Anticoagulant Drugs - BB Flashcards
Heparin - general
Polymer - glycosaminoglycan structure
- Molecules of varying chain lengths
Activates anti-thrombin III (ATIII) - a naturally occurring anticoagulant
Occurs naturally (found in mast cells)
Used as medication in 2 forms:
1 - Unfractioned - widely varying polymer chains
2 - Low molecular weight - smaller polymers only
Clotting factors that unfractioned heparin (UFH) inhibits:
VIA ATIII
- thrombin (II)
- XII (12)
- XI (11)
- IX (9)
- Xa (10)
Administration of UFH
IV/ SC - acute onset
Highly variable response to a dose:
- Because of binding to plasma proteins/ cells
- Dose must be adjusted to reach target PTT
Clotting tests in UFH:
- Increased PTT (intrinsic pathway) - because affects many components of this pathway
- Increased Thrombin Time
- Can increase PT at high doses
Reversal agent for heparin (UFH)
Protamine
UFH - not as effective with LMWH
Binds heparin and neutralises the drug
Used in:
- heparin overdose
- Cardiac surgery - where very high dose is needed for heart-lung bypass
- Quick reversal is needed at end of surgery
Uses of UFH:
Acute management:
- DVT/PE - MI - Stroke
Prophylaxis:
- For DVT in hospitalised patients (SC)
Side effects of UFH:
- Bleeding/ thrombocytopenia (rare)
- Osteoporosis (in long term use)
- Elevated AST/ALT (mild)
Heparin and thrombocytopenia:
2 Types:
- Non-immune thrombocytopenia
- mild 10-20% reduction in platelets
- Due to direct suppressive effect on platelet production
- HIT - Heparin-Induced Thrombocytopenia
- Immune mediated reaction
- Immune complexes bind to PF4-Heparin complex
- TII hypersensitivity reaction
HIT:
Heparin induced thrombocytopenia
Type II hypersensitivity
Immune complexes bind to PF4-Heparin complex and these can cause:
- Removal by splenic macrophages (reduced platelets) - Platelet aggregation/activation (THROMBOSIS)
Presentation of HIT:
5-10 days after exposure to heparin (in 0.2-5% of heparin patients)
- Abrupt fall in platelets (>50%)
- Arterial/venus thrombosis (can develop ischaemic limb/DVT)
Diagnosis and management of HIT:
Presumptive Diagnosis: - in ptx on heparin with:
- Significan drop in platelet count
- Thrombosis formation
Definitive diagnosis:
- HIT antibody testing - (takes days to come back and you dont want to wait)
Management:
- Give alternative drug treatment
- Lepirudin or Bivalirudin (Direct thrombin inhibitors)
LMWH - effects
Only inhibits factor Xa (indirectly through activation of ATIII)
- Limited compared to UFH
LMWH - administration
(Enoxaparin)
Predictable dosing - no need to titrate (based on weight)
- Because of reduced binding to plasma proteins and cells
Given subcutaneously (SQ)
Lower incidence of HIT
Clotting tests in LMWH:
- Will not affect thrombin time (unlike UFH)
- PTT is not sensitive to changes in LMWH-dose-induced changes
- Response curve is shallow - UFH’s is steep - Monitoring of LMWH done using Anti Xa Levels
Monitoring of LMWH:
Anti Xa levels used (not PTT like in UFH)
Ususally no monitoring is needed - EXCEPT in:
- Obestiy
- Renal failure
Anti-Xa Level:
Xa substrate linked to chromophore (which illuminates when substrate is split) is mixed with patient sample
- Low Xa activity - small amount of substrate splitting and therefore small amount of illuminaiton
- High Xa activity - lots of substrate splitting - therefore greater illumination
Illumination is converted into a number - called ANTI-Xa ACTIVITY
Factor Xa inhibitors:
Indirect:
- LMWH
- UFH
Direct:
- Rivaroxaban
- Apixaban
Direct factor Xa inhibitors:
Rivaroxaban
Apixaban
Uses of Rivaroxaban and Apixaban
Used in AF as alternatives to warfarin
Direct Factor Xa inhibitors (Rivaroxaban and Apixaban) - general
- ORAL DRUGS (DOACs)
- Do not require monitoring of PT/INR
- Standard dosing
Direct Factor Xa inhibitors (Rivaroxaban and Apixaban) - test changes
Can increase PT and PTT (factor Xa in both pathways)
Will not affect thrombin time
Direct thrombin Inhibitors: (DTIs) - Name the drugs
Hirudin
Lepirudin
Bivalirudin
Desirudin
Argatroban
Dabigatran - Only oral (DOAC)
Test changes in DTIs:
Prolonged PT, PTT, and thrombin time
- Thrombin activity common to all these tests
What can cause prolonged thrombin times?
- Unfractionated heparin (ATIII)
2. Direct thrombin inhibitors (DTIs)
Uses of DTIs:
- Patients with HIT - (stop heparin start DTI)
- Hirudin, lepirudin, bivalirudin, desirudin, argatroban
- PTT often monitored whilst being administered - ACS/ Coronary interventions
- Bivalirudin - Atrial Fibrillation:
- (Dabigatran) - Oral (alternative to warfarin)
- Standard dosing doesn’t require PT/INR monitor
Warfarin Mechanism of Action:
Antagonist to vitamin K (epoxide reductase inhibitor)
- Epoxide reductase reduces vitamin K so that it can be used to activate clotting factors
Reduces levels of vitamin K dependent clotting factors (II, VII, IX, X)
Vitamin K in Clotting cascade:
Reduced vitamin K Forms Gla residues in clotting factors (Gamma-carboxylation)
- Then becomes oxidated
- Epoxidase Reductase - reduces vitamin K back to usable form
Dietary sources of Vitamin K
Green leafy vegetables (K1 form)
- Cabbage, kale, spinach
- Egg yolk
- Liver
K2 form of vitamin K
Synthesised by GI bacteria
Administration of warfarin:
Takes days to achieve effects - because time required for clotting factors to fall
Dose adjusted to reach target PT/INR (once a month check needed)
- Because drugs effect varies with diet (vitamin K) - Antibiotics may also kill GI bacteria - dec vit K - Increasing INR - Some drugs interfere with the metabolism of warfarin
Warfarin Blood tests:
PT/INR used to measure effect because:
- factor VII - has shortest half-life and will fall the fastest - therefore extrinsic pathway is most sensitive
PTT will also be increased - but less sensitive to warfarin
Thrombin time will be normal
Prothrombotic effects of warfarin:
Protein C is vitamin K dependent with a short half-life
- is an anti-clotting factor
Initial warfarin treatment leads to a transient protein C deficiency (pro-thrombotic)
- Brief - as other factors will fall shortly after
Mitigating prothrombotic effects of warfarin:
Other drugs such as heparin are given anytime warfarin is started in clot disorders (DVT/PE)
- however this is less relevant as often heparin is used for acute onset anyway before prophylaxis is started (because of its immediate effect)
ATRIAL FIBRILLATION - EXCEPTION:
- No active clots, just a risk of clots
- warfarin is often started without heparin
- brief increase in risk of clot is very low
Anticoagulants in pregnancy:
Warfarin - crosses placenta (avoided in pregnancy) - especially in 1st trimester
- can cause Fetal Warfarin Syndrome - abnormal foetal development
Unfractionated heparin is often used in pregnancy as it does not cross the placenta
Warfarin skin necrosis:
Rare complication of warfarin therapy
- Occurs in ptx with protein C defiiency
- Can also occur at high doses
Initial exposure to warfarin causes decreased protein C - resulting in skin thromboses
Large dark, purple skin lesions
Warfarin uses:
Stroke prevention in ptx with atrial fibrillation
Mechanical heart valves
DVT/PE - treated with warfarin for at least a few months
Chronic oral coagulation:
Indications are:
- AF
- Mechanical heart valve
- Prior DVT/PE
Drugs used:
- Warfarin:
- Pros: oral drug, cheap
- Cons: Monthly INR monitoring - NOACs/DOACs:
- Rivaroxaban/ apixaban and Dabigatran
- Pros: Consistant dosing - no INR monitoring
- Cons: Expensive, cannot be used in certain patients
DOACs:
2x direct factor Xa inhibitors:
- Rivaroxaban
- Apixaban
1x Direct thrombin inhibitor:
- Dabigatran
CANNOT BE USED IN PTX with:
- Dialysis
- Mechanical heart valves
Reversal agents for rivaroxaban and apixaban
Andexanet alpha - inactive decoy that binds the drug
Reversal agent for Dabigatran:
Idarucizumab - anti-dabigatran monoclonal antibody
3 Thrombolytic drugs:
tPA
Streptokinase
Urokinase
(all 3 increase conversion of plasminogen into plasmin)
Risks of thrombolytic agents:
MAJOR bleeding risk as they break down clotting factors as well as fibrin
Reversal of warfarin:
- Fresh Frozen Plasma (FFP)
- Corrects deficiencies in any clotting factor
- PT/PTT will normalise after infusion
- Used if severe bleeding and increased INR
- Vitamin K (oral or IV)
- IV can cause anaphylaxis
- Used if raised INR and no bleeding
INR 3-5 - hold warfarin
INR 5-9 - Hold warfarin, oral vitamin K
INR >9 - Consider IV vitamin K, FFP
Raised INR + Severe Bleeding - > Administed FFP
