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Coagulopathy

Outline

 Basic of Normal Hemostasis (35 minutes) Theera

 Clinical and Laboratory Approach to Bundarika


Bleeding Patients (35 minutes)

 Management of Bleeding Patients Yingyong


(35 minutes)

Question and answer (15minutes) All


Outline

 Dasar normal Hemostasis ( 35 menit ) Theera

 Klinis dan laboratorium Pendekatan Perdarahan Bundarika


Pasien ( 35 menit )

 Manajemen Perdarahan Pasien ( 35 menit ) Yingyong

Pertanyaan dan jawaban ( 15minutes ) All


Normal Hemostasis
Normal hemostasis
 Blood vessel
 Platelet
 Coagulation factors
 Fibrinolytic system
 Natural anticoagulants
Normal Hemostasis
• hemostasis yang normal
• Pembuluh darah
• trombosit
• faktor koagulasi
• sistem fibrinolitik
• antikoagulan alami
Red blood cell
Platelet
Red blood cell
Platelet
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Red blood cell
Platelet
Von Willebrand factor
Fibrin polymer
Red blood cell
Platelet
Von Willebrand factor
Fibrin polymer
Red blood cell
Platelet
Von Willebrand factor
Fibrin polymer
Normal Hemostasis
Blood vessel
 Endothelium
 Connective tissue or collagen
Normal Hemostasis
• Pembuluh darah
• endotelium
• jaringan ikat atau kolagen
Normal Hemostasis
Blood vessel
 Endothelium
Thrombogenesis
Antithrombotic Effect
 von Willebrand factor
 Tissue thromboplastin  Thrombomodulin
 Endothelin  Platelet derived relaxing
factor (PDRF)
 Prostacyclin (PGI2)
 Tissue plasminogen
activator
Normal Hemostasis
Blood vessel
 Endothelium
 Connective tissue or collagen
Normal Hemostasis
• Pembuluh darah
• endotelium
• jaringan ikat atau kolagen
Normal Hemostasis
Blood vessel
 Endothelium
 Connective tissue or collagen

 Collagen direct bind and activate platelet


 Release von Willebrand factor to bind platelet
Normal Hemostasis
Pembuluh darah
• endotelium
• jaringan ikat atau kolagen

• Kolagen mengikat langsung dan


mengaktifkan platelet
• Melepaskan faktor von Willebrand untuk
mengikat trombosit
Normal Hemostasis
Platelet
 Adhesion
 via glycoprotein (GP)
 Shape change
 from disc to ameboid form
 Release
 ADP, thromboxane A2, vWF
 Aggregation
 via glycoprotein (GP)
• trombosit
• Adhesi : melalui glikoprotein ( GP )
• perubahan bentuk: dari disk ke bentuk
ameboid
• Melepaskan : ADP , tromboksan A2 , vWF
• Pengumpulan: melalui glikoprotein ( GP )
Normal Hemostasis
Platelet

ligand receptor
 adhesion vWF GP Ib/IX/V
collagen GP Ia/IIa
 aggregation fibrinogen GP IIb/IIIa
Normal Hemostasis
Platelet

Platelet plug formation and


vasoconstriction

Primary hemostatic plug formation


which is enough to stop bleeding from
small and shallow wound
• Platelet
pembentukan sumbat trombosit dan
vasokonstriksi

pembentukan steker hemostatik primer yang


cukup untuk menghentikan pendarahan dari
luka kecil dan dangkal
Normal Hemostasis
Factor XII
HMWK/PK Coagulation pathway
Factor XI Factor XIa

Factor IX Factor IXa


Factor VIIa
Factor VIIIa Tissue
factor

Factor X Factor Xa
Factor X
Factor Va

Prothrombin
Normal Hemostasis
Factor XII
HMWK/PK Extrinsic pathway
Factor XI Factor XIa

Factor IX Factor IXa


Factor VIIa
Factor VIIIa Tissue
factor

Factor X
Intrinsic pathway Factor Xa
Factor X
Factor Va

Common pathway Prothrombin


Thrombin
Normal Hemostasis
Factor XII
HMWK/PK Coagulation pathway
Factor XI Factor XIa

Factor IX Factor IXa


Factor VIIa
Factor VIIIa Tissue
factor

Factor X Factor Xa
Factor X
Factor Va

Prothrombin
Normal Hemostasis
Factor XII
HMWK/PK Natural anticoagulant
Factor XI Factor XIa

Factor IX Factor IXa


Factor VIIa
Factor VIIIa Tissue
factor heparin
antithrombin
Factor
Activated X
proteinC Factor Xa
Factor X
Protein S
Factor Va

ProteinC Prothrombin
Normal Hemostasis
Fibrinolytic system
High Molecular Weight
Kininogen (HMWK)
Tissue plasminogen act
Prekallekrein (PK)
F.XII UrokinaseFibrin polymer
Plasminogen Plasmin

Fibrin degradation prod


Streptokinase (FDP)
Normal Hemostasis
Fibrinolytic system
• Tinggi Berat Molekul Kininogen ( HMWK )
• Prekallekrein ( PK )
• F.XII
Normal Hemostasis

“New concept !”

Cell-based model of coagulation


(Model berbasis sel koagulasi)
Normal Hemostasis

1. Initiation
Hemostasis occurs on two surfaces:
TF- bearing cells and platelet

IIa (Hemostasis terjadi pada dua permukaan : TF- sel


dan platelet bantalan)

2. 3. Propagation
Amplification
IIa
X prothrombin
VIII/vWF VIIIa
TF VIIa X V
a a
TF-expressing cell thrombinV Va

VIIa TF
I XI XIa
thrombin
X
prothrombin
IXa

platelet

I X
X
XIa IXa VIII X V
a a a
Activated platelet
Hoffman M et al. Blood Coagul Fibrinolysis.
1998; 9(suppl 1): S61-S65.
X prothrombin
VIII/vWF VIIIa
TF VIIa X V
a a
TF-expressing cell thrombinV Va

VIIa TF
I XI XIa
X
prothrombin thrombin
IXa

platelet

I X
X
XIa IXa VIII X V
a a a
Activated platelet

Hoffman M et al. Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65.


Cell-based model “Three
overlapping phases”
 Initiation phase
“TF-bearing cell to generate F.Xa,
F.IXa and (little amount of)
thrombin”
 Amplification phase
“Gererate cofactor F.V and F.VIII by
little amount of thrombin from
initiation phase”
 Propagation phase
• berbasis sel Model " Tiga fase yang
tumpang tindih "
• fase inisiasi " TF - bearing sel untuk
menghasilkan F.Xa , F.IXa dan ( jumlah
sedikit ) trombin "
• fase amplifikasi " Gererate kofaktor F.V
dan F.VIII oleh sejumlah kecil trombin dari
fase inisiasi "
• fase propagasi " Besar jumlah produksi
trombin ( ledakan trombin ) pada platelet
diaktifkan "
Approach to Hemostatic
Disorders:
Clinical and Laboratory Approach
(Pendekatan Gangguan hemostatik : Klinis dan
Laboratorium pendekatan)

Bundarika Suwanawiboon, M.D.


Division of Hematology
Department of Medicine
What is the diagnosis?
Clinical Evaluation of Bleeding Patients
(Evaluasi klinis Bleeding Pasien)

“80% of correct diagnosis can be made by


history taking and physical examination.”
" 80 % dari diagnosis yang benar dapat
dilakukan dengan anamnesis dan
pemeriksaan fisik . "
History Taking
Identify if the bleeding problem is due to
Local vs. systemic defect
Location: single vs. multiple sites
Severity: Spontaneous? Appropriate to trauma?
Hereditary vs. acquired disorder
Onset
Family history
Underlying disease
Medication
Primary vs. secondary hemostatic disoder
sejarah Mengambil
• Mengidentifikasi jika masalah perdarahan adalah karena
• lokal vs cacat sistemik
Lokasi : tunggal vs beberapa situs Keparahan : Spontan ?
Sesuai dengan trauma ?
gangguan diperoleh vs turun-temurun
Serangan
Sejarah keluarga
penyakit yang mendasari
Obat
• Primer vs hemostatik disoder sekunder
Primary Hemostasis Secondary Hemostasis

Onset Immediate Delayed


Sites Superficial Deep
Skin Petechiae, superficial Deep ecchymosis,
ecchymosis hematoma

Mucosal Common Rare

Others Rare Retroperitoneal


hematoma, hemarthrosis
Primary Hemostatic defect Secondary Hemostatic defect
Laboratory Investigation of
Hemostatic Disorders
(Investigasi Laboratorium
Gangguan hemostatik)
Assessment of Primary Hemostasis
Platelet
Complete blood count (CBC)
Bleeding time/ PFA-100
Platelet aggregation study
Blood vessel
Bleeding time
von Willebrand factor (vWF)
Bleeding time
vWF Antigen, vWF: RCO, vWF multimer, FVIII
Penilaian Hemostasis Primer
• trombosit
hitung darah lengkap ( CBC )
Waktu perdarahan / PFA - 100 studi
agregasi platelet
• Pembuluh darah
waktu perdarahan
• Faktor von Willebrand ( vWF ) waktu
perdarahan vWF Antigen , vWF : RCO ,
vWF multimer , FVIII
Complete Blood Count (CBC)
Platelet number
Normal platelet count: 150,000 –400,000/uL
> 100,000/uL Bleeding unlikely
< 20,000/uL ↑ risk for spontaneous
bleeding
Must exclude pseudothrombocytopenia

Assess for platelet morphology


Hitung Darah Lengkap ( CBC )
• jumlah trombosit
jumlah trombosit yang normal : 150.000 -
400.000 / uL
>100.000 / uL Perdarahan mungkin
< 20.000 risiko / uL ↑ untuk spontan
berdarah
Harus mengecualikan pseudothrombocytopenia
• Menilai morfologi platelet
Thrombocytopenia

Giant platelet Pseudothrombocytopenia

Bernard-Soulier Syndrome
Etiology of Thrombocytopenia
Decreased Production
• Hypoproliferation • Aplastic Anemia, Amegakaryocytic
thrombocytopenia, infection, toxins, drugs
Infiltrative marrow disease, TAR
• Ineffective Thrombopoiesis • Megaloblastic anemia
Increased Destruction
• Immune • Alloimmune, Autoimmune: ITP, SLE

• Non-immune • DIC, TTP, HUS


Others
• Splenic sequestration • Hypersplenism
• Dilutional • Massive blood transfusion
Bleeding Time
Bleeding Time: Interpretation
Normal value* : 1-9 min
Prolonged bleeding time:
Thrombocytopenia/ anemia (Hct < 20%)
Hereditary platelet dysfunction
von Willebrand disease
Severe hypofibrinogenemia
Blood vessels disorders
Uremia
Myeloproliferative disorders
Medication: Aspirin, NSAIDs,other antiplatelet drugs
Perdarahan Waktu : Interpretasi
• Nilai normal * : 1-9 min
• Berkepanjangan waktu perdarahan :
Trombositopenia / anemia ( Ht < 20 % )
disfungsi trombosit turun-temurun Penyakit von
Willebrand hipofibrinogenemia parah
Gangguan pembuluh darah
uremia
gangguan mieloproliferatif Obat : Aspirin ,
NSAID , obat antiplatelet lainnya
Platelet Aggregation Study
Normal Platelet Response

Arterioscler Thromb Vasc Biol 2000 20:285


Epinephrine ADP Collagen Ristocetin Arachidonic
acid
Normal +++ +++ +++ +++ +++
Glanzmann’s - - - +++ -
Thrombasthenia
Bernard-Soulier +++ +++ +++ - +++
Syndrome
Storage Pool + +* +* +++ ++
Disease (no secondary wave)
Aspirin + ++ + ++ -
Effect
von Willebrand Factor
Synthesized in endothelial cells and
megakaryocytes

Two important functions:


Carrier protein for plasma FVIII
Ligand binding to platelet GPIb receptor to
initiate platelet adhesion
von Willebrand Factor
• Disintesis dalam sel endotel dan
megakariosit

• Dua fungsi penting : Protein pembawa


untuk FVIII plasma Ligan mengikat platelet
reseptor GPIB untuk memulai adhesi
platelet
Primary Hemostasis: vWF

Arterioscler Thromb Vasc Biol 2000 20:285


von Willebrand Factor Panel
vWF antigen
vWF ristocetin cofactor activity
vWF multimer analysis
FVIII level
von Willebrand Factor Panel
• antigen vWF
• vWF aktivitas ristocetin kofaktor
• analisis multimer vWF
• tingkat FVIII
vWD Laboratory Diagnosis
Test/Type 1 2A 2B 2M 2N 3

BT N or ↑ ↑↑ N or ↑ ↑↑ N ↑↑↑↑
vWF:Ag ↓ ↓ ↓ ↓ or N ↓ or N ↓↓↓↓
vWFR:Co ↓ ↓↓↓ ↓↓ ↓ ↓ or N ↓↓↓↓
LD-RIPA - - ↑ - - -
FVIII N or ↓ N or ↓ N or ↓ N ↓↓↓ ↓↓↓
Multimer N but ↓ abnormal abnormal N but ↓ N but ↓ absent
vWF Multimer Analysis

Hoffmann. 4th Ed.Hematology Basic Principles and Practice


Assessment of Secondary Hemostasis

Screening tests: Additional Tests


PT Fibrinogen
aPTT Thrombin Time
Mixing study Reptilase time
Coagulation factor
assays
D-dimer
Fibrin Degradation
Product
Euglobulin lysis time
Penilaian Hemostasis sekunder

• Tes skrining : • Tes tambahan


• PT fibrinogen
• aPTT • trombin Waktu
• penelitian • waktu Reptilase tes
pencampuran faktor koagulasi
• D - dimer
• Fibrin Degradasi
• Produk Euglobulin
lisis waktu
Accurate Sample Collection is the Key

Always use 3.2% sodium citrate tube and


sent to the lab immediately.
Fill tube to the proper level.
(anticoagulant to plasma ratio = 1:9)
Modification may be required based on Hct
Sodium citrate (ml) = (100 – Hct pt) x 0.5 / 55*
* normal plasma vol.
Koleksi Contoh akurat adalah
Kunci
• Selalu gunakan 3,2 % tabung sodium
sitrat dan dikirim ke laboratorium segera .
• Isi tabung ke tingkat yang tepat . (
Antikoagulan rasio plasma = 1 : 9 )
• Modifikasi mungkin diperlukan
berdasarkan Ht c
• Natrium sitrat ( ml ) = ( 100 - Ht pt ) x 0,5 /
55 *
• * Yang normal plasma vol
Intrinsic Pathway Extrinsic Pathway

XII TF
XIIa

HK/PK
HMWK VIIa VII
XI XIa
XIa Tenase
IX IXa/ VIIa/TF
IX IXa
VIIIa/PL
VIIIa

XX Xa
Xa
Ca++++
Ca
IIII Ca++++
Ca IIa
IIa
Va/PL
Va/PL

Fibrinogen
Fibrinogen Fibrin
Fibrin
XIIIa
Common Pathway X-linkedFibrin
Prothrombin Time (PT)

PT : test extrinsic and common pathway


Activated Partial Thromboplastin Time
(aPTT)

aPTT : test intrinsic and common pathway


Mixing Study
Deficiency Correctable
Normal
coagulation
time
+ 50%

Uncorrectable
Inhibitor
prolonged
0% 100% coagulation
time
Prolonged PT or aPTT occurs when
coagulation factor < 35-40% <35%
Interpretation of Abnormal
Coagulogram

Isolated prolonged PT

Isolated prolonaged aPTT

Prolonged PT and aPTT


Interpretasi Coagulogram
Abnormal
• Terisolasi berkepanjangan PT
• Terisolasi prolonaged aPTT
• Berkepanjangan PT dan aPTT
Isolated prolonged PT

Mixing study

Correctable Uncorrectable

Deficiency Inhibitor

Hereditary: FVII FVII (rare)


Lupus anticoagulant
Acquired:
Early liver impairment
Vitamin K antagonist
Vitamin K deficiency
Isolated prolonged aPTT

Bleeding No bleeding

Mixing study Mixing study

Correctable Uncorrectable Correctable Uncorrectable

Deficiency Inhibitor Deficiency Inhibitor

Factor VIII /vWD Factor VIII Factor XII Factor XII


Factor IX Factor IX HMWK HMWK
Factor XI Factor XI Prekallekrein Prekallekrein
Heparin Lupus
anticoagulant
Acquired FVIII inhibitor
Prolonged aPTT and PT

Mixing study

Correctable Uncorrectable

- FII,FV or FX deficiency - FII, V, or X inhibitor


- FV and VIII deficiency - Lupus anticoagulant
- Liver disease - LAC + Factor inhibitor
- Vitamin K antagonist
- Vitamin K deficiency
- DIC
Bleeding Disorders with
Normal PT and aPTT
Factor XIII deficiency
Dysfibrinogenemia
Mild isolated factor deficiency
a2 -antiplasmin deficiency
Elevated fibrin degradation products
Platelet disorders
Vascular disorders
Perdarahan Gangguan dengan
normal PT dan aPTT
• Faktor defisiensi XIII
• Dysfibrinogenemia
• defisiensi faktor terisolasi ringan
Kekurangan -antiplasmin a2
• produk degradasi fibrin meningkat
• kelainan trombosit
• gangguan pembuluh darah
Further Diagnostic Tests

Specific coagulation factor assay

Coagulation factor inhibitor assay

Lupus anticoagulant panel


Tes Diagnostik lanjut
• koagulasi tertentu assay
• faktor Koagulasi assay
• faktor penghambat panel antikoagulan
lupus
Other Tests for Secondary Hemostasis

Fibrinogen
D-dimer
Fibrin(ogen) degradtion product
Thrombin time
Reptilase time
Euglobulin lysis time
Tes lain untuk Hemostasis
sekunder
• fibrinogen
• D - dimer
• Fibrin ( Ogen ) produk degradtion
• waktu trombin
• waktu Reptilase
• Euglobulin lisis waktu
Fibrinogen
Functional level (200-400 mg/dl)
↓ Fibrinogen (esp. < 100 )
DIC
Fibrinolytic therapy
Primary fibrinolytic state
Congenital afibrinogenemia
Acquired/congenital dysfibrinogenemia
↑ Fibrinogen
Inflammatory states/acute illness
May associated with shortened PT/aPTT
Fibrinogen
• tingkat fungsional ( 200-400 mg / dl )
• ↓ Fibrinogen ( esp . < 100 )
• DIC
• terapi fibrinolitik
• negara fibrinolitik utama
• afibrinogenemia kongenital
• Diakuisisi / bawaan dysfibrinogenemia
• ↑ Fibrinogen
• keadaan inflamasi / penyakit akut
• Mungkin terkait dengan dipersingkat PT / aPTT
D-Dimer
Measured cross-linked fibrin degradation
product by plasmin
More sensitive and specific for fibrinolysis than
Fibrin(ogen) Degradatioin Product (FDP)
↑ D-dimer:
DIC
Acute thromboembolic episodes
Post-trauma or surgery
Malignancy
D-Dimer
• Diukur cross-linked fibrin degradasi produk
oleh plasmin
• Lebih sensitif dan spesifik untuk fibrinolisis
dari fibrin ( Ogen ) Degradatioin Produk (
FDP )
• ↑ D - dimer :
• DIC
• episode tromboemboli akut
• Pasca - trauma atau operasi
• Keganasan
Fibrin(ogen) Degradation Product
↑ levels in
Primary fibrinolytic syndromes
DIC
After lytic therapy
Acute thromboembolic episodes
After injury/surgery
Fibrin ( Ogen ) Degradasi
Produk
• ↑ tingkat di
• sindrom fibrinolitik utama
• DIC
• Setelah terapi litik episode tromboemboli
akut
• Setelah cedera / operasi
Thrombin Time
Thrombin Time (TT)
Assess the ability to convert fibrinogen  fibrin by
adding thrombin to plasma

Prolonged TT:
Inhibitor of thrombin: heparin, anti-thrombin antibody
Hypofibrinogenemia or dysfibrinogenemia
Inhibitor of fibrin polymerization: fibrin degradation
product, paraprotein
trombin Waktu
• Trombin Waktu ( TT ) Menilai kemampuan
untuk mengkonversi fibrinogen fibrin
dengan menambahkan trombin untuk
plasma
• TT berkepanjangan : Inhibitor trombin :
heparin , anti - trombin antibodi
Hipofibrinogenemia atau
dysfibrinogenemia Inhibitor polimerisasi
fibrin : produk degradasi fibrin ,
paraprotein
Euglobulin Lysis Time
Euglobulin fraction of plasma is precipitated by
acetic acid and thrombin added.
Lysis of clot is observed.
Normal : > 120 min
Shortened ELT:
DIC
Liver disease
Primary fibrinogenolysis: malignancy, e.g. prostate
carcinoma
Euglobulin Lisis Waktu
• Euglobulin fraksi plasma diendapkan oleh
asam asetat dan trombin menambahkan .
• Lisis bekuan diamati .
• Yang normal : > 120 min
• ELT disingkat :
• DIC
• Penyakit hati
• fibrinogenolysis utama : keganasan , misalnya karsinoma prostat
Management of
Bleeding Patients
Manajemen Perdarahan Pasien

Yingyong Chinthammitr
27 June 2007
Objectives
• Efficient practice of replacement therapy
• Management of common bleeding
problems
tujuan
• Praktek efisien dari terapi penggantian
• Manajemen masalah perdarahan umum
Goal of replacement Rx
• Treatment of bleeding
• Prevention of bleeding before procedure

• Not treat only lab. esp. in irreversible


causes of coagulopathy
Tujuan dari penggantian Rx
• Pengobatan perdarahan
• Pencegahan perdarahan sebelum
prosedur

• Tidak memperlakukan hanya lab . esp . di


penyebab ireversibel koagulopati
WB = Whole blood
1 unit WB

PRC = Pack Red Cell


PRP = Platelet-rich plasma
PRC PRP

FFP = Fresh frozen plasma


PC = Platelet concentrates
FFP PC (other: apheresis PLT = 4-6 u)

CRP = Cryo-removed plasma,


FFP with cryo.-removed
Cryo. = Cryoprecipitate
CRP Cryo (F VIII 100 u, vWF, Fibrinogen,
F XIII)
Other products
• Factor concentrates : VIII, IX
• Prothrombin complex concentrates (PCC)
• Activated PCC (APCC)
• DDAVP
• Vitamin K injection
• Recombinant F VIIa (novoseven)
• Tranexamic acid – antifibrinolysis
• Fibrin glue – two bottles: Fibrinogen & Thrombin
Produk-produk lain
• Konsentrat faktor : VIII , IX
• Protrombin kompleks konsentrat ( PCC )
• Diaktifkan PCC ( APCC )
• DDAVP
• Vitamin K injeksi Rekombinan F VIIa (
novoseven )
• Asam traneksamat - antifibrinolysis
• Lem fibrin - dua botol : Fibrinogen &
Thrombin
Recombinant Factor VIIa (NovosevenR)

EFFECTIVE+SAFE but VERY EXPENSIVE

- Hemophilia with inhibitor (alloantibody)


- Factor VIII inhibitor (autoantibody)

- Uncontrolled bleeding from coagulopathy (liver


failure)
- Uncontrolled bleeding from thrombocytopenia
- Uncontrolled bleeding from platelet dysfunction
(uremia , congenital defect)
- Severe surgical and traumatic hemorrhage
Rekombinan Factor VIIa ( NovosevenR )
EFEKTIF + AMAN tapi sangat mahal
- Hemofilia dengan inhibitor ( alloantibody )
- Faktor VIII inhibitor ( autoantibodi )
- Perdarahan yang tidak terkontrol dari
koagulopati ( gagal hati )
- Perdarahan yang tidak terkontrol dari
trombositopenia
- Perdarahan yang tidak terkontrol dari
disfungsi platelet ( uremia , bawaan cacat)
- Perdarahan bedah dan trauma berat
X II VIII/vWF VIIIa + free vWF
TFPI Xa
Xa VIIa VIIa XI
TF
TF TF
TF Va IIa
Platelet
V XIa
V
Tissue factor--bearing cell
Va

TF
TF
TF
IX VIIa X
II
IXa
IX
IIa
XI a Xa
VIIIa
VaVa
Activated
Activated
platelet
X II VIII/vWF VIIIa + free vWF
TFPI Xa
Xa VIIa VIIa XI
TF
TF TF
TF Va IIa
Platelet
V XIa
V
Tissue factor--bearing cell
Va

TF
TF
TF

VIIa X
II

IIa
Xa

VaVa
Activated
Activated
platelet
Fibrin Glue
- มี 2 ขวด คือ
1. Thrombin
2. Fibrinogen, F XIII (cryoprecipitate)

Thrombin XIIIa
Fibrinogen ------------->Fibrin ------> Cross-linked
Fibrin
เติม Calcium ใน Thrombin
อาจเติม Tranexamic acid ใน Fibrinogen
ใช้ อุปกรณ์ two syringes with one
air-line
Tranexamic acid
- anti-fibrinolysis
- adjunctive Rx in areas with
high fibrinolysis (Oral cavity,
GI tract, GU tract)
- Contraindication : DIC,
Thrombosis, Renal bleeding
(obstructive uropathy)
- IV : 10 mg/kg/dose q 8 h
- Oral : 25 mg/kg/dose q 8 hr
- Oral wash in dental bleeding
• asam traneksamat
• - Anti – fibrinolisis
• - Ajuvan Rx di daerah dengan fibrinolisis tinggi (
Rongga mulut , saluran pencernaan , GU
saluran )
• - Kontraindikasi : DIC , Thrombosis , ginjal
perdarahan ( uropati obstruktif )
• - IV : 10 mg / kg / dosis q 8 h
• - Oral : 25 mg / kg / dosis q 8 jam
• - Mencuci Oral pendarahan gigi
Bleeding
Berdarah
• Thrombocytopenia
• Coagulopathy
• Combined

• trombositopenia
• koagulopati
• bergabung
Platelet level & Bleeding

• > 100,000/mm3 No bleeding tendency


• < 100,000/mm3 Bleeding time prolongation
• < 50,000/mm3 Bleeding after trauma , surgery
• < 10,000/mm3 Spontaneous bleeding
• < 5,000/mm3 High risk for spontaneous CNS bleeding
tingkat platelet & Pendarahan
• > 100.000 / mm3 ada kecenderungan
perdarahan
• < 100.000 / mm3 Pendarahan waktu
perpanjangan
• < 50.000 / mm3 Perdarahan setelah
trauma , operasi
• < 10.000 / mm3 perdarahan spontan
• < 5.000 / mm3 risiko tinggi untuk
perdarahan CNS spontan
Thrombocytopenia & Bleeding

• Platelet level
• Platelet function
• Anemia
• Local problem
• Coexisting coagulopathy
Trombositopenia & Pendarahan
• tingkat platelet
• fungsi trombosit
• Anemia
• masalah lokal
• hidup bersama koagulopati
Platelet transfusion
• Symptomatic Rx , not Rx cause
• Dose: 1 unit per 10 kg BW
• Indication
– Bleeding associated with thrombocytopenia
– Prophylaxis, before invasive procedure/surgery
• Contra-indication
– TTP (Thrombotic thrombocytopenic purpura)
/HUS (Hemolytic uremic syndrome), HIT
(Heparin-induced thrombocytopenia)
transfusi trombosit
• Gejala Rx , tidak Rx penyebab
• Dosis : 1 unit per 10 kg BW
• Indikasi Perdarahan yang berhubungan
dengan trombositopenia Profilaksis ,
sebelum prosedur invasif / operasi
• Kontra - indikasi TTP ( trombotik purpura
thrombocytopenic ) / HUS ( uremik
hemolitik sindrom ) , HIT ( Heparin
diinduksi trombositopenia )
Prophylaxis in thrombocytopenia
Condition Threshold
Chronic stable thrombocytopenia <5,000 or
(underproduction e.g. aplastic anemia) No

Post-chemo stable patient <10,000


Unstable (fever or infection or <20,000
coagulopathy or platelet dysfunction)

Invasive procedures, surgery <50,000


Neurosurgery, ocular Sx <100,000
Plasma derivatives: FFP, Cryo.

• No medications added
• Return to blood bank if not use within 30 min
• Most adverse transfusion reactions occur in the
first 15 min.
• Time of transfusion – not exceed 4 hr
• Rate in adult (good cardiac condition)
: 200 - 300 mL/hr
• NOT for: volume expansion, protein (alb, glob)
nutrient
turunan plasma : FFP , Cryo .
• Tidak ada obat ditambahkan
• Kembali ke bank darah jika tidak menggunakan
dalam waktu 30 menit
• Kebanyakan reaksi transfusi yang merugikan
terjadi dalam 15 menit .
• Waktu transfusi - tidak melebihi 4 jam
• Tingkat pada orang dewasa ( kondisi jantung
yang baik ) : 200-300 mL / jam
• TIDAK untuk : ekspansi volume , protein ( alb ,
gumpal ) nutrisi
Cirrhosis
• FFP 10-15 ml/kg
• Vitamin K 10 mg IV
• Pitfalls
– Uncorrected localized bleeding problem e.g. varice,
mucosal lesion
– Overdependence on PT
– Goal: to correct or prevent bleeding, Not to achieve a
normal PT
– Timing of FFP therapy before an invasive procedure
Cirrhosis
• FFP 10-15 ml / kg
• Vitamin K 10 mg IV
• perangkap
• Dikoreksi masalah perdarahan lokal mis varice ,
lesi mukosa
• Overdependence di PT
• Tujuan : untuk memperbaiki atau mencegah
perdarahan , Tidak untuk mencapai normal PT
• Waktu terapi FFP sebelum prosedur invasif
Vitamin K deficiency

- Vitamin K : fat-soluble vitamin


- Vitamin K-dependent factors :
II,VII,IX,X ; Protein C,S,Z
- Vit.K : K1(green vegetables), K2(gut
flora), K3(synthetic water-soluble)
Defisiensi vitamin K
• Vitamin K : vitamin yang larut dalam
lemak
• Vitamin K tergantung faktor : II , VII , IX , X
; Protein C , S , Z
• Vit.K : K1 ( sayuran hijau ) , K2 ( flora usus
) , K3 ( sintetik yang larut dalam air )
Vitamin K deficiency

* Neonatal : hemorrhagic disease of the


newborn
* Children & Adult :
- low intake
- absorption defect - cholestasis, fat
malabsorption syndrome
- broad-spectrum antibiotics (+low intake)
Defisiensi vitamin K
• * Neonatal : penyakit hemoragik pada bayi
baru lahir
• * Anak-anak & Dewasa :
• - asupan rendah
• - penyerapan cacat
• - kolestasis , sindrom malabsorpsi lemak
• - antibiotik spektrum luas ( + asupan
rendah)
Vitamin K deficiency
Defisiensi vitamin K

• Vit. K 10 mg IV slowly, sc
• FFP
• Prothrombin complex concentrate (PCC)

• Vit . K 10 mg IV perlahan-lahan , sc
• FFP
• Protrombin kompleks konsentrat ( PCC )
HEMARTHROSIS AND HEMOPHILIC ARTHROPATHY
Hemophilia A
• Cryoprecipitate
• Factor VIII concentrates
• FFP
• DDAVP

Hemophilia B
vWD
• DDAVP • FFP
• Cryoprecipitate • Cryo. Removed Plasma
• F IX concentrates
• F VIII concentrates
• FFP
Hemophilia A
• Kriopresipitat
• konsentrat faktor VIII
• FFP
• DDAVP
Hemophilia B
vWD
• DDAVP • FFP
• kriopresipitat • Cryo . dihapus
• konsentrat F VIII Plasma
• FFP • konsentrat F IX
Rx of Bleeding episodes
in Hemophilia
Site Level (%) Rx Length
Joint 30-40 1 dose
Muscle 30-40 1-3 doses
Hematuria 30-40 1 dose
Retroperitoneal 50 5-7 d
GI 50 5-7 d
Neck 100 7-10 d
Intracranial 100 10-14 d
Hemophilia A with hemarthrosis
• 60 kg.
• Raise F VIII to 30 %
• 1 u/kg raise 2%
• F VIII half life = 12 hr
– Raise 30% -> 15 u/kg = 15x60 = 900 u
– Cryo. 9 bags ( cont. ~5 bags q 12 hr)
Hemofilia A dengan
hemarthrosis
• 60 kg .
• Naikkan F VIII sampai 30 %
• 1 u / kg menaikkan 2 %
• F VIII paruh = 12 jam
• Angkat 30 % - > 15 u / kg = 15x60 = 900 u
• Cryo . 9 tas ( cont. ~ 5 tas q 12 jam )
Hemophilia B with hemarthrosis
• 60 kg.
• Raise F IX to 30 %
• 1 u/kg raise 1%
• F IX half life = 24 hr
– Raise 30% -> 30 u/kg = 30x60 = 1800 u
– FFP 1800 ml. ( cont. 900 ml. q 24 hr)
Hemofilia A dengan
hemarthrosis
• 60 kg .
• Naikkan F VIII sampai 30 % 1 u / kg
menaikkan 2 %
• F VIII paruh = 12 jam
• Angkat 30 % - > 15 u / kg = 15x60 = 900 u
• Cryo . 9 tas ( cont. ~ 5 tas q 12 jam )
Warfarin-associated
coagulopathy & bleeding
• Life-threatening Bleeding
– withhold warfarin, FFP/PCCs, vit. K 5-10 mg.
i.v., provide medical support (e.g. PRC)
• Major, non-life-threatening Bleeding
– withhold warfarin, FFP/PCCs, vit. K 1-10 mg.
i.v., provide medical support (e.g. PRC)

J Thromb Haemost 2006;4:1853-63


koagulopati warfarin terkait &
pendarahan
• Perdarahan mengancam jiwa
- menahan warfarin , FFP / PCCs , vit . K 5-
10 mg . i.v. , memberikan dukungan medis
( mis PRC )
• Mayor , non - mengancam jiwa
Pendarahan
-menahan warfarin , FFP / PCCs , vit . K 1-
10 mg . i.v. , memberikan dukungan medis
( mis PRC )
Warfarin-associated
coagulopathy & No bleeding
INR 4.5-10 INR >10
– Withhold warfarin – Withhold – Withhold warfarin
– Vit. K 1 mg. warfarin – Vit. K 1 mg. i.v.
– Reintroduce at a – Recheck INR – Recheck INR in 24
lower dose on the in 24-48 hr hr
following day
– Recheck INR in
< 72 hr

Identify and correct the cause of elevated INR


Beware of re-thrombosis from overcorrection
J Thromb Haemost 2006;4:1853-63
koagulopati warfarin terkait &
ada perdarahan
INR 4.5-10 INR >10
• menahan warfarin
• Vit . K 1 mg . • menahan warfarin
• Memperkenalkan kembali • Vit . K 1 mg . i.v.
pada dosis yang lebih rendah
pada hari berikutnya • Recheck INR di 24
• Recheck INR di < 72 jam jam
• menahan warfarin
• Recheck INR dalam 24-48 jam
Heparin

• Unfractionated heparin (prolonged APTT)


– Bleeding: hold heparin, protamine (1 mg/100
u heparin)
– No bleeding: hold heparin (Hf. life 1 hr)
• LMWH (normal APTT)
– Bleeding: protamine (neutralize all anti-IIa but
75% of anti-Xa)
Heparin
• heparin tak terpecah ( APTT berkepanjangan )
- Perdarahan : tahan heparin , protamin ( 1 mg /
100 u heparin )
- Tidak ada perdarahan : tahan heparin ( . Hf
hidup 1 hr )
• LMWH ( APTT normal)
- Perdarahan : protamin ( menetralisir semua anti -
IIa namun 75 % dari anti - Xa)
DIC
• Rx cause
• Bleeding
– FFP , PLT concentrate
– Cryoprecipitate raise fibrinogen > 100 mg/dL
:1 bag/5 kg BW raise fibrinogen 100 mg/dL
DIC
• Rx penyebab
• Berdarah
- FFP , PLT konsentrat
- Kriopresipitat meningkatkan fibrinogen >
100 mg / dL : 1 tas / 5 kg BW
meningkatkan fibrinogen 100 mg / dL
Treatment of DIC

* Treat associated disease


* Bleeding - Replacement therapy
* Thrombosis - heparin : purpura fulminans,
acral/dermal ischemia, retained dead fetus
syndrome, giant hemangioma, aortic
aneurysm without rupture, solid tumor
* AT concentrate, APC
• Pengobatan DIC

• Treat penyakit yang berhubungan


• Perdarahan - Terapi Penggantian
• Trombosis - heparin : purpura fulminans , acral /
dermal iskemia , ditahan sindrom mati janin ,
hemangioma raksasa , aneurisma aorta tanpa
pecah , tumor padat
• AT konsentrat , APC
Massive blood transfusion

• > Total blood volume in 24 hour


• Dilution and/or consumption of PLT, Coag.
Factors
• LAB: platelet, coagulogram, fibrinogen
• PLT > 50,000, PT <1.5 times the midpoint
of normal range, Fibrinogen >100 mg/dL
: generally adequate for hemostasis
transfusi darah masif
• > Volume darah total di 24 jam
• Pengenceran dan / atau konsumsi PLT ,
COAG . faktor
• LAB : trombosit , coagulogram , fibrinogen
• PLT > 50.000 , PT < 1,5 kali titik tengah
kisaran normal , Fibrinogen > 100 mg / dL
: umumnya memadai untuk hemostasis
Platelet dysfunction

• Stop Antiplatelet agents before surgery


– Aspirin : 7 days (irreversible inhibition)
– NSAID : 1-4 days (reversible inhibition)
– Clopidogrel : 10 days
• agen berhenti antiplatelet sebelum operasi -----
Aspirin : 7 hari ( irreversible penghambatan )
NSAID : 1-4 hari ( reversible penghambatan )
Clopidogrel : 10 hari
Uremic bleeding
Treatment Regimen Onset Duration
*PRC /LPB Hct ~30% 1h While Hct at this level
*EPO 50-100 U/kg Hct 30% Same
(~6 wk)
*Cryoppt. 10 units 1h 24–36 h[Effective ~ 50%]
*DDAVP 0.3-0.4 mcg/kg 1 h 4–8h
IV or SC
2-3 mcg/kg intranasal
*Conjugated 0.6 mkd IV 6h 14 d (IV)
estrogen 50 mkd po 2d 5 d (PO)
x 5 days
*Dialysis
Thank you for your attention

Question…