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Pendahuluan
Jk proses hemostasis berfx
normal tdk tjd perdarahan
yg berlebihan maupun
pembentukan trombus yg
tdk diinginkan
Tx yg memodifikasi jalur
koagulasi, fibrinolisis, &
agregasi trombosit berguna
utk pasien yg mengalami
pembedahan or penykt CV

7an utama intervensi tx thd

mekanisme hemostatik:
1. Menghambat koagulasi darah
2.Menstimulasi lisis dari trombus yg
telah terbentuk ttp tdk diharapkan
3.Menghambat fungsi platelet

Prosedur pembedahan tertentu spt operasi

sendi panggul & bypass kardiopulmoner
dimana darah mengalami kontak dengan
material asing, mengawali proses koagulasi
darah dan tjd pembentukan trombus
Pd keadaan tsb pemberian antikoagulan
profilaksis, biasanya heparin atau koumarin,
efektif mengurangi pembentukan trombus yg
tdk diharapkan

Aktivasi yg cepat dr sistem fibrinolisis utk

melisiskan trombus & mengawali antikoagulasi
utk meminimalkan pembentukan bekuan lbh
lanjutefektif dlm manajemen keadaan klinis
spt trombosis vena dlm, infark miokard akut, &
emboli pulmoner dimana trombus telah
terbentuk
Uji klinik mendukung penggunaan obat
penghambat fx trombosit pd manajemen peny
CV & stroke

 Among patients with nonvalvular atrial

fibrillation, anticoagulation that results
in an INR of 2.0 or greater reduces not
only the frequency of ischemic stroke
but also its severity and the risk of
death from stroke.

 Figure 1. Pathophysiology of Pulmonary Embolism.

Pulmonary embolism usually originates from the deep veins of
the legs, most commonly the calf veins. These venous thrombi
originate
predominantly in venous valve pockets and at other sites of
presumed venous stasis (inset, bottom). If a clot propagates to
the knee
vein or above, or if it originates above the knee, the risk of
embolism increases. Thromboemboli travel through the right
side of the heart
to reach the lungs. LA denotes left atrium, LV left ventricle, RA
right atrium, and RV right ventricle.

Mekanisme interaksi sistem koagulasi, fibrinolitik, dan

agregasi trombosit lht gb 1
Pemb darah dilapisi sel endotel, yg mrpk permukaan
nontrombogenik
Jk darah mengalami kontak dg jaringan lain atau dg
Ke-2
permukaan benda asing:
proses
berhub
Trombosit diaktifkan oleh,mis. paparan kolagen
sgt erat
Koagulasi darah diinisisasi oleh mis. faktor jaringan
Pembersihan trombi ol sistem fibrinolitik
tergantung pada pembentukan plasmin

Pembuluh darah yg rusak

Adesi trombosit

Inisiasi koagulasi

Trombin

Pelepasan mediator

Fibrin

Agregasi trombosit

Trombus

Gambar 1. Peran trombin

& trombosit & interaksinya
dlm trombosis

Fibrinolisis

Produk degradasi fibrin

Mekanisme Aksi (lanjt)

Agregasi Trombosit
Koagulasi
Fibrinolisis

Gambar 2

Koagulasi
darah tjd sbg
hasil dr
konversi
sequential dari
satu seri
protein mjd
enzim
protease yg
aktif scr
katalitik (gb2)

Proses koagulasi tdr atas 2 jalur: ekstrinsik &

intrinsik
Jk endotelium mengalami kerusakan, darah
mengalami kontak dg sel yg mengekspresikan
faktor jaringan (suatu lipoprotein membran)
bersama F VII mengaktifkan F X mjd Xa
F Xa bersama kofaktor Va & trombosit aktif
mengubah protrombin mjd trombin. Trombin kmdn
mengubah fibrinogen mjd monomer fibrin, yg scr
spontan mengalami polimerisasi mjd bekuan fibrin
Selain membekukan fibrinogen, trombin
mengaktifkan trombosit & mengubah faktor V &
VIII mjd bentuk aktif (Va & VIIIa)
Faktor VIIIa, trombosit aktif bersama IXa
mengubah X mjd Xa mll jalur alternatif (jalur
intrinsik)

 Peristiwa akhir dr proses koagulasi adlh fibrin

cross-linking & fibrinolisis.
Fibrin distabilisasi ol F XIIIa (transglutaminase).
Fibrinolisis yg dikatalisis ol plasmin mencairkan
bekuan.
Kebanyakan enzim yg terlibat dlm koagulasi termsk
dlm serin
protease. Plasma jg mengandung berbagai inhibitor
protease yg mengatur kaskade koagulasi
2 antikoagulan utama, heparin & koumarin
menghambat koagulasi yg menghasilkan hal yg sama
(mis pe< deposit fibrin), ttp dg meknsme kerja yg
sgt berbeda

Heparin diperoleh dr mukosa intestinal babi or

paru2 sapi memp BM 15kDa
Heparin bekerja dg berikatan dg AT-III
(glikoprotein plasma), yg berfx sbg inhibitor utama
enzim pembekuan serin protease
AT-III menghambat serin protease dg membentuk
komplek molar 1:1 stabil. Heparin terikat pada
lysine-rich site dari AT-III, meningkatkan kec
inhibisi, t.u faktor Xa & trombin, jg faktor IXa &
XIa; heparin berdisosiasi dr komplek tsb & dpt
berinteraksi lg dg molekul AT-III yg lain (gambar
3)

Mskpun heparin dosis rendah bekerja t.u dg

menetralisis faktor Xa, pd dosis tinggi bekerja
mencegah aktivasi trombosit, faktor V & VIII
Heparinheterogen; fraksi yg paling kuat terikat
pd AT-III yg menghasilkan efek antikoagulan
paling kuat
Fragmen heparin dg BM rendah memp t1/2 lbh
panjang dibanding heparin standar shg bisa
diberikan dg frek <

Antitrombin III

Gambar 3

heparin

Komplek inaktif

Plasma serin
protease

Komplek ternari

warfarin & dikumarol

Menyerupai mirip struktur vit K & bkrja dg
menghambat regenerasi vit K
Protein tgt vit K termsk faktor pembekuan VII, IX,
& X, protrombin, & protein antikoagulan C & S ke6
ptotein tsb dalam terminal as aminonya memp residu
as glutamat yg mengalami karboksilasi ol enzim
mikrosomal hepar membentuk residu GLA yg berfx
sbg binding site untuk Ca2+.

Koumarin menghambat sintesis faktor pembekuan

fungsional ttp tdk memp efek langsung pd faktor yg
disintesis sblmnya. Dg dmkn kelambatan tjd sblm
efek antikoagualan terlihat scr klinis
Faktor yg pertama menurun: faktor VII,yg memp
t1/2 5 jam, diikuti faktor lain yg memp t1/2 lbh
panj. Efek antikoagulan tercapai sepenuhnya dlm 23 hr
Krn warfarin mempunyai onset antikoagulan yg
lambat, tx heparin dpt diberikan pd 5 hr pertama
akan melawan kemungkinan hiperkoagulasi transien
krn supresi sintesis protein C oleh warfarin

Protein

Residu
glutamat

Protein
residu

Glutamat
karboksilase

karboksi glutamat

Vit K epoksid

Vit K
Epoksid reduktase

Warfarin blok

Aktivasi & kmdn agregasi trombosit mrpk komponen utama

trombosis & mkn terlibat dlm inisiasi trombosis vena
Interaksi trombosit dg kolagen dinding pembuluh darah
mrpk lk pertama dlm agregasi trombosit
Aktivasi trombst ini menyebabkan pembentukan & pelepasan
TXA2 dr as arakhidonat yg tdpt pd fosfolipid membran
trombosit
TXA2 : agregator & vasokonstriktor poten .
Aktivasi trombst jg menyebabkan sekresi ADP dr granula
trombosit. TXA2 & ADP beraksi mll reseptor spesifik
binding site pd membran trombosit utk fibrinogen

Fosfolipid (dari membran sel)

Kortikosteroid

Fosfolipase A2

Bradikinin

Angiotensin
_

Asam Arakhidonat

siklooksigenase

5-lipooksigenase

Leukotrien

NSAID

PGG2

Prostasiklin (PGI2)
PGE2

PGH2
_

Tromboxan A2

Dipiridamol

 Pendekatan tx utama utk mengurangi agregasi

trombosit adlh mll inhibisi siklooksigenase
Aspirin scr irreversibel menghambat
siklooksigenase trombosit shg menghambat
pembentukan TXA2.
Aspirin jg menghambat sintesis PGI2 (inhibitor
agregasi), mskp diduga dosis kecil hy menghambat
TXA2 kurang menghambat biosintesis PGI2

Aspirin:
me insidensi infark miokard & kematian pd
pasien unstable angina,
me insidensi infark miokard pd pasien stable
angina
efektif sbg obat antitrombotik pd pasien yg
menjalani angioplasti koroner atau operasi
bypass
Utk tx pasien transient ischemic attack
Namun dmkn tdpt resiko ulserasi GIT yg doserelated pd penggunaan aspirin jk panjang

 Ibuprofen & indometasin (suatu NSAID)

menghambat siklooksigenase scr kompetitif.
Sulfinpirazon dimetabolisme mjd suatu produk
yg dpt menghambat siklooksigenase
Dipiridamol: antirombotik yg biasanya
digunakan bersama aspirin
Tiklopidin: suatu antitrombosit yg digunakan
utk tx stroke rekuren pd pasien yg intoleran
thd aspirin

Clopidogrel &
Ticlopidine
Clopidogrel and ticlopidine reduce platelet aggregation by inhibiting the ADP
pathway of platelets.
These drugs are thienopyridine derivatives that achieve their antiplatelet effects
by irreversibly blocking the ADP receptor on platelets. Unlike aspirin, these
drugs have no effect on prostaglandin metabolism. Randomized clinical trials
with both drugs report efficacy in the prevention of vascular events among
patients with transient ischemic attacks, completed strokes, and unstable
angina pectoris. Use of clopidogrel or ticlopidine to prevent thrombosis is now
considered standard practice in patients undergoing placement of a coronary
stent.
Adverse effects of ticlopidine include nausea, dyspepsia, and diarrhea in up to
20% of patients, hemorrhage in 5%, and, most seriously, leukopenia in 1%.
The leukopenia is detected by regular monitoring of the white blood cell count
during the first 3 months of treatment. Development of thrombotic
thrombocytopenic purpura (TTP) has also been associated with the ingestion
of ticlopidine. The dosage of ticlopidine is 250 mg twice daily. It is particularly
useful in patients who cannot tolerate aspirin. Doses of ticlopidine less than
500 mg/d may be efficacious with fewer adverse effects.

Clopidogrel has fewer adverse effects than ticlopidine and is rarely

associated with neutropenia.
Thrombotic thrombocytopenic purpura associated with clopidogrel has
recently been reported.
Because of its superior side effect profile and dosing requirements,
clopidogrel is preferred over ticlopidine. The antithrombotic effects of
clopidogrel are dose-dependent; within 5 hours after an oral loading
dose of 300 mg, 80% of platelet activity will be inhibited. The
maintenance dose of clopidogrel is 75 mg/d, which achieves
maximum platelet inhibition. The duration of the antiplatelet effect is
710 days.
Blockade of Platelet Gp IIb/IIIa Receptors
The glycoprotein IIb/IIIa inhibitors are used in patients with acute
coronary syndromes. These drugs target the platelet IIb/IIIa receptor
complex (Figure 341). The IIb/IIIa complex functions as a receptor
mainly for fibrinogen and vitronectin but also for fibronectin and von
Willebrand factor.
Activation of this receptor complex is the "final common pathway" for
platelet aggregation. There are approximately 50,000 copies of this
complex on the platelet surface. Persons lacking this receptor have a
bleeding disorder called Glanzmann's thrombasthenia.

Abciximab, a humanized monoclonal antibody directed against the

IIb/IIIa complex including the vibronectin receptor, was the first agent
approved in this class of drugs. It has been approved for use in
percutaneous coronary intervention and in acute coronary syndromes.
Eptifibatide is an analog of the sequence at the extreme carboxyl
terminal of the delta chain of fi-brinogen, which mediates
the binding of fibrinogen to the receptor.
Tirofiban is a smaller molecule with similar properties.
Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa receptor by
their occupancy of the
receptor but do not block the vibronectin receptor.
The three agents described above are administered parenterally. Oral
formulations of IIb/IIIa antagonists have been developed and are in
various stages of development. Thus far, however, lack of efficacy and
significant thrombocytopenia have prevented progress with the oral
analogs.

Additional AntiplateletDirected Drugs

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting
adenosine uptake and
cyclic GMP phosphodiesterase activity. Dipyridamole by itself has little or
no beneficial effect.
Therefore, therapeutic use of this agent is primarily in combination with
aspirin to prevent
cerebrovascular ischemia. It may also be used in combination with
warfarin for primary prophylaxis
of thromboemboli in patients with prosthetic heart valves. A combination of
dipyridamole
complexed with 25 mg of aspirin is now available for secondary
prophylaxis of cerebrovascular
disease.
Cilostazol is a newer phosphodiesterase inhibitor that promotes
vasodilation and inhibition of
platelet aggregation. Cilostazol is used primarily to treat intermittent
claudication.

Bekuan fibrin dicairkan t.u ol aksi proteolitik dr

plasmin (enzim yg dihasilkan dr aktivasi
plasminogen)
3 aktivator plasminogen yg digunakan scr klinis:
u-PA, streptokinase, & t-PA.
u-PA & t-PA : enzim proteolitik yg memecah
ikatan yg rentan dlm plasminogen utk menghslkan
plasmin

Streptokinase (produk bakterial) membentuk suatu

komplek dg plasminogen yg mmknkan
plasminogen mengaktifkan molekul plasminogen
lain mjd plasmin
Plasmin menyerang tdk hy fibrin, tp jg fibrinogen,
faktor V, & VIII
Obat fibrinolitik dpt msbbkan perdrhan selain
mencairkan bekuan
Human recombinant (ru-PA & rt-PA) memp
keuntungan dibdg streptokinase: kemampuan
selektif utk terikat pd bekuan fibrin
streptokinase >murah, tp > imunogenik & tdk
dpt digunakan scr cepat

Warfarin: antikoagulan yg diberikan peroral

Heparin diberikan infus IV or subkutan
Efek antikoagulan max heparin tjd segera stlh pemberian
dosis tunggal, sdgkan warfarin tjd 36-48 jam.
T1/2 heparin dg BM rendah lbh panj dibanding heparin alami,
shg heparin dg BM rendah efektif diberikan sekali sehari mll
injeksi SC
Warfarin dimetab di liver, terikat kuat pd albumin plasma,
sdgkan heparin tdk
Aspirin dihidrolisis dlm plasma mjd as salisilat, dg t1/2 15-20
mnt. As salisilat lbh lanjut didegradasi di hepar. Efek
antitrombotik aspirin berlgsg minimal 2 hr krn trombosit dlm
sirkulasi tdk dpt mensintetsis siklooksigenase. Trombosit
baru hrs diproduksi utk mengembalikan konsentrasi TXA2

Antikoagulan & antitrombosit digunakan utk

mencegah peny tromboemboli
Heparin efektif utk mencegah & utk tx trombosis
vena & emboli paru
Pd trombosis vena minidose heparin diberikan dg
infus IV kontinus pd dosis yg tdk mempengaruhi
waktu perdarahan in vitro
Dosis > pd proses trombosis yg sdg berlangsung

Respon antikoagulan thd heparin bervariasi

luas pd pasien dg penyakit tromboemboli
Efikasi klinik dioptimalkan jk efek
antikoagulan dipertahankan di atas nilai
minimum yg ditentukan. Resiko perdarahan
me jk dosis heparin dikan APTT digunakan
utk monitor tingkat antikoagulasi.
Antikoagulan oral efektif dlm pencegahan
primer & sekunder tromboemboli vena

Mslh utama yg berhub dg semua obat

antitrombosis adalah perdarahan, mskp
digunakan pd dosis tx
Efek entikoagulan heparin yg berlebihan ditx
dg penghentian obat, jk tjg perdarahan dpt
dibrikan antagonisnya (protamin sulfat)
Pembalikan efek warfarin dpt dicapai dg
tranfusi plasma yg mengandung faktor
pembekuan & pemberian vit K
Perdarahan krn fibrinolisis yg berlbhan dpt
ditx dg asam aminokaproat (Amikar), yg mrpk
inhibitor kompetitif plasmin

Trombositopeni transien (3-15 hr stlh inisiasi tx

heparin) yg tjd krn pembentukan komplek imun
hentikan tx heparin, hitung trombosit akan normal
dlm 4 hr
Heparin adlh anticoagulant of choice pd wanita hamil
& menyusui krn tdk melintasi plasenta shg tdk
menghslkan efek pd fetus.
Antikoagulan oral dpt melintasi plasenta &
menimbulkan abnormalitas SSP atau perdarahan pd
janin
Krn tx warfarin sering berlangsung slm bbrp bulan
hingga tahun, kemungkinan interaksi obat sgt tinggi.
Hal ini krn ikatan albumin plasma yg tinggi & cara
eliminasinya

Heparin: mesbbkan perdarahan, trombositopenia, hipersensitivitas,

hiperkoagulabilitas jika dihentikan
Warfarin : mesbbkan perdarahan, interaksi obat, menginduksi enzim yg
memetabolisme obat, bbrp pasien resisten
Streptokinase: mesbbkan perdarahan dg menyerang fibrinogen & faktor V &
VIII, imunogenik
Urokinase: mesbbkan perdarahan dg menyerang fibrinogen & faktor V & VIII,
mahal
RT-PA: mesbbkan perdarahan dg menyerang fibrinogen & faktor V & VIII, mahal
Aspirin: Iritasi GI tgt dosis, hipersensitivitas, Reyes syndrom pd anak2
Tiklopidin: netropenia reversibel, rash kulit

Obat gangguan
perdarahan

Vit K
Fraksi plasma
Inhibitor fibrinolitik: Asam aminokaproat
Inhibitor Protease Serin: Aprotinin

Vit K
Memberikan aktivitas biologik pd protrombin dan
faktor VII, IX, & X dg berperan dlm modifikasi
posribosomal
Tersedia dlm bentuk tablet 5 mg & ampul 50 mg
efek terlihat setlh 6 jam & komplit stlh 24 jam pd
pengobatan depresi aktivitas protrombin krn
kelebihan warfarin atau defisiensi vit K
Pemberian IV hrs pelan, krn infus cepat dpt
menyebbkan dispnea, chest & back pain, & bahkan
kematian

Vit K
Diberikan pd semua bayi baru lahir mencegah
perdarahan t.u pd bayi prematur
Def vit K sering tjd pd pasien ICU krn diet yg
buruk, nutrisi parenteral, pembedahan, tx
antibiotik multipel, & uremia, bayi dg ibu yg
mendpt antiepilepsi (fenobarbital, primidon atau
fenitoin)
Gagal hepar berat yg menyebabkan sintesis
protein & diathesis hemoragik tdk responsif thd
vit K

Fraksi plasma

Defisiensi faktor koagulasi plasma dpt

menyebbkan perdarahan. Perdarahan spontan tjd
apbl aktivitas faktor < 5% normal
Defisiensi Faktor VIII (hemofilia klasik atau
hemofilia A) & Faktor IX (Christmas disease atau
hemofilia B) penyebab dr kebanyakan defek
koagulasi bawaan
Fibrinogen: utk peny afibrinogenemia & sindrom
defibrinasi
Penggunaan fraksi plasma konsentrat beresiko
penularan penyakit hepatitis & AIDS. Faktor VIII
dan IX rekombinan sdh disintesis & telah terbukti
dpt digunakan scr klinis.

Inhibitor fibrinolitik: Asam

aminokaproat
Asam aminokaproat yg scr kimiawi mirip dg as
amino lisin, adlh inhibitor fibrinolitik sintetik
Scr kompetitif menghambat aktivasi
plasminogen
Diabsorbsi peroral & diekskresi mll ginjal
Asam traneksamat adlh analog Asam
aminokaproat & memp sifat yg mirip

Inhibitor fibrinolitik: Asam aminokaproat

Penggunaan klinik: sbg tx adjuvan pd hemofilia,
sbg tx perdarahan krn obat fibrinolitik, & sbg
profilaksi perdarahan krn aneurisma
intrakranial, perdarahan GIT pasca operasi,
perdarahan pasca prostatektomi, perdarahan
VU
ES al: trombosis intravakular krn inhibisi
aktivator plasminogen, hipotensi, miopati,
diare

Inhibitor Protease Serin:

Aprotinin
Aprotinin adlh inhibitor protease serin yg
menghambat fibrinolisis dg membebaskan
plasmin & mungkin mempunyai efek
antihemoragik lain
Mengurangi perdarahan -sebyk 50%-krn
pembedahan khususnya pd prosedur open
heart, jg pd pasien bypass a. coronaria
Dpt menyebabkan anafilaksi shg tes dg dosis
kecil diperlukan sblm dosis terapeutik
diberikan

Lets Have a Great Year!