Coagulation

Question 1

Clotting cascade: what are the 3 parts

Answer 1

Initiation Amplification Propagation

Question 2

Describe what happens in initiation

Answer 2

Tissue factor on vascular compartment at all times Factor VII, X and prothrombin in interstitial space on contact with TF make thrombin

Question 3

Describe what happens in Amplification

Answer 3

TF from subendothetial cells platlets, factor VIII, vWF have contact with thrombin TF expressing cells Factor V from activated palletise cleaves Factor VIII from vWF activates Fator XI binds to activated platelet surfaces

Question 4

Describe what happens in Propagation

Answer 4

Tissue Factor/Factor VIIa found on surface of Tissue Factor expressing cells generates IXa combines with co-factor VIIIa on platelet surface activates factor X Xa + Va = thrombin Thrombin splits with fibrinogen into fibropeptides A&B Weak hydrogen bonds form fibrin monomers XIII has covalent bonding

Question 5

What types of heparin do you know?

Answer 5

Naturally occurring: highly sulphated glycosaminoglycan carb weighing between 3000 and 50,000 Daltons Produced by basophils and mast cells Unfractionated heparin: Synthetic 5000 and 25,000 Daltons Binds and potentiates antithrombin III by 1000-fold Activated antithrombin III inhibits thrombin and other serine proteases that promote blood clotting Low molecular weight heparin: 2000 - 8000 Daltons LMWH do not target antithrombin III but directly inhibit factor Xa

Question 6

What is a unit of activity (for heparin)

Answer 6

One unit = preparation required to keep 1ml of cats blood fluid for 24hours at 0C

Question 7

What is the difference between unfractionated and LMWH heparins

Answer 7

In order to inactivate thrombin, heparin must be able to bind to both antithrombin III molecule and the thrombin molecule To do this it must have a size greater than 18 saccharide ternary units Small molecules are only able to inhibit activity of other proteases such as factor Xa

Question 8

How is heparin used clinically

Answer 8

UFH:

infusion: DVT/PE/bypass/ECMO/Vascular

1/2 life 1hr so needs to be infusion. 5000units followed by weight based infusion

APTT measured 6hrs following start

Aim APTT 1.5-2x normal

LMWH:

BD s/c DVT/PE/prophylaxis

Question 9

How is heparin therapy monitored

Answer 9

Activated partial thromboplastin time (APTT) measures intrinsic clotting cascade (VIII, IX, XI, XII) and final common pathway

Prolonged by UFH

LMWH inhib Xa

doesnt affect APTT

Question 10

Side effects of heparin therapy

Question 11

What are the vitamin K dependent clotting factors

Question 12

Tell me about Wafarin

Answer 12

Presented as a tablet 0.5/1/3/5mg

titrated to pt’s INR

used in Prophylaxis and treatment DVT/PE/heart valves/vessel occulsion

Mechanism of action:

Inhibits synthesis of vit K dependent clotting factors (II, VII, IX, X)

Precursors of clotting factors synthesised in liver. Carboxylated during this reaction Vit K is oxidised

Wafarin prevents Vit K returning to its reduced state

Only after synthesis of new factors, takes 72 hours to work

irreversible

Effects:

Haem: increase PT and INR

Drug interactions: affected by drugs that induce/inhib liver enzymes, cholestyramine decreases absorption of fat solube vit A, D, E K therefore potentiates effects of wafarin

Hypersensitivity

Teratogenic

Operations: stop 1 week before INR <2

Rapid reversal: beryplex/FFP

slow reversal vit K

Absorption/distribution:

well absorbed orally

99% protein

VoD 0.1-0.16 L/kg

t1/2 35-45hrs

Met/execretion:

hepatic met

excreted urine and faeces