Anticoagulation Flashcards
heparin discovered in ___by____
1916 by J. Mclean
heparin purified
1920s
1st used to anticoagulate blood for
transfusion in
1924 Resulted in febrile reactions
heparin is obtained from _____ today
bovine lung. Much cheaper than the prior source: Bovine Liver
Research discovered peptide Protamine in
1937 Neutralizes the anticoagulant effects of heparin
Gibbon reported heparin-induced anticoagulation for CPB in animals in
- Lead to the selection of heparin for anticoagulation and Protamine to neutralize in first human CPB operation.
heparin advantages
Readily available, with predictable response in majority of patients
Relatively low incidence of side effects Readily reversible with Protamine Easy to monitor anticoagulant effects Easy to monitor concentration in blood Lower cost
Heparin structure
Highly sulfated glycosaminoglycan. present in mast cells. Close relative to heparan, a lower sulfated form
present on endothelial cells
how does heparin work
Predominantly works via potentiation of Antithrombin III (AT III) to neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)
unfractionated heparin
Contains heparin molecules of varying lengths
Longer chains (higher MW) bind better with AT-III and thrombin
Specific pentasaccharide sequence along heparin chain required for AT-III interaction
Molecular weights range from 3,000-40,000+ Daltons Distribution of MW varies depending on source Actions and potency varies from batch to batch
mucosal heparin
Lower MW Higher dose required for
the same response
Need 25-30% less Protamine to neutralize
Lower MW which 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
United States Pharmacopoeia (USP) units
1USP unit = amount of heparin that maintains fluidity of 1mL of citrated sheep plasma for 1 hour after recalcification.
British Pharmacopoeia (BP) units
Sulfated ox blood activated with thromboplastin
European Pharmacopoeia (EU) units
Recalcified sheep plasma in the presence of kaolin and cephalin incubated for 2 minutes therefore constituting an aPTT for sheep plasma
heparin pharmokinetics
Poor lipid solubility, safe for BBB & placenta Biphasic elimination with peak effects at 1-2 minutes
post administration via central line Delayed in states of low CO or with peripheral injection
Redistribution after 4-5 minutes to normal elimination
Dose dependent half-life (what’s this?)
100U/kg dose = 61 ± 9 minutes 200U/kg dose = 93 ± 6 minutes 400U/kg dose = 126 ± 24 minutes
majority of heparin is bound to____ but some _____
proteins, migrate to tissues
clearance of heparin
Portions are excreted in urine depolymerized with fewer
sulfate groups that reduces activity by 50%.
Endothelial cells, liver, and kidneys all play a role to varying degrees
ypothermia delays clearance and increases half-life
Heparin concentration is virtually constant for 40-100 min at 25*C (which is WHAT in Fahrenheit?)
ATIII increases heparin by
1,000-10,000X Only larger chain molecules (1/3) of heparin bind to AT III. Smaller chains primarily have anti-Xa effect and minimal anti-IIa effects. Patients have varied response to doses of heparin based on many factors. Standard dosing does NOT guarantee of adequacy of anticogulation
Initial dosing
Loading dose of 200-400U/kg given 5,000 to 20,000U added to prime
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
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 amount determined from graph
acceptable act values
No clot formation in oxygenator with ACT >300 seconds
ACT600 seconds seems unwise Young et al (1978) found fibrin formation when ACT dropped below 400
seconds (study involving 9 rhesus monkeys)
Recommended minimum value of 480 seconds do to 10% interspecies variation and 10% test variability
gravlee protocol
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 (24o to 30o C)
Monitor ACT every 30 minutes during bypass or more frequently if patient shows heparin resistance
heparin complications
Heparin binds to platelets No specific binding site yet determined Binding decreases with decreased MW (i.e.. LMWH) Transient decrease in platelet count Prolonged bleeding time
Insufficient heparinization on bypass causes consumption of clotting factors.
Bleeding Due to heparin rebound
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
causes of heparin resistance
ATIII Deficiency
Familial/ Congenital
Acquired (Due to continued heparin therapy or estrogen based contraceptives)
Extreme thrombocytosis Platelet count > 500,000
Septicemia
rare
Hypereosinophilic Syndrome
Nitroglycerin Clinically relevant only when > 300 mcg/min
Familial ATIII Deficiency
Inherited (Familial/ Congenital) Autosomal dominant 1/2000 to 20,000 people Usually ATIII < 50% normal
Presents @ 15-30 years old with low limb venous thrombosis or Pulmonary Embolism
Factors precipitating occurrence: Pregnancy
Infection Surgery
Thrombosis after surgery Inability to get adequate anticoagulation for cardiac surgery
Treatment: Familial ATIII Deficiency
Life long antithrombotic therapy after diagnosis
Decreases incidence of thromboembolic events by 65%
Infants and newborns: 60-80% adult ATIII levels
So why don’t they have problems?
Newborns don’t have thrombotic activity like adults do.
@ 3 months: 90% of adult levels Explains heparin resistance of newborns. Heparin resistance can occur even when therapeutic levels of plasma heparin concentration has been reached
Inability of Heparin to suppress the activity of thrombin
Acquired ATIII Deficiency
More common than Familial ATIII Deficiency. Occurs when patients are on Heparin pre-op or
have chronic DIC ATIII levels plateau around 60% of normal
Treatment of ATIII Deficiency in the OR
Transfusion of FFP
Administration of Recombinant ATIII (Thrombate or ATryn)
Cost$$$
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
Heparin Induced Thrombocytopenia
Clinical condition characterized by a drop in platelet counts to <100,000 or 50% reduction from baseline
Typically occurs between 2-10 days after initiation of heparin therapy, but can be w/in hours.
Seen in 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
Not immune-mediated
Appears within the first two days of patient’s exposure to heparin (either LMWH or unfractionated)
Mild, clinically irrelevant drop in platelet count
Platelet count normalizes with continued heparin therapy
Not clinically significant, EXCEPT.
Type II HIT
Immune-mediated
Appears 4-14 days after a patient’s exposure to (mostly unfractionated) heparin
Moderate to severe drop in platelet count (either a relative or absolute decrease)
Does NOT spontaneously resolve with continued heparin therapy
Potentially life-threatening
HIT syndrome is closely related to
HIT antibody (90%)
Sensitivity
The proportion of “sick” critters who are correctly identified by the test as having condition “X”
specificity
The proportion of healthy critters correctly identified by the test as not having the condition “X”
positive predictive value
The proportion of critters with positive tests that are true positives for condition “X”
negative predictive value
The proportion of critters with negative tests who are true negatives for condition “X”
HIT Antibody Epidemiology
Extremely difficult to get accurate information about HIT antibody prevalence or incidence after prolonged or repeated exposure to heparin.
Antibody presence alone does not constitute HIT!
Most individuals with HIT antibodies do not have HIT syndrome!
Detection of HIT antibodies alone is highly sensitive and specific for HIT, but it has a very poor positive predictive value.
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.
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.
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.
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).
Soooo…how DO you Dx HIT Syndrome?
Thrombocytopenia Absolute or relative drop from baseline
Timing thrombosis, Thrombosis, THROMBOSIS!
Deep vein thrombosis, MIs, strokes, skin lesions, GI necrosis, peripheral gangrene, arterial thrombosis, pulmonary embolism, etc., etc., etc.
Lack of any other potential causes of profound thrombocytopenia
Drugs, hypersplenism, cancer, hemodilution, etc. Greinacher Scoring System
Get a hematologist involved early and often!
Risk Factors for HIT
Unfractionated vs. LMW heparin Bovine vs. Porcine derived heparin Race Sex
Surgical patients vs. medical patients Cardiac patients bad…orthopedic
patients worst.
Post-organ transplant Age?
ncidence in patients receiving extended heparin antithrombotic therapeutic exposure.
.5-5%
___incidence in patients receiving “normal” iatrogenic extended heparin exposure.
.05-1%
____prevalence in all heparin exposed patients
.2%
____of HIT Syndrome patients are cardiac surgery patients!
50%
____D evelop thrombosis when managed solely by cessation of heparin therapy when unusual thrombosis is diagnosed.
50%
______develop thrombosis within one month if thrombosis was not present at time of diagnosis and even after platelet levels normalize.
1/3
MORBIDITY AND MORTALITY
Vein vs. artery? CVP catheter
~11% require limb amputation Even more require other amputations
Toes, fingers, nipples, ears Acute, massive, global pulmonary
thromboembolism
DIC ~25-30% DIE!
Treatment
Anticoagulation DTIs (Direct Thrombin Inhibitors) Factor Xa inhibitors Heparinoids(?)
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
DTI: Lepirudin (Refludan)
A recombinant leech-saliva anticoagulant
(Yum!) Normal T 1⁄2 is ~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.
Measured by aPTT or ECT Fairly immunogenic (who’d have guessed??!) SubQ or IV
DTI:Bivalirudin (Angiomax)
A synthetic form of hirudin (gotta love
leech saliva!) Shorter T 1⁄2 of ~25 minutes
Both metabolized (proteolytic cleavage) and renally excreted so T 1⁄2 is 3-4 hours with severe renal dysfunction.
Less immunogenic than lepirudin IV only
Not commonly used, presumably due to shorter half-life and less experience.
Also monitored by aPTT or ECT
DTI: Argatroban
*Most commonly used therapy and D.O.C.
for HIT. T 1⁄2 ~50 minutes Hepatic clearance
MUCH less immunogenic than the leech- derived alternatives, therefore better for long-term use.
~50% lower incidence of hemorrhagic incidents than the leech-derived drugs
Very bad if residual warfarin is present Monitored with aPTT or ACT
Treatment: Factor Xa Inhib
Treatment: Factor Xa Inhibitor
Danaproid (Orgaron)
A mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate
Cross-reacts with HIT sera, so it affects monitoring and has resulted in many treatment failures from underdosing.
Not available in U.S. A. (but used extensively overseas)
Autotransfusion and Cell Salvage
Pretty simple, really: DON’T
USE HEPARIN
So you’re going to do a HIT case, eh?
Endeavour to BE SURE a hematologist is on board.
“Do we need to D/C the heparin drip before we anesthetize this HIT patient?”
Be proactive. Be prepared.
But it’s only my second week doing cases and we’ve never done a HIT patient before!
Non-heparinized everything. Choice of anticoagulant. What to monitor? NO STASIS!
Discontinue agent 20-30 minutes prior to CPB termination.
MUF
Recirculate with added agent and drain circuit ASAP.
…and then?
Wait… and wait…
and wait… (don’t worry, you’ll be busy
running the cell-saver!)
Avoid giving products for first several hours (or as long as you can distract the surgeon.)
We’re done?
No more heparin (duh!)
If truly HIT, continue to treat (NOTHING seems to aggravate HIT like cardiopulmonary bypass!)
Prevention, or “I don’t want to do another one of these cases!”
Obtain medical history regarding previous sensitization to heparin; earlier monitoring may be required if patient previously received heparin
Baseline and monitoring levels on all patients receiving heparin
Limit heparin duration whenever possible to <4 days Avoid heparin flushes
Use warfarin early to minimize the length of heparin administration in patients requiring longer-term anticoagulation, except when HIT is diagnosed
Routinely initiate oral anticoagulation at start of heparin therapy in patients who need longer-term oral anticoagulation
Use LMWH if possible
Activated Clotting Time
Whole blood clotting time accelerated by using celite or kaolin activator (XII, XI)
Placed in warming block to prevent hypothermia interference
Volume required depends on instrument used
Normal values are between 90-120s
Results can be artificially prolonged by hypothermia, hemodilution, and aprotinin (celite)
Relative value, not a specific indicator of coagulation abnormalities
Heparin Concentration
When a baseline value is correlated to an ACT, this concentration can be an anticoagulation endpoint since it is not affected by outside values
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 Decreased bleeding when [ ] maintained??
Activated Partial Thromboplastin Time (aPTT)
Tests Intrinsic coagulation pathway (VIII, IX, XI) Plasma is separated in citrated tube and spun to
activate XII
Known [ ] of platelet phospholipid and Ca++ are added
Normal values are 26-39s Very sensitive to heparin. Not useful during CPB
Slide 65
Prothrombin Time (PT)
Tests extrinsic pathway (VII)
Plasma separated in citrated collection tube
Known [ ] of tissue phospholipid and Ca++ are added
Normal values ~ 10-13s but large institutional variances occur. International Normalizing Ratio (INR) developed to standardize PT.
INR= ratio of patients PT at institution to mean value at institution
Less sensitive to heparin
Thrombin time
Specific for common pathway
Plasma isolated in citrated collection tube
Ca++ and [ ] thrombin are 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
Other coag testing
Platelet count
Automated or manual
Quantity only – NOT a platelet function test
Thromboelastography (TEG) 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
TEG Thromboelastograhy
Measures the “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” *Visual interpretation is as much an “art” as it is a “science”
*You will receive an entire presentation specifically on TEGs
