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Perf Tech > Anticoagulation > Flashcards

Anticoagulation Flashcards

1
Q

heparin discovered in ___by____

A

1916 by J. Mclean

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2
Q

heparin purified

A

1920s

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3
Q

1st used to anticoagulate blood for

transfusion in

A

1924 Resulted in febrile reactions

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4
Q

heparin is obtained from _____ today

A

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

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5
Q

Research discovered peptide Protamine in

A

1937  Neutralizes the anticoagulant effects of heparin

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6
Q

Gibbon reported heparin-induced anticoagulation for CPB in animals in

A
  1. Lead to the selection of heparin for anticoagulation and Protamine to neutralize in first human CPB operation.
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7
Q

heparin advantages

A

 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

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8
Q

Heparin structure

A

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

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9
Q

how does heparin work

A

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

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10
Q

unfractionated heparin

A

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

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11
Q

mucosal heparin

A

 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

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12
Q

lung heparin

A

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

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13
Q

United States Pharmacopoeia (USP) units

A

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

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14
Q

British Pharmacopoeia (BP) units

A

 Sulfated ox blood activated with thromboplastin

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15
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

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16
Q

heparin pharmokinetics

A

 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

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17
Q

majority of heparin is bound to____ but some _____

A

proteins, migrate to tissues

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18
Q

clearance of heparin

A

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?)

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19
Q

ATIII increases heparin by

A

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

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20
Q

Initial dosing

A

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

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21
Q

empiric dosing

A

 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

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22
Q

Heparin-Dose response curve (Bull)

A

 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

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23
Q

acceptable act values

A

 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

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24
Q

gravlee protocol

A

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

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25
Q

heparin complications

A

 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

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26
Q

heparin resistance

A

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

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27
Q

causes of heparin resistance

A

 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

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28
Q

Familial ATIII Deficiency

A

 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

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29
Q

Treatment: Familial ATIII Deficiency

A

 Life long antithrombotic therapy after diagnosis

 Decreases incidence of thromboembolic events by 65%

30
Q

Infants and newborns: 60-80% adult ATIII levels

 So why don’t they have problems?

A

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

31
Q

Acquired ATIII Deficiency

A

 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$$$

32
Q

Platelet Dysfunction

A

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

33
Q

Heparin Induced Thrombocytopenia

A

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

34
Q

Type I HIT

A

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.

35
Q

Type II HIT

A

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

36
Q

HIT syndrome is closely related to

A

HIT antibody (90%)

37
Q

Sensitivity

A

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

38
Q

specificity

A

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

39
Q

positive predictive value

A

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

40
Q

negative predictive value

A

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

41
Q

HIT Antibody Epidemiology

A

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.

42
Q

ELISA assay

A

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.

43
Q

HIPA (Heparin-Induced Platelet

Aggregation Assay):

A

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.

44
Q

C-SRA (Serotonin Release Assay):

A

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.

45
Q

PaGIA (Particle Gel Immunoassay)

A

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).

46
Q

Soooo…how DO you Dx HIT Syndrome?

A

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!

47
Q

Risk Factors for HIT

A

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?

48
Q

ncidence in patients receiving extended heparin antithrombotic therapeutic exposure.

A

.5-5%

49
Q

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

A

.05-1%

50
Q

____prevalence in all heparin exposed patients

A

.2%

51
Q

____of HIT Syndrome patients are cardiac surgery patients!

A

50%

52
Q

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

A

50%

53
Q

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

A

1/3

54
Q

MORBIDITY AND MORTALITY

A

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!

55
Q

Treatment

A

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

56
Q

DTI: Lepirudin (Refludan)

A

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

57
Q

DTI:Bivalirudin (Angiomax)

A

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

58
Q

DTI: Argatroban

A

*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

59
Q

Treatment: Factor Xa Inhibitor

A

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)

60
Q

Autotransfusion and Cell Salvage

A

Pretty simple, really: DON’T

USE HEPARIN

61
Q

So you’re going to do a HIT case, eh?

A

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.

62
Q

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

A

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!)

63
Q

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

A

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

64
Q

Activated Clotting Time

A

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

65
Q

Heparin Concentration

A

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??

66
Q

Activated Partial Thromboplastin Time (aPTT)

A

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

67
Q

Prothrombin Time (PT)

A

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

68
Q

Thrombin time

A

 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

69
Q

Other coag testing

A

 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

70
Q

TEG Thromboelastograhy

A

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

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