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

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

4. 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

5. 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

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

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

9. 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)

10. 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)

11. Incidence of thrombosis in United States of America
Disease US incidence Total in US /year Definable
/ cases reason
Deep Vein Thrombosis /  80%
Pulmonary Embolus /  80 %
Fatal Pulmonary Emb /  80 %
Myocardial Infarction /  67 %
Fatal MI /  67 %
Cerebrovascular thromb /  30 %
Fatal Cereb. Trhromb /  30 %
Total serious thromb. In US /  50 %
Total deaths from above thrmb /  50 %
Bick RL, Clin Appl Throm Hemos 3, Suppl 1, 1997

12. 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

13. 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)

14. 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

15. 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

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

17. 10 % symptomatic (DVT/PE) 90 % asymptomatic Could be life-threatening
Fatal pulmonary emboli
Symptom
(+)
asymptomatic

18. 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

19. 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

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

21. 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

22. 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

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

24. 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 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 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 Mar 11;156(5):531–536
Alpert JS, Dalen JE. Epidemiology and natural history of venous thromboembolism. Prog Cardiovasc Dis 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

25. 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)

26. 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

28. 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

29. 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.

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

31. 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 Jul-Aug;82(4)423–428

32. POST THROMBO-
PHLEBITIC SYNDROME

33. VTE PROPHYLAXIS

34. 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.

35. Thank you