anti-coagulation in hemodialysis_20.06.2014

7/25/2019 Anti-coagulation in Hemodialysis_20.06.2014

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Anticoagulationin Dialysis

Santosh Varughese

Dept. of NephrologyCMC Vellore


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Anticoagulation Needed !!

Anticoagulation Needed !!


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Overview

Coagulation cascade

Heparin as an anticoagulant

Low molecular weight heparins

Anticoagulation in Hemodialysis

Regional anticoagulationHeparin Induced Thrombocytopenia

Potential drugs of the future


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Scanning Electron Micrograp

Diagram


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Physical Process of ClottingPhysical Process of Clotting

vasoconstriction

exposure ofsubendothelial cells

platelets aggregate - plug

blood

subendothelial cells

platelets

injured tissue

platelets adhere to exposed cells


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Coagulation Phase

Two major pathways Intrinsic pathway

Etrinsic pathway

!oth con"erge at a common point

#$ soluble factors are in"ol"ed in clotting

!iosynthesis of these factors are dependenton %itamin and &'

(ost of these factors are proteases

)ormally inacti"e and se*uentially acti"ated


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Chemical Process of ClottingChemical Process of Clotting

XIIa

XI

XIa

IX

IXa

X

Xa

II

IIa

X

Xa

VII

VIIa

V Va

VIIIa

Fibrinogen

Fibrin CLOT

monomers

IIa

IIa

XIII

HMWK

TF

IIa

XIIIa

VIII

XII


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Coagulation Cascade


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Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

Fibrin polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affected

ByHeparin

Vit. K dependent FactorsAffected b Oral Anticoa ulants


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Intrinsic Pathway All clotting factors are

within the blood vessels

Clotting slower Activated partial

thromboplastin test (aPTT)

Extrinsic Pathway Initiating factor is outside

the blood vessels tissue

factor Clotting faster in

!econds

Prothrombin test (PT)


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Heparin Chemical structure

"n#ractionated $eparin %"#$&

(iture of polyanionic branched glycosaminoglycans

+ide range of mol, wts -./// 0 $//// 1a 0 mean #2 ///3 42 monosaccharide chains 56


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Heparins

#stisolated by (acLean 7 Howell 0 #8#9

L(+H appro"ed for use 0 #88$

Isolated from porcine intestinal mucosa or bo"ine lung

Humans 0 mast cells and basophilic granulocytes

Acts both in-vitro 7 in-vivo

Half0life # 0 2 hrs 0 monitor aPTT

Ad"erse effect 0 hemorrhage 0 antidote 0 protaminesulphate


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Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

Fibrin polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affected

ByHeparin

Vit. K dependent FactorsAffected b Oral Anticoa ulants


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Antithrombin III Inhibits the ollowingerine Proteases

Antithrombin IIIInhibits the ollowingerine Proteases

Coagulation

:actor ;IIa

:actor ;Ia

:actor I;a

:actor ;a

Thrombin

:ibrinolysis

Plasmin

Inhibitory acti!ity against these en'ymes is accelerate% by heparin


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Action of Heparin

$/< of =:H binds to AT with high

affinity

Conformational change >

Con"erts AT from a slow to a "ery

rapidly ?#/// times5 acting inhibitor of

thrombin

Also AT interacts with@

I;a ;a ;Ia, ;IIa plasmin BalliBrein

and trypsin


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Action of Heparin


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Action of Heparin


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Heparin mechanism of action

Heparin

Antithrombin IIIThrombin


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Heparin mechanism of action

Heparin

Antithrombin IIIThrombin


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Anticoagulant properties

#, Inhibits the thrombin0mediated con"ersion of

fibrinogen to fibrin

', Inhibits the aggregation of platelets by thrombin

$, Inhibits acti"ation of fibrin stabiliing enyme

4, Inhibits acti"ated factors ;II ;I I; ; and II


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" Heparin vs #ow $ol %t Heparin

Inacti"ation of thrombin by heparin>AT compleHeparin molecule with at least #9 monosaccharides

!maller mol %' & sufficient to inhibit factor *a

%+,-$&


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nti&'a ( anti&IIa )atio


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Pharmaco*inetics & "H

Poor oral absorption at physiological pH

1oes not cross DI membrane because the sulfate groups are

ionied

Administered I% or C

)on0specific interactionsanticoagulatory bioa"ailability of =:H

after #st bolus injection 3 only $/response relationship

Clearance of =:H 0 hepatic metabolism 7 renal clearance of

desulfated fragmentsdose reduction in impaired hepatic or renal

function necessary to a"oid o"erdosage


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Pharmaco*inetics $%H

L(+Hs 0 reduced polysaccharide chain length superior

pharmacoBinetic properties in normal renal function

FC Injection > bioa"ailability 3 #//


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"se in )enal ailure

Antithrombotic properties of "#$> #stdescribed 3 8/ yrs ago

1ifferent dosing schedules in renal failure described

In H1 0 repeated bolus application F continuous infusion

Considerable inter0indi"idual "ariability of pharmacoBinetics

fixed dosing is usually inappropriate

(onitoring by acti"ated partial thromboplastin time ?aPTT5 or

acti"ated clotting time ?ACT5 after initial bolus

PIT#A++ G$// different laboratory methods a"ailable to assay

aPTT > differing "alues for the same sample

)o reliable studies comparing complication rates in normals "s

impaired renal function a"ailable


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#$%Hs

(ore data in H1 than C&1 stage III or I%

ingle bolus injection recommended at beginning of H1

Possible need for an indi"idual dosing schedule or regular drug

monitoringsustained anticoagulation after a single bolus )o elimination "ia either H1 FH: > #storder elimination profile

Theoretically could be filtered with high0flu membranes?mol, wt $///>8/// 1a5

)egati"e electrical charge L(+H>AT>factor ;a complees

Low permeability

Responsible for prolonged anticoagulatory effect


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#$%Hs

Enoaparin 0 effecti"e anti0factor ;a conc 3 #/ h after a bolus

:aster decline of anti0factor ;a acti"ity 0 reviparin7 tinzaparin

) Comparati"e studies -pharmacoBinetic and clinical end0points6 for different L(+Hs in renal failure

Uncertain whether LMWHs offer any advantage over UFH for

anticoagulation during HD Recent meta0analysis >

)o differences in bleeding e"ents 7 etracorporeal circuit stability


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#$%Hs in C+, III ( I-

Conflicting data

e"ere F fatal bleeding complications described with unadjusted

dosage of L(+Hs

1oes )T mean that use of =:H with aPTT monitoring is safer

EE)CE -Efficacy and afety of ubcutaneous Enoaparin in )on0

wa"e Coronary E"ents6 7 TI(I ##! -Thrombolysis in (yocardial Infarction6

'< had a calculated creatinine clearance J$/ mlFmin

ignificantly increased risB of major haemorrhage compared with

those without se"ere renal impairment whether they were

treated with =:H or enoaparin


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#$%Hs in C+, III ( I-

Troughlevelsbut not peaB le"els rose after repeated doses when

creat clearance J4/ mlFminpossible accumulation of drug

tudies Conclude >

Either dose reduction !"#$!"%# &g'(g instead of )"!$)"*# &g'(g+ or

Dose adaptation ,ased on anti-factor a &onitoring

to a"oid bleeding complications through o"erdose

Tinaparin > ad"antageous

) correlation of factor ; acti"ity 7 Renal :ailure

) accumulation of Tinaparin in Renal :ailure


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http://bmj.com/content/vol325/issue7367/images/large/anti1.f6r.jpeg


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http://bmj.com/content/vol325/issue7367/images/large/anti1.f6r.jpeg


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%hy Anticoagulate .

Interaction of plasma with the dialysis membrane produces

acti"ation of the clotting cascade

1e"elopment of thrombosis in the etracorporeal circuit

thrombin deposition in dialyer hollow fibers and resultingdialyer dysfunction

1ialyer thrombogenicity 0 dialysis membrane composition

surface charge surface area and configuration,

Rate of blood flow through the dialyer ultrafiltration rateprescribed ?due to hemoconcentration5 and the length diameter

and composition of blood lines

Patient0specific "ariables 0 ac*uired and inherited

coagulopathies neoplasia malnutrition hemoglobin

concentration and congesti"e heart failure,


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!etter Control of Anticoagulation Leads toIncreased 1ialyer Reuse Potential for Long Term Cost a"ings

)o Compromise in 1ialysis Efficacy ?&tF%5useph R, et,al, Am K &idney 1is $2@98084 '///


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Advantages

Easy to administer

Low cost

Relati"ely short biologic half0life

In routine hemodialysis practice the intensity ofanticoagulation is not measured

ome circumstances0 the acti"ated clotting time ?ACT5

+hole blood is mied with an acti"ator of the etrinsicclotting cascade and the time necessary for blood tofirst congeal is measured,


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Administration

A simple method of heparin administration is the systemic

administration of 2/ to #// =FBg of heparin at the initiation of

dialysis fre*uently followed by a bolus of #/// =Fhour,

+hen ACT is being measured the target ACT 0 2/< abo"e

baseline

In fractional anticoagulation a smaller initial bolus of heparin is

administered ?#/ to 2/ =FBg5 followed by an infusion of 2// to

#/// =Fhour,

:ractional hepariniation can be used to achie"e less intensi"e

anticoagulation where the target ACT is maintained at '2 Hattersley0 Acti"ated Clotting Time

1iatomaceous earth acti"ator perator defined miing and clot detection

Dlobal assay 0 Contact acti"ation of cascade


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Particulate Contact Activation

Initiation of intrinsic coagulation cascade

:actor ;II ?Hageman factor5

PreBalliBrein ?:letcher factor5 1ramatically shortens contact acti"ation period o"er

Lee0+hite time

Proposed as both screening assay for coagulation

defects and for heparin monitoring


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AC/ Automation & 0121

HE(CHR) introduced semi0automated

less operator dependence

two assaysCA2#/ ?later :TCA2#/5

> diatomaceous earth

acti"atedP'#4 glass bead acti"ated


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Hemo/ec AC/ & 01345s

Li*uid Baolin acti"ator

1ifferent technology 1ifferent results


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$onitoring with AC/

!enefits Industry tandard ince #8M/s Recommended as primary method in guidelines

Easy to run

1isad"antages Each system yields different numbers

High sensiti"ity to hypothermia and hemodilution?with eceptions5

Little or no correlation to heparin le"el in serum

especially true for pediatric patients


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)egional anticoagulation

Effecti"e in pre"enting etracorporeal thrombogenesis with

minimal systemic anticoagulation

Etracorporeal circuit alone is anticoagulated by administering

2// to M2/ =Fhour into arterial line ?often with 2// unit bolus atthe initiation of dialysis5 and by the parallel administration of

protamine into the "enous line,

=se of regional anticoagulation re*uires fre*uent checBs of the

ACT from the arterial and "enous lines with adjustments of theheparin and protamine infusion rates to maintain the ACT for the

patient at baseline while the ACT in the dialysis circuit is

prolonged #/ seconds or longer,


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)egional anticoagulation

!ecause heparin has a longer half0life than protamine

additional protamine should be gi"en at the end of the

dialysis procedure to pre"ent a rebound heparin

bleeding risB,,

!ecause of these difficulties regional anticoagulation is

rarely employed,


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)ecommendations

#, Patients who are bleeding are at significant risB for bleedingha"e a baseline major thrombostatic defect or are within Mdays of a major operati"e procedure or within #4 days ofintracranial surgery should undergo dialysis without heparin or

by regional anticoagulation,', Patients who are within M' hours of a biopsy of a "isceral

organ should undergo dialysis without heparin or by regionalanticoagulation,

$, Patients who are more than M days past a major surgery or M'hours past a biopsy can ha"e dialysis by fractionalhepariniation, If they ha"e pre"iously recei"ed fractionalhepariniation they can be considered for systemicanticoagulation,


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)ecommendations

4, Patients with pericarditis should ha"e dialysis withoutheparin or by regional anticoagulation,

2, Patients who ha"e undergone minor surgical

procedures within the pre"ious M' hours should ha"edialysis by fractional anticoagulation,

., Patients anticipated to undergo a major surgicalprocedure within 9 hours of hemodialysis should

undergo dialysis without heparin or with tight fractionalanticoagulation, If they are within 9 hours of a minorprocedure fractional anticoagulation is appropriate,


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igns of Clotting

Etremely darB blood

hadows or blacB streaBs in the dialyser :oaming N

clot formation in drip chambers and "enous trap Rapid filling of transducers with blood

!lood in post0dialyser "enous lineunable to continue

into "enous chamber Presence of clots at arterial side header


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Anticoagulation schedules

)o heparin dialysis

tandard anticoagulation


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Anticoagulation schedules

)o heparin dialysis

tandard anticoagulation

(inimum0dose heparin

Regional anticoagulation with protamine re"ersal

Regional citrate anticoagulation

Citrate dialysate

Prostacyclin regional anticoagulation Low molecular weight heparins


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Heparin Induced /hrombocytopenia

1ecrease in platelet count during or shortly following eposure toheparin

$IT type I?Called heparin0associated thrombocytopenia in the past5

!enign form not associated with increased risB of thrombosis (echanism > unBnown O ))0immune 0 probably related to

platelet pro0aggregating effect

Affects 3 #/< pts on heparin

(ild transient asymptomatic thrombocytopenia ?rarely less than#/////5

1e"elops early ?usually in #st two days of starting heparin5

1isappears *uicBly when heparin is withdrawn


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Heparin Induced /hrombocytopenia

$IT type II

Affects 3 # 0 $< pts on heparin > 2 > #/ days after starting R

Immune0mediated associated with risB of thrombosis Recently proposed name changes@ HIT type IQ be changed to

non0immune heparin associated thrombocytopeniaQ and HIT

type IIQ to HITQ (ost Important drug0induced thrombocytopenia 0 'nd(C after

bleeding


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)is* actors for HI/ & II

1uration of heparin R -4 to #/ days6

Type of heparin used

!o"ine lung =:H G porcine intestine =:H G porcine intestine L(+H

tatus of patients post0operati"e G medical G obstetric

Chronic haemodialysis

Pre"alence of P:4>heparin abs 0 was ',9>#' contro"ersial

Recent retrospecti"e analysis 0 significantly increased morbidity 7

mortality due to bleeding N thromboembolic e"ents in H1 pts with with

HIT0II antibodies ,ureebe +. et al. $eparinassociated antiplateletantibodies increase morbidity and mortality in

hemodialysis patients/ !urgery 011234'56 727879'


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Potential drugs of the future

Coumadin anticoagulants #8$/s

Heparin disco"ery #8'/

L(+H use in = #88$

1irect Thrombin Inhibitors

Hirudin #984

Refludan #889Argatroban '///

!i"alirudin '///


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/argets of New Inhibitors

Fibrinogen Fibrin

ThrombinProthrombin

Xa + Va

X

Tissue Factor-VIIa

IXa

#ondiparinux

Idraparinux$irudin

:ivalirudin

Argatroban

*imelagatran

IX

VIIIa

TFPI

NPc!

FVIIai

PC


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ondaparinu6

IIaIIaIIII

FibrinogenFibrinogen FibrinFibrin

c"otc"ot

#$trinsic#$trinsic

%ath&a'%ath&a'IntrinsicIntrinsic

%ath&a'%ath&a'

TIII XaTIII TIII

Fon(a%arinu$Fon(a%arinu$

XaXa

ntithrombin

IIP"ate"ets


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ondaparinu6

!ioa"ailability 3 #//

anti-coagulation in hemodialysis_20.06.2014

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