Establishment of the heparin
degradation curve using ACT
Tests using heparinase and ACT
Use of low molecular weight heparin
& ACT
Establishment of the heparin degradation curve using ACT
HEPARIN DOSE-RESPONSE CURVE
·
Based
on ACT
·
A
quantitative neutralisation of heparin method
·
Assumes
a linear dose response relationship between heparin and ACT
Determination of heparin dose prior to CPB
1.
Take
a control ACT(1) prior to heparinisation
2.
Administer
200U/Kg
3.
Measure
ACT(2) 5 min later
4.
Construct
heparin - ACT graph
5.
Extrapolate
an imaginary line through ACT(1) & ACT(2) to intersect with 480 second line
to find point ACT(3)
6.
There
difference in Heparin dose given to give ACT(2) point and the ACT(3) point is
the additional heparin needed to raise the ACT in the patient to 480 sec
Determination of amount of heparin required to
maintain anticoagulation
1.
Correct
the previous determined heparin-dose response curve by determining the ACT
[ACT(4)] 5 minutes after giving the supplementary heparin given prior to CPB
a) Correct the line by
drawing it from ACT(1) to midway between points ACT(3) & ACT(4)
2.
Measure
ACT on CPB (eg on rewarming)
3.
Use
this ACT value to determine the amount of heparin within the patient and how
much heparin is required to be added to bring the ACT back up to 480 (assuming
a drop in ACT)
Determination of amount needed to neutralise heparin
·
Undertaken
just prior to termination of CPB
·
Determine
amount of circulating heparin remaining
·
Assumes
only heparin is responsible for prolongation of ACT
1.
Determine
circulating heparin (see ‘determination of amount of heparin required to
maintain anticoagulation’)
2.
1.3
mg of protamine is used to neutralise each remaining 100 units of heparin
ACT levels on CPB
·
All
variables (vol blood, temp) must be controlled for reproducible results
·
Ranges
for optimal ACT values during CPB have not been established
·
Commonly
minimally acceptable ACT values are 300-480
·
ACT
< 300 have been reported without clinical effect
·
However,
the deleterious consequences of too low an ACT far exceed too high an ACT
·
Therefore
a minimum of 400 is acceptable
·
Initially
300—400 u/kg usually gives an acceptable ACT for CPB
·
If
the ACT is too low: 1) give
additional 5K—10K
2)
Construct heparin response curve
·
ACT
are determined on CPB at interval of no longer than:
1) Hypothermic: 60 min
2) Normothermic: 30 min
3) Rewarming: 30 min
·
Additional
dosages of 5K—10K are given as needed
·
Hypothermia
prolongs ACT {even when warmed sample to 37°C??}
·
On
rewarming from hypothermia, the ACT may drop to unsafe levels; therefore
require more frequent monitoring
·
Avoidance
of heparin underdose does not warrant overdosage:
i) Dose of heparin
determines dose of protamine
ii) Protamine’s toxic
effects are partially dose dependent
iii) High heparin dosages
are associated with increased incidence of heparin rebound
Heparin resistance
·
Shallow
dose-response curves: attenuated response to heparin
·
Failure
to treat and manage heparin resistance prior to CPB:
·
Low
grade activation of coagulation
·
Consumption
of platelets & procoagulants
·
Post
operative coagulopathy
1.
Technical
reasons
a)
Mislabelled
syringe
b)
Heparin
not injected intravascularly
c)
Heparin
of low activity (old or nonrefrigerated vials)
2.
Heparin
resistance [many result in 2° ATIII def]
a)
Previous
heparin use
b)
Pregnancy
c)
Oral
contraceptives
d)
IABP
e)
Shock
f)
Streptokinase
use
g)
ATIII
deficiency
h)
DIC
i)
Infective
endocarditis
j)
Intracardiac
thrombus
k)
Elderly
patient
3.
Management
a)
Additional
heparin
b)
FFP
2 units (adult) [don’t forget to heparinise bag]
APTT estimation on CPB
·
The
APTT is so sensitive to heparin induced anticoagulation that it would become
unclottable at heparin concentrations below
those deemed acceptable for CPB
·
However,
this sensitivity translates into an advantage in determining small residual
quantities of heparin after protamine neutralisation
Tests using heparinase and ACT
1.
Consists
of two cartridges
a)
one
has kaolin as the activating agent to determine ACT
b)
the
other has heparinase to remove any heparin in the blood sample and kaolin to
determine the heparin free ACT
2.
This
cartridge allows:
a)
verification
of the presurgical presence of heparin
b)
assessment
of the effect of CPB on the baseline ACT
c)
confirmation
of heparin reversal following protamine
d)
identification
of post surgical heparin rebound
e)
identification
of heparin in excessively bleeding postoperative patients
3.
Values
a)
The
heparinase channel provides the baseline ACT
b)
The
baseline ACT may rise due to dilutional coagulopathy
Use of low molecular weight heparin & ACT
LMWH
·
Low
molecular weight heparins are derived from low molecular fractions of
unfractionated heparin (produced by either chemical or enzymatic depolymerisation)
·
They
range in molecular weight from 4000 to
6500 daltons [in contrast to UFH: of 5000 to 30000 daltons ] of which
50-75% of the molecules are less than 18 saccharide units in length.
·
A
consequence of the smaller molecule size is a reduced ability to inactivate
factor IIa (thrombin) [inactivation of thrombin is mediated only by saccharide
chains > 18 units; molecules < 18 units are unable to simultaneously bind
ATIII & IIa, however still retain their ability to catalyse the inactivation
Xa via ATIII]
·
A
further feature of LMWH is a reduced interaction with platelets which when
coupled with its reduced effect on thrombin inhibition shows improved
antithrombotic activity associated with a minimal effect on bleeding
enhancement.
·
However
because of its 80-90% cross reactivity rate with heparin induced anti platelet
antibody it cannot be recommended in HIT patients.
·
Half
life is at least twice as long as heparin
Monitoring
·
LMWH
therapy complicates heparin monitoring because the APTT & ACT is much less
sensitive to Xa inhibition than IIa inhibition
·
Factor
Xa must be measured in the laboratory (no simple bedside test)
Heparinoid
·
In
many ways, Orgaran, a non heparin [heparinoid] glycosaminoglycan retrieved as a
byproduct of heparin production, derived from porcine intestinal mucosa.,
shares many of the features shown by the low molecular weight heparins.
·
Like
LMWH it is a smaller molecule than UFH averaging 6000 daltons with the effect
being that the molecule is long enough to potentiate anti Xa activate by
AT-III, but less adequate for thrombin inhibition. It is actually a much more
selector inhibitor of Xa than LMWH.
·
Furthermore,
Orgaran also has a virtual lack of effect on platelets thereby maintaining
their physiological function.(unimpaired haemostatic plug formation)
·
BUT
additionally, and more importantly is orgaran’s low cross-reaction rate (12%)
with heparin dependent antibodies in HIT type II.
·
WHY?
Although derived from the same raw material as heparin & LMW heparins, the
manufacturing process ensures isolation and purification of a substance free
from heparin.(as it does not contain any heparin fragments)
•may be associated with
excessive bleeding when used in the high concentrations required for CPB
•This is related to the lack
of a protamine-like reversal agent and the long half life [25 hr] elimination
for Orgaran
·
Therefore
plasma may be required for excessive bleeding
Monitoring
·
Monitoring
of Orgaran requires the assessment of plasma anti-Xa levels; APTT or ACT do not
reflect the degree of anticoagulation due to their relative insensitivity to
plasma anti Xa activity (one sees lower than normal accepted levels for APTT
& ACT with adequate anticoagulation; however some studies show a high
correlation between ACT, APTT & anti Xa)
·
The
optimal levels of plasma anti-Xa activity has yet to be determined, but a
minimum Xa activity of 0.7 U/ml is required to prevent clotting during CPB
·
Organon
expect the range to be 1.5-2.0 during CPB based on their suggested dosing
schedule
·
There
is no antagonist to orgaran with the effect of protamine being considerably
attenuated
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