Presentation on homeostasis and thrombosis

2. Haemostasis
and
Thrombosis

3. Haemostasis
“Arrest of blood loss from damaged blood vessels”
Thrombosis
“Pathological formation of haemostatic plug within the vasculature (in vivo) in
the absence of bleeding”
Predisposing factors by Rudolph Virchow;
1. Injury to the vessel wall
2. Altered blood flow
3. Abnormal coagulability of the blood (during later stage of pregnancy & oral
contraceptives)
Types of thrombus
1) Arterial thrombus
2) Venous thrombus
Clot
“It is amorphous structure and forms in static blood in vitro”

4. Embolus
“Any detached, traveling
intravascular mass(solid,
liquid, or gaseous) carried
by circulation which is
capable of clogging capillary
beds.
Three distinct ways of Drug affect on thrombosis and haemostasis;
1) Blood coagulation (fibrin formation)
2) Platelet function
3) Fibrin removal (fibrinolysis)

6. Coagulation cascade

7. Drugs acting on coagulation cascade
1. Direct thrombin inhibitor:
Based on proteins made by Hirudo medicinalis, the medicinal
leech.
Lepirudin, desirudin, bivalirudin and Argatroban are given
parenterally dabigatran is active orally
MOA: it binds to thrombin’s active site and inhibits its enzymatic
actions
USES: Heparin induced thrombocytopenia
2. In Direct thrombin inhibitor:
Heparin:
 Unfractionated,Large sulfated polysaccharide polymer obtained
from animal having Mol. Wt 15,000 to 20,000
 Parenteral administration
 Slows time for blood clotting and prevent growth of a clot
 Side effects are bleeding, headache, skin rashes, HIT
 Contraindicated in severe thrombocytopenia
 Highly acidic so neutralized by basic protamine

9. LMWH:
 Fractionated having high BA, Long duration and less frequently required
 Expensive
3. Vit K Epoxide reductase inhibitor:
Warfarin:
 Prevent clot from forming in the blood helps keep existing clots from
getting worse
 It interact with vit K containing products, NSAIDs etc
 VIT K, Rifampicin,carbamezepine decreases warfarin effect
 Metronidazole, cipro, Lovastatin increase effect of warfarin
 OD in evening
 Contraindicated in pregnancy(fetal bleeding), peptic ulcer
 Antidote is FFP or Vit K
 Blood testing for PT is necessary to calculate international normalized
ratio
4. Direct Xa inhibitors: e.g Rivaroxaban
MOA: It binds to factor Xa active site and inhibits its enzymatic actions
USES: Venous thrombosis and pulmonary embolism

10. Property Heparins Warfarin
Structure Large acidic polysaccharide
polymer
Small lipid soluble molecule
Route of administration Parenteral Oral
Site of action Blood Liver
Onset of action Rapid(minutes) Slow(days),limited by half
lives of preexisting normal
factors
Mechanism of action Activates antithrombin III, which
proteolyzes coagulation factors
including thrombin and factor Xa
Impairs post-translational
modifications of factors
II,VII,IX and X
Monitoring activated PTT for unfractionated
heparin but not LMWH
Prothrombin time
Antidote Protamine for unfractionated
heparin, protamine reversal of
LMWH is incomplete
Vit K1,plasma,prothrombin
complex concentrates
Use Mostly acute,over days Chronic,over weeks to
months
Use in pregnancy Yes No

11. Platelet activation

12. Antiplatelet drugs
1) COX inhibitor:
Aspirin: Non-selective,ir-reversible COX inhibitor,reduces platelet
production of TXA2
2) ADP receptor Antagonist:
Clopidogrel: Prodrug, its active metabolite irreversibly inhibits platelet
ADP receptors, administered orally
3) Dipyridamole: Phosphodiesterase inhibitor (degrade cyclic nucleotides)
4) Antagonist of GPIIb/IIIa receptors:
Abciximab: inhibit platelet aggregation by interfering with GPIIb/IIIa
binding to fibrinogen and other ligands. It is administered parenterally
Eptifibatide,tirofiban are Reversible and small sized.
5) Epoprostenol (synthetic PGI2) is chemically unstable, infused IV.
Acts on prostanoid phosphate receptors on vascular smooth muscles and
platelets and Stimulating adenylate cyclase causing vasodilation and
inhibit aggregation by any pathway

13. Clinical uses
•Acute MI
• High risk of MI or history of MI, Angina etc
• Following coronary artery bypass grafting
• Unstable coronary syndromes(clopidogrel plus aspirin)
• Epoprostenol in haemodialysis
• Thrombotic stroke to prevent recurrence (dipyridamole added
to aspirin)
• Following coronary artery angioplasty and or stenting(IV
Antagonist of GPIIb/IIIa receptors in addition to aspirin)

14. Fibrinolytic system

15. Fibrinolytic drugs
1) Streptokinase
• Protein extracted from cultures of streptococci
• Activates plasminogen
• Intravenously
• Additive effect with Aspirin in MI
• Action blocked by Ab that appears almost 4 days after initial dose
atleast one year gap
• SK burst plasmin formation,generating kinins and hypotension
2) Tissue plasminogen activator
• Alteplase is normal human plasminogen activator
• Reteplase is mutated forms with longer elimination half life
• Tenecteplase mutated form with longer half life
Clinical uses of fibrinolytic drugs
• MI
• Acute thrombotic stroke within 3 hrs of onset(tPA) in selected patients

16. • Acute arterial thromboembolism
• Clearing thrombosed shunts and cannulae
• Life-threatening DVT and pulmonary embolism SK given
promptly
• Tranexamic acid inhibits plasminogen activationan and thus
fibrinolysis
in bleeding
• Aprotinin used for hyperplasminemia and risk of blood loss
during cardiac surgery

17. THANKS