Skenario

A ten years old boy was brought to islamic sultan agung hospital's emergency "traditional
circumciser" referral due to his unstoppable bleeding for over than an hour after being
circumcised. from anamnesis, patient has a history of bleeding that is difficult to stop from
his grandmother (maternal line). The doctor gave aid to stop the bleeding and to consider
giving blood component transfusion if the patient continues to bleed

Translate

Seorang anak berusia sepuluh tahun dibawa ke IGD RS Islam Sultan Agung karena telah
melakukan "sunat tradisional" dirujuk karena perdarahan tak terbendung selama lebih dari
satu jam setelah disunat. Dari anamnesis, pasien memiliki riwayat perdarahan yang sulit
berhenti dari neneknya (garis ibu). Dokter memberi bantuan untuk menghentikan pendarahan
dan mempertimbangkan untuk memberikan transfusi darah jika pasien terus menerus
berdarah

1. What the function of Hemostasis?

2. What the difference of Hemostasis and coagulation?
3. How is the mechanism of Hemostasis?
4. What does the blood coagulation process?
5. Describe the component of hemostasis!
6. What is the factor of influence Hemostasis?
7. What are disorder of Hemostasis?
8. What kind of examination to determine Hemostasis disorder?
9. Mention the factors to start blood coagulation?

1. What the function of Hemostasis?

 Menutup kebocoran pembuluh darah
 Membatasi kehilangan darah yang berlebihan
 Memberi kesempatan untuk perbaikan pembuluh darah
FK UI.Buku Ajar Ilmu Penyakit Dalam. Jilid II. Edisi V.

To maintain blood dilution so that the blood flowing in the veins and close damage
blood vessel walls, there by reducing blood loss in the event of damage to blood
vessels
Prof.Dr.I Made Bakta.Hematologi Klinik Ringkas.EGC
Conclusion:
“ If there is trauma in body, hemostasis can help to decrease the bleeding. It also
can to keep stabilization of blood.”

2. What the difference of Hemostasis and coagulation?

“Hemostasis is a process to stop ruptur blood vessels
Coagulation more to process in blood clotting”
 Hemostasis and coagulation are the reaction process to control the bleeding through
the trombosit formation and fibrin clot in injured area

Sylvia A Price. Patofisiologi. 2005. Edisi 6. Jakarta: EGC

“So coagulation and hemostasis have not different. Coagulation is a part of
hemostasis.”

3. How is the mechanism of Hemostasis?

a. Konstriksi pembuluh darah
Ketika pembuluh darah terpotong →otot polos dinding pembuluh berkontraksi
→Kontraksi terjadi akibat adanya spasme miogenik setempat dan berbagai refleks
syaraf →vasokonstriksi utama oleh platelet yang melepaskan vasokonstriktor
yaitu tromboksan A
b. Pembentukan sumbat platelet
- Bila celah yang luka berukuran kecil maka akan dibentuk sumbat platelet
bukan oleh bekuan darah
- Bila uka besar maka trombosist akan bersinggungan dengan pembuluh darah
yang rusak – menempel lalu membengkak – mensekresi sejumlah ADP dan
enzimnya membentuk tromboksan A2 ADP – mengkatifkan agregasi trombosit
– sehingga trombosit semakin banyak dan terbentuk sumbat trombosit yang
awalnya longgar – namun dalam proses pembekuan mulailah ada benang
fibrin – melekat sehingga terbentuk sumbat yang kuat
c. Pembentukan bekuan darah
Bekuan mulai terbentuk 15-20 detik – zat zat aktivator dr dinding
pembulu darah yg rusak akan mengawali aktivasi bekuan – pembuluh yang
luka akan terisi bekuan darah – bekuan akan mengalami retraksi dan
mengalami penutupan luka – trombosit juga memiliki peranan penting
d. Akhirnya terjadi pertumbuhan jaringan fibrosa ke dalam bekuan darah
- Biasanya bekuan yang terbentuk pada luka kecil di dinding pebuluh darah
akan diinvasi oleh fibroblas
- Bila sejumlah besar darah merembes ke jaringan dan terjadi pembekuan
jaringan yg tidak dibutuhkan maka zat khusu yg terdapat dlm bekuan itu akan
mengahancurkan bekuan itu
Buku ajar fisiologi kedokteran edisi 11 . Guyton dan Hall. EGC . Jakarta
a. Sistem Vaskuler

b. Sistem Trombosit
1. Adesi trombosit
2. Agregasi trombosit
c. Sistem Koagulasi
 d. Sistem Fibrinolisis

Buku Ajar Fisiologi Kedokteran, Guyton & Hall Edisi 11

Hematologi Klinik Ringkas, Prof. Dr. I Made Bakta

4. What does the blood coagulation process?

Begins 30 seconds to several minutes after phases I and II have commenced.
- The overall process involves the formation of the insoluble protein Fibrin from the
plasma protein Fibrinogen through the action of the enzyme Thrombin. Fibrin
forms a network of fibers which traps blood cells and platelets forming a
thrombus or clot.
- This process depends on the presence in the blood of 11 different clotting factors
(proteins) and calcium (Factor IV). Ultimately, these factors will generate the
production of Prothrombin Activator (Factor X). Depending on the initial trigger
for the clotting reactions, there are two pathways leading to the formation of the
thrombus; the Extrinsic Pathway and the Intrinsic Pathway.
a) Extrinsic Pathway
Is initiated with material outside of or "extrinsic" to the blood. This material,
Tissue Thromboplastin (Factor III), is released by damaged tissue cells. Factor
III permits the clotting process to take a chemical shortcut. As a result, the
extrinsic pathway is a very rapid process, i.e., within 12 to 15 seconds.
However, the production of Thrombin is low and the resulting clot is small.
This pathway is most effective as a "quick patch" process.
- Damaged tissue releases Tissue Thromboplastin (Factor III).
- Tissue Thromboplastin activates Factor VII (Calcium dependent step).
- Factor VII activates Factor X - Prothrombin Activator (Calcium
dependent step).
b) Intrinsic Pathway
Is initiated by the blood coming in contact with exposed collagen in the blood
vessel wall, i.e., material within the blood or blood vessel wall. This process is
considerably slower (5 to 10 minutes) but results in the formation of larger
amounts of thrombin. This allows the formation of larger clots.
- Factor XII is activated by making contact with exposed collagen
underlying the endothelium in the blood vessel wall.
- Factor XII activates Factor XI.
- Factors XII and XI (contact activation product) jointly activate Factor IX.
- Factor IX activates Factor VIII.
- Factor VIII together with Calcium ions and Factor III from platelets
(Platelet Thromboplastin) activate Factor X - Prothrombin Activator.
Since Factor III is released from activated platelets, the completion of the
Intrinsic Pathway depends on there being an adequate number of platelets
in circulation.

It should be noted that both pathways lead to the same reaction, namely, the
activation of Factor X - Prothrombin Activator. From this point on, both
pathways follow the same course to Fibrin formation. For this reason the steps
from Factor X activation to Fibrin formation are referred to as the Common
Pathway.
 Common Pathway
a. Factor X (active) engages in a series of reactions with Factor V,
Calcium ions and phospholipids derived from platelets. This
composite of clotting factors and their reactions is referred to as the
Factor V Complex or Prothrombin Activator.
b. Factor V Complex initiates the conversion of Prothrombin to active
form of the enzyme Thrombin.
c. Thrombin accelerates the formation of Fibrin threads from
Fibrinogen (Factor I).

http://faculty.ucc.edu/biology-potter/hemostasis.htm
 http://web.squ.edu.om/medLib/MED_CD/E_CDs/oral%20medicine/docs/ch17.pdf

1. Injured skin caused the blood out of the vessels. Platelets also come out with blood
and then touching the rough surfaces and cause platelet rupture. Platelets will secrete
a substance (enzyme) called trombokinase.
2. Trombokinase will go into the blood plasma prothrombin and will transform into an
active enzyme called thrombin. The changes affected calcium ion (Ca ² +) in the
blood plasma. Prothrombin is a protein that is soluble compound containing blood
globulin. This substance is an enzyme that has not actively formed by the liver.
Formation is assisted by vitamin K.
3. Thrombin that is formed will change into benangbenang firbrinogen fibrin. The
formation of fibrin threads will cause the wound closed so that blood does not flow
out again. Fibrinogen is a protein that is soluble in the blood.
(Hoffbrand AV, Moss PAH, Pettit JE. Essential Haemotology. 5th ed. Massachusetts:
Blackwell; 2006. p.267-75.)

5. Describe the component of hemostasis!

Important components involved in hemostasis process consists of:
• Blood vessels
Permeability, fragility and vasekontriksi are properties owned by vascular
• Platelets
In ultrasutruktu, platelets consist of:
Peripheral Zone
Consisting of glikokalik, an extra membrane that is located in the outermost part;
plasma membrane and inside there are deeper there is an open channel system

Sol-gel zone
Consists of microtubules, microfilaments, dense tubular system (containing adenine
nucleotides and calcium). Moreover, there are also trombostenin, a protein essential
for the function of the contractile

Organelles Zone
Consists of dense granules, mitochondria, and release granules containing fibrinogen
A, PDGF, lysosomal enzymes

• cascade of coagulation factors

 Factor Koagulasi

Faktor I : fibrinogen - perkursor fibrin (protein terpolimerasi)

Faktor II : protrombin - prekursor enzim proteolitik trombin dan
mungkin akselerator lain pada konversi protrombin
Faktor III : tromboplastin - aktivator lipoprotein jaringan pada protrombin
Faktor IV : kalsium - diperlukan untuk aktivasi protrombin dan
pembentukan fibrin
Faktor V : akselerator plasma globulin
Faktor VII : faktor stabil, akselarator konversi protrombin serum
Faktor VIII : Faktor antihemofilik A
Faktor IX : faktor Chirstmas, Faktor B
Faktor X : Faktor stuart, faktor stuart power
Faktor XI : Prekursor tromboplastin plasma
Faktor XII : Faktor Hageman
Faktor XIII : faktor stabilisasi fibrin
PK : Prekallekrein, Faktor Fletcher
HMWK : High Molecular Weight Kininogen, Fitzgerald Factor

(Patofisologi, Price & Wilson)

• Inhibitors of coagulation
a. coagulation inhibitor
Inhibitor is to limited the over coagulation so the fibrin form just in injured area.
Kind of inhibitor coagulation
- AT III
o Consist of glikoprotein that synthesize by hepar.
 o As the resist of factor IIa, Xa, IXa, XIa, XIIa, and kalikrein.

-Protein C
o As the resist of factor Va and VIII

- Protein S
o Sintesize by hepar and depend on vit. K
o As the cofactor of protein C

• Fibrinolysis
Fibrinolysis system function destroys fibrin clot
(Buku ajar ilmu penyakit dalam Jilid 2 Edisi IV)

6. What is the factor of influence Hemostasis?

Faal koagulasi ( komponen vaskuler, komponen trombosit, komponen koagulasi) :
berakhir dengan pembentukan fibrin stabil.
Faal fibrinolisis ( komponen fibrinolisis ) : berakhir dengan pembentukan plasmin.
Sumber : hematologi klinik ringkas.

a. Sistem vaskular
Luka endotel rusak kolagen terpapar adhesi trombosit trombosit
teraktivasi perubahan bentuk trombosit reaksi pelepasan  agregasi
trombosit sumbat trombosit

Luka sel endotel melepas (5 hidroksitriptamin, serotonin, epineprin)

vasokontriksi aliran darah berkurang perdarahan berhenti.

b. Trombosit(FAAL TROMBOSIT)
Reaksi adhesi segera setelah terjadi luka pada pembuluh darah, sel-sel
trombosit beradhesi pada jaringan kolagen subendotelial pada tempat luka
tersebut. Agar faal adhesi dapat berlangsung baik diperlukan 2 hal, yaitu:
adanya faktor von willebrand yang cukup dan adanya fosfolipid yang adekuat
pada lapisan permukaan trombosit.
Reaksi release kontak anatara sel trombosit dengan jaringan kolagen
subendotelial atau trombin dapat merangsang terjadinya reaksi release ini.
Pada reaksi ini ADP, serotonin, faktor IV trombosit dan tromboksan A2
dikeluarkan melalui open ended canalicular system. Tromboksan dan
serotonin menyebabkan vasokontriksi lokal sedang ADP menyebabkan reaksi
agregasi.
Reaksi agregasi zat ADP dan juga tromboksan-A2 menyebabkan trombosit
beragregasi pada tempat luka. Dengan demikian terbentuklah platelet plug dan
perdarahan dapat berhenti.
Aktivitas prokkoagulan salah satu aktivitas prokoagulan yang penting ialah
produksi faktor III trombosit (PF-3), yaitu suatu fosfolipid yang dihasilkan
oleh lapisan permukaan trombosit. PF-3 ini berperan penting pada proses
hemostasis sekunder (koagulasi).
 Reaksi fusi ADP kadar tinggi, beberapa enzim dan trombostenin
menyebabkan trombosit yang telah beragregasi mengadakan fusi secara
ireversibel
(Buku Ajar Ilmu Penyakit Dalam Jilid II, FKUI)

c. Faktor koagulasi darah

Faktor I fibrinogen
Faktor II protrombin
Faktor III faktor jaringan
Faktor IV kalsium
Faktor V faktor labil, Ac-globulin
Faktor VII faktor stabil, akselarator konversi protrombin serum
Faktor VIII Faktor antihemofilik
Faktor IX faktor Chirstmas, Faktor B
Faktor X Faktor stuart, faktor stuart power
Faktor XI Prekursor tromboplastin plasma
Faktor XII Faktor Hageman
Faktor XIII faktor stabilisasi fibrin
Faktor Fletcher prekalikrein
Faktor fitzgerald kininogen dengan berat molekul besar trombosit
(Fisiologi Kedokteran, Guyton n Hall)

d. Fibrinolisis dan akhirnya perbaikan jaringan

Fibrinolisis adalah respon hemostatik yang normal terhadap kerusakan vaskular.
Plasminogen diubah menjadi plasmin oleh aktivator2 baik dari dinding pembuluh
darah atau dari jaringan. Jalur yang terpenting terjadi setelah pelepasan aktivator
plasminogen jaringan dari sel endotel. Proses ini meningkatkan kemampuannya
untuk menguabah plasminogen yang terikat pada trombus menjadi plasmin. Kerja
tPA yang bergantung pada fibrin ini sangat membatasi pembentukan plasmin oleh
tPA pada bekuan fibrin. Pelepasan tPA terjadi setelah stimulus. Protein C aktif
merangsang fibrinolisis dengan menghancurkan inhibitor tPA dalam plasma.
Trombin menghambat fibrinolisis dengan mengaktifkan inhibitor fibrinolisis yang
diaktifkan trombin.

Urokinase adalah suatu tPA yang awalnya disolasi dari urin manusia. Plasmin
mampu memecah fibrinogen, fibrin, faktor V, VIII, serta banya protein lain.
Pemecahan ikatan peptida pada fibrin dan fibrinogen menghasilkan berbagai
produk degradasi. Fragmen terkecil D dan E dapat dideteksi dalam jumlah besar
dalam plasma pasien dengan KID.

(Kapita Selekta Hematologi, A.V.Hoffbrand)

7. What are disorder of Hemostasis?

• hemophilia A and B
• Thrombocytopenia
This autosomal recessive disorder caused due to the failure of the primary platelet
aggregation deficient membrane glycoprotein IIb and IIIa . This situation usually
occurs in the neonatal period and usually fail to aggregate platelets in vitro to each
agonist .
• Von Willbrade Disease
Von Willebrand disease is a hereditary bleeding disorder caused by a deficiency of
von Willebrand factor ( FVW ) . FVW helps platelets adhere to the vessel walls and
wench with each other , which is necessary for normal blood clotting .
• Idhiophatic Thrombocoytophenic Purpura ( ITP )
The highest incidence is estimated to occur in women aged 15-50 years . ITP is the
most common cause of anemia or thrombocytopenia without neutropenia.biasanya are
idiopathic but can be found associated with other diseases ( systemic lupus
eritromatosus , HIV , CLL , Hodgkin 's disease , etc. )
pathogenesis :
Sensitization of platelets by autoantibodies ( usually IgG ) cause the premature
removal of platelets from the circulation by the reticuloendothelial system
macrophages , particularly limpa.masa platelet life is 7 days but in case of ITP
lifetime is shortened into a few hours .
• Trombopati
• Disseminated Intravascular Coagulation ( DIC )

Sumber : Bakta, I Made, Hematologi Klinik Dasar, EGC, 2006; Jakarta

 Hemofili A dan B
 Trombositopenia
Kelainan resesif autosomal ini menyebabkan kegagalan agregasi trombosit primer
karena terjadi defisiensi glikoprotein membran Iib dan IIIa. Keadaan ini biasanya
muncul pada masa neonatus dan biasanya trombosit gagal beragregasi secara in
vitro terhadap setiap agonis.
 Von Willbrade Disease
Penyakit von Willebrand adalah kelainan pendarahan herediter disebabkan oleh
defisiensi faktor von Willebrand ( FVW ). FVW membantu trombosit melekat
pada dinding pembuluh dara dan antara sesamanya, yang diperlukan untuk
pembekuan darah yang normal.
 Idhiophatic Thrombocoytophenic Purpura ( ITP )
Insidensi tertinggi diperkirakan terjadi pada wanita usia 15-50 tahun. ITP adalah
penyebab tersering trombositopenia tanpa anemia atau neutropenia.biasanya
bersifat idiopatik tetapi dapat ditemukan terkait dengan penyakit lain (lupus
eritromatosus sistemik,HIV,CLL,penyakit hodgkin,dll)
Patogenesis :
 Sensitisasi trombosit oleh autoantibodi (biasanya IgG) menyebabkan
disingkirkannya trombosit tersebut secara prematur dari sirkulasi oleh makrofag
sistem retikuloendotel,khususnya limpa.masa hidup trombosit adalah 7 hari
namun pada kasus ITP masa hidup ini memendek menjadi beberapa jam.
 Trombopati
 Disseminated Intravaskuler Coagulation ( DIC ) = Koagulasi Intravaskular
Menyeluruh
Sumber : Bakta, I Made, Hematologi Klinik Dasar, EGC, 2006; Jakarta
- Vascular disorder = skin and mucosa bleeding, bleeding can classified by alergik
and nonalergik purpura
 Nonalergik purpura = this disease not cause by alergik but
vasculitis(inflammation of blood vessel) so it can destroy
the blood vessel integrity for example in lupus eritematosus
sistemik
 Alergik purpura = this disease cause by the imunologik
destruction of blood vessel that it form the petechiae in the
body. In the children usually appear the symptoms like in
digestive track, arthritis. The patient hit by infection and
then cause the rupture of blood vessel
Sylvia A Price. Patofisiologi. 2005. Edisi 6. Jakarta: EGC

Defisiensi pada faktor-faktor akan menyebabkan :

factor clinical syndrome cause
deficiency
I Afibrinogenemia depletion during pregnancy with
premature detachment of the placenta ;
congenital (rare)
II Hipoprotrombinemia decrease in the synthesis by the liver;
usually secondary to vitamin K
deficiency
V Parahemofilia Congenital
VII Hipokonvertinemia Congenital
VIII Hemofilia A Congenital defects caused by various
kinds of keainan gene on the X
chromosome that codes for faktoe VIII ;
because the disease is inherited as a sex-
linked trait
IX Hemofilia B Congenital
X Def Stuart-Power Congenital
Factor
XI Def PTA Congenital
XII Ciri Hageman Congenital

Buku Ajar Fisiologi Kedokteran, William F. Ganong

8. What kind of examination to determine Hemostasis disorder?
 Anamnesis dan pemeriksaan fisik
a. Mencari riwayat perdarhan abnormal
b. Mencari kelainan yang mengganggu hemostatis, contoh penyakit hati kronik,
SLE (systemic lupus erythematosus), gagal ginjal kronik, keganasan
hematologik.
c. Riwayat pemakaian obat
d. Riwayat perdarahan dalam keluarga
 Tes Penyaring
a. Tes untuk menilai pembentukan hemostatic plug
- Platelet count
- Apusan darah tepi
- Tes torniquet
b. Tes untuk menilai pembentukan thrombin
- APTT (activating plasma thromboplastin time) menilai instrinsik
pathway
- PPT (plasma prothrombin time)- extrinsic pathway
c. Tes untuk menilai reaksi thrombin-fibrinogen
- Thrombin time
- Stabilitas bekuan dalam salin fisiologik dan 5 M urea
d. Tes parakoagulan
 Tes Khusus
- Tes faal trombosit
- Tes Ristocetin
- Faktor pembekuan
- Pengukuran alpha-2 antiplasmin
 History and physical examination
a. Finding a history of abnormal perdarhan
b. Look for abnormalities that interfere with hemostatic, examples of chronic
liver disease, SLE (systemic lupus erythematosus), chronic renal failure,
hematological malignancy.
c. A history of drug use
d. Family history of bleeding in
 Test Filters
a. Tests to assess the hemostatic plug formation
- Platelet count
- Peripheral blood smear
- Test torniquet
b. Tests to assess the formation of thrombin
- APTT (activating plasma thromboplastin time) assess the intrinsic
pathway
 - PPT (plasma prothrombin time) - extrinsic pathway
c. Tests to assess the thrombin-fibrinogen reaction
- Thrombin time
- Stabikitas clot in physiological saline and 5 M urea
d. Test parakoagulan
 Special Tests
- Tests of platelet function
- Test ristocetin
- Clotting factor
- Measurement of alpha-2 antiplasmin
Prof.Dr.I Made Bakta.Hematologi Klinik Ringkas.EGC

9. Mention the factors to start blood coagulation?

 protein yg menghambat enzim proteolitik ~ Inhibitor Protease :

 Antitrombin III (AT III)
- Hambat : Trombin,Plasmin,Kalikrein,XIIa,XIa,Xa,IXa,VIIa
- Cofaktor Heparin
 α-2 Makroglobulin (Spektrum paling luas)
- Membentuk komplek dengan enzim proteolitik  aktivitas turun
 C1 Inhibitor
- Hambat : C1 ( fungsi utama)
- Hambat : XIIa,XIa,Kalikrein
 α1 Antitripsin  paling tinggi kadarnya di dalam plasma
- Inaktifkan trombin, XIa, Kalikrein, HMWK
 Protein C
Inaktifkan Va, VIIIa
- Beredar dalam bentuk tidak aktif  diaktifkan oleh trombin dg
adanya cofaktor trombomodulin yg dikeluarkan sel endotel
- Bentuk aktif  memecah Va, VIIIa  non aktif (cofaktor protein S)
Hemostasis definitif tercapai apabila fibrin yang dibentuk oleh koagulasi darah
ditambahkan pada massa trombosit tersebut serta oleh retraksi atau pemadatan bekuan
yang diinduksi oleh trombosit.

- Aliran Darah : Mengencerkan faktor pembekuan darah aktif dari tempat luka
Mekanisme Pembersihan seluler
- Hati  bersihkan faktor pembekuan aktif 
sirkulasi darah menghilangkan  tromboplastin jaringan fibrin
Hepatosit  menghilangkan F IXa, Xa, VIIa