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2014 Pleno Pakar Pc2 Blok EMD

Dr.Datten Bangun MSc,SpFK
Dept.Farmakologi & Therapeutik
Fak.Kedokteran USU
MEDAN
Virchow’s Triad
Thrombus
=Thrombus in the left heart chambers can lead
to embolic stroke and other systemic embolic
events, while
= Pulmonary emboli and paradoxical emboli
originate from either deep venous thrombus
or thrombus in the right heart chambers.
• Low cardiac output, decreased physical
activity, and peripheral edema all predispose
to venous thrombi.
Thrombi
According to location & composition
Arterial
• Occur in areas of rapid
flow (arteries)
• In response to an
injured or abnormal
vessel wall
• White
• Composed:
primarily of platelets, also
fibrin & occasional
leukocytes

Associated with
MI
Stroke
ischemia

Venous
•Occur primarily in the
venous circulation
•In response to venous
stasis or vascular injury
•Red
•Composed
almost entirely of fibrin &
erythrocytes

•Associated with
Congestive Heart Failure,
Cancer
Surgery.


Antithrombotic Agents: Mechanism of
Action
Anticoagulants: prevent clot formation and
extension
Antiplatelet drugs: interfere with platelet
activity
Thrombolytic agents: dissolve existing
thrombi
HFSA 2010 Practice Guideline
Acute HF—VT Prophylaxis
• Recommendation 12.16 (NEW in 2010) 1 of 2
• Venous thromboembolism prophylaxis with low
dose unfractionated heparin, low molecular weight
heparin, or fondaparinux to prevent proximal deep
venous thrombosis and pulmonary embolism is
recommended for patients who are admitted to the
hospital with ADHF and who are not already
anticoagulated and have no contraindication to
anticoagulation.
Strength of Evidence = B
HFSA :Heart Failure Society of America
HFSA 2010 Practice Guideline
Acute HF—VT Prophylaxis
• Recommendation 12.16 (NEW in 2010) 2 of 2
• Venous thromboembolism prophylaxis with a
mechanical device (intermittent pneumatic
compression devices or graded compression
stockings ) to prevent proximal deep venous
thrombosis and pulmonary embolism should
be considered for patients who are admitted to the
hospital with ADHF, who are not already
anticoagulated, and who have a contraindication to
anticoagulation.
Strength of Evidence = C
Risk Factor – Atrial Fibrillation Class/Level of
Evidence

For patients with ischemic stroke or TIA with paroxysmal (intermittent) or permanent AF,
anticoagulation with a vitamin K antagonist (target INR 2.5; range, 2.0 to 3.0) is
recommended.
Class I; LOE A
For patients unable to take oral anticoagulants, aspirin alone is recommended.

The combination of clopidogrel plus aspirin carries a risk of bleeding similar to that of
warfarin and therefore is not recommended for patients with a hemorrhagic
contraindication to warfarin.
Class I; LOE A

Class III; LOE B
New
Recommendation
For patients with AF at high risk for stroke (stroke or TIA within 3 months, CHADS
2
score of
5 or 6, mechanical valve or rheumatic valve disease) who require temporary interruption
of oral anticoagulation, bridging therapy with an LMWH administered subcutaneously is
reasonable.
Class IIa; LOE C
New
Recommendation

Recommendations for Patients With Cardioembolic
Stroke Types
©2010 American Heart Association, Inc. All rights reserved.
ANTIPLATELET THERAPY
=Aspirin: Primary prevention of MI in high risk
persons
= inhibits cyclo-oxygenase
= thromboxane A2 synthesis
= inhibits both COX 1 and COX 2
irreversibly
Secondary prevention of MI,TIA & stroke
• Clopidogrel: for persons who can’t take aspirin
• Aspirin+clopidogrel: Acute coronary
syndromes
==
The Most Plausible Mechanism Of Aspirin In
Reducing Risks Of Cardiovascular Disease
Aspirin irreversibly acetylates the active site of
cyclooxygenase, which is required for the
production of thromboxane A2, a powerful
promoter of platelet aggregation

Possible Additional Beneficial Mechanisms of
Action of Higher Doses of Aspirin on CVD
• Enhance nitric oxide formation
• Decrease inflammation
• Stabilize endothelial function



Effects On Platelets
ASA Irreversible inhibition
NSAIDS Reversible inhibition
Possible but unproven small clinical
CVD benefits of naproxen
Possible but unproven inhibition of
clinical CVD benefits of aspirin by
ibuprofen

COXIBS Prothrombotic effects and
risks of similar magnitude
to NSAIDS on CVD
Acetaminophen No effects on platelets but
risks on liver and kidneys
Hennekens CH, Borzak S: JCPT, 2008
Double Cheeseburger,
Large Fries, Jumbo
Coffee.. Oh And An
Aspirin -Gotta Take
Care Of The Ticker
Y’Know.
Aspirin May
Reduce Risk Of
Heart Attack
New Yorker Magazine. 1988.
Blood Vessel Injury
IX
IXa
XI
XIa
X
Xa
XII
XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin Thrombin
Fibrinogen
Fribrin monomer
Fibrin polymer
XIII
Intrinsic Pathway Extrinsic Pathway
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral
Anticoagulants
5/98 MedSlides.com 15
Coagulation Cascade
XIIa
XIa
IXa
Intrinsic Pathway
(surface contact)
Xa
Extrinsic Pathway
(tissue factor)
VIIa
Thrombin (IIa)
Thrombin-Fibrin
Clot
aPTT
PT
Heparin / LMWH
(AT-III dependent)
Hirudin/Hirulog
(direct antithrombin)
Courtesy of VTI
Coumarins
Warfarin, Dicumarol
• Mechanism of action:
• Block the Vitamin K-dependent
glutamate carboxylation of
precursor clotting factors II, VII, IX
and X
• 8-12 hour delay in action because of T1/2 of
clotting factors in plasma
• recovery needs synthesis of new clotting factors
• action is reversed with vitamin K

Warfarin: Indications
Prophylaxis and/or treatment of:
Venous thrombosis and its extension
Pulmonary embolism
Thromboembolic complications associated with
AF and cardiac valve replacement
Post MI, to reduce the risk of death,
recurrent MI, and thromboembolic events
such as stroke or systemic embolization
Prevention and treatment of cardiac
embolism
Prothrombin Time (PT)
Historically, a most reliable and “relied upon”
clinical test
However:
Proliferation of thromboplastin reagents with
widely varying sensitivities to reduced levels of
vitamin K-dependent clotting factors has occurred
Concept of correct “intensity” of anticoagulant
therapy has changed significantly (low intensity)
Problem addressed by use of INR (International
Normalized Ratio)
J Clin Path 1985; 38:133-134; WHO Tech Rep
Ser. #687 983.
INR: International Normalized Ratio
A mathematical “correction” (of the PT ratio) for
differences in the sensitivity of thromboplastin
reagents
Relies upon “reference” thromboplastins with known
sensitivity to antithrombotic effects of oral
anticoagulants
INR is the PT ratio one would have obtained if the
“reference” thromboplastin had been used
Allows for comparison of results between labs and
standardizes reporting of the prothrombin time
( )
Patient’s PT in Seconds
Mean Normal PT in Seconds
INR =
ISI
INR = International Normalized Ratio


ISI = International Sensitivity Index
INR Equation
Mean
Normal
(Seconds)
PTR ISI INR
12
12
13
11
14.5
1.3
1.5
1.6
2.2
2.6
A
B
C
D
E
Blood from a
single patient
Patient’s
PT
(Seconds)
16
18
21
24
38
Thromboplastin
Reagent
How Different Thromboplastins
Influence the PT Ratio and INR
Mean
Normal
(Seconds)
PTR ISI INR
12
12
13
11
14.5
1.3
1.5
1.6
2.2
2.6
3.2
2.4
2.0
1.2
1.0
2.6
2.6
2.6
2.6
2.6
A
B
C
D
E
Blood from a
single patient
Patient’s
PT
(Seconds)
16
18
21
24
38
Thromboplastin
reagent
How Different Thromboplastins
Influence the PT Ratio and INR
Conversion from Heparin to Warfarin
May begin concomitantly with heparin
therapy
Heparin should be continued for a minimum
of four days
Time 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)
* Elderly, frail, liver disease, malnourished: 2 mg/day
Warfarin: Dosing & Monitoring
Start low
Initiate 5 mg daily*
Educate patient
Stabilize
Titrate to appropriate INR
Monitor INR frequently (daily then weekly)
Adjust as necessary
Monitor INR regularly (every 1–4 weeks) and adjust
Indication INR
Range Target
Prophylaxis of venous thrombosis (high-risk surgery) 2.0–3.0 2.5
Treatment of venous thrombosis
Treatment of PE
Prevention of systemic embolism
Tissue heart valves
AMI (to prevent systemic embolism)
Valvular heart disease
Atrial fibrillation
Mechanical prosthetic valves (high risk) 2.5–3.5 3.0
Certain patients with thrombosis and the antiphospholipid syndrome
AMI (to prevent recurrent AMI)
Bileaflet mechanical valve in aortic position, NSR 2.0–3.0 2.5
Warfarin: Current Indications/Intensity
Warfarin
Fibrinolytics
• Streptokinase, Urokinase, Alteplase (rt-PA),
Reteplase, Tenecteplase
• MOA: Plasminogen activators
• Plasmin degrades fibrin and breaks up thrombi

Streptokinase

• Derived from bacterial protein
• Antigenic (abys after 4 days)
• Cleaves Plasminogen
• Low fibrin specificity
• Cheap
Urokinase
• Intrinsic compound
• Isolated from urine or renal cell cultures
• Non-antigenic
• Cleaves plasminogen
• Not licensed for MI
Tissue plasminogen activator
• Intrinsic compound
• Recombinant DNA manufacture
• Non-antigenic
• Short half-life – give heparin afterwards
• Higher fibrin specificity
• Expensive
• ? More effective