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2. INDIAN DENTAL ACADEMY
Leader in continuing dental education
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3. Clinical Thrombosis
• >2.5 million cases of deep venous
thrombosis (DVT) per year
• >600,000 cases of pulmonary embolism
(PE) per year
• >50,000 deaths per year from PE
• PE contributes to another 150,000 deaths
per year
• > 11,000 postsurgical PE deaths per year
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4. Indications For Antithrombotic Therapy
•
•
•
•
Venous thromboembolic disease
– Deep venous thrombosis (DVT)
– Pulmonary embolism (PE)
– Primary prophylaxis of DVT or PE
Arterial thromboembolic disease
• Prosthetic heart valves
• Mitral valve disease, especially with atrial fibrillation
• Congestive cardiomyopathies, especially with atrial fibrillatio
• Atrial fibrillation
• Mural cardiac thrombi
• Transient ischemic attacks
• Stroke in evolution
Disseminated intravascular coagulation
Maintenance of patency of vascular grafts, shunts, bypasses
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12. Recombinant Human Activated
Protein C
• Drotrecogin alfa (activated)- Xigris
• Indicated for Severe Sepsis in Adults
with Acute Organ Dysfunction with High
Risk of Death
• Reduction in Death as Primary End
Point
• Antithrombotic, Antiinfammatory,
Profibrinolytic Properties
• Serious Bleeding is Major Side Effect
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21. Antithrombin III Inhibits the
Following Serine Proteases
• Coagulation
• Fibrinolysis
•
•
•
•
•
• Plasmin
Factor XIIa
Factor XIa
Factor IXa
Factor Xa
Thrombin
Inhibitory activity against all these enzymes is substantially accelerated by heparin
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22. Heparin
• Heterogeneous; 3,000-30,000 d
• Average=15,000 d (~45monosaccharide
chains)
• About 1/3 of dose binds to AT III
• To form the AT III:Heparin:Clotting Factor
Complex- requires at least 18 saccarides
except
• Unique high affinity pentasaccaride heparin
sequences catalyze inhibition of Xa by AT
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24. Anticoagulant Properties of Heparin
1. Inhibits the thrombin-mediated conversion
of fibrinogen to fibrin
2. Inhibits the aggregation of platelets by
thrombin
3. Inhibits activation of fibrin stabilizing
enzyme
4. Inhibits activated factors XII, XI, IX, X
and II
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27. Unfractionated Heparin
• High Dose
– Treatment of venous/arterial thrombi
– Requires monitoring
– IV- 5,000 Units bolus, then 30,000-35,000
units/24 hrs
– 80 Units/kg bolus, then 18 Units/kg/hr to
maintain aPTT in therapeutic range
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29. Monitoring of Anticoagulant
Therapy
Heparin
s.q. – no monitoring required
i.v. - partial thromboplastin time (P.T.T.)
*daily or more frequent if PTT varies
mechanism – measures intrinsic pathway
therapeutic goal – 2-2.5 times normal
control value (-30 sec)
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35. Indications for and Contraindications to
Parenteral Anticoagulant Agents
Anticoagulant Agent
Class
Approved & Appropriate
Indications
Contraindication
Unfractionated heparin
Antithrombin III
inhibitor
Treatment of venous
thromboembolism or unstable
angina; used when rapid reversal is
important
? Prophylactic treatment
Enoxaparin
(Lovenox)
Low-molecularweight heparin
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism or
unstable angina
Dalteparin
(Fragmin)
Low-molecularweight heparin
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism or
unstable angina
Regional anesthesia
Low-molecularweight heparin
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism
Regional anesthesia
Tinzaparin
(Innohep)
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Regional anesthesia
Pregnancy
Prosthetic Heart Valves
36. Indications for and Contraindications to
Parenteral Anticoagulant Agents (cont’d)
Ardeparin
Low-molecular-weight
heparin
Approved; not being
marketed
Regional anesthesia
Lepirudin
Hirudin derivative
Heparin-induced
thrombocytopenia with
thrombosis
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Argatroban
Direct thrombin inhibitor
Heparin-induced
thrombocytopenia with
thrombosis
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Danaparoid
Heparinoid
Prophylaxis against
thrombosis in heparininduced
thrombocytopenia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Bivalirudin
Hirudin derivative
Unstable angina or
angioplasty
Unknown
Fondaparinux
(Arixtra)
Prophylaxis in highSynthetic factor Xa
risk patients?
inhibitor
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Unknown
38. Heparin-Antibiotic Interactions
• The second-generation cephalosporins- cefamandole,
cefotetan, and cefoperazone, contain an Nmethylthiotetrazole (NMTT) side chain. This NMTT group can:
• - Dissociate from the parent antibiotic in solution or in vivo
and competitively inhibit vitamin K action, leading to
prolongation of the prothrombin time and bleeding.
• - This side chain is also associated with a disulfiram-like
reaction to alcohol.
• - Clinical bleeding has been less frequently reported with
Cefotetan than with cefoperazone or cefamandole.
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40. Mechanisms of HIT
•
Type 1: In most of these cases, the fall in platelet count occurs within
the first two days after heparin initiation, often returns to normal with
continued heparin administration, and is of no clinical consequence.
The mechanism of the thrombocytopenia is non-immune and appears
to be due to a direct effect of heparin on platelet activation.
•
Type 2: Approximately 0.3 to 3 percent of patients receiving heparin
develop an immune thrombocytopenia, mediated by antibodies to a
heparin-platelet factor 4 complex. One study, for example, randomly
assigned 665 patients to therapy with unfractionated heparin or LMW
heparin. Type 2 HIT developed in 2.7 percent of patients treated with
unfractionated heparin but in none of those receiving LMW heparin.
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42. Therapy of HIT
• There are two recommended approaches:
– Use of the heparinoid danaparoid
– The direct thrombin inhibitor lepirudin (recombinant
hirudin)
– Based upon the data published to date, either
danaparoid or lepirudin should be used to treat HIT
that is complicated by thrombosis; these agents
should also be considered for prophylactic therapy in
patients with HIT without thrombosis until the
platelet count has recovered
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60. Contraindications to Antithrombotic
Therapy
•
General risk factors
-Pre-existing coagulation or platelet defect, thrombocytopenia, or
other bleeding abnormality
-Inaccessible ulcerative lesion (e.g., gastrointestinal tract lesion)
-Central nervous system lesion (e.g., caused by stroke, surgery,
trauma)
-Spinal anesthesia or lumbar puncture
-Malignant hypertension
-Bacterial endocarditis
-Advanced retinopathy
-Old age (relative)
-Aspirin or other antiplatelet drugs
-Neoplastic disease
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61. Contraindications to Antithrombotic
Therapy
• Specific to warfarin (ambulatory patients)
-Early and late pregnancy
-Poor patient cooperation,
understanding, reliability
-Unsatisfactory laboratory or patient
follow-up
-Occupational risk to trauma
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62. Contraindications to Antithrombotic
Therapy
• Specific to thrombolytic agents
-Recent thoracic, abdominal, or central
nervous system surgery
-Recent cerebrovascular accident, trauma, or
neoplasm
-Bleeding ulcer
-Hypertension
-Anticipated invasive procedures (arterial
punctures, biopsies, central lines)
-Concurrent hemostatic dysfunction
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