Anti-coagulants during Hemodialysis

Anti-coagulants during

Hemodialysis

Bancha Satirapoj, MDDivision of Nephrology

Department of MedicinePhramongkutklao Hospital and College of

Medicine

Dialysis and Thrombosis

Kidney disease Inflammation Endothelial injury Expression and activity of procoagulant factors

Dialysis process Needle, blood line, blood flow Platelet-platelet aggregation Platelet-erythrocyte aggregation Extrinsic and Intrinsic pathway activation

Coagulation cascade

Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin**

Extrinsic pathway

*Rosenberg RD, et al. N Engl J Med 1999;340:1555–64.

** Wessler S, et al. Thrombo Diath Haemorrh 1974;32:71–8.

Intrinsic pathway

1

50

Xa X

II

FibrinFibrinogen

Clot

Xa Va

PLCa2+

IIa

VIIIaCa2+

PL

IXa

Extrinsic pathwayIntrinsic pathway

Dialyzer surfacePKK: HMWK↓KK

XII

XIIa

XI XIa

IX Ixa

X

Prothrombin

Fibrinogen Fibrin

Leukocyte activation

Tissuefactor

VIIa VII

XIII

XIIIa

VIIIa VIII

V Va

Xa

Thrombin

Citrate

Ca2+

Ca2+

Ca2+

Ca2+

DTI

LMWH

HEPARIN

Adapted from Shen JI, et al. Am J Kidney Dis. 2012; 60(3):473-486

Fibrin clot

ANTICOAGULATION IN

HEMODIALYSIS PATIENTS

Anticoagulation with RRT

Prevent clotting of the filter and reduction in membrane permeability

Adequate RRT Blood loss in the clotted filter

Unfractionated Heparin

Unfractionated Heparin Sulfate polysaccharide 45 saccharide units MW 10-16 kDa Most common anticoagulant

used for long-term hemodialysis

potential surface of heparin

Heparin action

Stop the coagulation cascade and promoting anticoagulation

UFH activity Half-life of UFH = 1 hour in patients with kidney failure

Half-life of UFH = 30 minutes in patients with normal kidney function

Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis

Loading Dose

Maintenance Infusion

Parameters for Adjustment

25-50 IU/kg 800-1,500 IU/hStop 30-60 min before end of treatment

If excessive bleeding or clotting occurs, adjust maintenance infusion by 500 IU/hIf excessive bleeding or clotting occurs, adjust loading dose by 500 IUIf clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h


Loading Dose




If excessive bleeding or clotting occurs, adjust maintenance infusion by 500 IU/h

1000-2500 U

If excessive bleeding or clotting occurs, adjust loading dose by 500 IUIf clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h


Loading Dose






Loading Dose






Loading Dose






Loading Dose





Monitor Anti-coagulations

No routinely measure anticoagulation parameters Dialyzer clotting Prolonged bleeding following dialysis

Monitoring with the activated partial thromboplastin time (aPTT)

Dialysis-specific factors: clotting Low blood flow High hematocrit High ultrafiltration rate Vascular access stenosis Poor needle placement

Anti-coagulant treatments

STANDARD ANTICOAGULATION Heparin: pharmacodynamic

modeling Using an initial bolus followed by a constant fixed infusion of heparin to maintain an activated clotting time (ACT) of 200 to 250 seconds

Normal = 90 to 140 seconds

Improved dialyzer reuse after use of a population pharmacodynamic model to determine heparin doses

Dialyzer reuse rates increased significantly over time in the treatment group but remained unchanged in the control group (P<0.003)

Ouseph R, Brier ME, Ward RA Am J Kidney Dis. 2000;35(1):89.Use of a heparin model can improve dialyzer reuse rates

treatment control05

1015202530

prepost

Num

ber o

f use

s

*

UFH Bleeding

Heparin-induced thrombocytopenia

Hypertriglyceridemia Anaphylaxis Hyperkalemia Bone mineral disease

Decreased clotting of the dialysis circuit

Low cost Widely available Short half-life Reversible with

protamine

RisksBenefits

Low molecular weight heparin


MW 4-5 kDa 18 saccharide units

LMWH inactivate factor XaLesser effect on thrombin (factor IIa)


LMWH VS HEPARIN More specific binding action

>UFH Easier to dose by weight Single prefilled syringe injection Increased half-life 2-4 hr Prefer IV > SC

No agents for reverse its effects

LMWH for Anticoagulation During Long-term Hemodialysis

LMWH MW(kDa)

Anti-Xa: anti-IIa

ratio

HF(hr)

Dose Dose in High risk of

bleeding

Enoxaparin

4,500 3.9 13.9 0.7 mg/kg 0.5 mg/kg

Nadroparin

4,300 3.3 2.5-3.5

BW <50 kg-0.3 mL (2,850 IU)BW 50–69 kg- 0.4 mL (3,800 IU) BW ≥70 kg-0.6 mL (5700 IU)

35 IU/kg

Tinzaparin

6,500 1.6 2.3 2,500 IU 2,000 IU

Dalteparin

6,000 2.5 2.2 5,000 IU 40-50 IU/kg2,500 IU

LMWH for Anticoagulation During Long-term Hemodialysis

LMWH MW(kDa)

Anti-Xa: anti-IIa

ratio

HF(hr)

Dose Dose in High risk of

bleeding

Enoxaparin

4,500 3.9 13.9 0.7 mg/kg 0.5 mg/kg

Nadroparin

4,300 3.3 2.5-3.5

BW <50 kg-0.3 mL (2,850 IU)BW 50–69 kg- 0.4 mL (3,800 IU) BW ≥70 kg-0.6 mL (5700 IU)

35 IU/kg

Tinzaparin

6,500 1.6 2.3 2,500 IU 2,000 IU

Dalteparin

6,000 2.5 2.2 5,000 IU 40-50 IU/kg2,500 IU

Monitor anticoagulations No routinely measure anticoagulation

parameters Dialyzer clotting Prolonged bleeding following dialysis

Monitoring with the activated partial thromboplastin time (aPTT) is not accurate

Measurement of anti-factor Xa levels keep 0.4-0.6 IU/mL or high risk bleeding 0.2-0.4 IU/mL

Efficacy and safety

1 2 3 4 5_7 8_100

1020304050607080

heparinclexane

Comparison of LMWH (enoxaparin) and standard heparin for HD anticoagulation 36 chronic HD pts Randomly assigned to enoxaparin (1 MKD) or

standard heparin, followed for 12 wks

Saltissi D, et al. Nephrol Dial Transplant 1999;14:2698-703.Grade

* *+

**** + +

Freq

uenc

y of

clo

t for

mat

ion

(%) Single-dose protocol of enoxaparin is an

effective and very convenient alternative to sodium heparin

Meta-analysis: LMWH VS HEPARINBleeding: vascular access compression time

Lim W, et al. J Am Soc Nephrol 2004;15:3192-206.

LMWH and unfractionated heparin are similarly safe in preventing

extracorporeal circuit thrombosis

Meta-analysis: LMWH VS HEPARINExtracorporeal circuit thrombosis

Lim W, et al. J Am Soc Nephrol 2004;15:3192-206.

LMWH and unfractionated heparin are similarly effective in preventing

extracorporeal circuit thrombosis

Adverse effects

Adverse effects: LMWH VS HEPARIN

Thrombocytopenia Osteoporosis Hyperkalemia Hyperlipidemia

HEPARIN-INDUCED THROMBOCYTOPENIA IN HEMODIALYSIS Frequency of HIT is suggested to

be 8.1% of patients exposed to heparin

Significantly lower (1.8%) in patients exposed to LMWH

Syed S, Nat Rev Nephrol 2009;5:501-11.

HEPARIN-INDUCED THROMBOCYTOPENIA Type I HIT

Heparin binds, activates, and depletes platelets.

Typically occurs within the first 4 days of starting heparin therapy

Mild thrombocytopenia with average 100,000/mm3

Resolves with time

Heparin therapy does not need to be stopped

HEPARIN-INDUCED THROMBOCYTOPENIA Type II HIT

Usually occurs 5-12 day

Heparin binds to platelets, releasing platelet factor 4 (PF4)

More platelet aggregation

Paradoxical thrombus formation with limb-threatening ischemia

HEPARIN-INDUCED THROMBOCYTOPENIA

Extensive cross-reactivity (>90 percent) between the LMWH and standard heparin in terms of antibody recognition

HEPARIN-INDUCED THROMBOCYTOPENIA

No heparin hemodialysisRegional citrate hemodialysis

Change to peritoneal dialysis

Other anti-coagulants

Heparin-induced thrombocytopenia (HIT)

In a patient with HIT All heparin must be stopped Using direct thrombin inhibitors

(argatroban) or Factor Xa inhibitors (danaparoid or fondaparinux) > other or no anticoagulation during RRT (1A)

In a patient with HIT who does not have severe liver failure Using argatroban rather than other

thrombin or Factor Xa inhibitors during RRT(2C)

KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012



Effect of LMWH on bone metabolism in patients on maintenance hemodialysis 40 patients on stable hemodialysis using

unfractionated heparin (UFH) for more than 24 months

Tartrate-resistant acid phosphatase (TRACP) reflecting osteoclastic activity was elevated in 35% of patients.

Following LMWH treatment, TRACP was reduced by 13% (p<0.05)

Lai KN, et al. Int J Artif Organs 2001;24:447-55.

LMWH may partially alleviate osteoporosis associated with UFH administration in patients

on maintenance hemodialysis.

Bone Mineral Disease

UFH is known to increase the risk of osteoporosis in pregnancy



Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of LMWH and unfractionated heparinComparison of unfractionated heparin (UH) and low

molecular weight heparin (LMWH) protocols

Hottelart C, et al. Artif Organs. 1998;22(7):614-617.

UH LMWH P value

Heparin dose per session

6,160 ± 1,350

2,220 ± 310

-

Plasma potassium

5.66 ± 0.83

5.15 ± 0.68

p < 0.05

Plasma aldosterone(pg/ml)

274 ± 205

435 ± 465

NS

Plasma aldo/RA (pg/ng/h)

112 ± 86

149 ± 123

p < 0.05

Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of LMWH and unfractionated heparinComparison of unfractionated heparin (UH) and low

molecular weight heparin (LMWH) protocols


UH LMWH P value

Heparin dose per session

6,160 ± 1,350

2,220 ± 310

-

Plasma potassium

5.66 ± 0.83

5.15 ± 0.68

p < 0.05

Plasma aldosterone(pg/ml)

274 ± 205

435 ± 465

NS

Plasma aldo/RA (pg/ng/h)

112 ± 86

149 ± 123

p < 0.05

Hyperkalemia Hypoaldosteronism with resultant

hyperkalemia is a known side effect of UFH

Predialysis potassium levels decreased from 5.66 mEq/L to 5.15 mEq/L when patients were given LMWH instead of UFH




Reduced lipid concentrations during four years of dialysis with LMWH

Deuber HJ, Schulz W. Kidney Int 1991;40:496-500.

-20 -10 0 10 20 30Time, months

500-400-300-200-100-

0-Trig

lyce

rides

, mg/

dL

Triglyceride levels were decreased when patients switched to LMWH and rebounded when they reverted to UFH

Heparin

LMWH

Heparin

Reduced lipid concentrations during four years of dialysis with LMWH


-20 -10 0 10 20 30Time, months

350-300-250-200-150-100-

50-0-Ch

oles

tero

l, m

g/dL

Cholesterol levels were decreased when patients switched to LMWH and rebounded when they reverted to UFH

Heparin

LMWH

Heparin

Hypertriglyceridemia/VLDL and IDL

Depletion of lipoprotein lipase (LPL)

Bolus of heparin will release LPL into the free circulation

Ultimately depletes its stores, leading to a build-up of triglycerides

Cholesterol, VLDL, IDL and Triglyceride levels were decreased when patients switched to LMWH and rebounded when they reverted to UFH




Prevent clotting with

High risks of bleedingPostoperative patients

Recent history of a bleeding event

Prevent clotting with High risks of bleeding Normal saline flushing Regional anti-coagulation with

protamine reversal Regional Citrate anticoagulation Prostacyclin regional

anticoagulation

Normal saline flushing No heparin hemodialysis for high risk of

bleeding Pretreating with 2000-5000 U of heparin with

0.9%NaCL 1 L BFR 250 to 500 mL/min Saline flushes 100-200 mL q 15-30 min into

the arterial limb Minimize hemoconcentration and fibrin

strands

Careful monitoring of the arterial and venous pressure alarms and saline volume

Normal saline flushing

Risk for air embolismLow efficiency

Regional anti-coagulation with protamine reversal Earliest method to reduce

hemodialysis associated bleeding Constant infusion of heparin into

the dialyzer inlet line Simultaneous constant infusion of

protamine prior to the blood returning to the patient

Protamine binds to heparin and eliminates its anticoagulant activity

Regional anticoagulation with protamine reversal

Regional anticoagulation with protamine reversal

Technical difficulties

Rebound bleeding 2-3 hours after dialysis as the RE system releases free heparin from the protamine-heparin complex back into circulation

Regional citrate anticoagulation Reduced incidence of bleeding compared to

standard heparin protocols Trisodium citrate solution into the arterial

side of the dialyzer Fall free plasma calcium induced by binding

to citrate for the anticoagulant activity Citrate-calcium complex is removed across

the dialyzer Reversed by 5% CaCl2 infuse into the

venous return at a rate of 0.5 mL/min

Janssen MJ, et al Nephrol Dial Transplant. 1993;8(11):1228.

Regional citrate anticoagulation

Other metabolic complication (acidosis, alkalosis, hypernatremia, hypocalcemia, hypercalcemia)

Requires strict protocol

Frequent measurements of plasma electrolytes Hypocalcemia or hypercalcemia Hypernatremia (due to the hypertonic

sodium citrate solution) Metabolic alkalosis (due to

bicarbonate generated during the metabolism of citrate)

Regional citrate anticoagulation

Apsner R, et al. Am J Kidney Dis. 2005;45(3):557.

KDIGO Clinical Practice Guideline for AKI 2012Recommendations: Anti-coagulation

Impaired coagulation ?

Intermittent RRT

Choose RRT Modality

Proceed withoutanticoagulation

Use anticoagulation adapted to this

condition

Underlying condition requiresSystemic

anticoagulation?



Regional CitrateAnticoagulation

Contraindicationto Citrate?Increased Bleeding Risk?

CRRT

Heparin Heparin

Increased Bleeding Risk?

Yes

Yes

Yes

No

No

No

KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

New anticoagulant in dialysis

Cost Argatroban not safe in

hepatic impairment Hirudin and derivatives

have prolonged half-life No reversal agent Can be used in patients

with history of HITa

Cost Prolonged half-life No reversal agent Possibility of cross-

reaction with HIT antibodies

Can be used in patients with history of HITa

Direct thrombin inhibitors Heparinoids

Shen JI, et al. Am J Kidney Dis. 2012; 60(3):473-486

Dialysis-specific factors: clotting Low blood flow High hematocrit High ultrafiltration rate Vascular access stenosis Poor needle placement

Anti-coagulant treatments

Different anticoagulants in AKI patients

Anticoagulant Advantage Disadvantage

Heparin (unfractionated)

Wide availabilityLarge experienceShort half-lifeAntagonist availableMonitoring with routine tests(aPTT or ACT)Low costs

Narrow therapeutic index – risk of bleedingUnpredictable kinetics – monitoring requiredHITHeparin resistance

Adapted from KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012



Heparin (unfractionated)

Wide availabilityLarge experienceShort half-lifeAntagonist availableMonitoring with routine tests(aPTT or ACT)Low costs

Narrow therapeutic index – risk of bleedingUnpredictable kinetics – monitoring requiredHITHeparin resistance

Low-molecular-weightheparin

More predictable kinetics– Weight-based dosing possibleMore reliable anticoagulant response– No monitoring requiredSingle predialysis dose may besufficient in IHDReduced risk of HIT

Risk of accumulation in kidney failureMonitoring requires non routine test (anti–Factor Xa)Different drugs not interchangeableIncomplete reversal by protamineIn most countries more expensive than unfractionated heparinAdapted from KDIGO Clinical Practice Guideline for Acute

Kidney Injury 2012



Saline flush No bleeding complication





Saline flush No bleeding complication


Citrate Strict regional anticoagulation– reduced bleeding risk

Risk of accidental overdose with potentially fatal consequencesInsufficient citrate metabolism in patients with reduced liver function and shock states resulting in accumulation with metabolic acidosis and hypocalcemiaOther metabolic complication (acidosis, alkalosis, hypernatremia, hypocalcemia, hypercalcemia)Increased complexityRequires strict protocol


Thank you for your attention

Phramongkutklao Hospital and College of Medicine

Anticoagulation options for standard 4 h hemodialysis session

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Anti-coagulants during Hemodialysis