Chapter 34

Drugs Used in Disorders of

Coagulation
LEARNING OBJECTIVES:
1.Understand the coagulation mechanism
2.Define the terms antithrombotics and
thrombolytics
3.Classify the drugs used in coagulation disorder
4.Describe the mechanism of action of each drug
5.Give the clinical significance of each agent
6.Discuss the adverse effects of each class or drug

EVENTS IN
HEMOSTASIS
PLATELET MIGRATION AND AGGREGATION
Product: PLATELET PLUG (white
thrombus/primary hemostasis)
ACTIVATION OF COAGULATION CASCADE
Product: PERMANENT CLOT (red
thrombus/secondary hemostasis)

PLATELET MIGRATION AND

ACTIVATION

PLATELET ADHESION
Platelet membrane

receptors include;
The glycoprotein (GP) Ia

receptor binding to collagen (C);

GP Ib receptor binding von
Willebrand factor (vWF)

PLATELET ACTIVATION
Platelet membrane receptors include;
GP IIb/IIIa, which binds fibrinogen and other
macromolecules
Aggregating Substances:
Adenosine Diphosphate (ADP)
Thromboxane A2 (TXA2)
Serotonin (5-HT)

Aggregating Substances
Thromboxane A2 (TXA2) is synthesized

from arachidonic acid within platelets and

is a platelet activator and potent
vasoconstrictor.
Products secreted from platelet granules;
Adenosine Diphosphate (ADP), a powerful

inducer of platelet aggregation, and

Serotonin (5-HT), which stimulates
aggregation and vasoconstriction.

PLATELET AGGREGRATION

ACTIVATION OF BLOOD
COAGULATION CASCADE
Occurs within 6-12 hours from time of injury
GOAL: To activate thrombin (Clotting Factor

IIa), which is required in converting fibrinogen

(Clotting Factor I) to its activated form (Fibrin)
Fibrin polymerized form of fibrinogen that

stabilizes the platelet plug

Deposit onto platelet plug and glues platelets together
Attracts other cells esp. RBC to deposit onto the platelet

plug (red thrombus)

2 Pathways:
Extrinsic - dominant
Intrinsic

Blood Coagulation Cascade (Extrinsic

Pathway)

Initiation of clotting

soluble

insoluble

REGULATION OF
THROMBOSIS
Plasmin
Antithrombin III
Protein C and Protein S

PLASMIN
A protease; responsible for facilitating

FIBRINOLYSIS
FIBRINOLYSIS process of fibrin digestion
t-PA

ANTITHROMBIN III; PROTEIN

C and S
Antithrombin III (ATIII)
ROLE: Directly inactivates activated clotting

factors (IIa, IXa, Xa, XIa, XIIa, XIIIa)

Protein C and S
Attenuate the blood clotting cascade by

proteolysis of two co-factors Va and VIIIa.

ANTITHROMBOTICS and
THROMBOLYTICS
ANTITHROMBOTICS
a. Anticoagulants
- slow down clotting/prevent
formation of clotting
b. Antiplatelets
- prevent platelet aggregation
THROMBOLYTICS
- degrade clots that have
already formed

Drugs Used in
Coagulation Disorders
ANTICOAGULANTS (ANTITHROMBOTICS)
Endogenous anticoagulant Protein C
Mucopolysaccharide Antithrombin III
Heparin
Vitamin K analogue Warfarin
Direct thrombin inhibitors
Hirudin (leech protein)
Lepirudin
Bivalirudin
Argatroban
Dabigatran

Drugs Used in
Coagulation Disorders
ANTIPLATELETS (ANTITHROMBOTICS)
GP IIb/IIIa receptor antagonist
Abciximab (monoclonal antibody)
Eptifibatide
Tirofiban
ADP receptor antagonist
Ticlopidine
Clopidogrel
TXA2 (COX) inhibitor
Aspirin
PDE/adenosine uptake inhibitor
Dipyridamole
Cilostazol

Drugs Used in
Coagulation Disorders
THROMBOLYTICS
(FIBRINOLYTICS)
Streptokinase
Anistreplase
Urokinase
Alteplase
Reteplase

HEPARIN
A heterogeneous mixture of sulfated

mucopolysaccharides
An indirect thrombin inhibitor (parenteral)

HEPARIN
FORMS:
Regular Heparin/ HMW Heparin/

Unfractionated Heparin
LMW Heparins
Enoxaparin
Dalteparin
Fondaparinux
Fraxiparin
Danaproid

MECHANISM OF ACTION
REGULAR HEPARIN:
Binds and forms an active complex to
antithrombin III (inhibits clotting factors
IIa, IXa, Xa, XIa, XIIa, XIIIa)
The binding accelerates ATIIIs
action by 1000-fold
LMWHs:
More selective binding at Xa.

CLINICAL USES
Given when initiating anti-coagulation

therapy
Mx of acute coronary syndrome
Tx (IV) and prevention (IV or SQ) of
pulmonary embolism
Mx of Deep Vein Thrombosis (DVT)
When anticoagulation is necessary
during pregnancy

Toxicity and Miscellaneous

effects of Heparin
BLEEDING
Close monitoring is recommended

Should be used with caution in hypersensitive

patients
Increased hairloss and reversible alopecia
Osteoporosis - long-term therapy
Heparin accelerates the clearing of postprandial
lipemia by causing the release of lipoprotein lipase
from tissues
Heparin-induced thrombocytopenia (HIT)
Long-term use is associated with
mineralocorticoid deficiency

CONTRAINDICATIONS
HIT

Active tuberculosis

Hypersensitivity to the

Ulcerative lesions of

drug
Active bleeding
Hemophilia
Significant
thrombocytopenia
Purpura
Severe hypertension
Intracranial hemorrhage
Infective endocarditis

the gastrointestinal
tract
Threatened abortion
Visceral carcinoma
Advanced hepatic or
renal disease

CONTRAINDICATIONS
Should be avoided

in patients who
have recently had
surgery of the
brain, spinal cord,
or eye, and in
patients who are
undergoing lumbar
puncture or
regional anesthetic
block

Should be used in

pregnant women
only when clearly
indicated

REVERSAL OF EFFECTS OF
HEPARIN
PROTAMINE SULFATE
Highly basic
100 units of Heparin = 1 mg Protamine

Sulfate (IV)

WARFARIN &
THE COUMARIN
ANTICOAGULANTS

Historical Drugs:
Dicumarol: Now used as
rodenticide
SE: inc. risk of GI bleeding,
ulceration,
Indanediones: Phenindione
SE: thrombocytopenia, fatal

WARFARIN
The only oral anticoagulant used in clinics
S-isomer is the active isomer
Mechanism of Action:
Inhibits hepatic synthesis of Vitamin K-

dependent clotting factors

Blockade of gamma-carboxylation of several
glutamate residues in clotting factors X, IX,
VII, II
8- to 12-hour delay in the action

Mechanism of Action
Protein carboxylation
reaction is coupled to
the oxidation of Vit.K

Hydroquinone form
(active)

Vitamin K epoxide
(inactive)

INDICATIONS
Deep venous thrombosis
Isch.heart disease
RHD
Pulmonary Embolism

WARFARIN
The therapeutic range for oral

anticoagulant therapy is defined in terms of

an Prothrombin Time-International
Normalized Ratio (PT-INR)

Category
Most Patients

PT-INR
2-3

Px has
prosthetic
heart valves

2.5-3.5

DRUG INTERACTIONS
INCREASED PT-INR: INCREASED RISK OF
HEMORRHAGE/BLEEDING
Pharmacokinetic:
Reduced plasma protein binding: Pyrazolone

derivatives
Enzyme Inhibitors: Amiodarone, Cotrimoxazole,
Cimetidine, Azole Antifungals, Macrolides,
Metronidazole
Pharmacodynamic:
ASA (high doses), 3rd Generation Cephalosporins,

Heparin, Chronic liver disease, Hyperthyroidism

DRUG INTERACTIONS
DECREASED PT-INR: INCREASED RISK OF
THROMBOSIS
Pharmacokinetic:
Enzyme Inducers: Barbiturates, Rifampin
Some drugs that prevent absorption

Pharmacodynamic:
Vitamin K, Diuretics, Hypothyroidism

UNDERSIRABLE EFFECTS
Cutaneous necrosis within the 1st week of

treatment
Purple Toe" syndrome - seen after at least 3 weeks
of warfarin use due to cholesterol embolization
Bleeding / hemorrhage
GI upset
Complications in pregnancy (CI):
Within 1st trimester - abnormal bone development -

teratogenic effect
Within 3rd trimester - hemorrhagic disorder in the
newborn - present with necrotizing enterocolitis (fatal in
newborn)

DIRECT THROMBIN
INHIBITORS
PARENTERAL
Hirudin from leech saliva
Lepirudin - recombinant form of Hirudin
Bivalirudin
Argatroban
ORAL
Ximelagatran withdrawn from the market
Dabigatran

DIRECT THROMBIN
INHIBITORS

Exert their

Intrinsic

anticoagulant effects
by directly binding
to the active site of
thrombin

Extrinsic

Xa

Fibrin

Thrombin
Fibrinog
en

Prothrombin

Therapeutic uses
Lepirudin - use in patients with thrombosis

related to heparin-induced thrombocytopenia

Bivalirudin - FDA-approved for use in
percutaneous coronary angioplasty
Argatroban - FDA-approved for use in
patients with HIT with or without thrombosis
and coronary angioplasty in patients with HIT
Dabigatran - approved for use in Europe for
prevention of venous thromboembolism in
patients who have undergone hip or knee
replacement surgery

Summary of anticoagulants

ANTITHROMBOTICS
(ANTIPLATELET DRUGS)

MECHANISM OF ACTION OF
ANTITHROMBOTIC AGENTS
DRUG

MECHANISM OF ACTION

ASPIRIN

Inhibits COX, thus prevents TXA2 and

PGs

CLOPIDOGREL
& TICLOPIDINE

Inhibit ADP pathway of platelet

formation

DIPYRIDAMOLE PDE inhibitor, thus increasing cAMP

levels to potentiate PGI2 (platelet
aggregation inhibitor)
ABCIXIMAB,
EPTIFIBATIDE,
TIROFIBAN

Inhibit glycoprotein IIb/IIIa, necessary

molecule for platelet aggregation

A
S
PI
RI
N

ASPIRIN
For primary prophylaxis of myocardial

infarction
325 mg/day

For secondary prevention of vascular

events among patients with a history of

vascular disease

CLOPIDOGREL
AND
TICLOPIDINE

General MOA of Antithrombotic

Drugs

USES AND UNDESIRABLE EFFECTS

OF ANTITHROMBOTIC AGENTS
DRUG

INDICATION

UNDESIRABLE EFFECTS

ASPIRIN

Reduces the risk of MI in

patients with unstable
angina

GI ulcer, bleeding,
hemorrhage

CLOPIDOGREL
& TICLOPIDINE

Reduction of
atherosclerotic events,
prevent thrombosis

Ticlopidine: Nausea,
dyspepsia, hemorrhage,
leukopenia
Clopidogrel: fewer adverse
effects than ticlopidine

DIPYRIDAMOLE

Prevents emboli

May worsen angina,

dizziness, headache,
syncope, GI disturbances,
rash

ABCIXIMAB,
EPTIFIBATIDE,
TIROFIBAN

Acute coronary
syndrome

Bleeding

THROMBOLYTIC AGENTS
Streptokinase
Urokinase
Anistreplase
Tissue Plasminogen Activator (TPA)
Alteplase
Reteplase

USES OF FIBRINOLYTICS
In the management of acute myocardial

infarction
Indicated in cases of ;
pulmonary embolism with hemodynamic

instability,
severe deep venous thrombosis such as the
superior vena caval syndrome, and
ascending thrombophlebitis of the iliofemoral
vein with severe lower extremity edema
Recombinant t-PA has also been approved for

use in acute ischemic stroke within 3 hours of

symptom onset

Drugs Used in Bleeding

Disorders
VITAMIN K
PLASMA FRACTIONS
DESMOPRESSIN ACETATE
FIBRINOLYTIC INHIBITORS:

AMINOCAPROIC ACID
SERINE PROTEASE INHIBITORS:
APROTININ (removed from the market)

VITAMIN K
Two natural forms exist:
Vitamin K1 (phytonadione) is found in food
Vitamin K2 (menaquinone) is found in human

tissues and is synthesized by intestinal

bacteria
Used in treating Warfarin overdosage
Vit.K3 (menadione) water soluble; ineffective

in warfarin overdosage
Vitamin K1 is currently administered to all

newborns to prevent the hemorrhagic

disease of vitamin K deficiency

PLASMA FRACTIONS
Used for the treatment of blood clotting

factors deficiencies such as;

Factor VIII deficiency (classic hemophilia,

or hemophilia A)
Factor IX deficiency (Christmas disease, or
hemophilia B)
Humate-P
is a factor VIII concentrate approved by the

FDA for the treatment of bleeding associated

with von Willebrand disease

DESMOPRESSIN ACETATE
Increases the factor VIII activity of patients

with mild hemophilia A or von Willebrand

disease
Can be used in preparation for minor
surgery such as tooth extraction
Available in high-dose intranasal
desmopressin

CRYOPRECIPITATE
Plasma protein fraction obtainable from

whole blood
Contains 300 mg of fibrinogen
Used to treat deficiencies or qualitative
abnormalities of fibrinogen
May also be used for patients with factor
VIII deficiency and von Willebrand disease if
desmopressin is not indicated and a
pathogen-inactivated, recombinant, or
plasma-derived product is not available

AMINOCAPROIC ACID
A synthetic inhibitor of fibrinolysis
An adjunctive therapy in hemophilia
As therapy for bleeding from fibrinolytic

therapy,
Prophylaxis for rebleeding from intracranial
aneurysms
Has been used in patients with postsurgical
gastrointestinal bleeding and
postprostatectomy bleeding and bladder
hemorrhage secondary to radiation- and
drug-induced cystitis

AMINOCAPROIC ACID
Adverse effects of the drug include;
Intravascular thrombosis from inhibition of

plasminogen activator
Hypotension
Myopathy
abdominal discomfort
diarrhea, and
nasal stuffiness
Should not be used in patients with

disseminated intravascular coagulation or

genitourinary bleeding of the upper tract
because of the potential for excessive clotting

TRANEXAMIC ACID
Is an analog of aminocaproic acid
Same properties as Aminocaproic acid