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

THANKS