ANTICOAGULANTS
MEDPHARM 2010
PART ONE
HEMOSTASIS & THROMBOSIS
Coagulation Cascade - Secondary Hemostasis
Series of protease enzymes
and their cofactors
Extrinsic
Takes place on phospholipid
surface (platelet or
endothelium)
Common
Consists of extrinsic, intrinsic
and common pathways
Results in formation of
stable fibrin clot
Intrinsic
The Coagulation and Fibrinolytic Pathways
Kohler H and Grant P. N Engl J Med 2000;342:1792-1801
Hemostasis requires a fine balance between
procoagulant and regulatory factors
Deficiency
Coagulation
Proteins/
Platelets/
Vessel wall
PC
PS
ATIII…
Thrombosis
Deficiency/
Abnormality
Bleeding
Thrombosis
• Definition
– Formation of a mass of platelets, coagulation
proteins and RBCs (thrombus) in a blood vessel
• Hemostatic thromboses
– Self-limited and localized, prevent excessive blood
loss, represent the body’s natural response to
acute vascular injury.
• Pathologic thromboses
– A pathologic process, during which the balance of
procoagulant and anticoagulant components of the
coagulation system is lost
– Clot forms at site free of significant vascular injury
or there is failure to localize the thrombus, and the
vessel may be occluded
Thrombosis - Pathogenesis
• 3 primary influences
predispose to
thrombus formation
Virchow’s Triad (1856):
1.Endothelial Injury
2.Stasis
3.Hypercoagulability
Fate of the Thrombus
Propagation
1) Dissolution (cleared
by fibrinolysis)
2) Embolization
3) Propagation
4) Organization and
recanalization
Dissolution
Embolization
Organization and recanalization
Clinical significance of thrombosis
1. Obstruction of arteries and veins
– Ischemia or necrosis of downstream tissue
2. Embolization
Arterial Thrombosis
• Most common cause of death in Western
industrialized countries
– Myocardial infarction due to thrombotic occlusion of a
coronary artery is the #1 cause of death
• Endothelial damage
– Atherosclerosis
–
–
–
–
Hypertension
Hypercholesterolemia
Radiation
Endotoxins (in bacterial infection)
Atherosclerotic Plaque Disruption and Platelet Activation
Mohler E. N Engl J Med 2007;357:293-296
Venous Thrombi
• Most occur in the superficial
or deep veins of the leg
(DVT)
• Superficial thrombi
– Swelling and pain
– Rarely embolize
• DVT
– Pain, redness and swelling
– Asymptomatic in 50%
Pathophysiology of Pulmonary Embolism
Tapson V. N Engl J Med 2008;358:1037-1052
Thromboembolism
• Detached fragment from a thrombus is
carried to a distant site and lodges in the
vascular system
• Pulmonary
• Systemic
Pulmonary Thromboembolism
• Definition: a fragment of a thrombus dislodges and then travels
through the venous circulation to the heart and then lands in the
pulmonary arterial circulation
• Scope of the problem:
– Primary cause of death in 100,000/year in US, and a contributing
cause of death in another 100,000/year
– Cause of death in 10-15% of hospitalized patients
• Clinical symptoms (most are clinically silent)
–
–
–
–
–
Chest pain
Cough
Shortness of breath
Rapid heart rate (tachycardia)
Rapid respirations (tachypnea)
Pulmonary Thromboembolism
OUTCOMES
1.
Most are clinically silent (60-80%)
•
2.
Small
Sudden death, right heart failure or cardiovascular
collapse (5%)
•
3.
Occurs with obstruction of >60% of pulmonary circulation
Pulmonary hemorrhage
•
•
4.
From obstruction of medium-sized vessel
Infarction occurs in patients with compromised bronchial
circulation
Pulmonary hypertension (2-3%)
•
Multiple small thromboemboli
Systemic Thromboembolism
Emboli within the arterial circulation
• Most arise from thrombi in the
cardiac chambers in the setting
of myocardial infarction
• Many others originate from
thrombi on ulcerated
atherosclerotic plaques
Infarction
• Ischemic necrosis caused by occlusion of
either the arterial supply or venous
drainage
– Ischemia
• Isch = stop (Greek)
• Hema = blood
Infarction
• Scope of the problem
–More than half of all deaths in the US
are caused by cardiovascular
disease
• Myocardial infarction
• Cerebral infarction
Causes of Infarction
• Thrombosis
• Embolism
99% of • Twisting of vessels
infarction (torsion)
• Vasospasm
• Compression of blood
supply
• Rupture of a vessel
Vulnerability to hypoxia
• The susceptibility of a tissue to hypoxia
influences the likelihood of infarction
– Neurons: 3-4 minutes
– Myocardial cells: 20-30 minutes
– Fibroblasts in myocardium: several hours
Oxygen content of blood
• Patients with diminished oxygen content
are more susceptible
– Anemia or pulmonary disease
– Even partial obstruction of a small vessel may
lead to infarction, whereas under normal
circumstances it would be without effect
The Coagulation and Fibrinolytic Pathways
Kohler H and Grant P. N Engl J Med 2000;342:1792-1801
Simplified View of the Coagulation Cascade
Extrinsic
Intrinsic
Common
Prothrombin Time
Extrinsic pathway
Monitor warfarin
INR
Activated Partial
Thromboplastin Time
Intrinsic pathway
Monitor heparin
ANTICOAGULANT & ANTITHROMBOTIC
DRUGS
Target
Activated clotting factors
Clotting factors
Thrombin
Platelets
Blood clot
Drug
Heparin
Warfarin
Bivalirudin
Aspirin
Clopidogrel
Abciximab
r-tissue plasminogen activator
HEPARIN FACTORY
HEPARIN
• Source biological
• Unfractionated(UFH)
• Low molecular
weight(LMWH)
• Target:activated
factors
As heparin enters the circulation, it binds to heparin-binding proteins (ie,
other plasma proteins), ECs, Ms, and ATIII
Hirsh, J. et al. Chest 2004;126:188S-203S
Molecular weight distributions of LMWHs and heparin
Hirsh, J. et al. Chest 2004;126:188S-203S
DRUG TARGETS
• Unfractionated
heparin(UFH)
DRUG TARGETS
• LOW MOLECULAR
WEIGHT
HEPARIN(LMWH)
• Enoxaparin
HEPARINS
HEPARIN
ABSORPTION
-
NIL
DISTRIBUTION
-
LIMITED
METABOLISM
-
HEPATIC- RE –
CELLS
ELIMINATION
-
UNKNOWN
Simplified View of the Coagulation Cascade
Extrinsic
Intrinsic
Common
Prothrombin Time
Extrinsic pathway
Monitor warfarin
INR
Activated Partial
Thromboplastin Time
Intrinsic pathway
Monitor heparin
HEPARIN TEST of CONTROL
ACTIVATED PARTIALTHROMBOPLASTIN
TIME
OR
aPTT or PTT
A THERAPEUTIC VALUE, ~ 0.3 u/ml
REVERSAL
UFH – Protamine
LMWH – Protamine not fully effective
SIDE EFFECTS OF HEPARIN
Bleeding
Thrombocytopenia-HIT with
Arterial & venous thromboembolism
Hypersensitivity
Osteoporosis
Monitor
aPTT & platelet count
Stead L and Judson K. N Engl J Med 2006;355:e7
HEPARIN
ADVERSE REACTION
HEMORRHAGE
TREATMENT
REDUCE THE DOSE
DISCONTINUE THE DRUG
PROTAMINE SULFATE
TRANSFUSION
HEPARIN-INDUCED
THROMBOCYTOPENIA-HIT
• A prothrombotic, panvascular disorder
• Venous thromboembolic events/ arterial
thromboembolic events – 4:1
• The antigen is heparin+platelet factor 4
• The antibody is HIT-IgG
• There is platelet activation and thrombin
generation
Immune-Mediated Thrombocytopenia
Warkentin T. N Engl J Med 2007;356:891-893
A schematic representation of steps that occur during platelet activation in a
patient with HIT
Kelton, J. G. Chest 2005;127:9S-20S
HIT (UFH & LMWH)
• Venous thromboembolism
• Arterial thrombosis
• Adrenal vein thrombosis – adrenal
necrosis
• Skin necrosis
• Anaphylactic reactions
• Disseminated intravascular necrosis
• Warfarin – increases risk of
microthrombosis
HIT Rx
Direct thrombin inhibitor
Argatroban or Lepirudin
WARFARIN NOT USED
Warfarin causes venous gangrene
FONDAPARINUX
Active pentasaccharide moiety of herapin
Parenteral use
PE/DVT Treatment and prophylaxis
Inhibitor of activated factor x (Xa)
Thrombin unaffected
Monitoring not required
FONDAPARINUX
DIRECT THROMBIN RECPETOR
(IIa) ANTAGONISTS
HEPARIN ALTERNATIVES
Hirudin
Bivalirudin
Argatroban
Thrombin Generation
Di Nisio, M. et al. N Engl J Med 2005;353:1028-1040
Mechanism of Action of Direct Thrombin Inhibitors as Compared with Heparin
Di Nisio, M. et al. N Engl J Med 2005;353:1028-1040
CLINICAL PHARMACOLOGY
DRUG
VTE/PE TREATMENT
UFH
X monitor with APTT,
H/H and platelet count
X (low dose)
LMWH
X monitor H/H &
platelet count
X
FONDAPARINUX
X monitor H/H
VTE PROPHYLAXIS
X
ORAL ANTICOAGULANT
WARFARIN A vitamin k antagonist
ROLE of VITAMIN K
WARFARIN – DRUG INTERACTIONS
Diminished warfarin actions
Ethanol
Enhanced warfarin actions
Ethanol
Aspirin
Cimetidine
Simplified View of the Coagulation Cascade
Extrinsic
Intrinsic
Common
Prothrombin Time
Extrinsic pathway
Monitor warfarin
INR
Activated Partial
Thromboplastin Time
Intrinsic pathway
Monitor heparin
PROTHROMBIN TIME
• Reported in real time seconds(pt/control)
With the ratio standardized to the reagents
used:
The value reported is the INR or
International Normalized Ratio
PROTHROMBIN TIME
WARFARIN MANAGEMENT
INR excessive,not bleeding - adjust dose
BLEEDING
stop warfarin
transfuse
give prothrombin complex(clotting
factors)
give vitamin K1
INR subtherapeutic
increase warfarin dose slowly
ANTICOAGULANT THERAPY
Heparin(UFH)
TREATMENT: Full dose,iv
Deep venous thrombosis (DVT)
Pulmonary embolism (PE)
After acute myocardial infarction
PROPHYLAXIS: Low dose, subcutaneous
Prevention of DVT & PE
LMWH
Prevention & treatment DVT/PE
ANTICOAGULANT THERAPY
Warfarin
Prevention of thromboembolism
DVT/PE
Atrial fibrillation
w/ Valvular heart disease
w/ Acute myocardial infarction
w/ Prosthetic heart valves
w/ Recurrent systemic embolization
NOT for stroke or peripheral vascular disease
PLATELET ORIGIN
Atherosclerotic Plaque Disruption and Platelet Activation
Mohler E. N Engl J Med 2007;357:293-296
Arterial thrombogenesis
AntiPlatelet
Drugs
Weitz, J. I. et al. Chest 2004;126:265S-286S
ANTIPLATELET DRUGS
Aspirin
Clopidogrel
Abciximab
Prasurgrel
Sites of Action of Antiplatelet Therapy on Mechanisms of Platelet
Activation and Aggregation
Schulman, S. P. JAMA 2004;292:1875-1882.
Copyright restrictions may apply.
PROSTAGLANDIN SYNTHESIS
Production of prostaglandins from arachidonic acid and their main physiologic
actions
Sanderson, S. et. al. Ann Intern Med 2005;142:370-380
The absolute risk of vascular complications is the
major determinant of the absolute benefit of
antiplatelet prophylaxis
Patrono, C. et al. Chest 2004;126:234S-264S
CLOPIDOGREL (Plavix)
Inhibits ADP mediated platelet aggregation
A prodrug that requires 2 step bioactivation
by cytochrome P-450
Biovalibility ~ 15%
ADRs
Bleeding
TTP (thrombotic thrombocytopenic purpura)
TTP
•
•
•
•
•
•
•
Thrombocytopenia
Microangiopathic hemolytic anemia
Fever
Neurologic changes
Renal abnormalities
Case rate 3.7/year/million
Mortality 10-20%
TTP CAUSE
Autoantibody vs a metalloproteinase that
degrades vonWillebrand factor
The impaired proteolysis leads to binding of
large multimers of vWF to platelets with
microthrombi production
ADP block prevents expression of
glycoprotein IIb/IIIa which binds large
multimers of vWF
Simplified Model of von Willebrand Factor Functions in Platelet-Plug Formation
Mannucci P. N Engl J Med 2004;351:683-694
CLOPIDOGREL
ANTIPLATELET THERAPY
• Aspirin: Primary prevention of MI in high
risk persons
Secondary prevention of MI,TIA & stroke
• Clopidogrel: for persons who can’t take
aspirin
• Aspirin+clopidogrel: Acute coronary
syndromes
Sites of Action of Antiplatelet Therapy on Mechanisms of Platelet Activation and Aggregation
Schulman, S. P. JAMA 2004;292:1875-1882.
Copyright restrictions may apply.
GLYCOPROTEIN IIb/IIIa
RECEPTOR ANTAGONISTS
ABCIXIMAB
Integrelin
Others
USE: Acute coronary syndromes
The balance between the formation and degradation of FN
Nesheim, M. Chest 2003;124:33S-39S
A 65-year-old woman with chronic atrial fibrillation was admitted for an elective exchange of an
implanted defibrillator for idiopathic dilated cardiomyopathy
Ryan R and Brophy D. N Engl J Med 2007;357:2495
A classification of stroke by mechanism with estimates of
the frequency of various categories of abnormalities
Albers, G. W. et al. Chest 2004;126:483S-512S
END