Drugs for coagulation disorders

Objectives
At the end of this session, you will be able to:
explain how Blood Clots are formed.
explain how the blood clots are broken down
describe drugs that can be used to regulate
clotting
 Three important dysfunctions of
blood:
1. Thromboembolism,
formation of an unwanted clot within a blood
vessel
2. Bleeding, and
3. Anemia.
Thromboembolism (undesirable blood clots)
Thrombus VS. Embolus
A clot that adheres to a vessel wall is called a
thrombus,
whereas an intravascular clot that floats in the
blood is termed an embolus.
Thus, a detached thrombus becomes an embolus.
Both thrombi and emboli are dangerous,
because they may occlude blood vessels and deprive
tissues of oxygen and nutrients
Stroke
Myocardial infarction
Pulmonary embolism
Angina
 A Blood Clot
Consists of a fibrin
enmeshed with platelets
and RBCs
There are two major
facets of the clotting
mechanism
the platelets, and
the thrombin system

Arterial thrombosis -------- a platelet-rich clot

Venous thrombosis --------- a fibrin-rich clot
 Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury

Tissue Factor
XII XIIa

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X

Prothrombin Thrombin
Factors affected
By Heparin Fibrinogen Fribrin monomer

Vit. K dependent Factors Fibrin polymer

XIII
Affected by Oral Anticoagulants
 QQQQQ??????

Explain at least the final steps of coagulation

cascade (e.g start from factor Xa)?
How many factors?
Role of vit K?
Embolus vs thrombus?
Drugs Used to Treat Bleeding
Cont...
Drugs Used to Treat Bleeding
Drugs Used to Treat Bleeding

Bleeding problems such as hemophilia

use of anticoagulants may also give rise to
hemorrhage
hemophilia is a consequence of a deficiency in
plasma coagulation factors, most frequently
Factors VIII and IX
Blood clots much more slowly than the usual
Excessive bleeding from even minor injuries
 Treatment
Concentrated preparations of these factors are
available from human donors.
Blood transfusion is also an option for treating
severe hemorrhage
Protamine sulfate
antagonizes the anticoagulant effects of heparin
Vitamin K
Can stop bleeding due to the oral anticoagulants
The response to vitamin K is slow, requiring about 24
hours (time to synthesize new coagulation factors).
Thus, if immediate hemostasis is required, fresh-
frozen plasma should be infused.
 QQQQ??????
Treatment options for hemorrhage?
If it is due to oral anticoagulants?
If it is due to parentral anticoagulants?
If it is due to Haemophilia?
What if you need immediate haemostasis?
 Drugs that inhibit clotting
Classes of Drugs
Prevent coagulation
Anticoagulant drugs
Heparin
warfarin

Dissolve clots
Fibrinolytic drugs

inhibit platelete aggregation

Antiplatelete drugs
 Heparin
Sulphated carbohydrate
Administration parenteral (IV or deep SC)
Short acting
Its anticoagulant effect requires the presence of
antithrombin III
Heparin increase the rate of complex formation 1000-fold
Leads to inactivation of thrombin
 Heparin mechanism of action
Heparin

Thrombin
Antithrombin III
If thrombin is not formed or
if its function is impeded
(for example, by
antithrombin III),
coagulation is inhibited
LMWH-antithrombin complex inhibits only factor Xa
 Therapeutic uses
Heparin and the LMWHs limit the expansion
of thrombi by preventing fibrin formation
Used for the treatment of
acute deep-vein thrombosis
pulmonary embolism
prophylactically to prevent postoperative venous
thrombosis
Heparin and LMWHs are the anticoagulants of
choice for treating pregnant women
because these agents do not cross the placenta.
Why not?
(due to their large size and negative charge).
 Adverse effects
Adverse effect: hemorrhage
Antidote : protamine sulphate
combines ionically with heparin to form a stable, 1:1
inactive complex
 Oral anticoagulants
Warfarin
A Coumarin derivative Structurally related to vitamin K
Active orally
Inhibits production of active clotting factors
Clearance is slow - 36 hrs half life
Delayed onset 8 - 12 hrs
Thus, if an immediate effect is required, heparin must be
given in addition
Overdose - reversed by vitamin K infusion
For rapid reversal, a concentrate of clotting factors (fresh
frozen plasma which contain clotting factors) must be
given
Can cross placenta - do not use during pregnancies
Adverse effect: hemorrhage
 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).
Warfarin inhibits the enzyme epoxide reductase in the liver,
thereby inhibiting coagulation.
 Drug interaction- with Warfarin
Category Mechanism Representative Drugs

Drugs that Increase Decrease binding to Aspirin, Sulfonamides

Warfarin Activity Albumin

Inhibit Degradation Cimetidine, Disulfiram

Inhibition of platelets Aspirin

Drugs that promote
bleeding
Inhibition of clotting heparin
Factors
 Drug interaction with Warfarin

Drugs that decrease Induction of metabolizing Barbiturates

Enzymes Phenytoin
Warfarin activity
Promote clotting factor Vitamin K
Synthesis

Reduced absorption cholestyramine

colestipol
 Qqqq???
Anticoagulants are less useful in preventing
arterial thrombosis. Why?
ans
Because in faster flowing vessels thrombi are
composed mainly of platelets with little fibrin
 Antiplatelet drugs
Example: Aspirin
Prevents platelet aggregation /adhesion
Clinical use - prevents arterial thrombus
Myocardial infarction (MI), stroke, heart valve replacement
and shunts
Aspirin inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the synthesis of
thromboxane A2 (prostaglandins)
TXA2 is a powerfull inducer of platelet aggregation
Inhibits platelet aggregation
 Fibrinolytics
Enhance degradation of clots
Activation of endogenous protease
Plasminogen (inactive form) is converted to Plasmin (active
form)
Plasmin breaks down fibrin clots
Streptokinase- used together with aspirin in the t/t of MI
Alteplase can be an alternative when streptokinase is
contraindicated
 Anticoagulant drugs to treat
thromboembolism

Drug Class Prototype Action Effect

Anticoagulant Heparin Inactivation of clotting Prevent venous

Parenteral Factors Thrombosis

Anticoagulant Warfarin Decrease synthesis of Prevent venous

Oral Clotting factors Thrombosis

Prevent arterial
Antiplatelet Aspirin Decrease platelet
Thrombosis
drugs aggregation

Thrombolytic Streptokinase Fibinolysis Breakdown of

Drugs thrombi
 Hot seating
Heparin
Your route?
Tell us your mechanism of action
Can you work with out antithrombin III?
Your main AE?
Who is your antidotes?
How do you interact with your antidote?
Are you teratogenic?
Warfarin
How do you affect blood coagulation?
Your main AE?
Who is your antidote?
Your interaction with others?
Are you teratogenic?
 Objectives
Now, you are able to:
Explain how Blood Clots are formed.
Explain how the blood clots are broken down
Describe drugs that can be used to regulate
clotting