Topic 2 Flashcards
1
Q
Year?
Heparin first discovered by J. McLean
-so it’s one of the oldest drugs in continuous use
A
1916
2
Q
Year?
Heparin Purification
A
1920’s
3
Q
Year?
Heparin 1st used to anticoagulate blood for transfusion
-Resulted in febrile reactions
A
1924
4
Q
Year?
heparin pure enough for IV administration
A
1936
5
Q
Heparin can be obtained from
A
bovine lung bovine liver (cheaper)
6
Q
Year?
Research discovered peptide Protamine
-Neutralizes the anticoagulant effects of heparin
A
1937
7
Q
Year?
Gibbon reported heparin-induced anticoagulation for CPB in animals
-Lead to the selection of heparin for anticoagulation and Protamine to neutralize in first human CPB operation.
A
1939
8
Q
Most widely used anticoagulant for cardiac surgery
A
Heparin
9
Q
Heparin is readily available, with…
A
predictable response in majority of patients
10
Q
Heparin has a relatively low incidence of…
A
side effects
11
Q
Heparin is readily reversible with…
A
Protamine
12
Q
Heparin is easy to monitor…
A
anticoagulant effects and concentration in blood
13
Q
Heparin is lower in
A
cost
14
Q
Heparin is highly sulfated glycosaminoglycan present in…
A
mast cells
15
Q
Heparin is a close relative to heparan, which is a….
A
lower sulfated form present on endothelial cells
16
Q
Heparin predominantly works via potentiation of …
A
Antithrombin III (AT III) -to neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)
17
Q
Heparin work on serine proteases…
A
VII, IX, X, XI, XII
7, 9, 10, 11, 12
18
Q
Unfractionated heparin contains heparin molecules of…
A
varying lengths
- Distribution of MW varies depending on source
- Actions and potency varies from batch to batch
19
Q
Longer chains (higher MW) bind better with…
A
AT-III and thrombin
20
Q
Specific pentasaccharide sequence along heparin chain required for…
A
AT-III interaction
21
Q
Heparin molecular weights range from…
A
3,000-40,000+ Daltons
22
Q
Heparin is a highly…
A
negatively charged molecule
-highest negative charge density of any biological molecule
23
Q
Heparin is very very
A
Acidic
24
Q
Mucosal Heparin-
Has a lower…
A
Molecular weight
25
Mucosal Heparin-
| Higher dose required for ...
the same response
26
Mucosal Heparin-
| Need ____% less Protamine to neutralize
25-30%
27
Mucosal Heparin-
| Lower MW which uses...
Xa inhibition
| – not reversed by Protamine
28
Mucosal Heparin-
| More expensive to
produce
29
Mucosal Heparin-
| LESS likely to cause
HITT
30
Lung Heparin-
| Has a higher...
Molecular weight
31
Lung Heparin-
| Has a greater Potency, which means...
Lower dose required
32
Lung Heparin-
| More protamine required due to...
more ATIII interactions
33
Lung Heparin-
| Cheaper to
produce
34
Lung Heparin-
| MORE likely to cause
HITT
35
1 USP unit =
amount of heparin that maintains fluidity of 1mL of citrated sheep plasma for 1 hour after recalcification
36
BP unit =
Sulfated ox blood activated with thromboplastin
37
EU unit =
Recalcified sheep plasma in the presence of kaolin and cephalin incubated for 2 minutes therefore constituting an aPTT for sheep plasma
38
Heparin has poor ___ solubility
lipid
| -safe for BBB & placenta
39
Heparin has biphasic elimination with peak effects at ____ post administration via _____
1-2 minutes
central line
-Delayed in states of low CO or with peripheral injection
40
Heparin- Redistribution after _____ to normal elimination
4-5 minutes
41
Heparin has a dose ______ half-life
dependent
42
Half life: 100U/kg dose =
61 ± 9 minutes
43
Half life: 200U/kg dose =
93 ± 6 minutes
44
Half life:400U/kg dose =
126 ± 24 minutes
45
Majority of heparin is protein bound in
plasma, but some migrates to tissues
46
Clearance of heparin via
1. Portions are excreted in urine depolymerized with fewer sulfate groups that reduces activity by 50%.
2. Endothelial cells
3. Liver
4. Kidneys
47
Hypothermia delays ______ and increases _____
clearance
| half-life
48
Heparin concentration is virtually constant for ____ at ____
40-100 min at 25*C
49
AT III activity is increased _____ in the presence of heparin
1,000-10,000X
50
Only larger chain molecules (1/3) of heparin bind to
AT III
51
Smaller chains primarily have
anti-Xa effect and minimal anti-IIa effects
52
Standard dosing does NOT guarantee of adequacy of
anticogulation
53
Initial dosing
- Loading dose of 200-400U/kg given
| - 5,000 to 20,000U added to prime
54
Empiric dosing
- Loading dose given and ACT verified
- After that, give additional heparin (50 to 100U/kg) every 30 minutes or as infrequently as every 2 hours.
- No ACT checked due to theory of existing variables that make ACT inaccurate
55
Heparin-Dose response curve
- Create graph based on baseline ACT and ACT following loading dose of heparin
- Provides “personalized” response for each patient
- Additional heparin given when ACT falls below specified value – additional amount determined from graph
56
Gravlee Protocol (6)
1. Prime with 3U of heparin per ml of pump prime
2. Initial dose 300U/kg IV
3. Draw sample for ACT 2 to 5 min after infusion
4. Give additional heparin as needed to achieve ACT above 400 sec before initiation of bypass
5. Give additional heparin as needed to maintain ACT above 400 sec during normothermic bypass or 480 sec during hypothermic bypass (24 to 30C)
6. Monitor ACT every 30 min during bypass or more frequently if patient shows heparin resistance
57
Heparin binds to
platelets
58
Heparin binding decreases with
decreased MW (low molecular weight heparin)
59
Insufficient heparinization on bypass causes
consumption of clotting factors
60
Heparin Resistance=
Need for higher than normal heparin doses to induce sufficient anticoagulation for the safe conduct of bypass.
-When more than 600u/kg given and ACT still is <300 seconds
61
Heparin Resistance causes
1. ATIII Deficiency
2. Extreme thrombocytosis
3. Septicemia (rare)
4. Hypereosinophilic Syndrome (rare)
5. Nitroglycerin (rare)
62
ATIII Deficiency
Familial/ Congenital
| Acquired (Due to continued heparin therapy or estrogen based contraceptives)
63
Extreme thrombocytosis
Platelet count > 500,000
64
Nitroglycerin
Clinically relevant only when > 300 mcg/min
65
Familial ATIII Deficiency: Inherited (Familial/ Congenital)=
1. Autosomal dominant
2. 1/2000 to 20,000 people
3. Usually ATIII < 50% normal
4. Presents @ 15-30 years old with low limb venous thrombosis or Pulmonary Embolism
66
Familial ATIII Deficiency Treatment:
Life long antithrombotic therapy after diagnosis
| -Decreases incidence of thromboembolic events by 65%
67
Infants and newborns: ____ adult ATIII levels
60-80%
- @ 3 months: 90% of adult levels
- Explains heparin resistance of newborns
68
Heparin resistance can occur even when therapeutic levels of
plasma heparin concentration has been reached
| -Inability of Heparin to suppress the activity of thrombin
69
Acquired ATIII Deficiency is more common than
Familial ATIII Deficiency
70
Acquired ATIII Deficiency=
Occurs when patients are on Heparin pre-op or have chronic DIC
-ATIII levels plateau around 60% of normal
71
Treatment of ATIII Deficiency in the OR=
1. Transfusion of FFP
| 2. Administration of Recombinant ATIII (Thrombate or ATryn)
72
Platelet Dysfunction=
Heparin (larger MW) readily binds to platelets inducing release of PF4, activation of GPIIb/IIIa receptors, degranulation, and aggregation.
-Can lead to HIT
73
Heparin Induced Thrombocytopenia=
1. Clinical condition characterized by a drop in platelet counts to <100,000 or 50% reduction from baseline
2. Typically occurs between 2-10 days after initiation of heparin therapy, but can be w/in hours.
3. Seen in 5-28% of patients receiving heparin
4. Plt counts return to baseline 4 days after d/c heparin
5. Less common with LMWH, and porcine mucosal
74
Type I HIT- is not
immune-mediated
| -Not clinically significant
75
Type I HIT-
| Appears within the first
two days of patient’s exposure to heparin (either LMWH or unfractionated)
76
Type I HIT-
| Mild, clinically irrelevant drop in platelet count, then the
Platelet count normalizes with continued heparin therapy
77
Type II HIT- is
Immune-mediated
78
Type II HIT-Appears
4-14 days after a patient’s exposure to (mostly unfractionated) heparin
79
Type II HIT-Moderate to severe
drop in platelet count (either a relative or absolute decrease)
80
Type II HIT-Does NOT spontaneously
resolve with continued heparin therapy
81
Type II HIT-Potentially
life-threatening
82
HIT syndrome is very, VERY closely associated with the
HIT antibody
| >90% correlation
83
Sensitivity=
The proportion of “sick” critters who are correctly identified by the test as having condition “X”
84
Specificity=
The proportion of healthy critters correctly identified by the test as not having the condition “X”
85
Positive Predictive Value=
The proportion of critters with positive tests that are true positives for condition “X”
86
Negative Predictive Value=
The proportion of critters with negative tests who are true negatives for condition “X”
87
HIT Antibody Epidemiology-
| Extremely difficult to get accurate information about HIT antibody prevalence or incidence after
prolonged or repeated exposure to heparin
88
HIT Antibody Epidemiology-
| Antibody presence alone
does not constitute HIT
89
HIT Antibody Epidemiology-
| Most individuals with HIT antibodies
do not have HIT syndrome
90
HIT Antibody Epidemiology-
| Detection of HIT antibodies alone is highly sensitive and specific for HIT, but it has a
very poor positive predictive value
91
4 HIT Antibody Diagnostic Tests
1. ELISA assay
2. HIPA (Heparin-Induced Platelet Aggregation Assay)
3. C-SRA (Serotonin Release Assay)
4. PaGIA (Particle Gel Immunoassay)
92
ELISA assay=
Measures antibodies to the heparin/PF4 complexes.
- Sensitivity >90%, but low specificity due to many false-positives.
- Commonly used as an initial screening test, but frequently has a slow turn-around time and very labor intensive
93
HIPA (Heparin-Induced Platelet Aggregation Assay)=
Measures the presence of antibodies to the heparin/PF4 complexes.
- Fairly high specificity, but only fair sensitivity (~50%), therefore best used as a confirmational test in conjunction with a more sensitive test.
- Also has a potentially slow turn-around time
94
C-SRA (Serotonin Release Assay)=
Measures serotonin released by platelets activated by the HIT antibodies.
- Very good sensitivity (~90%) and specificity approaching 100% makes C-SRA test the “gold standard” for HIT antibody diagnosis.
- Definitely has a slow turn-around time and is expensive and complex
95
PaGIA (Particle Gel Immunoassay)=
Uses polystyrene particles that are coated with PF4-heparin complexes to which patient serum is added and compared to a standard.
- A new test that’s easy and quick.
- High specificity, but cross-reacts with IgA and IgM antibodies so there’s lots of false positives (high negative predictive value).
96
how DO you Dx HIT Syndrome
1. Thrombocytopenia
2. Timing
3. THROMBOSIS!
4. Greinacher Scoring System
5. Lack of any other potential causes of profound thrombocytopenia
97
HIT Risk Factors
```
Unfractionated vs. LMW heparin
Bovine vs. Porcine derived heparin
Race
Sex
Surgical patients vs. medical patients
Post-organ transplant
Age
```
98
HIT Syndrome-
| ____% incidence in patients receiving extended heparin antithrombotic therapeutic exposure.
0.5-5.0%
99
HIT Syndrome-
| _____% incidence in patients receiving “normal” iatrogenic extended heparin exposure.
0.05-0.1%
100
HIT Syndrome-
| Nationally ____% prevalence in all heparin exposed patients
0.2%
101
HIT Syndrome-
| ____% of HIT Syndrome patients are cardiac surgery patients
50%
102
HIT Syndrome-
| ____% develop thrombosis when managed solely by cessation of heparin therapy when unusual thrombosis is diagnosed
50%
103
HIT Syndrome-
____ develop thrombosis within one month if thrombosis was not present at time of diagnosis and even after platelet levels normalize
1/3rd
104
HIT Syndrome-
| ____% die
25-30%
105
HIT Treatment
Anticoagulation
- DTIs (Direct Thrombin Inhibitors)
- Factor Xa inhibitors
- Heparinoids(?)
106
HIT Treatment- Do NOT use
warfarin or their ilk for the first 5 days!
(It steals Vitamin-K dependent factors necessary for activating protein C, thus temporarily acting as a pro-coagulant) In fact, give Vitamin K if patient has been receiving warfarin
107
HIT DTI Treatments (3)
1. Lepirudin (Refludan)
2. Bivalirudin (Angiomax)
3. Argatroban
108
Lepirudin (Refludan) half life
~80 minutes
-Can be MUCH longer since it is cleared by renal excretion (~48 hours in patients with severe renal dysfunction), and many of these patients have taken renal hits from HIT.
109
Lepirudin (Refludan) and Bivalirudin (Angiomax) are measured by
aPTT or ECT
110
Bivalirudin (Angiomax) half life
25 minutes
111
Lepirudin (Refludan) and Bivalirudin (Angiomax) is metabolized by
(proteolytic cleavage) and renally excreted
112
Bivalirudin (Angiomax) is less
immunogenic than lepirudin
113
Argatroban is the most commonly used therapy and D.O.C. for
HIT
114
Argatroban half life and clearance
50 minutes
| Hepatic clearance
115
Argatroban is MUCH less
immunogenic than the leech-derived alternatives, therefore better for long-term use
116
Argatroban has a 50% lower incidence of
hemorrhagic incidents than the leech-derived drugs
117
Argatroban is Very bad if
residual warfarin is present
118
Argatroban is monitored by
aPTT or ACT
119
HIT Factor Xa Inhibitor Treatments
Fondaparinux (Arixtra)
| Danaproid (Orgaron)
120
Fondaparinux (Arixtra)-
| A synthetic cousin of LMWH, but without
the heparin-related problems
121
Fondaparinux (Arixtra)-
| Unlike heparin, does not directly
inhibit thrombin
122
Fondaparinux (Arixtra)-
| Like heparin, binds to
ATIII
123
Fondaparinux (Arixtra)-
| Does not have unpleasant
warfarin interactions like the DTIs
124
Fondaparinux (Arixtra)-
| Half life and clearance
20 hours.
| Cleared unchanged by the kidneys
125
Danaproid (Orgaron)-
| A mixture of
heparan sulfate
dermatan sulfate
chondroitin sulfate
126
Danaproid (Orgaron)-
| Cross-reacts with
HIT sera
| -so it affects monitoring and has resulted in many treatment failures from under dosing
127
Activated Clotting Time=
1. Whole blood clotting time accelerated by using celite or kaolin activator (XII, XI)
2. Normal values are between 90-120s
128
Heparin Concentration=
Measured by cartridges containing various known amounts of Protamine and tissue thromboplastin activator. Based on Hep:Prot titrations, channel that clots off first is closest to actual heparin concentration.
-Useful for detecting heparin reversal
129
Activated Partial Thromboplastin Time (aPTT)=
Tests Intrinsic coagulation pathway (VIII, IX, XI)
Normal values are 26-39s
Very sensitive to heparin. Not useful during CPB
130
Prothrombin Time (PT)=
Tests extrinsic pathway (VII)
Normal values ~ 10-13s
Less sensitive to heparin
131
Thrombin Time=
Specific for common pathway
Normal values are <17s
Sensitive to effects of heparin
