Anticoagulation on dialysis Feb 08/2014

Report
ANTICOAGULATION
ON
DIALYSIS
FEB 08/2014
Hanadi Alhozali,MBBS,ABIM,FRCPC
Assistant professor consultant internal
medicine and Nephrology KAUH/Jeddah
Glomerular- based disease and Renal disease
in pregnancy
OBJECTIVES
History
 Hemostatic changes in renal dysfunction.
 Standard anticoagulation on hemodialysis.
 Alternative anticoagulation in dialysis patients
at increase risk of bleeding.
 Other anticoagulation: LMWH
 Heparin-induced thrombocytopenia (HIT)



Anticoagulation required during IHD/CRRT to
prevent clotting in the extracorporeal service.
Anticoagulation crucial to prevent undesirable
blood loss and provide constant optimal solute
clearance.
HISTORY OF ANTICOAGULATION


1914 Abel developed and tested the first efficient
dialysis system in animal at Johns Hopkins
University School of Medicine. Their “vividiffusion” apparatus consisted of a filtering device
made of cellulose trinitrate (collodion) tubes and an
attached burette containing hirudin solution used
as anticoagulant.
That same year, Hess and McGuigan
recommended high blood flows to avoid clotting or
need for anticoagulation.
Abel J, Roundtree L, Turner B. On the removal of diffusible substances from the circulating
blood of living animals by dialysis. J Pharmacol Exp Ther 5:275-316, 1914
Hess J, McGuigan W. The condition of the sugar in the blood. Pharmacology 6:45-55, 1914

The first human hemodialysis was performed in a
uremic patient by Haas in 1924 at the University
of Giessen in Germany. He used a tubular device
made of collodion and hirudin for
anticoagulation.
Haas G. Versuche der Blutauswaschung am Lebenden mit Hilfe der
Dialyse. Klin Wochenschrift 4:13, 1925
Benedum J. Pioneer of dialysis, George Haas (1886-1971). Med Hist 14:196217, 1979
HEMOSTATIC CHANGES IN DIALYSIS
Bleeding diathesis:
 Platelets dysfunction and abnormal platelets
endothelial interaction.
 Uremic toxins, increase NO production and
anemia are major contributing factors.
 Skin and mucosal bleeding(Nasal/GI) and
Excessive bleeding after invasive procedure.
 Normal coagulation (PT/APTT) unless there is
coagulopathy.
 Increase risk of bleeding (prolonged BT) with use
of ASA (Cyclooxygenase independent)

Thrombosis in dialysis:
Dialysis and CKD patients at increase risk for
venous thromboembolism and access thrombosis.
Chitalia et al;circulation,2013 Jan
Wattanaki k et al;JASN,2008Jan
STANDARD ANTICOAGULATION
Sodium heparin:
 Indirect systemic
anticoagulation by binding
itself to antithrombin III (a
natural anticoagulant).
 Heparin enhance the
anticoagulant activity of
antithrombin III .
 Antithrombin III
inactivate thrombin and
factor Xa and to lesser
extent IXa , XIa and XIIa.
Action time 3-5 minutes and
half life 1.5 hour.

SODIUM HEPARIN
Now commercially derived from porcine
intestinal mucosa or bovine lung.
 Molecular weight ranging from 10,000 to 16,000
daltons.
 Highly negatively charged and binds nonspecifically to endothelium, platelets, circulating
proteins, macrophages and plastic surfaces.
 UFH is cleared by both renal(35%) and hepatic
mechanisms and is metabolized by endothelium.

UFH
The loading dose bolus may be 500 units or 1000
units and infusion may vary from 500 units
hourly to 1000 units hourly
 Heparin administration usually ceases at least
1h-30 minutes before the end of dialysis.
 Monitoring with APTT or whole blood activated
clotting time aiming (ACT)for 150% of pre
dialysis value (200-250 seconds).
 Protamine sulfate as antidote.

UFH
Advantages:
1.Safety record unless the patient has bleeding
2.Proven efficacy
3.Inexpenisive
 Disadvantage:
1. Lack of routine/accurate monitoring of
anticoagulation effect.
2.The need for an infusion pump and the costs of
nursing time.
3.Risk of Heparin-induced thrombocytopenia (HIT)
greater with UFH.

ANTICOAGULATION IN HIGH RISK FOR
BLEEDING
1.No Heparin Dialysis:
 Indicated in patients with active bleeding, major
surgery, acute HIT, recent trauma/head injury
and systemic anticoagulation.
 Multiple flushes of 25–50 ml of saline every 15–
30 min, in association with a high blood flow rate
 In some units the blood lines and dialyzer are
pretreated with 2000–5000 U of UF heparin and
then flushed with 1 L of normal saline, to coat
the lines.
NO HEPARIN DIALYSIS
Disadvantage:
1.Labour intensive
2.Clotting still occurs in 2% of cases with complete
clotting of lines or dialyzer, requiring line changes
or conversion to low dose heparin in 7% of cases.
3.Risk of clotting exacerbated by poor access blood
flow, venous catheter, hypotension and concomitant
blood transfusion.
4.NO significant clearance difference compared to
full anticoagulation.

Schwab SJ et al;Am J Med. 1987;83(3):405.
MINIMUM DOSE HEPARIN
The protocol usually involves boluses of 500 units
of heparin every 30 minutes to keep the activated
clotting time >150 but <200 seconds.
 Alternately, a continuous infusion of heparin
with frequent activated clotting time (ACT)
monitoring can be used to achieve the same
degree of anticoagulation.
 Disadvantage:
Close nursing observation and still carry risk of
bleeding.

REGIONAL ANTICOAGULATION
Aim of regional anticoagulation is
to restrict the anticoagulant effect to the dialysis
circuit and prevent systemic anticoagulation in
patient at risk for bleeding:
1.Protamine reversal anticoagulation.
2.Regional citrate anticoagulation(RCA).
3.Regional prostacyclin anticoagulation.
4.Heparin coated membrane.

REGIONAL ANTICOAGULATION WITH
PROTAMINE REVERSAL
Oldest method used in dialysis associated
bleeding.
 Constant infusion of heparin into the dialyzer
inlet line and the simultaneous, constant infusion
of protamine prior to the blood returning to the
patient.
 The infusion pump rates are adjusted to keep the
whole blood ACT in the dialyzer circuit at 250
seconds and the blood returning to the patient at
its pre dialysis baseline value.


Disadvantage: “Abandoned”
1:Technical difficulties.
2: Rebound bleeding 2-4 hours after the end of
dialysis as the reticuloendothelial system releases
free heparin from the protamine-heparin complex
back into the general circulation.
REGIONAL CITRATE ANTICOAGULATION
(RCA)
Continuous infusion of isosmotic trisodium
citrate solution (102 mmol/L) into the arterial
side of the dialyzer.
 Citrate bind to plasma calcium
fall in plasma
calcium
preventing the coagulation
cascade
anticoagulation.
 The citrate infusion rate is adjusted to keep the
ACT above 200 seconds in the arterial limb.

The citrate infusion rate is adjusted to keep the
ACT above 200 seconds in the arterial limb.
 Carful monitoring to prevent hypocalcemia or
hypercalcemia.
 Shown to be safe ,effective and reduce incidence
of bleeding compare to standard heparin in IHD
and CRRT.

Janssen MJ et al;NDT1993;8(11):1228
Martin k et al ;NDT(2010)25:337-3342

1.
2.
3.
4.
5.
Disadvantage:
Calcium disturbance
Metabolic alkalosis (Metabolism of citrate to
HCO3)
Hypernatremia( Hypertonic sodium citrate
solution)
Close nursing observation.
Contraindicated in patient can not metabolized
citrate such as : liver failure
HEPARIN COATED MEMBRANE
Heparin coated dialysis membrane in high risk
patient for bleeding.
 Recent studies showed contradicting results.
 Heparin-coated AN69 ST when compared to RCA
was associated with massive clotting rate (39%
vs 13%).
Am J Kidney Dis. 2007;49(5):642


Prospective study showed AN69 ST allowed 50%
reduction in UFH and with out increase in
massive clotting.
NDT(2008)23:2003-2009
OTHER
Citrate dialysate:
Citric acid-based dialysate result in reduced clotting by
lowering the calcium and interfering with clotting
cascade.

Am J Kidney Dis. 2000;35(3):493
Prostacyclin regional anticoagulation:
Prostacyclin is a vasodilator and inhibitor of platelet
aggregation.
Infusion of prostacyclin (Eporostenol) into the dialyzer
circuit at 4 to 8 ng/kg per minute.
Monitoring by APTT.
Limitation: Hypotension , flushes, headache,
expensive.

Blood Purif. 1991;9(5-6):296
EUROPEAN BEST PRACTICE GUIDELINES
FOR ANTICOAGULATION IN HEMODIALYSIS
Anticoagulation with significant risk of
bleeding:
 We recommend that systemic anticoagulation
should be avoided or kept to a minimum. This
may be achieved by using a high blood flow rate
and regular flushing of the extracorporeal circuit
with saline every 15-30 minutes or regional
citrate infusion. Low-dose unfractionated heparin
may be used with caution in patients with
intermediate risk of bleeding. (1C)

Nephrol Dial Transplant 2002; 17: Supplement 7 S1-S111
LMWH
Lower molecular weight of 2–9 kDa, mostly 5
kDa – thus consisting of ≤ 15 saccharide units.
 The shorter chain length results in:
1.Less coagulation inhibition, but
2.Superior pharmacokinetics, higher
bioavailability, less non-specific binding and longer
half-life.
3.LMWH dosage simpler and more predictable
than UF heparin.

LMWH
In addition
 Less impact on platelet function, and thus may
cause less bleeding
 Binds anti-thrombin III and inhibits factor Xa.
 But most LMWH (50–70%) does not have the
second binding sequence needed to inhibit
thrombin because of the shorter chain length.
In most cases the affinity of LMWH for Xa versus
thrombin is of the order of 3:1.
 The anticoagulant effect of LMWH can be
monitored by the anti-factor Xa activity in
plasma:
A common target range is
 0.4– 0.6 IU/ml anti-Xa but a
More conservative range
 0.2– 0.4 IU/ml is recommended in patients with a
high risk of bleeding

LMWH
Cleared by renal/dialysis mechanisms, so dosage
must be adjusted .
 When high flux dialyzers are used, LMWH is
more effectively cleared than UF heparin.
 There are multiple forms of LMWH e.g.
Enoxaparin, Dalteparin, Nadroparin, Reviparin
Tinzaparin .
 Often administered into the arterial line of the
dialysis circuit

ENOXAPARIN
One of the most commonly used LMWH
 Has the longest half-life.
 Derived from pigs intestinal mucosa.
 Predominantly renal cleared.
 Dose reduction need to be made in the elderly
and in very obese patients, to avoid lifethreatening bleeding.
 Enoxaparin can be administered as a Single
dose(1.0-0.7m/kg/dialysis session) and generally
does not require to be monitored.

Generally does not accumulate in 3/week dialysis
regimens, but there is a risk of accumulation in
more frequent schedules
 No simple antidote and in the case of severe
hemorrhage:1. Activated factor VII concentrate may be
required.
2.Protamine 1 mg given by slow infusion should be
administered to neutralize 1 mg of enoxaparin.
< 60% reversible with protamine

LMWH

Systematic review of 11 trials comparing the use
of LMWH and UFH in HD patients concluded
that there was NO difference in the incidence of
bleeding complications, bleeding from the
vascular access after HD or thrombosis of the
extracorporeal circuit .
J Am Soc Nephrol 2004; 15:3192-3206

One of the study the Clexane was associated
with slightly significant frequency of minor Hg
between dialysis. (7.7 vs 2.8 P<0.001). However,
when Clexane dose adjusted in the affected
patients (the mean dose was 0.69+/-0.25mg/kg)
the events decrease by 44% (from 7.7 to 4.3%)
P=0.087.
NDT(1999)14:2698-2703
The long term use of Enoxaparin has been
assessed in long-term (7 years) prospective three
phase interventional study.
 The mean dose used was 0.43+/0.16mg/kg/dialysis session .
 The long term use of the LMWH(EN) in HD with
a reduced dose is safe and comparable to UFH in
platelet counts &lipid profile.

Blood purif 2009;27:242-245
LMWH VS UFH?
Convenience of administration
 Less Nursing demand.
 Longer duration of action.
 No need for frequent monitoring unless the
patient at slight risk of bleeding.
 Lower incidence of HIT Type II in patients
exposed to LMWH compared with UF heparin.

N Eng J Med 1995;332:1330-1335
UFH Inhibit mineralocorticoid metabolism and
reduced adrenal aldosterone secretion, but
LMWH has been shown to have less inhibition in this
regard.
 Less common side effect such as: osteoporosis, hair loss
and lipid disturbance
( TG and Cholesterol
HDL).

LMWH VS UFH?
1.Once a patient develops heparin-induced
thrombocytopenia (HIT), LMW heparin cannot be
used as a safe substitute.
2.The cost of LMWH still significantly exceeds UF
heparin.
3.Frequent monitoring (Anti-Xa level) required in
high risk patients.
4.Commercially available are extracted from pigs.
EUROPEAN BEST PRACTICE GUIDELINES
FOR ANTICOAGULATION IN HEMODIALYSIS


Anticoagulation without added risk of
bleeding:
We recommend that patients without increased
bleeding risk should be given unfractionated
heparin or LMWH during HD to reduce the risk
of clotting of the extracorporeal system. (1A)
Nephrol Dial Transplant 2002; 17: Supplement 7 S1-S111
HEPARIN-INDUCED THROMBOCYTOPENIA
(HIT)
There are two well-described syndromes of HIT,
the
 HIT type I :relatively benign 10-20% nonimmune
Resolve without clinical significant..
 HIT Type II :2–15% of patients exposed to
heparin
 More commonly in females and surgical cases
 In dialysis patients the incidence varies between
2.8% and 12%.
 Onset 4-10 days after exposure.

incidence is 5–10 times more common with UF
heparin than with patients receiving only LMWH
 The risk with LMWH is reportedly very low, in
the order of <1%.
 Mechanism of HIT which results in both platelet
activation and activation of the coagulation
cascade.

CLINICAL PRESENTATION



Significant thrombocytopenia and high risk of
thromboembolic phenomena.
Recovery phase: signaled by recovery of platelet
levels, heparin/LMWH must still be avoided .
Diagnosis: antibodies against heparin–PF4
complex, detection of heparin-induced platelet
aggregation or platelet release assays.

In patients with HIT Type II all heparin products
must be avoided, including:
1.Topical preparations, coated products as well as
intravenous preparations.
2.Systemic anticoagulation without heparin is
mandatory in the acute phase. Untreated, there is a
major risk of venous and arterial thrombosis, estimated
at >50% within 30 days.
Dialysis patients may have:
‘no heparin’ dialysis / switched to P.D/ RCA or
anticoagulation with non- heparins agents:
 The available agents commonly used include
Danaparoid, Hirudin, and Argatroban.


Venous catheters must not be heparin locked, but
can be locked with recombinant tissue
plasminogen activator or citrate ( trisodium
citrate 46.7%).
DANAPAROID
Extracted from pig gut mucosa .
 Heparinoid of molecular weight of 5.5 kDa
 Binds to antithrombin (heparin cofactor I) and
heparin cofactor II and has some endothelial
mechanisms, but minimal effect on platelets.
 More selective for Xa than even the LMWH .
 May have unique features, which interfere with
the pathogenesis of HIT Type II.

DANAPAROID
Can been given as a single dose of 34.4 anti-Xa
units/kg at the initiation of hemodialysis .
 Very long half-life of about 25 h in normal.
 Longer with chronic renal impairment (30 hr)
 No reversal Agent.
 Monitored by Anti-Xa level.
 Can be used in pregnancy.

RECOMBINANT HIRUDIN (LEPIRUDIN)
Originally discovered in the saliva of leeches
 Binds thrombin irreversibly at its active site and
the fibrin-binding site.
 Polypeptides of molecular weight of 7 kDa with
no cross-reactivity to the HIT antibody.
 Renally cleared, so its half-life in renal
impairment is > 35 h.
 Monitored with APTT and NO antidote available
but cleared by HF/Plamapheresis.
 Hirudin can be used as an anticoagulant for HD.
 Not available due to lake of the raw material.

Kidney Int Suppl. 1999
ARGATROBAN
Appears to be the treatment of choice in the USA
 Synthetic derivative of L-arginine
 Acts as a direct thrombin inhibitor and
 Short half-life of 40–60 min
 Not effected by renal function
 Hepatic clearance means prolonged duration of
action in patients with liver failure.
 APTT monitoring and No reversal agent.

Kidney Int. 2004;66(6):2446.
EUROPEAN BEST PRACTICE GUIDELINES
FOR ANTICOAGULATION IN HEMODIALYSIS.

Anticoagulation in patients with HIT type 2
We suggest that patients with HIT type 2 or
HITTS should not be prescribed unfractionated
heparin or low molecular weight heparin (LMWH)
(2B).
CONCLUSION
Anticoagulation in Hemodialysis is an area in
dialysis that in continuous development and
evolution.
 Nephrologist required to have good
understanding:
1.Management of high risk for bleeding on dialysis.
2.UFH vs LMWH depend on your local practice and
resources.
3.Management of HIT type II.

THANK YOU

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