Pharmacological Agents for

Coagulation Disorders

 Hemostasis refers to the finely regulated

dynamic process of maintaining fluidity of
the blood, repairing vascular injury, and
limiting blood loss while avoiding vessel
occlusion (thrombosis) and inadequate
perfusion of vital organs
Common causes of dysregulated hemostasis:
Hereditary or acquired defects
Secondary effects of infection or CA

Mechanism of Blood Coagulation

Intrinsic System
the direct contact of the first clotting factor (factor
XII) with the damaged vessel wall activates the
clotting factor and initiates the cascade
Extrinsic System
tissue factor (known also as thromboplastin) is
released from the damaged vascular cell
Tissue factor directly activates clotting factor VII,
which then activates subsequent factors in the
clotting mechanism

 Both the intrinsic and extrinsic

systems ultimately lead to the
conversion of prothrombin to
thrombin
Thrombin is an enzyme that quickly
converts the inactive fibrinogen
molecule to fibrin

Clot Breakdown
Tissue plasminogen activator (t-PA)
converts plasminogen to plasmin
Plasmin, also known as fibrinolysin, is an
enzyme that directly breaks down the
fibrin mesh, thus destroying the clot
(Fibrinolysis)

Endogenous anticoagulant proteins:

protein C, protein S, and antithrombin III

Anticoagulants

 Heparin (Unfractionated, LMW)

Oral Anticoagulants
- Anisindione (Miradon)
- Dicumarol (generic)
- Warfarin (Coumadin)

 DVT 1 indication for anticoagulant therapy

Other indications:
after surgical procedures (joint replacement,
mechanical heart valve replacement)
following certain cardiovascular incidents
(myocardial infarction, ischemic stroke)

when patients will be relatively inactive for

extended periods of time

Heparin
1 drug used in the initial
treatment of venous thrombosis
Heparin works by potentiating the
activity of a circulating protein
known as antithrombin III

UFH
High-molecular-weight (HMW), also known
as UFH, fractions of heparin with high
affinity for antithrombin markedly inhibit
blood coagulation by inhibiting all three
factors, especially thrombin and factor Xa
Unfractionated heparin
- Calciparin
- Liquaemin

LMWH
Low-molecular-weight (LMW) fractions of
heparin inhibit activated factor X but have
less effect on thrombin
Low molecular weight heparins:
- Ardeparin (Normiflo)
- Dalteparin (Fragmin)
- Enoxaparin (Lovenox)
- Tinzaparin (Innohep)

Advantages
LMWHs can be administered by subcutaneous
injection into fat tissues decreasing the
need for repeated intravenous administration
Dosing schedules of LMWHs are typically
easier (once per day), compared to 2 or more
daily injections of unfractioned heparin

less risk of adverse effects such as hemorrhage

and death

 primary method of treating acute venous

thrombosis
LMWHs are now used routinely to prevent
or treat deep vein thrombosis (DVT)
following various types of surgery or
medical conditions (ischemic stroke, CA)
More predictable pharmacokinetic profile
which allows weighted-adjusted subQ
administration s lab monitoring

Administration and Dosage

Continuous IV infusion (infusion pump)initial: 80100 units/kg, continuous
infusion: 1522 units/kg/h to maintain
the anti-Xa activity in the range of 0.30.7
units/mL
Therapy routinely is monitored by the
aPTT or PTT (activated partial
thromboplastin time)

 Low-dose prophylaxis: subcutaneous

administration of heparin
5000 units every 812 hours.

Because of the danger of hematoma

formation at the injection site, heparin
must never be administered
intramuscularly.

 Subcutaneous administration for

long term management of pts
(warfarin is CI) ex: pregnancy
35 000 U every 8-12 hours

 Prophylactic enoxaparin
Subcutaneously; 30 mg twice daily or 40 mg
once daily.
Full-dose enoxaparin
1 mg/kg; subcutaneously every 12 hours ;
anti-factor Xa level of 0.51 unit/mL
Selected patients may be treated with
enoxaparin 1.5 mg/kg once a day, with a target
anti-Xa level of 1.5 units/mL.

 Dalteparin
5000 units subcutaneously od
200 units/kg od for venous disease
120 units/kg every 12 hours acute
coronary syndrome
LMWH should be used with caution in
patients with renal insufficiency or body
weight >150 kg.

Monitoring of Heparin Effect

activated partial thromboplastin time (aPTT or
PTT ) is necessary in patients receiving UFH
protamine titration (0.20.4 unit/mL) or anti-Xa
units (0.30.7 unit/mL)
Weight-based dosing of the LMWH levels are not
generally measured except in the setting of renal
insufficiency, obesity, and pregnancy.
anti-Xa units (0.51 unit/mL for twice-daily 4
hours after administration and ~1.5 units/mL for
once-daily)

Adverse Effects of Heparin

Hemorrhage - 1
Increased loss of hair and reversible
alopecia
Osteoporosis, fractures and
mineralocorticoid deficiency long term
therapy
Heparin Induced Thrombocytopenia (HIT)
a systemic hypercoagulable state
Caution: Allergic reaction

Contraindications

HIT
Hypersensitivity to the drug
Active bleeding
Hemophilia
Significant thrombocytopenia
Purpura
Severe htn
Recent surgery of the brain, SC or
eye
Pts undergoing lumbar puncture
or regional anesthetic block

Intracranial hemorrhage
Infective endocarditis
Active tuberculosis
Ulcerative lesions of GI
tract
Threatened abortion
Visceral carcinoma
Advanced hepatic or
renal disease

Oral Anticoagulants

block the conversion of vitamin K epoxide to

vitamin K

impairs the hepatic synthesis of several clotting

factors

dec. level of circulating clotting factors (II,VII,

IX, X)

dec. blood coagulation and thrombogenesis

Warfarin (Coumadin)
one of the most commonly
prescribed drugs
8- to 12-hour delay in the action
100% bioavailability
Half life: 36 hrs

 Prevention of stroke in atrial

fibrillation, clotting on new
prosthetic heart valves, and clots
in dilated cardiomyopathy

Administration and Dosage

Initial: 510 mg
Initial adjustment of the
prothrombin time takes about 1
week, which usually results in a
maintenance dose of 57 mg/d

Adverse Effects and CI

Warfarin
Pregnancy
Hemorrhagic disorder in the fetus
Birth defect abN bone formation
Cutaneous necrosis
Frank infarction of the breast, fatty tissues,
intestine, and extremities Rare
Dicumarol
gastrointestinal distress (nausea, stomach cramps,
diarrhea)

Other Anticoagulants

 Lepirudin (Refludan)
- a drug that directly inhibits thrombin; it
can be administered intravenously to prevent
excessive clotting in conditions such as
heparin-induced thrombocytopenia

 Fondaparinux (Arixtra)
newer agent that can be administered by
subcutaneous injection to prevent DVT
following orthopedic procedures (hip, knee
replacement) and other surgeries
inhibits clotting factor Xa

 Ximelagatran
is new drug that is currently being
developed to prevent or treat DVT. It
directly inhibits thrombin, but has the
advantage of oral administration

Antithrombotic Drugs

Aspirin
Suppresses platelet aggregation by
inhibiting the synthesis of
prostaglandins and thromboxanes
Prevents platelet-induced
thrombus formation

 Standard therapy during the acute

phase of myocardial infarction
Prolonged use of Aspirin one of the
primary pharmacological methods
used to prevent reinfarction and
maintain coronary artery patency

 Helps prevent the type of stroke caused

by cerebral ischemia and infarction
Reduces the risk of ischemic stroke in
people with atrial fibrillation
Prevents thrombus formation in
peripheral veins and thromboembolism
following surgical procedures

 Suggested daily dosage = 75 to 325

mg/day
Adult Aspirin tablet = 325 mg/day
Pediatric Aspirin tablet = 160 mg/day
Antithrombotic effects can be achieved
at very low Aspirin doses

Glycoprotein IIb-IIIa Inhibitors

Most powerful inhibitors of platelet
activity

Block (antagonize) the GP receptor on

the platelet membrane that is
stimulated by fibrinogen and other
chemical mediators

 Primarily used during balloon

angioplasty and other percutaneous
coronary interventions that help reestablish coronary artery blood flow
Not typically administered orally
Abciximab (ReoPro), Eptifibatide
(Integrilin), Tirofiban (Aggrastat)

ADP Receptor Inhibitors

Produce moderate inhibiton of platelet
activity

Aspirin < ADP Receptor inhibitors <

GP IIb-IIIa inhibitors
Reduces platelet-induced clotting by
inhibiting the receptors for ADP

Dipyridamole
Used alone or in combination with
Aspirin to decrease platelet-induced
clotting
Helpful in preventing ischemic stroke
and myocardial infarction

Potential alternative to other antiplatelet

drugs in treating arterial thrombosis

Sulfinpyrazone
Usually administered to treat gouty
arthritis

Decreases platelet aggregation by

inhibiting prostaglandin synthesis
Alternative to Aspirin in preventing
reinfarction after a heart attack

Cilostazol
Newer phosphodiesterase inhibitor
that promotes vasodilation and
inhibition of platelet aggregation
Used primarily to treat intermittent
claudication

Adverse Effects

Increased risk of bleeding

Gastric irritation
Liver and kidney toxicity
Hypotension (Abciximab, Eptifibatide)
GI distress (Clopidogrel, Dipyridamole)
Blood dyscrasias (Ticlopidine)
Kidney stones formation (Sulfinpyrazone)

Thrombolytic
Drugs

 Dissolved clots that have already formed

Converting plasminogen to plasmin
IV administration -> produce beneficial effects

Contraindication:
Hx of hemorrhagic stroke

Intracranial neoplasm
Active internal bleeding

Possible aortic dissection

Streptokinase
Most commonly used type of
thrombolytic
Indirectly activates plasmin to the
precursor molecule plasminogen
Dosage: 100,000units/hr for 24-72
hrs.

Urokinase
Directly converts plasminogen to
plasmin
Dosage: 300,000units/hr for 12 hrs
Streptokinase and Urokinase
Both bring the activation of
plasmin

Tissue plasminogen activator (t-PA)

Generic name: ALTEPLASE
Rapidly and effectively initiates clot
breakdown
Joins streptokinase as one of the primary
thrombolytic agents
Used preferentially during ischemic stroke
Dosage: 20mg/hr

Anistreplase (Eminase)
AKA: Anisoylated plasminogenstreptokinase activator complex (APSAC)
Formed by combining plasminogen with
streptokinase
More selective for clots that have already
formed
Less effect on systemic fibrinolysis
Dosage: 30units over 3-5mins

Reteplase and Tenecteplase

Actions similar to t-PA (alteplase)
Administration through IV bolus injection
ADVERSE EFFECTS OF THROMBOLYTIC
DRUGS
Hemorrhage -> major adverse effect
Fever
Allergic reaction (itching,nausea,headache
and other symptoms)

Treatment of Clotting
Deficiencies

Hemophilia
Replacing the missing clotting factor
Can be administered on a regular basis
or during acute hemorrhagic episode

Deficiency of Vitamin K-dependent

clotting factors
Treated by administering exogenous
Vitamin K
Available for oral or parenteral
administration

Antifibrinolytics
Prevent the activation of plasmin thus
preserving clot formation
Aminocaproic Acid (Amicar) and
Tranexamic Acid (cyklokapron)
For patient with hemophilia to prevent clot
breakdown when undergoing surgery
Oral or IV administration

Adverse Effects:

Nausea
Diarrhea
Dizziness
Headache

THANK YOU and

GOD BLESS!