Agenda
Heparin
resistance
BJA, 2002 vol 88, no 4, 467-469
 J A M Anderson and E L Saenko

Overview
 Heparin
was discovered in 1916
 Most widely used anticoagulant but not
all its actions are fully understood
 Eg: pain relief in i.v administration for
the treatment of DVT, how HIT
developed and what is the relevance of
the occurrence of heparin resistance
Indications
 Prevention
of VTE
 Treatment of VTE
 Acute coronary syndrome
 Surgery: cardiac bypass
Introduction
Heparin is a negatively charged sulphated
glycosaminoglycan composed of alternating
uronic and glucoronic acid residues
 Commercially prepared are isolated fr porcine
int mucosa or bovine lungs. There are
heterogenous mixtures of polysacharide
chains ranging in molecular weight from 3000
to 30,000.
 Mode of action:

MOA 1
1. Antithrombin dependent
 -Activate AT Hep-AT complex

inactivate thrombin, fXa and
other coagulation factors
 The combination of disaccharide units makesup pentasacharide sequence containing high
affinity binding site for AT. This sequence
occurs in only about 1/3 rd of heparin chains
and is randomly distributed

MOA 2
2. AT independent
 Direct Inhibition of the intrinsic tenase
complex ( PL complex of FVIIIa, FIXa which
generates Fxa)
 * In plasma milieu, AT-dependent effect
predominates

In vivo, variation in response to a fixed dose
of heparin occurs bet individuals
 Pharmacokinetics limitation of heparin caused
by the binding of hep to plasma proteins 
Heparin resistance state

Significance to
know the ‘R’ state
 1.
Prevent over administration of
heparin hemorrhagic consequences
 Particularly during post-op or in the
setting of cardiac bypass surgery and to
consider alternative therapy
In VTE  the phenomenon is of
unclear clinical practice
 2.
Definition of heparin
resistance state
1. In the context of VTE:
 The need for more than 35,000 u/24 hour to
prolong the APTT into the therapeutic range

2. Cardiac bypass procedure:
 The definition is based on the ACT with at
least one ACT < 400 secs after heparinization
and/or the need for exogenous antithrombin
administration

Questions
 1.
What causes heparin resistance
 2.
Which patient groups are
susceptible?

Some answers can be gained from the
understanding on the limitation of UFH
Limitations of
heparin
 1.
Biophysical
 Reflects the inability of hep-AT complex
to inactivate FXa bound to platelets
within the prothrombinase, the PL memb
bound fVa – fXa complex,
 in addition to the resistance of fibrin
bound thrombin to inactivation by
heparin
Limitation of
heparin 2
2. Pharmacokinetic
 A. Reflects the binding of hep to plasma
proteins including PF4, fib, fVIII and histidine
rich glycoprotein
 As many heparin- binding poteins are acute
phaase proteins/reactants- the phenomenon
is often encountered in acutely ill pts,
malignancy, peri or post partum periods and
drugs ( aprotinin and nitroglycerin – hep
clearance)
 B. Lowering of the AT levels by heparin 
contributes to the resistance state

How to monitor the
anticoagulant effects of
heparin in the lab? … not easy
1. APTT  failed to prolonged
 APTT has its own limitations:
 Influenced by:
 -blood collection
 -Sampling tube composition
 -Type of anticoagulant
 -Time of sampling to avoid PF4 mediated
neutralization of heparin


* APTT response to heparin varies
APTT response to
Heparin
 Possibolity
of ApTT lies in the target
range for heparin therapy whilst the
heparin levels is suboptimal occurs in
acquired/congenital factor deficiency,
LA, warfarin effects.
Monitor
2. Anti- Xa monitorring
 Less dose of heparin is required compared to
when APTT is used as monitorring agent
 The development of heparin resistance is
therefore an indication for the use of the
heparin assay to measure the anticoagulant
effect of the drug
 Chromogenic anti fXa assays have limitations:
assay variation and technique
 Bedside anti fXa monitorring test to permit a
quicker and more accurate asessment of the
true anticoagulant activity of heparin: bypass
surgery

Monitor

3. ACT

At present ACT, is the most commonly used
lab test to control heparin effects on
extracorporeal membrane

ACT results also dependent on the
instrumentation, vary with the presence of
haemodilution and hypothermia
Heparin Resistance
and CPB
CPB circuitECM: activate the coagulation
pathway  fXa generation. The inhibition of
Fxa in these situations involves the AT
dependent mechanisms of heparin.
 Imbalance of activation of FX via extrinsic vs
intrinsic p/way


In general, hep is given 3mg/kg body wt to
prevent extracorporeal clot formation with
repeated doses to maintain ACT > 400 sec to
maintain level at 3iu/ml
Solution to heparin
resistance during CPB
Potential solution: Argatroban: a selective,
reversible thrombin inhibitor
 Hirudin also a direct thrombin inhibitor :
prevent clotting within the CPB circuit of pts
with HIT

Ecarin clotting time to monitor the
antithrombotic effects (PT activation by the
snake venom)
 Pentasacharide: a selective synthetic fXa
inhibitors: once daily subcut dose without
monitoring requirement (prevention of venous
thrombosis)

Conclusion
 Heparin
still remains the optimal means
of anticoagulation in CPB, but
improvements are needed in terms of
practical bedside monitorring of its
anticoagulant effects.
 Bedside monitorring permit reasessment
of the optimal level of ACT to achieve
prior to starting the bypass circuit
Significance of
heparin resistance
In the context of VTE- heparin R has its
clinical relevance?
 What is the outcome of pts treated with
empirical doses of heparin when APTT cannot
be prolonged into the therapeutic range?
 The optimal means of monitorring the
anticoagulant effects in cardiac surgery? to
avoid bleeding post-op and usage of blood
products
 Oral heparin in future and synthetic indirect
and direct fXa inhibitors.
