Coagulation And Anticoagulants

Question 1

Describe the events that take place after cutting yourself

Answer 1

• blood vessel damage
• disruption to the endothelium leading to exposure of the proteins under the lining - tissue factor and collagen
• primary haemostasis (recruitment of platelets)
• secondary haemostasis (activation of coagulation factors)
  ^ occurs simultaneously

Question 2

Describe the events of primary homeostasis

Answer 2

• hole in endothelium causes exposure of Von Willebrand factor which attracts platelets through a receptor which allows adhesion activating them causing release of granular contents
• results in more platelet activation and eventual aggregation
• leads to exposure of phospholipids
• plug formed in hole made by clot

Question 3

Describe the events that take place in secondary haemostasis

Answer 3

• coagulation cascade = every step requires phospholipids + calcium
• initiation
• propagation
• regulation

Question 4

Describe initiation of the coagulation cascade

Answer 4

• exposed tissue factor activates factor VII
• this activates factor X which activates prothrombin factor (II) and factor V resulting in activation of the prothrombinase complex leading to conversion of prothrombin to thrombin
• thrombin converts fibrinogen to fibrin and activates factor XIII which cross-links the fibrin to increase the strength

Question 5

Describe propagation of the coagulation cascade

Answer 5

• production of thrombin in initiation activates factor XI which activates factor IX
• factor VIII is also activated which stimulates the prothrombinase complex leading to production of more thrombin allowing more conversion of fibrinogen to fibrin and cross-linked fibrin

Question 6

Describe regulation of the coagulation cascade

Answer 6

• antithrombin (naturally occurring anticoagulant) downregulates all coagulation factors in cascade
• thrombin can also downregulate itself by binding to thrombomodulin leading to activation of protein C (naturally occurring) which works with protein S (naturally occurring) to downregulate factor V and factor VIII reducing thrombin production and in turn pibrin production
• tissue factor protein inhibition (naturally occurring) is stimulated by the activation of factor X which blocks activation of factor VII when it comes into contact with tissue factor

Question 7

Describe the process of fibrinolysis

Answer 7

• plasmin from plasminogen (conversion activated by feedback from fibrin) is able to break down fibrin to degradation products including D-dimer
• fibrin feeds back by producing tPA and uPA (plasminogen activators)
• plasmin production regulated by alpha 2 anti-plasmin and plasminogen activator inhibitors (downregulates tPA and uPA)

Question 8

What are the methods of coagulation analysis?

Answer 8

• bleeding time (not done anymore)
• FBC, platelet function tests in haemostasis lab using light transmission aggregometry

Question 9

Describe the process of light transmission aggregometry

Answer 9

• platelet rich plasma
• red cells are removed
• stimulation of aggregation through addition of agonists/agents
• light flow through sample is measured by detector
• as aggregation ensues, light transmission decreases

Question 10

What are the tests for secondary haemostasis?

Answer 10

• prothrombin time (PT)
• activated partial thrombophlebitis time (APTT)
• prothrombin clotting time (TCT)
• individual coagulation factor assays

Question 11

Why are citrate samples used in assessment of haemostasis?

Answer 11

It chelates calcium to stop the clotting process in the sample

Question 12

Describe prothrombin time

Answer 12

• dependent on factor VII, V, II and fibrinogen (extrinsic + common)
• patient plasma + thromboplastin (tissue factor + phospholipids)
• body temperature
• Ca added
• time measured to clot (9-13s)

Question 13

Describe INR

Answer 13

• standardised form of prothrombin time
• used for monitoring of K+ antagonists like warfarin
• dependent on factor II, VII, IX and X

Question 14

Describe APTT

Answer 14

• patient’s plasma + contact factor (kaolin/silica) + phospholipid
• body temperature
• Ca added
• time measured to clot (26-38s)
• dependent on factors VIII, IX, XII (+ II, V and X) - intrinsic + common

Question 15

Describe TCT

Answer 15

• measure of fibrinogen into fibrin clot
• patient plasma + bovine thrombin excess
• time to clot measured (9-16s)

Question 16

What are the types of anti-thrombotic agents?

Answer 16

• anticoagulants: inhibit 1 or several components of coagulation cascade
• fibrinolytic agents: enhance lysis of fibrin clot
• anti-platelet agent: inhibit platelet activation/aggregation

Question 17

Anticoagulants (function and examples)

Answer 17

• main function to inhibit formation of fibrin clot
• eg. Heparin/fondaparinux: antagonise activated factor X
• warfarin: vit K antagonist, lowers factor II, VII, IX and X
• DOACs eg. Dabigatran inhibits thrombin

Question 18

What are the side effects of heparin?

Answer 18

• thrombocytopenia (bleeding risk)
• osteoporosis (with prolonged use)
• hyperkalaemia (rare)

Question 19

Indications for heparin

Answer 19

• for short-acting anticoagulant effect
• acute DVT/PE
• during cardiac bypass (UFH)
• ACS (+ antiplatelet agents)
• venous thrombosis
• post-op
• obstetrics

Question 20

Describe aspects of warfarin

Answer 20

• high inter-individual variability
• delayed onset/offset
• long half life
• narrow therapeutic window
• drug/food interactions
• requires regular INR monitoring
• rapid reversal with vitamin K

Question 21

What are the contraindications of DOACs?

Answer 21

• pregnancy + breast feeding
• liver disease with cirrhosis
• coagulopathies
• certain drugs

Question 22

What are the 2 types of fibrinolytic drugs?

Answer 22

• kinases (eg. Streptokinase, urokinase): more direct action on fibrin
• tissue plasminogen activators tPAs (eg. Altepase, tenecteplase): stimulate the conversion of plasminogen to plasmin

Question 23

Describe the action of kinases with specific examples

Answer 23

• bind to plasminogen allowing release of plasmin to enhance breakdown of fibrin
• act on clot bound and free plasminogen (systemic bleeding risk)
• streptokinase: derived from bacteria so is antigenic and wont work if recent infection/previous use
• urokinase: grown from renal cells in culture and not antigenic

Question 24

Describe the action of tPA derivatives with its uses

Answer 24

• stimulate plasminogen to cleave plasmin from it to break down fibrin
• selective for clot bound plasminogen
• used for acute MI (if unsuitable for PCI), ischaemic stroke (selectively due to bleeding risk), PE with haemodynamic instability

Question 25

Describe the advantages and uses of catheter directed thrombolysis

Answer 25

Advantages:
- smaller doses
- administered directly into vessel requiring thrombolysis
- less systemic effect

Uses:
- acute limb ischaemia
- massive DVT
- blocked CVC

Question 26

Describe the mechanisms of anti-platelet drugs

Answer 26

• inhibit platelet receptors
• inhibit platelet signalling pathways

Question 27

Describe the action of clopidogrel/ticlodipine

Answer 27

• irreversible blockage of ADP receptor on platelet
• blocks signalling pathway in platelet which reduces binding of fibrinogen

Question 28

Describe the mechanism of abciximab and tirofiban

Answer 28

• glycoprotein IIb/IIIa antagonists
• reduces platelet aggregation and binding of fibrinogen

Question 29

Describe the mechanism of aspirin

Answer 29

• irreversibly inhibits the cyclooxygenase pathway in platelet cell
• blocks conversion of arachidonic acid to thromboxane A2
• decreases platelet activation

Question 30

Describe the mechanism of dipyridamole

Answer 30

• acts on ADP receptors of platelet cells to increase platelet concentration of cAMP
• reduced aggregation of platelets

Question 31

What are the indications of anti-platelet drugs?

Answer 31

• cardiovascular disease
• acute MI (aspirin indefinitely + clopidogrel
• secondary prevention of CVD
• cerebrovascular disease (without AF)
• acute stroke/TIA/secondary prevention
• peripheral vascular disease