Anticoagulation for CPB- Exam 1 Flashcards
What year was heparin discovered and by who?
1916, J. McLean
When was heparin purified?
1920’s
When was heparin the first used as a blood anticoagulated for transfusion?
1924, but results in febrile reactions
When was heparin pure enough for IV administration?
12 years after it was used as an anticoagulate; 1936
Heparin sources
Bovine Lung (previous bovine liver)
When did research discover peptide protamine?
1937, discovered it could neutralize effects of heparin
Who reported heparin induced anticoagulation for CPB in animals and when?
1939, Gibbon
Heparin Advantages
Readily available
Predictable response in majority of patients
Low incidence of side effects
Reversible with protamine
Easy to monitor anticoagulant effects (ACT)
Easy to monitor concentration in blood
Lower cost than alternatives
What are circulating mast cells called?
Basophils
What does heparin consist of?
Highly sulfated glycosaminoglycan present in mast cells
Heparin Relative
heparan; a lower sulfated form present on endothelial cells
How does heparin work?
Potentiation of ATIII to neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)
Heparin neutralizes which serine proteases?
VII, IX, X, XI, XII
Unfractionated Heparin
contains heparin molecules of varying lengths
What types of heparin chains bind better with ATIII and thrombin?
Longer chains (higher MW)
What sequence on heparin is required for ATIII interaction?
Specific pentasaccharide sequence along heparin chain
Heparin MW
3,000- 40,000 Daltons
Distribution of MW varies depending on source
Heparin Charge and Acidity
Highly negatively charged (highest negative charge density of any biological molecule)
Very, very acidic
Mucosal Heparin
Lower MW Higher dose required for same response Need 25-30% less Protamine to neutralize (Ultra low MW uses Xa inhibition- not reversed by Protamine) More expensive to produce less likely to cause HIT
Lung Heparin
Higher MW Greater Potency (lower dose required) more protamine required due to more ATIII interactions Cheaper to produce More likely to cause HIT
USP Units
United States Pharmacopoeia units
1 USP unit
amount of heparin that maintains fluidity of 1 mL of citrated sheep plasma for 1 hour after recalcification
BP units
British Pharmacopoeia units; sulfated ox blood activated with thromboplastin
EU units
European Pharmacopoeia units; recalcified sheep plasma in the presence of kaolin and cephalin incubated for 2 minutes therefore constituting an aPTT for sheep plasma
Heparin potency is measured by….
Activity, not number of molecules
Heparin Pharmacokinetics
Poor lipid solubility, safe for BBB and placenta
Biphasic elimination with peak effects at 1-2 min post admin via central line
Delayed in states of low CO or w. peripheral injection
Redistribution after 4-5 minutes to normal elimination
dose dependent half-life
Heparin’s Dose Dependent 1/2 life
100U/kg dose = 61 +/- 9 min
200U/kg dose = 93 +/- 6 min
400 U/kg dose= 126 +/- 24 min
Where is the majority of heparin bound?
Plasma; but some migrate to tissues
Clearance of Heparin
Portions excreted in urine depolymerized w. fewer sulfate groups that reduces activity by 50%
Endothelial cells, liver, and kidneys all play a role to varying degrees
Role of Hypothermia and 1/2 life
Delays clearance and increases 1/2 life
Heparin concentration is virtually consistent for 40-100 min at 25 degrees C
Converting C to F
C x (9/5) + 32 =F
ATIII activity is increased _______x in the presence of heparin
1,000- 10,000x
Which chain molecules bind to ATIII?
only larger chain molecules (1/3) of heparin bind to ATIII
Why wont smaller chains of heparin bind to ATIII?
They primarily have anti-Xa effect and minimal anti-IIa effects
Loading Dose of heparin
200-400U/kg (typically 300 U/kg)
How much heparin is usually added to prime?
5,000 to 20,000 U
Empiric Dosing of Heparin
Loading dose given/ACT verified.
Give additioal 50-100U/kg ever 30 min or as infrequently as every 2 hrs
No ACT checked due to theory of exiting variables that make ACT inaccurate
Heparin-Dose response curve (Bull)
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 amt determined from graph
ACT value indicating no clot formation in oxygenator
> 300 seconds
ACT considered life threatening
< 180 seconds inadequate
Questionable ACT values
180-300 seconds
When is value of 180 sec ok?
ECMO or other long-term support
Recommended ACT prior to starting bypass
480 seconds (provides good safety margin over 300 seconds)
Due to 10% interspecies variation and 10% test variability
Unwise to maintain ACT greater than what
> 600 seconds
Gravlee Heparin Dosing Protocol
Prime ECC with 3U heparin/mL pump prime
Initial dose 300U/kg IV
Draw sample 2-5 min after infusion
Give add’l heparin to get ACT > 400 seconds before bypass
Give add’l heparin to maintain ACT>400 seconds during normothermic bypass
Give add’l heparin as needed to maintain ACT>480 second during hypothermic bypass (24 - 30 degrees C)
Monitor ACT every 30 min (or more frequently if showing heparin resistance)
MW of Heparin and binding to platelets
Binding decreases with decreased MW
Heparin Resistance
When more than 600u/kg given and ACT still is 500,000
Septicemia/Hypereosinophilic syndrome/NTG
When is NTG clinically relevant
> 300 mcg/min
Familial ATIII Deficiency
Autosomal Dominant
1/2000 to 20,000 people
ATIII < 50% normal
15-30 y/o w. low limb venous thrombosis or PE
Precipiating factors: Pregancy, Infx, surgery (thrombosis, inability to get adequate anticoag for cardiac surgery)
Familial ATIII Deficiency Tx
Life long antithrombotic tx after dx
Decreases incidence of thromboembolic events by 65%
ATIII levels in infants and newborns
60-80% adult ATIII levels
But: don’t have thrombotic activity like adults do
@ 3 mo. 90% adult levels
Explains heparin resistance of newborns
Acquired ATIII Deficiency
More common than familial
When pts are on Heparin pre-op or have chronic DIC
ATIII levels plateau at 60% normal
Tx of ATIII Deficiency in OR
Transfusion of FFP
Administration of Recombinant ATIII (Thrombate or ATryn)
Expensive
What can cause HIT?
Large MW Heparin binds to plts releasing PF4, activates GPIIb/IIIa receptors, degranulation, and aggregation
HIT
Drop in plt counts to <100,000 or 50% reduction from baseline
2-10 days after initiation of heparin tx, but can be hrs
5-28% of patients receiving heparin
Plt counts return to baseline 4 days after d/c heparin
Less common with LMWH and porcine mucosal
Type I HIT
Non immune-mediated
First 2 days of exposure (LMWH or unfractionated)
Mild, clinically irrelevant drop in plt count
Plt count normalizes with continue heparin tx
not clinically significant
Type II HIT
Immune-mediated
4-14 days after patient’s exposure to (mostly unfractionated heparin)
Moderate to severe drop in plt count (relative or absolute decrease)
Dose not spontaneous resolve w. continued heparin tx
potentially life threatening
What is the correlation between HIT syndrome and HIT antibody?
> 90% correlation
Sensitivity
Proportion of “sick” correctly identified by test as having condition
Specificity
Proportion of healthy correctly identified by test as not having coniditon
PPV
proportion with positive tests that are true positives for condition x
NPV
proportion with negative tests who are true negatives for condition x
4 HIT Antibody Diagnostic Tests
ELISA Assay
HIPA
C-SRA
PaGIA
ELISA Assay
Measures antibodies to the heparin/PF4 complexes
Sensitivity > 90%, but low specificity due to many false-postiives
Commonly used as initial screening test, but frequently has a slow turn-around time and very labor intensive
HIPA
Heparin-Induced Platelet Aggregation Assay; measure the presence of antibodies to the heparin/PF4 complexes
Fairly high specificity, but only fair sensitivity (~50%),therefore best use as confirmation test in conjunction with a more sensitive test
Slow turn around
C-SRA
Serotonin Release Assay; measures serotonin released by platelets activated by the HIT antibodies
Very good sensitivity (~90%) and specificity approaching 100% making C-SRA test the gold standard, slow turn around, expensive complex
Gold standard for HIT antibody testing
C-SRA
PaGIA
Particle Gel Immunoassay; uses polystyrene particles that are coating with PF4-heparin complexes to which patient serum is added and compared to a standard
easy and quick
High specificity, but corss-reacts with IgA and IgM antibodies so there’s lots of false positives (high NPV)
How to Dx Hit?
Thrombocytopenia (absolute/relative drop from baseline)
Timing
Thrombosis (DVT, MIs, Stroke, lesions, GI necrosis)
Lack of other potential causes of profound thrombocytopenia
Greinacher Scoring System (hematologist)
HIT Risk Factors
Unfractionated (greatest risk factor) vs LMW Heparin
Bovine (worse) vs Porcine derived heparin
Race (blacks 2x more likely)
Sex (females more likely)
Surgical patients vs medical patients (cardiac bad, ortho worse)
Post-organ transplant
Age- over 60 ( are we not as careful though? )
Incidence of HIT in patients receiving extended heparin antithrombotic therapeutic exposure
0.5 to 5.0%
Incidence of HIT in patients receiving normal iatrogenic extended heparin exposure
0.05 to 0.1 %
National prevalence in all heparin exposed patients (HIT)
~0.2%
Percent of HIT syndrome patients that are cardiac surgery patients
~50%
Percent developing thrombosis when managed solely by cessation of heparin therapy when unusual thrombosis dx
~50%
How many develop thrombosis within one month if thrombosis was not present at the time of dx even after plt levels normalize
~1/3
What percent of HIT patients require limb amputation?
11%
Even more require other toes, fingers, nipples, ears
Where is HIT more common?
Veins/CVP catheter
What percent of HIT patients die?
25-30%
What can happen with HIT?
DIC
Acute, massive, global pulmonary thromboembolism
Death
amputations
HIT Tx
Anticoagulation by Direct Thrombin Inhibitors
Factor Xa inhibitors
Heparinoids
NO warfarin for 5 days
Why shouldnt a HIT patient use warfarin?
Warfarin steals vitamin-K dependent factors necessary for activating protein C, thus termporarily acting as a pro-coagulant)
Give the patient vitamin K
Direct Thrombin Inhibitor (DTI) Drugs
Lepirudin (refludan)
Bivalirudin (Angiomax)
Argatroban
Lepirudin (Refludan)
DTI Recombinant leech-saliva anticoagulant Normal 1/2 life ~80 min (~48 hrs in patients with renal dysf) Cleared by renal excretion Measured by aPTT or ECT Fairly immunogenic SubQ or IV
Bivalirudin (Angiomax)
Synthetic form of hiruin (leech saliva)
1/2 life 25 minutes
Metabolized and renally excreted so 1/2 life 3-4 hrs with renal problems
Less immunogenic than lepirudin
IVonly
Not common, presumable shorter 1/2 life and less experience
Also monitored by aPTT and ECT
Argatroban
Most commonly used tx and drug of choice for HIT
1/2 life 50 min
Hepatic clearance
Much less immunogenic than leech derived alternatives
better long term
50% lower incidence of hemorrhagic incidence than leech derived
VERY BAD if residual warfarin present (start vit. K first)
Monitored with aPTT or ACT
HIT Tx Factor Xa Inhibitors
Fondaparinux (Arixtra)
Danaproud (orgaron)
Fondaparinux (Atrixa)
Factor Xa inhibitor; HIT Tx Synthetic cousin of LMWH, w/o heparin problems Does not directly inhibit thrombin Binds to ATIII You can take with warfarin 1/2 life= 20 hrs cleared unchanged by kidneys subQ only Monitored by Anti-Xa assay (best) or ACT
Danaparoid (Orgaran)
Mostly overseas, used to be used in US
mixture of heparin sulfate, dermatan sulfate, and chondroitin sulfate
cross reacts w. HIT sera, so affects monitoring and has resulted in treatment failures from underdosing
Not available in USA
What should you keep in mind when using autotransfusion and cell salvage?
Don’t use heparin!!
HIT Patients on Bypass
Non-heparinized everything
Monitor Acts, maybe ECTs
No stasis
D/c agent 20-30 min prior to CPB termination
MUF
recirculate added agent and drain circuit ASAP
run cell-saver while you wait
avoid giving products for first several hours
limit heparin to <4 days for prevention; LMWH
Coagulation Testing
ACT Heparin concentration aPTT PT Thrombin Time Plt count FSP FDP TEG
ACT
Blood clotting time accelerated using celite or kaolin activator (XII, XI)
placed in warming block to prevent hypothermia interface
normal values 90-120s
results artificially prolonged by hypothermia, hemodilution, and aprotinin (celite)
relative value; not specific indicator of coag abnormalities
Heparin Concentration Testing
anticoag endpoint
measured by cartridges containing various known amts of protamin 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
decreased bleeding when [ ] maintained
aPTT
tests intrinsic pathway (VIII, IX, XI)
plasma separated in citrated tube and spun to activate XII
Known [ ] of platelet phospholipid and Ca ++ are added
Normal values are 26-39s
sensitive to heparin, not useful on CPB
PT
extrinsic pathway (VII)
plasma separated in citrated collection tube
known [ ] tissue phospholipid and Ca ++ are added
normal values ~10-13 but large institutional variances occur
international normalizing ratio developed to standardize
less sensitive to heparin
INR
international normalizing ratio
ratio of patients PT at institution to mean value at institution
Thrombin Time
Specific for common pathway
plasma isolated in citrated collection tube
ca++ and [ ] thrombin added to trigger fibrin clots
sensitive to effects of heparin
large doses of thrombin convert this test to a measurement of fibrinogen
normal values are <17s
Platelet count tests
automated or manual
quantity only- not a platelet function test
thromboelastography helps measure platelet function
Fibrin degradation (split) products
product of clot lysis
elevated levels can lead to inhibition of fibrin monomer cross-linking and even induce platelet dysfunction
Thromboelastography (TEG)
Measures efficiency of clot formation including:
How long it takes for clotting to begin
Speed of clot formation
Clot strength
Fibrinolysis
Platelet function (used for platelet mapping)
