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 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

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):473-486

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/h Stop 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, add second 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/h Stop 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, add second 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/h Stop 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, add second 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/h Stop 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, add second 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/h Stop 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, add second 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/h Stop 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, add second 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

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.

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

Low molecular weight heparin

Low molecular weight heparin MW 4-5 kDa 18 saccharide units LMWH inactivate factor Xa Lesser 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 (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/kg

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 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/kg

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

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;14:2698-703.

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;15:3192-206.

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;15:3192-206.

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 hemodialysis Regional 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) LMWH may partially alleviate osteoporosis associated with UFH administration in patients on maintenance hemodialysis. Lai KN, et al. Int J Artif Organs 2001;24:447-55.

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

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 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):614-617.

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):614-617.

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 500- 400- 300- 200- 100- 0- LMWH Triglycerides, mg/dL Heparin Heparin -20 -10 0 10 20 30 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;40:496-500.

Reduced lipid concentrations during four years of dialysis with LMWH 350- 300- 250- 200- 150- 100- 50- 0- LMWH Heparin Heparin Cholesterol, mg/dL -20 -10 0 10 20 30 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;40:496-500.

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 bleeding Postoperative 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 embolism Low 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 Requires strict protocol Other metabolic complication (acidosis, alkalosis, hypernatremia, hypocalcemia, hypercalcemia)

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.

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

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):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 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

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

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

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

Thank you for your attention Phramongkutklao Hospital and College of Medicine

Anticoagulation options for standard 4 h hemodialysis session