Antitrombin 3 Inactive Thrombin (IIa) V, VIII, XIII, Fibrinogen
Inactive Factor Xa Common Pathway Inactive Factor IXa, XIIa Contact
activation Pathway Antitrombin 3 Heparin Binds to Antithrombin III
and Speeds up its action by a 1000-fold Also Releases Tissue factor
pathway inhibitor form endothelium Binds to platelets and inhibits
platelet aggregation
Slide 5
UFH is made up of heparin molecules of varied sizes (530 kDa).
Larger fragments: Anti-IIa activity and are cleared rapidly
(measured by APTT) Smaller fragments: Inhibit Xa (normal APTT
because of its delayed clearance ) UFH is made up of heparin
molecules of varied sizes (530 kDa). Larger fragments: Anti-IIa
activity and are cleared rapidly (measured by APTT) Smaller
fragments: Inhibit Xa (normal APTT because of its delayed clearance
)
Slide 6
Warkentin, 2003
Slide 7
Slide 8
Protocols Heparin infusion prior to filter Bolus with 10-30
units/kg Infuse heparin at 5-20 units/kg/hr Post filter ACT
measurement Adjust post filter ACT 180-200 secs Interval of
checking is local standard and varies from 1-4 hr increments
Heparin infusion prior to filter Bolus with 10-30 units/kg Infuse
heparin at 5-20 units/kg/hr Post filter ACT measurement Adjust post
filter ACT 180-200 secs Interval of checking is local standard and
varies from 1-4 hr increments
Slide 9
Anticoagulant effect Filter efficacy Circuit life Complications
Anticoagulant effect Filter efficacy Circuit life Complications
Monitoring Efficacy of UFH for prolonging filter life is
proportional to the APTT and not to the heparin dose APTT is
maintained between 3445 seconds, or an APTT of 1.52.0 times normal
Efficacy of UFH for prolonging filter life is proportional to the
APTT and not to the heparin dose APTT is maintained between 3445
seconds, or an APTT of 1.52.0 times normal
Slide 10
Advantages
Slide 11
Unpredictable and complex pharmacokinetics resulting in dosing
variability Heparin-induced thrombocytopenia Heparin resistance
because of low patient antithrombin levels Risks of hemorrhage
(bleeding episodes: 1050%, mortality 15%) Unpredictable and complex
pharmacokinetics resulting in dosing variability Heparin-induced
thrombocytopenia Heparin resistance because of low patient
antithrombin levels Risks of hemorrhage (bleeding episodes: 1050%,
mortality 15%) Disadvantages
Slide 12
Anticoagulant effects are restricted to the circuit, lower risk
of bleeding Difficulty in estimating the amount of protamine
required Initial ratio of 100 between prefilter heparin (in units)
and postfilter protamine (in mg) Subsequent adjustment according to
APTT Requires measurement of both circuit and patient APTT The
heparinprotamine complex is taken up by the reticuloendothelial
system and broken down, then heparin and protamine are released
back into the circulation Protocols are cumbersome and difficult to
standardize Protamine infusion is associated with hypotension,
anaphylaxis, cardiac depression, leukopenia, and thrombocytopenia
Anticoagulant effects are restricted to the circuit, lower risk of
bleeding Difficulty in estimating the amount of protamine required
Initial ratio of 100 between prefilter heparin (in units) and
postfilter protamine (in mg) Subsequent adjustment according to
APTT Requires measurement of both circuit and patient APTT The
heparinprotamine complex is taken up by the reticuloendothelial
system and broken down, then heparin and protamine are released
back into the circulation Protocols are cumbersome and difficult to
standardize Protamine infusion is associated with hypotension,
anaphylaxis, cardiac depression, leukopenia, and thrombocytopenia
Regional Unfractionated HeparinProtamine
Slide 13
Have higher anti-Xa Pharmacokinetics is more predictable
because of less plasma protein binding More reliable anticoagulant
response Lower incidence of HIT Reversal with protamine is less
effective Dalteparin, enoxaprin, and nadroparin have been studied
in CRRT Excreted renally, their effects are prolonged in renal
failure Special coagulation assays are required to monitor anti-Xa
activity Have higher anti-Xa Pharmacokinetics is more predictable
because of less plasma protein binding More reliable anticoagulant
response Lower incidence of HIT Reversal with protamine is less
effective Dalteparin, enoxaprin, and nadroparin have been studied
in CRRT Excreted renally, their effects are prolonged in renal
failure Special coagulation assays are required to monitor anti-Xa
activity Low Molecular Weight Heparins
Slide 14
Longer filter survival times, and lower cost, bleeding
complications not increased Determination of anti-Xa levels aiming
at 0.250.35 IU/ml is recommended
Slide 15
174 patients No significant difference in survival up to day 30
There were more metabolic disturbances with citrate
anticoagulation
Slide 16
Regional anticoagulation with citrate does not eliminate any
need for heparin since, many other indications for systemic
anticoagulation may emerge during therapy Citrate anticoagulation
has distinct advantages with regard to haemofilter patency and the
risk of HIT and bleeding
Slide 17
For patients who are at low risk of bleeding and do not have
other contraindications to heparin such as HIT, consider using UFH
For patients who are at high risk for bleeding and who do not have
liver failure, consider using regional citrate anticoagulation
Neither citrate nor heparin anticoagulation should be regarded as a
therapeutic standard, since there is no advantage of one of these
substances with regard to patient mortality.
Slide 18
Optimal anti-thrombotic activity Minimal bleeding complications
Negligible systemic effects Inexpensive Have a short half-life Can
be easily reversed Monitoring methods should be simple and
available Optimal anti-thrombotic activity Minimal bleeding
complications Negligible systemic effects Inexpensive Have a short
half-life Can be easily reversed Monitoring methods should be
simple and available The ideal anticoagulant should provide
Slide 19
Heparin was used to be manufactured in factories from porcine
intestine or bovine lung