HEMOSTASIS - DIATESIS HEMORAGIS - TROMBOSISVaskular

TrombositKoagulasi

A. VASKULAR* Vasokonstriksi* Aktifasi trombosit* Aktifasi faktor Koagulasi

B. TROMBOSIT* Adesi* Agregasi* 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 VS FIBRINOLISIS

NOMENCLATUR FAKTOR PEMBEKUAN DARAH

IFibrinogenIIProtrombinIIITissue factorIVIon calsiumVProaccelerinVI-VIIProconvertinVIIIAnti hemophilic factorIXPlasma tromboplastin componentXStuart factorXIPlasma tromboplastin antecedentXIIHageman factorXIIIFibrin stabilizing factor -High moleculer weight kininogen -Pre kalikrein

Jalur Intrinsik Jalur Ekstrinsik

XII VIIKontak CaTromboplastin Jaringan XIIaHMWK XI XIa

IX IXa VIIa PF3, VIII, Ca

X Xa V, PF3, Ca Fibrinogen Protrombin Trombin

Fibrin monomer

Fibrin polimer Solubel

XIII XIIIa Ca Fibrin polimer InSolubel

Intrinsik Extrinsik Eksogen

XIIa, Kalikrein t-PAUrokinase Aktifator Plasminogen

Plasminogen terikat Plasmin terikatFibrin

FDP

Plasminogen bebas Plasmin bebasFibrinogenFc V, Fc VIII

Anti Plasmin

PEMERIKSAAN PENYARING KELAINAN HEMOSTASIS1. RUMPEL LEEDE TEST tu ketahanan ddg kapiler, tetapi juga fgs / jml trombosit

2. BLEEDING TIME Normal 1 6 menit tu extra vasc, tetapi juga ddg kapiler & trombosist4. TROMBOSIT Normal 150000 400000 / mm3

3. CLOTHING TIME Normal 1 4 menit

5. PROTROMBIN TIME (PT)(11 15 )INR menguji antikoagulan oral Jalur ekstrinsik, Fc X, Fc V, protrombin, fibrinogen

6. ACTIVATED PARTIAL THROMBOPLASTIN TIME ( APTT ) ( 20 40 ) Jalur intrinsik, Fc X, Fc V, Protrombin, fibrinogen Heparin 1,5 2,5 x normal

7. TROMBIN TIME (16 20) menguji fibrinogen, heparin, FDP

8. PEMERIKSAAN Fc XIII

Kelainan hemostasis Primer Vaskuler & Trombosit Sekunder Fc Koagulasi PENDEKATAN KLINIS KELAINAN HEMOSTASIS Anamnesis * Sejak kanak-kanak Hemofili * Perdarahan masif saat pemotongan tali pusat Deff Fc XIII Afibrinogenemia Deff Fc VII * Delayed bleeding extr. Gigi * Perdarahan trauma / operasi / sirkumsisi Pemeriksaan * Ptekia * Purpura * Ekimosis * Hematoma * Hamartrosis * Epistaksis, Perdarahan gusi, hemoptisis, hematemesis, melena, hematuria, metroragia

TROMBOSITOPENI

PRODUKSI KONSUMSI

Disorders with increased platelet consumption Disorders with immune mechanism Autoimmuneidiopathic thrombocytopenic purpura Alloimmunepost transfusion purpura, neonatal alloimmune thrombocytopenia Infection-associatedinfectious mononucleosis, HIV, malaria Drug-inducedheparin, penicillin, quinine, sulphonamides, rifampicin

Thrombotic thrombocytopenic purpura/haemolytic uraemic Syndr.

Hypersplenism and splenomegaly

Disseminated intravascular coagulation

Massive transfusion

Acquired disorders of reduced platelet production*

Drug induced Leukaemia Metastatic tumour Aplastic anaemia Myelodysplasia Cytotoxic drugs Radiotherapy Associated with infection Megaloblastic anaemia *Due to bone marrow failure or replacement

Idiopathic thrombocytopenic purpura ( ITP ) (Immune thrombocytopenic purpura ) ITP AKUTAnak / dewasa mudaPredileksi sex (-)Riwayat infeksi virus ( 1-3 mg )Perdarahan akutOnset 2 6 minggu ( remisi spontan pada 80 % kasusITP KRONIKWanita muda pertengahanJarang riwayat infeksi sebelumnyaPerdarahan menyusupOnset bulan tahunJarang remisi spontan

DIAGNOSIS

ANAMNESIS

PEMERIKSAAN FISIK

LABORATORIUM * DARAH RUTIN* FAAL HEMOSTATIK* BMP* PETANDA IMUN

PENATALAKSANAAN

- TRANSFUSI TROMBOSIT - HINDARI TRAUMA / DRUG INDUCED- KORTIKOSTEROID- IMUNOGLOBULIN

BILA REFRAKTER - IMUNOSUPRESIF SIKLOFOSPAMID, AZATIOPRIN, VINKRISTIN- SPLENEKTOMI

HEMOFILIHEMOFILI A : DEFISIENSI FC VIIIHEMOFILI B : DEFISIENSI FC IX

* HEREDITER, X LINKED RESESIF

* MANIFESTASI PERDARAHAN : TGT KADAR FC VIII - 50 100 % PERDARAHAN (-)- 25 50 % PERDARAHAN SETELAH TRAUMA BESAR- 5 25 % PERDARAHAN SETELAH TRAUMA KECIL PERDARAHAN SPONTAN (-)- 1 5 % PERDARAHAN SETELAH TRAUMA KECIL, KADANG DENGAN PERDARAHAN SPONTAN- 0 % PERDARAHAN SPONTAN KE SENDI, OTOT, HEMATOM

LABORATORIUM* APTT MEMANJANG * FC VIII MENURUN

PENATALAKSANAAN* UMUM* SUBSTITUSI FC VIII* KRIOPRESIPITAT

KOAGULASI INTRAVASKULAR DISEMINATA( K I D )Sinonim Konsumsi koagulopati, hiperfibrinolisis, defibrinasi, sindr. TrombohemoragiEtiologi KID FulminanBidang Obgin : emboli cairan amniom, abrupsi plasenta, eklaqmsia, abortus, IUFDHematologi: RX transfusi, hemolisis berat, leukemia M3-4Infeksi: septikemia, viremia, parasitemiaTrauma, luka bakarAlat prostesisPenyakit hati akutKelainan vaskularKID derajat rendahKeganasan, Penyakit autoimun, GVHD,Penyakit kardiovaskular, Penyakit hati/ginjal kronis,

PATOFISIOLOGIXIIKerusakan Endotel KolagenPrekalikerinKininogenXIIaKompleks Ag-AbKalikreinKininXI perm , hipotensi, syokEndotoksinXia X XaPlasminogenPlasminKerusakan jaringan

Aktifitas tromboplastin + VIIProtrombinKerusakan trombositP.F.1.2Komplemen FosfolipidFibrinogen FDP lisis eri/trombositADPTrombinFibrin D. Dimer

Kerusakan eritrosit

Tanda dan Gejala KlinikA. Plasmin generation (haemorrhage) * Spontaneous bruising * Petechiae * Gastrointestinal bleeding * Respiratory tract bleeding * Persistent bleeding at venepuncture sites * Bleeding at surgical wounds * Intracranial bleeding

B.Thrombin generation (thrombosis) * Renal failure * Coma * Liver failure * Respiratory failure * Skin necrosis * Gangrene * Venous thromboembolism

C. Cytokine and kinin generation (shock)* Tachycardia * Hypotension * Oedema

PATOFISIOLOGISYSTEMIC ACTIVATION OF COAGULATIONINTRAVASCULAR DEPOSITION OF FIBRINDEPLETION OF PLATELETSBLEEDINGTROMBOSIS

PEMERIKSAAN LABORATORIUM

FAAL HEMOSTASIS- Trombosit menurun- Hapusan darah tepi burr cell & fragmentosit- Protrombin Time (PT) memanjang- APTT memanjang

BUKTI HIPERAKTIFITAS KOAGULASI / FIBRINOLISIS- D-Dimer meningkat

BUKTI KONSUMSI INHIBITOR- Aktifitas antitrombin menurun- Protein C menurun- Protein S menurun

DISFUNGSI ORGAN- Ureum / kreatinin meningkat- LDH meningkat- Analisis gas darah

SKORING DIC Penilaian adanya kelainan dasar / etiologi terkait DIC(jika tak ada penilaian tidak dilanjutkan)

* Hitung trombosit : > 100.000 = 0 50000 100.000= 1 < 50.000= 2

* D-Dimer: < 500= 0 500 1000= 2 > 1000= 3

* Protrombin Time: < 3 detik= 0 4 6 detik= 1 > 6 detik= 2

* Fibrinogen: < 100 mg/dl= 1 > 100 mg/dl= 0

Jumlah : 5 sesuai DIC, < 5 sugestif DIC

PENATALAKSANAAN* Terapi penyakit dasar* Antikoagulan Heparin / LMWH* Terapi pengganti komponen darah- FFP : 10 15 ml / kgbb- Trombosit- PRC / WRC- Kriopresipitat : bila hipofibrinogenemia ( 10 kantong naik 60 100 mg )* Antitrombin III : Tidak direkemendasikan serentak heparin* Anti fibrinolitik : tidak direkomendasikan

TROMBOSIS

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

ThrombosisArterial thrombosis (white thrombus)Venous thrombosis (red thrombus)

Pathophysiology thrombosis

HIGH FLOW : ARTERIAL CIRCULATIONWhite Thrombus

SLOW FLOW : VENOUS CIRCULATION

Incidence of thrombosis in United States of AmericaDisease US incidence Total in US /year Definable /100.000 cases reason

Deep Vein Thrombosis 159/100.000 398.000 80% Pulmonary Embolus 139/100.000 347.000 80 %Fatal Pulmonary Emb. 94/100.000 235.000 80 %Myocardial Infarction 600/100.000 1.500.000 67 %Fatal MI 300/100.000 750.000 67 % Cerebrovascular thromb.600/100.000 1.500.000 30 %Fatal Cereb. Trhromb.396/100.000 990.000 30 % Total serious thromb. In US 1498/100.000 3.742.000 50 %Total deaths from above thrmb. 790/100.000 1.990.000 50 %

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

Diagnosis Anamnesis Riwayat penyakit (Faktor risiko medis & bedah), Manifestasi klinisPemeriksaan fisikPemeriksaan LaboratoriumPemeriksaan lain:Venografi (Golden Standard)USG/ DopplerDuplex scanImpedance Plethysmography

FAKTOR RISIKO TROMBOSIS ARTERIHipertensi, hiperkolesterolemia, hiperlipoproteinemia, merokok, diabetes melitus, hiperhomosisteinemia, trombositosis, polisitemia

FAKTOR RISIKO TROMBOSIS VENAImobilisasi, operasi, trauma jaringan yang luas, kehamilan, pil kontrasepsi, defisiensi AT3 / protein C/S / Fc XII, PNH

MANIFESTASI KLINIS & PEMERIKSAAN KLINIS

ARTERI / VENAORGAN

ORGANOTAKMATATHTJANTUNGPARUORGAN VISERALEXTREMITAS

DVT >< AILPatogenesis, Perjalanan Penyakit,Komplikasi, Prognosis DVT AIL

Dasar STASIS ISKEMIA

Perjalanan Akut Kronik penyakit (kel. tungkai/tempat lain) Kronik Akut (tromboemboli/trombosis) Komplikasi akut PE Nekrosis amputasi

Prognosis Baik / fatal Fatal lokal / sistemik

DVT >< AILDiagnosis: Keluhan dan Tanda DVT AILKeluhan (stasis) (iskemia) utama/awal - edema tungkai nyeri: biasanya unilateral - tromboemboli: onset akut - silent DVT - trombotik: pelan-pelan - nyeri dan keras (intermittent claudication)

Keluhan & - nyeri - 6 Ps: pain, pallor, pares- tanda - pitting edema thesia,paralysis,pulseless- - flebitis:inflamasi ness, poikylothermia - dilatasi v.superfisial - awal: nyeri & parestesia - sianosis (ileofemoral) - palpasi denyut arteri -

PEMERIKSAAN LABORATORIUMDVT: - D-dimer: - D-dimer < 500 ng/ml menyingkirkan DVT atau PE - nilai prediktif negatif pada DVT & PE: 98 % - sensitif tetapi tidak spesifik: pasca bedah, DIC, infeksi, dll D-dimer (+) - metoda ELISA: cepat dan akurat - Pemeriksaan hemostasis lain: kelainan dasar DVT ? trombofilia herediter/didapat ? (defisiensi AT III, Protein C, APS, dll) penentuan lamanya terapi antitrombosis

PENATALAKSANAAN- MEDIS- BEDAH

ANTITHROMBOTIC DRUGS:

ANTIPLATELET DRUGS ANTICOAGULANT DRUGSTHROMBOLYTIC AGENTS

ANTIPLATELET DRUGS

ASPIRINDIPYRIDAMOLCLOPIDOGREL AND TICLOPIDINE

ANTICOAGULANT DRUGS

WARFARINHEPARINHIRUDIN AND DIRECT THROMBIN INHIBITORS

COMPARATIVE CHARACTERISTICS OF ANTICOAGULANTS

Oral administrationFixed dosingFast onset and offsetPredictive kineticsNo coagulationmonitoringWarfarinHeparinLMWH

Dose and administrationUFH : initial dose: bolus 75-100 u/kgBB followed by continous infusion to achieve aPTT between 1.5 to 2.5 times controlLMWH :1 mg/kgBB or 0.1 ml/10kgBB sc twice dailyFondaparinux : 7.5 mg for 50-100 kgBB sc daily

Warfarin - ActionInhibits the synthesis of (in order of potency)Factor IIFactor XFactor VIIFactor IX

Conversion from Heparin to WarfarinMay begin concomitantly with heparin therapyHeparin should be continued for a minimum of four daysTime to peak antithrombotic effect of warfarin is delayed 96 hours (despite INR)When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days)

THROMBOLYTIC AGENTS

STREPTOKINASETISSUE PLASMINOGEN ACTIVATOR

***************************Thrombi are composed of fibrin and blood cells. The relative proportion of one type of cell to another and to fibrin is influenced by hemodynamic factors; therefore, the proportions differ in arterial and venous thrombosis.Arterial thrombi formed under conditions of high flow are composed mainly of platelet aggregates bound together by fibrin strands. The resulting thrombi are sometimes referred to as "white" thrombi because they have few red blood cells. These thrombi are usually flat, tightly adherent and relatively small.Arterial thrombi usually occur in association with preexisting vascular disease, the most common of which is atherosclerosis. They produce clinical manifestations by inducing tissue ischemia primarily through the obstruction of local blood flow.

Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 p 1151.Cotran RS, Kumar V, Robbins SL, eds. Robbins pathologic basis of disease, 5th ed. Philadelphia: W.B. Saunders, 1994 p 107.Falk E, Fuster V, Shah P. Interrelationship between atherosclerosis and thrombosis. In: Verstraete M, Fuster V, Topol EJ. Cardiovascular Thrombosis, 2nd ed. Philadelphia: Lippincott-Raven, 1998 pp 5, 53.*Unlike the arterial thrombi that form on arterial intimae, venous thrombi form in areas of stasis and are composed of red cells with a large amount of interspersed fibrin and relatively fewer platelets. These "red" thrombi are large, friable casts of the venous channel with branching arms that may extend into tributary veins. Too often, such thrombi have only a weak proximal attachment to the venous intima, usually at a valve or a bifurcation and may detach and embolize to occlude downstream vessels.Venous thrombi usually occur in the lower limbs, particularly in the deep veins of the calf or thigh. They are usually silent but produce acute symptoms if they cause inflammation of the vessel wall or obstruction to flow, if they damage the venous valves or if they embolize into the pulmonary circulation.

Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 p 1151.Cotran RS, Kumar V, Robbins, SL. Robbins pathologic basis of disease, 5th ed. Philadelphia: W.B. Saunders, 1994 pp 107-110.**

When short-term heparin followed by long-term warfarin are used, both anticoagulants can be started simultaneously. Heparin should be continued for a minimum of four days because the peak antithrombotic effect of warfarin is delayed for about 96 hours, independently of the INR, until Factor II (prothrombin is reduced). Heparin can be discontinued after a minimum of four days when the INR reaches the therapeutic range.