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Drugs for Coagulation
disorders
• There are a number of different categories
of drugs which modify the coagulation
process:
• I. Anticoagulants
• II. Antiplatelet agents
• III. Thrombolytics
I. Anticoagulants
A. The coagulation cascade
• The coagulation cascade begins when
injured cells release thromboplastin.
• Thromboplastin converts the clotting factor
prothrombin to thrombin.
• Thrombin then converts the plasma
protein fibrinogen to long strands of fibrin
and activates several clotting factors (V,
VIII, XIII, and protein C)
• The fibrin strands form an insoluble web
B. Types of anticoagulants
• The mechanism of action of anticoagulant
medications involves either the
inactivation of various existing
coagulation factors, or
• preventing the synthesis of coagulation
factors (the vitamin K antagonists)
• Anticoagulant medications do NOT
dissolve clots.
1. heparins
• a. standard heparin
• b. low molecular weight (LMW) heparins
• Heparins are indicated for the treatment
of:
• deep vein thrombosis (DVT)
• prophylaxis and treatment of venous
thrombi, alone
• prophylaxis and treatment of venous
thrombi in conjunction with pulmonary
emboli
• Heparins are NOT direct thrombin
inhibitors.
• Instead, heparins prevent thrombin
formation by binding to clotting factors in
the circulation.
• These clotting factors then bind to and
inactivate thrombin, the major enzyme in
the clotting pathway.
• The main commercial sources of standard
heparin are the lungs and intestines of
cattle (bovine) and pigs (porcine).
• LMW heparins are derived from porcine
heparin.
• They are smaller in size as they only
contain the anticoagulant fraction of
heparin, and not the additional saccharide
chains that standard heparin has.
a. Standard heparin
• Standard heparin has an immediate onset
of action if administered IV, it peaks
within 5-10 minutes, and its duration is 2-6
hours.
• Standard heparin has an onset of action of
20 minute – 1 hour if administered SC, it
peaks within 2 hours, and its duration is 812 hours.
• Standard heparin IV administration:
bolus of 10,000 – 12,000 units followed by
5,000-10,000 units every 4-6 hours
• Standard heparin SC administration:
bolus of 10,000 – 12,000 units followed by
15,000-20,000 units every 12 hours
b. Low molecular weight (LMW)
heparins
• LMW heparins are ONLY administered
SC, have a rapid onset of action, generally
peak within 3-6 hours, and have a duration
of 12-24 hours depending on the agent.
Specific LMW heparins include:
•
• i. dalteparin (Fragmin):
• Indicated for prophylaxis of Deep Vein
Thrombosis (DVT) in patients undergoing
abdominal surgery or hip replacement
surgery.
• ii. enoxaprin (Lovenox):
• Indicated for prophylaxis of DVT in
patients undergoing abdominal, hip, or
knee surgery.
• iii. fondaparinux (Arixtra):
• Indicated for both the treatment of and
prophylaxis of DVT and pulmonary
embolism (PE).
• iv. tinzaparin (Innohep):
• Indicated for both the treatment of and
prophylaxis of DVT.
• LMW heparins have certain advantages
over standard heparin:
• 90% bioavailability (standard heparin has
30%)
• LMW heparin can be dosed based on
body size without coagulation test
monitoring (if patient has normal kidney
function)
• Adverse effects of heparins:
• hemorrhage
• anemia in elderly with Lovenox, due to
decreased clearance
• fever
• hair loss
• thrombocytopenia (↓ in no. of platelets)
• Black box warning for LMW heparin use in
patients concurrently receiving epidural or
spinal anesthesia as it increases the risk
for epidural or spinal hematomas
2. thrombin inhibitors
• Unlike the heparins, these drugs bind
directly to thrombin. They are all
administered IV.
• a. argatroban (Argatroban)
• indicated for patients with, or at risk for
thrombocytopenia who are undergoing
percutaneous coronary intervention (PCI).
• b. bivalirudin (Angiomax): used, along with
aspirin, in patients with unstable angina
who undergo PCI. This treatment is
intended to reduce the risk of acute
ischemic complications
• c. lepirudin (Refludan): derives from the
natural product hirudin, found in leech
saliva.
• Leeches have been used for bloodletting
since the times of the ancient Greeks.
3. anticoagulants which prevent the
synthesis of coagulation factors
• This category of anticoagulant is
significantly different from the heparins in
that it can be administered orally.
• This type of anticoagulant has a longer
onset because of the time required to clear
the normal clotting factors from the
circulation before an effect can be
observed.
• The only drug in this class is warfarin
sodium (Coumadin): 2-10 mg
• Its onset of activity is about 12-72 hours.
• However, its duration of action is longer (2
to 10 days) even after drug administration
has been discontinued.
• Coumadin is indicated for the treatment of
DVT and prevention of myocardial reinfarction
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Adverse effects include:
GI disturbances
hypotension
hair loss
headache
hemorrhage (most serious)
• A black box warning indicates that there is
an ↑ risk of hemorrhage in:
• patients over 65
• patients with a history of GI bleeding
• INR > 4
• INR (international normalized ratio) is a
test used to monitor coagulation status.
• People not on anticoagulants have an INR
of 1
• An INR of 2 – 3 is needed for a
therapeutic effect with warfarin
II. Antiplatelet agents
• Antiplatelet agents exert an anticoagulant
effect by interfering with various aspects of
platelet function.
• Antiplatelet agents are indicated for the
treatment of :
• thrombocytopenia
• acute coronary syndrome
• prevention of myocardial re-infarction
• and reducing coronary events
• The 2 subclasses of antiplatelet agents
are:
• A. nonselective COX inhibitors
• B. adenosine diphosphate (ADP) receptor
blockers
A. nonselective COX inhibitors
• Normally, the cyclooxygenase enzyme
pathway in platelets results in the
production of thromboxane A2, a potent
platelet aggregator.
• Aspirin, in doses from 81 mg (baby
aspirin) to 325 mg (adult analgesic dose)
irreversibly blocks a step in this pathway,
preventing the synthesis of thromboxane
A2.
• Therefore, thromboxane will not be active
until new platelets are formed.
B. ADP receptor blockers
• These drugs interfere with a receptor on
the membrane of platelets, preventing
them from aggregating.
• Adenosine diphosphate (ADP) normally
binds to these membrane receptors in
platelets, resulting in the coagulation of the
platelets.
• The drugs in this class block the receptor
so that ADP cannot bind.
• All of the drugs in this class are
administered orally.
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1. ticlopidine (Ticlid): 250 mg, bid
2. clopidogrel (Plavix): 75 mg
3. cilostazol (Pletal): 100 mg, bid
4. prasugrel (Effient): 5 – 10 mg with food
5. anagrelide (Agrylin): 1.0 mg, bid
III. Thrombolytics
• Thrombolytics are enzymes used to
dissolve blood clots.
• They convert plasminogen to plasmin,
which is then able to degrade the fibrin
present in clots.
• Their primary functions are: to break apart
pulmonary emboli and coronary artery
thromboses during acute MI.
• They need to be administered as soon as
possible once it has been established that
a clot or infarct has occurred.
• Other disorders for which they may be
indicated are:
• DVT
• stroke
• occluded central venous access devices
• For the treatment of acute MI: administer
the drug within 1-6 hours of the onset of
symptoms.
• There is a longer window of opportunity for
use of these drugs in treating a pulmonary
embolism. Here the time for initiation of
therapy may be up to a few days.
• All drugs in this class are enzymes that
must be administered IV.
A. streptokinase
• Streptokinase (Streptase, Kabbikinase):
generally, 250,000 IU over 30 minutes,
then 100,000 IU/hour for up to 72 hours
• Larger doses may be used in the
treatment of MI
B. urokinase
• urokinase (Abbokinase): IV 4400-6000 IU
administered over several minutes to 12
hours
• A symptomatic ulnar artery occlusion
before and after urokinase infusion
therapy.
C. thrombolytics produced via
recombinant DNA
• alteplase (Activase, Cathflo), reteplase
(Retavase) and tenecteplase (TNKase)
are thrombolytic enzymes produced
through recombinant DNA technology
• alteplase: based on patient weight, not to
exceed 100 mg. Generally, a 15 mg bolus,
followed by 50 mg over next 30 minutes
then 35 mg over the next 60 minutes
• reteplase: 10 unit bolus over 2 minutes,
wait 30 minutes, repeat
• tenecteplase: a single bolus, over 5
seconds based on body weight, not to
exceed 50 mg
• Generally used in conjunction with aspirin
and heparin therapy
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Adverse effects of the thrombolytics:
hemorrhage
rash/itching
headache
nausea
bronchospasm
cardiogenic shock or arrhythmias with the
recombinants