Heparin and Dialysis – HHD and PD

Nikhil ShahHome Dialysis Fellow

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

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.

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.

Actions of Heparin

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

Actions of LMWH

Types of Heparin

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.

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.

Direct Thrombin Inhibitors

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.

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

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

Davenport A. What are the anticoagulation options for intermittent hemodialysis? Nature Reviews Nephrology http://www.nature.com/doifinder/10.1038/nrneph.2011.88

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.

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

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

Adverse Effects of Heparin

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

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

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

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.

HIT

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.

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

HIT

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

HIT - Diagnosis

• 4T criteria

Low 0-3 pts, Intermediate 4-5 pts, High 6-8 pts

IP Heparin

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.

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 formation1. 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.

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.

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 dayCanavese 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.

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.

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 Assay1.

Kaplan GG, Manns B, McLaughlin K. Heparin induced thrombocytopaenia secondary to intraperitoneal heparin exposure. Nephrol Dial Transplant. 2005 Nov 1;20(11):2561–2.

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!

Thank you