Anticoagulants, Thrombolytics, and Direct Thrombin Inhibitors Flashcards
(142 cards)
1
Q
What are procoagulants?
A
Promote coagulation
2
Q
What are anticoagulants?
A
Inhibit coagulation
3
Q
Do procoagulants or anticoagulants normally predominate?
A
Anticoagulants
4
Q
When are procoagulants activated in normal physiology?
A
When a vessel is ruptured
5
Q
What is the process of normal hemostasis?
A
- Damage occurs to a blood vessel
- Vascular constriction (immediate)
- Platelets immediately begin to adhere to the cut edges of the vessel and release chemicals to attract even more platelets (immediate)
- Platelet plug forms
- Clotting factors cause strands of fibrin to stick together and seal the inside of the wound (15-20 seconds up to 1-2 minutes)
- Clot dissolution (few hours to 1-2 weeks)
6
Q
How do platelets participate in clot formation? (3 ways)
A
- anchoring sites for coagulation factor activation complexes
- Delivery “vehicles” releasing hemostatically active proteins
- Major structural components of the clot
7
Q
What participants are required for clot formation?
A
Vascular endothelium
Platelets
Plasma-mediated hemostasis
8
Q
What is the vascular endothelial role in hemostasis?
A
Normal, intact vascular endothelium provides nonthrombogenic surface (antiplatelets, anticoagulants, profibrinolytics)
Damage to endothelium exposes the underlying extracellular matrix and releases collagen, von Willebrand factor, hormones, cytokines, and other procoagulants
9
Q
What 3 things can induce prothrombotic endothelial changes?
A
Thrombin, hypoxia, and high fluid shear stress
10
Q
Where are platelets formed?
A
bone marrow
11
Q
What is the normal concentration of platelets?
A
150,000-300,000 per microliter
12
Q
At what platelet level can spontaneous bleeding occur?
A
50,000
13
Q
At what platelet level is it lethal and can definitely cause spontaneous hemorrhage?
A
20,000
14
Q
How long is the life of a platelet?
A
8-12 days
15
Q
How are platelets removed?
A
Macrophages in the spleen
16
Q
What are the 3 major phases platelets undergo when they are exposed to the extracellular matrix in damaged endothelium?
A
Adhesion
Activation
Aggregation
17
Q
What is platelet adhesion?
A
Exposure to subendothelial matrix proteins (collagen, vWF, fibronectin) allows platelets to adhere to vascular wall
18
Q
Which of the molecules involved in platelet adhesion is particularly important?
A
vWF - bridging molecule between the subendothelial matrix and platelets (glycoprotein 1b, factor IX, factor V receptor complexes)
19
Q
What is platelet activation?
A
Occurs after platelets adhere to endothelial damaged wall, series of physical and biochemical changes that occur
- platelets release granular contents (ADP, calcium, serotonin, histamine, epinephrine, TXA2, etc) resulting in recruitment and activation of additional platelets
- platelets develop pseudopod-like membrane extensions to increase platelet surface area
20
Q
What is platelet aggregation?
A
- activators released during the activation phase recruit additional platelets to the site of injury
- newly activated glycoprotein IIb/IIIa receptor on the platelet surface bind fibrinogen to provide for cross-linking with adjacent platelets
21
Q
What is plasma mediated hemostasis?
A
Amplification of thrombin generated from an inactive precursor (prothrombin)
Trace plasma proteins, activated by exposure to tissue factor or foreign substances, initiate a cascading series of reactions culminating in conversion of soluble fibrinogen to insoluble fibrin clot
22
Q
What is thromboxane A2 (TXA2) and how is it produced?
A
Produced by activated platelets and has prothrombotic properties, stimulates activation of new platelets as well as increases platelet aggregation (mediates expression of glycoprotein complex IIb/IIIa in cell membrane of platelets)
23
Q
What is another property of thromboxane A2 that makes it especially important during tissue injury and inflammation?
A
Vasoconstrictor
24
Q
Where are most coagulation factors synthesized?
A
liver
25
How are coagulation factors identified?
Roman numerals assigned in order of discovery
26
Where is vWF synthesized?
endothelial cells
27
Which factors are vitamin K dependent?
Factor II, VII, IX, and X
28
Are most factors enzymes?
Yes, with a few exception
29
Do coagulation factors circulate as active or inactive proteins?
Inactive
30
What is factor I?
Fibrinogen
31
What is factor II?
Prothrombin
32
How can you determine if a factor is an active or inactive enzyme?
a lower-case letter "a" indicates active enzyme
33
What is another name for the intrinsic pathway of coagulation?
"contact activation system"
34
What is the process of the intrinsic pathway of coagulation?
- Begins with damage to blood vessels
- Formation of the primary complex on collagen and thrombin generation by way of factor XII and ultimately merges to the common pathway and activates factor X
35
What is another name for the extrinsic pathway of coagulation?
"Tissue factor pathway"
36
What is the process of the extrinsic pathway of coagulation?
- Initial step in plasma-mediated hemostasis
- Begins with exposure of blood plasma to tissue factor
- After injury factor VIIa circulating the plasma forms a complex with tissue factor, factor X and calcium to promote the conversion of X to Xa
37
What is the common pathway of coagulation?
- Common to both intrinsic and extrinsic pathways
- Formation of thrombin which causes subsequent fibrin formation
- SIgnal amplification
38
Where is prothrombin (factor II) produced and what is required for the formation of prothrombin?
Produced in liver
Vitamin K required for its formation
- Lack of vitamin K or liver disease will result in decreased prothrombin levels and bleeding tendencies
39
Where are the receptors for prothrombin?
attaches to receptors on the surface of platelets
40
Where is fibrinogen (factor I) formed?
liver
| liver disease can decrease the concentration of circulating fibrinogen
41
What is a clot primarily composed of?
plasminogen, plasmin, fibrin, and fibrin degradation products
42
What is the process of forming a blood clot?
- thrombin converts fibrinogen to fibrin
- covalent bonds between fibrin molecules and cross-linking of fibers creates a meshwork in all directions of blood cells, platelets and plasma which adhere to the surface of the damaged blood vessel
43
How are blood clots lysed?
- plasminogen activated to plasmin by tissue plasminogen activator (t-PA)
- plasmin digests fibrin fibers, fibrinogen, factor V, factor VIII, prothrombin, and factor XII
44
What are anticoagulants?
prevent clot formation or extension of existing clot
| Ex: Warfarin, heparin, LMWH, direct thrombin inhibitors
45
What are antiplatelet agents?
reduce platelet aggregation, prevent stroke, MI, TIA
| Ex: ASA, plavix, ticlid, NSAIDS
46
What are GP IIB/IIIA inhibitors?
prevent platelet aggregation on the surface of the platelet
| Ex: Abxicimab (reopro), eptifibatide (Integrillin)
47
Do anticoagulants have an effect on a clot after it is formed?
No
48
What anticoagulant is used to prevent blood coagulation outside of the body?
citrate ion - any substance that deionizes the blood calcium will prevent coagulation
49
How does citrate work?
negatively charged citrate ion combines with calcium in the blood to cause an un-ionized calcium compound
50
How is citrate eliminated?
removed by liver and polymerized into glucose or metabolized
51
What happens with the citrate if there is liver damage or mass blood transfusion?
citrate ion may not be removed quickly enough and this can greatly depress the level of calcium ion in the blood --> citrate toxicity
52
What is the mechanism of action of heparin?
- binds to antithrombin (antithrombin III) and enhances 1,000 times the ability of antithrombin to inactivate a number of coagulation enzymes (thrombin, factors Xa, XII, XI, and IX)
- neutralized thrombin prevents the conversion of fibrinogen to fibrin
53
Where does heparin come from?
bovine (cattle), porcine (pig), and endogenous
54
What clotting pathways does heparin block?
classic intrinsic and final common pathway
55
How is heparin prescribed?
units
56
How does the United States Pharmacopoeia (USP) define 1 unit of heparin?
amount of heparin that maintains the fluidity of 1 mL of citrated sheep plasma for 1 hour after re-calcification
57
How many units/mL must heparin contain?
120 UPS units/mL
58
Why is heparin prescribed in units?
Commerical preparations vary in the number of USP units/mL
59
Is heparin lipophilic or hydrophilic?
Hydrophilic, poor lipid solubility and large molecule
60
Can heparin be given PO?
No, due to poor lipid solubility
61
Is the dose-response relationship of heparin linear?
No
100 units/kg IV elimination 1/2 time was 56 minutes
400 units/kg IV elimination 1/2 time was 152 minutes
62
What can prolong elimination 1/2 time of heparin?
Hypothermia
63
How long does the action of heparin work?
1.5-4 hours
64
How much does 100 units/kg (or 0.5-1 mg/kg) affect blood clotting time?
Increases from a normal 6 minutes to 30 or more minutes which occurs almost instantly
65
How is injected heparin destroyed?
heparinase, an enzyme in the blood
66
What are the tests used to monitor heparin?
aPTT
| ACT
67
What is the aPTT test?
activated plasma thromboplastin time
| 1.5-2.5 times pre-drug value (30-35 seconds)
68
When would you check an ACT after the administration of heparin?
- baseline before heparin
- 3-5 mins post administration
- 30 mins to 1 hour intervals post administration
69
When would you want to use an ACT over a aPTT?
most widely used and is reliable for high heparin concentrations
70
What can influence the results of an ACT?
hypothermia
thrombocytopenia
aprotinin
coagulation deficiencies
71
What is the value for a normal/control ACT?
80-120 seconds
72
Where would you want an ACT for CPB?
>400-450 seconds
73
Where would you want an ACT for interventional aneurysm clipping/coiling?
>250 seconds
74
How does an ACT test work?
mixes whole blood with activation substance (celite or kaolin) which initiates activation of the clotting cascade and counts the seconds until a clot is formed
75
What is the commonly used LMWH?
Enoxaparin (Lovenox)
76
What are the differences between Lovenox and unfractionated heparin?
- Lovenox more expensive
- Approximately 1/3 the size of heparin
- Less protein binding than heparin and more bioavailability
- Longer elimination 1/2 time = once daily dosing
77
What are some advantages of giving Lovenox?
- reduced dosing frequency and lack of need for monitoring
- more predictable pharmacokinetic response
- fewer effects on platelet function
- reduced risk for HIT
78
What is the MOA of lovenox?
binds to and accelerates antithrombin III, inhibits factors Xa and IIa (Xa>IIa)
79
What does the inhibition of factor Xa cause with the administration of lovenox?
inhibits the conversion of prothrombin to thrombin and results in decreased thrombin activity and prevention of fibrin clot formation
80
Which factors does protamine neutralize?
Neutralizes anti-factor IIa activity and has limited activity on Xa, cannot completely reverse Lovenox
81
What is the dose for heparin when using it for DVT prophylaxis?
5,000 units SUBQ every 8-12 hours
82
What is the dose for lovenox when using it for DVT prophylaxis?
30 mg SUBQ every 12 hours
83
What is the treatment for DVT using hepain?
Bolus of 5,000 units IV followed by infusion to maintain aPTT 1.5-2.5
84
What is a heparin bridge?
stopping coumadin 5-7 days prior to surgery and administering heparin until day of surgery, coumadin restarted on the evening of surgery and heparin restarted day after surgery and continued until INR is therapeutic
85
What are some side effects of heparin?
- hemorrhage/hematomas
- thrombocytopenia (HIT)
- allergic reaction
- hypotension with large doses
- altered protein binding - displaces alkaline drugs from protein-binding sites
- chronic exposure can progress to reduction of antithrombin activity
86
How can heparin produce the side effect of hypotension?
Occurs during large IV bolus of heparin during CPB that can cause modest decreases in MAP and PA pressures, thought to occur from decreased SVR resulting from direct heparin-induced relaxant effect on vascular smooth muscle
87
What is important to remember regarding anticoagulant therapy and epidurals/catheter placement?
anticoagulants need to be stopped before catheter placed, once catheter in place ok to restart anticoagulants until catheter is to be D/C'd
88
What is important to remember when administering heparin?
can come in different concentrations so always verify dose before administering
89
What is Heparin Induced Thrombocytopenia (HIT)?
Heparin-dependent antibodies that agglutinate platelets and produce thrombocytopenia
90
What platelet count indicates severe HIT?
count
91
What platelet count indicates mild HIT?
count
92
Which is more common, mild or severe HIT?
Mild, occurs in 30-40% of patients (severe occurs in 0.5-6%)
93
What is antithrombin deficiency?
- Resistance to heparin
- No antithrombin present for heparin to bind to
- Common in cardiac cases
- Ex: gave 20,000 units of heparin in cardiac case but no changes seen in ACT
94
What is the treatment for antithrombin deficiency?
- 2-4 units FFP in adults
| - antithrombin concentrate 1,000 units
95
What can be used to reverse heparin?
- Protamine
- FFP
- Prothrombin complex concentrate (PCC)
96
What are the different procoagulants?
```
*Protamine
Desmopressin (DDAVP)
FFP
Factor 7A
Phytonadione (Vitamin K)
Prothrombin complex concentrate
Tranexamic acid
Fibrinogen
Prothrombin
Aminocaproic acid (Amicar)
Conjugated estrogen (IV)
```
97
What is the MOA of protamine?
it is a positively charged alkaline molecule that combines with the negatively charged acidic heparin to form a stable complex void of anticoagulant activity
98
How is the heparin-protamine complex eliminated?
reticuloendothelial system
99
What is the dose of protamine?
- 1 mg for every 100 units of heparin given
| - also guided by last ACT and estimated amount of heparin IV administered within the last 2 hours
100
How should protamine be administered?
Should be administered slowly in a peripheral IV, if given too fast in a central line can cause histamine release resulting in pulmonary HTN and systemic hypotension
- don't exceed 50 mg in any 10 minute period
101
Besides systemic hypotension and pulmonary HTN from fast infusion of protamine, what is another common adverse effect?
Allergic reaction
102
What things can trigger an allergic reaction to protamine?
- protamine containing insulin (NPH) (approximately 0.5 mg protamine per 100 units of NPH)
- fish allergy (controversial)
- vasectomies or infertile males (presence of circulating antisperm antibodies)
103
How is protamine obtained?
simple protein principles obtained from the sperm of salmon and other species of fish
104
Which patients are at the highest risk for a reaction to protamine?
if they had a prior reaction to protamine (189 fold)
allergy to fish (24.5 fold)
exposure to NPH insulin (8.2 fold)
105
What is the MOA of coumadin?
competitively inhibits vitamin-K dependent coagulation proteins (factors II, VII, IX, and X)
106
How is coumadin monitored?
PT/INR
107
What is a goal INR for someone on Coumadin?
2.0-3.0
108
Is Coumadin safe to use in a parturient?
No, crosses placenta and severely teratogenic
109
What is the onset of Coumadin?
3-4 days, effects are seen on 8-12 hours due to depletion of factor VII however full clinical effects are not appreciated for several days
110
What is the duration of a single dose of Coumadin?
2-4 days
111
What is the half-life of Coumadin?
40 hours
112
What is the International Normalized Ratio (INR)?
Used to monitor Coumadin, compares ratio of patient's PT to control PT with calculations done to determine a ratio to one decimal place, no units
113
What conditions would require a slightly higher INR of 2.5-3.5?
- Mechanical heart valve
- Prevention of recurrent MI
- History of VTE with INR 2-3
114
For a patient having minor surgery, when should they stop Coumadin?
stop 1-5 days preop for PT 20% within baseline
115
For immediate surgery within 24-48 hrs of someone taking Coumadin, what should be done to bring PT down to normal range?
IV vitamin K (10-20 mg PO or 1-5 mg IV at rate of 1 mg/min)
| PT to normal range within 4-24 hours
116
For emergency surgery on someone taking Coumadin, what should be given to normalize PT?
FFP or PCC
117
How do antiplatelet drugs work?
suppresses platelet function (inhibits platelet aggregation)
| Ex: ASA, plavix, NSAIDS
118
What is the MOA of aspirin?
exerts antithrombotic effects by inhibiting platelet aggregation, biochemical mechanism accounting for this action is irreversible inhibition of COX-1 by the acetyl group of ASA that causes acetylation of cyclooxygenase
Inhibition of COX prevents conversion of arachidonic acid to thromboxane A2 (key factor in platelet activation and thrombus formations)
119
How long do the effects of ASA last?
effects are irreversible and last the life of the platelet
120
What is the primary prophylaxis dose of ASA?
81 mg
121
What is ASA primary prophylaxis?
treatment with ASA in the absence of an established diagnosis of cardiovascular disease
122
What is ASA secondary prophylaxis?
treatment with ASA in the presence of overt CV disease or conditions conferring particular risk
Ex: afib, angina, previous MI, stroke, CHF, CABG, PCI, vascular surgery, DM, noncardiac stents, renal insufficiency
123
Should primary prophylaxis be continued until day of surgery?
Should be continued but can be held for a few days at the discretion of the surgeon or procedural physician due to a possible heightened risk for perioperative bleeding
124
Should secondary ASA prophylaxis be continued until day of surgery?
Should be continued until day of surgery except for intracranial neurosurgical procedures, intramedullary spine surgery, surgery of the middle ear or posterior eye, and prostate
125
What is the MOA of plavix?
inhibitor of platelet aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets
126
How is Plavix metabolized and why is this important?
metabolized by CYP450 and must be metabolized to produce active metabolite
127
What are some indications for Plavix?
- secondary prevention of MI, CVA
- coronary artery stenting
- acute coronary syndrome
- peripheral artery disease
- PCI
128
How long should elective surgical procedures be delayed after DES placement?
at least 6 months but ideally 12 months
129
What is the MOA of NSAIDS?
reversibly depress thromboxane A2 production by platelets
130
How do thrombolytics work>?
Possess inherent fibrinolytic effects or enhances body's fibrinolytic system
131
What is the primary reason to use a thrombolytic?
restore circulation through a previously occluded vessel
- STEMI
- Acute ischemic stroke
- Acute massive PE
132
What are the contraindications to thrombolytics?
trauma
severe HTN
active bleeding
pregnancy
133
What is the window of time you are able to administer thrombolytics?
6 hours within initial onset of clot symptoms
134
What is the MOA of t-PA?
converts plasminogen to plasmin which breaks down fibrin
135
How can t-PA be administered?
can be given systemically or directly into emboism
136
What is the 1/2 life of t-PA?
about 5 mins, usually administered as bolus followed by infusion
137
What are some adverse effects of thrombolytics?
bleeding
| re-thrombosis (anticoagulants such as heparin are usually co-administered and continued after thrombolytic therapy)
138
What does the efficacy of thrombolytics depend on?
the age of the clot, older clots have more cross-linking and are more compacted which makes them more difficult to dissolve
139
What is the MOA of direct thrombin inhibitors?
act as anticoagulants by directly inhibiting the enzyme thrombin (factor II)
140
What makes direct thrombin inhibitors different than anticoagulants such as heparin?
does not require cofactor such as antithrombin
141
How do bivalent DTIs work?
block simultaneously the active site and secondary binding site (exosite 1) and act as competitive inhibitors of fibrin
142
How do univalent DTIs work?
block only the active site and can therefore both inhibit unbound and fibrin-bound thrombin
