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Perf Tech > Topic 2 > Flashcards

Topic 2 Flashcards

1
Q

Year?
Heparin first discovered by J. McLean
-so it’s one of the oldest drugs in continuous use

A

1916

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2
Q

Year?

Heparin Purification

A

1920’s

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3
Q

Year?
Heparin 1st used to anticoagulate blood for transfusion
-Resulted in febrile reactions

A

1924

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4
Q

Year?

heparin pure enough for IV administration

A

1936

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5
Q

Heparin can be obtained from

A 
bovine lung
bovine liver (cheaper)
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6
Q

Year?
Research discovered peptide Protamine
-Neutralizes the anticoagulant effects of heparin

A

1937

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7
Q

Year?
Gibbon reported heparin-induced anticoagulation for CPB in animals
-Lead to the selection of heparin for anticoagulation and Protamine to neutralize in first human CPB operation.

A

1939

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8
Q

Most widely used anticoagulant for cardiac surgery

A

Heparin

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9
Q

Heparin is readily available, with…

A

predictable response in majority of patients

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10
Q

Heparin has a relatively low incidence of…

A

side effects

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11
Q

Heparin is readily reversible with…

A

Protamine

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12
Q

Heparin is easy to monitor…

A

anticoagulant effects and concentration in blood

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13
Q

Heparin is lower in

A

cost

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14
Q

Heparin is highly sulfated glycosaminoglycan present in…

A

mast cells

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15
Q

Heparin is a close relative to heparan, which is a….

A

lower sulfated form present on endothelial cells

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16
Q

Heparin predominantly works via potentiation of …

A 
Antithrombin III (AT III) 
-to neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)
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17
Q

Heparin work on serine proteases…

A

VII, IX, X, XI, XII

7, 9, 10, 11, 12

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18
Q

Unfractionated heparin contains heparin molecules of…

A

varying lengths

  • Distribution of MW varies depending on source
  • Actions and potency varies from batch to batch
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19
Q

Longer chains (higher MW) bind better with…

A

AT-III and thrombin

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20
Q

Specific pentasaccharide sequence along heparin chain required for…

A

AT-III interaction

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21
Q

Heparin molecular weights range from…

A

3,000-40,000+ Daltons

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22
Q

Heparin is a highly…

A

negatively charged molecule

-highest negative charge density of any biological molecule

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23
Q

Heparin is very very

A

Acidic

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24
Q

Mucosal Heparin-

Has a lower…

A

Molecular weight

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25
Q

Mucosal Heparin-

Higher dose required for …

A

the same response

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26
Q

Mucosal Heparin-

Need ____% less Protamine to neutralize

A

25-30%

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27
Q

Mucosal Heparin-

Lower MW which uses…

A

Xa inhibition

– not reversed by Protamine

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28
Q

Mucosal Heparin-

More expensive to

A

produce

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29
Q

Mucosal Heparin-

LESS likely to cause

A

HITT

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30
Q

Lung Heparin-

Has a higher…

A

Molecular weight

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31
Q

Lung Heparin-

Has a greater Potency, which means…

A

Lower dose required

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32
Q

Lung Heparin-

More protamine required due to…

A

more ATIII interactions

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33
Q

Lung Heparin-

Cheaper to

A

produce

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34
Q

Lung Heparin-

MORE likely to cause

A

HITT

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35
Q

1 USP unit =

A

amount of heparin that maintains fluidity of 1mL of citrated sheep plasma for 1 hour after recalcification

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36
Q

BP unit =

A

Sulfated ox blood activated with thromboplastin

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37
Q

EU unit =

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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38
Q

Heparin has poor ___ solubility

A

lipid

-safe for BBB & placenta

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39
Q

Heparin has biphasic elimination with peak effects at ____ post administration via _____

A

1-2 minutes
central line
-Delayed in states of low CO or with peripheral injection

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40
Q

Heparin- Redistribution after _____ to normal elimination

A

4-5 minutes

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41
Q

Heparin has a dose ______ half-life

A

dependent

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42
Q

Half life: 100U/kg dose =

A

61 ± 9 minutes

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43
Q

Half life: 200U/kg dose =

A

93 ± 6 minutes

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44
Q

Half life:400U/kg dose =

A

126 ± 24 minutes

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45
Q

Majority of heparin is protein bound in

A

plasma, but some migrates to tissues

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46
Q

Clearance of heparin via

A
  1. Portions are excreted in urine depolymerized with fewer sulfate groups that reduces activity by 50%.
  2. Endothelial cells
  3. Liver
  4. Kidneys
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47
Q

Hypothermia delays ______ and increases _____

A

clearance

half-life

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48
Q

Heparin concentration is virtually constant for ____ at ____

A

40-100 min at 25*C

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49
Q

AT III activity is increased _____ in the presence of heparin

A

1,000-10,000X

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50
Q

Only larger chain molecules (1/3) of heparin bind to

A

AT III

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51
Q

Smaller chains primarily have

A

anti-Xa effect and minimal anti-IIa effects

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52
Q

Standard dosing does NOT guarantee of adequacy of

A

anticogulation

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53
Q

Initial dosing

A
  • Loading dose of 200-400U/kg given

- 5,000 to 20,000U added to prime

54
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
55
Q

Heparin-Dose response curve

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
56
Q

Gravlee Protocol (6)

A
  1. Prime with 3U of heparin per ml of pump prime
  2. Initial dose 300U/kg IV
  3. Draw sample for ACT 2 to 5 min after infusion
  4. Give additional heparin as needed to achieve ACT above 400 sec before initiation of bypass
  5. Give additional heparin as needed to maintain ACT above 400 sec during normothermic bypass or 480 sec during hypothermic bypass (24 to 30C)
  6. Monitor ACT every 30 min during bypass or more frequently if patient shows heparin resistance
57
Q

Heparin binds to

58
Q

Heparin binding decreases with

A

decreased MW (low molecular weight heparin)

59
Q

Insufficient heparinization on bypass causes

A

consumption of clotting factors

60
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

61
Q

Heparin Resistance causes

A
  1. ATIII Deficiency
  2. Extreme thrombocytosis
  3. Septicemia (rare)
  4. Hypereosinophilic Syndrome (rare)
  5. Nitroglycerin (rare)
62
Q

ATIII Deficiency

A

Familial/ Congenital

Acquired (Due to continued heparin therapy or estrogen based contraceptives)

63
Q

Extreme thrombocytosis

A

Platelet count > 500,000

64
Q

Nitroglycerin

A

Clinically relevant only when > 300 mcg/min

65
Q

Familial ATIII Deficiency: Inherited (Familial/ Congenital)=

A
  1. Autosomal dominant
  2. 1/2000 to 20,000 people
  3. Usually ATIII < 50% normal
  4. Presents @ 15-30 years old with low limb venous thrombosis or Pulmonary Embolism
66
Q

Familial ATIII Deficiency Treatment:

A

Life long antithrombotic therapy after diagnosis

-Decreases incidence of thromboembolic events by 65%

67
Q

Infants and newborns: ____ adult ATIII levels

A

60-80%

  • @ 3 months: 90% of adult levels
  • Explains heparin resistance of newborns
68
Q

Heparin resistance can occur even when therapeutic levels of

A

plasma heparin concentration has been reached

-Inability of Heparin to suppress the activity of thrombin

69
Q

Acquired ATIII Deficiency is more common than

A

Familial ATIII Deficiency

70
Q

Acquired ATIII Deficiency=

A

Occurs when patients are on Heparin pre-op or have chronic DIC
-ATIII levels plateau around 60% of normal

71
Q

Treatment of ATIII Deficiency in the OR=

A
  1. Transfusion of FFP

2. Administration of Recombinant ATIII (Thrombate or ATryn)

72
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

73
Q

Heparin Induced Thrombocytopenia=

A
  1. Clinical condition characterized by a drop in platelet counts to <100,000 or 50% reduction from baseline
  2. Typically occurs between 2-10 days after initiation of heparin therapy, but can be w/in hours.
  3. Seen in 5-28% of patients receiving heparin
  4. Plt counts return to baseline 4 days after d/c heparin
  5. Less common with LMWH, and porcine mucosal
74
Q

Type I HIT- is not

A

immune-mediated

-Not clinically significant

75
Q

Type I HIT-

Appears within the first

A

two days of patient’s exposure to heparin (either LMWH or unfractionated)

76
Q

Type I HIT-

Mild, clinically irrelevant drop in platelet count, then the

A

Platelet count normalizes with continued heparin therapy

77
Q

Type II HIT- is

A

Immune-mediated

78
Q

Type II HIT-Appears

A

4-14 days after a patient’s exposure to (mostly unfractionated) heparin

79
Q

Type II HIT-Moderate to severe

A

drop in platelet count (either a relative or absolute decrease)

80
Q

Type II HIT-Does NOT spontaneously

A

resolve with continued heparin therapy

81
Q

Type II HIT-Potentially

A

life-threatening

82
Q

HIT syndrome is very, VERY closely associated with the

A

HIT antibody

>90% correlation

83
Q

Sensitivity=

A

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

84
Q

Specificity=

A

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

85
Q

Positive Predictive Value=

A

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

86
Q

Negative Predictive Value=

A

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

87
Q

HIT Antibody Epidemiology-

Extremely difficult to get accurate information about HIT antibody prevalence or incidence after

A

prolonged or repeated exposure to heparin

88
Q

HIT Antibody Epidemiology-

Antibody presence alone

A

does not constitute HIT

89
Q

HIT Antibody Epidemiology-

Most individuals with HIT antibodies

A

do not have HIT syndrome

90
Q

HIT Antibody Epidemiology-

Detection of HIT antibodies alone is highly sensitive and specific for HIT, but it has a

A

very poor positive predictive value

91
Q

4 HIT Antibody Diagnostic Tests

A
  1. ELISA assay
  2. HIPA (Heparin-Induced Platelet Aggregation Assay)
  3. C-SRA (Serotonin Release Assay)
  4. PaGIA (Particle Gel Immunoassay)
92
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
93
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
94
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
95
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).
96
Q

how DO you Dx HIT Syndrome

A
  1. Thrombocytopenia
  2. Timing
  3. THROMBOSIS!
  4. Greinacher Scoring System
  5. Lack of any other potential causes of profound thrombocytopenia
97
Q

HIT Risk Factors

A 
Unfractionated vs. LMW heparin
Bovine vs. Porcine derived heparin
Race
Sex
Surgical patients vs. medical patients
Post-organ transplant
Age
98
Q

HIT Syndrome-

____% incidence in patients receiving extended heparin antithrombotic therapeutic exposure.

99
Q

HIT Syndrome-

_____% incidence in patients receiving “normal” iatrogenic extended heparin exposure.

100
Q

HIT Syndrome-

Nationally ____% prevalence in all heparin exposed patients

101
Q

HIT Syndrome-

____% of HIT Syndrome patients are cardiac surgery patients

102
Q

HIT Syndrome-

____% develop thrombosis when managed solely by cessation of heparin therapy when unusual thrombosis is diagnosed

103
Q

HIT Syndrome-
____ develop thrombosis within one month if thrombosis was not present at time of diagnosis and even after platelet levels normalize

104
Q

HIT Syndrome-

____% die

105
Q

HIT Treatment

A

Anticoagulation

  • DTIs (Direct Thrombin Inhibitors)
  • Factor Xa inhibitors
  • Heparinoids(?)
106
Q

HIT Treatment- Do NOT use

A

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

107
Q

HIT DTI Treatments (3)

A
  1. Lepirudin (Refludan)
  2. Bivalirudin (Angiomax)
  3. Argatroban
108
Q

Lepirudin (Refludan) half life

A

~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.

109
Q

Lepirudin (Refludan) and Bivalirudin (Angiomax) are measured by

A

aPTT or ECT

110
Q

Bivalirudin (Angiomax) half life

A

25 minutes

111
Q

Lepirudin (Refludan) and Bivalirudin (Angiomax) is metabolized by

A

(proteolytic cleavage) and renally excreted

112
Q

Bivalirudin (Angiomax) is less

A

immunogenic than lepirudin

113
Q

Argatroban is the most commonly used therapy and D.O.C. for

114
Q

Argatroban half life and clearance

A

50 minutes

Hepatic clearance

115
Q

Argatroban is MUCH less

A

immunogenic than the leech-derived alternatives, therefore better for long-term use

116
Q

Argatroban has a 50% lower incidence of

A

hemorrhagic incidents than the leech-derived drugs

117
Q

Argatroban is Very bad if

A

residual warfarin is present

118
Q

Argatroban is monitored by

A

aPTT or ACT

119
Q

HIT Factor Xa Inhibitor Treatments

A

Fondaparinux (Arixtra)

Danaproid (Orgaron)

120
Q

Fondaparinux (Arixtra)-

A synthetic cousin of LMWH, but without

A

the heparin-related problems

121
Q

Fondaparinux (Arixtra)-

Unlike heparin, does not directly

A

inhibit thrombin

122
Q

Fondaparinux (Arixtra)-

Like heparin, binds to

123
Q

Fondaparinux (Arixtra)-

Does not have unpleasant

A

warfarin interactions like the DTIs

124
Q

Fondaparinux (Arixtra)-

Half life and clearance

A

20 hours.

Cleared unchanged by the kidneys

125
Q

Danaproid (Orgaron)-

A mixture of

A

heparan sulfate
dermatan sulfate
chondroitin sulfate

126
Q

Danaproid (Orgaron)-

Cross-reacts with

A

HIT sera

-so it affects monitoring and has resulted in many treatment failures from under dosing

127
Q

Activated Clotting Time=

A
  1. Whole blood clotting time accelerated by using celite or kaolin activator (XII, XI)
  2. Normal values are between 90-120s
128
Q

Heparin Concentration=

A

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

129
Q

Activated Partial Thromboplastin Time (aPTT)=

A

Tests Intrinsic coagulation pathway (VIII, IX, XI)
Normal values are 26-39s
Very sensitive to heparin. Not useful during CPB

130
Q

Prothrombin Time (PT)=

A

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

131
Q

Thrombin Time=

A

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

Perf Tech (8 decks)

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