T H ROMBOSIS

IRZA WAHID
SUBDIVISION OF HEMATOLOGY & MEDICAL ONCOLOGY DEPARTEMENT OF INTERNAL MEDICINE FACULTY OF MEDICINE ANDALAS UNIVERSITY

HEMOSTASIS : Hemo + Stasis

Vaskular

Trombosit

Koagulasi

HEMOSTASIS : Hemo + Stasis

A. VASKULAR * Vasokonstriksi Reflektoris dipertahankan oleh Fc lokal : 5-HT, serotonin, epinefrin
* Aktifasi trombosit adhesi , agregasi sumbat trombosit * Aktifasi faktor Koagulasi via jalur intrinsik & ekstrinsik

B. TROMBOSIT
Adesi
Vaskular robek , sel endotel rusak, subendotel terbuka Trombosit lengket dg permukaan asing terutama kolagen Sangat tergantung fc vWF yg disintesis sel endotel & megakariosit

Agregasi
dicetuskan ADP, dan dibantu Ca dan fibrinogen trombosit lengket satu sama lain perubahan bentuk trombosit menjadi cakram

RX pelepasan isi trombosit

Granula padat : ADP, ATP, Ca, Epinefrin, Norepinefrin, Granula alfa : Fibrinogen, vWF, FV, PF 4, bTG, Lisosom : Enzim asam hidrolase

C. SISTIM KOAGULASI
NOMENCLATUR FAKTOR KOAGULASI
I II III IV V VI VII VIII IX X XI XII XIII Fibrinogen Protrombin Tissue factor Ion calsium Proaccelerin Proconvertin Anti hemophilic factor Plasma tromboplastin component Stuart factor Plasma tromboplastin antecedent Hageman factor Fibrin stabilizing factor High moleculer weight kininogen Pre kalikrein

TEORI CASCADE ATAU WATERFALL (BY Mac Farlane, Davie & Ratnoff)
Tiap Fc koagulasi diubah menjadi bentuk aktif oleh Fc sebelumnya Dimulai dari 2 jalur yakni : * Jalur intrinsik vaskular robek permukaan asing(kolagen) kontak dg Fc XII * Jalur ekstrinsik : vaskular robek tromboplastin jar. + Ca kontak dg Fc VII

Diakhiri dengan jalur bersama * Aktifasi Fc X

Jalur Intrinsik

Jalur Ekstrinsik

XII
Kontak XIIa HMWK XI IX XIa IXa PF3, VIII, Ca X Xa V, PF3, Ca Ca

VII
Tromboplastin Jaringan

VIIa

Fibrinogen Protrombin Trombin

Fibrin monomer
Fibrin polimer Solubel XIII Ca XIIIa Fibrin polimer InSolubel

FIBRINOLISIS
Proses penghancuran deposit fibrin oleh sistim fibrinolitik sehingga aliran darah terbuka kembali 3 komponen utama : * Plasminogen plasmin * Aktifator plasminogen * Inhibitor plasmin

Intrinsik

Extrinsik

Eksogen

XIIa, Kalikrein

t-PA Aktifator Plasminogen

Urokinase

Plasminogen terikat

Plasmin terikat

Fibrin

FDP

Plasminogen bebas

Plasmin bebas

Fibrinogen Fc V, Fc VIII

Anti Plasmin

 Thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart

Arterial thrombosis (white thrombus) Venous thromboembolism (red thrombus)

* Deep vein thrombosis * Pulmonary embolism

High Flow

Slow Flow

Fibrin

RBCs

Platelets

Fibrin

RBCs

Platelets

White Thrombus

Red Thrombus

Incidence of thrombosis in United States of America

Disease US incidence /100.000 Total in US /year Definable cases reason 80% 80 % 80 % 67 % 67 % 30 % 30 % 50 % 50 %

Deep Vein Thrombosis 159/100.000 398.000 Pulmonary Embolus 139/100.000 347.000 Fatal Pulmonary Emb. 94/100.000 235.000 Myocardial Infarction 600/100.000 1.500.000 Fatal MI 300/100.000 750.000 Cerebrovascular thromb. 600/100.000 1.500.000 Fatal Cereb. Trhromb. 396/100.000 990.000 Total serious thromb. In US 1498/100.000 3.742.000 Total deaths from above thrmb. 790/100.000 1.990.000 Bick RL, Clin Appl Throm Hemos 3, Suppl 1, 1997

Pathophysiologic of Thrombosis
Triad of Virchow

Abnormality of Vessel wall

Abnormality of Blood flow

Abnormality of The blood

Plaque ruptures

Venous Hypotonia

Shears stress Shears rate Turbulence

Venous stasis

Platelet hyper aggregation

Hyper coagulability state Thrombophilic state Fibrinolysis deficient Thrombocytosis

Arterial Thrombosis

Venous Thrombosis

Arterial Thrombosis

Venous Thrombosis

Arterial Thrombosis

Endothelial Perturbation

Hyper viscosity Hyper fibrinogenemia

Venous Thrombosis

TROMBOSIS ARTERI - OTAK - TELINGA - MATA - JANTUNG - EXTREMITAS

Risiko trombosis arterial

Kelainan vaskular
Aterosklerosis Merokok Hypertensi Diabetes Mellitus Obesitas Riwayat keluarga positif High Lipoprotein(a) High Low-density lipoprotein High Kolesterol Hypertriglyceridemia Defisiensi estrogen Hyper Homocystinemia Kepribadian (stress)

Kelainan aliran
Aterosklerosis Hyperviscosity syndromes Hyperglisemia Hyperlipidemia Polycythemia Leukostasis syndromes Dysfibrinogenemia

Kelainan koagulasi
Antiphospholipid syndrome Sticky platelet syndrome Cancer procoagulant (CP) Protein S defects Protein C defects APC resistance (factor V Leiden) Antithrombin defects Heparin cofactor II defects Plasminogen defects Tissue plasminogen activators defects Plasminogen activator inhibitor defects Factors XII defects

TROMBOSIS VENA (VTE) - DVT - PE

VTE: A strong relationship between DVT and PE

Almost 50% of patients with proximal DVT of the leg have asymptomatic PE1

Migration

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

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

* 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

* 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

TREATMENT PREVENTION

- NON FARMAKOLOGI
- FARMAKOLOGI * ANTI PLATELET * ANTIKOAGULAN * TROMBOLITIK

- BEDAH

Targets for Anticoagulants

Intrinsic pathway (surface contact) XII XI
Heparins and LMWH2

Extrinsic pathway (tissue damage)

XIIa XIa IX VIII VIIIa X V II Fibrinogen Va Xa

Tissue factor

IXa

VIIa

VII

Vitamin K antagonists3
Direct thrombin inhibitors4

Factor Xa inhibitors5
1Adapted

with permission from 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. 4Weitz JI, Hirsh J. Chest. 2001;119(suppl):95S-107S. 5Herbert JM, et al. Cardiovasc Drug Rev. 1997;15:1.

IIa IIa

(Thrombin) Fibrin

COMPARATIVE CHARACTERISTICS OF ANTICOAGULANTS

Oral
administration Fixed dosing Fast onset and offset Predictive No coagulation kinetics monitoring

Warfarin

dabigatran

Heparin LMWH

TROMBOLITIK
STREPTOKINASE STAPILOKINASE UROKINASE

CONCLUSION
Venous thromboembolism is the formation or presence of a blood clot inside a vein. The third thrombosis after cerebral thrombosis. High incidence in medical illnes. Primary prevention of VTE in the hospital with risk factors for medical illnes is essential Heparin & LMWH still a first choice. Warfarin & Dabigatran as alternative