Objectives

To learn how Blood Clots are formed.

How the blood clots are broken down ?
What drugs can be used to regulate
clotting ?
How to rectify clotting deficiencies
Classes of Drugs
Prevent coagulation
Dissolve clots
Prevent bleeding and hemorrhage -
Hemostatic
Overcome clotting deficiencies
(replacement therapies)
Blood Clotting
Vascular Phase
Platelet Phase
Coagulation Phase
Fibrinolytic Phase
Vascular Phase
Vasoconstriction
Exposure to tissues activate Tissue
factor and initiate coagulation
Tissue Factor
Platelet phase
blood vessel wall (endothelial cells) prevent platelet
adhesion and aggregation
platelets contain receptors for fibrinogen and von
Willebrand factor
after vessel injury Platelets adhere and aggregate.
Release permeability increasing factors (e.g.
vascular permeability factor, VPF)
Loose their membrane and form a viscous plug
Coagulation Phase
Two major pathways
Intrinsic pathway
Extrinsic pathway
Both converge at a common point
13 soluble factors are involved in clotting
Biosynthesis of these factors are dependent on Vitamin K1
and K2
Normally inactive and sequentially activated
Hereditary lack of clotting factors lead to
hemophilia -A

Intrinsic Pathway
All clotting factors are
within the blood
vessels
Clotting slower
Activated partial
thromboplastin test
(aPTT)

Extrinsic Pathway
Initiating factor is
outside the blood
vessels - tissue factor
Clotting - faster - in
Seconds
Prothrombin test (PT)
Blood Vessel Injury
IX
IXa
XI
XIa
X
Xa
XII
XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin Thrombin
Fibrinogen
Fribrin monomer
Fibrin polymer
XIII
Intrinsic Pathway Extrinsic Pathway
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Anticoagulant drugs to treat
thromboembolism
Drug Class Prototype Action Effect
Anticoagulant
Parenteral
Heparin
Inactivation of clotting
Factors
Prevent venous
Thrombosis
Anticoagulant
Oral
Warfarin Decrease synthesis of
Clotting factors
Prevent venous
Thrombosis
Antiplatelet
drugs
Aspirin Decrease platelet
aggregation
Prevent arterial
Thrombosis
Thrombolytic
Drugs
Streptokinase Fibinolysis
Breakdown of
thrombi
Heparin
Sulphated carbohydrate
Different sizebovine lungs
Administration - parenteral- Do not inject IM -
only IV or deep s.c.
Half-life 1 - 5 hrs - monitor aPTT
Adverse effect: hemorrhage
Antidote : protamine sulphate
Heparin mechanism of
action
Heparin
Antithrombin III
Thrombin
Oral anticoagulants
Examples: Coumarins - warfarin, dicumarol
Structurally related to vitamin K
Inhibits production of active clotting factors
Clearance is slow - 36 hrs
Delayed onset 8 - 12 hrs
Overdose - reversed by vitamin K infusion
Can cross placenta - do not use during late
pregnancies

Mechanism of action
Descarboxy Prothrombin Prothrombin
Reduced Vitamin K Oxidized Vitamin K
NADH NAD
Warfarin
Normally, vitamin K is converted to vitamin K epoxide in the liver.
This epoxide is then reduced by the enzyme epoxide reductase.
The reduced form of vitamin K epoxide is necessary for the synthesis of many
coagulation factors (II, VII, IX and X, as well as protein C and protein S).
Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting
coagulation. ( )
Warfarin Side Effect
Severe Side effects:
Severe bleeding
Bleeding from the rectum or black stool
Skin conditions such as hives, a rash or itching
Swelling of the face, throat, mouth, legs, feet or hands
Bruising that comes about without an injury you remember
Chest pain or pressure
Nausea or vomiting
Fever or flu-like symptoms
Joint or muscle aches
Diarrhea
Difficulty moving
Numbness of tingling in any part of your body
Painful erection lasting four hours or longer

Warfarin Side Effect
Other less serious warfarin side effects:
Gas
Feeling cold
Fatigue
Pale skin
Changes in the way foods taste
Hair loss
Drug interaction- with Warfarin
Drugs that Increase
Warfarin Activity
Decrease binding to
Albumin

Inhibit Degradation

Decrease synthesis of
Clotting Factors
Aspirin, Sulfonamides


Cimetidine, Disulfiram

Antibiotics (oral)
Category Mechanism Representative Drugs
Drug interaction with Warfarin
Drugs that promote
bleeding
Inhibition of platelets Aspirin

Inhibition of clotting heparin
Factors antimetabolites
Drugs that decrease
Warfarin activity
Induction of metabolizing Barbiturates
Enzymes Phenytoin

Promote clotting factor Vitamin K
Synthesis
Reduced absorption cholestyramine
colestipol
Antiplatelet drugs
Example: Aspirin
Prevents platelet aggregation /adhesion
Clinical use - prevents arterial thrombus
Myocardial infarction (MI), stroke, heart valve
replacement and shunts
Other antiplatelet drugs are -
Dipyridamole, sulfinpyrazone and
Ticlopidine

Mechanism of action
Aspirin inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the
synthesis of thromboxane 2
(prostaglandins)
Inhibits platelet aggregation
Prophylactic use of Aspirin
Low dose daily.
Prevents ischemic attack (ministroke) and MI
335 mg/day reduced the risk of heart attack in
patients over 50
More than 1000 mg/day NO EFFECT
Contraindication - DO NOT give to patients with
glucose 6-PO4 dehydrogenase deficiency

Fibrinolysis
Enhance degradation of clots
Activation of endogenous protease
Plasminogen (inactive form) is
converted to Plasmin (active form)
Plasmin breaks down fibrin clots
Fibrinolysis
Exogenously administered drugs
Streptokinase - bacterial product
- continuous use - immune reaction

Urokinase - human tissue derived
no immune response

Tissue plasminogen activator (tPA) - genetically
cloned
no immune reaction
EXPENSIVE

Drug preparations : To reduce
clotting
Heparin (generic, Liquaemin sodium)
Parenteral - 1000 - 40,000 U/ml
Warfarin (generic , Coumadin)
Oral : 2 - 20 mg tablets
Dipyridamole (Persantine)
Oral : 25,50,75 mg tablets

Drug preparations : to lyse clots
Alteplase recombinant (tPA, Activase)
20, 50 mg Lyophilized powder - reconstitute for iv

streptokinase (Kabikinase, streptase)
Parenteral : 250000 - 1.5 million units per vial .
Lyophilized powder. Reconstitute for iv

Urokinase ( Abbokinase)
Parenteral : 250000 units per vial. Powder to
reconstitute to 5000 u/ml for injection


Drug preparations: clotting
deficiencies
Vitamin K ( Phytonadione (K1), Mephyton
Oral : 5 mg tablets

Plasma fractions - for hemophilia
Antihemophilic factor ( VIII, AHF)
Parenteral

Factor IX complex (konyne HT, proplex T)
Parenteral : in vials




Drug preparations : to stop
bleeding
Systemic use : aminocaproic acid (Amicar);
Tranexamic acid (cyclokapron),Vitamin K

Local adsorbable drugs
Gelatin sponge (Gelfoam)
Gelatin film
Oxidized cellulose ( Oxycel)
Microfibrillar collagen (Avitene)
Thrombin