1. Anti-coagulants during Hemodialysis
Bancha Satirapoj, MD
Division of Nephrology
Department of Medicine
Phramongkutklao Hospital and College of Medicine

2. 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

3. Coagulation cascade
Intrinsic pathway
Extrinsic pathway
VIIIa
Ca2+ PL
IXa 1
Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin** Xa X Xa Va PL
Ca2+ 50
IIa II
Fibrin
Fibrinogen
*Rosenberg RD, et al. N Engl J Med 1999;340:1555–64.
** Wessler S, et al. Thrombo Diath Haemorrh 1974;32:71–8.
Clot

4. Extrinsic pathway Intrinsic pathway Dialyzer surface Xa Thrombin
XII
XIIa
PKK: HMWK ↓ KK
Leukocyte
activation
Tissue
factor
Dialyzer surface
VIIIa VIII
VIIa VII
XI XIa
IX Ixa X
Prothrombin
Fibrinogen Fibrin
LMWH
Ca2+ Xa
HEPARIN
DTI
Ca2+
XIII
XIIIa
V Va
Ca2+
Thrombin
Ca2+
Fibrin clot
Citrate
Adapted from Shen JI, et al. Am J Kidney Dis. 2012; 60(3):

5. ANTICOAGULATION IN
HEMODIALYSIS PATIENTS

6. Anticoagulation with RRT
Prevent clotting of the filter and reduction in membrane permeability
Adequate RRT
Blood loss in the clotted filter

7. Unfractionated Heparin

8. Unfractionated Heparin
Sulfate polysaccharide
45 saccharide units
MW kDa
Most common anticoagulant used for long-term hemodialysis
potential surface of heparin

9. Heparin action
Stop the coagulation cascade and promoting anticoagulation

10. 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

11. 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/h
Stop 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, add
second bolus dose or add maintenance infusion by 500 IU/h

12. 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/h
Stop min before end of treatment
If excessive bleeding or clotting occurs, adjust maintenance infusion by 500 IU/h U
If excessive bleeding or clotting occurs, adjust loading dose by 500 IU
If clotting persists with loading dose >4,500 IU, add
second bolus dose or add maintenance infusion by 500 IU/h

13. 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/h
Stop 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, add
second bolus dose or add maintenance infusion by 500 IU/h

14. 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/h
Stop 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, add
second bolus dose or add maintenance infusion by 500 IU/h

15. 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/h
Stop 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, add
second bolus dose or add maintenance infusion by 500 IU/h

16. 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/h
Stop 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, add
second bolus dose or add maintenance infusion by 500 IU/h

17. Monitor Anti-coagulations
No routinely measure anticoagulation parameters
Dialyzer clotting
Prolonged bleeding following dialysis
Monitoring with the activated partial thromboplastin time (aPTT)

18. Dialysis-specific factors: clotting
Low blood flow
High hematocrit
High ultrafiltration rate
Vascular access stenosis
Poor needle placement
Anti-coagulant treatments

19. 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

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

21. UFH Benefits Risks Decreased clotting of the dialysis circuit Low cost
Widely available
Short half-life
Reversible with protamine
Bleeding
Heparin-induced thrombocytopenia
Hypertriglyceridemia
Anaphylaxis
Hyperkalemia
Bone mineral disease

22. Low molecular weight heparin

23. Low molecular weight heparin
MW 4-5 kDa
18 saccharide units
LMWH inactivate factor Xa
Lesser effect on thrombin (factor IIa)

24. Low molecular weight heparin

25. 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

26. LMWH for Anticoagulation During Long-term Hemodialysis
(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
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/kg

27. LMWH for Anticoagulation During Long-term Hemodialysis
(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
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/kg

28. 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 IU/mL or high risk bleeding IU/mL

29. Efficacy and safety

30. 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
 Single-dose protocol of enoxaparin is an effective and very convenient alternative to sodium heparin * *+
Frequency of clot formation (%) * * * * + +
Grade
Saltissi D, et al. Nephrol Dial Transplant 1999;14:

31. Meta-analysis: LMWH VS HEPARIN Bleeding: vascular access compression time
LMWH and unfractionated heparin are similarly safe in preventing extracorporeal circuit thrombosis
Lim W, et al. J Am Soc Nephrol 2004;15:

32. Meta-analysis: LMWH VS HEPARIN Extracorporeal circuit thrombosis
LMWH and unfractionated heparin are similarly effective in preventing extracorporeal circuit thrombosis
Lim W, et al. J Am Soc Nephrol 2004;15:

33. Adverse effects

34. Adverse effects: LMWH VS HEPARIN
Thrombocytopenia
Osteoporosis
Hyperkalemia
Hyperlipidemia

35. 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:

36. 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

37. HEPARIN-INDUCED THROMBOCYTOPENIA
Type II HIT
Usually occurs day
Heparin binds to platelets, releasing platelet factor 4 (PF4)
More platelet aggregation
Paradoxical thrombus formation with limb- threatening ischemia

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

39. HEPARIN-INDUCED THROMBOCYTOPENIA
No heparin hemodialysis
Regional citrate hemodialysis
Change to peritoneal dialysis
Other anti-coagulants

40. 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

41. Adverse effects: LMWH VS HEPARIN
Thrombocytopenia
Osteoporosis
Hyperkalemia
Hyperlipidemia

42. 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)
LMWH may partially alleviate osteoporosis associated with UFH administration in patients on maintenance hemodialysis.
Lai KN, et al. Int J Artif Organs 2001;24:

43. UFH is known to increase the risk of osteoporosis in pregnancy
Bone Mineral Disease
UFH is known to increase the risk of osteoporosis in pregnancy

44. Adverse effects: LMWH VS HEPARIN
Thrombocytopenia
Osteoporosis
Hyperkalemia
Hyperlipidemia

45. 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 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
Hottelart C, et al. Artif Organs. 1998;22(7):

46. 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 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
Hottelart C, et al. Artif Organs. 1998;22(7):

47. Hyperkalemia
Hypoaldosteronism with resultant hyperkalemia is a known side effect of UFH
Predialysis potassium levels decreased from mEq/L to 5.15 mEq/L when patients were given LMWH instead of UFH
Hottelart C, et al. Artif Organs. 1998;22(7):

48. Adverse effects: LMWH VS HEPARIN
Thrombocytopenia
Osteoporosis
Hyperkalemia
Hyperlipidemia

49. Reduced lipid concentrations during four years of dialysis with LMWH
500-
400-
300-
200-
100- 0-
LMWH
Triglycerides, mg/dL
Heparin
Heparin
Time, months
Triglyceride levels were decreased when patients switched to LMWH and rebounded when they reverted to UFH
Deuber HJ, Schulz W. Kidney Int 1991;40:

50. Reduced lipid concentrations during four years of dialysis with LMWH
350-
300-
250-
200-
150-
100-
50- 0-
LMWH
Heparin
Heparin
Cholesterol, mg/dL
Time, months
Cholesterol levels were decreased when patients switched to LMWH and rebounded when they reverted to UFH
Deuber HJ, Schulz W. Kidney Int 1991;40:

51. 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:

52. Adverse effects: LMWH VS HEPARIN
Thrombocytopenia
Osteoporosis
Hyperkalemia
Hyperlipidemia

53. Prevent clotting with High risks of bleeding
Postoperative patients
Recent history of a bleeding event

54. Prevent clotting with High risks of bleeding
Normal saline flushing
Regional anti-coagulation with protamine reversal
Regional Citrate anticoagulation
Prostacyclin regional anticoagulation 

55. Normal saline flushing
No heparin hemodialysis  for high risk of bleeding
Pretreating with U of heparin with 0.9%NaCL 1 L
BFR 250 to 500 mL/min
Saline flushes mL q min into the arterial limb
Minimize hemoconcentration and fibrin strands
Careful monitoring of the arterial and venous pressure alarms and saline volume

56. Normal saline flushing
Risk for air embolism
Low efficiency

57. 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

58. Regional anticoagulation with protamine reversal

59. 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

60. 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.

61. Regional citrate anticoagulation
Requires strict protocol
Other metabolic complication (acidosis, alkalosis, hypernatremia, hypocalcemia, hypercalcemia)

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

63. Use anticoagulation adapted to this condition
KDIGO Clinical Practice Guideline for AKI 2012 Recommendations: Anti-coagulation
Yes
Proceed without
anticoagulation
Impaired coagulation ?
Yes
Use anticoagulation adapted to this condition
Underlying condition requires
Systemic anticoagulation?
Choose RRT Modality
CRRT
Intermittent RRT
Contraindication
to Citrate?
Regional Citrate
Anticoagulation No
Increased Bleeding Risk? No
Increased Bleeding Risk?
Yes No
Heparin
Heparin
Proceed without
anticoagulation
Proceed without
anticoagulation
KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

64. New anticoagulant in dialysis
Direct thrombin inhibitors
Heparinoids
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
Shen JI, et al. Am J Kidney Dis. 2012; 60(3):

65. Dialysis-specific factors: clotting
Low blood flow
High hematocrit
High ultrafiltration rate
Vascular access stenosis
Poor needle placement
Anti-coagulant treatments

66. Different anticoagulants in AKI patients
Advantage
Disadvantage
Heparin (unfractionated)
Wide availability
Large experience
Short half-life
Antagonist available
Monitoring with routine tests
(aPTT or ACT)
Low costs
Narrow therapeutic index – risk of bleeding
Unpredictable kinetics – monitoring required
HIT
Heparin resistance
Adapted from KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

67. Different anticoagulants in AKI patients
Advantage
Disadvantage
Heparin (unfractionated)
Wide availability
Large experience
Short half-life
Antagonist available
Monitoring with routine tests
(aPTT or ACT)
Low costs
Narrow therapeutic index – risk of bleeding
Unpredictable kinetics – monitoring required
HIT
Heparin resistance
Low-molecular-weight
heparin
More predictable kinetics
– Weight-based dosing possible
More reliable anticoagulant response
– No monitoring required
Single predialysis dose may be
sufficient in IHD
Reduced risk of HIT
Risk of accumulation in kidney failure
Monitoring requires non routine test (anti–Factor Xa)
Different drugs not interchangeable
Incomplete reversal by protamine
In most countries more expensive than unfractionated heparin
Adapted from KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

68. Different anticoagulants in AKI patients
Advantage
Disadvantage
Saline flush
No bleeding complication
Risk for air embolism
Low efficiency
Adapted from KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

69. Different anticoagulants in AKI patients
Advantage
Disadvantage
Saline flush
No bleeding complication
Risk for air embolism
Low efficiency
Citrate
Strict regional anticoagulation
– reduced bleeding risk
Risk of accidental overdose with potentially fatal consequences
Insufficient citrate metabolism in patients with reduced liver function and shock states resulting in accumulation with metabolic acidosis and hypocalcemia
Other metabolic complication (acidosis, alkalosis, hypernatremia, hypocalcemia, hypercalcemia)
Increased complexity
Requires strict protocol
Adapted from KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

70. Thank you for your attention
Phramongkutklao Hospital and
College of Medicine

71. Anticoagulation options for standard 4 h hemodialysis session