This document discusses heparin and its use in hemodialysis and peritoneal dialysis. It provides details on: - The types of heparins including unfractionated heparin and low molecular weight heparins. - The mechanisms of action of heparins including binding to antithrombin III to inhibit coagulation factors. - The use of heparin in hemodialysis including bolus doses and continuous infusions to prevent clotting in the dialysis circuit. - The limited systemic absorption of intraperitoneal heparin used in peritoneal dialysis to prevent fibrin deposition.

1. Heparin and Dialysis – HHD
and PD
Nikhil Shah
Home Dialysis Fellow

2. Outline
• What are Heparins
• Mechanism of Action
• Pharmacology
• History
• Types
• Use of Heparin in Hemodialysis
• Adverse Effects
• HIT - Management
• IP Heparin
• Current Role
• Systemic Effects

3. Introduction
• Clotting is the Achilles Heel of Hemodialysis
• Cellular elements of the blood
• platelets, monocytes and leukocytes, are activated by passage through the
dialysis circuit, by the drop in pressure, and changes in flow through the
access device
• Leads to blebbing of surface membrane and release of surface membrane
microparticles, which are a potent source of tissue factor.
• Tissue factor
• activates both the intrinsic and extrinsic clotting pathways
• accelerates thrombin generation, leading to the deposition of fibrin and activated
platelets on the dialyzer.

4. Actions of Heparin
• Heparin on its own does not have any intrinsic activity
• Binds to Anti Thrombin III
• Antithrombin is a glycosylated, single-chain polypeptide, Synthesized in the
liver, Antithrombin inhibits activated coagulation factors involved in the
intrinsic and common pathways
• Heparin acts as an accelerant
• When the concentration of heparin in plasma is 0.1-1 units/mL, thrombin,
factor IXa, and factor Xa are inhibited rapidly (t1/2 <0.1 second) by
antithrombin.
• This effect prolongs both the aPTT and the thrombin time (i.e., the time
required for plasma to clot when exogenous thrombin is added);
• the PT is affected to a lesser degree.

5. Actions of Heparin

6. Actions of Heparin
• UFH works by binding to antithrombin III (AT), through
a key pentasaccharide motif, which catalyses the
reaction between AT and thrombin
• AT also inhibits activated factor Xa

7. Actions of LMWH

8. Types of Heparin

9. Pharmacology
• Heparin is not one product
• series of repeating
mucopolysaccharide molecules, with a
molecular weight ranging from 3 kDa
to 30 kDa
• which are highly and negatively
charged due to the presence of
alternating sulfated d-glucosamine
and d-glucuronic acid groups
• pharmacological testing is based on
the negative charge of the molecules,
and anticoagulant activity assumed to
be related to charge.

10. Low Molecular Weight Heparins
• LMWH binds to and accelerates
the activity of antithrombin III.
• By activating antithrombin III,
LMWH preferentially potentiates
the inhibition of coagulation
factors Xa and IIa.

11. Direct Thrombin Inhibitors

12. History of Heparin
• Discovered 100 years ago
• Dr Jay McLean Medical Student and Prof Howell were the first to
discover a substance which causes anticoagulation
• Canadian Charles Best (Nobel Prize 1923 with Dr Banting for Insulin)
purified and commercially produced at Connaught Labs in Toronto
• Swedish scientist Erik Jorpes developed parenteral heparin safe for IV
use.

13. Heparin in Hemodialysis
• a single bolus of UFH which may
then require a smaller second
bolus, or use a smaller initial bolus
dose followed by a continuous
infusion which is stopped around
20 minutes prior to the end of the
dialysis session
• Adjusting bolus and infusion doses
and stop times clinically by
monitoring clot formation in
dialyzer and venous air detector
chamber and time to stop bleeding
from access needle sites,
• large number of negative charges
• UFH can non-selectively
electrostatically bind to plastic
tubing in the extracorporeal circuit,
especially when infused slowly at
high concentrations.
• UFH can bind to capillary dialyzer
surfaces
• also to plasma proteins, circulating
monocytes, leukocytes and the
endothelium

14. LMWH In Hemodialysis
• Due to the variability of UFH
preparations, LMWHs were
developed to provide a more
reliable and predictable
anticoagulant effect
• LMWHs primarily prevent
activation of factor X, and have a
lesser effect against thrombin
• LMWHs simply require a single
bolus injection at the start of
dialysis
• Widely used in Europe
• Hardly used elsewhere due to cost.
• UFH is the standard of choice
• Other advantages of LMWH
• reported shorter needle site bleeding
times post dialysis
• either similar or less circuit clotting
and bleeding episodes than UFH
• improved urea clearances due to
reduced dialyzer membrane fouling
• fewer cases of heparin induced
thrombocytopenia

15. Davenport A. What are the
anticoagulation options for
intermittent hemodialysis? Nature
Reviews Nephrology
http://www.nature.com/doifinder/1
0.1038/nrneph.2011.88

16. 1.
Shen JI, Winkelmayer WC. Use and Safety of Unfractionated Heparin for
Anticoagulation During Maintenance Hemodialysis. American Journal of Kidney
Diseases. 2012 Sep;60(3):473–86.

17. Other Guidelines
• European guidelines
• UFH at 50 IU/kg as an initial
bolus, then 800-1,500 IU per
hour of dialysis
• CSN
• No specific recommendations
• NARP

18. Dialyzing patients with high risk for bleeding
• Heparin Regional
anticoagulation
• heparin is added before the blood
enters the dialysis circuit, but is
reversed by protamine, which is
infused prior to the blood
returning to the patient
• Citrate Regional Anticoagulation
• Citrate infused once the blood
leaves the patient and calcium
infused back before returning
• AN69 ST Membrane
• Needs to be flushed with
heparinized saline pre HD
• Still exposed to some Heparin
• Low Dose Heparin
• Most practical
• Zero Heparin Dialysis
• Continuous infusion with UF
• Saline flushes

19. Adverse Effects of Heparin

20. Adverse Effects of Heparin
• Bleeding
• Wasse et al studied a cohort of dialysis
patients from the US Renal Data System
Morbidity and Mortality Studies to
identify risk factors for upper GI bleeding
• use of any antiplatelet or anticoagulant
medication at baseline was not associated
with increased risk of upper-GI bleeding
• Chacati and Godon conducted an autopsy
study of 94 patients with ESRD (75 had
been receiving hemodialysis) and 258
controls without ESRD
• after the first month, hemodialysis may
reverse some of the metabolic
derangements
• that heparin does not necessarily confer an
increased risk of bleeding in this
population.
• Cerebral hemorrhage
• Again most cases of cerebral hemorrhage
occurred more than 1 hour after Heparin
was stopped
• No difference in the incidence related to
dose
• Other Bleeding
• Variceal
• Pleural
• Opthalmic
• Small studies no change in the bleeding
rates with or without heparin

21. Adverse Effects of Heparin
• Hypertriglyceridemia
• Heparin is known to cause
hypertriglyceridemia, likely through
the depletion of lipoprotein lipase
(LPL), the enzyme that breaks down
triglycerides
• bolus of heparin will release LPL into
the free circulation, ultimately
• depletes its stores, leading to a build-
up of triglycerides
• No convincing data in reducing TGs
• No convincing data about LMWH
which have a lower rise in TG, will
affect the mortality
• Anaphylaxis
• Very rare
• Occurs because of sensitivity to
porcine or bovine heparin
• Change to the other type of heparin
recommended if it occurs

22. Adverse Effects of Heparin
• Bone mineral Disease
• Heparin is known to worsen BMD
in pregnant patients
• Several studies in dialysis
populations have not convincingly
shown that it makes a difference
• Hyperkalemia
• Hypoaldosteronism with resultant
hyperkalemia is a known side
effect of UFH
• Heparin decreases aldosterone by
decreasing both the number and
sensitivity of angiotensin II
receptors on adrenal zona
glomerulosa cells.
• Bath K can be adjusted to deal
with this if it occurs
• No convincing evidence

23. Adverse Effects of Heparin
• Biofilms and Catheter related
sepsis
• Heparin potentiates the formation
of biofilms
• analysis found that a bolus of UFH
midtreatment (but not loading
bolus or total UFH dose) was a risk
factor for catheter-related sepsis.

24. HIT

25. HIT - Two types of HIT
• In the milder form, type I HIT
• heparin binds, activates, and depletes platelets.
• occurs within the first 4 days of starting heparin therapy and thus is seen in
incident hemodialysis patients.
• The thrombocytopenia is mild, with average platelet levels of 100 – 109 and
typically resolves with time.
• No antibodies are formed, and heparin therapy does not need to be stopped.

26. HIT – Type II
• heparin exposure induces both bleeding and thromboembolic complications
• Heparin binds to platelets, releasing platelet factor 4 (PF4), which in turn binds
heparin
• Antibodies then can bind to the heparin-PF4 complex, causing a cascade of more
platelet aggregation that leads to severe thrombocytopenia (platelets 50 109 per
1 L of blood) and subsequent bleeding complications.
• The binding of these heparin-induced antibodies to endothelial cells also can
cause paradoxical thrombus formation
• Occurs 5-12 days after Heparin exposure
• All types of Heparin stopped
• Should have systemic anticoagulation with DRI for 2-3 months to prevent
thromboembolic conditions

27. HIT
• Incidence 0.26% - 3.5%
• Circuit clotting
• Access clotting
• Serious complications – DVT, PE – 4-8% UK study

28. HIT - Diagnosis
• 4T criteria
Low 0-3 pts, Intermediate 4-5 pts, High 6-8 pts

31. IP Heparin

32. Pharmacology – IP Heparin
• the mean t 1/2 of heparin in the peritoneal cavity being 10.8 +/- 0.93
hr.
• antithrombin III - repeated dilution and outflow sequences of dialysis
the cofactor concentrations rapidly fell to negligible levels that were
incapable of activating any heparin present.
• Systemic blood coagulation was unaffected by single 10000 U doses
of heparin administered intraperitoneally in that plasma A-PTT values
were not lengthened when measured over the ensuing six hours.
Furman KI, Gomperts ED, Hockley J. Activity of intraperitoneal heparin during peritoneal dialysis. Clin Nephrol. 1978
Jan;9(1):15–8.

33. Role of Heparin In PD
• Standard Practise
• UofA Current uses
• Instill and Cap Off – 2000 Units used – total volume 5 ml – all in the catheter
• Fibrin build up – 500 units/L of PD fluid
• Peritonitis – First 48 hours/ Bags clear – 500 units/L
• What does Heparin Do and what dose1
• fibrin formation was determined by fibrinopeptide A, a thrombin-induced split product of
fibrinogen
• effect of two different heparin concentrations (7500 U/L and 500 U/L) on dialysate
fibrinopeptide A (FPA) concentrations in 6 patients
• there was no difference in reduction of fibrin formation between the two different
concentrations of heparin (FPA with 7500 U/L heparin: 20.6 ± 5.6 ng/mL; 500 U/L: 22.8 ±
6 ng/mL; no heparin: 152.2 ± 11.8 ng/mL)
• 500 U/L heparin per liter dialysate prevents the intraperitoneal fibrin formation
1. Gries E, Paar D, Graben N, Bock KD. Intraperitoneal heparin in peritoneal dialysis and its effect on fibrinopeptide A in plasma
and dialysate. Haemostasis. 1989;19(1):21–5.

34. Systemic Effects Of IP Heparin
• 8 patients on CAPD
• When 2.5 U/ml or 5 U/ml of heparin was given intraperitoneally, t1/2 of
heparin activity in the dialysate was 0.5 to 2 hrs, and 6 hrs after
administration its activity was 0.5 U/ml and 1.4 U/ml respectively.
• Whole blood clotting time - hardly affected because the transfer of heparin
to the plasma was minimal.
• AT-III level in the dialysate was only 1.5% of those in the plasma.
• We conclude that the intraperitoneal administration of heparin at these
doses is effective in preventing fibrin precipitation when intraperitoneal AT-
III levels are expected to be relatively increased such as at the start of CAPD
or in the presence of peritonitis.
Takahashi S, Shimada A, Okada K, Kuno T, Nagura Y, Hatano M. Effect of intraperitoneal administration of heparin to patients
on continuous ambulatory peritoneal dialysis (CAPD). Perit Dial Int. 1991 Jan 1;11(1):81–3.

35. Systemic Effects of IP Heparin
• Rabbit Study
• 99-Tc-labeled heparin was given intraperitoneally along with dialysate in a New Zealand
white rabbit model.
• Three different protocols were used: a single 15-minute cycle with heparin 500 U/L, 6
successive 15-minute cycles with heparin 500 U/L, and a single 3-hr cycle with heparin 2500
U/L.
• Labeled heparin was found in blood, organs, and urine.
• The total amount of recovery ranged from 1.5% to 20%, and depended on the amount of
heparin used and the duration of its presence in the rabbit peritoneal cavity
• Rx of combination of large molecular weight and negative charge prevent systemic
absorption of heparin across the peritoneal membrane
• DVT
• patient on CAPD with deep-vein thrombosis (DVT) was successfully treated with low-
molecular-weight heparin with resulting therapeutic antifactor-Xa activity in the plasma of
0.5 to 0.8 units. (Dose used: 6000 to 8000 antifactor Xa U/2-L dialysate bag, given four times
a day
Canavese C, Salomone M, Mangiarotti G, Pacitti A, Trucco S, Scaglia C, et al. Heparin transfer across the rabbit peritoneal membrane. Clin Nephrol. 1986
Sep;26(3):116–20.
Schrader J, Tönnis HJ, Scheler F. Long-term intraperitoneal application of low molecular weight heparin in a continuous ambulatory peritoneal dialysis patient
with deep vein thrombosis. Nephron. 1986;42(1):83–4.

36. Systemic Effects of IP Heparin
• Nadig et al
• collected 194 dialysate samples from 17 patients over a period of 24 months.
• Measured thrombin-antithrombin III (TAT) complexes as an indicator of
thrombin formation, D-dimers as an indicator of fibrinolysis, and plasminogen
activator inhibitor-1 (PAI-1).
• routine IP heparin was not indicated even in the presence of peritonitis, and
that low D-dimer levels in dialysate at initial sampling could identify the
minority of cases that had an imbalance favoring coagulation
• the use of heparin should be restricted to the minority of patients with
defects in fibrinolysis due to high levels of PAI-1. This subset could be
identified by demonstrating low levels of D-dimer at the time of dialysate
sampling
Nadig C, Binswanger U, Felten A von. Is heparin therapy necessary in CAPD peritonitis? Perit Dial Int. 1997 Jan 1;17(5):493–
6.

37. HIT from IP Heparin
• Calgary case
• 52/M, New start PD patient
presented with cloudy bag, no org
grew, but was on Antibiotics
protocol
• Received 1000 Units/Bag x 7days
• Platelet count dropped from 260
to 25 with petechial hemorrhages
and epistaxis
• HIT was confirmed by Serotonin
Release Assay
1.
Kaplan GG, Manns B, McLaughlin K. Heparin induced
thrombocytopaenia secondary to intraperitoneal heparin
exposure. Nephrol Dial Transplant. 2005 Nov 1;20(11):2561–2.

39. Take Home Message
• HD
• Heparin usually safe – UFH
• LMWH – Not the best evidence
for clear cut benefit – but can be
used safely
• Dosing – Individual patient based
and flexible
• Watch out for complications
• PD
• Does heparin during PD Peritonitis
have a great benefit – Evidence is
not great
• Heparin – at higher doses and
longer dwells DOES get absorbed
systemically
• Uses the lowest and shortest
course
• HIT can occur because of IP
heparin – Watch out!

40. Thank you