Anticoagulation

in Dialysis
Santosh Varughese
Dept. of Nephrology
CMC Vellore

Anticoagulation
AnticoagulationNeeded
Needed!!!!

Overview
Coagulation cascade
Heparin as an anticoagulant
Low molecular weight heparins
Anticoagulation in Hemodialysis
Regional anticoagulation
Heparin Induced Thrombocytopenia
Potential drugs of the future

Scanning Electron Micrograph

Diagram

Coagulation Factors
Factor

Name

Fibrinogen

II

Prothrombin

III

Tissue Factor or thromboplastin

IV

Ca2+

Proaccelerin

VII

Proconvertin

VIII

Antihemophilic A factor

IX

Antihemophilic B factor or Christmas factor

Stuart factor

XI

Plasma thromboplastin antecedent

XII

Hageman factor

Physical Process of Clotting

exposure of subendothelial cells

injured tissue

vasoconstriction

blood
subendothelial cells
platelets

platelets adhere to exposed cells

platelets aggregate - plug

Coagulation Phase
Two major pathways
Intrinsic pathway
Extrinsic pathway

Both converge at a common point

13 soluble factors are involved in clotting
Biosynthesis of these factors are dependent
on Vitamin K1 and K2
Most of these factors are proteases
Normally inactive and sequentially activated

Chemical Process of Clotting

HMWK

XI
IX

XII

XIIa
X

XIa
VIII

IXa
VIIIa

IIa

II
Xa

IIa

Va
Xa

X
VII

IIa
IIa

VIIa
TF

XIII

Fibrinogen

Fibrin
monomers

XIIIa

CLOT

Coagulation Cascade

IntrinsicPathway

ExtrinsicPathway
TissueInjury

BloodVesselInjury

TissueFactor

XIIa

XII

Thromboplastin

XIa

XI

IXa

IX

Xa

X
Factorsaffected
ByHeparin

VIIa

Prothrombin

Vit.KdependentFactors
AffectedbyOralAnticoagulants

Fibrinogen
XIII

VII

X
Thrombin
Fribrinmonomer
Fibrinpolymer

Intrinsic Pathway

Extrinsic Pathway

All clotting factors are

within the blood vessels
Clotting slower
Activated partial
thromboplastin test (aPTT)

Initiating factor is outside

the blood vessels - tissue
factor
Clotting - faster - in
Seconds
Prothrombin test (PT)

Heparin Chemical structure

Un-Fractionated Heparin [UFH]
Mixture of polyanionic branched glycosaminoglycans
Wide range of mol. wts [6000 - 30000 Da - mean 15 000
~ 45 monosaccharide chains )]

Heparins
1st isolated by MacLean & Howell - 1918

LMWH approved for use

- 1993
Isolated from porcine intestinal mucosa or bovine lung
Humans - mast cells and basophilic granulocytes
Acts both in-vitro & in-vivo
Half-life 1 - 5 hrs - monitor aPTT
Adverse effect - hemorrhage - antidote - protamine
sulphate

IntrinsicPathway

ExtrinsicPathway
TissueInjury

BloodVesselInjury

TissueFactor

XIIa

XII

Thromboplastin

XIa

XI

IXa

IX

Xa

X
Factorsaffected
ByHeparin

VIIa

Prothrombin

Vit.KdependentFactors
AffectedbyOralAnticoagulants

Fibrinogen
XIII

VII

X
Thrombin
Fribrinmonomer
Fibrinpolymer

Antithrombin
AntithrombinIII
IIIInhibits
Inhibitsthe
theFollowing
Following
Serine
SerineProteases
Proteases
Coagulation

Factor XIIa
Factor XIa
Factor IXa
Factor Xa
Thrombin

Fibrinolysis
Plasmin

Inhibitory activity against these enzymes is accelerated by heparin

Action of Heparin
30% of UFH binds to AT with high
affinity
Conformational change
Converts AT from a slow to a very
rapidly (1000 times) acting inhibitor of
thrombin

Also AT interacts with:

IXa, Xa, XIa. XIIa, plasmin, kallikrein
and trypsin

Action of Heparin

Action of Heparin

Heparin mechanism of action

Heparin
AntithrombinIII

Thrombin

Heparin mechanism of action

Heparin
AntithrombinIII

Thrombin

Anticoagulant properties
1. Inhibits the thrombin-mediated conversion of
fibrinogen to fibrin
2. Inhibits the aggregation of platelets by thrombin
3. Inhibits activation of fibrin stabilizing enzyme
4. Inhibits activated factors XII, XI, IX, X and II

UF Heparin vs Low Mol Wt Heparin

Inactivation of thrombin by heparinAT complex
Heparin molecule with at least 18 monosaccharides

Smaller mol [3K - 9K] sufficient to inhibit factor Xa

[LMWH]

Anti-Xa / anti-IIa Ratio

Pharmacokinetics - UFH
Poor oral absorption at physiological pH
Does not cross GI membrane because the sulfate groups are
ionized
Administered IV or SC
Non-specific interactions anticoagulatory bioavailability of UFH
after 1st bolus injection ~ only 30%
Almost linear doseresponse relationship
Clearance of UFH - hepatic metabolism & renal clearance of
desulfated fragments dose reduction in impaired hepatic or renal
function necessary to avoid overdosage

Pharmacokinetics -LMWH
LMWHs - reduced polysaccharide chain length superior
pharmacokinetic properties in normal renal function
S/C Injection bioavailability ~ 100% even at low doses
Longer dose-independent elimination half-life
Less non-specific binding to platelets, endothelial cells,
macrophages and osteoblasts lower incidence of side effects
[HIT-II or osteopenia]
Main pharmacological limitation - LMWHs principally cleared by the
renal route biological half-life is prolonged in patients with renal
failure

Use in Renal Failure

Antithrombotic properties of UFH 1st described ~ 90 yrs ago
Different dosing schedules in renal failure described
In HD - repeated bolus application / continuous infusion
Considerable inter-individual variability of pharmacokinetics
fixed dosing is usually inappropriate
Monitoring by activated partial thromboplastin time (aPTT) or
activated clotting time (ACT) after initial bolus
PITFALL - >300 different laboratory methods available to assay
aPTT differing values for the same sample
No reliable studies comparing complication rates in normals vs
impaired renal function available

LMWHs
More data in HD than CKD stage III or IV
Single bolus injection recommended at beginning of HD
Possible need for an individual dosing schedule or regular drug
monitoring sustained anticoagulation after a single bolus
No elimination via either HD /HF 1st order elimination profile
Theoretically could be filtered with high-flux membranes
(mol. wt 30009000 Da)
Negative electrical charge
LMWHATfactor Xa complexes
Low permeability
Responsible for prolonged anticoagulatory effect

LMWHs
Enoxaparin - effective anti-factor Xa conc ~ 10 h after a bolus
Faster decline of anti-factor Xa activity - reviparin & tinzaparin
NO Comparative studies [pharmacokinetic and clinical endpoints] for different LMWHs in renal failure
Uncertain whether LMWHs offer any advantage over UFH for
anticoagulation during HD
Recent meta-analysis
No differences in bleeding events & extracorporeal circuit stability

LMWHs in CKD III / IV

Conflicting data
Severe / fatal bleeding complications described with unadjusted
dosage of LMWHs
Does NOT mean that use of UFH with aPTT monitoring is safer
ESSENCE [Efficacy and Safety of Subcutaneous Enoxaparin in NonQwave Coronary Events] & TIMI 11B [Thrombolysis in Myocardial Infarction]
2% had a calculated creatinine clearance <30 ml/min
Significantly increased risk of major haemorrhage compared with
those without severe renal impairment whether they were
treated with UFH or enoxaparin

LMWHs in CKD III / IV

Trough levels but not peak levels rose after repeated doses when
creat clearance <40 ml/min possible accumulation of drug
Studies Conclude
Either dose reduction (0.50.75 mg/kg instead of 1.01.25 mg/kg) or
Dose adaptation based on anti-factor Xa monitoring

to avoid bleeding complications through overdose

Tinzaparin advantageous
NO correlation of factor X activity & Renal Failure
NO accumulation of Tinzaparin in Renal Failure

Why Anticoagulate ?
Interaction of plasma with the dialysis membrane produces
activation of the clotting cascade
Development of thrombosis in the extracorporeal circuit,
thrombin deposition in dialyzer hollow fibers, and resulting
dialyzer dysfunction
Dialyzer thrombogenicity - dialysis membrane composition,
surface charge, surface area, and configuration.
Rate of blood flow through the dialyzer, ultrafiltration rate
prescribed (due to hemoconcentration), and the length, diameter
and composition of blood lines
Patient-specific variables - acquired and inherited
coagulopathies, neoplasia, malnutrition, hemoglobin
concentration and congestive heart failure.

 Better Control of Anticoagulation Leads to

Increased Dialyzer Reuse
Potential for Long Term Cost Savings
No Compromise in Dialysis Efficacy (Kt/V)

Ouseph, R. et.al. Am J Kidney Dis 35:89-94; 2000

Advantages
Easy to administer
Low cost
Relatively short biologic half-life
In routine hemodialysis practice, the intensity of
anticoagulation is not measured
Some circumstances- the activated clotting time (ACT)
Whole blood is mixed with an activator of the extrinsic
clotting cascade, and the time necessary for blood to
first congeal is measured.

Administration
A simple method of heparin administration is the systemic
administration of 50 to 100 U/kg of heparin at the initiation of
dialysis, frequently followed by a bolus of 1000 U/hour.
When ACT is being measured, the target ACT - 50% above
baseline
In fractional anticoagulation, a smaller initial bolus of heparin is
administered (10 to 50 U/kg), followed by an infusion of 500 to
1000 U/hour.
Fractional heparinization can be used to achieve less intensive
anticoagulation where the target ACT is maintained at 25%
(fractional) or 15% (tight fractional) above the baseline value.
Reserved for patients at higher risk for bleeding complications.

Activated Clotting Time

Lee-White clotting time
Manual
No activator
Very slow

1966 Hattersley- Activated Clotting Time

Diatomaceous earth activator
Operator defined mixing and clot detection
Global assay - Contact activation of cascade

Particulate Contact Activation

Initiation of intrinsic coagulation cascade
Factor XII (Hageman factor)
Prekallikrein (Fletcher factor)

Dramatically shortens contact activation period over

Lee-White time
Proposed as both screening assay for coagulation
defects and for heparin monitoring

ACT Automation - 1969

HEMOCHRON introduced
semi-automated
less operator dependence
two assays
CA510 (later FTCA510)
diatomaceous earth
activated
P214 glass bead activated

HemoTec ACT - 1980s

Liquid kaolin activator
Different technology
Different results

Monitoring with ACT

Benefits
Industry Standard Since 1970s
Recommended as primary method in guidelines
Easy to run

Disadvantages
Each system yields different numbers
High sensitivity to hypothermia and hemodilution
(with exceptions)
Little or no correlation to heparin level in serum

especially true for pediatric patients

Regional anticoagulation
Effective in preventing extracorporeal thrombogenesis with
minimal systemic anticoagulation
Extracorporeal circuit alone is anticoagulated by administering
500 to 750 U/hour into arterial line (often with 500 unit bolus at
the initiation of dialysis) and by the parallel administration of
protamine into the venous line.
Use of regional anticoagulation requires frequent checks of the
ACT from the arterial and venous lines with adjustments of the
heparin and protamine infusion rates to maintain the ACT for the
patient at baseline while the ACT in the dialysis circuit is
prolonged 10 seconds or longer.

Regional anticoagulation
Because heparin has a longer half-life than protamine,
additional protamine should be given at the end of the
dialysis procedure to prevent a rebound heparin
bleeding risk..
Because of these difficulties, regional anticoagulation is
rarely employed.

Recommendations
1.

2.
3.

Patients who are bleeding, are at significant risk for bleeding,

have a baseline major thrombostatic defect, or are within 7
days of a major operative procedure or within 14 days of
intracranial surgery should undergo dialysis without heparin or
by regional anticoagulation.
Patients who are within 72 hours of a biopsy of a visceral
organ should undergo dialysis without heparin or by regional
anticoagulation.
Patients who are more than 7 days past a major surgery or 72
hours past a biopsy can have dialysis by fractional
heparinization. If they have previously received fractional
heparinization, they can be considered for systemic
anticoagulation.

Recommendations
4. Patients with pericarditis should have dialysis without
heparin or by regional anticoagulation.
5. Patients who have undergone minor surgical
procedures within the previous 72 hours should have
dialysis by fractional anticoagulation.
6. Patients anticipated to undergo a major surgical
procedure within 8 hours of hemodialysis should
undergo dialysis without heparin or with tight fractional
anticoagulation. If they are within 8 hours of a minor
procedure, fractional anticoagulation is appropriate.

Signs of Clotting
Extremely dark blood
Shadows or black streaks in the dialyser Foaming +
clot formation in drip chambers and venous trap
Rapid filling of transducers with blood
Blood in post-dialyser venous lineunable to continue
into venous chamber
Presence of clots at arterial side header

Anticoagulation schedules
No heparin dialysis

Standard anticoagulation

Anticoagulation schedules

No heparin dialysis
Standard anticoagulation
Minimum-dose heparin
Regional anticoagulation with protamine reversal
Regional citrate anticoagulation
Citrate dialysate
Prostacyclin regional anticoagulation
Low molecular weight heparins

Heparin Induced Thrombocytopenia

Decrease in platelet count during or shortly following exposure to
heparin

HIT type I
(Called heparin-associated thrombocytopenia in the past)
Benign form not associated with increased risk of thrombosis
Mechanism unknown, ? NON-immune - probably related to
platelet pro-aggregating effect
Affects ~ 10% pts on heparin
Mild, transient, asymptomatic thrombocytopenia (rarely less than
100,000)
Develops early (usually in 1st two days of starting heparin)
Disappears quickly when heparin is withdrawn

Heparin Induced Thrombocytopenia

HIT type II
Affects ~ 1 - 3% pts on heparin 5 10 days after starting Rx
Immune-mediated, associated with risk of thrombosis
Recently proposed name changes: HIT type I be changed to
non-immune heparin associated thrombocytopenia and HIT
type II to HIT
Most Important drug-induced thrombocytopenia - 2nd MC after
bleeding

Risk Factors for HIT - II

Duration of heparin Rx [4 to 10 days]
Type of heparin used
Bovine lung UFH > porcine intestine UFH > porcine intestine LMWH

Status of patients
post-operative > medical > obstetric

Chronic haemodialysis
Prevalence of PF4heparin abs - was 2.812%
Cinical relevance of high prevalence controversial
Recent retrospective analysis - significantly increased morbidity &
mortality due to bleeding + thromboembolic events in HD pts with with
Mureebe L, et al, Heparin-associated antiplatelet
HIT-II antibodies
antibodies increase morbidity and mortality in
hemodialysis patients. Surgery 2004;136: 848853

Potential drugs of the future

Coumadin anticoagulants
Heparin discovery
LMWH use in US

1930s
1920
1993

Direct Thrombin Inhibitors

Hirudin
Refludan
Argatroban
Bivalirudin

1894
1998
2000
2000

Targets of New Inhibitors

Tissue Factor-VIIa

TFPI
NAPc2
FVIIai

X
IX
Fondiparinux
Idraparinux

IXa
VIIIa

APC

Xa + Va
Prothrombin

Thrombin

Fibrinogen

Fibrin

Hirudin
Bivalirudin
Argatroban
Ximelagatran

Fondaparinux
Intrinsic
pathway

Extrinsic
pathway

Antithrombin
ATIII

ATIII

Fondaparinux

ATIII

Xa

Xa

II
Fibrinogen

Platelets

IIA

IIa
Fibrin
clot

Fondaparinux
Bioavailability ~ 100%
Maximum concentration is achieved in 2 hours and
steady state in 3 hours
Half-life is 17-22 hours
Majority of dose is excreted unchanged in urine
Alternative agent for LMWH
Treatment of HIT
No true antidote although Factor VIIa may be of benefit
Ongoing trials with Idraparinux

Direct Thrombin Inhibitors

Heparin binding site

IIa
Catalytic
site

IIa

Substrate
Recognition
Site

Hirudin

Argatroban
Melagatran

IIa

Ximelagatran - Prodrug of melagatran

First oral direct thrombin inhibitor
Good GI absorption - levels in 2-3 hours
Not protein bound - Half-life 3-4 hours
Eliminated via kidneys
Impressive results as an oral anticoagulant
Does not require monitoring of anticoagulation
Effects - ??? better than warfarin
Some thromboembolic events
Unclear significance of LFT abnormalities

How much is
it going to
cost?

ENOXAPARIN 40 MG
= $27.89
FONDAPARINUX 2.5 MG = $41.29
XIMELAGATRAN
????

The only place success

comes before work is in a
dictionary!