test 7 Flashcards
J. McLean (1916)
-heparin discovery
1920
heparin purification
1924
1st used to anticoagulate blood for transfusion
1936
- heparin pure enough for IV
- discovered bovine lung is cheaper
- used to be bovine liver
1937- Chargaff and Olson
discovered peptide Protamine
1939 – Gibbon
heparin-induced anticoagulation for CPB in animals
1953
– First CPB case
Heparin
Most widely used anticoagulant for cardiac surgery
Readily available
Predictable response in majority of patients
Relatively low incidence of side effects
Readily reversible with Protamine (otherwise you rely on metabolism)
Easy to monitor anticoagulant effects
ACT
Easy to monitor concentration in blood
Heparin Concentration
Low cost
Heparin :
Structure and Function
o Highly sulfated glycosaminoglycan
o Present in mast cells.
o Not sure about normal physiological purpose
o Close relative to heparan
o A lower sulfated form present on endothelial cells
o Predominantly works via potentiation of Antithrombin III (AT III)
o Neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)
Heparin has a wide variety of sizes
o Contains heparin molecules of varying lengths
o Longer chains (higher MW) bind better with AT-III and thrombin
o Specific pentasaccharide sequence along heparin chain required for AT-III interaction
o Molecular weights range from 3,000-40,000+ Daltons
o Mean: 15,000 Daltons
o Distribution of MW varies depending on source
o Tissue source, animal source, purification method
o Actions and potency varies from batch to batch
o Highly negatively charged molecule
o Very, VERY acidic
Low molecular weight heparin works really well with what?
Factor Xa
Heparin: Sources
o Originally from liver extracts
o Also found in intestinal mucosa and lung tissue
o Most common sources:
o Porcine intestinal mucosa (pig)
o Bovine lung tissue (cow)
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 HITLung Heparin
Higher MW
Greater Potency
Lower dose required
More protamine required due to more ATIII interactions
Cheaper to produce
More likely to cause HITUnited 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.
International Standard (IU)
- Mean of pharmacopial methods
- Because mass and potency (units) varies between preparations (molecules are different sizes)
- Record units, not milligrams (records potency)
Heparin: Pharmacokinetics
o Poor lipid solubility, safe for BBB & placenta
o Peak effects at 1-2 minutes post administration via central line
o Redistribution after 4-5 minutes to normal elimination
-1/2 life increases with dosage
Majority of heparin is protein bound in plasma, but some migrates to tissues
Clearance: portion excreted in the urine
-hypothermia delays clearance and increases 1/2 life
What happens to ATIII when heparin present
AT III activity is increased 1,000-10,000 times
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 anticoagulation
Where does heparin act?
- mostly on thrombin and Xa
- also on IX, VIIIa, and prothrombinase complex
Heparin: Dosing Protocols
Initial dosing
Loading dose of 200-400U/kg give
5,000 to 20,000U added to prime
Empiric dosing
-Check ACT then give additional hep ( 50-100 units/kg) every 30 minutes to 2 hours no matter what the ACT
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
Heparin: Acceptable ACT Values original work by Bull
No clot formation in oxygenator with ACT >300 seconds
ACT <180 seconds inadequate – considered life threatening
ACT between 180 and 300 seconds questionable
value of 180 seconds OK for ECMO other long-term support
Recommend ACT at least 480 seconds prior to initiation of bypass (provides good safety margin over 300 seconds)
Maintaining ACT >600 seconds seems unwise
Heparin: Acceptable ACT Values Young research (1978)
-Raised minimum ACT from 300 sec to 480 sec.
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
Hepcon vs ACT
use both if available
Gravlee Protocol
Prime ECC with 5 units of heparin per milliliter of pump prime
Initial dose 350-400 u/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
Extreme thrombocytosis
Platelet count > 500,000
Septicemia (rare)
Hypereosinophilic Syndrome (rare)
Nitroglycerin (rare)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
Treatment for Familial ATIII Deficiency
Life long antithrombotic therapy after diagnosis
Decreases incidence of thromboembolic events by 65%
Heparin resistance can occur even when therapeutic levels of plasma heparin concentration has been reached
Inability of Heparin to suppress the activity of thrombin
What does ATIII do?
- blocks the thrombin
- if levels low, high thrombin levels leading to more clotting
Familial ATIII Deficiency in newborns
-They have heparin resistance
-they have 60-80% of ATIII than adults because their systems are immature
Newborns don’t have thrombotic activity like adults do.
Studies show that ATIII levels above 65% are less likely to exhibit embolic events like that which occur when levels reach less than 50%
-this is why they don’t have problems
@ 3 months: 90% of adult levels
Explains heparin resistance of newborns
Acquired ATIII Deficiency
More common than Familial ATIII Deficiency.
Occurs when patients are on Heparin pre-op
Decrease ATIII levels ~5-7%/day
Plateau around 60% of normal
Treatment – Heparin Resistance (4)
- Give additional Heparin
- ATIII supplementation with FFP
- ATIII supplementation with ATIII concentrate
- No treatment – just go on bypass
Heparin Resistance -
Treatment: Give more heparin
Account for increased protein binding
Ceiling effect at 4.0 u/mL
Higher concentration unlikely to increase ACT further
**Caution
Heparin rebound (Treat with Protamine)
Heparin Resistance -
Treatment: Give FFP
2 units
Appx 1 unit ATIII / 1 mL FFP
2 units FFP = 500 mL FFP = 500 units ATIII
**Time delay to thaw
**Transfusion riskHeparin Resistance -
Treatment: Give ATIII Concentrate
Ex: Atryn – recombinant AT, Thrombate – Human purified AT
Sometimes not available due to $$
Offers targeted approach
Less volume
Less transfusion related complications – TRALI
Heparin Resistance -
Treatment: Accept low ACT and go on bypass
Fear of sub-therapeutic anticoagulation
Protocol:
Heparin Concentration to 4.0+ or >600 u/kg heparin given
ACT <400 sec
Assume ATIII deficiency
Give 500-1000 units ATIII
What does HIT stand for?
Heparin Induced Thrombocytopenia
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
Heparin Induced
Thrombocytopenia (HIT) types
Separate and distinct conditions
Type I
Type II
HIT – Type 1
Mild decrease in platelet count
Due to the pro-aggregatory effects of heparin
Normalizes with continued therapy
Appears within first 2 days of exposure to heparin
As long as platelet count isn’t too low, can receive heparin for CPB
HITT – Type 2: Heparin Induced Thrombocytopenia and Thrombosis
Aka. The “big hit” More severe / life threatening 0.5-4% of patients on heparin therapy Develops w/in 5-10 days, or upon re-exposure to heparin w/in 6 months. **IMMUNE MEDIATED** Moderate to severe drop in platelet count Does not spontaneously resolve Potentially life-threatening!!!
What happens when a HITT patient is exposed to heparin
Heparin exposure -> formation of Antibody (IgG)
Fc part binds to heparin-PF4 complex on surface of platelet
Fab part causes platelet activation , renders hypercoagulable
characteristics of HITT
Characterized by severe thrombocytopenia (<50,000) and formation of thrombus in 75% of patients
Can lead to stroke, MI, PE, limb threatening ischemia.
Patient history vital in determining re-exposure
HIT Antibody Epidemiology
Just because the patient has the antibody does NOT mean they have HIT
MOST patients with HIT antibodies DO NOT have HIT syndrome
Detection of HIT antibodies alone is highly sensitive and specific for HIT, but has a poor positive predictive value
HIT Antibody Tests: ELISA Assay (antigen assay)
-measures how many antibodies there are
HIT Antibody Tests: HIPA (Heparin-Induced Platelet Aggregation Assay)
Functional test (tells you funciton of the antibodies)
Measures what happens to the antibodies in the presence of that heparin platelet factor 4 complex
-needs to be used in conjunction with other more sensitive test
-slow turn around time
HIT Antibody Tests: C-SRA (Serotonin Release Assay)
– measures serotonin released by platelets activated by the HIT antibodies
Considered “gold standard”
Expensive, slow turn around
HIT Antibody Tests: PaGIA (Particle Gel Immunoassay)
Newer, quicker than serotonin release assay
4T Test
- Do they have thrombocytopenia?
- timing - how early the onset is gives them a higher score
- do they have thrombosis
- any other causes for thrombocytopenia
See platelet count decrease after heparin exposure… what do you do
Consider HIT
Run tests – don’t assume!
-Get a hematologist involved!!
HITT reaction
Antibodies become undetectable several weeks after d/c of heparin
Reaction doesn’t occur with every exposure
HIT 1: Can get heparin
HITT 2 with undetected antibodies + 90 days w/o heparin exposure: can get heparin
HITT 2 and a recent exposure to heparin: Heparin alternative OR Profound platelet-inhibiting drug
Heparin Alternatives
Low Molecular Weight Heparins
Defibrinogenating Agents (Not discussing)
Ancrod
Direct Thrombin Inhibitors (don’t require cofactors like ATIII)
Hirudin
Bivalirudin/ Angiomax
Argatroban
Heparin Alternatives: Low Molecular Weight Heparin
Short heparin chains have lower affinity for platelets (don’t have the sequence to bind with thrombin)
Bind less to plasma proteins
Do not bind endothelial cells in culture (less heparin rebound)
Increase bioavailablity
More constant dose-response curve
Reduced ability to inhibit thrombin, but are potent inhibitors of factor
Xa.
Longer half life than unfractionated heparin.
110-200 minutes
Renal excretion elimination
Less bleeding complications
Less likely to cause HIT (illicit less immune response)
Problematic for use on bypass b/c Xa inhibition is less responsive to Protamine neutralization than thrombin inhibition.
Hard to measure
Direct Thrombin Inhibitors: Hirudin
o Obtained from salivary glands of leeches
o Inhibits thrombin independent of ATIII
o Inhibits clot-bound and circulating thrombin
o T1/2 = 30-60mins with normal renal function
o Renal Clearance
o Ecarin Clotting Time (ECT) required for monitoring. Values of 300s have been shown to be adequate for CBP
o Bolus followed by continuous infusion (b/c half life is so short)
-doesn’t need a cofactor
Alternatives to Heparin: Bivalirudin/ Angiomax
Also a direct thrombin inhibitor like Hirudin
Synthetic derivative of Hirudin
Binds fluid and clot-bound thrombin
Enzymatic action cleaves thrombin and bivalirudin
-cleaves itself so you don’t need to worry about reversal agents
Inhibits activity of bivalirudin
Constant infusion
T1/2 ~ 24min
need to avoid stasis in CPB circuit and patient (chest cavity)
Linear dose response to ACT’s up to 300s
MINIMUM ACT 2.5x baseline accepted as therapeutic
Alternatives to Heparin: Argatroban
Inhibits thrombin by only binding to it’s catalytic site
Approved for use on HIT patients
Inhibits circulating and clot bound thrombin
Half life of 40 minutes
Liver metabolism
Good for RI patients
-good for renal dysfunction
-problems with bleeding and clotting in the same patient because it inhibits some activity and activates others
Cell saver and HIT
DON’T USE HEPARIN!!!
-CPD instead
Coagulation Testing: Activated Clotting Time
Whole blood clotting time accelerated by using celite or kaolin activator (XII, XI)
Coagulation Testing: Heparin Concentration
o When a baseline value is correlated to an ACT, this concentration can be an anticoagulation endpoint since it is not affected by outside values
Coagulation Testing: Activated Partial Thromboplastin Time (aPTT)
o Tests Intrinsic coagulation pathway (VIII, IX, XI)
o Very sensitive to heparin. Not useful during CPB
Coagulation Testing: Prothrombin Time (PT)
o Tests extrinsic pathway (VII)
o Normal values ~ 10-13s
o Less sensitive to heparin
Coagulation Testing: Thrombin Time
o Specific for common pathway
o Normal values are <17s
o Sensitive to effects of heparin
Coagulation Testing: Platelet count
o Quantity only – NO functional testing
Coagulation Testing: Fibrin degradation (split) products
o Product of clot lysis
