Drugs Used in Disorders of

Coagulation
TOPIC OUTLINE:
1. Hemostasis

2. Classifications of Drugs
a) Anti-thrombotics
b) Thrombolytics
c) Pro-thrombotics
Hemostasis

— Stimuli of Clot Formation:

— Endothelial Injury
— Blood stasis
— Presence of foreign material
inside the body
EVENTS IN HEMOSTASIS

1) PLATELET MIGRATION AND AGGREGATION

Product: PLATELET PLUG
2) ACTIVATION OF COAGULATION CASCADE
Product: PERMANENT CLOT
3) DEGRADATION OF CLOT
PLATELET MIGRATION AND AGGREGATION
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
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
— Vitamin K-dependent anti-clotting factors
— Attenuate the blood clotting cascade by proteolysis of two co-
factors Va and VIIIa.
 DRUGS

ANTI-THROMBOTICS

THROMBOLYTICS

PRO-THROMBOTICS
 ANTI-THROMBOTICS
ANTICOAGULANTS
— Direct Thrombin Inhibitors

— Indirect Thrombin Inhibitors

 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 anticoagulant effects by directly
binding to the active site of thrombin
Therapeutic uses
— Lepirudin - used in patients with thrombosis related to
heparin-induced thrombocytopenia
— Bivalirudin - FDA-approved for use in percutaneous
transluminal 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
 INDIRECT THROMBIN INHIBITORS

PARENTERAL
• Heparin

ORAL
• Warfarin
 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 ATIII’s 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
Monitoring
 CONTRAINDICATIONS
— HIT
— Hypersensitivity to the drug
— Active bleeding
— Hemophilia
— Significant thrombocytopenia
— Purpura
— Severe hypertension
— Intracranial hemorrhage
— Infective endocarditis
— Active tuberculosis
— Ulcerative lesions of the
gastrointestinal tract
— Threatened abortion
— Visceral carcinoma
— Advanced hepatic or renal
disease
CONTRAINDICATIONS
— Should be avoided in — Should be used in pregnant
patients who have recently women only when clearly
had surgery of the brain, indicated
spinal cord, or eye, and in
patients who are
undergoing lumbar
puncture or regional
anesthetic block
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 hypersensitivity rxn
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

Warfarin inhibits the hepatic synthesis of

Vitamin K-dependent clotting factors.
Mechanism of Action
INDICATIONS
— Deep venous thrombosis
— Ischemic 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 PT-INR
Most Patients 2-3

Px has prosthetic 2.5-3.5

heart valves
 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, 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)
ANTIPLATELETS
ANTIPLATELETS
— TXA2 (COX) Synthesis Inhibitor
— Aspirin
— ADP Receptor Antagonists
— Ticlopidine
— Clopidogrel
— PDE/adenosine uptake Inhibitors
— Dipyridamole
— Cilostazol
— GP IIb/IIIa Receptor Antagonists
— Abciximab (monoclonal antibody)
— Eptifibatide
— Tirofiban
A
S
P
I
R
I
N
ASPIRIN
— For primary prophylaxis of myocardial infarction
— NMT 325 mg/day
— For secondary prevention of vascular events among patients
with a history of vascular disease
CLOPIDOGREL
AND
TICLOPIDINE
CLOPIDOGREL AND
TICLOPIDINE
DIPYRIDAMOLE AND
CILOSTAZOL
GP IIB/IIIA INHIBITORS
 USES AND UNDESIRABLE EFFECTS
OF ANTITHROMBOTIC AGENTS
DRUG INDICATION UNDESIRABLE EFFECTS
ASPIRIN Reduces the risk of MI in GI ulcer, bleeding, hemorrhage
patients with unstable
angina
CLOPIDOGREL Reduction of atherosclerotic Ticlopidine: Nausea, dyspepsia,
& TICLOPIDINE events, prevent thrombosis hemorrhage, leukopenia

Clopidogrel: fewer adverse

effects than ticlopidine
DIPYRIDAMOLE Prevents emboli May worsen angina, dizziness,
headache, syncope, GI
disturbances, rash
ABCIXIMAB, Acute coronary syndrome Bleeding
EPTIFIBATIDE,
TIROFIBAN
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
— Used in treating Warfarin overdosage
— Vitamin K2 (menaquinone) is found in human tissues and is
synthesized by intestinal bacteria
— 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