Coagulation/anticoagulation Flashcards
What are some risk factors for clotting?
60+ Active cancer or cancer treatment Dehydrated Obese History/family history of VTE HRT or COC Pregnancy Critical condition Surgery
What are some risk factors for a bleed?
Epidural Surgery Active bleeding Blood disorder INR >2 Acute stroke Uncontrolled hypertension Concurrent use of anticoagulants
Long-haul flyers could reduce the risk of blood clts by
Wearing compression stockings.
People prefer which type of compression stockin?
Knee high. (thigh high not liked)
When would we use UFH unfractionated heparins instead of LMWH?
- Impaired renal function
2. If patient has a high risk of bleeding - they have short half-lifes.
What is UFH dosing adjusted according to?
The APTT: activated partial thromboplastin time, which is a measure of the activity of the intrinsic and common pathways of coagulation.
What is the APTT?
APTT: activated partial thromboplastin time.
Why are UFH preferred instead of LMWH in patients with a high bleed risk?
UFH have a shorter half life than LMWH,.
The clotting time for APTT lies between
27-35 seconds
What is the difference between APTT, APTT ratio and INR?
APTT is ~30s, APTT ratio = (APTT value)/control value = ~1.5 etc.
It is the same principle as INR.
What does the prothrombin time measure?
Prothrombin time (PT) is a blood test that measures how long it takes blood to clot. A prothrombin time test can be used to check for bleeding problems. PT is also used to check whether medicine to prevent blood clots is working. A PT test may also be called an INR test.
What are the properties of an ideal anticoagulant?
- Orally active
- Rapid (several hours) immediate response.
- Wide therapeutic index
- Little or no inter-individual or intra-individual variability.
- No drug/food interactions.
- Predictable PD/PK
- No routine monitoring required.
- No routine dose adjustment needed.
- Highly efficacious in reducing thromboembolic events
- Good safety profile.
A measure of the common and intrinsic pathways of coagulation.
APTT: activated partial thromboplastin time.
How do LMWH compare with the ideal qualities for an anticoagulant?
Has all of them except oral activity.
- SC injection not orally active X
- Rapid (several hours) immediate response.
- Wide therapeutic index
- Little or no inter-individual or intra-individual variability.
- No drug/food interactions.
- Predictable PD/PK
- No routine monitoring required.
- No routine dose adjustment needed.
- Highly efficacious in reducing thromboembolic events
- Good safety profile.
LMWH are used to treat
DVT/PE & UA
LMWH are used for prohylaxis of
thrombo-prophylaxis in medical or surgicial situations.
How are LMWH heparins dosed?
According to patient weight, given SC
Give examples of three LMWH
Tinzaparin
Dalteparin
Enxaparin
What are the differences in license between tinzaparin, dalteparin and enoxaparin?
All are licensed for DVT, PE, Prophylaxis.
Tinzaparin is NOT licensed for UCAD while dalteparin and enoxaparin are. (unstable coronary artery disease).
What is the VTE treatment dose of Tinzaparin?
175ui/kg OD
What is the VTE treatment dose of Dalteparin?
200iu/kg OD
What is the VTE treatment dose of Enoxaparin?
1.5mg/kg OD
What is the UCAD dose of Dalteparin?
120ui/kg BD
How frequently is Dalteparin used for UCAD and what dose?
BD, 120ui/kg
A LMWH which has a VTE treatment dose of 175iu/kg OD.
Tinzaparin.
A LMWH which has a VTE treatment dose of 200ui/kg OD.
Dalteparin.
UCAD dose 120ui/kg BD
What is the UCAD dose of enoxaparin?
1mg/kg BD.
PT is a measure of which pathway?
Extrinsic
PT measure what?
Time to clot formation which is normally about 12 seconds.
How is PT converted into INR?
Using an international sensitivity index (ISI) to enable comparisons between different tissue thromboplastins.
What is the normal INR?
1.0-1.2
What is the calculation to work out INR?
INR = PT(patient)/PT(mean normal)*ISI
How does Warfarin compare to the ideal characteristics of anticoagulants?
Orally admin.
Not rapid onset.
Not wide index of action.
Variability in dose response present.
Interactions with food or drugs common: antibiotics.
Unpredictable PD/PK due to patient variability.
Routine monitioring is needed.
Dose adjustment can be frequently needed.
Only highly effective when INR therpeutic levels.
Only good safety profile when therapeutic INR.
Why are interactions with warfarin so common? (2)
IT is metabolished by the liver cytochrome p450 system - other drugs can interfere with this metabolism.
Warfarin is highly bound to plasma proteins like albumin - other protein bound drugs can have a competitive effect.
How can warfarin overdose be treated?
Beriplex: NICE recommend prothrombin complex concentrates for emergency reversal of warfarin.
Beriplex P/N contains all the vitamin K- dependent coagulation factors as well as the coagulation inhibitors Protein C and S.
Warfarin inhibits the effective synthesis of the vitamin K-dependent clotting factors: II, VII, IX and X, as well as the regulatory factors ______ and ________.
Warfarin inhibits the effective synthesis of biologically active forms of the vitamin K-dependent clotting factors: II, VII, IX and X, as well as the regulatory factors protein C, and protein S
________ is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires __________ __________ for its activity.
Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity
_________ is a vitamin K-dependent anticoagulant protein.
Protein S is a vitamin K-dependent anticoagulant protein
What does DOAC stand for?
Direct Acting (ORAL) AntiCoagulants.
What is apixiban?
DOAC with less bleeding risk, half-life of 12 hours.
Direct inhibitor of activated factor X (factor Xa)
What are the 4 indiciatons for Apixiban use?
- VTE prevention post knee or hip replacement.
- Treatment of DVT and
- Prophylaxis of recurrent DVT and PE.
- Non-valvular AF
What is Dabigatran?
Another DOAC.
Orally active.
Direct thrombin inhibitor
What are the indications for dabigatran?
VTE prevention post knee or hip replacement.
Treatment of DVT and prophylaxis of recurrent DVT and PE.
Stroke prevention in patients with AF
Why would you use Apixiban instead of Dabigatran?
Less bleed risk.
What is edoxaban?
Direct inhibitor of activated factor X (Factor Xa) Same as apixiban.
What are the indications for the use of Edoxaban? (3)
Prevention of stroke and systemic embolism.
Treatment of DVT, PE.
Prevention of recurrent DVT and PE (VTE).
Direct thrombin inhibitor
Dabigatran
DOAC used for prevention of stroke and systemic embolism
Edoxaban.
What do edoxaban, apixiban and rivaroxaban have in common?
All direct inhibitors of activated factor X (Factor Xa)
Caution should be taken when using dabigatran in patients with
Renal failure.
Direct thrombin inhibitor that can be used for stroke prevention in patients with AF
Dabigatran
Dabigatran has interactions with what drugs?
Verapamil and quinine/quinidine.
What is Rivaroxaban, how does it work?
DOAC
A direct inhibitor of activated Factor X (Factor Xa)
What is Rivaroxaban licensed to treat?
- VTE prevention post knee or hip replacement.
- Treatment of DVT and prophylaxis of recurrent DVT and PE.
- Stroke prevention in patients with AF.
How should Rivaroxaban be taken and why?
With food: increased BA.
What are the limits of the DOACs?
Limited reversibility - what if an accident with severe bleeding occurs? how do we restore coagulation?
Although one of the benefits is that we do not have to monitor the patients as much - we also do not know if the patients are taking them correctly.
What does the baseline monitoring for DOACs consist of?
- Prothrombin time
- Liver function
- Renal Function
- BP
What DOACs can be used for VTE prevention in hip and knee replacement?
Dabigatran
Rivaroxaban
Apixaban.
NOT Edoxaban.
What DOACS can be used for the prevention of non-valvular AF?
Dabigatran Rivaroxaban Apixaban Edoxaban ALL of them.
What DOACS can be used for the treatment of DVT?
ALL of them
Dabigatran
Rivaroxaban
Edoxaban
What DOAC cannot be used for VTE prophylaxis in hip and knee replacement?
Edoxaban.
How should patients be swapped from warfarin to xarelto (Rivaroxaban)?
When the INR is < 2.5.
Why should INR values not be used to measure the anticoagulant activity of Rivaroxaban?
Not valid.
How should patients be swapped from warfarin to Apixaban?
When INR < 2.0
When should patients be swapped from warfarin onto Edoxaban?
INR: <2.5
How is an overdose of dabigatran treated?
Activated charcoal within 1-2 hours
How is rivaroxaban overdose treated?
Activated charcoal reduces absorption if used within 2-4 hours of ingestion.
How is apixaban overdose treated?
Activated charcoal up to 3 hours post ingestion.
How can bleeding be managed with DOACs?
Stop the drug.
Fluid replacement to ensure good urine output.
PCC or rFVII
IV tranexamic acid
Haemodialysis - not for FXa inhibitors as they are highly protein bound. Only for Dabigatran.
What is Idarucizumab?
Fully humanised monoclonal antibody fragment which has a highly specific binding affinity with dabigatran therefore reversing any anticoagulant activity of dabigatran and its metabolites.
SO EXPENSIVE: 5g = £2,400.
Andexanet Alpha is being developed for reversal of the actions of which DOACs?
Rivaroxaban
Apixaban
Edoxaban
All factor Xa inhibitors.
Aripazine is being developed for the reversal of the anticoagulant effect of
All DOACs, oral factor Xa inhibitors, fondaparinux, LMWHs and unfractionated heparins.
How does Andexanet Alpha work?
Factor Xa decoy that binds the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban.
What is Ciraparantag?
Small synthetic water-soluble molecule that binds to a wide range of anticoagulants from binding to their endogenous targets.
What are the most important contra-indications for DOACs?
A lesion or condition, if considered a significant risk factor for major bleeding. This may include: GI ulcers. Varices Haemorrhage Brain/Spinal/Eye surgery.
Treatment with other anticoagulant agents.
What is betrixaban?
Pipeline. Oral, once-daily Factor Xa inhibitor, an important validated target in the blood coagulation pathway, to prevent life-threatening thrombosis.
What is the coagulation cascade made up of?
3 pathways.
Intrinsic
Extrinsic
Final common.
What is the intrinsic pathway?
Factor XII is activated by contact with ‘damaged’ surface which ultimately leads to the activation of factor X.
What is the extrinsic pathway?
The activation of ‘tissue factor’ - Factor VII is released from damaged cells + calcium ions which causes the activation of factor X.
What is the final common pathway?
Activated Factor 10 from both the intrinsic and extrinsic pathway helps to convert prothrombin into thrombin which in turn converts fibrinogen to activated fibrin.
Activated ___________ from both the intrinsic and extrinsic pathway helps to convert __________ into __________ which in turn converts _______ to activated _____.
Activated Factor 10 from both the intrinsic and extrinsic pathway helps to convert prothrombin into thrombin which in turn converts fibrinogen to activated fibrin.
What is the MOA of heparins?
Activates antithrombin which induces inactivation of thrombin.
Potentiates naturally occurring inhibitors of activated factor 10. (Xa)
What monitoring for UFH? [5]
- Weight
- Renal function
- FBC: due to heparin induced thrombocytopenia - on initiation and again if the treatment lasts more tha 4 days.
- U+Es: risk of hyperkalaemia (all heparins)
- APTT
NB. Osteoporosis risk is high with UFHs.
Monitoring for heparins?
- Weight
- Renal function
- FBC but greater risk of HIT in UFH.
- Hyperkaleamia so U+Es.
- Use antifactor Xa in special circumstances if pregnant, low weight, children, renal failure to measure the efficacy and if dose is correct - and for HIGH weight.
HIT type _ is more common.
HIT Type 2, entails platelet counts falling and thombosis.
UFH –> FBC when?
Intiation and again if treatment lasts more than 4 days.
What is warfarin?
Vit-K-epoxide-reductase inhibitor - transient risk of increased clot change on initiation due to decreasing innate anticoagulants protein S and C.
Bridging with heparins occurs to overcome this.
Warfarin side effects:
Skin rashes, alopecia, bleeding, bruising.
Anticoagulant book for all!
Apixaban has less bleed risk in
Elderly.
Rivaroxaban works by
Inhibiting Activated Xa.
Taken once daily with food.
Has a positive impact on ACS.
Dabigatran works by
Directly inhibiting thrombin - reversible via idacruziamb.
Not for renally impaired. 80% renal clearance.
Anticoagulation for someone <40kg
Warfarin
and children.
NOT pregnancy -> LMWH
Anticoagulation for heart valve mechanical?
Warfarin
eGFR <40 anticoagulants
Apixaban, rivaroxaban not DABIGATRAN
Which doac not for renally impaired?
Dabigatran
Warfarin has many drug-drug interactions because:
Protein bound and CYP450
How does a warfarin to rivaroxaban switch occur?
Stop warfarin, wait until INR below 2.5 (5-6days) then start rivaroxaban at BNF dose.
What is the largest risk factor for VTE that is not hereditary?
COC
UFH doses are based on weight/renal function but adjusted according to
APTT
Protoamine sulphate
Reversal agent for heparins, LMWH, UFHs etc.
Anticoagulation in pregnancy
LMWH - based off pre-pregnancy or early pregnancy weight.
If a patient who is pregnant has a history of DVT in a previous pregnancy, how is this managed?
Start anti-embolism stockins as soon as pregnancy confirmed.
Start prophylaxis dose LMWH 4 weeks before time of previous DVT in pregnancy occured.
