Anticoagulant Dr Murni1

Georgina Follows Hdx foundation module

Anticoagulation and Anticoagulation and its use in its use in

haemodialysishaemodialysis

Basic clinical dialysis,

Murni IndrastiSub Bag Nefrologi / HipertensiBag Penyakit Dalam FK UNDIP/RS Dr Kariadi

•HEMOSTASIS

hemostasishemostasis

• f BV injury

Agregasi trombosit

Cascade koagulasi

Konstrisip.drh

Hemostasis plugstabil

HEMOSTASISHEMOSTASIS1. Hemostasis primer;1. Hemostasis primer; - vasokonstriksi p.drh- vasokonstriksi p.drh - erbentuknya pletelet plug- erbentuknya pletelet plug2. Hemostasis sekunder2. Hemostasis sekunder - aktivasi koagulasi kaskade- aktivasi koagulasi kaskade - deposisi dan stabilisasi fibrin- deposisi dan stabilisasi fibrin3. Hemostasis tersier3. Hemostasis tersier - disolusi fibrin klot- disolusi fibrin klot - plasminogen aktivasi- plasminogen aktivasi

Hemostasis primerHemostasis primer

1. Kerusakan dd p drh akan memaparkan protein sub endotel kolagen ke subendotel

2. Trombosit berikatan dengan kolagen melalui reseptor colagen spesifik glikoprotein 1a / 2a

Hemostasis sekunderHemostasis sekunder

Kaskade koagulasi

1.Jalur intrinsik

2.Jalur ekstrinsik

Sehingga terbentuk fibrin

HemostasisHemostasis

- Hemostasis primer; trombosit segera membentuk plug pd lokasi injury - Hemostasis sekunder; terjadi bersamaan 1. faktor pembekuan dalam sirkulasi

m.aktivasi kaskade kompleks 2. Membentuk fibrin strands 3 Fibrin strand memperkuat trombosit plug

Fibrinolisis; suatu proses degradasi Fibrinolisis; suatu proses degradasi fibrinfibrin

• Plasmin akan memecah fibrin menyebabkan produksi fragmen dalam sirkulasi yang akan dibersihkan oleh bbg protease atau oleh ginjal dan hati

• Plasmin diproduksi dalam bentuk inaktif plasminogen didalam hati.

• Perdarahan & trombosis Perdarahan & trombosis problem sering terjadi problem sering terjadi pd HDpd HD

• Perdarahan terutama disebabkan kelainan Perdarahan terutama disebabkan kelainan trombosit & dinding pembuluh darah walau jml trombosit & dinding pembuluh darah walau jml trombosit sering normal, ada banyak bukti trombosit sering normal, ada banyak bukti adanya defek pd glikoprotein trombosit reseptor adanya defek pd glikoprotein trombosit reseptor IIb/IIIa thd fibrinogen & glikoprotein (GP) Ib vWF. IIb/IIIa thd fibrinogen & glikoprotein (GP) Ib vWF.

• Terapi antikoagulan selama HD, & penggunaan Terapi antikoagulan selama HD, & penggunaan obat anti platelet sering menyebabkan tendensi obat anti platelet sering menyebabkan tendensi perdarahan.perdarahan.

• Waktu perdarahan & kadar urea merupakan Waktu perdarahan & kadar urea merupakan petunjuk kasar thd perdarahan.petunjuk kasar thd perdarahan.

• Faktor yg menyebabkan trombosis pd penderita Faktor yg menyebabkan trombosis pd penderita HD yaitu : Hipotensi, Hiperhomosisteinemi, HD yaitu : Hipotensi, Hiperhomosisteinemi, Disfungsi endotel, inflamasi, malnutrisiDisfungsi endotel, inflamasi, malnutrisi

• Kontak darah dgn udara pd drip chamber akan Kontak darah dgn udara pd drip chamber akan menyebabkan terbentuknya klot extrakorporeal menyebabkan terbentuknya klot extrakorporeal diawali dgn timbunan & agregasi trombosit terbentuk diawali dgn timbunan & agregasi trombosit terbentuk tromboksan aII & terjadi aktifasi dari jalur koagulasi tromboksan aII & terjadi aktifasi dari jalur koagulasi intrinsik, terjadi formasi trombin & deposisi fibrin.intrinsik, terjadi formasi trombin & deposisi fibrin.

• Pemberian heparin mencegah terjadinya klot.Pemberian heparin mencegah terjadinya klot.• Heparin akan berikatan dgn antitrombin III pd Heparin akan berikatan dgn antitrombin III pd

sirkulasi & menghambat faktor koagulasi I, IX, XI, XII, sirkulasi & menghambat faktor koagulasi I, IX, XI, XII, dan menyebabkan inaktifasi dari faktor diatas.dan menyebabkan inaktifasi dari faktor diatas.

• Waktu paruh heparin 30-120 mnt & memanjang dgn Waktu paruh heparin 30-120 mnt & memanjang dgn adanya disosiasi heparin dari komplek antitrombin IIIadanya disosiasi heparin dari komplek antitrombin III

Faktor yg berpengaruh terjadinya klot Faktor yg berpengaruh terjadinya klot pd ekstrakorporeal :pd ekstrakorporeal :

• Low blood flowLow blood flow• High hematocritHigh hematocrit• High ultrafiltration rateHigh ultrafiltration rate• Dialysis access recirculationDialysis access recirculation• Intradialytic blood and blood product Intradialytic blood and blood product

transfusiontransfusion• Intradialytic lipid infusionIntradialytic lipid infusion• Use drip chambers (air exposure, foam Use drip chambers (air exposure, foam

formation, turbulence)formation, turbulence)

Pemberian heparin pd HD :Pemberian heparin pd HD :

Reguler :Reguler :• Priming 2000 unit diikuti 1000 unit/jam, 1 jam terakhir Priming 2000 unit diikuti 1000 unit/jam, 1 jam terakhir

tanpa heparintanpa heparin

Heparin minimal :Heparin minimal :• Priming 2000 unit diikuti 250 unit/jam, 1 jam terakhir Priming 2000 unit diikuti 250 unit/jam, 1 jam terakhir

tanpa heparintanpa heparin

Target clotting time during dialysisTarget clotting time during dialysisRoutine heparin Tight heparin

Desired range Desired range

Test Reagent Baseline value

During dialysis

At end of

dialysisDuring dialysis

At end of

dialysis

WBPTT Actin FS 60-85 sec+ 80%(120-140)

+ 40%(85-105)

+ 40%(85-105)

+ 40%(85-105)

ACTa Siliceous earth 120-150 sec

+ 80%(200-250)

+ 40%(170-190)

+ 40%(170-190)

+ 40%(170-190)

LWCTb None 4-8 min 20-30 9-16 9-16 9-16

WBPTT : Whole Blood Partial Thromoplastin Time; ACT : Activated Clotting Time; LCWT : Lee-White Clotting TimeaThere are various methods of performing the ACT, and the baseline value with some methods is much lower, e.g 90-120 sec.bBaseline values of the LWCT vary greatly depending on how the test is performed

Komplikasi pemberian heparinKomplikasi pemberian heparin

• Lipid. Heparin mengaktifasi lipoproteinlipase dan Lipid. Heparin mengaktifasi lipoproteinlipase dan meningkatkan trigliserid, menurunkan HDL kolesterol.meningkatkan trigliserid, menurunkan HDL kolesterol.

• Trombositopeni. Heparin akan menimbulkan Trombositopeni. Heparin akan menimbulkan terbentuknya antiboditerbentuknya antibodi- HAT1 : menurunnya jml trombosit dose dependent- HAT1 : menurunnya jml trombosit dose dependent- HAT2 : terbentuknya imunoglobulin G thd heparin/ - HAT2 : terbentuknya imunoglobulin G thd heparin/ platelet platelet

faktor IVfaktor IV• PruritusPruritus• Hiperkaliemi. Oleh karena supresi aldosteronHiperkaliemi. Oleh karena supresi aldosteron


Heparin• Discovered in 1916 by McLean

• Anticoagulant found in the liver

• Porcine and bovine preparations

• Molecular weight = 3000 to 30000 Daltons

• Binds to thrombin inhibitor ANTITHROMBIN III > inactivates active Factor X and inhibits conversion of prothrombin to thrombin



Advantages of HeparinAdvantages of Heparin• I.V. – direct access

• Cheap

• Metabolised naturally by the liver

• Acts quickly and effectively on the intrinsic pathway

• Reversed quickly and easily by Protamine

• Long, established history of use



Disadvantages of HeparinDisadvantages of Heparin• Bleeding

• Hyperlipidaemia

• Thrombocytopenia

• Allergic reactions

• Pruritis

• Alopecia

• Osteoporosis



Assessment of coagulation• Clotting times – APTT (Actual Partial thromboplastin Time) or ACT (Activated Clotting Time) – 120 secs

• Observe for signs of clotting

- Darkened blood

- Streaks in dialyser

- Clots / fibrin rings in chambers

- Blood entering venous isolator

- Rising / falling venous pressure



Factors affecting coagulation• Blood flow

• High haematocrit levels

• EPO

• Blood transfusion

• Intra-dialytic lipid infusion

• High UF rate

• Type of circuit

• Medication



Factors affecting coagulation cont.• Individual clotting abnormalities

• Type of dialyser

• Membrane

- Natural membranes e.g. cuprophane – relatively high platelet activation

- Synthetic membranes vary. Polysulphone more compatible with blood than Cuprophane and Cellulose



Contraindications for heparin use

• Pericarditis

• Pre and post surgery, < 48 hour

• Following temporary line insertion

• Coagulation abnormalities, therapy antiplatelet

• Thrombocytopenia, < 150 X l0 9/L

• Intracranial haemorrhage

• Any active bleeding

• Uraemic patients

• Heparin free dialysis : flushing the dialyzer with 100ml Nacl 0,9% Every 30-60 minute



Contraindications for heparin use cont.

• Peptic ulcer

• Aortic aneurysm

• Cerebral aneurysm

• Severe liver disease

• Hypersensitivity / allergic reactions



Standard Heparin (UFH) Dose

• bolus dose 2500 U ( 50U/kgBB), maintenance 1000/jam

• atau initial HD: loading dose of 250-500 U followed by infusion

rate 250-500, max 2000U

•Heparin Free Dialysis

• Obtain baseline clotting time

• 5000u heparin rinse

• High blood flow rate

• 100-200 mls saline flush every 30 mins



• L.M.W.H. – inhibits Factor X, little thrombin inhibition,

APTT / ACT minimally prolonged.

Advantages

• Safe, effective & decreased bleeding risk

• Simple – single dose required

• Reduced cholesterol and triglyceride levels

• Reduced alopecia

Disadvantages

• Expensive, long half life, not use ACT’s


BLEEDING & BLEEDING & THROMBOSISTHROMBOSIS

Murni IndrastiMurni IndrastiSub Bagian Nefrologi-HipertensiSub Bagian Nefrologi-Hipertensi

SMF Penyakit Dalam RSUP Dr Kariadi SemarangSMF Penyakit Dalam RSUP Dr Kariadi Semarang


Highlight

• contact with plastic tubing, the dialysis membran and air in the HD circuit stimulates the clothing cascades• excessive clotting in the dialysis circuit and filter need to be discarded, in adult, this can mean the loss of 120-250 ml of blood• clotting within an HD circuit can be minimised through aprpropiate use of anticoagulant therapy• periodic anticoagulation is normally given during the dialysis treatment



Aims and objectives• To gain understanding of the mechanisms involved in the clotting process and coagulation assessment.

• To gain understanding of heparin, its administration, advantages and disadvantages.

• To gain understanding of any contraindications to heparin uses.

• To gain understanding of any alternatives to heparin usage.



IntroductionBlood comes into contact with extrinsic factors during haemodialysis.

Heparin is the most commonly used anticoagulant during dialysis.

Administration of heparin• Bolus dose at the beginning of dialysis

•Continuous infusion during dialysis.

•Both of these methods are prescribed and can be altered to tailor each patients needs.


Perdarahan pd penderita dialisisPerdarahan pd penderita dialisis• Inadekwat dialsysisInadekwat dialsysis• Anemi Anemi • Hb < 9Hb < 9• TrombositopeniTrombositopeni

- Penyakit imun (SLE)- Penyakit imun (SLE)- Obat-obatan misal : mycophenolate, azathioprine, - Obat-obatan misal : mycophenolate, azathioprine,

ciclophospamide ciclophospamide- Gangguan sumsum tulang- Gangguan sumsum tulang

• KoagulopatiKoagulopati- Heparin pd HD- Heparin pd HD- Meningkatnya waktu paruh LMW heparin- Meningkatnya waktu paruh LMW heparin- Sepsis (DIC)- Sepsis (DIC)- Post plasma varesis hilangnya faktor pembekuan- Post plasma varesis hilangnya faktor pembekuan

Penatalaksanaan perdarahan akut serius pd penderita HDPenatalaksanaan perdarahan akut serius pd penderita HD• Stop HD, resusitasi pasienStop HD, resusitasi pasien• Ambil darah utk crossmed & pem. koagulasiAmbil darah utk crossmed & pem. koagulasi• Pd penderita dgn warfarin diberikan terapi FFP (BB 80 4 Pd penderita dgn warfarin diberikan terapi FFP (BB 80 4

unit FFP), vit K 10-20 mg i.vunit FFP), vit K 10-20 mg i.v• Pd penderita trombosit < 50.000 diberikan TC Pd penderita trombosit < 50.000 diberikan TC • Pd penderita dgn heparin diberikan protamin 1 mg i.v Pd penderita dgn heparin diberikan protamin 1 mg i.v

tiap 100 unit heparin, dosis maksimum 50 mg dlm 10 tiap 100 unit heparin, dosis maksimum 50 mg dlm 10 mnt sisanya diberikan dlm per-infus dlm 8 jammnt sisanya diberikan dlm per-infus dlm 8 jam

• Pd penderita disfungsi trombosit diberikan Desmopresin Pd penderita disfungsi trombosit diberikan Desmopresin (DDAVP) DDAVP akan memobilisasi faktor VIII & vWF (DDAVP) DDAVP akan memobilisasi faktor VIII & vWF jaringan dari endoteljaringan dari endotel

• Perbaikan anemi dgn transfusi sampai Hb 9Perbaikan anemi dgn transfusi sampai Hb 9• Tingkatkan dosis dialisis pd penderita dgn dialisis tak Tingkatkan dosis dialisis pd penderita dgn dialisis tak

adekwatadekwat

Penatalaksanaan perdarahan AV vistula post Penatalaksanaan perdarahan AV vistula post dialisisdialisis

• Diberikan kompres es Diberikan kompres es • Bila masih berdarah diberikan DDAVPBila masih berdarah diberikan DDAVP

Cara pemberian DDAVPCara pemberian DDAVP • DDAVP i.v 0.3 DDAVP i.v 0.3 gr/kg dlm 50cc NaCL 0.5gr/kg dlm 50cc NaCL 0.5• Waktu paruh faktor VIII plasma 5-8 jam & Waktu paruh faktor VIII plasma 5-8 jam &

vWF 8-10 jamvWF 8-10 jam• DDAVP bisa menyebabkan vasodilatasi & DDAVP bisa menyebabkan vasodilatasi &

akan tetapi hipotensi berkurang dgn akan tetapi hipotensi berkurang dgn pemberian infus lambat selama 30 menitpemberian infus lambat selama 30 menit

• Dosis ulangan diberikan 12-24 jam setelah Dosis ulangan diberikan 12-24 jam setelah dosis awaldosis awal

Penatalaksanaan perdarahan dari CVCPenatalaksanaan perdarahan dari CVC

• Berikan tekanan lokal (dgn es)Berikan tekanan lokal (dgn es)• Kalau perlu dijahit Kalau perlu dijahit • Bila perdarahan msh berlanjut diberikan Bila perdarahan msh berlanjut diberikan

DDAVPDDAVP• Evaluasi RW pd hematom yg besar & pd Evaluasi RW pd hematom yg besar & pd

hemotoraxhemotorax• Rawat pasienRawat pasien


GROUP WORKGROUP WORK

A patient complains of loss of hair over the past couple of months. She has minimal heparin on dialysis, but still no change, what would you do??

A patient has just completed dialysis and you notice that the kidney is very dark. The patient is already on high doses of heparin. What would you do??



FutureFuture

• Coating of elements Coating of elements of circuit with active of circuit with active heparin.heparin.

• Non-thrombogenic Non-thrombogenic membranes.membranes.

• Heparinised coated Heparinised coated cartridges capable of cartridges capable of removing heparin removing heparin infused into the extra infused into the extra corporeal circuit.corporeal circuit.



QUESTION???QUESTION???

• Which pathway Which pathway is initiated during is initiated during haemodialysis?haemodialysis?



The Coagulation CascadeThe Coagulation CascadeVascular ConstrictionVascular Constriction

Platelet plug formationPlatelet plug formation

Formation of blood Formation of blood clotsclots



The Coagulation CascadeThe Coagulation CascadeVascular ConstrictionVascular Constriction

Platelet plug formationPlatelet plug formation

Formation of blood Formation of blood clotsclots



Extrinsic pathwayExtrinsic pathway• Damaged tissue – thromboplastin released – initiates formation of prothrombinase in presence of Factor X and calcium ions.

•The coagulation cascade then occurs by using thrombin – an enzyme that converts fibrinogen into fibrin. This forms a mesh trapping the formed elements of blood – thus forming a CLOT.


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Anticoagulant Dr Murni1

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