Hemodialysis anticoagulation

Hemodialysis anticoagulation
Dr Abdullah Ansari
SR Nephrology
SGPGI Lucknow

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

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

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

Factors Favoring Clotting of the Extracorporeal
Circuit
Low blood flow
High hematocrit
High ultrafiltration rate
Dialysis access recirculation
Intradialytic blood and blood product transfusion
Intradialytic lipid infusion
Use of drip chambers (air exposure, foam formation, turbulence)

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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)

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

Talk Outline
Unfractioned Heparin
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
Heparin related
Citrate related
Others

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)

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

When to stop heparin infusion ???
Continue heparin infusion until the end of the dialysis session

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

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

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

• 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

Recurrent clotting warrants individual reevaluation
and adjustments in heparin dosing

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

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

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

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

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

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

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

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

Algorithm for evaluating and
treating suspected HIT

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

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

Low Molecular Weight
Heparin (LMWH)

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

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

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

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

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

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

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

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.

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.

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

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”

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

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

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

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

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

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

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

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)

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

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

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

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

Regional Heparinization
With Protamine Reversal

Regional heparinization with protamine
reversal
Heparin is administered @500 to 750 U/hr into the arterial line
Protamine is simultaneous administration into the venous line
The infusion pump rates adjusted to keep ACT in dialyzer circuit at
200 seconds and blood returning to patient at its predialysis baseline

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

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

• 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

Regional Citrate
Anticoagulation

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

Regional citrate anticoagulation: Procedure
Continuous infusion of isosmotic trisodium citrate (102 mmol/L) into arterial limb
which complexes calcium
A calcium-free dialysate can further reduce the free calcium level
Citrate infusion rate adjusted to keep ACT above 200 sec in arterial limb
Regional anticoagulation reversed by infusion of 5% calcium chloride into venous
limb @0.5mL/min
About 1/3 of infused citrate dialyzed away and remaining 2/3 entering circulation
quickly metabolized by patient

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

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

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

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

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

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

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

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

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

Their use primarily in management of HIT

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)

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

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

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

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

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

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

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

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

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

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

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

Hemodialysis anticoagulation

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