Anticoagulation in hemodialysis Dr.. Scope Introduction Introduction Coagulation cascade Coagulation cascade Hemostatic abnormalities in renal insufficiency

Anticoagulation in Anticoagulation in hemodialysishemodialysis

Dr. Dr.

ScopeScope

IntroductionIntroduction Coagulation cascadeCoagulation cascadeHemostatic abnormalities in renal insufficiency

Anticoagulation for hemodialysisAnticoagulation for hemodialysisUnfractionated heparin No heparin dialysisNo heparin dialysis LMWHLMWH Regional anticoagulationRegional anticoagulation

Newer developmentsNewer developments ConclusionsConclusions

IntroductionIntroduction

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


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



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



Platelet-derived membrane microvesiclesMarkedly 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


Coagulation CascadeCoagulation Cascade

Coagulation CascadeComplex, multiply redundant and

includes intricate checks and balances


Coagulation CascadeCoagulation 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 factorThe extrinsic pathway is measured by the

prothrombin test


Hemostatic abnormalities inrenal 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 dysfunctionwhich is further enhanced with use of

anticoagulants during extracorporeal blood purification procedures



Clot formation and development of thrombosis can also occur at increased rates in dialysis patientsPulmonary embolism is more frequent in

dialysis patients than in age-matched controls



Patients on chronic intermittent hemodialysis frequently suffer fromVascular access thrombosis, the risk of

which is increased inPolytetrafluoroethylene grafts compared

with arteriovenous fistulas

Anticoagulation for hemodialysis Anticoagulation for hemodialysis (HD)(HD)

Anticoagulation is routinely required to prevent clotting ofThe 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 HDAnticoagulation for HD

The responsibility for prescribing and delivering anticoagulant for HD is shared between the Dialysis doctors and nurses

Dialysis is a medical therapyMust be prescribed by an

appropriately trained doctor

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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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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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Dosing regimens, while generally safe and effective, are somewhat unscientific

In terms of monitoringMost 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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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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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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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

(‘‘heparin-binding factor I’’)Heparin enhances the activity of this natural

anticoagulant protein 1000 to 4000-foldAntithrombin inactivates thrombin, factor Xa,

and to a lesser extent factors IXa, XIa, and XIIaAt 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 heparin-binding 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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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 First isolated from liver (hepar) mast cells of

dogsNow commercially derived from porcine

intestinal mucosa or bovine lungWhen administered intravenously

Half-life approx. 1.5 hHighly negatively charged and binds non-

specifically to endothelium, platelets, circulating proteins, macrophages and plastic surfaces

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In addition to removal by adherence, heparin is cleared by both renal and hepatic mechanisms and is metabolized by endothelium


Interestingly, UF heparin has both pro- and 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.


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


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


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


Use of UF heparin is Safe, simple and inexpensive andUsually encounters few problems

However, there are risks with HD anticoagulation which are important to be aware of and include The risk of bleedingSome 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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The disadvantages of UF heparin may include Lack of routine or accurate monitoring of

anticoagulation effectThe need for an infusion pump and the

costs of nursing timePerhaps 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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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 DialysisNo Heparin Dialysis

Dialysis without anticoagulation may be indicated in patients withHigh risk of bleedingAcute bleeding disorderRecent head injuryPlanned major surgeryTraumaAcute HIT syndrome or Systemic anticoagulation for other

reasons

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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 DialysisPartial clotting still occurs in 20% of cases with

complete 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 transfusionWhere 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 Low molecular weight heparin (LMWH)(LMWH)

Depolymerized fractions of heparin can be obtained 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 which help to make

LMWH dosage simpler and more predictable than UF heparin

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LMWHLMWH

LMWHIn 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 thrombinbecause of the shorter chain length

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LMWHLMWH

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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LMWHLMWH

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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EnoxaparinEnoxaparin

One of the most commonly used LMWH Has the longest half-lifePredominantly renally clearedDose reduction need to be made in the

elderly, in the presence of renal impairment and in very obese patients, to avoid life-threatening bleeding

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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 factor VII concentrate may be

required

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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 clearanceEffect and accumulation can be

monitored by the performance of anti-Xa levels

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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 bleedingThe product insert should always be

consulted

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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 monitoredYet 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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LMWHLMWH

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?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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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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UF heparin induces Inhibition of mineralocorticoid metabolim

and reduced adrenal aldosterone secretion, but LMWH has been shown to have less inhibition in

this regardOther 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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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.


LMWH is however recommended as the agent of choice for routine haemodialysis by the European Best Practice GuidelinesThe 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 haemodialysisBecause 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, dose-independent 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/protamineUF heparin/protamine

Historically, the use of UF heparin/protamine was prototypical of regional anticoagulationUF heparin is infused into the arterial

line and protamine into the venous lineProtamine

Basic protein that binds heparin, forming a stable compound and eliminating its anticoagulant effect

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Full neutralization of heparin can be achieved with A dose of 1 mg protamine/100 units

heparinProtamine 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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Most authors agree that Procedure can be technically challenging

and No significant advantage over ‘low-dose’

heparin regimensReactions to protamine are not uncommon

and may be seriousAs 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 Citrate regional anticoagulationanticoagulation

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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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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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 is metabolized to bicarbonate

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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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The procedure Complex and high riskRequirement for two infusion pumps and Point of care calcium measurementEither high or low calcium levels in the

patient may risk severe acute complicationsHypertonic citrate may risk hypernatraemiaMetabolism of citrate generates a metabolic

alkalosis

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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 Prostacyclin regional anticoagulationanticoagulation

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 Heparin-induced thrombocytopaenia (HIT)thrombocytopaenia (HIT)

There are two well-described syndromes of HIT, the First relatively benignSecond potentially devastating

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HIT Type IHIT Type I

HIT type I 10–20% of patients treated with UF heparinMild 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 IIHIT Type II

HIT Type IIHIT Type IIMuch more serious and devastating than

HIT Type IGenerally occurs within the first 4–10

days of exposure to heparinLate onset is less commonMechanism of HIT which results in both

platelet activation and activation of the coagulation cascade

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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 heparinMore commonly in females and surgical

cases In dialysis patients the incidence varies

between 2.8% and 12%

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HIT Type II Occurs in incident patients or after re-

exposure to heparin after an intervalOf 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 Two clinical phasesAcute 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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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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Untreated, there is a major risk of venous and arterial thrombosis, estimated at >50% within 30 days

Most of the clots are described as venousArterial thrombi are often platelet-rich

white thrombi (white clot syndrome) which can cause limb ischaemia and cerebral or myocardial infarcts

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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 non-heparins

The available agents commonly used include Danaparoid, Hirudin, Argatroban, Melagatran and Fondaparinux

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HIT Type IIHIT 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

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DanaparoidDanaparoid

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 IIExtracted from pig gut mucosa Heparinoid of molecular weight of 5.5

kDa83% heparan sulphate, 12% dermatan

sulphate and 4% chondroitin sulphate

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Danaparoid Binds to antithrombin (heparin cofactor I) and

heparin cofactor II and has some endothelial mechanisms, 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 Very long half-life of about 25 h in normals

Longer with chronic renal impairment (e.g. 30 h)

No reversal agentClinically, significant accumulation

should be tested by Anti-Xa estimation before any invasive

procedure

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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

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Hirudin

Hirudin Prolonged half-life Renally cleared, so its half-life in renal

impairment is > 35 hStudies 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

their own right, and up 74% of patients receiving Hirudin i.v. can develop anti-Hirudin antibodies,

which can further prolong the half-life

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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

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Argatroban

Synthetic derivative of L-arginineAppears to be the treatment of choice in

the USAActs as a direct thrombin inhibitor andBinds irreversibly to the catalytic site

Short half-life of 40–60 minNot effected by renal functionHepatic clearance means prolonged

duration of action in patients with liver failure

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Argatroban

Anticoagulant effect can be monitored by a variant of the APTT – the ecarin clotting time

No available reversal agent

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Melagatran

Direct thrombin inhibitorAvailable orally as a prodrug, which

is taken twice a dayRenally cleared and has a prolonged

half-lifeNo antidote

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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

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Fondaparinux

Synthetic pentasaccharide of 1.7 kDa,Copy of an enzymatic split product of

heparinSynthetic 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 testingWith a prolonged half-life it can be

administered alternate daysRenally cleared, it may accumulate in

renal failureRemoved to some degree by high flux

haemodialysis or haemodiafiltration

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ConclusionsConclusions

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


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


Continuous development of new anticoagulant drugs and associated clinical recommendations This is an area that dialysis clinicians

should revisit at timely intervals

Documents

Anticoagulation in hemodialysis Dr.. Scope Introduction Introduction Coagulation cascade Coagulation cascade Hemostatic abnormalities in renal insufficiency