Anticoagulation in hemodialysis

1
Anticoagulation in hemodialysis

• Dr.

2
Scope

• Introduction
• Coagulation cascade
• Hemostatic abnormalities in renal insufficiency
• Anticoagulation for hemodialysis
• Unfractionated heparin
• No heparin dialysis
• LMWH
• Regional anticoagulation
• Newer developments
• Conclusions

3
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 11178189
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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 11178189
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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 11178189
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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 11178189
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Coagulation Cascade

• Coagulation Cascade
• Complex, multiply redundant and includes
  intricate checks and balances

Hemodialysis International 2007 11178189
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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 11178189
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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 dysfunction
• which is further enhanced with use of
  anticoagulants during extracorporeal blood
  purification procedures

Hemodialysis International 2007 11178189
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Hemostatic abnormalities inrenal 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 11178189
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Hemostatic abnormalities inrenal insufficiency

• Patients on chronic intermittent hemodialysis
  frequently suffer from
• Vascular access thrombosis, the risk of which is
  increased in
• Polytetrafluoroethylene grafts compared with
  arteriovenous fistulas

12
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 1415
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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 doctors 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
  (540, 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 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 100040
  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

25
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 can directly
  inhibit thrombin
• When heparin binds antithrombin it causes a
  conformation change, which results in a 100040
  000x increase in the natural anticoagulant effect
  of anti-thrombin.

26
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.

27
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 23 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

28
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

29
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

30
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 2550 ml of saline every
  1530 min, in association with a high blood flow
  rate
• In some units the lines are pretreated with
  20005000 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
• 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 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
• Chemical or enzymatic treatment of UF heparin
• Anionic glycosaminoglycans but
• have a lower molecular weight of 29 kDa, mostly
  _at_ 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 (5070) 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 31
• 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 life-threatening 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 factor VII concentrate may be required

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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 lt 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 3192206.
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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,
  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/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 24 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 citratecalcium 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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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 35 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
• 1020 of patients treated with UF heparin
• Mild thrombocytopaenia occurs (lt100 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 410 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 gt 20 000
• Clinical HIT Type II is reported to occur in
• 215 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 510 times more
  common with UF heparin than with patients
  receiving only LMWH
• The risk with LMWH is reportedly very low, in the
  order of lt1

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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 heparinPF4 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 gt90 cross-reactivity with
  LMWH

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HIT Type II

• Untreated, there is a major risk of venous and
  arterial thrombosis, estimated at
• gt50 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
  non-heparins
• The available agents commonly used include
  Danaparoid, Hirudin, Argatroban, Melagatran and
  Fondaparinux

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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

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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

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Danaparoid

• 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 2228 1
  LMWH 31 typically)
• Low cross-reactivity with HIT antibodies
  (6.510) 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 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 gt 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 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-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 4060 min
• Not effected by renal function
• Hepatic 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 inhibitor
• Available orally as a prodrug, which is taken
  twice a day
• Renally cleared and has a prolonged half-life
• No 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 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 be administered
  alternate days
• Renally cleared, it may accumulate in renal
  failure
• Removed to some degree by high flux haemodialysis
  or haemodiafiltration

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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

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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

88
Conclusions

• Continuous development of new anticoagulant drugs
  and associated clinical recommendations
• This is an area that dialysis clinicians should
  revisit at timely intervals

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Thank You!