heparin Resistance
Download
Report
Transcript heparin Resistance
Journal
Session
Dr Wan Zaidah Abdullah
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 circuitECM: 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.
Thank you