Anticoagulants, Antiplatelets, Thrombolytics Flashcards
anticoagulants
prevent clot formation or extension of existing clot
anti-platelet agent
reduce platelet aggregation on the surface of the platelet
thrombolytics
converts endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed blood clots
herbal agents
have various mechanisms of anticoagulation
what is the primary source of endogenous anticoagulation factors?
capillary endothelium
prevention of blood coagulation outside the body
- siliconized containers (stored donated blood)
- heparin in CPB or artificial kidney machines
- citrate ion
tissue plasminogen inhibitor
polypeptide produced by endothelial cells; acts a a natural inhibitor of the extrinsic pathway by inhibiting TF-VIIa complex
protein C pathway (APC)
consists of four key elements:
- protein C
- thrombomodulin
- endothelial protein C receptor
- protein S
protein C
enzyme with potent anticoagulant, profibrinolytic, and anti-inflammatory properties; activated by thrombin to form activated protein C and acts by inhibiting activated factors V and VIII
SERPIN (serine protease inhibitors)
- antithrombin, previously known as ATIII
- main inhibitor of thrombin
- binds and inactivates thrombin, factor IIa, and factor Xa
- enzymatic activity enhanced by the presence of heparin
- AT synthesized in the liver and plasma half-life is 2.5-3.8 days
AT deficiency
- hereditary estimated 1 in 2000-5000
- acquired deficiency (i.e. prolonged heparin infusions of >4-5 days) decreased plasma AT activity by 50-60% of normal
citrate ion
- any substance that deionizes the blood calcium will prevent blood coagulation
- negatively charged citrate combines with positively charged calcium in the blood to cause an un-ionized calcium compound
- citrate ion removed by the liver
- liver damage or MTP –> can greatly increase citrate and lead to hypocalcemia
types of anticoagulants
- vitamin K antagonists
- un-fractionated heparin
- low molecular weight heparin and fondaparinux
- direct thrombin inhibitors
- direct oral anticoagulants
coumarin
- precursor to modern day coumadin
- vitamin K antagonist
Vitamin K Antagonist drug
coumadin (warfarin)
Vitamin K Antagonist MOA
- inhibition of vitamin K resulting in defective vitamin K dependent coagulation proteins (II, VII, IX, and X)
- blocks action of vitamin K
Vitamin K Antagonist PK/PD
- rapidly, completely absorbed
- 97% protein bound
- e ½ 24-36 hours after oral admin
- crosses placenta
- metabolized to inactive metabolites excreted in bile and urine
- onset 3-4 days
- DOA 2-4 days
Vitamin K Antagonist dose/route
2.5-10 mg orally (varies)
Vitamin K Antagonist clinical use
effective prevention of thromboembolisms
Vitamin K Antagonist INR 2-3
Afib, tx VTE/PE, prevent VTE, tissue heart valves
Vitamin K Antagonist INR 2.5-3.5
mechanical heart valve, prevent recurrent MI, hx VTE with INR 2-3
Vitamin K Antagonist considerations
- not to be used in parturient, teratogenic
- measured by PT/INR
- affects factors for varied amounts of time
Vitamin K Antagonist surgical management
- minor – d/c 1-5 days preop for PT 20% within baseline; restart 1-7 days postop
- immediate surgery (24-48 hours) or active bleeding – give vitamin K [2.5-20 mg oral, 1-5 mg IV]
- emergency – FFP or 4-factor concentrate (Kcentra)
unfractionated heparin MOA
- naturally occurring polysaccharide that inhibits coagulation
- released endogenously by mast cells and basophils
- unfractionated derived from porcine intestine or bovine lung; enhance the naturally occurring effects of antithrombin
- binds to AT enhances 1000x ability of AT to inactivate coagulation enzymes
- neutralized thrombin so no conversion of fibrinogen to fibrin
unfractionated heparin PK/PD
- large molecule weight, only about 1/3 binds to AT, so this is responsible for anticoagulation effect
- poor lipid solubility, cannot cross lipid barriers
- bound to plasma proteins
- DOA 1.5-4 hours
- degraded by enzyme in blood (heparinase)
- monitored by biologic activity
- dose-dependent relationship with elimination ½
- decrease in body temp prolongs elimination ½
unfractionated heparin VTE prophylaxis dose
5,000 units SubQ Q8-12 hours
unfractionated heparin VTE treatment dose
5,000 units IV + continuous infusion for goal PTT 1.5-2.5x control
unfractionated heparin CPB dose
400 units/kg IV
unfractionated heparin vascular intervention dose
100-150 units/kg IV
unfractionated heparin clinical uses
- SQ VTE and PE prophylaxis (ERAS, ortho, post-MI, hemodialysis)
- warfarin bridge
- vascular or non CPB cases (ACT > 200-300 seconds)
- interventional aneurysm clipping/coil (ACT >250 seconds)
- CPB (ACT > 400-480 seconds)
unfractionated heparin considerations
- 1 unit of activity = amount of heparin that maintains the fluidity of 1 mL of citrated plasma for 1 hour after re-calcification
- safe in obstetrics does not cross placenta
unfractionated heparin monitoring
- aPTT 1.5-2.5x pre drug value
- ACT 3-5 min post admin; 30 min-1hr intervals post admin
- HEPTEM
unfractionated heparin side effects
- hemorrhage, hematoma
- HIT (heparin induced thrombocytopenia)
- allergic reaction
- hypotension with large dose
- altered protein binding
- chronic exposure –> reduce AT activity
unfractionated heparin reversal
protamine 1-1.5 mg for each 100 units of heparin
intraspinal hematoma
- incidence 0.1 per 100,000
- more likely to occur in anticoagulated or thrombocytopenic patients, patient with neoplastic disease, liver disease, or alcoholism
- IV heparin and neuraxial anesthesia –> 1 hour delay between needle placement and heparin admin; catheter removed 1 hour before heparin admin 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
- clinical suspicion confirmed with lab test for antibodies
mild/type 1 HIT
- 30-40% heparin treated patients
- non-immune mediated
- plt count <100,000
- typically presents 3-15 days post initiation of therapy
severe/type 2 HIT
- 0.5-6% heparin treated patients
- immune mediated
- plt count <50,000
- typically presents 6-10 days after initiation of therapy
heparin allergic reaction
- heparin obtained from animal tissues, caution used for those with preexisting allergy
- fever, urticaria, hemodynamic changes
AT deficiency
- AT deficiency = resistance to heparin
- no antithrombin means nothing for heparin to bind to
- occurs in up to 22% of patients undergoing cardiac surgery
- patients who received intermittent or continuous heparin therapy may manifest a progressive, paradoxical reduction in AT
- decrease may paradoxically increase thrombotic tendency
- treatment - restore normal values; 2-4 units FFP in adults, or AT concentrate
Low Molecular Weight Heparin (LMWH)
Derived from unfractionated heparin by chemical depolymerization –> fragments 1/3 size of heparin
Low Molecular Weight Heparin (LMWH) drug
Enoxaparin (Lovenox)
Low Molecular Weight Heparin (LMWH) MOA
- binds to and accelerates AT; inhibits factors Xa and IIa (Xa>IIa)
- decreased thrombin activity and prevention of fibrin clot formation
Low Molecular Weight Heparin (LMWH) PK/PD
- low molecular weight
- less protein binding
- elimination ½ 24 hours
Low Molecular Weight Heparin (LMWH) advantages
- decreased dosing frequency (1x daily)
- less need for monitoring
- more predictable PK response
- fever effects on plts
- reduced risk for HIT
Low Molecular Weight Heparin (LMWH) disadvantages
- more expensive
- surgery delayed for 12 hours post dose
- protamine only neutralizes 65%; more complete reversal with FFP
Direct Oral Anticoagulants (DOACs) types
- Direct thrombin IIa inhibitor
- Direct factor Xa inhibitor
Direct Oral Anticoagulants (DOACs) uses
- tx VTE
- prevent embolic stroke
- prophylaxis in patients undergoing surgery
Direct Oral Anticoagulants (DOACs) advantages
- rapid onset with peak in 24 hrs
- predictable PD
- minimal drug interactions
- no required routine lab monitoring
Direct Thrombin IIa Inhibitor drug
Dabigatran (Pradaxa)
Direct Thrombin IIa Inhibitor PK/PD
- metabolized via renal elimination (~80%)
- elimination ½ 12 hours
Direct Thrombin IIa Inhibitor monitoring
coagulation assay –> dilute thrombin time, aPTT, ROTEM (but less specific than thrombin time)
Direct Thrombin IIa Inhibitor reversal
idarucizumab (Praxbind); specific to dabigatran; binds with 350 fold higher affinity than thrombin, ½ 45 min
Direct Factor Xa Inhibitor drugs
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Edoxaban (Savaysa)
Direct Factor Xa Inhibitor PK/PD
hepatic metabolism (~65-70%)
Direct Factor Xa Inhibitor monitoring
- coagulation assay –> anti Xa (not widely available)
- PT can be helpful for rivaroxaban only
- ROTEM not sensitive
management of DOAC-treated patients undergoing surgery
- minimal bleeding risk - no DOAC interruption likely safe
- low bleeding risk - recommend stop DOACs for 24 hours prior to elective surgery
- high bleeding risk - interruption of DOAC therapy 48 hours prior to elective surgery (longer for dabigatran and impaired renal fxn)
antiplatelet agents
- COX inhibitors
- P1Y12 receptor antagonists
- Glycoprotein IIB/IIIA inhibitors
antiplatelet therapy MOA
- suppress platelet function (inhibit aggregation) for the prevention of thrombosis
- indicated for patients at risk for CVA, MI, or other vascular thrombosis complications
Cyclooxygenase Inhibitors
Aspirin
NSAIDs
Aspirin MOA
- inhibit platelet aggregation
- inhibit thromboxane A2 synthesis by interfering with COX 1 and 2 isoenzymes and subsequent release of ADP by plts and their aggregation
- acetyl group of ASA causes acetylation of COX
Aspirin PK/PD
irreversible effects, last the life of a platelet (8-12 days)
Aspirin dose
81-325 mg PO
Aspirin perioperative management
- primary prophylaxis – should be continued in perioperative period up to/including DOS; may be held for a few days at discretion of surgeon or procedural physician due to heightened risk for perioperative bleeding
- secondary prophylaxis – should be continued in perioperative period up to/including DOS; stopping needs explicit discussion with CV physician
Aspirin definite surgical contraindications
HOLD ASA –> intracranial, middle ear, posterior eye, intramedullary spine; possibly in prostate surgery
NSAIDs
Ketorolac, Naprosyn, Ibuprofen
NSAIDs MOA
same MOA as aspirin but reversibly depress thromboxane A2 synthesis by platelets
NSAIDs PK/PD
temporary 24-48 hours
NSAIDs surgical considerations
often held prior to surgery
P2Y12 Receptor Antagonists drugs
Clopidogrel (Plavix)
Ticagrelor (Brillinta)
P2Y12 Receptor Antagonists MOA
inhibitors of platelet activation/aggregation through irreversible binding of its active metabolite to P2Y12 class of ADP receptors on plts
P2Y12 Receptor Antagonists PK/PD
- clopidogrel – prodrug must be metabolized by CYP450 to produce active metabolite that inhibits plt aggregation for life of platelet
- Ticagrelor – no need for hepatic activation
P2Y12 Receptor Antagonists clinical use
- secondary prevention of MI, CVA
- coronary stent
- ACS
- PAD
- BMS or DES
P2Y12 Receptor Antagonists surgical considerations
- d/c 7 days before elective surgery
- plt transfusion useful for emergent surgery and restoring hemostasis
Platelet Glycoprotein IIb/IIIa Antagonists Drugs
Abciximab (ReoPro)
Tirofiban (Aggrastat)
Eptifibatide (Integrilin)
Platelet Glycoprotein IIb/IIIa Antagonists MOA
- act at the corresponding fibrinogen receptor that is important for plt aggregation
- blocks fibrinogen, and thus the final common pathway of platelet aggregation
Platelet Glycoprotein IIb/IIIa Antagonists PK/PD
- renal excretion
- half-life 2.5 hrs (except abciximab half-life is 12 hrs with clinical effects lasting 48 hrs
Platelet Glycoprotein IIb/IIIa Antagonists clinical use
- ACS
- angioplasty failures
- stent thrombosis
Platelet Glycoprotein IIb/IIIa Antagonists surgical considerations
- their effects can be monitored with ACTs and reversible with the clearance of the drug
- ACT maintained between 200-400 seconds
- plt counts monitored and therapy d/c if thrombocytopenia develops (<100,000)
- drug can be reversed with plt transfusion
herbal anticoagulants
- garlic
- ginkgo
- ginseng
- black cohosh
- fish oil
- feverfew
garlic
inhibits plt aggregation, d/c 7 days before surgery
ginkgo
inhibits plt activating factor, d/c for 36 hrs before surgery
ginseng
inhibits plt 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; contains small amounts of anti-inflammatory compounds including salicylic acid
fish oil
claims to prevent/treat athersclerotic CV disease (800-1500 mg/day); also used to decrease triglycerides; dose dependent bleeding risk increases with dose >3g/day
feverfew
claims to prevent migraines; increases risk of bleeding b/c it individually inhibits plt aggregation; has additive effects with other antiplatelet drugs; additive effects with warfarin
fibrinolysis
- plasminogen = serum protein that is absorbed into the clot at its formation
- plasminogen cleaved into plasmin which breaks down fibrin and fibrinogen
- tissue plasminogen activator and urokinase-type plasminogen activators are released from the capillary endothelium
fibrin specific thrombolytics
- alteplase
- reteplase
- tenecteplase
non-fibrin-specific thrombolytics
-streptokinase
thrombolytics MOA
- converts plasminogen to the active form plasmin, plasmin breaks down fibrin
- more capable of dissolving newly formed clots (platelet rich and weaker fibrinogen bonds)
thrombolytics clinical use
- restore circulation through previously occluded vessel (STEMI, acute ischemic stroke, acute massive PE)
- contraindicated in trauma, severe HTN, active bleeding, pregnancy
thrombolytics treatment considerations
- common risk –> hemorrhage or bleeding
- often 6 hour window for treatment
- efficacy of thrombolytic depends on the age of the clot, older clot has more cross-linking and are more compacted = more difficult to dissolve
thrombolytics adverse effects
- bleeding
- re-thrombosis
alteplase t-PA MOA
fibrin specific thrombolytic drug synthesized by endothelial cells
alteplase t-PA PK/PD
short ½ life – about 5 min
alteplase t-PA clinical use
limited to use in the first 3-6 hours of ischemic stroke
alteplase t-PA route
systemic IV admin or directly into embolism
streptokinase MOA
- protein produced by beta-hemolytic streptococci
- not enzyme, but non-covalently binds to plasminogen and converts it to plasminogen-activator complex that acts on other plasminogen molecules to generate plasmin
streptokinase PK/PD
e ½ about 20 min
streptokinase considerations
- bacterial product may stimulate antibody production and subsequent allergic reactions
- least expensive of the thrombolytic drugs
