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8/10/2019 1 Anticoagulation in hemodialysis.ppt
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Anticoagulation in
hemodialysisDr.
8/10/2019 1 Anticoagulation in hemodialysis.ppt
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Scope
Introduction Coagulation cascade
Hemostatic abnormalities in renal insufficiency
Anticoagulation for hemodialysis Unfractionated heparin
No heparin dialysis
LMWH
Regional anticoagulation Newer developments
Conclusions
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Introduction
Adequate anticoagulation in hemodialysisprocedures relies on
Knowledge of the
Basic principles of hemostasis and notably theclotting cascade
Hemostatic abnormalities in renal insufficiency aswell as activation of clotting on artificial surfaces
Hemodialysis International 2007; 11:178 –189
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Introduction
Hemostasis defined as a
Process of fibrin clot formation to seal a site ofvascular injury without resulting in total occlusion of
the vessel Multiple processes including both cellular elements
and numerous plasma factors with enzymatic activityis 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
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Introduction
The initial hemostatic response to stop bleedingis 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 exposeprocoagulant phospholipids such asphosphatidylserine
Hemodialysis International 2007; 11:178 –189
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Introduction
Platelet-derived membrane microvesicles
Markedly increase the phospholipid surface onwhich 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
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Coagulation Cascade
Coagulation Cascade
Complex, multiply redundant and includesintricate checks and balances
Hemodialysis International 2007; 11:178 –189
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Coagulation Cascade
Intrinsic pathway
Activated by damaged or negatively charged surfacesand 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
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Hemostatic abnormalities inrenal insufficiency
The accumulation of uremic toxins causescomplex disturbances of the coagulationsystem
Uremia can lead to an increased bleedingtendency, e.g.,
Due to platelet dysfunction
which is further enhanced with use ofanticoagulants during extracorporeal bloodpurification procedures
Hemodialysis International 2007; 11:178 –189
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Hemostatic abnormalities inrenal insufficiency
Clot formation and development ofthrombosis can also occur at increasedrates in dialysis patients
Pulmonary embolism is more frequent indialysis patients than in age-matched controls
Hemodialysis International 2007; 11:178 –189
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Hemostatic abnormalities inrenal insufficiency
Patients on chronic intermittenthemodialysis frequently suffer from
Vascular access thrombosis, the risk of which
is increased in
Polytetrafluoroethylene grafts compared witharteriovenous fistulas
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Anticoagulation for hemodialysis (HD)
Anticoagulation is routinely required toprevent clotting of
The dialysis lines and dialyser membranes,
In both acute intermittent haemodialysis andcontinuous 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
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Anticoagulation for HD
The responsibility forprescribing and deliveringanticoagulant for HD is
shared between the
Dialysis doctors and nurses
Dialysis is a medical therapy
Must be prescribed by anappropriately trained doctor
Nephrology 2010;15:386 –392
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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 includebroad instructions such as
‘no heparin’, ‘low heparin’ or ‘normal heparin’
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Anticoagulation for HD
In a mature dialysis unit the dose anddelivery of anticoagulant is, however, theresponsibility 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 andeffective, are somewhat unscientific
In terms of monitoring
Most units do not practise routine monitoring,
Although the anticoagulant effect ofunfractionated heparin (UF heparin) can be
monitored with some accuracy by the APTT orthe activated clotting time tests whereindicated
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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) afterdialysis
Know - too little anticoagulation if ‘streaking’ in the dialyser, excessively raised
transmembrane pressure or evidence of thrombusin the venous bubble trap – indicated by darkblood, swelling of the trap or rising venouspressure
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Anticoagulation for HD
The nurses
Know that patients dialysing with a venousdialysis 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 andsafe anticoagulation for HD can bedelivered with
Low risk and high efficiency
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Unfractionated heparin
Constitute a mixture of anionicglucosaminoglycans of varying molecular size(5 –40, mean 15 kDa)
Mechanism: Indirect due to the binding to antithrombin (‘‘heparin-
binding 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 throughplatelet 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 heparin-
binding factor II – which can directly inhibitthrombin
When heparin binds antithrombin it causes aconformation change, which results in a 1000 –40 000¥ increase in the natural anticoagulanteffect of anti-thrombin
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Unfractionated heparin
Heparin is ineffective against thrombin orfactor 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 withoutbleeding, Laboratory testing (aPTT or as bedside test ‘‘activated clotting time,’’ ACT) of its effect isrequired
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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 andhepatic mechanisms and is metabolized by
endothelium
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Unfractionated heparin
Interestingly, UF heparin has both pro-and anti-coagulant effects
At high doses heparin can also bind to
heparin-binding factor II – which candirectly inhibit thrombin
When heparin binds antithrombin it causes
a conformation change, which results in a1000 –40 000x increase in the naturalanticoagulant effect of anti-thrombin.
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Unfractionated heparin
Heparin-bound anti-thrombin inactivates multiplecoagulation factors including covalent binding ofthrombin and Xa and lesser inhibition of VII,IXa, XIa, XIIa.
By inactivating thrombin, UF heparin inhibitsthrombininduced platelet activation as well
Of note, UF heparinbound anti-thrombininactivates thrombin (IIA) and Xa equally
Only UF heparin with more than 18 repeatingsaccharide units inhibits both thrombin and Xa,whereas shorter chains only inhibit Xa.
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Unfractionated heparin
For haemodialysis,
UF heparin can be administered, usually into thearterial limb, according to various regimens, but
Most commonly is administered as a loading dosebolus followed by either an infusion or repeat bolus at2 –3 h
The initial bolus is important to overcome the highlevel of non-specific binding, following which there isa more linear dose : response relationship
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Unfractionated heparin
The most important risk of UF heparin is the HITsyndrome (HIT Type II)
Other risks or effects attributed to UF heparin
that have been reported include hair loss, skinnecrosis, osteoporosis, tendency forhyperkalaemia, changes to lipids, a degree ofimmunosuppression, vascular smooth musclecell proliferation and intimal hyperplasia
Beef-derived heparin can be a risk for thetransmission of the prion causing JacobCreutzfeld type encephalopathy
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Unfractionated heparin
Use of UF heparin is Safe, simple and inexpensive and
Usually encounters few problems
However, there are risks with HDanticoagulation which are important to be awareof and include The risk of bleeding
Some risks are not immediately obvious – such asinadvertent over-anticoagulation in high-risk patientsbecause of excessive heparin volume used to lock thevenous dialysis catheter at the end of dialysis
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Unfractionated heparin
The disadvantages of UF heparin mayinclude 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 ofHeparin-induced thrombocytopaenia (HIT
Type II), which is greatest with the use of UFheparin
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Unfractionated heparin
At times the routine anticoagulationprescription 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 variationsappear in the literature continuously
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No Heparin Dialysis
Dialysis without anticoagulation may beindicated in patients withHigh 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 involvesMultiple 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 flushedwith 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 withcomplete clotting of lines or dialyser, requiring
Line change in 7% of ‘no heparin’ dialyses
The risk of clotting may be exacerbated by
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 lesseffective dialysis and result in lower clearances
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Low molecular weight heparin (LMWH)
Depolymerized fractions of heparin can beobtained by Chemical or enzymatic treatment of UF heparin
Anionic glycosaminoglycans but 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 whichhelp to make
LMWH dosage simpler and more predictable than UF
heparin Nephrology 2010;15:386 –392
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LMWH
LMWH
In addition
Less impact on platelet function, and thusmay 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 inhibitthrombin
because of the shorter chain length
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LMWH
In most cases the affinity of LMWH for Xaversus thrombin is of the order of 3:1
The anticoagulant effect of LMWH can bemonitored by the anti-factor Xa activity inplasma
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LMWH
LMWH
Cleared by renal/dialysis mechanisms, sodosage must be adjusted to account for this
When high flux dialysers are used, LMWH ismore 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 theelderly, in the presence of renal impairmentand in very obese patients, to avoid life-
threatening bleeding
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Enoxaparin
Generally does not accumulate in 3/weekdialysis regimens, but there is a risk ofaccumulation in more frequent schedules
No simple antidote and in the case ofsevere haemorrhage-
Activated factor VII concentrate may be
required
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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 patientswith 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 HDanticoagulation 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 successfullyanticoagulate 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 Tinzaparinand newer LMWH vary somewhat, especially
in Anti-Xa/anti-IIa effect
The higher this ratio the more Xa selective the agent andconsequently the less effect protamine has on reversal
EnoxaparinHigh 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 devastatingand deadly complication, in patients exposed
to LMWH compared with UF heparin Another advantage of LMWH is the
Longer duration of action and predictability ofdosage effect, allowing the convenience of a single
subcutaneous injection at the start of dialysiswithout 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 toplatelets, circulating plasma proteins andendothelium
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Is LMWH better?
UF heparin induces
Inhibition of mineralocorticoid metabolim andreduced adrenal aldosterone secretion, but
LMWH has been shown to have less inhibition inthis regard
Other deleterious effects associated with UFheparin are also generally less common with
the use of LMWH including
The risk of osteoporosis, hair loss, endothelial cellactivation and adhesion molecule activation
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Is LMWH better?
A meta-analysis including 11 studies waspublished in 2004 and showed that
LMWH and UF heparin were similarly safe and
effective in preventing extracorporeal circuitthrombosis, with
No significant difference in terms of bleeding,vascular compression time or thrombosis
J. Am. Soc. Nephrol. 2004; 15: 3192 –206.
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Is LMWH better?
LMWH is however recommended as the agent ofchoice for routine haemodialysis by theEuropean Best Practice Guidelines The single factor weighing against the use of LMWH
as the routine form of anticoagulation for dialysis iscost
More and more dialysis units are assessing thecost/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 ofLMWH, to ensure therapeutic dosing or toexclude accumulation prior to a
subsequent dialysis Because of the high bioavailability, dose-
independent clearance by renal
mechanisms, and predictable effect, thereis 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 thedialysis 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 UFheparin/protamine was prototypical ofregional anticoagulation
UF heparin is infused into the arterial line andprotamine into the venous line
Protamine
Basic protein that binds heparin, forming a stablecompound and eliminating its anticoagulant effect
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UF heparin/protamine
Full neutralization of heparin can beachieved with
A dose of 1 mg protamine/100 units heparin
Protamine has a shorter half-life than heparinso
There may be an increased risk of bleeding 2 –4 hafter 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 uncommonand may be serious
As all forms of heparin are absolutelycontraindicated in HIT Type II this form of regionalanticoagulation 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 orhypertonic trisodium citrate infusion into thearterial 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 inpatients at increased risk of bleeding or for dialysisanticoagulation in the stable phase of HIT Type II
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Citrate regional anticoagulation
The citrate –calcium complex
Partially removed by the dialyser
The procedure may require, or be enhanced by,
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 ismetabolized to bicarbonate
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Citrate regional anticoagulation
To neutralize the effect of citrate,
Calcium chloride solution is infused into thevenous 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
Nevertheless, the technique has beenused with
Great success in some hands, with
Few bleeding complications and improvedbiocompatibility with reduced granulocyteactivation and
Less deposition of blood components in the lines
or on the dialyser
Simplified protocols have been proposed
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HIT Type I
HIT type I
10 –20% of patients treated with UF heparin
Mild thrombocytopaenia occurs (<100 000) as aresult of heparin activation of platelet factor 4 (PF4)surface receptors, leading to platelet degranulation
Mechanism is non-immune and early in onset, afterthe initiation of heparin
The syndrome generally resolves spontaneouslywithin 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 HITType I
Generally occurs within the first 4 –10 days ofexposure to heparin
Late onset is less common
Mechanism of HIT which results in bothplatelet activation and activation of thecoagulation 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 re-exposure to heparin after an interval
Of importance the incidence is 5 –10 timesmore common with UF heparin than withpatients receiving only LMWH
The risk with LMWH is reportedly very low, inthe 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 systemicanticoagulation is not required
Dialysis anticoagulation remains a challenge as all forms ofheparin must be avoided
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HIT Type II
Untreated, there is a major risk of venousand arterial thrombosis, estimated at
>50% within 30 days
Most of the clots are described as venous
Arterial thrombi are often platelet-rich whitethrombi (white clot syndrome) which can
cause limb ischaemia and cerebral ormyocardial infarcts
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HIT Type II
In patients with HIT Type II all heparin productsmust be avoided, including Topical preparations, coated products as well as
intravenous preparations
Systemic anticoagulation without heparin ismandatory in the acute phase For haemodialysis, patients may have
‘no heparin’ dialysis or anticoagulation with non-heparins
The available agents commonly used includeDanaparoid, Hirudin, Argatroban, Melagatran andFondaparinux
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HIT Type II
Alternatively, regional citrate dialysis has provedeffective in this setting
Each approach or alternative agent provides its ownchallenges and there may be a steep learning curve.Both UF heparin and LMWH are contraindicated
Venous catheters must not be heparin locked, but canbe locked with recombinant tissue plasminogen activatoror citrate ( trisodium citrate 46.7%)
Other alternatives to consider may include switching thepatient to peritoneal dialysis or using warfarin
In the longer term it may be possible to cautiouslyreintroduce UF heparin, or preferably LMWH, withoutreactivating HIT Type II
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Danaparoid
Currently, this agent remains drug ofchoice in most Australian hospitals for HITType II,
May have unique features, which interferewith 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
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Danaparoid
Danaparoid Binds to antithrombin (heparin cofactor I) and
heparin cofactor II and has some endothelialmechanisms, but Minimal impact on platelets and a low affinity for PF4
More selective for Xa than even the LMWH (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
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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 shouldbe tested by
Anti-Xa estimation before any invasiveprocedure
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Hirudin
Originally discovered in the saliva of leeches
Binds thrombin irreversibly at its active site andthe fibrin-binding site
Recombinant or synthetic variants are alsoavailable – including
Lepirudin, Desirudin and Bivalirudin
Hirudin and its cogeners are
Polypeptides of molecular weight of 7 kDa with nocross-reactivity to the HIT antibody
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Hirudin
Hirudin
Prolonged half-life
Renally cleared, so its half-life in renal
impairment is > 35 h
Studies have confirmed
Hirudin can be used as an anticoagulant for
HD
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Hirudin
Hirudin
No cross-reactivity with UF heparin or LMWH;however,
Hirudin and its analogues are antigenic in theirown right, and up 74% of patients receivingHirudin i.v. can develop anti-Hirudin antibodies,
which can further prolong the half-life
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b
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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 minNot effected by renal function
Hepatic clearance means prolonged durationof action in patients with liver failure
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Argatroban
Anticoagulant effect can be monitored bya variant of the APTT – the ecarin clottingtime
No available reversal agent
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M l t
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Melagatran
Reports of hepatotoxicity have impededfurther drug development
It has been suggested that Melagatran
may have a role in anticoagulationbetween dialysis treatments in patientswith HIT Type II
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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 anti-thrombin interaction
High affinity for anti-thrombin III but
No affinity for thrombin or PF4
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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 beadministered alternate days
Renally cleared, it may accumulate in renal
failureRemoved to some degree by high flux
haemodialysis or haemodiafiltration
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Conclusions
Anticoagulation is an essential part of thesafe and effective delivery of HD
Physicians accredited to prescribe dialysismust have a fundamental understandingof anticoagulation therapy in different
dialysis settings
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Conclusions
Essential for nephrologists to have a goodunderstanding of
The relative merits of UF heparin and LMWH,
To develop an approach to the clinicalmanagement of HIT Type II and otherimportant heparin-related complications
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