Anticoagulants-LeBlanc Flashcards
1
Q
What are some important anticoagulants?
A
Unfractionated or High Molecular Weight Heparin
Low Molecular Weight Heparins
Factor IIa and Xa Inhibitors
Warfarin (Coumadin)
2
Q
What are some important procoagulants?
A
Desmopressin Acetate
3
Q
What are some important anti platelet drugs?
A
Acetylsalicylic acid (Aspirin) Clopidogrel bisulfate (Plavix) Abciximab (ReoPro)
4
Q
What are some important thrombolytic agents?
A
Tissue Plasminogen Activator (t-PA)
Streptokinase
5
Q
What are some important antagonists?
A
Protamine sulfate
Aminocaproic acid
6
Q
Why is it that normally no intravascular coagulation occurs?
A
- dilution
- presence of plasma inhibitors
- activated clotting factors are rapidly removed by liver
7
Q
What are the physiological reactions that control blood loss after vascular damage occurs?
A
- platelet adhesion rxn
- platelet activation
- platelet aggregation
- formation of clot (coagulation)
- fibrinolysis
8
Q
What are the important categories of risk factors for thromboembolism?
A
- abnormalities of blood flow (a fib)
- abnormalities of clotting components (Protein C deficiency, pregnancy)
- abnormalities of surfaces in contact with blood (atherosclerosis)
9
Q
What are the 3 important hemostatic mechanisms?
A
- platelet aggregation & formation of platelet plug.
- vasoconstriction or vasospasm
- Blood coagulation
10
Q
What causes the vasoconstriction or vasospasms?
A
thromboxane A2, serotonin released by platelets-triggers powerful vasospasms
11
Q
What is the extrinsic coagulation pathway?
A
Coagulation occurs due to trauma originating from the extra-vascular space (formation of a macromolecular complex involving Thromboplastin or Tissue Factor, and Factor VII); the most important in vivo
12
Q
What is the intrinsic coagulation pathway?
A
Coagulation is triggered by trauma to the blood itself (from large glycoprotein complexes released by platelets)
13
Q
What does thrombin do? What does plasmin do?
A
Thrombin: makes fibrinogen into fibrin clot!
Plasmin: degrades fibrinogen into degradation products
14
Q
What is a summary of coagulation?
A
damaged vessel platelet adhesion mediators & thrombin released platelet aggregation fibrin formation thrombus formation fibrinolysis fibrin degradation products
15
Q
What is the rate limiting step for the coagulation pathway?
A
thrombin!
16
Q
What are the 3 major categories of anticoagulant drugs?
A
- direct acting anticoagulants
- indirect acting anticoagulants
- antiplatelet agents
17
Q
What are some important direct acting anticoagulants?
A
Calcium Chelators (useful for in vitro testing: sodium citrate, EDTA)
Heparin (Unfractionated and Low Molecular Weight Fractions)
Factor IIa and Xa inhibitors
18
Q
What are some indirect acting anticoagulants?
A
warfarin
19
Q
What are some Clinical Tests for Assessing Antiplatelet, Anticoagulant and Thrombolytic Therapies?
A
Bleeding time platelet count pro-thrombin time (alterations in extrinsic pathway--normal 12s) International NOrmalized Ratio. activated partial thromboplastin time (aPTT) fibrinogen degradation products, D dimer vWF function mixing studies
20
Q
What is a normal platelet count? Normal PT?
A
Platelet: 150K-400K
PT: 12 seconds
21
Q
What is a normal INR? therapeutic INR?
A
INR=PTpatient/PTnormal
INR normal=1
Therapeutic INR=2-3
22
Q
What is aPTT used to evaluate? What is a normal value?
A
intrinsic pathway of coagulation
24-34 seconds
23
Q
What does kaolin do?
A
this only triggers the intrinsic coagulation pathway
24
Q
What does a vwf study tell you?
A
measurement of factor 8 activity
25
What does a mixing study tell you?
are we dealing with a deficiency here or a clotting inhibitor?
26
What is heparin?
Heparin is an anionic mixture of linear mucopolysaccharide molecules with molecular weights in the range of 3,000 to 30,000
Active both in vivo and in vitro
27
Where does commercial heparin come from? Keep this in mind for allergies of patients.
Commercial heparin is prepared from bovine lung and porcine intestinal mucosa
28
What is the pharmacology of unfractionated heparin?
Inhibits blood coagulation by forming complexes with an α2-globulin (Antithrombin III) and each of the activated proteases of the coagulation cascade (Kallikrein, XIIa, XIa, IXa, Xa, and Thrombin). After formation of the heparin-ATIII-coagulation factor, heparin is released and becomes available again to bind to free ATIII
29
Which part of the pathway does heparin target? In your own words--what is its mechanism?
Targets the intrinsic pathway.
Measure with PTT.
It activates antithrombin III by binding it. Then antithrombin III has all this courage & boldness & it attacks the clotting factors with high affinity.
Less coagulation.
30
What does heparin do to thrombin?
inhibits the conversion of prothrombin into thrombin.
| this inhibits the conversion of fibrinogen into fibrin.
31
At low doses what does heparin primarily inhibit?
Factor 10a
32
At high doses what does heparin primarily inhibit?
Factors 5 & 8
| activation of platelets (b/c of antithrombin)
33
Aside from 10a & thrombin...what else can heparin sometimes inhibit?
factors 9a & 11a
34
What bad thing can happen with heparin?
Inhibits platelet function and increases vascular permeability; may induce moderate to severe thrombocytopenia (1-4% of patients treated for at least one week), a condition paradoxically favoring a hypercoagulability state (commonly referred to as Heparin-Induced Thrombocytopenia or HIT)
35
What is the best route of administration for heparin?
IV
can be deep subcu (2-4 hrs for effect)
NOT Oral (ineffective)
NOT IM (hematomas)
36
Is heparin safe during pregnancy?
yes, doesn't cross placenta into maternal milk
37
What is the dosing regimen of heparin? Half life?
Is prescribed on a “unit”basis
Half-life depends on the dose administered:
For doses of 100, 400 and 800 units/kg, t½ are 1, 2.5 and 5 hours respectively
38
What are the contraindications for heparin ?
Any situation where active bleeding must be avoided
Ulcerative lesions (GI tract, malignant cancers, etc.), intracranial hemorrhage, brain or spinal cord surgery
Patients with Thrombocytopenia or prior history of HIT
Patients susceptible to severe allergies; heparin is extracted from animal sources
Severe hypertension
Older patients, especially women
39
What do you do if you overdose a patient on heparin?
simple withdrawal
| protamine sulfate
40
HOw does protamine sulfate work? What is its dosing regimen?
Highly basic peptide that binds heparin and thus neutralizes its effects (1 mg of PS for every 100 units of Heparin; not to exceed 50 mg for any 10 min period)
41
Which things do you test after giving heparin?
```
PTT
anti-factor Xa heparin activity assay (6 hr intervals until stable--then daily)
hematocrit
platelet count
**look for signs of hemorrhage
```
42
What is a normal PTT value?
24-34 seconds
43
What is a normal anti-factor Xa heparin activity assay?
0.3-0.7
44
What are some examples of low molecular weight heparin? what do you lose when you give up the unfractionated form?
Lose: effect on factor 2a b/c of the shorter chain
Examples:
Dalteparin Sodium (®Fragmin)
Tinzaparin Sodium (®Innohep)
Enoxaparin (®Lovenox)
Fondaparinux (®Arixtra)
45
What are the advantages of using low molecular weight heparin?
Equal efficacy; however more predictable outcome and half-life is more than twice that of UFH
Less frequent dosing requirements (once or twice daily is sufficient)
Increased bioavailability from the subcutaneous site of injection (LMWH: ~ 90%; UFH: ~ 20%)
Less frequent bleeding
46
When should you def use unfractionated heparin instead?
```
Blood transfusions
Atrial fibrillation
Disseminated intravascular coagulation (DIC)
Open heart surgery
Pulmonary embolism
Venous thromboembolism
Venous catheter occlusion
```
47
Other direct anticoagulants
| What are some thrombin factor 2a inhibitors? What is their mechanism & route of admin?
Lepirudin (®Refludan) (leech)
Bivalirudin (®Angiomax) (similar to the leech)
Argatroban (structure based on L-arginine, which blocks factor 2a)
IV admin
**block the enzyme by binding to the catalytic site
48
Lepirudin, Bivalirudin, Argatroban have what clinical indication as factor 2a inhibitors?
patients that might develop HIT if given heparin
| if patients have had coronary angioplasty or bypass
49
What category does Dabigatran Etexilate (®Pradaxa or ®Pradax) fall into? What are its clinical indications?
Factor 2a inhibitor, direct anticoagulant
**first orally active factor 2a inhibitor
Thromboembolic disorders
Prophylactic anticoagulant used to minimize the risk of stroke in patients with non-valvular atrial fibrillation
50
Give the names of 2 factor 10a inhibitors?
Rivaroxaban (®Xarelto)
Apixaban (®Eliquis)
**both oral anticoagulants
51
What are the clinical indications for xarelto?
Deep vein thrombosis: treatment and secondary prophylaxis
Hip or knee surgery as a prophylactic agent
Non-valvular atrial fibrillation
Cerebrovascular accidents
Pulmonary embolism
52
What are the clinical indications for eliquis?
Non-valvular atrial fibrillation
| Cerebrovascular accidents
53
What are the general properties of warfarin?
The most common oral anticoagulant
Is only active in vivo after a latent period of 12 to 24 hours
The oral anticoagulants are structural analogues of vitamin K and their effects are like those of vitamin K depletion. Warfarin is a racemic mixture of two enantiomers (R and S forms)
54
What is the MOA of warfarin?
The vitamin K-sensitive step in the synthesis of clotting factors is the post-ribosomal carboxylation of specific glutamic acid residues. These amino acid residues chelate Ca2+
* *by blocking the transformation of KO-->KH....they block the carboxylation of prothrombin into thrombin.
* *inhibits synthesis of vit K dependent clotting factors
55
What are the Vit K dependent clotting factors?
2, 7, 9, 10
56
What does warfarin do to Protein C & S?
these guys are natural anticoagulants.
Warfarin actually down regulates them! At first when you administer warfarin, it is a little procoagulant b/c of this down regulation.
57
What is the relationship b/w Protein C & S?
Protein S is a cofactors of Protein C
58
WHat happens when protein C is bound to thrombomodulin?
it alters the specificity for thrombin
| favors the degradation of factors 5a & 8a
59
What are the half lives of factors 2, 7, 9, 10?
2: 60 hours
7: 6 hours
9: 24 hours
10: 40 hours
60
How is warfarin metabolized?
bound to plasma albumin
cyt p450 in liver makes it into inactive metabolites
excreted in the urine
61
How do you monitor the effects of warfarin?
PT
| INR
62
How can you overdose with warfarin ?
Vit K supplementation
| transfusion
63
What are some contraindications for warfarin?
Conditions where active bleeding must be avoided, Vitamin K deficiency and severe hepatic or renal disease, where intensive salicylate therapy is required, and in pregnant women (pass the placental barrier)
64
Why is it that newborns are more sensitive to oral anticoagulants than adults?
lower vit k levels
| lower rates of metabolism
65
What are some drugs that diminish the response to warfarin?
Inhibition of drug absorption (Cholestyramine)
Induction of hepatic microsomal enzymes
Stimulation of the synthesis of clotting factors
66
What are some drugs that increase the response to warfarin?
Displacement of anticoagulant from plasma proteins
Inhibition of hepatic microsomal enzymes
Reduction in availability of Vitamin K
Inhibition of synthesis of clotting factors
Decreased platelet aggregation (e.g. Aspirin)
67
What is a procoagulant drug?
desmopressin acetate
Is a synthetic analogue of the pituitary antidiuretic hormone (ADH)
Stimulates the activity of Coagulation Factor VIII
68
What is the clinical use for
Hemophilia A
Severe Classic Von Willebrand's Disease
For abnormal factor 8 antigen
69
GIve 4 important anti-platelet drugs.
1. Aspirin!!
2. Ticlopidine (®Ticlid)
3. Clopidogrel bisulfate (®Plavix)
4. Abciximab (®ReoPro)
70
What is the MOA Of aspirin?
IRREVERSIBLE
inhibits COX-1
can't make thromboxane A2 (which causes platelet aggregation & vasoconstriction)
also can't release ADP from platelets
71
T/F Low dose (160-320 mg) may be more effective at inhibiting Thromboxane A2 than PGI2 which has the opposite effect and is synthesized by the endothelium
True.
72
What is the MOA of ticlopidine?
alternative antiplatelet
inhibits ADP from getting to platelet receptor--thereby preventing aggregation
impairs the GP3a2b receptor
73
Clopidogrel bisulfate (®Plavix) MOA?
same as ticlopidine, but less side effects
inhibits ADP--prevents platelet aggregation
impairs GP3a2b receptor
74
What's the deal with Abciximab (®ReoPro)?
A chimeric monoclonal antibody inhibitor (Fab fragment) of platelet glycoprotein IIb/IIIa.
Prevents binding of fibrinogen and von Willebrand Factor.
Prevents platelet aggregation.
75
What's the clinical indication for abciximab?
Primary use: acute coronary syndromes and percutaneous coronary intervention.
76
What is the basic MOA of thrombolytic therapies?
well...basically activation of plasmin--it eats away at clots
both pathological & good ones (watch out hemorrhage!)
77
When are thrombolytic agents indicated?
extensive pulmonary emboli, severe iliofemoral thrombophlebitis and acute coronary occlusion
78
What is Tissue Plasminogen Activator (t-PA) ?
released from endothelial cells in response to various signals, including stasis produced by vascular occlusion. t-PA binds to Fibrin and converts Plasminogen, which also binds to Fibrin, to Plasmin.
**serine protease. It is a poor Plasminogen activator in the absence of Fibrin.
thrombolytic yo!
79
What happens to free plasmin?
rapidly inhibited in the plasma by an α2-antiplasmin. Fibrin-bound Plasmin is protected from inhibition.
80
What is streptokinase (streptase)?
protein produced by β-hemolytic streptococci. It has no intrinsic enzymatic activity, but forms a stable non-covalent 1:1 complex with Plasminogen.
**conformational change: free plasminogen-->plasmin
another thrombolytic yo!
81
What are some contraindications to thrombolytic therapy?
```
Active bleeding or hemorrhagic disorder.
Previous cerebrovascular accident or active intracranial bleeding.
GI bleeding w/i 3 mo
surgery in the next 10 days
HTN: diastolic over 110
```
82
What is Aminocaproic acid? WHat is its clinical use?
prevents binding of plasminogen & plasmin to fibrin
potent inhibitor of fibrinolysis
clinical use: reversing states associated with too much fibrinolysis
83
What is the effect of nitroglycerin ?
vasodilator
84
What risk factors are there for DVT?
bed rest
coronary artery disease
MI
obesity
85
What are the ways to make a final DVT diagnosis?
Doppler (duplex included)
D dimer
Impedence Plethysmography (pneumatic cuffs for detection of blood volume)
86
when should the PTT test be done after giving heparin?
no sooner than 6 hours after administration
87
When should you start warfarin if you are using a warfarin, heparin combo?
same day
