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Perf tech II > test 7 > Flashcards

test 7 Flashcards

1
Q

J. McLean (1916)

A

-heparin discovery

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2
Q

1920

A

heparin purification

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3
Q

1924

A

1st used to anticoagulate blood for transfusion

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4
Q

1936

A
  • heparin pure enough for IV
  • discovered bovine lung is cheaper
  • used to be bovine liver
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5
Q

1937- Chargaff and Olson

A

discovered peptide Protamine

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6
Q

1939 – Gibbon

A

heparin-induced anticoagulation for CPB in animals

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7
Q

1953

A

– First CPB case

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8
Q

Heparin

A

 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

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9
Q

Heparin :

Structure and Function

A

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)

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10
Q

Heparin has a wide variety of sizes

A

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

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11
Q

Low molecular weight heparin works really well with what?

A

Factor Xa

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12
Q

Heparin: Sources

A

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)

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13
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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14
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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15
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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16
Q

British Pharmacopoeia (BP) units

A

Sulfated ox blood activated with thromboplastin

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17
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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18
Q

International Standard (IU)

A
  • Mean of pharmacopial methods
  • Because mass and potency (units) varies between preparations (molecules are different sizes)
  • Record units, not milligrams (records potency)
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19
Q

Heparin: Pharmacokinetics

A

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

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20
Q

What happens to ATIII when heparin present

A

 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

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21
Q

Where does heparin act?

A
  • mostly on thrombin and Xa

- also on IX, VIIIa, and prothrombinase complex

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22
Q

Heparin: Dosing Protocols

A

 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

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23
Q

Heparin: Acceptable ACT Values original work by Bull

A

 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

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24
Q

Heparin: Acceptable ACT Values Young research (1978)

A

-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

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25
Q

Hepcon vs ACT

A

use both if available

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26
Q

Gravlee Protocol

A

 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

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27
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

28
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

29
Q

Causes of Heparin Resistance

A 
 ATIII Deficiency
         Familial/ Congenital
         Acquired
 Extreme thrombocytosis
         Platelet count > 500,000
 Septicemia (rare)
 Hypereosinophilic Syndrome (rare)
 Nitroglycerin (rare)
30
Q

Familial ATIII Deficiency (Inherited (Familial/ Congenital))

A

 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

31
Q

Treatment for Familial ATIII Deficiency

A

 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

32
Q

What does ATIII do?

A
  • blocks the thrombin

- if levels low, high thrombin levels leading to more clotting

33
Q

Familial ATIII Deficiency in newborns

A

-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

34
Q

Acquired ATIII Deficiency

A

 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

35
Q

Treatment – Heparin Resistance (4)

A
  1. Give additional Heparin
  2. ATIII supplementation with FFP
  3. ATIII supplementation with ATIII concentrate
  4. No treatment – just go on bypass
36
Q

Heparin Resistance -

Treatment: Give more heparin

A

 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)

37
Q

Heparin Resistance -

Treatment: Give FFP

A 
 2 units
        Appx 1 unit ATIII / 1 mL FFP
        2 units FFP = 500 mL FFP = 500 units ATIII
 **Time delay to thaw
 **Transfusion risk
38
Q

Heparin Resistance -

Treatment: Give ATIII Concentrate

A

 Ex: Atryn – recombinant AT, Thrombate – Human purified AT
 Sometimes not available due to $$
 Offers targeted approach
 Less volume
 Less transfusion related complications – TRALI

39
Q

Heparin Resistance -

Treatment: Accept low ACT and go on bypass

A

 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

40
Q

What does HIT stand for?

A

Heparin Induced Thrombocytopenia

41
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

42
Q

Heparin Induced

Thrombocytopenia (HIT) types

A

Separate and distinct conditions
Type I
Type II

43
Q

HIT – Type 1

A

 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

44
Q

HITT – Type 2: Heparin Induced Thrombocytopenia and Thrombosis

A 
 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!!!
45
Q

What happens when a HITT patient is exposed to heparin

A

 Heparin exposure -> formation of Antibody (IgG)
 Fc part binds to heparin-PF4 complex on surface of platelet
 Fab part causes platelet activation , renders hypercoagulable

46
Q

characteristics of HITT

A

 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

47
Q

HIT Antibody Epidemiology

A

 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

48
Q

HIT Antibody Tests: ELISA Assay (antigen assay)

A

-measures how many antibodies there are

49
Q

HIT Antibody Tests: HIPA (Heparin-Induced Platelet Aggregation Assay)

A

 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

50
Q

HIT Antibody Tests: C-SRA (Serotonin Release Assay)

A

– measures serotonin released by platelets activated by the HIT antibodies
 Considered “gold standard”
 Expensive, slow turn around

51
Q

HIT Antibody Tests: PaGIA (Particle Gel Immunoassay)

A

 Newer, quicker than serotonin release assay

52
Q

4T Test

A
  • Do they have thrombocytopenia?
  • timing - how early the onset is gives them a higher score
  • do they have thrombosis
  • any other causes for thrombocytopenia
53
Q

See platelet count decrease after heparin exposure… what do you do

A

 Consider HIT
 Run tests – don’t assume!
-Get a hematologist involved!!

54
Q

HITT reaction

A

 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

55
Q

Heparin Alternatives

A

 Low Molecular Weight Heparins
 Defibrinogenating Agents (Not discussing)
 Ancrod
 Direct Thrombin Inhibitors (don’t require cofactors like ATIII)
 Hirudin
 Bivalirudin/ Angiomax
 Argatroban

56
Q

Heparin Alternatives: Low Molecular Weight Heparin

A

 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

57
Q

Direct Thrombin Inhibitors: Hirudin

A

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

58
Q

Alternatives to Heparin: Bivalirudin/ Angiomax

A

 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

59
Q

Alternatives to Heparin: Argatroban

A

 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

60
Q

Cell saver and HIT

A

DON’T USE HEPARIN!!!

-CPD instead

61
Q

Coagulation Testing: Activated Clotting Time

A

 Whole blood clotting time accelerated by using celite or kaolin activator (XII, XI)

62
Q

Coagulation Testing: Heparin Concentration

A

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

63
Q

Coagulation Testing: Activated Partial Thromboplastin Time (aPTT)

A

o Tests Intrinsic coagulation pathway (VIII, IX, XI)

o Very sensitive to heparin. Not useful during CPB

64
Q

Coagulation Testing: Prothrombin Time (PT)

A

o Tests extrinsic pathway (VII)
o Normal values ~ 10-13s
o Less sensitive to heparin

65
Q

Coagulation Testing: Thrombin Time

A

o Specific for common pathway
o Normal values are <17s
o Sensitive to effects of heparin

66
Q

Coagulation Testing: Platelet count

A

o Quantity only – NO functional testing

67
Q

Coagulation Testing: Fibrin degradation (split) products

A

o Product of clot lysis

Perf tech II (16 decks)

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