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red thrombus
 Trombosis adalah pembentukan suatu massa
abnormal di dalam sistem peredarah darah mahluk
hidup yang berasal dari kompnen komponen darah,
 Keadaan ini sering mengakibatkan kecacatan atau
 Survei KRT depkes 1998: PJK dan Stroke penyebab
kematian di Indonesia
Cardiovascular Disease
30% of all deaths in Canada

54% ischemic heart disease

20% stroke

23% heart attack

What Causes Ischemic Stroke?

Thrombotic Embolic


Head CT:
Ischemic Stroke
Arterial Thrombosis
Myocardial Infarction
Myocardial infarction and mural thrombosis
Clot on bicuspid aortic valve
T ooMuch Anticoagulation
in a Thromboticpatient

2 1

Bleeding Balance Thrombosis

Summary of Presentation
• Background on hypercoagulable states

• Description of :
-Factor V Leiden
-Prothrombin 20210 mutation
-Protein C, Protein S and Antithrombin
-Heparin-Induced Thrombocytopenia
-Antiphospholipid Antibodies
Embolus in the aorta

Risk factors?




Clot breaks off from another location and travels in arteries.

Deep Vein Thrombosis
Peripheral Vascular Disease
30% Progression to Pulmonary Embolism
Arterial to arterial embolization

10% of all arterial emboli.

Chronic ischemia and types of foot ulcers

Arterial Venous Neuropathic

Blood Flow

Abnormal Abnormal
Vessel Wall Blood

The Hypercoagulable State


Dr. Rudolph Virchow

Mechanisms of Thrombosis

Clinical associations with venous

thrombotic disease

Estrogen therapy
Types of Thrombosis
Arterial: platelet-based (white) thrombus

Platelet-VWF interactions critical

Associated with end-stage atherosclerosis

Venous: Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis
Fibrin Clot Formation
Fibrin Network

(scanning EM)

“enzyme cascade”

Davie & Ratnoff

“waterfall sequence”
Thrombosis intravital
Virchow's 3 intravascular
Alteration of:
1. Vessel wall - endothelial injury - dominant
2. Blood flow- stasis, turbulence
3. Blood – hypercoagulability

may combine
Localization - detailed
Arterial – occlusive; mixed
coronary, cerebral, femoral
atherosclerosis, vasculitis, trauma
Venous – occlusive, long cast; red; 90% legs
autopsy dif. dg. postmortem clot
Heart – valves – vegetations
infective or sterile (rheum., NBTE, SLE)
Heart chambers, aneurysms of heart or aorta
Mural; infarction; embolisation: brain, kidney, spleen
1. Vessel wall – endothelial injury – dominant
exposure of subendothelial collagen
+ adherence of platelets
exposure of tissue factor, local depletion
of prostacyclin and plasminogen activator
 Atherosclerosis – ulceration
 Necrosis – myocardial infarction
 Trauma
 Inflammation – vasculitis
 Hypertension, turbulent flow, bact. endotoxins
 Homocystein, cholesterol, radiation, smoking
2. Alterations in normal blood flow
Normal = laminar
Turbulence – arteries, heart;
combined turb. + stasis (endot. injury + stasis)
Stasis – veins, heart
Ulcerated atherosclerotic plaques – endot. +turb.
Aneurysms – local stasis
Mitral valve stenosis – stasis – left atrial dilation
Hyperviscosity syndromes – polycythemia; sickle cell
anemia (occlusions stasis; small vessels)
3. Hypercoagulability
Any alteration of coagulation pathway
predisposing to thrombosis
 Primary (genetic)
Mutations in factor V = Leiden mutation
2-15% of popul. APC resistance
antithrombin III, protein C, S deficiencies
fibrinolysis def., hyperhomocysteinemia
↑prothrombin levels - 1%, allelic variations
 Thrombo(embolism) – recurrent, young,
no or insignificant other causes
 Secondary (acquired) - high risk or low risk
3. Hypercoagulability
 Secondary (acquired)
 ↑ High risk of thrombosis - immobilization, myocard
infarction, tissue damage (trauma, burns, surgery),
cancer, prosthetic cardiac valves, DIC, heparin-induced
thrombocytopenia, antiphospholipid antibody syndrome
(with/out autoimmune dis. - SLE)
 ↓Lower risk of thrombosis -atrial fibrillation,
cardiomyopathy, nephrotic syndrome, hyperestrogenic
states, oral contraceptives (3x), pregnancy (8x), sickle
cell anemia, smoking

Thrombotic diathesis - often complicated, multifactorial

Abnormal Clotting

 Thrombus
 Clot develops in intact, unbroken vessel
 Blocks circulation to tissues beyond thrombus
 Embolus
 Thrombus that comes loose, flows
 Ultimately lodges in narrow vessel, blocks
 Pulmonary embolism
 Cerebral embolism

Blood.ppt 06 Feb. 2013

Limiting Clotting

 Factors that limit & prevent clotting

 Normal intact endothelium
 Heparin, inhibits thrombin

 Aspirin, inhibits platelet aggregation and

platelet plug formation

Blood.ppt 06 Feb. 2013

37 Limiting Clotting
 Leeches
 Hirudin from leech
Hirudo medicinalis

Blood.ppt 06 Feb. 2013

Circulatory Disorders
Antiplatelet Drugs
Aspirin, Dipyridamole (Persantine), Ticlopidine (Ticlid)
abciximab (ReoPro), tirofiban (Aggrastat)
 Action: To prevent thrombosis in the arteries by
suppressing platelet aggregation via diff. methods
 Use: Prevention of MI/stroke for clients w/ family hx

- prevention of a repeat MI, stroke in clients having TIA’s

 Persantine & Ticlid = similar to ASA but more expensive

 ReoPro & Aggrastat = mainly for acute coronary

syndromes. Route = IV
Circulatory Disorders
 Use = Acute MI - w/ in 4 hrs to dissolve clot & unblock artery,
so decrease necrosis to myocardium & hospital stay is
 Other uses: Pulmonary embolism, DVT, Noncoronary arterial
 Streptokinase, Urokinase, Tissue plasminogen activator (t-
PA), anisoylated plasminogen streptokinase activator
complex (APSAC)
 Streptokinase & Urokinase are enzymes that act to convert
plasminogen to plasmin
 t-PA and APSAC activate plasminogen by acting specifically on
Circulatory Disorders
Peripheral Vasodilators
 Peripheral vasodilators more effective for disorders
resulting from vasospasm (Raynaud’s disease) than
from vessel occlusion or arteriosclerosis
 Vasodilators have diff. actions but all promote
 Isoxsuprine (Vasodilan) - Beta-2 adrenergic agonist
- causes vasodilation on arteries w/in skeletal
muscles, bronchodilation may also occur
- SE = lightheadedness, dizziness, orthostatic
hypotension, tachycardia, GI distress
Circulatory Disorders
Peripheral Vasodilators
 Pentoxifylline (Trental) - an antihemorrheologic
agent - improves microcirculation & tissue perfusion
inc. in tissue O2. Not a vasodilator, but dilates rigid
arteriosclerotic bld vessels - arterioles, capillaries &
- Use = clients w/ intermittent claudication
- Take w/ food
- Avoid smoking d/t nicotine increases vasoconstriction
Anti-Xa oral
 Rivaroxaban
Anti-Xa indirect

 Fondaparinux
 Idraparinux
Antithrombine direct

 Dabigatran

Thromb Haemost 2006

 Prepared from porcine gut mucosa after removal of heparin
 Contains 83% heparan sulphate
 12% dermatan sulphate
 5% chondroitin sulphate
 Only 5% of heparan sulphate contains the pentasaccharide sequence
common to the heparins that has high affinity to ATIII
 High affinity content contains tri- and di- sulphated saccharides
 The low affinity component of heparan sulphate for ATIII has
antithrombotic activity via an endothelial cellular mechanism
 Histidine rich glycoprotein interacts with the low affinity component of
heparan sulphate and is the ony plasma protein to modulate the
antithrombotic activity (like LMWH)
 Dermatan sulphate activates heparin cofactor II, acting at level of FIIa
 Almost no effect on platelet function
 MW 6500, and ~ 100% bioavailable
 Xa: Iia ratio 28:1
 t1/2 elimination of anti-Xa & thrombin generation inhibition are 25 & 7
hours post s/c or IV doses and are dose/route independent
 Steady state levels in 4-5 days using Xa
 Renally excreted
 Contraindicated if hypersensitivity to sulphite (asthmatics)
Prevention of Blood Clot Formation

Müller, 1997
Choice of medication for stroke
What is the cause of the stroke?

Atherosclerosis Unknown Heart

Antiplatelet therapy Warfarin


Albers GW, et al. Chest 1998;114:683S-698S

Barnett HJ et al. N Engl J Med. 1998;339:1415-1425
Prevention of recurrent stroke
Stroke caused by atrial fibrillation

Relative Risk Reduction

Benefit of aspirin
Benefit of warfarin

20% 15%


EAFT Study Group Lancet 1993, 342: 1255-62

Aspirin for prevention of stroke

Aspirin benefit independent of dose and


 FDA, AHA & ACCP all recommend

 an aspirin dose between 50 and 325 mg/day

Albers GW at al Neurology 1999;53(suppl. 4):S25-S38

FDA. Federal Register. 1998;63:56802.
Albers GW, et al. Chest 2001, 119: 300S-320S.
Medications that prevent stroke
“Blood thinners”
Anticoagulants Antiplatelet Agents
 Coumadin (warfarin)  Aspirin

 Exanta Aspirin/extended release

dipyridamole (Aggrenox)
 Heparins
 Clopidogrel (Plavix)

 Ticlopidine (Ticlid)