DIATHESIS HAEMORRHAGIC

dr. H. Irza Wahid, SpPD-KHOM, FINASIM

SubBagian Hematologi Onkologi Medik
Bagian Ilmu Penyakit Dalam
FK UNAND / RSUP Dr M Djamil Padang
 HEMOSTASIS HOMEOSTASIS
Sistem Vaskular (Primary Hemostasis 1)
Proses kontraksi pembuluh darah (vasokonstriksi) serta aktivasi trombosit
dan pembekuan darah.
Sistem Trombosit (Primary Hemostasis 2)
Pembentukan dan stabilisasi sumbat trombosit melalui beberapa tahap
yaitu adesi trombosit, agregasi trombosit dan reaksi pelepasan
Sistem Pembekuan Darah (Secondary Hemostasis)
Rangkaian reaksi enzimatik yang melibatkan protein plasma yang disebut
sebagai faktor pembekuan darah, fosfolipid dan ion kalsium.

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 1. THE PRIMARY HAEMOSTATIC SYSTEM:
Primary haemostasis
Platelet aggregation

trombosit
Adhesion
endothelial cells
Activation
sub endothelial tissue

Vascular Aggregation
injury
White clot

Formation of
platelet plug

exposed sub
3
endothelial tissue
Raju et al., 2008
 2. SECONDARY HAEMOSTASIS

Prothrombin Thrombin Activation of the

Factor Xa coagulation cascade
Intrinsic Fibrinogen Fibrin
leads to generation of
Pathway Extrinsic thrombin and, in turn,
(colagen) Pathway (TF)
fibrin

Coagulation cascade
leads to clot formation

Clot
growth
Fibrin threads

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 Sistem Fibrinolisis
INTRINSIK EXTRINSIK EKSOGEN

XIIA, KALIKREIN UROKINASE

T-PA
AKTIFATOR PLASMINOGEN
(PAI-1)

PLASMINOGEN TERIKAT PLASMIN TERIKAT FIBRIN

FDP

PLASMINOGEN BEBAS PLASMIN BEBAS FIBRINOGEN

FC V, FC VIII

ANTI PLASMIN
RAHAYUNINGSIH,2009
HEMOSTASIS

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 PERDARAHAN NORMAL
Luka akibat cedera pembuluh darah adanya
trauma Normal
Luka karena operasi / sunatan / cabut gigi Normal
Haid / Menstruasi Normal
Perdarahan saat melahirkan Normal
 Manifestasi Perdarahan Abnormal
Terbagi 2 :
1. Perdarahan ke dalam kulit atau jaringan petekia, purpura, ekimosis,
hematoma
2. Perdarahan dg gejala darah keluar dari tubuh epistaksis, perdarahan
gusi, hematemesis, melena, hematuria dan metroragia

Faktor yg mempengaruhi derajat perdarahan :

Individu
Derajat abnormalitas konsentrasi faktor dan atau fungsi faktor koagulasi
Jenis faktor koagulasi yang dipengaruhi/defisiensi
Heterozigot atau homozigot

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 hematoma
 petechia-spotted
(macula)
MACULA-
HEMATOMA
VASCULITIC
PURPURA
 PERDARAHAN ABNORMAL???
TELUSURI PENYEBABNYA.

Vaskular

Trombosit Koagulasi
SCREENING TESTS FOR BLEEDING DISORDERS

Test Abnormality detected

Blood count and film Anaemia, leukaemia, disseminated
intravascular coagulation
Platelet count Thrombocytopenia
Activated partial thromboplastin time Deficiency of all coagulation factors
except VII, especially follows VIII and
IX;
heparin
Prothrombin time Deficiency of factors I, II, V, VII, and
X;
warfarin
Thrombin time or fibrinogen Hypofibrinogenaemia or
dysfibrinogenaemia; heparin; fibrin
degradation products
Bleeding time Test of platelet-vessel wall interaction
 KELAINAN PEMBULUH DARAH

I. Keturunan
Telangiectasiae (Rendu-Osler-Weber disease)
Aneurysm of fine vessels
Ehlers-Danlos syndrome, Marfans syndrome,
retinocerebral angiomatosis (von Hippel-Lindau
syndrome), encephalotrigeminal angiomatosis (Sturge-
Kalisher-Weber syndrome)
II. Didapat
Hemorrhagic vasculitis Henoch-Schnlein purpura
Immune vasculitis
Systemic vasculitis
Avitaminosis of vitamin C
 KELAINAN TROMBOSIT

Thrombocytopenia (decrease in the number of platelets)

I. Werlhofs disease - autoimmune thrombocytopenic purpura
II. Symptomatic
Immune (heteroimmune, isoimmune,)
Toxic (in phosphorus poisoning etc.)
Methaplastic (in hematological malignancies or myelocarcinosis)
Drug-induced (cytostatics)
Thrombocytopathy
I. Congenital (deficiency of platelet membrane glycoprotein)
Glanzmann's Thrombasthenia
II. Acquired (normal platelet count in blood and bone marrow but its
functions are decreased)
Drugs (after intake of antiplatelet agents: aspirin, Ticlide);
Immune, toxic, septic processes;
Hematological malignancies and anemias
 KELAINAN FAKTOR PEMBEKUAN

Congenital disorders
Von Willebrand disease MC with minimal bleeding
Factor VIII Deficiency - Hemophilia A or Classic
Type
Factor IX Deficiency Hemophilia B
Acquired disorders
Vit. K deficiency
Oral anti-coagulants
Coumarin derivatives = warfarin inhibit Vit. K
factors
Liver diseases synthesis of factors
THROMBOSIS
INTRODUCTION

Thrombosis is still the main problem in

the world.

High morbidity.

High mortality.

Preventable.
 INCIDENCE OF THROMBOSIS IN US

Disease US incidence Total in US /year Definable

/100.000 cases reason

Deep Vein Thrombosis 159 398.000 80%

Pulmonary Embolus 139 347.000 80 %
Fatal Pulmonary Emb. 94 235.000 80 %
Myocardial Infarction 600 1.500.000 67 %
Fatal MI 300 750.000 67 %
Cerebrovascular thromb. 600 1.500.000 30 %
Fatal Cereb. Trhromb. 396 990.000 30 %
Total serious thromb. In US 1498 3.742.000 50 %
Total deaths from above thrmb. 790 1.990.000 50 %

Bick RL, Clin Appl Throm Hemos 3, Suppl 1, 1997

 CV thrombosis Other causes
1,000,000 400,000

COPD Leading causing Cancer

90,000 Mortality in the USA 500,000

Pulmonary disease/flu Trauma/accident

80,000 90,000

Semin Thromb 21,Sup 1, 2000

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 PATHOPHYSIOLOGIC OF THROMBOSIS

Triad of Virchow

Abnormality of Abnormality of Abnormality of

Vessel wall Blood flow The blood

Plaque Venous Shears stress Venous Platelet Hyper

ruptures Hypotonia Shears rate stasis hyper coagulability state
Turbulence aggregation Thrombophilic state
Fibrinolysis deficient
Thrombocytosis

Arterial Venous Arterial Venous Arterial

Thrombosis Thrombosis Thrombosis Thrombosis Thrombosis

Endothelial Hyper Venous

Perturbation viscosity Thrombosis
Hyper
fibrinogenemia
 THROMBOSIS IS THE FORMATION OR PRESENCE OF A BLOOD CLOT
INSIDE A BLOOD VESSEL OR CAVITY OF THE HEART

Fibrin RBCs Platelets Fibrin RBCs Platelets

Arterial Trombosis Vein Trombosis

White Thrombus Red Thrombus

 ARTERIAL THROMBOSIS

1. Stroke non haemorrhagic/

TIA, migraine
2. Myocardial
infarction/unstable angina
3. Acute abdomen (mesenterial
thrombosis )
4. Fetal loss syndrome/
recurrent miscarriage
5. Loss of vision
6. Loss of hearing
7. Gangrene

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 RISIKO TROMBOSIS ARTERIAL

Kelainan vaskular Kelainan aliran Kelainan koagulasi

Aterosklerosis Aterosklerosis Antiphospholipid syndrome
Merokok Hyperviscosity Sticky platelet syndrome
Hypertensi syndromes Cancer procoagulant (CP)
Diabetes Mellitus Hyperglisemia Protein S defects
Obesitas Hyperlipidemia Protein C defects
Riwayat keluarga positif Polycythemia APC resistance (factor V Leiden)
High Lipoprotein(a) Leukostasis Antithrombin defects
High Low-density syndromes Heparin cofactor II defects
lipoprotein Dysfibrinogenemia Plasminogen defects
High Kolesterol Tissue plasminogen activators
Hypertriglyceridemia defects
Defisiensi estrogen Plasminogen activator inhibitor
Hyper Homocystinemia defects
Kepribadian (stress) Factors XII defects
 TROMBOSIS VENA
VTE: A STRONG RELATIONSHIP BETWEEN
DVT AND PE
Almost 50% of patients with
proximal DVT of the leg Migration
have asymptomatic PE1

Embolus
DVT (mainly asymptomatic)
is found in around 80% Thrombus
of patients with PE2

1. Pesavento R, et al. Minerva Cardioangiologica. 1997;45:369375

2. Girard P, et al. Chest. 1999;116:903908
 COMPLICATIONS OF VTE:
LEG ULCER, A SEVERE CONSEQUENCE

Annual incidence of leg ulcer after a DVT = 12%1

Venous ulcer, a highly chronic condition:1

Cases not healed at 4 months: 50%
2 years: 20%
5 years: 8%
Around 60% of patients have two or more recurrences of venous
ulcer

Venous ulcer, a very costly disease:

Direct medical costs if no healing at 12 weeks
US$10,0002
1. Kurz X, et al. Int Angiol. 1999;18(2):83102
2. Blair SD, et al. BMJ. 1988;297:11591161
 Diagnosis
1. Anamnesis Riwayat penyakit (Faktor risiko
medis & bedah), Manifestasi klinis
2. Pemeriksaan fisik
3. Pemeriksaan Laboratorium
4. Pemeriksaan lain:
ANGIOGRAFI (Golden Standard)
USG/ Doppler
Duplex scan
Impedance Plethysmography
 PLATELET FUNCTION TEST
FOR ARTERIAL THROMBOSIS

* LIGHT THROMBOCYTE AGGREGOMETRY (LTA)

STILL A GOOD STANDARD
AGONIS : ADP, AA, EPINEPHRIN, RISTOCETIN, COLAGEN

* FLOWCYTOMETRY
GLYCOPROTEIN IA, IIA, VI, THROMBIN RESEPTOR (PAR 1)
CLASSICAL AGONIS, DENSE GRANUL, ANIONIC PHOSPOLIPID

* MEASUREMENT OF ADENIN NUCLEOTIDES

* WB AGGREGOMETRY

* ELISA / RIA / WESTERN BLOT

THROMBOGLOBULIN BETA
PLATELET FC IV
 COAGULATION FUNCTION TEST
FOR ARTERIAL AND VENOUS THROMBOSIS

* PROTHROMBIN TIME (PT) INR

FIRST PROPOSED BY QUICK IN 1935
FUNCTION OF THE TISSUE FACTOR PATHWAY ( EXTRINSIC PATHWAY).
ADDING TISSUE FACTOR AND PHOSPHOLIPIDS TO PLASMA AND THEN MEASURING
THE TIME IN SECONDS TO CLOT FORMATION FOLLOWING THE
ADDITION OF CALCIUM.
* ACTIVATED PARTIAL THROMBOPLASTIN TIME (APTT)
FUNCTION OF THE CONTACT-FACTOR PATHWAY ( INTRINSIC PATHWAY )
FVIII, FIX, FXI, AND FXII), AS WELL AS THE COMMON PATHWAY (I, FII, FV, FX).
THE APTT IS THE TIME TO CLOT IN SECONDS WHEN CONTACT ACTIVATOR AND
PHOSPHOLIPIDS ARE ADDED TO PLASMA IN THE PRESENCE OF CALCIUM
* THROMBIN TIME (TT)
ADDING EQUAL VOLUMES OF PLASMA AND THROMBIN AND MEASURING THE
AMOUNT OF TIME UNTIL A CLOT FORMS.
THE TT IS SENSITIVE TO HEPARIN, DIRECT THROMBIN INHIBITORS AND TO DEFECTS
AND DEFICIENCIES OF FIBRINOGEN.
* FIBRINOGEN
* D- DIMER
* FRACTION PROTROMBIN 1 + 2
* ENDOGENOUS THROMBIN POTENTIALE
MANAGEMENT
MANAGEMENT TREATMENT
PREVENTION
- NON PHARMACOLOGY

- PHARMACOLOGY
* ANTI PLATELET
* ANTICOAGULANT
* THROMBOLITIC

- SURGERY
 MANAGEMENT OF ARTERIAL
THROMBOSIS OF THE LIMB
Arterial thrombosis of the Limb
Heparinisasi

Stratifikasi
Audible 30% Audible > 30%
(Threatened) (Viable)
Inaudible

Intraoperative Iatrogenic Non Iatrogenic

angiography (Threatened) (Irreversible)

Thromboembolectomi Thrombolysis Primary

amputation
Long term
Intraoperative
Antithrombotic
thrombolysis
therapy
 Targets for Anticoagulants
Intrinsic pathway Extrinsic pathway
(surface contact) (tissue damage)

XII XIIa Tissue factor

XI XIa
Heparins and
LMWH2 IX IXa VIIa VII
Vitamin K antagonists3
VIII VIIIa
Direct thrombin inhibitors4
X Xa
Factor Xa inhibitors5
1Adapted with permission from V Va
Petitou M, et al. Nature. 1991;350(suppl):30-33.
2Hirsh J, et al. Chest. 2001;119(suppl):64S-94S.
3Hirsh J, Fuster V. Circulation. 1994;89:1449-1468.
II IIa
IIa (Thrombin)
4Weitz JI, Hirsh J. Chest. 2001;119(suppl):95S-107S.
5Herbert JM, et al. Cardiovasc Drug Rev. 1997;15:1.
Fibrinogen Fibrin
COMPARATIVE CHARACTERISTICS
OF ANTICOAGULANTS
Oral
Fixed Fast onset Predictive No coagulation
administration dosing and offset kinetics monitoring

Warfarin
dabigatran

Heparin
LMWH
TROMBOLISIS

A. Sistemik.
Indikasi:
1. Tromboemboli Pulmoner Akut
2. Tromboemboli Arteri Perifer Akut
3. Tromboemboli Vena Periver Luas
Kontra indikasi:
a. Uncontrollable clothing disorders,
b. High probability to bleeds:
Retinal, Pulmonary, Aneurysm, Cerebral, GI.
c. High probability to septic emboli,
d. Diastolic >100 mmHg or Systolic >200 mmHg,
e. Postoperative 6 days,
f. DVT>14 hari emboli A.Pulmonalis, V.Porta
HIGH DOSE SHORT TERM
TROMBOLISIS SISTEMIK
a. Initial dose:
a. First line Streptase 250.000 Iu (5000 Iu/kg) dalam 100 mL
NaCl 0,9% (Piggy bag) iv drip over 30 menit
b. Second line Urokinase 200.000 Iu/iv bolus (4400 Iu/kg)
over 10 menit
b. Maintenance:
Streptase
1,5 juta Iu/jam/iv drip (5000 Iu/kg/jam) selama 6 jam
Dilanjutkan dengan heparinisasi mulai 150 u/jam/iv drip,
monitor target aPTT 75-105 detik
Urokinase
200.000 Iu/jam/iv drip (4400 Iu/kg/jam) selama 6 jam
(expensive),
Dilanjutkan dengan heparinisasi mulai 150 u/jam/iv drip,
monitor target aPTT 75-105 detik