Anticoagulation in Hemodialysis

Brief overview of presentation

Hemostasis & basic coagulation cascade

Conventional anticoagulants

Newer drugs

Evidence based medicine

Introduction- Hemostasis

Hemostasis is defined as process of platelet – fibrin thrombus formation to seal a site of vascular injury without resulting in total occlusion of the vessel

On hemodialysis• All the part of the extracorporeal circuit are thrombogenic.• Intrinsic coagulation pathway is invariably activated at all times patient is taken on HD.• Without anticoagulation, 4 hrs HD will lead to a) 5-10 % cases to have clotting b) loss of 100-150ml blood lossc) Early loss of the dialyser

Factors favouring increased clotting

• Low blood flow rates• High UF rate• Intradialytic blood, blood products,albumin

and lipid infusion, iv drips – infusions• Dialysis access recirculation• High hematocrit of patient • Retained air in dialyser, inadequate priming

Signs of clotting

• Extremely dark blood in circuit• Black streaks in dialyser- clotted fibres Grade I clotting- < 10 % fibres Grade II clotting- 10- 50 % fibres Grade III clotting- > 50 % fibres• Clots in arterial side header• Foaming and clot in drip chamber and venous

trap• Rapid filling of the transducer monitors with

blood

Heparin- Unfractionated (UFH)

Monitoring of heparin

• aPTT (Kaolin)• WBPTT (Whole Blood PTT - Actin FS reagent)• ACT (Activated clotting time –silica )• Lee-White Clotting test (Capillary test)• Factor Xa assay• Factor Xa Clotting time

Heparin (UFH) prescription

a) Routine/ Regular heparin • Bolus f/b Continous infusion• Blous f/b Intermittent boluses

b) Tight/ low heparin

Routine heparin

A) Bolus f/b constant infusion

Bolus - 1000 U from the venous acsess tubing f/b saline flush and wait for 3- 5 min before initiating HD

Infusion - 1000 U/hr from the arterial line

B) Bolus f/b intermittent boluses

Bolus - 4000 U from the venous acsess tubing f/b saline flush and wait for 3- 5 min before initiating HD

Intermittent boluses - 1000 – 2000 U if necessary from the arterial line

Tight heparinBolus - 750 U from the venous access tubing f/b saline flush .Check WBPTT/ACT after 3 min• If levels not upto baseline + 40% give more

bolus• If yes then start HD

Infusion - 600 U/hr from the arterial lineContinue till the termination

Target to achieve- by WBPTT/ACT

Regular heparin Tight heparin Predialysis Post dialysis Predialysis Post dialysis

Baseline + 80 %

Baseline + 40 %

Baseline + 40 %

Baseline + 40 %

WBPTT- 60-80 sec ACT – 120-150 sec

When to terminate the heparin

Regular with continous infusion or int. bolus 1 hour before termination – AVF/GraftTill the end – Catheter

Tight heparin – Till the end

Normal heparin vs low dose heparin

Normal heparin - Infusion rates of 1000 u/hr

Low dose heparin - Infusion rates of 500 u/hr

Heparin associated complications

BOAT -PHD• Bleeding • Osteoporosis • Alopecia ,Anaphylaxis • Thrombocytopenia , thrombosis (HITT)

• Pruritus • Hyperkalemia• Dyslipidemia (Inc- TG, Dec- HDL)

No Heparin / Heparin free Dialysis

HITT syndromePericarditisAcute bleeding disorderCoagulopathy , thrombocytopeniaRecent surgery, Head injury Polytrauma

Heparin free HD

Initial rinse – Rinse the extracorporeal circuit with 3000 units UFH in 1 litre saline.

Drain- allow the heparinised saline to drain out completely before venous return to patient by filling the circuit with patients blood or normal saline

Blood flow rates- 400ml/min

Periodic saline rinse – 250 ml every 15 min• To reduce clot formation ??????• To inspect if there is ongoing clot formation

Disadvantages

• Partial clotting - 20% of cases• Complete clotting - 7%• Catheter clotting• Inadequate HD• Labour and cost intensive

Low molecular weight heparin (LMWH)

• Superior pharmacokinetics, • Higher bioavailability, • Less non-specific binding (Xa: Antithrombin activity = 3:1,Heparin has 1:1 and added inhib of TFPI)• Hence predictable dosing • Longer half-life

Other advantages

• Less dyslipidemia

• Less pruritus

• Less hyperkalemia

• Less osteoporosis

• Less HITT

Dose

Single loading dose of 125-250 anti factor XA Institute Choay Units (aXa ICU)/kg at the start of hemodialysis .

No monitoring needed.

LMWHEnoxaparin Dalteparin, Nadroparin, Reviparin Tinzaparin

More the Anti-Xa/anti-IIa activity (2-4 ), lesser the effect of protamine has on reversal

Enoxaparin High anti-Xa/anti-IIa ratio of 3.8, and is < 60% reversible with protamine

Is LMWH better?

A meta-analysis including 11 studies published in 2004 - “LMWH and UF heparin were similarly safe and

effective in preventing extracorporeal circuit thrombosis, with no significant difference in terms of bleeding, vascular compression time or thrombosis”

J. Am. Soc. Nephrol. 2004; 15: 3192–206.

Is LMWH better?

LMWH is however recommended as the agent of choice for routine haemodialysis by the European Best Practice Guidelines

“The single factor weighing against the use of LMWH as the routine form of anticoagulation for dialysis is cost”

USFDA has still not approved it for HD

Nephrology 2010;15:386–392

Heparinoids - Danaparoid

• Extracted from pig gut mucosa

• Heparinoid of molecular weight of 5.5 kDa, mixture of

84% heparan sulphate,12% dermatan sulphate and 4% chondroitin sulphate

Danaparoid• Binds to antithrombin 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 : 1LMWH - 3:1 UFH – 1:1

• 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

Dose –Bolus dose- 750 IU for wt >55kgIntermittent boluses – to achieve anti – Xa activity of 0.25-0.35

Disadvantage- No reversal agentLong action (30 hrs)10 % risk of HITT

Fondaparinux 7.5 mg s/c can be used - a syntheticpentasaccharide which is safe in HITT (do not cross react with PF4 antibodies)

Direct thrombin inhibitors- DTI’sHIRUDIN• Originally discovered in the saliva of leeches• Binds thrombin irreversibly at its active site and the

fibrin-binding site• Recombinant variants are also available – Lepirudin,– Desirudin and– Bivalirudin

Argatroban• Synthetic derivative of L-arginine• Binds irreversibly to the catalytic site• Short half-life of 40–60 min• Not effected by renal function• Hepatic clearance means prolonged duration

of action in patients with liver failure

• Bolus- 250 mcg/kg f/b 0.5 -2 mcg/kg/min to titrate to level of aPTT 1.5 -2 times normal

Argatroban

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

• No available reversal agent

Melagatran

• Experimental

• Available orally as a prodrug, which is taken twice a day

• Renally cleared and has a prolonged half-life

• No antidote

• Hepatotoxic

Citrasate / citricon dialysate solution

• Bicarbonate dialysis solution with low citrate concentration (2.4 meq/l)

• Done by adding citric acid instead of acetic acid at a low dose.

• Citrate chelates calcium and inhibits coagulation.

• As a part of low or heparin free HD

Regional anticoagulation for HD

To restrict the anticoagulant effect to the dialysis circuit and prevent systemic anticoagulation inpatients at increased risk of bleeding.

1) 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

• Dose of 1 mg protamine/100 units heparin

1) UF heparin/protamine

• Procedure can be technically challenging and• No significant advantage over ‘low-dose’

heparin regimens• Reactions to protamine are not uncommon

and may be serious• Can’t be used in HITT syndrome

2) Citrate regional anticoagulation• Isoosmotic trisodium citrate infusion is given into the arterial side of the dialysis circuit

• It chelates calcium and decreases coagulation in the extracorporeal circuit.

• But to avoid patient landing up with hypocalcemia, calcium chloride is infused at the venous end

Advantages over heparin free HD

• No need of very high blood flow rates

• Better outcomes as compared to heparin free method for avoiding clotting

Disadvantages • Risk of alkalemia as citrate metabolises to

bicarbonate – dialysate bicarb shoud be reduced

• Risk of hypernatremia

• Need hourly monitoring of ionised calcium, either hyper or hypocalcemia is dangerous

• Need two infusions- TSC and CaCl3

3) Prostacyclin regional anticoagulation

• Vasodilator and platelet aggregation inhibitor• Very short half-life of 3–5 min • Infused into the arterial line• Side effectsHeadache, light headedness,facial flushing,hypotension prohibitive cost