Anticoagulation

Question 1

heparin discovered in ___by____

Answer 1

1916 by J. Mclean

Question 2

heparin purified

Answer 2

1920s

Question 3

1st used to anticoagulate blood for

transfusion in

Answer 3

1924 Resulted in febrile reactions

Question 4

heparin is obtained from _____ today

Answer 4

bovine lung.  Much cheaper than the prior source: Bovine Liver

Question 5

Research discovered peptide Protamine in

Answer 5

1937  Neutralizes the anticoagulant effects of heparin

Question 6

Gibbon reported heparin-induced anticoagulation for CPB in animals in

Answer 6

1939. Lead to the selection of heparin for anticoagulation and Protamine to neutralize in first human CPB operation.

Question 7

heparin advantages

Answer 7

 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

Question 8

Heparin structure

Answer 8

Highly sulfated glycosaminoglycan. present in mast cells. Close relative to heparan, a lower sulfated form
present on endothelial cells

Question 9

how does heparin work

Answer 9

Predominantly works via potentiation of Antithrombin III (AT III) to neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)

Question 10

unfractionated heparin

Answer 10

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

Question 11

mucosal heparin

Answer 11

 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

Question 12

lung heparin

Answer 12

 Higher MW  Greater Potency
 Lower dose required
 More protamine required due to more ATIII interactions
 Cheaper to produce  More likely to cause HIT

Question 13

United States Pharmacopoeia (USP) units

Answer 13

 1USP unit = amount of heparin that maintains fluidity of 1mL of citrated sheep plasma for 1 hour after recalcification.

Question 14

British Pharmacopoeia (BP) units

Answer 14

 Sulfated ox blood activated with thromboplastin

Question 15

European Pharmacopoeia (EU) units

Answer 15

 Recalcified sheep plasma in the presence of kaolin and cephalin incubated for 2 minutes therefore constituting an aPTT for sheep plasma

Question 16

heparin pharmokinetics

Answer 16

 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

Question 17

majority of heparin is bound to____ but some _____

Answer 17

proteins, migrate to tissues

Question 18

clearance of heparin

Answer 18

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?)

Question 19

ATIII increases heparin by

Answer 19

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

Question 20

Initial dosing

Answer 20

 Loading dose of 200-400U/kg given  5,000 to 20,000U added to prime

Question 21

empiric dosing

Answer 21

 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

Question 22

Heparin-Dose response curve (Bull)

Answer 22

 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

Question 23

acceptable act values

Answer 23

 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

Question 24

gravlee protocol

Answer 24

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

Question 25

heparin complications

Answer 25

 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

Question 26

heparin resistance

Answer 26

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

Question 27

causes of heparin resistance

Answer 27

 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

Question 28

Familial ATIII Deficiency

Answer 28

 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

Question 29

Treatment: Familial ATIII Deficiency

Answer 29

 Life long antithrombotic therapy after diagnosis |  Decreases incidence of thromboembolic events by 65%

Question 30

Infants and newborns: 60-80% adult ATIII levels |  So why don’t they have problems?

Answer 30

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

Question 31

Acquired ATIII Deficiency

Answer 31

 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$$$

Question 32

Platelet Dysfunction

Answer 32

 Heparin (larger MW) readily binds to platelets inducing release of PF4, activation of GPIIb/IIIa receptors, degranulation, and aggregation.  Can lead to HIT

Question 33

Heparin Induced Thrombocytopenia

Answer 33

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

Question 34

Type I HIT

Answer 34

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.

Question 35

Type II HIT

Answer 35

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

Question 36

HIT syndrome is closely related to

Answer 36

HIT antibody (90%)

Question 37

Sensitivity

Answer 37

The proportion of “sick” critters who are correctly identified by the test as having condition “X”

Question 38

specificity

Answer 38

The proportion of healthy critters correctly identified by the test as not having the condition “X”

Question 39

positive predictive value

Answer 39

The proportion of critters with positive tests that are true positives for condition “X”

Question 40

negative predictive value

Answer 40

The proportion of critters with negative tests who are true negatives for condition “X”

Question 41

HIT Antibody Epidemiology

Answer 41

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.

Question 42

ELISA assay

Answer 42

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.

Question 43

HIPA (Heparin-Induced Platelet | Aggregation Assay):

Answer 43

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.

Question 44

C-SRA (Serotonin Release Assay):

Answer 44

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.

Question 45

PaGIA (Particle Gel Immunoassay)

Answer 45

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).

Question 46

Soooo...how DO you Dx HIT Syndrome?

Answer 46

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!

Question 47

Risk Factors for HIT

Answer 47

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?

Question 48

ncidence in patients receiving extended heparin antithrombotic therapeutic exposure.

Answer 48

.5-5%

Question 49

___incidence in patients receiving “normal” iatrogenic extended heparin exposure.

Answer 49

.05-1%

Question 50

____prevalence in all heparin exposed patients

Answer 50

.2%

Question 51

____of HIT Syndrome patients are cardiac surgery patients!

Answer 51

50%

Question 52

____D evelop thrombosis when managed solely by cessation of heparin therapy when unusual thrombosis is diagnosed.

Answer 52

50%

Question 53

______develop thrombosis within one month if thrombosis was not present at time of diagnosis and even after platelet levels normalize.

Answer 53

1/3

Question 54

MORBIDITY AND MORTALITY

Answer 54

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!

Question 55

Treatment

Answer 55

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

Question 56

DTI: Lepirudin (Refludan)

Answer 56

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

Question 57

DTI:Bivalirudin (Angiomax)

Answer 57

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

Question 58

DTI: Argatroban

Answer 58

*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

Question 59

Treatment: Factor Xa Inhibitor

Answer 59

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)

Question 60

Autotransfusion and Cell Salvage

Answer 60

Pretty simple, really: DON’T | USE HEPARIN

Question 61

So you’re going to do a HIT case, eh?

Answer 61

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.

Question 62

But it’s only my second week doing cases and we’ve never done a HIT patient before!

Answer 62

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!)

Question 63

Prevention, or “I don’t want to do another one of these cases!”

Answer 63

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

Question 64

Activated Clotting Time

Answer 64

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

Question 65

Heparin Concentration

Answer 65

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??

Question 66

Activated Partial Thromboplastin Time (aPTT)

Answer 66

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

Question 67

Prothrombin Time (PT)

Answer 67

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

Question 68

Thrombin time

Answer 68

 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

Question 69

Other coag testing

Answer 69

 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

Question 70

TEG Thromboelastograhy

Answer 70

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