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562 - Perfusion Technology II > Exam 7 - Heparin & Heparin Reversal > Flashcards

Exam 7 - Heparin & Heparin Reversal Flashcards

1
Q

J. McClean

A
  • Discovered Heparin in 1916
  • 12 years later put in IV
    • Bovine lung (cheaper)…previously liver
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2
Q

Chargaff and Olson

A
  • Protamine in 1937

- 1953 first CPB with protamine

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3
Q

Heparin benefits

A
  • Readily available
  • Low side effects
  • Reversible
  • Easy to monitor…ACT/[Heparin]
  • Cheap
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4
Q

Heparin Function

A
  • Present in mast cells…unknown purpose
  • Highly sulfated….relative of low sulfated, Heparan
  • Boosts ATIII…neutralizes 7/9/10/11/12
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5
Q

Heparin Structure

A
  • Highly fractionated
  • Long chains bind with ATIII/Thrombin/Xa
  • Short chain bind Xa only
  • 3k-40k daltons (mean = 15k)
  • actions/potency vary batch to batch
  • VERY negative…VERY acidic
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6
Q

Heparin source

A
  • Porcine intestinal mucosa (more LMWH…less potent)
    • 25-30% less protamine needed to reverse
    • LMWH more interaction with Xa…not reversed by protamine
    • more likely post-op bleed
    • expensive
  • Bovine lung tissue (more potent)
    • cheaper
    • HMWH
    • more likely to cause HIT
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7
Q

4 potency assays

A
  • International (common)
  • US
  • British
  • European
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8
Q

United States Pharmacopoeia (USP)

A
  • 1 USP = amount of heparin that maintains fluidity of 1 ml of citrates sheep plasma for 1 hour after recalcification
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9
Q

British Pharmacopoeia (BP)

A
  • Sulfated of blood activated with thromboplastin
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10
Q

European Pharmacopoeia (EU)

A
  • Recalcified sheep plasma w/ kaolin and cephalin incubated for 2 min…aPTT for sheep
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11
Q

International Units (IU)

A
  • Mean of all other methods
  • Units…not mg
  • Mass/potency varies between batches
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12
Q

Heparin pharmacokinetics

A
  • stays intravascular
  • hydrophilic / safe for BBB and placenta
  • still can bind to proteins in blood…can migrate to tissue
  • peaks at 1-2 min IV…unless low CO or with peripheral injection
  • distribution at 4-5 min
  • 13 min to wear off
  • dose dependent half-life…higher dose = higher half life
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13
Q

Heparin Clearance

A
  • part renal metabolism / part other metabolism
    • endo cells, liver, kidneys all play role
  • hypothermia delays clearance AND increases half life
  • [ ] constant for 40-100 min at 25C
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14
Q

ATIII + Heparin

A
  • ATIII increased 1000-10,000x w/ heparin
  • Only HMWH (1/3 of heparin) bind to ATIII
  • Standard dosing does NOT guarantee anticoagulation
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15
Q

Standard Initial dosing

A
  • LD of 200-400 units/kg

- 5k-20k added to prime

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16
Q

Empiric dosing

A
  • LD given
  • Give 50-100 units/kg every 30 - 120 min
  • No ACT needed after LD
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17
Q

Bull Heparin-dose response curve

A
  • graph based on baseline ACT and LD ACT
  • personalized dose response
  • Heparin given only if ACT falls below limit
  • Given based on curve
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18
Q

Heparin [ ] dose

A
  • Find heparin [ ] in blood

- maintain at that level

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19
Q

Acceptable ACT values

A
  • original work by Bull
  • > 300 is safe level
  • 480 is accepted (Young, et all. Raised to 480)
  • not strong science behind that number
  • may be lower for ECMO…180
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20
Q

Standard [heparin]

A

4.0 units / ml

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21
Q

[heparin] vs ACT

A
  • Use BOTH if available
  • ACT can be artificially high
  • ATIII deficiency can yield low ACT times w/ good [ ]
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22
Q

Gravel protocol

A
  • Prime w/ 5units/ml of pump prime
  • LD = 350-400 units/kg IV
  • draw sample 2-5 min after LD
  • give more heparin to get ACT > 400 to go on
  • give maintenance dose to keep ACT > 400
    • 480 if hypothermic (24-30C)
  • monitor every 30 min or more if needed
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23
Q

Heparin complications

A
  • Bind to platelets
    • decreases in LMWH
    • transient 5-7% decrease in platelet count per day
    • longer bleed time
  • Insufficient heparin [ ] can consume clot factors
    • bad for post-op recovery…more bleed post-op
  • Bleeding from rebound…comes back from tissues
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24
Q

Heparin resistance definition

A
  • when more than 600 units/kg given and ACT < 300
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25
Q

Heparin resistance causes

A
  • ATIII deficiency
    • congenital…run w/ lower [ ] on board
    • acquired…ATIII drop occurs once heparin is in
  • Extreme thrombocytosis…platelet count > 5000,000

Rare:

  • septicemia
  • hypereosinophillic syndrome
  • Nitroglycerin
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26
Q

Congenital ATIII deficiency

A
  • Autosomal dominant
  • 1 in 2k-20k
  • ATIII < 50% normal
  • Presents at 15-30 yo w/ venous thrombosis or PE
  • Factors precipitating occurrence:
    • pregnancy/infection/surgery
  • Hep resistance can still occur even if hep [ ] is good
    • super thrombin

Treatment:
- life long antithrombotic therapy….decreases events by 65%

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27
Q

Infant congenital ATIII deficiency

A
  • 60-80% of adult levels
    • still not <50%…so normally ok
  • at 3 months old: 90% of adults
  • explains heparin resistance
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28
Q

Acquired ATIII deficiency

A
  • more common than congenital
  • when patients are on heparin pre-op
  • around 60% of normal levels
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29
Q

Treatment of Heparin Resistance

A
  • give more heparin
  • ATIII boost w/ FFP
  • ATIII boost w/ ATIII concentrate
  • just go on bypass anyway
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30
Q

Treatment- give more heparin

A
  • ceiling effect at 4.0 u/ml
  • careful for heparin rebound
    • can treat with protamine
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31
Q

Treatment - give FFP

A
  • 2 units FFP = 500 ml FFP = 500 units ATIII
    Cons:
  • time delay to thaw
  • transfusion risk
    • can cause TRALI (pulmonary edema)
  • never give into circuit…directly to patient if possible
32
Q

Treatment - give FFP concentrate

A
  • Atryn
  • expensive
  • BUT low volume / less TRALI / targeted approach
33
Q

Heparin Induced Thrombocytopenia (HIT)

A
  • platelet count drop to <100,000 or 50% of baseline
  • occurs 2-10 days after heparin…but can be hours
  • incidence = 5-28% (just platelet drop part)
  • return normal 4 days d/c heparin
  • Less common with LMWH (porcine)
34
Q

HIT type I

A
  • mild decrease
  • not immune mediated / no big immune response
  • as long as plt count not too low…can get heparin on CPB
35
Q

HITT type II

A
  • severe / life threatening
  • incidence = 0.5-4% on heparin in 5-10 days or re-exposure
  • immune mediated
  • does not spontaneously resolve
  • plt count < 50k and 75% chance of thrombosis
  • patient history vital for determining re-exposure
36
Q

Re-exposure HITT antibody

A
  • IgG
  • Fc part (bottom) binds to heparin complex on platelet
  • Fab part (top of Y) activates platelets
  • presence of antibody dose NOT mean HITT imminent
37
Q

HIT antibody tests

A
  • ELISA Assay
  • HIPA Assay
  • C-SRA
  • PaGIA
38
Q

ELISA

A
  • antigen assay
  • use in conjunction with functional test
  • > 90% sensitive
  • 25-50% have antibodies….1-3% get HIT
  • good initial screen
  • slow turn around
  • labor intensive
39
Q

HIPA

A
  • Heparin induced platelet aggregation assay
  • FUNCTIONAL test
  • measure antibodies to complex
  • used in conjunction with more sensitive assays
  • slow turn around
40
Q

C-SRA

A
  • Serotonin release assay (serotonin from antibodies)
  • gold standard
  • expensive
  • slow turn around
41
Q

PaGIA

A
  • particle gel immunoassay
  • new
  • quick
42
Q

4T test

A
  • Thrombocytopenia
  • Timing
  • Thrombosis
  • oTher causes of thrombocytopenia (drugs, cancer, dilution)
43
Q

Moral of HIT story

A
  • see platelet drop after Heparin ….
  • consider HIT….
  • run tests and don’t assume
  • ask hematologist
44
Q

What HIT can get heparin

A

HIT I: yes
HIT II w/ no antibodies and 90+ days no heparin: yes
HITT II: heparin alternative / platelet inhibitor

45
Q

Heparin Alternatives

A
  • LMWH

- Direct thrombin inhibitors

46
Q

LMWH

A
  • FDA approved for DVT / prophylaxis
  • lower affinity for platelets…only Xa
  • less rebound…better dose-response curve
  • longer half-life…110-200 minutes
  • need less protamine….25-30% less
  • less bleeding complications
  • renal excretion
  • hard to measure
47
Q

Hirudin

A
  • Direct thrombin inhibitor
  • salivary gland of leeches
  • inhibits thrombin independent of ATIII
  • half life = 30-60 min…bolus then continuous infusion
  • renal clearance
  • ECT…like ACT
48
Q

Bivalirudin / Angiomax

A
  • direct thrombin inhibitor
  • synthetic of Hirudin
  • self-inhibitor as well…once it binds to thrombin
    • nor reversal drug needed
  • half life = 24 min
  • NEED to avoid stasis
  • use in crystalloid Cardioplegia
  • good for liver failure patients
  • run blood draws all case
  • ACT 2.5x baseline
49
Q

Argatroban

A
  • direct thrombin inhibitor
  • use for HIT patients
  • half life = 40 min
  • good for RI patients …liver metabolism
  • aPTT 1.5-3x baseline
  • patients clot and bleed at same time
50
Q

Cell saver and HIT

A
  • Don’t use heparin…saver will clot

- CPD or ACD

51
Q

ACT

A
  • activated clotting time
  • normal is 90-120
  • artificially high if:
    • Hypothermia / hemodilutoin / aprotinin
  • just a relative value
52
Q

Heparin concentration

A
  • useful for heparin reversal

- decreased bleeding when maintained

53
Q

aPTT

A
  • activated partial thromboplastin time
  • tests INTRINSIC pathway (8, 9, 11)
  • Normal = 26-39
  • not useful during CPB
54
Q

PT

A
  • prothrombin time
  • extrinsic pathway (7)
  • normal = 10-13
  • less sensitive to heparin
  • INR: used to normalize values
55
Q

Thrombin time

A
  • common pathway
  • normal = <17s
  • sensitive to heparin
56
Q

Platelet count

A
  • no functional testing

- quantity only

57
Q

Fibrin degradation products

A
  • product of clot lysis

- elevated levels cause platelet dysfunction

58
Q

Protamine

A
  • 67% arginine
  • salmon sperm (now recombinant tech)
  • very alkaline…very positive
  • binds with heparin to form salt
  • itself is anticoagulant if solo
  • heparin-protamine complex cleared by RES
59
Q

Reticuloendothelial System (RES)

A
  • part of immune system
  • clears stuff
  • now called MPS
    Consists of:
  • monocytes
  • macrophages
  • kupffer cells
60
Q

Other protamine uses

A
  • NPH insulin
  • PZI zinc insulin
  • both increase shelf life
61
Q

Anticoagulation effects of protamine

A
  • most tolerate excess of 1-2 mg/kg with no side effects
  • overdose can cause platelet dysfunction for hours
  • 6-15 mg/kg effects can be seen
    • hypertension
62
Q

Protamine fixed dose

A
  • give fixed amount
  • usually 1-1.3 mg per 100 units of heparin
  • based on total heparin given or heparin LD
    Good:
  • simple
  • no ACT
    Bad:
  • variable heparin half life…could be too much/little
63
Q

ACT/Heparin dose response curve for protamine

A 
- just like we do in class
Good:
- easy
- more accurate...less protamine given
- less blood products
Bad:
- needs ACT...and other factors influence ACT besides heparin
64
Q

Heparin concentration and protamine

A

Good:
- lower protamine doses vs ACT response curve
Bad:
- hard to test…usually only in lab
- takes time…may not reflect status quo [heparin]
- need plasma volume

65
Q

Protamine titration

A
  • use tubes w/ protamine to determine correct [heparin]
  • use to calculate heparin load with patient blood volume
    Good:
  • less protamine than fixed dose
  • less post-op bleed
  • less blood products
  • no heparin rebound
    Bad:
  • estimate patient blood volume
  • variability in heparin/protamine batches
66
Q

Protamine complications

A
  • heparin/Protamine complex activates coag cascade
  • allergic rxns
  • pulmonary hypertension
  • transient hypotension in most patients
67
Q

Protamine reaction classification I

A

I: mild hypotension
IIa: true anaphylaxis / antibody mediated
IIb: histamine/mediator release…no antibody mediation
IIc: delayed anaphylaxis / pulmonary edema
III: 0.6% of patients / pulmonary vasoconstriction / antibody mediated / pulmonary edema / need to flush quick

68
Q

Protamine reaction classification II

A

A: histamine release
B: true anaphylaxis / antibody mediated
C: sever…like type III

69
Q

Protamine pharmacological release

A
  • Protamine alone (not complex) can cause histamine release
  • from mast cells
  • cause hypotension
  • given on right side of heart
    • more time for protamine to bind to heparin
    • doesn’t enter lungs until end…lower observed dose
    • lungs have lots of mast cells
70
Q

Risk factors of Protamine

A
  • fish allergy….27%
  • post vasectomy
  • prior exposure (5% increase in risk)
71
Q

Risk increase for prior reaction

A

189x

72
Q

Risk increase for fish allergy

A

24.5x

73
Q

Risk increase for exposure to NPH insulin

A

8.2x

74
Q

Risk increase for any drug allergy

A

3x

75
Q

Risk increase for prior exposure

A

None

76
Q

Rate of administration of Protamine

A

< 5mg/minute

  • 15 mg/minute is more likely common
77
Q

Protamine alternatives

A
  • let heparin metabolize
  • plt concentrates
  • Hexadimethrine
  • Heparinase I
  • Lactoferrin
  • MUF
  • none of these are great options

562 - Perfusion Technology II (9 decks)

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