antagonists
platelet counts
therapy should be discontinued if thrombocytopenia develops
