Heparin /certified fixed orthodontic courses by Indian dental academy

Anticoagulant, Antithrombotic
and Anti-Platelet Drugs

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INDIAN DENTAL ACADEMY
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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

Indications For Antithrombotic Therapy
•

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•

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


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

Antithrombin III Inhibits the
Following Serine Proteases
• Coagulation

• Fibrinolysis

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•
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• Plasmin

Factor XIIa
Factor XIa
Factor IXa
Factor Xa
Thrombin

Inhibitory activity against all these enzymes is substantially accelerated by heparin

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

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

Heparin
•
•
•
•
•
•
•
•

Biologic Sources
Bioavailability
Metabolism
Elimination
Side Effects
Overdose
Contraindications
Pregnancy- YES

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

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)

Low Dose Unfractionated Heparin
• Surgical Prophylaxis
– 5,000 Units SQ 2 hr preop
– 5,000 Units SQ every 12 hours

• Medical Prophylaxis
– 5,000 Units SQ every 12 hours

• No monitoring required


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)


venous thromboembolism or
unstable angina

Regional anesthesia


venous thromboembolism

Regional anesthesia

Tinzaparin
(Innohep)


Regional anesthesia
Pregnancy
Prosthetic Heart Valves

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

Danaparoid

Heparinoid

Prophylaxis against
thrombosis in heparininduced
thrombocytopenia

thrombocytopenia

Bivalirudin

Hirudin derivative

Unstable angina or
angioplasty

Unknown

Fondaparinux
(Arixtra)

Prophylaxis in highSynthetic factor Xa
risk patients?
inhibitor

Unknown

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.


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.


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


Warfarin
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Bioavailability
Metabolism
Serum Protein Binding
Vitamin K Status
Protein C Effects
Elimination
Side Effects
Overdose
Contraindications
Pregnancy- NO

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

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

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

Platelet Receptor Mediated
Pathways: Drugs
Arachidonic Acid

ASA
NSAIDs

ADP

Ticlopidine
Clopidogrel

Thrombin
-Final Common Pathway
-Promotes Platelet
Adhesion (Fibrinogen,
vWF)

GP IIB/IIIA Inhibitors
Abciximab (ReoPro)
Eptifibatide (Integrilin)
Tirofiban


Anti Platelet Drugs
Drug

Mechanism

Uses

Aspirin

Permanently
inhibits COX-1
and COX-2

CAD
Stroke-TIAs

NSAIDs

Reversibly
inhibits COX-1

Limited

Dipyridamole

Inhibits PDE;
TIAs
increases cAMP

Ticlopidine
Clopidrgrel

Inhibits ADP
TIAs;Stroke
PlatAg;active
CAD;PVD
metabolite

Thank you
Leader in continuing dental education


Heparin /certified fixed orthodontic courses by Indian dental academy

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