Heparin in CRRT
Benan Bayrakci, 2014
McLean
Heparin Binds to Antithrombin III and
Speeds up its action by a 1000-fold
Antitrombin 3
Inactive Thrombin (IIa)
V, VIII, XIII, Fibrinogen
Antitrombin 3
Inactive Factor Xa
Common Pathway
Antitrombin 3
Inactive Factor IXa, XIIa
Contact activation Pathway
Also
• Releases Tissue factor pathway inhibitor form endothelium
• Binds to platelets and inhibits platelet aggregation
UFH is made up of heparin molecules of varied sizes (5–30 kDa).
Larger fragments: Anti-IIa activity and are cleared rapidly (measured by APTT)
Smaller fragments: Inhibit Xa (normal APTT because of its delayed clearance)
Warkentin, 2003
Warkentin, 2003
Protocols
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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
Monitoring
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Anticoagulant effect
Filter efficacy
Circuit life
Complications
• Efficacy of UFH for prolonging filter life is proportional
to the APTT and not to the heparin dose
• APTT is maintained between 34–45 seconds, or an
APTT of 1.5–2.0 times normal
Advantages
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Most commonly used anticoagulant worldwide for CRRT
Widely available
Simple to monitor
Inexpensive
Familiar to physicians
Easy to administer
Reversible with protamine
Disadvantages
• Unpredictable and complex pharmacokinetics
resulting in dosing variability
• Heparin-induced thrombocytopenia
• Heparin resistance because of low patient
antithrombin levels
• Risks of hemorrhage
(bleeding episodes: 10–50%, mortality 15%)
Regional Unfractionated Heparin–Protamine
• 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 heparin–protamine 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
Low Molecular Weight Heparins
• 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
Longer filter survival times, and lower cost, bleeding complications not increased
Determination of anti-Xa levels aiming at 0.25–0.35 IU/ml is recommended
174 patients
No significant difference in survival up to day 30
There were more metabolic disturbances
with citrate anticoagulation
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
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.
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
The ideal anticoagulant should provide
• 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
Heparin was used to be manufactured in factories from porcine intestine or bovine lung