HYPOFIBRINOLYSISA Risk Factor for

ARTERIAL THROMBOSIS AND VENOUS THROMBOSIS

Pertemuan Ilmiah Tahunan VIIKATAN DOKTER INDONESIA

KOTA BOGORBogor, 9 November 2013

Dr Marthino Robinson, SpPDDinas Kesehatan Kota Bogor

RSAD SALAK RSIA MELANIA

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

Triad Virchow1) ALIRAN DARAH2) KOMPOSISI DARAH3) PEMBULUH DARAH

ABNORMALITAS Triad Virchowmendukung terjadinyatrombosis vena

• Trombosis Vena (fibrin-rich “red clots”)Terkait terjadinya ‐ Hiperkoagulabilitas‐ Aliran lambat atau statik

• bermula dibelakang katup

TM thrombomodulin; EPCR endothelial protein C receptor; II prothrombin; IIa thrombin; TF tissue factor; Fgn fibrinogen; RBC red blood cells.

SLOW FLOW : VENOUS CIRCULATION

Fibrin PlateletsRBCs

Red Thrombus

ABNORMALITAS Triad Virchowmendukung terjadinyatrombosis arteri

• Trombosis Arteri (platelet-rich “white clots” ) terbentuk setelah terjadinya- Plak pecah- Pemaparan thd materi procoagulant (seperti lipid-rich

macrophages (foam cells), collagen, tissue factor- kerusakan endotel, kondisi aliran cepat.

TM thrombomodulin; II prothrombin; IIa thrombin; Fgn fibrinogen; TF tissue factor.

HIGH FLOW : ARTERIAL CIRCULATION

Fibrin PlateletsRBCs

White Thrombus

Imbalance ofFactors which activated coagulation (Procoagulant)

Factors which activated control coagulation and fibrinolysis (Protection to developing thrombus).

Pathogenesis of Thrombosis

HEMOSTASISPrimary Hemostasis

Blood vessel contraction Platelet Plug Formation

Secondary Hemostasis Activation of Clotting Cascade Deposition & Stabilization of Fibrin

Tertiary Hemostasis Dissolution of Fibrin Clot Dependent on Plasminogen Activation

KESEIMBANGAN ANTAR SISTEM (Koagulasi dan Fibrinolisis)diperlukan untuk mencegah terjadinya kondisi patologik:

perdarahan atautrombosis

Scheme of thecoagulation-anticoagulation system

Activation of the coagulation systemculminates in generation of thrombin, which cleaves fibrinogen to form fibrin clots with platelets on the site of vascular injury. Coagulation systemis negatively regulated by :• tissue factor pathway inhibitor (TFPI), • antithrombin (AT), and • activated protein C (APC).

Fibrinolytic system also regulates coagulation by generation of plasmin, which dissolves fibrin clots. Fibrinolytic systemis negatively regulated by : • plasminogen activator inhibitor 1 (PAI-1).

Trombosis

Clot Lysis Time (CLT) : Time from the midpoint of clear to maximum turbidity transition

(clot formation) To the midpoint of maximum turbid to clear transition (clot lysis)

Determinants of CLT : Plasminogen activator inhibitor-1 (PAI-1) Plasminogen, thrombin-activatable fibrinolysis inhibitor (TAFI),

prothrombin, and 2-antiplasmin. Fibrinogen, factor VII, X, and XI contributed minimally.

ReferencesReduced plasma fibrinolytic potential is a risk factor for venous thrombosisBLOOD, 1 FEBRUARY 2005

Hypofibrinolysis is a risk factor for arterial thrombosis at young age2009, British Journal of Haematology,

Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1BLOOD, 8 JULY 2010 VOLUME 116, NUMBER 1

HYPOFIBRINOLYSISA Risk Factor for

ARTERIAL THROMBOSIS AND VENOUS THROMBOSIS

HYPOFIBRINOLYSISa Risk Factor forVenous Thrombosis (DVT)We determined the plasma fibrinolytic potential of patients enrolled in the Leiden Thrombophilia Study (LETS),( a population-based case control study on risk factors for DVT). Plasma fibrinolytic potential was determined in 421 patients and 469 control subjects by means of a tissue factor–induced and tissue-type plasminogen activator (tPA)–induced clot lysis assay.

Plasma hypofibrinolysis constitutes a risk factor for venous thrombosis, with a doubling of the risk (at clot lysis times that are present in 10% of the population)

Reduced plasma fibrinolytic potential is a risk factor for venous thrombosisTon Lisman et al. BLOOD, 1 FEBRUARY 2005 VOLUME 105, NUMBER 3

HYPOFIBRINOLYSISa Risk Factor forArterial Thrombosis (CAD, IS, PAD)We determined the plasma fibrinolytic potential of 335 young survivors of a first arterial thrombosis,including CAD (n = 198), IS (n = 103) and PAD (n = 34), enrolled in a population-based case–control study and of 330 healthy individuals.

Clot Lysis Times (CLTs) Pasien secara bermakna lebih tinggi (vs Control)

hipofibrinolisis dijumpai pada 10% populasi umum meningkatkan resiko trombosis arteri

Hypofibrinolysis is a risk factor for arterial thrombosis at young age. 2009 British Journal of Haematology, 145, 115–120

HYPOFIBRINOLYSISa Risk Factor forvenous and arterial thrombosisElevated plasma clot lysis time (CLT) BLOOD, 8 JULY 2010

Hypofibrinolysis

Deposit Fibrin(Mikrotrombus)

BERPOTENSI ATEROGENESISdi setiap tahap perkembangan lesi

meningkatkanpertumbuhan plak

Wien Klin Wochenschr. 1993;105(15):417-24. Fibrinogen and atherosclerosis. Smith EB. Department of Clinical Biochemistry, Medical School, Aberdeen Royal Infirmary, U.K.

MENGATASI HIPOFIBRINOLISISmembantu mencegah aterogenesis

PRINCIPLES THERAPY OF THROMBOSIS BASED ON PATHOGENESISPATHOGENESIS THERAPY

- PLATELET ADHESION

- PLATELET AGGREGATION

- BLOOD COAGULATION ANTI-COAGULANT

THROMBOLYTIC- THROMBOSIS AGENT AND/OR

ANTI-COAGULANT

ANTIPLATELET

Hypofibrinolysis ?

TROMBOLES (Lumbrokinase) MECHANISM OF ACTION1. - directly dissolve fibrinogen and fibrin,

- convert plasminogen to plasmin, - increase endogenous human t-PA activity

2. inhibit platelet activation and aggregation 3. blocks the intrinsic coagulation pathway.

1) Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China, 2) Department of Natural Sciences, Northeastern State University, Broken Arrow, Oklahoma, USA3) Pharmaceutical School, Peking University, Beijing, China

3 in 11. Fibrinolytic

2. Anti Platelet3. Anti Coagulation

Terima Kasih

Pertemuan Ilmiah Tahunan VIIKATAN DOKTER INDONESIA

KOTA BOGORBogor, 9 November 2013

Dr Marthino Robinson, SpPD