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Anti-coagulants during
Hemodialysis
Bancha Satirapoj, MD
Division of Nephrology
Department of Medicine
Phramongkutklao 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
PL
Ca2+
IIa
VIIIa
Ca2+
PL
IXa
Extrinsic pathway
Intrinsic 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/h
If excessive bleeding or clotting occurs, adjust loading dose by 500 IU
If clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h
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/h
1000-2500 U
If excessive bleeding or clotting occurs, adjust loading dose by 500 IU
If clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h
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/h
If excessive bleeding or clotting occurs, adjust loading dose by 500 IU
If clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h
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/h
If excessive bleeding or clotting occurs, adjust loading dose by 500 IU
If clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h
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/h
If excessive bleeding or clotting occurs, adjust loading dose by 500 IU
If clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h
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/h
If excessive bleeding or clotting occurs, adjust loading dose by 500 IU
If clotting persists with loading dose >4,500 IU, addsecond bolus dose or add maintenance infusion by 500 IU/h
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 control0
5
10
15
20
25
30
prepost
Num
ber
of u
ses
*
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
Low molecular weight heparin
MW 4-5 kDa 18 saccharide units
LMWH inactivate factor XaLesser effect on thrombin (factor IIa)
Low molecular weight heparin
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
10
20
30
40
50
60
70
80
heparin
clexane
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
uen
cy o
f cl
ot
form
ati
on
(%
) 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
Adverse effects: LMWH VS HEPARIN
Thrombocytopenia Osteoporosis Hyperkalemia Hyperlipidemia
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
Adverse effects: LMWH VS HEPARIN
Thrombocytopenia Osteoporosis Hyperkalemia Hyperlipidemia
Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of LMWH and unfractionated heparin
Comparison 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 heparin
Comparison 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
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
Hottelart C, et al. Artif Organs. 1998;22(7):614-617.
Adverse effects: LMWH VS HEPARIN
Thrombocytopenia Osteoporosis Hyperkalemia Hyperlipidemia
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/d
L
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
Deuber HJ, Schulz W. Kidney Int 1991;40:496-500.
-20 -10 0 10 20 30Time, months
350-
300-
250-
200-
150-
100-
50-
0-Chole
stero
l, m
g/d
L
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
Deuber HJ, Schulz W. Kidney Int 1991;40:496-500.
Adverse effects: LMWH VS HEPARIN
Thrombocytopenia Osteoporosis Hyperkalemia Hyperlipidemia
Prevent clotting
with
High risks of
bleedingPostoperative patientsRecent 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?
Proceed withoutanticoagulation
Proceed withoutanticoagulation
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
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
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
Different anticoagulants in AKI patients
Anticoagulant Advantage Disadvantage
Saline flush No bleeding complication
Risk for air embolismLow efficiency
Adapted from KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012
Different anticoagulants in AKI patients
Anticoagulant Advantage Disadvantage
Saline flush No bleeding complication
Risk for air embolismLow efficiency
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
Adapted from KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012
Thank you for your attention
Phramongkutklao Hospital and College of Medicine
Anticoagulation options for standard 4 h hemodialysis session
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