Topic 2 Flashcards
1
Q
circulating mast cells called?
A
Basophils
2
Q
Heparin structure
A
Sulfated glycosaminoglycan present in mast
cells
3
Q
Heparan
A
close relative to heparin
lower sulfated form present on endothelial cells
4
Q
Heparin works predominantly via potentiation of …
A
potentiation of Antithrombin III (AT III) to neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)
5
Q
Unfractionated Heparin
A
most commonly used type of heparin by perfusionists (because it is cheaper)
6
Q
Long chains of unfractionated Heparin
A
(higher MW) bind better with AT-III and thrombin
7
Q
In unfractionated Heparin_____ required for AT-III interaction
A
Specific pentasaccharide sequence along heparin chain
8
Q
Unfractionated Heparin molecular weights
A
Range 3,000 - 40,000+ Daltons
Distribution of MW varies depending on source
9
Q
Highest negative charge density of any biological molecule
A
Heparin (very! acidic)
10
Q
Heparin Predominantly works via potentiation of Antithrombin III (AT III) to neutralize circulating thrombin and and other
activated serine proteases which are?
A
Activated serine proteases (VII, IX, X, XI, XII)
11
Q
Mucosal Heparin MW
A
lower than Lung Heparin
12
Q
Lung Heparin potency
A
greater potency than mucosal heparin so need a lower dose
13
Q
Heparin more likely to cause HIT ?
A
Lung Heparin
14
Q
Why does Lung Heparin need a larger protamine dose compared to Mucosal Heparin?
A
Lung Heparin requires more protamine due to having more ATIII interactions than Mucosal Heparin
15
Q
Mucosal Heparin protamine dose needed compared to Lung Heparin
A
Need 25-30% less Protamine to neutralize
Lower MW which uses Xa inhibition– not reversed by Protamine
16
Q
1 United States Pharmacopoeia (USP) unit
A
amount of heparin that maintains fluidity
of 1mL of citrated sheep plasma for 1 hour after
recalcification
17
Q
British Pharmacopoeia (BP) units
A
Sulfated ox blood activated with thromboplastin
18
Q
European Pharmacopoeia (EU) units
A
Recalcified sheep plasma in the presence of kaolin and cephalin incubated for 2 minutes therefore constituting an aPTT for sheep plasma
19
Q
Heparin half life with 100U/kg dose = __ min
A
61 ± 9minutes
20
Q
Heparin half life with 200U/kg dose = __ min
A
93± 6 minutes
21
Q
Heparin half life with 400U/kg dose = __ min
A
126 ± 24 minutes
22
Q
Heparin pharmacokinetics
_______ elimination with peak effects at __ minutes post administration via central line
—Delayed in states of ___ or with peripheral injection
A
Biphasic
1-2
low CO
23
Q
Heparin pharmacokinetics
Redistribution after ____ to normal elimination
A
4 - 5 min
24
Q
Hypothermia effect on Heparin
A
delays clearance and increases half-life
25
Heparin at 25*C
virtually constant for 40-100 min
26
Celsius to Fahrenheit
[°F] = [°C] × 9 / 5 + 32
short cut way (not totally accurate)
F = (C x 2) + 30
27
Fahrenheit to Celsius
[C] = [F] - 32 x 5 / 9
28
AT III in the presence of Heparin
is increased 1,000-10,000X
29
Size Chains of heparin that bind to AT III?
Only larger chain molecules (1/3) of heparin
30
Smaller Heparin chains primarily have ___ effect?
anti-Xa effect and minimal anti-IIa effects
31
In regards to the Initial Heparin dose:
- What is the loading does?
- What is the dose added to prime?
- Loading dose of 200-400U/kg given
| - 5,000 to 20,000U added to prime
32
Heparin Empiric dosing amount?
| The loading dose is given now what additional heparin amount do you give?
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)
33
Young et al (1978) found fibrin formation when ACT dropped _____
(study involving 9 rhesus monkeys)
below 400 seconds
Recommended minimum value of 480 seconds do to 10% interspecies variation and 10% test variability
34
Gravlee Heparin Protocol STEPS (6)
**Prime ECC with 3U of heparin per milliliter of pump prime
**Initial dose 300U/kg IV
**Draw sample for ACT 2 to 5 minutes after infusion
**Give additional heparin as needed to achieve ACT above 400 seconds
before initiation of bypass
Give additional heparin as needed to maintain ACT above 400 seconds
during normothermic bypass
**Give additional heparin as needed to maintain ACT above 480 seconds
during hypothermic bypass (24 to 30C)
**Monitor ACT every 30 minutes during bypass or more frequently if patient
shows heparin resistance
35
Heparin Complications
* *Heparin binds to platelets
* *Insufficient heparinization on bypass causes consumption of clotting factors.
* *Bleeding
36
Heparin binding to platelets causes
- Transient decrease in platelet count
| - Prolonged bleeding time
37
Heparin binding to platelets decreases with what?
Binding decreases with decreased MW (i.e.. LMWH)
38
Heparin binding site to platelets
No specific binding site yet determined
39
Heparin Resistance
When more than 600u/kg given and ACT still is <300 seconds
Higher than normal heparin doses for sufficient anticoagulation for bypass
40
Extreme thrombocytosis
Platelet count > 500,000
41
ATIII Deficiency causes?
Familial/ Congenital
| Acquired (Due to continued heparin therapy or estrogen based contraceptives)
42
Nitroglycerin
rare
| Clinically relevant only when > 300 mcg/min
43
Heparin Resistance causes (5)
```
Extreme thrombocytosis
Septicemia
Hypereosinophilic Syndrome (rare)
Nitroglycerin (rare)
ATIII Deficiency
```
44
ATIII Deficiency Inherited (Familial/Congenital)
| Factors precipitating occurrence: (3)
1. Pregnancy
2. Infection
3. Surgery
Thrombosis after surgery
Inability to get adequate anticoagulation for cardiac surgery
45
ATIII Deficiency Inherited (Familial/Congenital) affects __ people?
1/2000 to 20,000 people
46
ATIII Deficiency Inherited (Familial/Congenital)
| Presents at what age range? and with what physical expression?
Presents @ 15-30 years old with low limb venous thrombosis or Pulmonary Embolism
47
ATIII Deficiency Inherited (Familial/Congenital)
| Gene expression?
Autosomal dominant
48
ATIII Deficiency Inherited (Familial/Congenital) :
| Treatment ?
Life long antithrombotic therapy after diagnosis
| Decreases incidence of thromboembolic events by 65%
49
Infants and newborns have __ levels of ATIII
60-80% adult ATIII levels
they dont have problems because Newborns don’t have thrombotic activity like adults do
50
@ 3 months ATIII Levels
90% of adult levels
51
Acquired ATIII Deficiency occurs how?
Occurs when patients are on Heparin pre-op or have chronic DIC
ATIII levels plateau around 60% of normal
52
Acquired ATIII Deficiency treatment: (2)
Transfusion of FFP
| Administration of Recombinant ATIII (Thrombate or ATryn)
53
Platelet dysfunction can lead to
HIT
54
Heparin (Lrg MW) readily binds to platelets inducing release of : (4)
PF4
activation of GPIIb/IIIa receptors
platelet degranulation
platelet aggregation
55
HIT - Clinical condition characterized by a drop in platelet counts to ____ or _____from baseline
drop in platelet counts to <100,000 or 50% reduction from baseline
56
HIT - typically seen in ?
5-28% of patients receiving heparin
2-10 days after initiation of heparin therapy (can w/in hours)
57
HIT is less common with what types of Heparin?
LMWH and porcine mucosal heparin
58
HIT Type 1 --- appears when?
| ---platelet count normalizes when?
- not immune mediated
- appears withing first two days of heparin exposure (LMWH/unfractionated)
- platelet count normalizes with continues heparin therapy
NOT Clinically significant
59
HIT Type II - appears when?
| - resolves?
- immune mediated
- appears 4-14 days after heparin exposure (mostly unfractionated)
- can be life threatening
- does not spontaneously resolve with continued heparin therapy
60
HIT syndrom and HIT antibody have what correlation?
have a 90% correlation
Hit antibody causes HIT (but antibody presence alone does not mean they will get HIT!)
61
ELISA assay
measures IGG antibodies to heparin/PF4 complexes
| Sensitivity >90% (low specificity - many false positives)
62
4 HIT antibody diagnostic test
1) ELISA assay
2) HIPA
3) C-SRA
4) PaGIA
63
HIPA (Heparin-Induced Platelet Aggregation Assay)
Measures presence of antibodies to heparin/PF4 coplexes
| High specificity/ ~50% sensitivity
64
C-SRA (serotonin Release Assay)
- measures serotonin released by platelets activated by the HIT antibodies
- Sensitivity ~90% / Specificity ~100%
- GOLD STANDARD
- slow turn around/expensive/complex
65
PaGIA (Particle Gel Immunoassay)
Uses polystryrene particles coated with PF4-heparin complexes, patient serum added and compared to a standard
- quick and easy
- high specificity, but lots of false positives
66
How do you diagnosis HIT
- Clinical Diagnosis
- Thrombocytopenia (absolute or relative drop from baseline)
- THROMBOSIS
- Timing
- Greinacher Scoring System
67
HIT Risk Factores
- Race (African Americans more likely)
- Sex (females more likely)
- does not occur in pregnant women
- post organ transplant (very prone)
- cardiac and orthopedic(more) patients prone
68
% of HIT syndrome patients that are cardiac surgery patients
50%!
69
% of HIT national prevalence in all heparin esposures
~0.2%
| Includes quick procedures
70
% of HIT patients that require limb amputation
~11%
71
% HIT patients that die
25-30%
72
HIT Anticoagulation treatments (3):
- DTIs (Direct Thrombin Inhibitors)
- Factor Xa inhibitors
- Heparinoids
NEVER WARFARIN (if they did get warfarin give vitamin K)
73
Lepirudin (Refludan)
- what?
- T1/2
- Measured by?
- given?
HIT, DTI anticoagulation treatment
- recombinant leech-saliva anticoagulant
- T1/2 ~80 minutes (up to 48hrs with renal dysfunction)
- Measures by aPTT or ECT(eccrine clotting times)
- Given SubQ or IV
- Fairly immunogenic (allergic reaction)
74
Bivalirudin (Angiomax)
- what?
- T1/2
- immunogenic?
- Measured/monitored by?
- given?
HIT, DTI anticoagulation treatments
- synthetic form of hirudin(leech saliva)
- T1/2 ~25 min (3-4hrs with renal dysfunction)
- IV only
- less immunogenic than lepirudin (bc artificial)
- Measured by aPTT or ECT
- not common (newish/short half life
75
Argatroban
- T1/2
- clearance?
- immunogenic?
- Measured/monitored by?
HIT, DTI anticoagulation treatment
- MOST COMMON
- T1/2 ~50min
- clearance - hepatic
- much less immunogenic (better for long term use)
- Measured by aPTT or ECT
- 50% lower incidence of hemorrhagic incidents than leech derived drugs
76
Fondaparinux (Arixtra)
- what
- binds to
- T1/2
- clearance?
- given?
- Measured/monitored by?
HIT, Factor Xa Inhibitor, anticoagulant
- a synthetic cousin of LMWH (but w/no heparin probs) does not directly inhibit thrombin
- binds to ATIII
- T1/2 ~ 20 hours
- cleared unchanged by kidneys
- SubQ only
- Monitored by Anti-Xa assay or ACT
77
Danaproid (orgaron)
- what ?
- available?
HIT, Factor Xa Inhibitor, anticoagulant
- mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate
- cross-reacts with HIT sera, so difficult to diagnosis
- Not available in the US
78
What to do when you have a HIT patient? (6)
- Non-heparinized everything
- monitor - ACT/ECT
- NO stasis of blood
- discontinue coagulation agent 20-30 min prior bc no reversal agent
- MUF
- recirculate with added agent and drain circuit asap
79
ACT
whole blood clotting time accelerated bu using celite or kaolin activator (XII, XI)
normal value 92-128seconds
80
ACT results can be artificially prolonged by what? (3)
hypothermia, hemodilution, and aprotinin (celite)
81
aPTT
- tests INTRINSIC coagulation pathway (VIII, IX, XI)
- normal value - 26-39seconds
- very sensitive to heparin, NOT useful during CPB
82
PT
Tests Extrinsic Pathway VII
Normal value 10-14 seconds (lrg institutional variances)
-less sensitive to heparin than aPTT
83
aPTT and PT how do they do test?
plasma is separated in citrated tube and spun to activate XII, known concen of ...
aPTT- platelet phospholipid and Ca++ are added.
PT - tissue phospholipid and Ca++ are added
84
Thrombin Time
Specific for measuring Common pathway
Normal value <17 seconds
sensitive to effects of heparin
85
TT - how test works?
plasma isolated in citrated collection tube, Ca++ and concentration of thrombin are added to trigger clots
Lrg doses of thrombin convert this test to a measurement of Fibrinogen
86
```
Fibrin degradation (split) products
- elevated levels can lead to?
```
Product of clot lysis
| Elevated levels can lead to inhibition of fibrin monomer cross-linking and even induce platelet dysfunction
87
TEG measures ? (5)
The efficiency of clot formation:
- time takes for clotting to begin
- speed of clot formation
- clot strength
- fibrinolysis
- platelet function (platelet mapping)
