1. Anticoagulation for PCRRT
Dr. Peter Skippen, PICU.
BC Children’s Hospital,
Vancouver. CANADA.

2. Outline Normal Coagulation Anticoagulation: Options Heparin Citrate
Others
Conclusions
Thankyou again for the opportunity to speak at this meeting.
My topic today is antocagulation for CRRT.
I will start with a brief overview of normal coagulation, but will concentrate todays presentation on 2 types of antocagulation:
Heparin
Citrate

3. Mechanisms of Filter Thrombosis
TISSUE FACTOR
TF:VIIa
CONTACT PHASE
XII activation
XI IX
monocytes / platelets / macrophages
Ca++ X Va
VIIIa
Ca++
platelets Xa
Phospholipid surface
prothrombin
THROMBIN
NATURAL ANTICOAGULANTS
(APC, ATIII)
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
fibrinogen
CLOT

4. Coagulation in Critically Ill Child
Pre-existing inflammatory states
sepsis
trauma
shock
hypercoagulable / thrombohemorrhagic states
Organ failure states
liver / renal (2˚ coagulation abnormalities)
blood oncology / marrow failure
Perioperative
cardiopulmonary bypass
Medications
platelet effects
immunosuppressive / oncologic
thrombogenic / fibrinolytic

5. Factors Affecting Filter Life
Pre-existing condition of patient’s coag /anticoag system
Treatment characteristics
A-V vs. V-V
vascular access
diffusion vs. convection
filtration fraction
blood flow
membrane material and geometry
circuit alarms

6. Sites of Thrombus Formation
any blood surface interface
hemofilter
bubble trap
catheter
areas of turbulence / resistance
very high blood flow rates
luer lock connections / 3 way stopcocks
Any blood surface interface can be a site of thrombus generation. Particular areas of concern in the CRRT circuit are listed here.

7. Anticoagulation: Options
Technical aspects
cannulae
cannulation site
circuitry
blood flow rate FF
predilution?
No anticoagulation
Saline flush?
Hemodilution?
Heparin
unfractionated
LMWH
Citrate
Others
prostacyclin
danaparoid
hirudin
nafamostate mesylate
Our options for anticoagulation during CRRT are quite limited. There is NO gold standard. Every technique is associated with risks / benefits and complications.
It is essential to correct any technical imperfections in the circuit prior to commencing any treatment. Particularly important is the positioning of the cannulae, and ensuring that there is good free flow from both lumen of the DLC. These cannulae are a frequent source of problems in babies as they tend to kink at the skin entrance.
The main advantage that I see with pre-dilution is not prolonging the life of a filter and circuit but enhancing clearance. The other options of NOT anticoagulating are really temporizing in individual cases and can only be recommended for short term use. They do NOT address the more common problems of preventing clot in the greater majority of patients.
That leaves us with either systemic or regional anticoagulation. I am only going to deal with the more common techniques used. NEXT SLIDE

8. Unfractionated Heparin

9. Sites of Action of Heparin
LMWH
TISSUE FACTOR
TF:VIIa
CONTACT PHASE
XII activation
XI IX
monocytes platelets macrophages
Ca++ X Va
VIIIa
Ca++
platelets Xa
ATIII
Phospholipid surface
prothrombin
UF HEPARIN
THROMBIN
NATURAL ANTICOAGULANTS
(APC, ATIII)
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
fibrinogen
CLOT

10. Heparin - Problems bleeding unable to inhibit thrombin bound to clot
unable to inhibit Xa bound to clot
ongoing thrombin generation
direct activation of platelets
thrombocytopenia
extrinsic pathway unaffected
If you review the literature on anticoagulation with heparin for CRRT, the incidence of hemorrhagic complications is impressive and remains the most common complication.
Most of the research on the effects of heparin have come from cardiac surgery and the need to anticoagulate patients for CPB. It is absolutely critical to prevent clotting in these patients undergoing cardiac surgery. The doses of heparin and the desired ACT levels are far in excess of what we try to achieve during CRRT.
Even massive doses of unfractionated heparin are unable to inhibit clot bound thrombin.
Clot bound thrombin, we know, cleaves pro-thrombin generating more thrombin. Hence, there is ongoing thrombin generation in the presence of heparin and ongoing activation of the coagulation and fibrinolytic cascade.
NEXT SLIDE

11. Systemically Heparinized
No Heparin
Systemically Heparinized
In addition, heparin damages platelets, as can be demonstrated in this slide.
Thanks to Dr. Gail Annich in Ann Arbor at University of Michigan for allowing me to use this slide.
The slide represents scanning electron microscopy of the surface of extracorporeal circuits from an animal study. The right side of each image is a x 5 magnification of the area selected.
Figure A = a circuit that was not heparinized. Note the clumping of platelets and fibrin strands.
Figure B = represents a heparinized circuit - note the shape of the platelets
Figure C = a circuit where the clotting was prevented by a special circuit material that Dr. Annich and her colleagues have been working on, and heparin was NOT used - note the shape of the platelets now.
NO surface - no heparin
NO surface - heparinized
Compliments of Dr. Gail Annich, University of Michigan

12. Unfractionated Heparin
Hoffbauer R et al. Kidney Int. 1999;56:

13. LMWH: Theoretic Advantages
Reduced risk of bleeding
Less risk of HIT
LMWH may have some advantages. It can be used (with caution) in patients who have HITT (heparin induced thrombosis and thrombocytopenia).
NEXT SLIDE

14. LMWH
Hoffbauer R et al. Kidney Int. 1999;56:

15. LMWH no difference in filter life no difference in risk of bleeding
no quick antidote
need to monitor levels
risk of accumulation
renal clearance
minimal filter clearance
increased cost
Several publications have appeared recently, and unfortunately there appears to be no clear advantage in using this more expensive agent.

16. Citrate
Lets talk about citrate.
NEXT SLIDE

17. Citrate: Mechanism of Action
Binds calcium - essential coagulation co-factor
Citrate as CPD is the anticoagulant used to collect and store blood for transfusion. Every bloodbank to my knowledge uses it. IT WORKS!
As you can see from this slide, the effects of citrate on the ionized calcium levels in the blood are dose related. The body easily handles the citrate load by metabolism, particularly in the liver, but virtually everywhere as a substrate for the citric acid cycle (Krebs Cycle).

18. Citrate: Clinical Data
Citrate as CPD is the anticoagulant used to collect and store blood for transfusion. Every bloodbank to my knowledge uses it. IT WORKS!
As you can see from this slide, the effects of citrate on the ionized calcium levels in the blood are dose related. The body easily handles the citrate load by metabolism, particularly in the liver, but virtually everywhere as a substrate for the citric acid cycle (Krebs Cycle).

19. Sites of Action of Citrate
TISSUE FACTOR
TF:VIIa
CONTACT PHASE
XII activation
XI IX
monocytes / platelets / macrophages
Ca++ X Va
VIIIa
Ca++
platelets Xa
Phospholipid surface
prothrombin
CITRATE
THROMBIN
NATURAL ANTICOAGULANTS
(APC, ATIII)
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
fibrinogen
CLOT

20. Citrate: Advantages No need for heparin Less bleeding risk
Simple to monitor
Why bother?
Firstly, there are significant problems with heparin, as already alluded to.
If we could reduce the need or eliminate heparin from routine renal replacement therapies, one could anticipate the there would be less bleeding complications.
It is also theoretically and practically simple to monitor.

21. Citrate
Hoffbauer R et al. Kidney Int. 1999;56:

22. Citrate: Technical Considerations
ensure catheter patency
establish desired blood flow
pre-filter infusion
initial citrate flow = x 2 (mls/hr) BFR (mls/min)
systemic calcium infusion
aim for pre-filter ionized Ca++ < 0.4mmol/L
adjust dialysate as needed
anticipate alkalosis
adjust electrolyte replacements as necessary
Na+ / PO4-- / Ca++ / Mg++
We recently became interested in the use of citrate for a couple of reasons.
Firstly, it made sense. It should be safe if it is used during routine blood storage. I have used it in the past in 6 children and it seemed to work, but as for adjusting the rate of the citrate infusion, I went completely blind. Some of the important points that we have recently learnt include:
We know the level of citrate required to reduce the iCa level
We also know the level of iCa required before clotting is prevented in vitro and in-vivo
Because it is a type of regional anticoagulation, the citrate infusion should be run pre-filter.
To prevent eventual hypocalcemia and hypotension, the patient requires a systemic calcium infusion
But otherwise, in a patient with reasonable hepatic function, the citrate will be metabolized to bicarbonate.
Monitoring is different from what we would typically use for heparin. It is recommended that you follow ACT while running the citrate infusion. I can tell you assuredly, that this will be completely unreliable. Measure the ionized Calcium from the pre-filter sampling port.

23. Citrate: Problems metabolic alkalosis electrolyte disorders sugar load
metabolized in liver / skeletal muscle / other tissues
electrolyte disorders
hypernatremia
hypocalcemia
hypomagnesemia
sugar load
“citrate lock”?
hepatic failure
?cardiac toxicity
neonatal hearts
There are a number of problems that can occur if you are not careful.
Metabolic alkalosis will occur in every case. This can be dealt with by adjusting the replacement fluids and dialysate.
An added complication that can be added to the list from our recent clinical experience is hyperglycemia. The solution we use is a 3% citrate solution, which also contains 2.5% of dextrose in solution as well.

24. Citrate: Clinical Data

25. Citrate: Caution? Congenital metabolic diseases?
? mitochondropathies
Severe liver disease / hepatic failure
Excessive calcium requirements
Massive blood transfusions

26. Hirudin Highly selective / specific thrombin inhibitor
Minimal non-renal clearance
Long acting
No specific antagonist

27. Nafamostate Mesylate Synthetic protease inhibitor
Inhibits thrombin, Xa, XIIa, TF-VIIa complex
Low MW  high EC clearance
ACT for monitoring
No antidote but short half life

28. Conclusions Wide range of practice
UF heparin most commonly used anticoagulant
Citrate may be agent of choice in most situations?
In conclusion, practices differ widely, depending on the experience of the clinician and the patient case load.
Heparin remains the most commonly used anticoagulant, but its use is associated with significant risks.
Our initial experience with citrate is encouraging without the attendant risk of bleeding.