Anti-coagulation in Hemodialysis_20.06.2014
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Transcript of 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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%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 #//