Lec 10- anticoagulant 2

Question 1

Drugs affect haemostasis and thrombosis in 3 different ways

Answer 1

A) Blood coagulation- anticoagulants
B) Platelet function- antiplatelet drugs
C) firbrin removal (fibrinolytic)- clot busters

Question 2

A) anticoagulants

Answer 2

• INJECTABLE: heparin; low molecular weight heparins; ATIII independent anticoagulants
  -ORAL anticoagulants: Coumarin e.g. warfarin;
  NOAC (novel oral anticoagulants)
  -Direct thrombin inhibitor: dabigatran
  -Direct inhibitor of factor Xa e.g. apixaban, edoxaban, rivaroxaban

Question 3

Injectable anticoagulants- Heparin

Answer 3

• Used in: pregnancy; when rapid anticoagulant is required; poor renal function; bridging therapy; dialysis machines
• Heparin (unfractionated): family of mucopolysaccharides MW 3000-40,000
• Found in mast cells and endothelium
• Given IV- continuous infusion (effective immediately)
• Problem is that because there is such a range of sizes, there are many targets which it can affect meaning it is much harder to control

Question 4

Injectable anticoagulants- LMWH

Answer 4

• These are processed heparins which reduce the size of the heparins and make the size more uniform size, meaning it is better to control
• MW 1,000-10,000
• Enoxaparin, Dalteparin
• Dosing as IV (effective immediately) or SC bolus once or twice daily (Effective after 1-2 hours)

Question 5

How do heparins work- AT||| dependant

Answer 5

• AT||| (anti-thrombin 3), this protein is in the blood and binds various factors
• Heparin has complementary sites for both AT||| and cascade factors to bind, this means that these proteins can bind more easily meaning coagulation is inhibited
• Heparins can act on thrombin (IIa) and factor Xa, among many others
• LMWH cant inhibit thrombin but it can inhibit Xa

Question 6

ATIII independent

Answer 6

• These are thrombin inhibitors: argatroban (used in HIT), Bivalirudin
• Hirudin derived from the leech (still used on NHS)
• These directly bind to thrombin and inhibit there action

Question 7

Oral anticoagulants: warfarin

Answer 7

• Prevents the reduction of vitamin K (an essential step in activation) carboxylation of coagulant factors- Large dose of vitamin K can reverse the effects of warfarin
• Doesn’t affect the levels of coagulation factors (inactive or active) already in circulation
• Large number of interaction with other medicines
• Interacts with Vit K in food and alcohol
• Patients to carry alert card and have an INR (how long to clot) monitoring book

Question 8

How warfarin works

Answer 8

• Warfarin blocks the enzyme vitamin K reductase as a competative inhibitor
• This prevents the oxidised vitamin K from being turned back into vitamin K
• This means there is no Vitamin K which can gamma-carboxylate the factors II, VII, XI, X
• This means that thrombin will not be created, therefore fibrinogen won’t be cleaved into fibrin
• If someone has an overdose of warfarin this can be reversed by vitamin K

Question 9

NOAC’s

Answer 9

• Dabigatran, Rivaroxaban, Edoxaban- Thrombin inhibitor
• Treatment of VTE, DVT and prevention of stroke in AF
• Benefits over warfarin: less monitoring; Fewer dietary complications; less risk of a major bleed; more specific control
• Disadvantages: expensive; short half-life means no complicance= no effect; not all have reversal agents available

Question 10

B) anti-platelet drugs

Answer 10

• Aspirin inhibits COX so reduces PGH2 and TXA2 synthesis and so the activation of platelets and fibrin attachment is reduced
• Aggregation inhibitors (inhibit ADP induced aggregation inhibits ADP receptors (P2Y12 antagonist)): prasugrel; clopidogrel; ticagrelor (doesn’t prevent ADP binding but when bound P2Y12 receptor prevents ADP-induced signal transduction); dipyridamole
• Glycoprotein IIB/IIIA receptor antagonists: Abciximab; eptifibatide; tirofiban

Question 11

Use of antiplatelet agents

Answer 11

-Aspirin; clopidogrel and dipyridamole –> stroke
-Aspirin; clopidogrel; ticagrelor; prasugrel –> MI
-Glycoprotein IIB/IIIA receptor antagonists: STEMI, PCI
Monitoring: bleeding (Hb, RBC); Thrombocytopenia (platelets)
Contraindications: active bleeding; recent bleeding; recent brain surgery

Question 12

C) fibrinolysis

Answer 12

• When a thrombus forms, plasminogen is deposited on the fibrin strands
• This is used to get rid of the fibrin when the clot is no longer needed
• Activated by tissue plasminogen activator (t-PA) released from normal endothelial cells activates the plasminogen to form plasmin (fibrinolysis)
• Plasmin digests fibrin and fibrinogen and other coagulation factors
• Plasmin inhibitors are present in blood so that these actions remain local

Question 13

Clinical fibrinolysis

Answer 13

• Streptokinase, extracted from streptococcus bacteria, activates plasminogen
• Tenecteplase, alteplase- recombinant t-PA
• Used as thrombolytic agents once clots have formed e.g. following MI (not likely as should have PCI), stroke (main use for alteplase if can get to hospital within 1 hour

Question 14

Coagulation defects

Answer 14

• Haemophilia- factor VIII deficiency
• Liver disease: many of the clotting factors are made in the liver
• Neonates- vitamin K deficiency, they don’t have any when born so are given an injection.