Transcript Document

Anticoagulation in
hemodialysis
Dr.
Scope

Introduction



Coagulation cascade
Hemostatic abnormalities in renal insufficiency
Anticoagulation for hemodialysis




Unfractionated heparin
No heparin dialysis
LMWH
Regional anticoagulation
Newer developments
 Conclusions

Introduction

Adequate anticoagulation in hemodialysis
procedures relies on
 Knowledge
of the
 Basic
principles of hemostasis and notably the
clotting cascade
 Hemostatic abnormalities in renal insufficiency as
well as activation of clotting on artificial surfaces
Hemodialysis International 2007; 11:178–189
Introduction

Hemostasis defined as a


Process of fibrin clot formation to seal a site of
vascular injury without resulting in total occlusion of
the vessel
Multiple processes including both cellular elements
and numerous plasma factors with enzymatic activity
is arranged



(1) to activate clotting rapidly,
(2) to limit and subsequently terminate this activation, and
(3) to remove the clot by fibrinolysis in the end
Hemodialysis International 2007; 11:178–189
Introduction

The initial hemostatic response to stop bleeding
is the


Formation of a platelet plug at the site of vessel wall
injury
Platelets are activated by

Multitude of stimuli, the most potent of which are


Thrombin and collagen
Upon activation, platelets

Adhere to the subendothelial matrix, aggregate,
secrete their granule content, and expose
procoagulant phospholipids such as
phosphatidylserine
Hemodialysis International 2007; 11:178–189
Introduction

Platelet-derived membrane microvesicles
 Markedly
increase the phospholipid surface on
which coagulation factors form multimolecular
enzyme complexes with procoagulant activity

Hence, platelet activation also
 Leads
to propagation of plasmatic coagulation
Hemodialysis International 2007; 11:178–189
Coagulation Cascade

Coagulation Cascade
 Complex,
multiply redundant and includes
intricate checks and balances
Hemodialysis International 2007; 11:178–189
Coagulation Cascade

Intrinsic pathway



Activated by damaged or negatively charged surfaces
and the accumulation of kininogen and kallikrein
The activated partial thromboplastin time (APTT)
tends to reflect changes in the intrinsic pathway
Extrinsic pathway
Triggered by trauma or injury, which releases tissue
factor
 The extrinsic pathway is measured by the
prothrombin test

Hemodialysis International 2007; 11:178–189
Hemostatic abnormalities in
renal insufficiency
The accumulation of uremic toxins causes
complex disturbances of the coagulation
system
 Uremia can lead to an increased bleeding
tendency, e.g.,

 Due
to platelet dysfunction
 which is further enhanced with use of
anticoagulants during extracorporeal blood
purification procedures
Hemodialysis International 2007; 11:178–189
Hemostatic abnormalities in
renal insufficiency

Clot formation and development of
thrombosis can also occur at increased
rates in dialysis patients
 Pulmonary
embolism is more frequent in
dialysis patients than in age-matched controls
Hemodialysis International 2007; 11:178–189
Hemostatic abnormalities in
renal insufficiency

Patients on chronic intermittent
hemodialysis frequently suffer from
 Vascular
access thrombosis, the risk of which
is increased in
 Polytetrafluoroethylene
arteriovenous fistulas
grafts compared with
Anticoagulation for hemodialysis (HD)

Anticoagulation is routinely required to
prevent clotting of
 The
dialysis lines and dialyser membranes,
 In
both acute intermittent haemodialysis and
continuous renal replacement therapies

Field of anticoagulation is constantly
evolving
 Important
to regularly review advances in
knowledge and changing practices in this area
Semin. Dial. 2009; 22: 141–5
Anticoagulation for HD

The responsibility for
prescribing and delivering
anticoagulant for HD is
shared between the
 Dialysis

doctors and nurses
Dialysis is a medical therapy
 Must
be prescribed by an
appropriately trained doctor
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Anticoagulation for HD

The prescribing doctor usually determines
 which
anticoagulant agent will be used and
 the dosage range

The doctor’s prescription may include
broad instructions such as
 ‘no
heparin’, ‘low heparin’ or ‘normal heparin’
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Anticoagulation for HD

In a mature dialysis unit the dose and
delivery of anticoagulant is, however, the
responsibility of professional and
experienced dialysis nurses,
 who
have latitude within parameters
determined by detailed written policies or
standing orders
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Anticoagulation for HD
Dosing regimens, while generally safe and
effective, are somewhat unscientific
 In terms of monitoring

 Most
units do not practise routine monitoring,
 Although the anticoagulant effect of
unfractionated heparin (UF heparin) can be
monitored with some accuracy by the APTT or
the activated clotting time tests where
indicated
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Anticoagulation for HD

The dialysis nurses
 Know
- too much anticoagulation if
 The
needle sites continue to ooze excessively for a
prolonged period (e.g. more than 15 min) after
dialysis
 Know
- too little anticoagulation if
 ‘streaking’
in the dialyser, excessively raised
transmembrane pressure or evidence of thrombus
in the venous bubble trap – indicated by dark
blood, swelling of the trap or rising venous
pressure
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Anticoagulation for HD

The nurses
 Know
that patients dialysing with a venous
dialysis catheter are at greater risk of
thrombosis

With some trial and error,
 The
right dose of anticoagulant for any
patient can be empirically determined
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Anticoagulation for HD

In normal circumstances effective and
safe anticoagulation for HD can be
delivered with
 Low
risk and high efficiency
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Unfractionated heparin
Constitute a mixture of anionic
glucosaminoglycans of varying molecular size
(5–40, mean 15 kDa)
 Mechanism:

Indirect due to the binding to antithrombin (‘‘heparinbinding factor I’’)
 Heparin enhances the activity of this natural
anticoagulant protein 1000 to 4000-fold
 Antithrombin inactivates thrombin, factor Xa, and to a
lesser extent factors IXa, XIa, and XIIa
 At high doses, heparin also binds to ‘‘heparin-binding
factor II”

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Unfractionated heparin
Heparin can be directly procoagulant through
platelet activation and aggregation
 However, its main effect is anticoagulant,
through its binding to anti-thrombin
(antithrombin III or heparin-binding factor I)
 At high doses heparin can also bind to heparinbinding factor II – which can directly inhibit
thrombin
 When heparin binds antithrombin it causes a
conformation change, which results in a 1000–
40 000¥ increase in the natural anticoagulant
effect of anti-thrombin

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Unfractionated heparin

Heparin is ineffective against thrombin or
factor Xa
 If
they are located in a thrombus or bound to
fibrin or to activated platelets

UFH has a narrow therapeutic window of
adequate anticoagulation without
bleeding,
 Laboratory
testing (aPTT or as bedside test
‘‘activated clotting time,’’ ACT) of its effect is
required
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Unfractionated heparin

Unfractionated heparin
First isolated from liver (hepar) mast cells of dogs
 Now commercially derived from porcine intestinal
mucosa or bovine lung
 When administered intravenously



Half-life approx. 1.5 h
Highly negatively charged and binds non-specifically
to endothelium, platelets, circulating proteins,
macrophages and plastic surfaces
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Unfractionated heparin

In addition to removal by adherence,
heparin is cleared by both renal and
hepatic mechanisms and is metabolized by
endothelium
Unfractionated heparin
Interestingly, UF heparin has both proand anti-coagulant effects
 At high doses heparin can also bind to
heparin-binding factor II – which can
directly inhibit thrombin
 When heparin binds antithrombin it causes
a conformation change, which results in a
1000–40 000x increase in the natural
anticoagulant effect of anti-thrombin.

Unfractionated heparin
Heparin-bound anti-thrombin inactivates multiple
coagulation factors including covalent binding of
thrombin and Xa and lesser inhibition of VII,
IXa, XIa, XIIa.
 By inactivating thrombin, UF heparin inhibits
thrombininduced platelet activation as well
 Of note, UF heparinbound anti-thrombin
inactivates thrombin (IIA) and Xa equally
 Only UF heparin with more than 18 repeating
saccharide units inhibits both thrombin and Xa,
whereas shorter chains only inhibit Xa.

Unfractionated heparin

For haemodialysis,



UF heparin can be administered, usually into the
arterial limb, according to various regimens, but
Most commonly is administered as a loading dose
bolus followed by either an infusion or repeat bolus at
2–3 h
The initial bolus is important to overcome the high
level of non-specific binding, following which there is
a more linear dose : response relationship
Unfractionated heparin
The loading dose bolus may be 500 units
or 1000 units and infusion may vary from
500 units hourly to 1000 units hourly,
depending on whether the prescription is
‘low dose heparin’ or ‘normal heparin’
 Heparin administration usually ceases at
least 1 h before the end of dialysis

Unfractionated heparin
The most important risk of UF heparin is the HIT
syndrome (HIT Type II)
 Other risks or effects attributed to UF heparin
that have been reported include hair loss, skin
necrosis, osteoporosis, tendency for
hyperkalaemia, changes to lipids, a degree of
immunosuppression, vascular smooth muscle
cell proliferation and intimal hyperplasia
 Beef-derived heparin can be a risk for the
transmission of the prion causing Jacob
Creutzfeld type encephalopathy

Unfractionated heparin

Use of UF heparin is



Safe, simple and inexpensive and
Usually encounters few problems
However, there are risks with HD
anticoagulation which are important to be aware
of and include


The risk of bleeding
Some risks are not immediately obvious – such as
inadvertent over-anticoagulation in high-risk patients
because of excessive heparin volume used to lock the
venous dialysis catheter at the end of dialysis
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Unfractionated heparin

The disadvantages of UF heparin may
include
 Lack
of routine or accurate monitoring of
anticoagulation effect
 The need for an infusion pump and the costs
of nursing time

Perhaps the most important risk is that of
 Heparin-induced
thrombocytopaenia (HIT
Type II), which is greatest with the use of UF
heparin
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Unfractionated heparin
At times the routine anticoagulation
prescription needs to be varied
 Additional choices include

 ‘no
heparin’ dialysis,
 the use of low-molecular-weight heparin
(LMWH) instead of UF heparin, and
 the use of regional anticoagulation

New agents and new clinical variations
appear in the literature continuously
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No Heparin Dialysis

Dialysis without anticoagulation may be
indicated in patients with
 High
risk of bleeding
 Acute bleeding disorder
 Recent head injury
 Planned major surgery
 Trauma
 Acute HIT syndrome or
 Systemic anticoagulation for other reasons
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No Heparin Dialysis

The procedure involves
 Multiple
flushes of 25–50 ml of saline every
15–30 min, in association with a high blood
flow rate
 In some units the lines are pretreated with
2000–5000 U of UF heparin and then flushed
with 1 L of normal saline, to coat the lines

This form of dialysis anticoagulation is
 Very
labour-intensive and
 Usually only partially effective
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No Heparin Dialysis

No Heparin Dialysis

Partial clotting still occurs in 20% of cases with
complete clotting of lines or dialyser, requiring


The risk of clotting may be exacerbated by



Line change in 7% of ‘no heparin’ dialyses
Poor access blood flow, the use of a venous catheter,
hypotension or concomitant blood transfusion
Where a venous catheter is used, there is an increased risk
of catheter occlusion
‘No heparin’ dialysis may also provide less
effective dialysis and result in lower clearances
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Low molecular weight heparin (LMWH)

Depolymerized fractions of heparin can be
obtained by


Anionic glycosaminoglycans but


Chemical or enzymatic treatment of UF heparin
have a lower molecular weight of 2–9 kDa, mostly @
5 kDa – thus consisting of ≤ 15 saccharide units
The shorter chain length results in
Less coagulation inhibition, but
 Superior pharmacokinetics, higher bioavailability, less
non-specific binding and longer half-life, all of which
help to make
 LMWH dosage simpler and more predictable than UF
heparin
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
LMWH
LMWH
 In addition

 Less
impact on platelet function, and thus
may cause less bleeding
 Binds anti-thrombin III and inhibits factor Xa,
 But most LMWH (50–70%) does not have the
second binding sequence needed to inhibit
thrombin
 because
of the shorter chain length
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LMWH
In most cases the affinity of LMWH for Xa
versus thrombin is of the order of 3:1
 The anticoagulant effect of LMWH can be
monitored by the anti-factor Xa activity in
plasma

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LMWH

LMWH
 Cleared
by renal/dialysis mechanisms, so
dosage must be adjusted to account for this
 When high flux dialysers are used, LMWH is
more effectively cleared than UF heparin
 Often administered into the venous limb of
the dialysis circuit
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Enoxaparin

One of the most commonly used LMWH
 Has
the longest half-life
 Predominantly renally cleared
 Dose reduction need to be made in the
elderly, in the presence of renal impairment
and in very obese patients, to avoid lifethreatening bleeding
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Enoxaparin
Generally does not accumulate in 3/week
dialysis regimens, but there is a risk of
accumulation in more frequent schedules
 No simple antidote and in the case of
severe haemorrhage
 Activated
required
factor VII concentrate may be
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Enoxaparin

On the other hand patients dialysing with
a high flux membrane, as compared with
a low flux membrane,
 May
require a higher dose because of dialysis
clearance

Effect and accumulation can be monitored
by the performance of anti-Xa levels
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Enoxaparin

A common target range is
 0.4–

0.6 IU/ml anti-Xa but a
More conservative range
 0.2–
0.4 IU/ml is recommended in patients
with a high risk of bleeding
 The
product insert should always be consulted
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Enoxaparin

The use of LMWH such as enoxaparin for HD
anticoagulation is


Well supported in the literature
Enoxaparin can be administered as a



Single dose and generally does not require to be
monitored
Yet unclear whether enoxaparin can successfully
anticoagulate patients for long overnight (nocturnal)
HD
Against the utility of LMWH, the purchase price of
LMWH still significantly exceeds UF heparin
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LMWH

The other available forms of LMWH e.g.
 Dalteparin,
Nadroparin, Reviparin Tinzaparin
and newer LMWH vary somewhat, especially
in
 Anti-Xa/anti-IIa

effect
The higher this ratio the more Xa selective the agent and
consequently the less effect protamine has on reversal
 Enoxaparin
 High
anti-Xa/anti-IIa ratio of 3.8, and is < 60%
reversible with protamine
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Is LMWH better?

Significance is
 Lower
incidence of HIT Type II, a devastating
and deadly complication, in patients exposed
to LMWH compared with UF heparin
 Another advantage of LMWH is the
 Longer
duration of action and predictability of
dosage effect, allowing the convenience of a single
subcutaneous injection at the start of dialysis
without the need for routine monitoring
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Is LMWH better?

The use of LMWH is reported to cause
 Less
dialysis membrane-associated clotting,
fibrin deposition and cellular debris
 LMWH has less non-specific binding to
platelets, circulating plasma proteins and
endothelium
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Is LMWH better?

UF heparin induces
 Inhibition
of mineralocorticoid metabolim and
reduced adrenal aldosterone secretion, but
 LMWH
has been shown to have less inhibition in
this regard
 Other
deleterious effects associated with UF
heparin are also generally less common with
the use of LMWH including
 The
risk of osteoporosis, hair loss, endothelial cell
activation and adhesion molecule activation
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Is LMWH better?

A meta-analysis including 11 studies was
published in 2004 and showed that
 LMWH
and UF heparin were similarly safe and
effective in preventing extracorporeal circuit
thrombosis, with
 No
significant difference in terms of bleeding,
vascular compression time or thrombosis
J. Am. Soc. Nephrol. 2004; 15: 3192–206.
Is LMWH better?

LMWH is however recommended as the agent of
choice for routine haemodialysis by the
European Best Practice Guidelines


The single factor weighing against the use of LMWH
as the routine form of anticoagulation for dialysis is
cost
More and more dialysis units are assessing the
cost/benefit ratio as in favour of the routine use
of LMWH for haemodialysis

Because of the potency, ease of administration,
predictable clinical effect and low rate of side effects
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Anti-Xa monitoring
May be used for dosing adjustment of
LMWH, to ensure therapeutic dosing or to
exclude accumulation prior to a
subsequent dialysis
 Because of the high bioavailability, doseindependent clearance by renal
mechanisms, and predictable effect, there
is generally no need to monitor routinely.

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Regional anticoagulation for HD

Aim of regional anticoagulation is
 To
restrict the anticoagulant effect to the
dialysis circuit and prevent systemic
anticoagulation,
 For
instance in patients at increased risk of
bleeding
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UF heparin/protamine

Historically, the use of UF
heparin/protamine was prototypical of
regional anticoagulation
 UF
heparin is infused into the arterial line and
protamine into the venous line
 Protamine
 Basic
protein that binds heparin, forming a stable
compound and eliminating its anticoagulant effect
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UF heparin/protamine

Full neutralization of heparin can be
achieved with
A
dose of 1 mg protamine/100 units heparin
 Protamine has a shorter half-life than heparin
so
 There
may be an increased risk of bleeding 2–4 h
after dialysis
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UF heparin/protamine

Most authors agree that
 Procedure
can be technically challenging and
 No significant advantage over ‘low-dose’
heparin regimens
 Reactions to protamine are not uncommon
and may be serious
 As
all forms of heparin are absolutely
contraindicated in HIT Type II this form of regional
anticoagulation cannot be used in that syndrome
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Citrate regional anticoagulation

Citrate binds ionized calcium and is a
 Potent

inhibitor of coagulation
Regional citrate regimens generally
 Utilize
isoosmotic trisodium citrate or
hypertonic trisodium citrate infusion into the
arterial side of the dialysis circuit
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Citrate regional anticoagulation

This methodology
 Avoids
the use of heparin and
 Limits anticoagulation to the dialysis circuit –
 Effects
which can be used for routine dialysis in
patients at increased risk of bleeding or for dialysis
anticoagulation in the stable phase of HIT Type II
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Citrate regional anticoagulation

The citrate–calcium complex


The procedure may require, or be enhanced by,


Partially removed by the dialyser
Use of calcium and magnesium-free dialysate
A low bicarbonate dialysate is also
recommended to

Rreduce the risk of alkalosis,

Especially in the setting of daily dialysis, as citrate is
metabolized to bicarbonate
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Citrate regional anticoagulation

To neutralize the effect of citrate,
 Calcium
chloride solution is infused into the
venous return at a rate designed to correct
ionized calcium levels to physiologic levels
 Plasma calcium must be measured frequently,
e.g.
 second
hourly, with prompt result turnaround
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Citrate regional anticoagulation

The procedure
 Complex
and high risk
 Requirement for two infusion pumps and
 Point of care calcium measurement
 Either high or low calcium levels in the patient
may risk severe acute complications
 Hypertonic citrate may risk hypernatraemia
 Metabolism of citrate generates a metabolic
alkalosis
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Citrate regional anticoagulation

Nevertheless, the technique has been
used with
 Great
success in some hands, with
 Few
bleeding complications and improved
biocompatibility with reduced granulocyte
activation and
 Less deposition of blood components in the lines
or on the dialyser

Simplified protocols have been proposed
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Prostacyclin regional anticoagulation

Utilizes prostacyclin as a

Vasodilator and platelet aggregation inhibitor
Very short half-life of 3–5 min
 Infused into the arterial line
 Of importance



Prostacyclin is adsorbed onto polyacrylonitrile
membranes
Side effects can include

Headache, light headedness, facial flushing,
hypotension and excessive cost
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Heparin-induced thrombocytopaenia
(HIT)

There are two well-described syndromes
of HIT, the
 First
relatively benign
 Second potentially devastating
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HIT Type I

HIT type I





10–20% of patients treated with UF heparin
Mild thrombocytopaenia occurs (<100 000) as a
result of heparin activation of platelet factor 4 (PF4)
surface receptors, leading to platelet degranulation
Mechanism is non-immune and early in onset, after
the initiation of heparin
The syndrome generally resolves spontaneously
within 4 days despite the continuation of heparin
Generally no sequelae of clinical significance
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HIT Type II

HIT Type II
 Much
more serious and devastating than HIT
Type I
 Generally occurs within the first 4–10 days of
exposure to heparin
 Late onset is less common
 Mechanism of HIT which results in both
platelet activation and activation of the
coagulation cascade
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HIT Type II

Severe platelet reduction occurs rapidly,
 Generally

platelet count remains > 20 000
Clinical HIT Type II is reported to occur in
 2–15%
of patients exposed to heparin
 More commonly in females and surgical cases
 In dialysis patients the incidence varies
between 2.8% and 12%
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HIT Type II

HIT Type II
 Occurs
in incident patients or after reexposure to heparin after an interval
 Of importance the incidence is 5–10 times
more common with UF heparin than with
patients receiving only LMWH
 The risk with LMWH is reportedly very low, in
the order of <1%
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HIT Type II

HIT Type II


Two clinical phases
Acute phase



Significant thrombocytopaenia and high risk of
thromboembolic phenomena
Avoidance of heparin and systemic anticoagulation are
essential
Second phase,


Signalled by recovery of platelet levels, heparin must still be
avoided (for a prolonged period if not forever) but systemic
anticoagulation is not required
Dialysis anticoagulation remains a challenge as all forms of
heparin must be avoided
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HIT Type II




With the onset of HIT Type II, heparin must be
immediately discontinued, even before confirmatory
results are available
Available tests for HIT Type II include detection of
antibodies against heparin–PF4 complex, detection of
heparin-induced platelet aggregation or platelet release
assays – but none is totally reliable
HIT acute phase will not resolve while heparin is
continued and HIT will recur on rechallenge with either
UF heparin or LMWH
Once HIT is established after exposure to UF heparin,
there is a >90% cross-reactivity with LMWH
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HIT Type II

Untreated, there is a major risk of venous
and arterial thrombosis, estimated at
 >50%

within 30 days
Most of the clots are described as venous
 Arterial
thrombi are often platelet-rich white
thrombi (white clot syndrome) which can
cause limb ischaemia and cerebral or
myocardial infarcts
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HIT Type II

In patients with HIT Type II all heparin products
must be avoided, including

Topical preparations, coated products as well as
intravenous preparations
Systemic anticoagulation without heparin is
mandatory in the acute phase
 For haemodialysis, patients may have



‘no heparin’ dialysis or anticoagulation with nonheparins
The available agents commonly used include
Danaparoid, Hirudin, Argatroban, Melagatran and
Fondaparinux
Nephrology 2010;15:386–392
HIT Type II





Alternatively, regional citrate dialysis has proved
effective in this setting
Each approach or alternative agent provides its own
challenges and there may be a steep learning curve.
Both UF heparin and LMWH are contraindicated
Venous catheters must not be heparin locked, but can
be locked with recombinant tissue plasminogen activator
or citrate ( trisodium citrate 46.7%)
Other alternatives to consider may include switching the
patient to peritoneal dialysis or using warfarin
In the longer term it may be possible to cautiously
reintroduce UF heparin, or preferably LMWH, without
reactivating HIT Type II
Nephrology 2010;15:386–392
Danaparoid

Currently, this agent remains drug of
choice in most Australian hospitals for HIT
Type II,
 May
have unique features, which interfere
with the pathogenesis of HIT Type II
Extracted from pig gut mucosa
 Heparinoid of molecular weight of 5.5 kDa

 83%
heparan sulphate, 12% dermatan
sulphate and 4% chondroitin sulphate
Nephrology 2010;15:386–392
Danaparoid

Danaparoid

Binds to antithrombin (heparin cofactor I) and
heparin cofactor II and has some endothelial
mechanisms, but


More selective for Xa than even the LMWH


Minimal impact on platelets and a low affinity for PF4
(Xa : thrombin binding : Danaparoid 22–28 : 1;
LMWH 3:1 typically)
Low cross-reactivity with HIT antibodies (6.5–
10%) although

Recommended to test for cross-reactivity before use
of Danaparoid in acute HIT Type II
Nephrology 2010;15:386–392
Danaparoid

Danaparoid
 Very
long half-life of about 25 h in normals
 Longer
with chronic renal impairment (e.g. 30 h)
No reversal agent
 Clinically, significant accumulation should
be tested by

 Anti-Xa
estimation before any invasive
procedure
Nephrology 2010;15:386–392
Hirudin
Originally discovered in the saliva of leeches
 Binds thrombin irreversibly at its active site and
the fibrin-binding site
 Recombinant or synthetic variants are also
available – including



Lepirudin, Desirudin and Bivalirudin
Hirudin and its cogeners are

Polypeptides of molecular weight of 7 kDa with no
cross-reactivity to the HIT antibody
Nephrology 2010;15:386–392
Hirudin

Hirudin
 Prolonged
half-life
 Renally cleared, so its half-life in renal
impairment is > 35 h

Studies have confirmed
 Hirudin
HD
can be used as an anticoagulant for
Nephrology 2010;15:386–392
Hirudin

Hirudin
 No
cross-reactivity with UF heparin or LMWH;
however,
 Hirudin
and its analogues are antigenic in their
own right, and up 74% of patients receiving
Hirudin i.v. can develop anti-Hirudin antibodies,

which can further prolong the half-life
Nephrology 2010;15:386–392
Hirudin

Hirudin


Because of the tendency to form antibodies, difficult
to use, as anaphylaxis can occur with a second course
The APTT

May be used to monitor Hirudin anticoagulant effect
but


The relationship is not necessarily linear
No antidote to Hirudin, but

Removed to some extent by haemofiltration/
plasmapheresis but not HD
Nephrology 2010;15:386–392
Argatroban

Synthetic derivative of L-arginine
 Appears
to be the treatment of choice in the
USA
 Acts as a direct thrombin inhibitor and
 Binds irreversibly to the catalytic site

Short half-life of 40–60 min
 Not
effected by renal function
 Hepatic clearance means prolonged duration
of action in patients with liver failure
Nephrology 2010;15:386–392
Argatroban
Anticoagulant effect can be monitored by
a variant of the APTT – the ecarin clotting
time
 No available reversal agent

Nephrology 2010;15:386–392
Melagatran
Direct thrombin inhibitor
 Available orally as a prodrug, which is
taken twice a day
 Renally cleared and has a prolonged halflife
 No antidote

Nephrology 2010;15:386–392
Melagatran
Reports of hepatotoxicity have impeded
further drug development
 It has been suggested that Melagatran
may have a role in anticoagulation
between dialysis treatments in patients
with HIT Type II

Nephrology 2010;15:386–392
Fondaparinux

Synthetic pentasaccharide of 1.7 kDa,
 Copy
of an enzymatic split product of heparin
 Synthetic analogue of the pentasaccharide
sequence in heparin that mediates the antithrombin interaction

High affinity for anti-thrombin III but
 No
affinity for thrombin or PF4
Nephrology 2010;15:386–392
Fondaparinux

Fondaparinux
 Can
be administered i.v. or s.c.
 Monitored by the use of anti-Xa testing
 With a prolonged half-life it can be
administered alternate days
 Renally cleared, it may accumulate in renal
failure
 Removed
to some degree by high flux
haemodialysis or haemodiafiltration
Nephrology 2010;15:386–392
Conclusions

Anticoagulation is an essential part of the
safe and effective delivery of HD

Physicians accredited to prescribe dialysis
must have a fundamental understanding
of anticoagulation therapy in different
dialysis settings
Conclusions

Essential for nephrologists to have a good
understanding of
 The
relative merits of UF heparin and LMWH,
 To develop an approach to the clinical
management of HIT Type II and other
important heparin-related complications
Conclusions

Continuous development of new
anticoagulant drugs and associated clinical
recommendations
 This
is an area that dialysis clinicians should
revisit at timely intervals