Hemodialysis anticoagulation

Anticoagulation lab tests
Unfractioned Heparin
Heparin induced thrombocytopenia
Low Molecular Weight Heparin (LMWH)
Heparin Free Dialysis
Regional Heparinization With Protamine Reversal
Heparin Coated Filters
Regional Citrate Anticoagulation
Citrasate
Heparinoids
Direct Thrombin Inhibitors
Platelet Inhibiting Agents

1. Hemodialysis anticoagulation Dr Abdullah Ansari SR Nephrology SGPGI Lucknow

2. Patients on HD are at risk of both bleeding tendency and thrombosis Bleeding Uremia associated Platelet dysfunction Endothelial abnormalities Anticoagulation during HD Thrombosis Systemic inflammation Endothelial damage Decreased protein C,S,AT III level & activity HD filters & lines Turbulent blood flow and high sheer stress during HD High hematocrit Blood transfusion

3. Blood Clotting in the Extracorporeal Circuit Exposure of blood to tubing’s, drip chambers, headersand dialysis membranes predisposes to blood clotting Thrombus formation can cause occlusion & malfunction, ultimately leading to discontinuation of dialysis If no anticoagulation is used 5-10% of dialysers may clot, resulting in loss of approximately 100-150 ml of blood

4. Mechanisms of Clotting in the Extracorporeal Circuit Intrinsic Pathway: The plasma proteins deposit on the artificial surfaces, and factor XII and HMW kallikrein accumulate and act as initiating factors for contact coagulation Extrinsic pathway: Leucocytes on contact with dialyser membrane get activated and release blebs of surface membrane rich in tissue factor

5. Factors Favoring Clotting of the Extracorporeal Circuit

6. Anticoagulation Monitoring Anticoagulation efficacy during HD sessions: Clinical monitoring: visual inspection Lab monitoring: clotting tests

7. Signs of Clotting in the Extracorporeal Circuit Extremely dark blood Shadows or black streaks in the dialyzer Foaming with subsequent clots drip chambers and venous trap Rapid filling of transducer monitors with blood Teetering (blood in postdialyzer venous line segment that is unable to continue into venous chamber but falls back into the line segment) Presence of clot at the arterial side header

8. Visual inspection The circuit is rinsed with saline solution while temporarily occluding the blood inlet

9. Signs of over-heparinization Prolonged compression time at the end of dialysis

10. Extracorporeal circuit pressures The difference between the postpump and venous pressure readings may indicate the location of the clotting An increased pressure difference (increased postpump pressure, decreased venous pressure) seen when clotting is confined to the dialyzer Both postpump and venous pressure readings are increased when clotting is occurring in or distal to the venous blood chamber A clotted or malpositioned venous needle also results in increased pressure readings

11. Anticoagulant dose adjustment In a survey conducted in Spanish dialysis centers, the most frequently used criteria to adjust anticoagulant dose were ECC clotting (88.2% of units), Bleeding of the vascular access after disconnection (75.3%), and Body weight (57.6%) Herrero-Calvo JA, Gonzales-Parra E, Perez-Garcia R, Tornero -Molina F: Spanish study of anticoagulation in haemodialysis . Nefrologia 32:143–152, 2012

12. Dialyzer clotting and reuse Dialyzer clotting is a common factor for poor performance with dialyzer reuse, causing increased frequency of discarded dialyzers The adoption of an improved heparin dosing regimen with routine dialysis may increase the rate of reuse

13. In study of 44 chronic hemodialysis patients, the optimal heparin loading dose and infusion rate (to attain a whole blood intradialytic clotting time of 150 percent of the predialysis level) significantly increased dialyzer reuse rates among the modeled, but not control, patient group

14. Lab Monitoring of Coagulation In patients at a low risk of bleeding, heparin is ordinarily prescribed empirically without monitoring of coagulation In patients at a high risk of bleeding, the need to monitor anticoagulation is often circumvented by using heparin-free dialysis

15. Blood for clotting studies Blood for clotting studies should be drawn from arterial line proximal to any heparin infusion site, to reflect the clotting status of the patient rather than that of the extracorporeal circuit It is difficult to obtain baseline clotting studies from a venous catheter locked with heparin, because of residual heparin in the catheter

16. Coagulation studies The ideal test for anticoagulation monitoring during HD should be Rapid Bedside Quantify the level of anticoagulation Identify under- or over-heparinization

17. Coagulation studies Activated partial thromboplastin time ( aPTT ) Whole-blood partial thromboplastin time (WBPTT) Activated clotting time (ACT) Lee–White clotting time (LWCT) Anti-factor Xa activity

18. Activated partial thromboplastin time ( aPTT ) The time it takes plasma to clot when exposed to substances that activate the contact factors aPTT assesses the intrinsic and common pathways of coagulation The citrated plasma is recalcified in presence of a thromboplastic material that does not have tissue factor activity (hence the term partial thromboplastin), and a negatively charged substance ( eg celite , kaolin, silica) which results in contact factor activation

19. Activated partial thromboplastin time ( aPTT ) This is for UFH monitoring only There is no standardization of aPTT test, analogous to INR for PT Thus, aPTT results vary with individual laboratories, however many centers report a ratio compared to control ( aPPTr )

20. Whole-blood partial thromboplastin time (WBPTT) This is similar to aPTT , but is a bedside test The clotting process is accelerated by addition of 0.2 mL of actin FS reagent ( Thrombofax ) to 0.4 mL of blood The mixture is set in a heating block at 37°C for 30 seconds and then tilted every 5 seconds until a clot forms It is for UFH monitoring only

21. Activated clotting time (ACT) The time it takes whole blood (rather than plasma) to clot when exposed to substances that activate the contact factors Like aPTT , this test assesses both intrinsic and common pathways It is performed by adding siliceous earth ( eg celite , kaolin) to freshly drawn whole blood It is for UFH monitoring only

22. Activated clotting time (ACT) The major use of the ACT is in adjusting heparin dosing during procedures in which large doses of heparin are used aPTT may not be useful at plasma heparin concentration >1 unit/mL, which prolongs the aPTT beyond the linear monitoring range In contrast, the ACT shows a dose-response to heparin concentrations in the range of 1 to 5 units/mL

23. Lee–White clotting time (LWCT) The Lee–White test is performed by adding 0.4 mL of blood to a glass tube and inverting the tube every 30 seconds until the blood clots Usually, the blood is kept at room temperature Disadvantages include the long time required for clotting, extensive use of technician time, poor standardization and reproducibility LWCT is the least desirable method

24. Anti-factor Xa activity This is performed by adding patient plasma to known amounts of reagent factor Xa The excess amount of factor Xa remaining in the sample is inversely proportional to the original amount of LMWH or UH An artificial factor Xa substrate is added that releases a colored compound when cleaved (chromogenic assay)

25. Anti-factor Xa activity Results of anti-factor Xa assays may differ between laboratories due to variability in the type of assays used Although UFH can be monitored by Xa activity, this is typically reserved for LMWHs and heparinoids Aim for a peak anti- Xa activity of 0.4–0.6 IU/mL, and <0.2 IU/mL at the end or shortly after completion of dialysis

26. Talk Outline

27. Unfractioned Heparin

28. Unfractionated heparin Heparin is the most commonly used anticoagulant Easy to administer A short half life Low cost UFH preparations constitute a mixture of anionic glucosaminoglycans of varying molecular size (5–40, mean 15 kDa )

29. Unfractionated Heparin: Mechanism of Action Heparin acts indirectly by binding to antithrombin III (‘‘heparin-binding factor I’’), mediated by a unique pentasaccharide sequence Binding of heparin to AT III enhances its activity by 1000 to 4000-fold AT III inactivates thrombin, factor Xa , and to a lesser extent factors IXa , XIa , and XIIa At high doses, heparin also binds to ‘‘heparin-binding factor II’’ and inhibits the generation of thrombin

30. UFH

31. Unfractionated Heparin: Pharmacokinetics Heparin has a rapid onset of action (3–5 min) Heparin has a half-life of 0.5 to 2.0 hr in patients receiving dialysis Heparin is metabolized by hepatic and vascular endothelial heparinases, and excreted in the urine Renal function does not affect elimination at therapeutic doses

32. Unfractionated Heparin: Pharmacokinetics Half-life can be modified by nonspecific binding to the endothelium, leukocytes and plasma proteins Heparin is highly charged and nonspecific binding to plastic tubing and dialyzer membrane surface may alter its pharmacokinetics

33. Advantages of Heparin Rapid onset and offset of action, allowing for more flexibility in dose titration or discontinuation when needed Ability to monitor using the activated partial thromboplastin time ( aPTT ), activated clotting time (ACT) or anti-factor Xa activity, which are widely available Lack of substantial renal elimination Extensive clinical experience Ability to reverse activity rapidly using protamine

34. Heparin prescriptions Those centers that reuse dialyzers tend to use more heparin in order to maximize reuse number There has been little research to convincingly demonstrate an optimal method of heparin dosing

35. Effect of body weight on the size of the heparin dose In a population pharmacokinetic study, the volume of distribution of heparin has been found to increase as body weight rises Dialysis centers do not regularly adjust heparin dosage in accordance with body weights (ranging between 50 and 90 kg) Smith BP, et al. Prediction of anticoagulation during hemodialysis by population kinetics in an artificial neural network. Artif Organs. 1998;22:731

36. Effect of prescription of oral anticoagulants on the size of the heparin dose Coumarin anticoagulants: patients with an INR of <2.5 require anticoagulation for dialysis, but those with metallic heart valves who have INR values >3.0 typically do not require heparin Antiplatelet agents: patients require standard heparin dosages, but heparin doses should be reduced or withheld in patients with thrombocytopenia (<50,000) Newer oral anticoagulants: little clinical data available currently, but caution is advised with the direct thrombin and anti- Xa inhibitors which are predominantly renally excreted

37. Categorization of bleeding risk to guide heparin dosing during hemodialysis Medium risk High risk Pericarditis Bleeding diathesis Recent bleeding <48 hours Clotting factor disorder Recent placement of tunneled catheter <24 hours Actively bleeding Minor surgery <72 hours Eye or major surgery <72 hours Eye or major surgery within 3 to 7 days Intracranial hemorrhage <7 days Saltissi D. Management of anticoagulation for hemodialysis. In: Dialysis Therapy, 3rd ed, Nissenson AR, Fine RN (Eds), Hanley and Belfus , Philadelphia, 2002.

38. Categorization of bleeding risk to guide heparin dosing during hemodialysis High-risk patients: heparin free or citrate hemodialysis or peritoneal dialysis (if feasible) Medium-risk patients: low-dose (or tight) heparin or no heparin, citrate protocols Avoid heparin if there is any doubt about the risk

39. Heparin administration methods Initial Bolus Followed by Method A Routine Heparin Constant infusion Method B Routine Heparin Single bolus or repeated bolus Method C Tight Heparin Constant infusion

40. Target clotting during HD Daugridas . Handbook of Dialysis. Chapter 14, 5 th edition, 2015

41. Target clotting during HD Daugridas . Handbook of Dialysis. Chapter 14, 5 th edition, 2015

42. Routine heparin prescriptions There are two basic techniques of administering routine heparin A heparin bolus followed by a constant infusion A heparin bolus followed by repeated bolus doses as necessary

43. Routine heparin , constant-infusion method Initial Bolus Infusion dose Intermittent HD 2,000 IU 1,200 IU/hour 50 IU/kg 800-1500 IU/ hr CRRT 2000-5000 IU (30 IU/kg) 500-1000 IU/ hr (5-10 IU/ hr ) European best-practice guidelines Daugridas . Handbook of Dialysis. Chapter 14, 5 th edition, 2015

44. Routine heparin , constant-infusion method

45. Routine heparin , constant-infusion method When to stop heparin infusion ??? Stopping heparin infusion 1 hour prior to the end of dialysis will result in the desired clotting time at the termination of the session

46. Routine heparin , constant-infusion method Anticoagulation monitoring ???? In clinical practice heparin therapy is ordinarily prescribed empirically, without monitoring of coagulation In patients at high risk of bleeding, the need to monitor anticoagulation is often circumvented by using heparin free dialysis

47. Routine heparin, single-dose-only or repeated-bolus method Administer the initial bolus dose (e.g., 4,000 units) Then give an additional 1,000- to 2,000-unit bolus dose if necessary

48. Tight heparin, constant-infusion method Recommended for patients who are at slight risk for bleeding the risk of bleeding is chronic and prolonged use of heparin-free dialysis unsuccessful because of frequent clotting A bolus dose followed by a constant infusion is the best technique because constant infusion avoids the rising and falling clotting times, as with repeated-bolus therapy

49. Tight heparin , constant-infusion method

50. Tight heparin, constant-infusion method Obtain baseline clotting time Initial bolus dose = 750 units Recheck WBPTT or ACT after 3 minutes Desired clotting time Not Desired clotting time Monitor clotting times every 30 minutes Keep WBPTT or ACT at baseline plus 40% Start dialysis and heparin infusion @ 600 IU/hour Administer a supplemental bolus dose

51. Tight heparin , constant-infusion method When to stop heparin infusion ??? Continue heparin infusion until the end of the dialysis session

52. Heparin Protocol for Continuous Therapies Initial therapy: Bolus of 2,000 - 5,000 IU heparin via the venous line at start of procedure Wait 2 - 3 min for the heparin to mix with the circulation Then start 500 - 1,000 IU/ hr constant heparin infusion into the arterial blood line Daugridas . Handbook of Dialysis. Chapter 14, 5 th edition, 2015

53. Heparin Protocol for Continuous Therapies Monitoring: PTT measured at the arterial and venous blood lines every 6 hr Maintain arterial PTT 40–45 s Maintain venous PTT >65 s If arterial PTT >45 s, decrease heparin by 100 IU/ hr If venous PTT <65 s, increase heparin by 100 IU/ hr , but only if arterial PTT <45 s If arterial PTT <40 s, increase heparin by 200 IU/ hr Daugridas . Handbook of Dialysis. Chapter 14, 5 th edition, 2015

54. Clotting inspite of heparin Dialyzer Priming Retained air in dialyzer (due to inadequate or poor priming technique) Inadequate priming of heparin infusion line Dialysis Circuit Kinking of dialyzer outlet blood line Vascular Access Inadequate blood flow due to needle/catheter positioning or clotting Excessive access recirculation due to needle/tourniquet position Frequent interruption of blood flow due to machine alarms Don’t always blame heparin

55. Clotting inspite of heparin Heparin Administration Incorrect heparin pump flow rate setting Inadequate loading dose Delayed starting of heparin pump Failure to release heparin line clamp Insufficient time delay after loading dose for systemic heparinization to occur

56. Clotting inspite of heparin Recurrent clotting warrants individual reevaluation and adjustments in heparin dosing

57. Post-therapy needle puncture site bleeding Reevaluation of the heparin dose Evaluation of vascular access (graft or fistula) for the presence of outflow stenosis Evaluation of needle insertion technique, poor technique or failure to rotate puncture sites Don’t always blame heparin

58. Bleeding complications of routine heparinization The risk of increased bleeding due to systemic anticoagulation is 25–50% in high-risk patients Denovo bleeding may involve CNS, retroperitoneum and mediastinum The tendency to bleed is potentiated by uremia-associated defects in platelet function and endothelial abnormalities

59. Urgent reversal (Protamine Sulfate)  Slow IV infusion given not exceeding 20-mg/minute and total dose should not exceed 50 mg in any 10-minute period Because of the relatively short half-life of IV heparin, the dose of protamine is calculated by estimating the amount of heparin remaining in the plasma at the time that reversal is required If this information is not available, a single dose of 25 to 50 mg can be given and the aPTT or anti-factor Xa activity rechecked 1 mg of protamine neutralize 100 units of heparin

60. Urgent reversal (Protamine Sulfate)  Protamine is a protein derived from fish sperm It carries a small but potential risk of anaphylaxis in exposed individuals, including diabetics who received protamine-containing insulin ( eg NPH) and individuals with fish allergy A Boxed Warning regarding the risks of hypotension, cardiovascular collapse, non-cardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction and pulmonary hypertension for exposed individuals

61. Heparin-induced thrombocytopenia (HIT) Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of exposure to heparin (UFH or LMWH) that occurs in up to 5 percent of patients exposed HIT is caused by autoantibodies to platelet factor 4 (PF4) complexed with heparin These antibodies cause thrombocytopenia and thrombosis by peripheral platelet consumption and platelet activation respectively

62. Mechanism of HIT

63. Risk factors for HIT Unfractionated rather than LMW heparin Higher heparin doses Female sex Surgery Age

64. Clinical manifestations of HIT Thrombocytopenia: The most common and often the first manifestation, occurring in up to 90 % patients Thrombosis: occurs in up to 50 %, venous being more common than arterial, thrombosis is the presentation in up to 25 % patients Bleeding uncommon, sometimes reported in unusual sites (GIT, CNS) Acute systemic anaphylactic reactions also been reported

65. Timings HIT typically occurs 5 to 10 days after the initiation of heparin Heparin-dependent antibodies usually develop between 5 and 8 days after heparin exposure Early onset of HIT ( ie , thrombocytopenia <24 hours of exposure) if the patient has been exposed to heparin in the previous one to three months and has circulating HIT antibodies The resolution of thrombocytopenia following heparin withdrawal and initiation of a non-heparin anticoagulant typically within 7 days

66. Algorithm for evaluating and treating suspected HIT

67. Management of HIT LMWH should not be used as they often cross-react with heparin-PF4 antibodies The alternative anticoagulants include the direct thrombin inhibitor ( argatroban , bivalirudin), the heparinoids (danaparoid), and fondaparinux Warfarin can be started once the patient has been stably anticoagulated with a non-heparin anticoagulant and the platelet count has recovered to ≥150,000/ microL

68. Others adverse effects of Heparin Lipids: Heparin activates lipoprotein lipase and increase triglycerides levels. Low levels of HDL associated with higher doses of heparin Hyperkalemia: Heparin suppresses aldosterone synthesis, associated hyperkalemia Pruritus: Heparin may be the cause of itching and other allergic reactions during dialysis. There is no evidence that removal of heparin from the ECC reliably improves uremic pruritus Anaphylactoid reactions: First use syndrome Osteoporosis: Long-term administration of heparin

69. Low Molecular Weight Heparin (LMWH)

70. LMWH LMWH produced by chemical or enzymatic cleavage of UFH to smaller size ~5 kDa LMWH contain the key pentasaccharide sequence, but is not long enough to bind both AT III and thrombin LMWH inhibits factor Xa , factor XIIa , and kallikrein, but cause so little inhibition of thrombin and factors IX and XI, that aPTT and thrombin time are raised by only 35% during the first hour, and are minimally prolonged thereafter, decreasing bleeding risk

71. UFH LMWH

72. LMWH: pharmacokinetics LMWH are metabolized in the liver and excreted by the kidney Renal clearance contributes approximately 10 to 40 % Patients with renal impairment have reduced clearance of LMWH and generally require dose adjustment Various LMWH have different anti- IIa activity compared with blocking factor Xa activation, measured as the relative ratio of anti- Xa to anti- IIa activity

73. LMWH vs UFH LMWH has Longer half-life Higher bioavailability Better correlation between dose and anticoagulant response, a fixed dose without laboratory monitoring

74. LMWH vs UFH LMWH has Less nonspecific binding to endothelium, plasma proteins and platelets Less platelet and leukocyte activation and fibrin deposition on dialyzer surfaces

75. LMWH vs UFH LMWH has Less bleeding and less thrombocytopenia Less risk of heparin induced osteoporosis Less hyperkalemia Less disturbance of lipid profile Anaphylactic reactions as with UFH

76. Limitations of LMWH Slightly delayed onset of action (20 to 30 minutes, rather than instantaneous for UFH by intravenous bolus) Longer duration of action, difficult to rapidly stop therapy Less easily inactivated with protamine sulphate Prolonged half-life in patients with renal failure Anti-factor Xa activity testing less widely available

77. Commonly used LMWH IHD dosing Name Molecular Weight (Da) Anti- Xa / IIa Activity Ratio Average Dialysis Bolus Dose Dalteparin 6,000 2.7 5,000 IU Nadroparin 4,200 3.6 70 IU/kg Reviparin 4,000 3.5 85 IU/kg Tinzaparin 4,500 1.9 1,500−3,500 IU Enoxaparin 4,200 3.8 0.5−0.8 mg/kg Daugridas . Handbook of Dialysis. Chapter 14, 5 th edition, 2015

78. Commonly used LMWH CRRT dosing Bolus Infusion Dalteparin 20 U/kg 10 U/kg per hour Enoxaparin and nadroparin may be used, but the experience is limited Sagedal S, Hartmann A. Low molecular weight heparins as thromboprophylaxis in patients undergoing hemodialysis/hemofiltration or continuous renal replacement therapies . Eur J Med Res . 2004;9:125–130. de Pont AC, Oudemans-van Straaten HM, Roozendaal KJ, Zandstra DF. Nadroparin versus dalteparin anticoagulation in high-volume, continuous venovenous hemofiltration: a double-blind, randomized, crossover study. Crit Care Med. 2000 Feb;28(2):421-5. 

79. Commonly used LMWH CRRT dosing LMWH are not widely used in CRRT because of a very prolonged half-life and high risk of bleeding associated No major benefit in terms of reduced bleeding episodes or increased filter survival associated with LMWH Joannidis M, Kountchev J, Rauchenzauner M, Schusterschitz N, Ulmer H, Mayr A, Bellmann R. Enoxaparin vs. unfractionated heparin for anticoagulation during continuous veno -venous hemofiltration: a randomized controlled crossover study. Intensive Care Med. 2007 Sep;33(9):1571-9. Epub 2007 Jun 12. 

80. European Renal Best Practice Nephrology Dialysis Transplantation , Volume 17, Issue suppl_7, July 2002

81. CARI Guidelines (2004/2005) The Caring for Australasians with Renal Impairment (CARI) guidelines have supported that “there is no apparent difference in terms of dialysis adequacy between UF heparin or LMWH and no clear difference in terms of risk of thrombosis or hemorrhage”

82. British Renal Association UFH as standard AC LMWH as alternative AC The National Kidney Foundation Most common AC is systemic heparin Alternatives include LMWH

83. LMWH are very expensive and generally not been found to be superior to UFH in terms of dialysis related bleeding UFH is widely used

84. Meta-analysis(2004) showing that LMWH and UFH were similarly safe and effective in preventing extracorporeal circuit thrombosis

85. LMWH monitoring aPTT is not accurate with LMWH Measurement of anti factor Xa required Coagulation tests are not routinely monitored with LMWH (because anti- Xa activity assays are not readily available) Hemonox test: A bedside anti- Xa assay has shown promising results to assess tinzaparin anticoagulation in hemodialysis in a preliminary study

86. A bedside anti- Xa assay has shown promising results to assess tinzaparin anticoagulation levels in one preliminary study

87. Reversal with protamine Protamine never completely neutralize the anti- Xa activity of LMWH (maximum: 60% to 75%), but it may neutralize the higher molecular weight fractions, which are most responsible for bleeding Excessive protamine doses may worsen bleeding potential If patient is not bleeding, consider not administering protamine since risks may outweigh benefits of administration

88. Reversal with protamine Enoxaparin 1 mg protamine per 1 mg of enoxaparin within 8 hours, 0.5 mg protamine per 1 mg of enoxaparin within 8 to 12 hours. If bleeding persists, 0.5 mg protamine per 1 mg of enoxaparin Dalteparin , tinzaparin , or nadroparin : 1 mg protamine per 100 anti-factor Xa units of LMWH within past 3 to 5 half-lives. If bleeding persists, repeat 0.5 mg protamine per 100 anti- Xa units of LMWH

89. Heparin free Dialysis

90. Indications for Heparin-free Dialysis Pericarditis Recent surgery, with bleeding complications or risk, especially: Vascular and cardiac surgery Eye surgery (retinal and cataract) Renal transplant Brain surgery Parathyroid surgery Coagulopathy Thrombocytopenia Intracerebral hemorrhage Active bleeding Heparin contraindication ( eg persons with heparin allergy)

91. Heparin-free Dialysis Procedure Heparin Rinse : Rinse extracorporeal circuit with saline containing 3,000 units of heparin/L Drain the heparin containing priming fluid by filling the circuit with either the patient’s blood or unheparinized saline at the outset of dialysis Set the blood flow rate to 300-400 mL/min if tolerated Periodic saline rinse with 50-250 mL of saline every 15-30 minutes

92. Heparin-free dialysis The procedure is simple and safe, many centers use heparin-free dialysis routinely in ICU setting Careful priming to minimize blood–air interfaces is important in preventing clotting The dialysis circuitry should be chosen to minimize the length of tubing, avoiding areas of stagnation and turbulence due to changes in internal lumen diameter, and three-way connectors Platelet activation is reduced by cooling the dialysate

93. Heparin-free CRRT The filters clot periodically and need to be changed at more frequent intervals If acute bleeding occurs while CRRT with heparin, the procedure can be continued after stopping heparin

94. Heparin-free CRRT Keeping the blood flows at 200 mL/min or higher may also prevent early or excessive clotting Predilution mode is preferred, it reduces the hemoconcentration within the hemofilter when plasma water is removed

95. Regional Heparinization With Protamine Reversal

96. Regional heparinization with protamine reversal 

97. Regional heparinization with protamine reversal: limitations  It is technically difficult Rebound bleeding 2 to 4 hours after dialysis as the reticuloendothelial system releases free heparin from the protamine-heparin complex back into the general circulation Alternatives like low-dose and no-dose heparin as well as citrate regional anticoagulation are available

98. Heparin coated filters

99. Heparin coated filters Heparin is a very negatively charged molecule that can adsorb to the dialyzer surface Heparin coated dialyzer membranes have been reported to allow heparin-free or heparin- reduced dialysis The effectiveness of heparin-coated filters are questioned

100. The effectiveness of heparin-coated dialysis membranes in patients at risk of bleeding was compared with regional citrate anticoagulation in a randomized, controlled study The coated membranes were associated with a significantly increased incidence of membrane clotting

101. Regional Citrate Anticoagulation

102. Regional citrate anticoagulation: Principle Calcium is a clotting factor required for the coagulation process The blood in extracorporeal circuit can be anticoagulated by lowering its ionized calcium concentration Citrate infusion in extracorporeal circuit chelates calcium Calcium citrate complexes are removed in effluent and those that return to the circulation are metabolized by liver and skeletal muscles

103. Regional citrate anticoagulation: Procedure

104. RCA vs Heparin-free dialysis The advantages over heparin-free dialysis are The blood flow rate does not have to be high Clotting rarely occurs The principal disadvantages are Requirement for two infusions (one of citrate and one of calcium) Requirement for monitoring the plasma-ionized calcium level

105. Adverse effects of RCA Hypocalcemia: Rapid secretion of parathyroid hormone. A slow but continuous demineralization occurs, bone fractures described with prolonged RCA Hypernatremia: Due to the hypertonic sodium citrate solution Metabolic alkalosis: Due to bicarbonate generated during the metabolism of citrate

106. Citrate accumulation and indications to stop RCA Citrate is metabolized in the Kreb’s cycle mainly in liver Citrate itself is not toxic, the impaired metabolism may cause some physiological derangements iCa is not released from citrate–calcium complex and hypocalcemia may occur Less bicarbonate is generated, new developing or worsening ongoing metabolic acidosis

107. Citrate accumulation and indications to stop RCA Worsening metabolic acidosis with increasing anion gap Decreasing ionized calcium requiring escalating calcium infusion rates Increasing total calcium A ratio of total calcium to ionized calcium >2.5

108. RCA in special situations: Liver failure Impaired liver has a reduced citrate metabolism and elevated citrate levels in the blood Liver failure was at first considered contraindications for RCA A number of studies show that RCA can be used safely in liver failure RCA successfully used in kidney failure following liver transplantation and also for liver support with MARS and Prometheus However, intensive monitoring for signs of citrate accumulation or a dose reduction required

109. RCA in special situations: Multiorgan failure and persistent lactic acidosis The metabolic pathway of citrate is oxygen dependent In patients with multiorgan failure, shock and persistent lactic acidosis with a negative lactate clearance, the risk of citrate accumulation and the mortality is extraordinarily high RCA might be contraindicated

110. Citrasate

111. Bicarbonate dialysis solution with low-concentration citrate ( Citrasate ) A small amount of citric acid is used instead of acetic acid as the acidifying agent When the acid and base concentrates are mixed, the resulting dialysis solution commonly contains 2.4 mEq /L (0.8 mmol/L) citrate Citrate by complexing with calcium, inhibits blood coagulation and platelet activation locally at the dialyzer membrane surface

112. Bicarbonate dialysis solution with low-concentration citrate ( Citrasate ) The amount of citrate used is low enough such that monitoring of ionized calcium is not required A small but significant change in serum calcium occur, usually not enough to cause symptoms Citrasate can be used with a reduced dose of heparin, or as part of a heparin-free dialysis technique Further studies needed to delineate the role of citrate-based dialysate

113. Heparinoids

114. Heparinoids Heparinoids are analogues of heparin that inhibit factor Xa , have a longer half-life than unfractionated heparin and cause fewer bleeding complications

115. Danaparoid Fondaparinux

116. Their use primarily in management of HIT

117. Heparinoids: Danaparoid Danaparoid (5.5 kDa ) is extracted from pig gut mucosa A mixture of 84% heparin, 12% dermatan and 4% chondroitin sulfates Binds to antithrombin (heparin cofactor I) and heparin cofactor II, but has minimal impact on platelets and a low affinity for PF Danaparoid may cross-react with HIT antibodies in up to 10% cases Danaparoid is more selective for Xa than LMWH ( Xa : thrombin binding Danaparoid 22 : 1, LMWH 3:1 typically)

118. Heparinoids: Danaparoid A very long half-life of 25 hr in normal, prolonged in renal failure 30 hr Anti- Xa monitoring sometimes required, aiming for a predialysis anti- Xa of ≤0.2 IU/mL In patients >55 kg, 3750 IU loading dose is recommended, while in patients <55 kg the loading dose is 2500 IU Subsequent doses titrated to achieve anti- Xa activity of 0.4–0.6 IU/ml

119. Heparinoids: Fondaparinux Fondaparinux (1.7 kDa ) is a synthetic analogue of the pentasaccharide sequence in heparin that mediates the anti-thrombin interaction Fondaparinux has a high affinity for anti-thrombin III but no affinity for thrombin or PF4 It does not cross-react with HIT antibodies

120. Heparinoids: Fondaparinux A typical predialysis dose is 2.5–5.0 mg, administered iv or sc Fondaparinux has a half life of 17 hr It is renally cleared and may accumulate in renal failure Anti- Xa monitoring sometimes required, aiming for a predialysis anti- Xa of ≤0.2 IU/mL Hemodiafiltration will increase losses of both danaparoid and fondiparinux , and higher dosages may be required

121. Direct Thrombin Inhibitors

122. Argatroban Lepirudin

123. Their use primarily in management of HIT

124. Thrombin inhibitors: Argatroban Argatroban is a synthetic peptide derived from arginine It has a short half-life of 40–60 min It is metabolized primarily by the liver, and its half-life is not effected by renal function Prolonged duration of action in patients with liver failure It does not cross-react with HIT antibodies It can be monitored by a variant of aPTT – the ecarin clotting time

125. Thrombin inhibitors: Argatroban An initial bolus of 250 mcg/kg followed by infusion at 2 mcg/kg/min or 10–15 mg/hour, titrated to achieve aPPTr of 2.0–2.5. The infusion is stopped 20–30 minutes prior to the end of dialysis There is no available reversal agent Argatroban is not significantly cleared during high-flux hemodialysis or hemodiafiltration due to protein binding

126. Thrombin inhibitors: Hirudin Hirudin was originally discovered in the saliva of leeches Binds thrombin irreversibly at its active site and fibrin-binding site Recombinant variants are - Lepirudin , Desirudin and Bivalirudin Hirudin and its analogues are polypeptides of 7 kDa They do not cross-react with HIT antibodies Hirudin has a prolonged half-life and is renally cleared, so its half-life in renal impairment is more than 35 hr

127. Thrombin inhibitors: Hirudin Hirudin and its analogues are antigenic and 74% of patients receiving iv Hirudin can develop anti-Hirudin antibodies, anaphylaxis can occur with a second course aPTT may be used for monitoring but the relationship is not necessarily linear There is no antidote to Hirudin It is partially removed by hemofiltration or plasmapheresis but not by hemodialysis

128. Thrombin inhibitors: Lepirudin A single loading dose may therapeutically anticoagulate patient for 1 week The loading dose for intermittent HD ranges from 0.2–0.5 mg/kg Subsequent bolus dose adjusted, aiming for a pre-dialysis APPTr <1.5 to prevent accumulation Lepirudin assays now developed targeting a therapeutic range of 0.5–0.8 mcg /mL Bleeding is a major risk and there is no antidote, so fresh frozen plasma or factor VIIa concentrates may be required

129. Thrombin inhibitors: Bivalirudin Bivalirudin is a reversible direct thrombin inhibitor It has a much shorter half-life than lepirudin of approximately 25 minutes, prolonged coagulation times return to normal approximately one hour after discontinuation The drug is metabolized in kidney, liver, and other sites A typical infusion rate is 1.0–2.5 mg/hour (0.009–0.023 mg/kg/hour) adjusted to achieve a target APPTr of around 1.5–2.0 Bivalirudin can be hemodialyzed

130. Platelet inhibiting agents

131. Prostanoids Prostacyclin is a vasodilator and inhibitor of platelet aggregation Its half-life is 3 to 5 minutes due to rapid metabolism by endothelial smooth muscle Prostacyclin regional anticoagulation involves the infusion of prostacyclin into the dialyzer circuit at 4 to 8 ng/kg/minute Side effects include headache, light headedness, facial flushing, hypotension and excessive cost Prostacyclin is adsorbed onto polyacrylonitrile membranes

132. Nafamostat maleate Nafamostat is a prostacyclin analog without the hypotensive activity It has a short half-life and used as a regional anticoagulant It is associated with an unacceptably high incidence of clot formation An initial bolus dose of 20 mg followed by an infusion of 40 mg/hour, adjusted to maintain a target aPPTr of 1.5-2.0 or ACT of 140–180 Nafamostat is adsorbed onto polyacrylonitrile membranes