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 Anticoagulatio n in hemodialysis Dr.

1 Anticoagulation in hemodialysis.ppt

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 Anticoagulation in

hemodialysisDr.

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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’  

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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 Anticoagulation for HD

In normal circumstances effective andsafe anticoagulation for HD can bedelivered with

Low risk and high efficiency

Nephrology 2010;15:386 –392

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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”  

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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

Nephrology 2010;15:386 –392

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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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A b

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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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F d i

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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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C l i

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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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