Anticoagulants, Antiplatelets, Thrombolytics Flashcards
(100 cards)
1
Q
anticoagulants
A
prevent clot formation or extension of existing clot
2
Q
anti-platelet agent
A
reduce platelet aggregation on the surface of the platelet
3
Q
thrombolytics
A
converts endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed blood clots
4
Q
herbal agents
A
have various mechanisms of anticoagulation
5
Q
what is the primary source of endogenous anticoagulation factors?
A
capillary endothelium
6
Q
prevention of blood coagulation outside the body
A
- siliconized containers (stored donated blood)
- heparin in CPB or artificial kidney machines
- citrate ion
7
Q
tissue plasminogen inhibitor
A
polypeptide produced by endothelial cells; acts a a natural inhibitor of the extrinsic pathway by inhibiting TF-VIIa complex
8
Q
protein C pathway (APC)
A
consists of four key elements:
- protein C
- thrombomodulin
- endothelial protein C receptor
- protein S
9
Q
protein C
A
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
10
Q
SERPIN (serine protease inhibitors)
A
- 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
11
Q
AT deficiency
A
- 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
12
Q
citrate ion
A
- 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
13
Q
types of anticoagulants
A
- vitamin K antagonists
- un-fractionated heparin
- low molecular weight heparin and fondaparinux
- direct thrombin inhibitors
- direct oral anticoagulants
14
Q
coumarin
A
- precursor to modern day coumadin
- vitamin K antagonist
15
Q
Vitamin K Antagonist drug
A
coumadin (warfarin)
16
Q
Vitamin K Antagonist MOA
A
- inhibition of vitamin K resulting in defective vitamin K dependent coagulation proteins (II, VII, IX, and X)
- blocks action of vitamin K
17
Q
Vitamin K Antagonist PK/PD
A
- 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
18
Q
Vitamin K Antagonist dose/route
A
2.5-10 mg orally (varies)
19
Q
Vitamin K Antagonist clinical use
A
effective prevention of thromboembolisms
20
Q
Vitamin K Antagonist INR 2-3
A
Afib, tx VTE/PE, prevent VTE, tissue heart valves
21
Q
Vitamin K Antagonist INR 2.5-3.5
A
mechanical heart valve, prevent recurrent MI, hx VTE with INR 2-3
22
Q
Vitamin K Antagonist considerations
A
- not to be used in parturient, teratogenic
- measured by PT/INR
- affects factors for varied amounts of time
23
Q
Vitamin K Antagonist surgical management
A
- 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)
24
Q
unfractionated heparin MOA
A
- 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
25
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
26
unfractionated heparin VTE prophylaxis dose
5,000 units SubQ Q8-12 hours
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unfractionated heparin VTE treatment dose
5,000 units IV + continuous infusion for goal PTT 1.5-2.5x control
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unfractionated heparin CPB dose
400 units/kg IV
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unfractionated heparin vascular intervention dose
100-150 units/kg IV
30
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)
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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
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unfractionated heparin monitoring
- aPTT 1.5-2.5x pre drug value
- ACT 3-5 min post admin; 30 min-1hr intervals post admin
- HEPTEM
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unfractionated heparin side effects
- hemorrhage, hematoma
- HIT (heparin induced thrombocytopenia)
- allergic reaction
- hypotension with large dose
- altered protein binding
- chronic exposure --> reduce AT activity
34
unfractionated heparin reversal
protamine 1-1.5 mg for each 100 units of heparin
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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
36
heparin induced thrombocytopenia
- heparin-dependent antibodies that aggregate platelets and leads to consumption which produces thrombocytopenia
- clinical suspicion confirmed with lab test for antibodies
37
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
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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
39
heparin allergic reaction
- heparin obtained from animal tissues, caution used for those with preexisting allergy
- fever, urticaria, hemodynamic changes
40
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
41
Low Molecular Weight Heparin (LMWH)
Derived from unfractionated heparin by chemical depolymerization --> fragments 1/3 size of heparin
42
Low Molecular Weight Heparin (LMWH) drug
Enoxaparin (Lovenox)
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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
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Low Molecular Weight Heparin (LMWH) PK/PD
- low molecular weight
- less protein binding
- elimination ½ 24 hours
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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
46
Low Molecular Weight Heparin (LMWH) disadvantages
- more expensive
- surgery delayed for 12 hours post dose
- protamine only neutralizes 65%; more complete reversal with FFP
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Direct Oral Anticoagulants (DOACs) types
- Direct thrombin IIa inhibitor
| - Direct factor Xa inhibitor
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Direct Oral Anticoagulants (DOACs) uses
- tx VTE
- prevent embolic stroke
- prophylaxis in patients undergoing surgery
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Direct Oral Anticoagulants (DOACs) advantages
- rapid onset with peak in 24 hrs
- predictable PD
- minimal drug interactions
- no required routine lab monitoring
50
Direct Thrombin IIa Inhibitor drug
Dabigatran (Pradaxa)
51
Direct Thrombin IIa Inhibitor PK/PD
- metabolized via renal elimination (~80%)
| - elimination ½ 12 hours
52
Direct Thrombin IIa Inhibitor monitoring
coagulation assay --> dilute thrombin time, aPTT, ROTEM (but less specific than thrombin time)
53
Direct Thrombin IIa Inhibitor reversal
idarucizumab (Praxbind); specific to dabigatran; binds with 350 fold higher affinity than thrombin, ½ 45 min
54
Direct Factor Xa Inhibitor drugs
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Edoxaban (Savaysa)
55
Direct Factor Xa Inhibitor PK/PD
hepatic metabolism (~65-70%)
56
Direct Factor Xa Inhibitor monitoring
- coagulation assay --> anti Xa (not widely available)
- PT can be helpful for rivaroxaban only
- ROTEM not sensitive
57
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)
58
antiplatelet agents
- COX inhibitors
- P1Y12 receptor antagonists
- Glycoprotein IIB/IIIA inhibitors
59
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
60
Cyclooxygenase Inhibitors
Aspirin
| NSAIDs
61
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
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Aspirin PK/PD
irreversible effects, last the life of a platelet (8-12 days)
63
Aspirin dose
81-325 mg PO
64
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
65
Aspirin definite surgical contraindications
HOLD ASA --> intracranial, middle ear, posterior eye, intramedullary spine; possibly in prostate surgery
66
NSAIDs
Ketorolac, Naprosyn, Ibuprofen
67
NSAIDs MOA
same MOA as aspirin but reversibly depress thromboxane A2 synthesis by platelets
68
NSAIDs PK/PD
temporary 24-48 hours
69
NSAIDs surgical considerations
often held prior to surgery
70
P2Y12 Receptor Antagonists drugs
Clopidogrel (Plavix)
| Ticagrelor (Brillinta)
71
P2Y12 Receptor Antagonists MOA
inhibitors of platelet activation/aggregation through irreversible binding of its active metabolite to P2Y12 class of ADP receptors on plts
72
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
73
P2Y12 Receptor Antagonists clinical use
- secondary prevention of MI, CVA
- coronary stent
- ACS
- PAD
- BMS or DES
74
P2Y12 Receptor Antagonists surgical considerations
- d/c 7 days before elective surgery
| - plt transfusion useful for emergent surgery and restoring hemostasis
75
Platelet Glycoprotein IIb/IIIa Antagonists Drugs
Abciximab (ReoPro)
Tirofiban (Aggrastat)
Eptifibatide (Integrilin)
76
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
77
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
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Platelet Glycoprotein IIb/IIIa Antagonists clinical use
- ACS
- angioplasty failures
- stent thrombosis
79
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
80
herbal anticoagulants
- garlic
- ginkgo
- ginseng
- black cohosh
- fish oil
- feverfew
81
garlic
inhibits plt aggregation, d/c 7 days before surgery
82
ginkgo
inhibits plt activating factor, d/c for 36 hrs before surgery
83
ginseng
inhibits plt aggregation and lowers blood glucose; check PT/PTT/glucose, d/c for 24 hours (preferably 7 days)
84
black cohosh
claims to be useful for menopausal symptoms; contains small amounts of anti-inflammatory compounds including salicylic acid
85
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
86
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
87
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
88
fibrin specific thrombolytics
- alteplase
- reteplase
- tenecteplase
89
non-fibrin-specific thrombolytics
-streptokinase
90
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)
91
thrombolytics clinical use
- restore circulation through previously occluded vessel (STEMI, acute ischemic stroke, acute massive PE)
- contraindicated in trauma, severe HTN, active bleeding, pregnancy
92
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
93
thrombolytics adverse effects
- bleeding
| - re-thrombosis
94
alteplase t-PA MOA
fibrin specific thrombolytic drug synthesized by endothelial cells
95
alteplase t-PA PK/PD
short ½ life – about 5 min
96
alteplase t-PA clinical use
limited to use in the first 3-6 hours of ischemic stroke
97
alteplase t-PA route
systemic IV admin or directly into embolism
98
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
99
streptokinase PK/PD
e ½ about 20 min
100
streptokinase considerations
- bacterial product may stimulate antibody production and subsequent allergic reactions
- least expensive of the thrombolytic drugs
