ANTICOAGULATION IN HEMODIALYSIS

Arlene S. Munoz MD, FPCP,FPSN

OBJECTIVES

• To be able to discuss blood clotting during

dialysis.
• To show the different anticoagulation
techniques, indications and its
complications
– unfractionated heparin
– low molecular weight heparin
– heparin free dialysis
– regional citrate anticoagulation
PATIENTS ON HEMODIALYSIS ARE AT RISK OF
BLEEDING AND THROMBOSIS

• BLEEDING
– uremia related platelet dysfunction
– endothelial abnormalities
– anticoagulants on HD
• THROMBOSIS
– exposure to filters and tubings
– activation of leukocytes and platelets
– high hematocrit
– low blood flow
– blood transfusion
ANTICOAGULATION

• process of hindering
the clotting of blood in
the extracorporeal
circuit
• to prevent blood loss
and optimal solute
clearance
Why anticoagulate?

• maximize effectiveness of treatment by

maintaining patency in the dialyzer blood
compartment
• dialyzer clotting rate (4hr session): 5-10%
• blood loss : 100-180ml
UNFRACTIONATED HEPARIN

• polysaccharide
containing large numbers
of linear and polydiverse
chains

• molecular weight of 3,000

to 30,000 Da

• changes the conformation

of antithrombin, leading to
rapid inactivation of
coagulation factors, in
particular factor IIa

• half life: 1.5 hrs

UNFRACTIONATED HEPARIN
UNFRACTIONATED HEPARIN

 ADVANTAGES  DISADVANTAGES
– rapid onset of action and - narrow therapeutic
clearance window
– ability to monitor using
aPTT -highly variable dose-
– lack of substantial renal response relationship
metabolism - HIT, osteoporosis
– extensive clinical with long term use
experience
– ability to reverse rapidly
with protamine sulfate
– inexpensive
ROUTINE HEPARIN PRESCRIPTIONS

• Routine heparin, constant infusion method

• Routine heparin, single- dose only or

repeated bolus method

• Tight heparin, constant infusion method

ROUTINE HEPARIN PRESCRIPTIONS

A. ROUTINE HEPARIN, constant infusion: 1,000 -

bolus: 1,000- 1,500 U or 50
CONSTANT INFUSION 1,500 U/hr until 15 -60
U/kg bolus
METHOD mins before end of dialysis

B. ROUTINE HEPARIN, bolus: 4,000 U

SINGLE DOSE ONLY OR additional bolus: 1,000 -
REPEATED BOLUS METHOD 2,000 U as necessary

constant infusion: 600

C. TIGHT HEPARIN bolus: 750 U
units/hr
ROUTINE HEPARIN PRESCRIPTIONS

A. ROUTINE HEPARIN, constant infusion: 1,000 -

bolus: 1,000- 1,500 U or 50
CONSTANT INFUSION 1,500 U/hr until 15 -60
U/kg bolus
METHOD mins before end of dialysis

B. ROUTINE HEPARIN, bolus: 4,000 U

SINGLE DOSE ONLY OR additional bolus: 1,000 -
REPEATED BOLUS METHOD 2,000 U as necessary

constant infusion: 600

C. TIGHT HEPARIN bolus: 750 U
units/hr
Routine heparin, constant infusion method
ROUTINE HEPARIN PRESCRIPTIONS

A. ROUTINE HEPARIN, constant infusion: 1,000 -

bolus: 1,000- 1,500 U or 50
CONSTANT INFUSION 1,500 U/hr until 15 -60
U/kg bolus
METHOD mins before end of dialysis

bolus: 4,000 U additional bolus: 1,000 -

2,000 U as necessary
B. ROUTINE HEPARIN,
SINGLE DOSE ONLY OR bolus: 2,000 U no repeated bolus
REPEATED BOLUS METHOD
75-100 u/kg 500-750 U/hr infusion

constant infusion: 600

C. TIGHT HEPARIN bolus: 750 U
units/hr
ROUTINE HEPARIN PRESCRIPTIONS

A. ROUTINE HEPARIN, constant infusion: 1,000 -

bolus: 1,000- 1,500 U or 50
CONSTANT INFUSION 1,500 U/hr until 15 -60
U/kg bolus
METHOD mins before end of dialysis

bolus: 4,000 U additional bolus: 1,000 -

2,000 U as necessary
B. ROUTINE HEPARIN,
SINGLE DOSE ONLY OR bolus: 2,000 U no repeated bolus
REPEATED BOLUS METHOD
75-100 u/kg 500-750 U/hr infusion

constant infusion: 600

C. TIGHT HEPARIN bolus: 750 U
units/hr
Tight ( minimal dose) heparin, constant infusion method
Tight (Minimal dose) heparin

• Recommended for:
- patients with slight risk of bleeding;
when the risk of bleeding is chronic and
prolonged
- where use of heparin-fee dialysis has
been unsuccessful because of frequent
clotting
STILL WITH CLOTTING PROBLEMS DESPITE
ANTICOAGULATION?
FACTORS THAT MAY RESULT TO CLOTTING

• DIALYZER PRIMING
– retained air in the dialyzer ( inadequate
priming or poor priming technique)
– inadequate priming of heparin infusion line

• DIALYSIS CIRCUIT
– kinking of dialyzer outlet blood line
FACTORS THAT MAY RESULT TO CLOTTING

• 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
FACTORS THAT MAY RESULT TO CLOTTING

• HEPARIN ADMINISTRATION
- incorrect heparin pump flow rate setting
- incorrect loading dose
- delayed starting of heparin pump
- failure to release heparin line clamp
- insufficient time delay after loading dose for
systemic heparinization to occur
HEPARIN-ASSOCIATED COMPLICATIONS

• BLEEDING

– risk is 25% to 50% in high-risk patients with

bleeding GI lesions ( gastritis, peptic ulcer,
angiodysplasia), recent surgery, pericarditis,
or thrombocytopenia
HEPARIN-ASSOCIATED COMPLICATIONS

- POST THERAPY NEEDLE PUNCTURE

SITE BLEEDING
 re-evaluate heparin dose
 re-evaluate vascular access ( graft or fistula)
for outflow stenosis
 evaluate needle insertion technique
HEPARIN-ASSOCIATED COMPLICATIONS

• HEPARIN-INDUCED THROMBOCYTOPENIA ( HIT)

• incidence of 3-5%

– TYPE 1
• reduction in platelet count occurs in a time and dose dependent
manner
• responds to reduction in heparin dose

– TYPE 2
• agglutination of platelets and paradoxical arterial/and or venous
thrombosis
• development of IgG and IgM antibodies against heparin-platelet 4
complex
OPTIONS FOR PATIENTS WITH HIT

• heparin free HD
• regional citrate HD
• shift to PD
• danaparoid, lepirudin, argatroban
OPTIONS FOR PATIENTS WITH HIT

• heparin free HD
• regional citrate HD
• shift to PD
• danaparoid, lepirudin, argatroban

DO NOT USE LOW MOLECULAR WEIGHT HEPARIN

HEPARIN-ASSOCIATED COMPLICATIONS

• LIPIDS - increase trigylceride levels

• PRURITUS
• ANAPHYLACTOID REACTIONS
• HYPERKALEMIA
• OSTEOPOROSIS
• ALOPECIA
LOW MOLECULAR WEIGHT HEPARIN

• molecular weight: 4,000 - 6,000

Da

• obtained by chemical degradation,

enzymatic digestion or seiving
crude heparin ( molecular weight
2,000 -25,000)

• inhibit factor Xa, factor XIIa, and

kallikrein, but cause little inhibition
of factors IX and XI that PTT and
thrombin time are raised by only
35% during the 1st hr and are
minimally prolonged thereafter,
decreasing bleeding risk
LOW MOLECULAR WEIGHT HEPARIN
LMWH
• ADVANTAGES • DISADVANTAGES
– greater bioavailability
– longer duration of
anticoagulant effect
– better correlation
between dose and
anticoagulant effect
– lower risk of HIT and
osteoporosis
– ease of administration
– slightly delayed onset
of action
– longer duration of
action
– less easily inactivated
by protamine
– -prolonged half life
– anti-factor Xa testing
for monitoring not
widely available
– expensive
GUIDELINES ON ANTICOAGULATION

BRITISH RENAAL NATIONAL KIDNEY

ERA-EDTA CARI
ASSOCIATION FOUNDATION

LOW DOSE UFH

LMWH (standard) OR
LMWH SYSTEMIC NO
(EVIDENCE LEVEL HEPARIN RECOMENDATION
A) (EVIDENCE LEVEL
1A)

Kessler et al. Anticoagulation in Chronic Hemodialysis: Progress Toward an Optimal Approach. Seminars in Dialysis. Vol 8 Issue 5. Sept-Oct 2015
LMWH vs. UNFRACTIONTED HEPARIN
• Overall, this meta-analysis identified no difference in bleeding events or thrombosis of the
extracorporeal circuit when LMWH was compared with UFH in patients who were receiving chronic
hemodialysis and are not at risk for bleeding or were receiving other antithrombotic agents. However,
recommendations about anticoagulation for chronic renal failure patients who undergo dialysis will
continue to be weak until larger, more rigorous randomized trials are conducted in this field

Lim et al. JASN Dec 2004 vol 15 no 12

• LMWH showed to be at least as safe as UFH for ECC anticoagulation in chronic

hemodialysis. The limited number of studies reporting on osteoporosis and HIT does not
allow any conclusion for these outcomes. Larger studies are needed to evaluate properly
the safety of LMWH in chronic hemodialysis.
Lazrak et al.BMC Neph seies
2017

• LMWH is as safe and effective as UFH. Considering the poor quality of studies included
for the review, larger well conducted RCTs are required before conclusions can be drawn.
Shantha et al.Peer J. 2015; 3e 385
COMMONLY USED LMWH COMPOUNDS

MOLECULAR Anti-Xa/IIa Average Dialysis

NAME
WEIGHT ( Da) Activity Ratio Bolus Dose

6,000
DALTEPARIN 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

Daugirdas. Handbook of Dialysis, Chapter 14 , 5th edition, 2015

HEPARIN-FREE DIALYSIS

• method of choice for patients who are actively

bleeding, with moderate to high risk of bleeding,
heparin contraindication ( allergy)

• simple and safe

• can be used in 90% of ICU patients with

temporary venous access with only 2% clotting
rate in the extracorporeal circuit

• need for close nursing observation

HEPARIN-FREE DIALYSIS INDICATIONS

• Pericarditis
• Recent surgery with bleeding
complications or risk-
– vascular and cardiac surgery
– eye surgery ( retinal and cataract)
– retinal transplant
– brain surgery
– parathyroid surgery
HEPARIN-FREE DIALYSIS INDICATIONS

• Coagulopathy
• Thrombocytopenia
• Intracerebral hemorrhage
• Active bleeding
• Routine use for dialysis of acutely ill
patients in many centers
HEPARIN-FREE PRESCRIPTION

• HEPARIN RINSE
– optional if with HIT
– 3,000 units heparin/L

• RELATIVELY HIGH BLOOD FLOW RATE

– 300 to 400 ml/min
– if CI: do ultrashort ( 1hr) periods of dialysis
interspersed with isolated UF
HEPARIN-FREE PRESCRIPTION

• PERIODIC SALINE RINSE

– allows inspection of dialyzer for clotting
– reduce propensity for dialyzer clotting

• DIALYZER MEMBRANE MATERIAL

– heparin coated dialyzer membanes

• DIALYZER SURFACE AREA

– smaller surface area dialyzers preferred
HEPARIN-FREE PRESCRIPTION

• UF
– high UF leads to hemoconcentration--platelet-
dialyzer membrane interaction---clot

• BLOOD PRODUCT TRANSFUSION OR LIPID

ADMINISTRATION
REGIONAL CITRATE ANTICOAGULATION

• alternative to systemic heparinization with

less risk of bleeding

• citrate binds to plasma calcium---->fall in

plasma calcium---->prevents the
coagulation cascade
REGIONAL CITRATE ANTICOAGULATION
REGIONAL CITRATE ANTICOAGULATION VS HEPARIN-FREE DIALYSIS

• ADVANTAGES • DISADVANTAGES
– blood flow rate does not – need for 2 infusions
need to be high – monitoring of plasma
– clotting rarely occurs ionized Ca levels
– prevention of platelet – metabolic alkalosis
activation/degranulation – hypernatremia
– costly
REGIONAL CITRATE ANTICOAGULATION VS HEPARIN-FREE DIALYSIS

• ADVANTAGES • DISADVANTAGES
– blood flow rate does not – need for 2 infusions
need to be high – monitoring of plasma
– clotting rarely occurs ionized Ca levels
– prevention of platelet – metabolic alkalosis
activation/degranulation – hypernatremia
– longer filter life

NOT WIDELY USED FOR INTERMITTENT HD

MORE POPULAR WITH CONTINUOUS FORMS OF DIALYSIS
CITRATE VS HEPARIN
• Regional citrate anticoagulation seems superior to heparin for filter lifetime
and transfusion requirements in ICU patients treated with CRRT.

Intensive Care Med. 2004; 30(2):260.Epub 2003 Nov 5

• Compared with systemic heparin, regional citrate anticoagulation

significantly increases hemofilter survival time, significantly
decreasesbleeding risk in critically ill patients requiring CRRT.
Kidney Int 2005; 67(6): 2361

• RCA is superior to heparin-based anticoagulation in terms of delivered RRT

dose and filter life span and is a safe and fesible method.

Crit Care 2015;19(1):91. Epub 2015 Mar 18

BICARBONATE DIALYSIS SOLUTION WITH LOW
CONCENTRATION CITRATE
• Bicarbonate solution
with citrate as
acidifying agent (2.4
meq/l)
• Citrate chelates Ca
and inhibits
coagulation
• Improved dialyzer
clearance and
reusability
• iCa monitoring not
required
TAKE- HOME MESSAGES

• Patients who are on HD or CRRT require

anticoagulation to prevent thrombosis in
the blood circuit.
• Anticoagulation in routine HD consists of a
standard dose of heparin given as a bolus
with mid-treatment dose. Alternatively,
heparin can be given initially as bolus
followed by constant infusion.
TAKE- HOME MESSAGES

• Options for patients at risk for bleeding

– no heparin HD
– minimum dose heparin
– regional citrate anticoagulation
– citrate dialysate
• Options for patients with HIT
– no heparin HD
– regional citrate HD
– shift to PD
THANK YOU!