1. and anti-thrombotic pharmocology Tom Williams
Coagulation
and anti-thrombotic pharmocology
Tom Williams

2. Basics of haemostasis Vasospasm Platelet plug Clot Formation
Cascade of clotting factors
Zymogen to protease
Components of clots
Fibrin
Platelets

3. Classic View Intrinsic Pathway
AKA Contact Activation Pathway
F-XII Binds to collagen / -ve charged surface
Hageman factor
Prekallikrein & HMWK
Activates F-XI
Activates F-IX
Activates F-X
Minor role
Extrinsic Pathway
Tissue Factor Pathway
Generates ‘Thrombin Burst’
TF (F-III / thromboplastin) combines with & activates F-VII
Activates F-X & F-IX
Generates Thrombin that activates F-VIII
Major role

4. Final Common Pathway Activates F-VIII & F-IX (tenase complex)
Activates F-X
Prothrombin to Thrombin
Fibrinogen to Fibrin

5. Clear?

6. Platelets Bind to collagen with gp Ia/IIa
Bound together with vWBF & Fibrinogen (gp IIb/IIIa complex)
Activated by
ADP
Collagen
Thrombin
Arachidonic Acid
Thromboxane A2

7. Others vWBF Calcium Phospholipids Found within platelet granules
Ligand for platelet adhesion & carrier protein for F-VIII
Calcium
Phospholipids
Found within platelet granules

8. Regulation Tissue Factor Pathway Inhibitior Antithrombin III
Activated by F-Xa
Inactivates F-VIIa - Tissue Factor complex
Antithrombin III
Inactivates thrombin, F-IXa, F-Xa, F-XIa
Thrombomodulin
Converts thrombin into an anticoagulant
Protein C & S
Protein C activated by thrombin (post thrombomodulin)
Inactivates F-Va & F-VIIIa

9. Clear?

10. Fibrinolysis Plasminogen from the liver
Incorporated into clots as they form
Tissue Plasminogen Activators (TPA) converts to plasmin
Cleaves fibrin into soluble degradation products
Degradation products inhibit action of thrombin

11. Warfarin Prevents the reduction of Vit K
Inhibits carboxylation of Factors II, VII, IX & X
Protein C also Vit K dependent
Slow onset of action (12h +) as acts on protein synthesis so has no effect on circulating proteins.
Metabolised by the liver
Monitored by INR or prothrombin time

12. Heparin Sulfated mucopolysaccharide
Catalyses the action of Antithrombin III
Inactivates thrombin, F-IXa, F-Xa, F-XIa
LMWH catalyse the interaction with F-Xa
Partial renal excretion
UFH monitored by APTT
Antagonised by protamine
Long term use causes osteoporosis
HITs

13. Fibrinolytics Streptokinase t-PA Anti-fibrinolytic
From -haemolytic strep
Forms a complex with plasminogen causing enzymatic activity
Antigenic (anaphylactic & reduced action)
t-PA
Recombinant tissue type plasminogen activators
Not antigenic
Anti-fibrinolytic
Tranexamic Acid
Inhibitor of plasminogen activation
Aprotinin
Inhibits free plasmin

14. Measurement of Coagulation
Prothrombin Time (PT)
Extrinsic & Common pathway
Time to clot with Tissue Factor & Ca2+
Normal 11-15s
INR is the ratio of PT to a standard sample
Activated Partial Thromboplastin Time (APTT)
Intrinsic & Common pathway
Time to clot with kaolin & Ca2+
Normal 35-40s

15. Other tests Specific clotting factor levels Thrombin Time
Activated Clotting Time (NPT)
Bleeding Time (NPT)
Thromboelastometry (NPT)

16. Haemophilia Von Willebrand’s Disease Haemophilia Most common
Poor platelet aggregation & low F-VIII
3 types (Low, Weird, very Low)
Treated with desmopressin, FFP or cryo
Haemophilia
A - Factor VIII
Desmopressin
Recombinant factor
B - Factor IX

17. DIC Generalised intravascular activation of haemostatic mechanism
Widespread fibrin formation
Activation of fibrinolysis
Consumption of platelets & coag factors
Haemorrhage dominant feature
Due to depleted factors, excessive fibrinolysis & inhibition by FDP
Mortality >80% in severe cases
Diagnosed with high D-Dimer & low coag factors & (sometimes) low platelets

18. Clear?