Exam 7 - Heparin & Heparin Reversal Flashcards
J. McClean
- Discovered Heparin in 1916
- 12 years later put in IV
- Bovine lung (cheaper)…previously liver
Chargaff and Olson
- Protamine in 1937
- 1953 first CPB with protamine
Heparin benefits
- Readily available
- Low side effects
- Reversible
- Easy to monitor…ACT/[Heparin]
- Cheap
Heparin Function
- Present in mast cells…unknown purpose
- Highly sulfated….relative of low sulfated, Heparan
- Boosts ATIII…neutralizes 7/9/10/11/12
Heparin Structure
- 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
Heparin source
- 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
4 potency assays
- International (common)
- US
- British
- European
United States Pharmacopoeia (USP)
- 1 USP = amount of heparin that maintains fluidity of 1 ml of citrates sheep plasma for 1 hour after recalcification
British Pharmacopoeia (BP)
- Sulfated of blood activated with thromboplastin
European Pharmacopoeia (EU)
- Recalcified sheep plasma w/ kaolin and cephalin incubated for 2 min…aPTT for sheep
International Units (IU)
- Mean of all other methods
- Units…not mg
- Mass/potency varies between batches
Heparin pharmacokinetics
- 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
Heparin Clearance
- 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
ATIII + Heparin
- ATIII increased 1000-10,000x w/ heparin
- Only HMWH (1/3 of heparin) bind to ATIII
- Standard dosing does NOT guarantee anticoagulation
Standard Initial dosing
- LD of 200-400 units/kg
- 5k-20k added to prime
Empiric dosing
- LD given
- Give 50-100 units/kg every 30 - 120 min
- No ACT needed after LD
Bull Heparin-dose response curve
- graph based on baseline ACT and LD ACT
- personalized dose response
- Heparin given only if ACT falls below limit
- Given based on curve
Heparin [ ] dose
- Find heparin [ ] in blood
- maintain at that level
Acceptable ACT values
- 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
Standard [heparin]
4.0 units / ml
[heparin] vs ACT
- Use BOTH if available
- ACT can be artificially high
- ATIII deficiency can yield low ACT times w/ good [ ]
Gravel protocol
- 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
Heparin complications
- 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
Heparin resistance definition
- when more than 600 units/kg given and ACT < 300
Heparin resistance causes
- 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
Congenital ATIII deficiency
- 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%
Infant congenital ATIII deficiency
- 60-80% of adult levels
- still not <50%…so normally ok
- at 3 months old: 90% of adults
- explains heparin resistance
Acquired ATIII deficiency
- more common than congenital
- when patients are on heparin pre-op
- around 60% of normal levels
Treatment of Heparin Resistance
- give more heparin
- ATIII boost w/ FFP
- ATIII boost w/ ATIII concentrate
- just go on bypass anyway
Treatment- give more heparin
- ceiling effect at 4.0 u/ml
- careful for heparin rebound
- can treat with protamine
Treatment - give FFP
- 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
Treatment - give FFP concentrate
- Atryn
- expensive
- BUT low volume / less TRALI / targeted approach
Heparin Induced Thrombocytopenia (HIT)
- 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)
HIT type I
- mild decrease
- not immune mediated / no big immune response
- as long as plt count not too low…can get heparin on CPB
HITT type II
- 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
Re-exposure HITT antibody
- 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
HIT antibody tests
- ELISA Assay
- HIPA Assay
- C-SRA
- PaGIA
ELISA
- 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
HIPA
- Heparin induced platelet aggregation assay
- FUNCTIONAL test
- measure antibodies to complex
- used in conjunction with more sensitive assays
- slow turn around
C-SRA
- Serotonin release assay (serotonin from antibodies)
- gold standard
- expensive
- slow turn around
PaGIA
- particle gel immunoassay
- new
- quick
4T test
- Thrombocytopenia
- Timing
- Thrombosis
- oTher causes of thrombocytopenia (drugs, cancer, dilution)
Moral of HIT story
- see platelet drop after Heparin ….
- consider HIT….
- run tests and don’t assume
- ask hematologist
What HIT can get heparin
HIT I: yes
HIT II w/ no antibodies and 90+ days no heparin: yes
HITT II: heparin alternative / platelet inhibitor
Heparin Alternatives
- LMWH
- Direct thrombin inhibitors
LMWH
- 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
Hirudin
- 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
Bivalirudin / Angiomax
- 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
Argatroban
- 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
Cell saver and HIT
- Don’t use heparin…saver will clot
- CPD or ACD
ACT
- activated clotting time
- normal is 90-120
- artificially high if:
- Hypothermia / hemodilutoin / aprotinin
- just a relative value
Heparin concentration
- useful for heparin reversal
- decreased bleeding when maintained
aPTT
- activated partial thromboplastin time
- tests INTRINSIC pathway (8, 9, 11)
- Normal = 26-39
- not useful during CPB
PT
- prothrombin time
- extrinsic pathway (7)
- normal = 10-13
- less sensitive to heparin
- INR: used to normalize values
Thrombin time
- common pathway
- normal = <17s
- sensitive to heparin
Platelet count
- no functional testing
- quantity only
Fibrin degradation products
- product of clot lysis
- elevated levels cause platelet dysfunction
Protamine
- 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
Reticuloendothelial System (RES)
- part of immune system
- clears stuff
- now called MPS
Consists of: - monocytes
- macrophages
- kupffer cells
Other protamine uses
- NPH insulin
- PZI zinc insulin
- both increase shelf life
Anticoagulation effects of protamine
- 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
Protamine fixed dose
- 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
ACT/Heparin dose response curve for protamine
- 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
Heparin concentration and protamine
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
Protamine titration
- 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
Protamine complications
- heparin/Protamine complex activates coag cascade
- allergic rxns
- pulmonary hypertension
- transient hypotension in most patients
Protamine reaction classification I
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
Protamine reaction classification II
A: histamine release
B: true anaphylaxis / antibody mediated
C: sever…like type III
Protamine pharmacological release
- 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
Risk factors of Protamine
- fish allergy….27%
- post vasectomy
- prior exposure (5% increase in risk)
Risk increase for prior reaction
189x
Risk increase for fish allergy
24.5x
Risk increase for exposure to NPH insulin
8.2x
Risk increase for any drug allergy
3x
Risk increase for prior exposure
None
Rate of administration of Protamine
< 5mg/minute
- 15 mg/minute is more likely common
Protamine alternatives
- let heparin metabolize
- plt concentrates
- Hexadimethrine
- Heparinase I
- Lactoferrin
- MUF
- none of these are great options
