THROMBOSIS Karmel L. Tambunan, Lugyanti Sukrisman Div of Hematology-Medical Oncology Dept of Internal Medicine Faculty of Medicine, Univ of Indonesia

Overview of Hemostasis Vascular Injury Exposed subendothelium Exposed tissue factor thrombin Platelet adhesion & aggregation Blood coagulation Vasoconstriction PF3 HEMOSTASIS

The primary haemostatic system: haemostasis and platelet plug formation Slide A8 Primary haemostasis Platelet aggregation trombosit Adhesion Activation Aggregation White clot endothelial cells sub endothelial tissue Vascular injury Formation of platelet plug exposed sub endothelial tissue

The haemostatic system: secondary haemostasis and clot formation Slide A9 Prothrombin Thrombin Activation of the coagulation cascade leads to generation of thrombin and, in turn, fibrin Factor Xa Intrinsic pathway Extrinsic pathway Fibrinogen Fibrin Coagulation cascade leads to clot formation Clot growth Fibrin threads

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

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

Thrombosis Mortality : Cause of death (>60%) in the western country (Turpie G.L., 1996) About 2 million individual die each year from an arterial or venous thrombosis or of the consequence thereof (Bick R.L., 1997)

Thrombosis Morbidity : Paralysis (non fatal thrombotic state) Cardiac disability (repeated coronary event) Fetal loss syndrome (placenta vascular thrombosis) Loss of vision (retinal vascular thrombosis) Loss of hearing (?) Stasis ulcers and others manifestations of postphlebitic syndrome (recurrent DVT)

Incidence of thrombosis in United States of America Disease 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

Pulmonary disease/flu 80,000 Trauma/accident 90,000 CV thrombosis 1,000,000 Other causes 400,000 Leading causing Mortality in the USA Cancer 500,000 COPD 90,000 Pulmonary disease/flu 80,000 Trauma/accident 90,000 Semin Thromb 21,Sup 1, 2000

Thrombosis in Indonesia Epidemiology data: not available Mortality The first cause of death 20.5%, (11.8 % cerebrovascular, 8.7 % coronary heart disease) (Ministry of Health 1997)

Causes of Thrombosis Clinical conditions  Arterial Venous Blood protein/platelet defects Atherosclerosis Cigarette smoking Hypertension Diabetes mellitus Low-density lipoprotein cholesterol Hypertriglyceridemia Positive family history Left ventricular failure Oral contraceptives Estrogens Lipoprotein(a) Polycythemia Hyperviscosity syndrome Leukostasis syndromes General surgery Orthopaedic surgery Arthroscopy Trauma Malignancy Immobility Sepsis Congestive heart failure Nephrotic syndrome Obesity Varicose veins Postphlebitic syndrome estrogens Antiphospholipid syndrome Activated protein C resistance (Fac. V Leiden) Sticky platelet syndrome Protein S defects Protein C defects Antithrombin defects Heparin cofactor II defects Plasminogen defects Tissue plasminogen activator defects Plasminogen activator inhibitor defects Factor XII defects Dysfibrinogenemia Homocystinemia

Arterial thrombosis Stroke non haemorrhagic/ TIA Myocardial infarction/unstable angina Acut abdomen (mesenterial thrombosis ) Fetal loss syndrome/ recurrent miscarriage Loss of vision Loss of hearing Gangrene

Venous thromboembolism : The disease encompasses deep vein thrombosis and pulmonary embolism.

10 % symptomatic (DVT/PE) 90 % asymptomatic Could be life-threatening Fatal pulmonary emboli Symptom (+) asymptomatic

Venous stasis Parietal lesion Coagulation anomaly Age > 60 yrs + obesity pregnancy Immobilization or paralysis Orthopaedic surgery Trauma of lower limbs Cardiac insufficiency Myocardial infarction (acute phase) Stroke Cancer General surgery Inherited or acquired haemostasis deficiencies Venous insufficiency or varicosis Previous history of DVT

A very large number of people are at high risk of VTE, especially in hospital populations. In one general hospital population, 19% of patients had three or more risk factors for VTE.1 going into 70% in some patients In another study conducted in a medical unit, 47% of patients had four or more risk factors.2 According to current guidelines, all these patients require VTE prophylaxis.3 _____________________________ 1. Anderson FA, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A. The prevalence of risk factors for venous thromboembolism among hospital patients. Arch Intern Med. 1992;152(8):1660–1664 2. Arcelus JI, Candocia S, Traverso CI, Fabrega F, Caprini JA, Hasty JH. Venous thromboembolism prophylaxis and risk assessment in medical patients. Semin Thromb Hemost. 1991;17(suppl 3):313–318 3. Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr et al. Prevention of venous thromboembolism. Chest. 2001;119:132–174S

Primary risk factors for VTE Major surgery Acute MI Major trauma Paralytic stroke Cancer Spinal cord injury Pelvic fracture

Secondary risk factors for VTE Congestive heart failure Previous VTE Immobilization Obesity Chronic respiratory failure Increasing age Haematological disorders Central venous cathether Varicose veins Pregnancy Oestrogen treatment Hospitalization

DVT risk Highest risk Major surgery Age >40 History of VTE Hip fracture THR or TKR CVA Spinal cord injury Trauma Malignancy Congenital hypercoagulability Low risk Minor surgery Age <40 No other risk factors Moderate risk Major surgery Age >40 High risk Major surgery Age >40 MI Additional risk factors VTE, venous thromboembolism; THR, total hip replacement; TKR, total knee replacement; MI, myocardial infarction; CVA, cerebrovascular accident Chest 1998;114:531S-60S

Pathogenesis : Triad Virchow Vascular lesion/disruption Blood component (coagulation imbalance) Venous stasis

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 There is a very strong association between PE and DVT: 90% of pulmonary emboli are as the result of DVT.3 A recent study showed that 82% of patients with acute PE had detectable DVT at the time PE was diagnosed.2 Silent PE occurs in more than 50% of patients with symptomatic proximal DVT.1 As the venous clot in the leg grows, it extends along the vein.4 DVT can develop into a chronic condition in which damage to the valves in the veins results in swelling of the leg, pain and venous hypertension (known as PTS). Parts of the clot can also detach, traveling in the blood to block vessels in the lungs, subsequently causing PE.4 If less than 50% of the pulmonary circulation is blocked, symptoms are generally limited to shortness of breath or are absent altogether. Very large emboli, however, can cause massive blockage of the pulmonary circulation and rapidly lead to death. Pesavento R, Lusiani L, Visona A, Bonanane A, Zanco P, Perissinotto et al. Prevalenza di embolia polmonare clinicamente silente nella trombosi venosa profonda degli arti inferiori. Minerva Cardioangiologica. 1997 Jul-Aug;45(7-8):369–375 Girard P, Musset D, Parent F, Maitre S, Phlippoteau C, Simmonneau G. High prevalence of detectable deep venous thrombosis in patients with acute pulmonary embolism. Chest. 1999 Oct;116(4):903–908 Perrier A, Bounameaux H, Morabia A, de Moerloose P, Slosman D, Didier D, Unger P-F, Junod A. Diagnosis of pulmonary embolism by a decision analysis-based strategy including clinical probability, D-dimer levels, and ultrasonography: a management study. Arch Intern Med. 1996 Mar 11;156(5):531–536 Alpert JS, Dalen JE. Epidemiology and natural history of venous thromboembolism. Prog Cardiovasc Dis. 1994 May-Jun;36(6):417–422 1. Pesavento R, et al. Minerva Cardioangiologica. 1997;45:369–375 2. Girard P, et al. Chest. 1999;116:903–908

DIAGNOSIS OF VTE: CLINICAL FINDINGS DVT: Non specific Pain, tenderness, unilateral leg swelling, superficial venous dilatation PE: Dyspnea, pleuritic pain, cough, hemoptysis Clinical prediction score for DVT/PE Laboratory test: D-dimer Hypoxemia, hypocapnia (PE)

DIAGNOSIS OF VTE: RADIOIMAGING DVT: Venography/phlebography (gold standard) Compression ultrasonography (CUS) Venous Doppler/duplex scanning PE: CXR: cardiomegaly, pleural effusion, atelectasis, elevated hemidiaphragm Pulmonary angiography (gold standard) Ventilation-perfusion lung scintigraphy Spiral CT

CURRENTLY AVAILABLE ANTITHROMBOTIC DRUGS ANTIPLATELET AGENTS ANTICOAGULANTS THROMBOLYTIC AGENTS ORAL PARENTERAL ORAL PARENTERAL -PARENTERAL -STREPTOKINASE -UROKINASE -tPA GPIIb/IIIa antagonists Aspirin Dypiridamol Ticlopidin Clopidogrel Coumarin Heparin LMWH Hirudin Argatroban melagatran Fondaparinux

Current anticoagulants affect concomitantly several of the coagulation factors highlighted in this slide. In contrast, new research in this field tend to develop selective inhibitors targeting only one coagulation factor. About 250 drugs, either synthetic or recombinant, are in development. They target either the last step of the cascade - thrombin; its early steps - TF, factor VII, factor IX; or its central step - factor Xa.

Complications of Deep Vein Thrombosis Permanent vascular damage to lower limb Post thrombotic venous insufficiency Postphlebitic syndrome Pulmonary embolism (PE) Pulmonary hypertension 4 2

VTE can have serious long-term effects. In a prospective long-term trial of 528 patients with symptomatic DVT treated with an initial course of full dose low molecular weight heparin (LMWH) followed by at least 3 months of oral anticoagulants, recurrent DVT developed in one third of patients within 8 years of a DVT diagnosis. Where established risk factors remained uncorrected, the incidence of recurrent DVT was even higher, with an approximately 1.5-fold increased risk with malignant disease and 2-fold increase with hypercoagulable states. One third of patients also developed post-thrombotic syndrome (PTS); the risk of PTS is closely linked to recurrent DVT. Prandoni P, Villata S, Bagatella P, Rossi L, Marchiori A, Piccoli A, et al. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica. 1997 Jul-Aug;82(4)423–428

POST THROMBO- PHLEBITIC SYNDROME

VTE PROPHYLAXIS

Major orthopaedic procedures are associated with very high rates of DVT and PE. Without prophylaxis, up to 13% of hip fracture patients may die as a result of PE. In the absence of prophylaxis, elective hip replacement and hip fracture are associated with DVT rates of approximately 50%, and rates may be even higher in total knee replacement. Given the high rates of DVT associated with orthopaedic surgery, the use of prophylactic measures that have been proven to be effective is essential. 1. Clagett GP, et al. Chest 1998;114 (suppl):531S-560S. 2. Geerts WH, et al. Chest 2001;119 Suppl 1:132–74S.

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