2. 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
6. 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
7. 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
8. 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)
9. 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
10. 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
11. 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
13. 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
14. Descarboxy Prothrombin Prothrombin
Reduced Vitamin K Oxidized Vitamin K
NADHNAD
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
15. 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
16. Other less serious warfarin side effects:
•Gas
•Feeling cold
•Fatigue
•Pale skin
•Changes in the way foods taste
•Hair loss
17. 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
18. 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
19. 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
20. Mechanism of action
Aspirin inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the synthesis of
thromboxane 2 (prostaglandins)
Inhibits platelet aggregation
21. 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
22. Fibrinolysis
Enhance degradation of clots
Activation of endogenous protease
Plasminogen (inactive form) is converted to Plasmin
(active form)
Plasmin breaks down fibrin clots
23. 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
25. 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
26. 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
27. 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