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Haemostasis
and
Thrombosis
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”
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)
Coagulation cascade
Drugs acting on coagulation cascade1. 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
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 RivaroxabanMOA: It binds to factor Xa active site and inhibits its enzymatic actions
USES: Venous thrombosis and pulmonary embolism
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 unfractionatedheparin but not LMWH
Prothrombin time
Antidote Protamine for unfractionatedheparin, protamine reversal of LMWH is incomplete
Vit K1,plasma,prothrombincomplex concentrates
Use Mostly acute,over days Chronic,over weeks to months
Use in pregnancy Yes No
Platelet activation
Antiplatelet drugs1) 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
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)
Fibrinolytic system
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
• 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
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