Antithrombotics

Warfarin

Half-Life: 35-45 hours (Acenocoumarol 10 hours, Phenindione 8 hours)

Bleeding requiring hospital admission (% per year):

Aspirin 2.6%
Warfarin 4.3%
Clopidogrel 4.6%
Warfarin + Aspirin 5.1%
Warfarin + Clopidogrel 12.3%
All 3 taken together 12%

CYP2C9 mutation: Increases warfarin half-life and leads to over-anticoagulation

VKORC1 gene: Decreases warfarin requirements and leads to over-anticoagulation

Target INR

Management of High INR

Major Bleeding PCC + 5mg Vit K IV

Non-Major Bleeding 1-3mg Vit K IV & investigate source of bleeding

INR >8 not bleeding 1-5mg Vit K PO

INR 5-8, not bleeding Withold 2 doses and reduce maintenance dose

What constitutes poor INR Control?

Any one of:

Two INR values <1.5 in last 6 months
Two INR values >5, or One INR Value >8 in the last 6 months
Time in Therapeutic Range (TTR) less than 65%

CYP450 Drugs

Warfarin Teratogenicity (FWS)

Pathophysiology

Osteocalcin carboxylation for bone formation is a vitamin K dependent process
Warfarin has low molecular weight —> easy transfer across the placenta —> foetus more anticoagulated than the mother due to immature foetal liver enzymes

Discontinuing warfarin for pregnancy

Take pregnancy test at first day of missed period, with goal of stopping warfarin prior to 6 weeks.

First Trimester - Foetal Warfarin Syndrome (FWS)

Occurs following warfarin exposure during gestational weeks 6-12
Affects ~10% of foetuses exposed. Possible dose-response relationship.
6% congenital abnormalities
Nasal hypoplasia —> neonatal respiratory distress
Stipling of vertebrae & epiphyses —> hypoplasia of extremities

Second and third trimester risks

Risk of foetal, placental and neonatal haemorrhage
Other reported adverse outcomes from warfarin use in pregnancy
- CNS – microcephaly, hydrocephalus, Dandy-Walker malformation
- Eyes – blindness
- Still birth, neonatal death, premature delivery
- Others – scoliosis, developmental delay, deafness, CHD, seizures

Breastfeeding

Warfarin is safe in breast feeding

Warfarin & Anti-platelets

Already on anti-platelet and need to start warfarin

If on single anti-platelet <12 months after ACS should continue (consider using aspirin >clopidogrel)
If on DAPT, discuss with cardiology ?shorter duration
If on anti-platelet for 1o prophylaxis, PVD, prev stroke or stable IHD then stop the anti-platelet

Already on warfarin and need to start anti-platelets

If requires coronary stent, consider using bare metal stent
If PCI not required, give DAPT for 4 weeks then stop cloidogrel
Review the indication for warfarin and assess risk/benefit

Perioperative Management

Elective surgery

Stop 5 days prior to surgery, check INR day -1, give vit k if INR >1.5, check INR day of surgery
Restart at normal dose, or 2 days of double dose, on the evening of surgery

Bridging

Meta-analysis found increased bleeding rate with no reduction in thrombotic risk.

However, consider if:

<3 months since VTE and surgery cannot be delayed
High risk VTE patient – e.g. prev VTE whilst on anticoagulation
Mechanical heart valves except bileaflet aortic
<3 months since stroke/TIA
History of stroke/TIA plus 3 of: CCF, uncontrolled HTN, >75yo, Diabetes

Post-op - Use prophylactic dose, restart bridging at 48 hours.

Patient Self-Test and Self-Management

Available devices – CoaguCheck, Protime, INRatio

Quality Assurance

Internal QA – electronic, on-board (control integrated onto test strip), liquid control with INR of 2-4
External QA – every 6 months, test same sample on patient device and anticoag clinic equipment

Clinical outcomes – Reduced mortality and VTE. Unchanged bleeding rate. Trial included 99 patients >85 y.o.

Patient selection – Motivated patient expected to need AC for >1 year and successfully competes training.

Training consists of Theory and Practical aspects.

Wells Score for PE

Clinical signs and symptoms of DVT +3

PE is No. 1 diagnosis or equally likely +3

HR >100 +1.5

3 days immobile or surgery in last 4 weeks +1.5

Prev PE or DVT +1.5

Haemoptysis +1

Active Malignancy or treatment for malignancy in last 6 months +1

0-4 (12% incidence of PE) = Unlikely. Check D-dimer. If negative no further action.

5+ = Likely. Perform CTPA

Duration of Treatment for VTE

Initial

3 months for PE and proximal DVT
6 weeks for calf-vein DVT (or no treatment)
6 months LMWH (?or edoxaban) for cancer-associated VTE

Continued beyond 3 months:

Not required for VTE: provoked by surgery, non-surgical transient risks or confined to the calf
Consider long-term treatment:
- Unprovoked VTE taking into account individual patient risks
- See DASH Score
PE 3-4x more likely to recur than DVT and 2-4x more likely to be fatal if symptomatic compared to a symptomatic DVT

DASH Score

D-dimer abnormal 1 months after stopping anticoagulation +2

Age under 50 years old +1

Male Sex +1

Hormone use at time of VTE -2

0 = 2.4% annual risk of recurrence

1 = 3.9% 1 or less: consider discontinuing

2 = 6.3% 2 or more: consider LT anticoagulation

3 = 10.8%

4 = 20%

N.B. Score is based on meta-analysis of prev studies (warfarin only). It is not externally validated. Designed for use in stable patients with a first unprovoked VTE. Five-year recurrence of unprovoked VTE for all comers is 25-30%.

HAS-BLED (2010)

Predicts 1 year risk of major bleeding after starting anticoagulation. One point each for:

Hypertension
Abnormal liver
(& Abnormal renal function)
Stroke history
Bleeding predisposition
Labile INR
Elderly
Drugs that also risk bleeding (aspirin etc)
(& Alcohol)

Score 0-1 = Low risk (1-3%)

Score 2 = Moderate risk (4%)

Score 3+ = High risk (>5%), consider alternatives to anticoagulation.

Unfractionated Heparin

Derived from pig intestine.

Approx 1/3 of heparin molecules carry a high affinity polysaccharide that binds to Antithrombin (AT).

High Molecular Weight (HMW) Heparin-AT complexes then bind to thrombin (Why only the HMW chains? Because the heparin chain must be of sufficient length (molecular weight) to bridge between AT and thrombin).

Heparin-AT-Thrombin complex inactivates thrombin, preventing fibrin formation and inhibiting thrombin-induced activation of platelets, FV and FVIII.

Non-complexed heparin molecules and Heparin-AT complexes of any molecular weight can inhibit free FXa.

Half-life: 45-90 min (Variable due to binding to other positively charged plasma proteins & surfaces)

Molecular weight: 3,000 – 30,000 Da

Xa:IIa activity ratio: 1

Drug monitoring: Only use APTT ratio if pre-treatment APTT is normal. Reagents highly variable. Alternatives include: Anti-Xa, ACT and TEG

Emergency reversal:

Protamine sulphate
Dose: 1mg neutralizes 80-100 units of heparin, given IV over 5 minutes. Max dose 50mg.
Calculate dose based on previous 2 hours exposure. E.g. IV UFH 1250u/hour —> Give 25mg protamine
Short half-life, repeat doses may be required
Forms a stable, inactive salt with the heparin
Derived from fish sperm --> SE: Anaphylaxis. Risk increase with repeat exposure, rapid admin, and vasectomy

Low Molecular Weight Heparin & Heparinoids

Half-life: Approx 4 hours

Molecular weight: 1,000 – 10,000 Da (Mean: 5000)

Xa:IIa activity ratio: 2.5 – 4 (depending on preparation)

Target therapeutic Anti-Xa level:

4-6 hour peak = 0.5-1.0 iu/ml.
Pre-dose trough = <0.3 iu/ml

Produced from heparin by chemical or enzyme depolymerisation --> fragments approx. 1/3 the size of heparin

Results in reduced ability to bind thrombin for reasons given above

Reduced binding to other plasma proteins

Benefits Vs UFH:

More predictable dose-response relationship
Longer half-life
Reduced risk of HIT

Emergency reversal

Protamine reverse 60% of LMWH in healthy vounteers
Give only if last LMWH dose within 8 hours of bleeding event
Dose: 1mg per 100 Anti-Xa units of LMWH. Repeat dose with 0.5mg per 100 units if required.
Consider rFVIIa if life-threatening bleeding despite the above and timeframe consistent with ongoing LMWH effect

Fondaparinux

Half-life: 17-21 hours

Synthetic pentasaccharide, Xa inhibitor

rFVIIa in life-threatening bleeding (causes partial correction in healthy volunteers

Danaparoid

Heparinoid, derived from a different fraction of porcine bioproducts

Half-life: 25 hours (Xa), 7 hours (Thrombin)

Xa:IIa activity ratio: 20

Plasmapheresis will remove danaparoid from circulation.

DOAC vs VKA Overview

DOAC Limitations

Short half-life and lack of monitoring —> potential compliance issues

Limited lab assessment in emergencies

Limited used in chronic renal impairment

When to maybe measure DOAC levels

Spontaneous or traumatic haemorrhage

Following overdose or to assess compliance

When take interacting drug

Emergency surgery, neuroaxial anaesthesia and elective surgery

Renal impairment

Bridging from one AC to another

Extremes of weight

Trough levels for accumulation in the very elderly

Warfarin still best for:

Mechanical Heart valves

Mitral Stenosis

Antiphospholipid syndrome

Long-term stable INR and patient choice

Poor renal function

History of GI bleed

Questionable compliance

Drug interactions that prevent use of DOAC

AC in ‘Non-Valvular’ AF (2017, 2016)

DOAC trials varied in how broad their definition of NVAF was in the exclusion criteria

Native valve disease

CHA2DS2VASc score 2 or more, plus aortic valve disease, tricuspid disease or MR
- Can be considered for a DOAC
Moderate to severe mitral stenosis
- Continue to use VKA only

Bioprostheses

Can be considered for DOAC after the third month since implantation (ESC)
(N.B. for TAVI patients without AF, dual antiplatelets are used, not AC. Trials underway for DOACs)

Mechanical prostheses

Continue to use VKA only

Dabigatran Etexilate

Half-life: 13-18 hours (see below)

Dose: 150mg BD (110mg BD if age >80 or >75 plus high bleeding risk)

Mechanism:

Pro-drug --> absorption is pH sensitive --> reduced absorption with use of PPI

Reversible, high affinity binding to thrombin

Direct Thrombin Inhibitor is a reference to heparin, i.e. anticoagulant effect is independent of antithrombin

Coag Assays:

PT normal in 30% of patients
APTT usually prolonged – rate of prolongation flattens out as drug concentration increases —> insensitive
TT very sensitive – at high concentration will be prolonged beyond a detectable time. If the TT is normal, patient is not taking dabigatran.
Haemclot Assay – a modified TT assay designed for dabigatran monitoring
Chromogenic Anti-IIa assay also available
ECT – directly assays thrombin activity in plasma —> linear dose-response to therapeutic doses of dabigatran

Drug levels: For 150mg BD, expected peak = 0.184mg/l and trough = 0.09mg/l

Factor assays and FGN all underestimated in presence of dabigatran if clot-based assays used.

DRVVT false positives occur

Perioperative table

80% renally excreted, independent of CYP450 enzymes

Re-start at full dose 6-12 hours after minor procedure, or 48-72 hours after major surgery.

Drug Interactions

P-gp pathway affects absorption of the exetilate pro-drug

Inhibitors increase plasma drug concentrations

Azoles, amiodarone, diltiazem, tacrolimus

Inducers reduce plasma drug concentrations

Rifampicin, St Johns Wort, Carbamazepine

Reversal

Activated charcoal if last dose within 2 hours prevents further absorption

Idarucizumab

Monoclonal antibody fragment. Rapid clearance. Licensed 2016.
Dose: 5g, given as 2x 2.5g bolus infusions within 15 minutes of each other.

Trials (“RE-“ studies)

AF: RE-LY

VTE Treatment: RE-COVER & RE-COVER2

VTE 2o prevention: RE-SOLVE & RE-MEDY

VTE LT 2o prevention: RE-SONATE

ACS: RE-DEEM

TKR prophylaxis: RE-MODEL & RE-MOBILISE

THR propjhylaxis: RE-NOVATE

Other Direct Thrombin Inhibitors

Argatroban

Half-life: 50 minutes

IV infusion, licensed for treatment of HIT

Monitor with APTT ratio (aim 1.5 – 3.0)

Rapid hepatic clearance via CYP450 3A4 enzyme

Hirudin

Natural peptide from Hirudo medicinalis (medical leech)

10% of patients develop anti-hirudin antibodies à actually increases half-life

Therapeutic drug concentration: 0.5-2.5 microg/ml

Monitoring: APTT, ECT, TT, ELISA, Chromogenic, Haemolclot

Lepirudin

Half-life: 1.3 hours

Continuous IV/SC infusion

Recombinant hirudin

Bivalirudin

Half-life: 25 minutes

Short, synthetic peptide. Binds to circulating and clot-bound thrombin

Reversible as thrombin slowly cleaves the drug (accounts for 80% of drug clearance. 20% renal)

Monitor with ACT during cardiac surgery

Factor Xa Inhibitors

Coag Assays:

PT usually more prolonged than APTT (Rivarox > Apix) but both may be normal
Monitor with product-specific Anti-Xa chromogenic assay
TT, FGN and D-dimer unaffected
DRVVT false positives

Drug Interactions:

CYP3A4 and P-gp inhibitors both increase rivaroxaban concentrations
- Ketaconazole, Ritonavir

Reversal:

Prothrombin complex concentrate (PCC)

Octaplex 30 units/kg (max 3000 units) / Beriplex 50 units/kg (max 5000 units)
This is a supportive measure rather than a reversal / antidote to the DOAC effect

Andexanet alfa

Recombinant modified human factor Xa decoy protein. ~£15,000 per treatment.
ANNEXA-4 2019. Single arm trial. 1o outcomes were change in anti-Xa activity and physician-assessed haemostatic efficiency.
Given as a bolus followed by infusion.
Approved by NICE in 2021 solely for use in the setting of life-threatening GI bleeding (and only for rivaroxaban or apixaban. Edoxaban is not included in the NICE recommendation)
ANNEXA-I. 530 adults with intracranial haemorrhage on rivaroxaban or apixaban. Andexanet vs Standard Care (87% of which got PCC). Study stopped early at interim analysis, due to superiority in primary outcome (‘effective haemostasis at one month’) vs usual care. No diff. in functional outcome or 30-day mortality. higher rate of thrombosis in andexanet arm. Written publication awaited (as of Oct 2023)
As of 2023, there has been no direct comparison of andexanet vs PCC

Perioperative:

Pre-op: See table for each drug

Post-op: Re-start at full dose 6-12 hours after minor procedure, or 48-72 hours after major surgery.

Rivaroxaban

Half-life: 7-11 hours

Dose: For treatment of VTE = 15mg BD for 21 days, then 20mg OD

Expected peak PT ratio = 1.3-16 and trough = normal

Trials: ROCKET-AF, EINSTEIN, RECORD, SELECT-D

Apixaban

Appears to have lower rate of bleeding complications compared to other DOACs (e.g. this and this) with the important caveat that there are no head to head trials to draw this conclusion from.

Half-life: 9-14 hours

Dose for treatment of VTE: 10mg BD for 7 days, then 5mg BD, then 2.5mg BD after 6 months if ongoing AC

For 5mg BD, expected peak = 0.128mg/l and trough = 0.05mg/l

Trials: ARISTOTLE, Caravaggio, ADAM

Edoxaban

Lactose free (unlike other Xa inhibitors)

Half-life: 10-14 hours

Dose for treatment of VTE: 5 days LMWH, followed by 60mg OD (30mg for CrCl 15-50, wt <60kg, interacting meds)

Trials: Hokusai-VTE (Non-inferiority to dalteparin for treatment of VTE in cancer)

Antiplatelet Agents

Aspirin

Mechanism:

Irreversible binding to cyclooxygenase (COX1)
--> prevents thromboxane A2 generation and so prevents plt aggregation
As platelets are non-nucleated they cannot produce new COX1
--> drug effect 7-10 days (lifespan of platelets)

Perioperative

Associated with 1.5-fold increase in post-op bleeding but not in the severity of the bleed
Continue through most surgery – exceptions: neuro and prostate surgeries
Management of Emergency surgery with high bleed risk:
- Consider 2 units platelets >2 hours since last dose (4-5 hours if enteric coated)
- (aspirin-inactivated platelets can still be recruited by thromboxane generated in the transfused platelets)

Half-life: 3 hours

Onset of action: 1 hour

Time from drug admin during which platelet transfusion will have reduced efficacy: 2 hours

Time to normal platelet function after discontinuation: 5-7 days

Clopidogrel

Mechanism:

Binds to P2Y12 --> preventing ADP-induced plt aggregation
(Normal action of ADP is to bind to P2Y12 and P2Y1, in turn activating Gp IIb/IIIa)

Metabolised by CYP2C19

Defective genotypes vary by ethnicity and can cause clopidogrel refractoriness

Perioperative

Emergency surgery with high bleed risk
- Consider 2-4 units platelets >12-24 hours since last dose (based on little evidence)
Stop day -7 prior to neuroaxial procedures

Half-life: 6 hours

Onset of action: 3-4 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 12-24 hours

Time to normal platelet function after discontinuation: 5-7 days

Dual Antiplatelet Therapy (ESC 2017)

Typical DAPT treatment durations

Minimum 4 weeks post bare metal
Minimum 12 months post drug-eluting
<12 months for newer bioabsorbable drug-eluting
May differ for high bleeding risk patients (e.g. NEJM 2021 - no difference 1 vs 3 months DAPT following drug eluting stent)

Thrombotic risk categories for patients on DAPT

Very high: ACS <8 days, drug eluting stent <8 days
High: ACS 8-30 days, drug eluting stent 8-30 days
Moderate: ACS 1-12 months, drug eluting stent 1-12 months
Low: Cerebrovascular and peripheral vascular disease, ACS >12 months, drug eluting stent >12 months

Perioperative

4-8% of patients need surgery within 12 months of starting DAPT
Hold clopidogrel from day -5, continue aspirin for most low risk procedures, inc neuroaxial ones
High bleeding risk, also omit aspirin day -3 to day +7
If high risk surgery cannot be deferred in a patient with recent ACS
- Continue aspirin, stop clopidogrel/ticagrelor day -5 or prasugrel day -7
For high thrombotic + high bleed risk CABG patients
- Stop antiplatelets, consider parenteral GpIIb/IIIa inhibitor day -3 to 4-6 hours post op

Peri-Procedure

Lumbar puncture: Do not perform whilst on DAPT. If clinically justified then performing LP can be considered whilst on aspirin alone.
Gastro procedures: BSG 2021 guideline

Bleeding (see pages 246-248 ESC guideline for flowchart):

Weigh bleeding severity against thrombotic risk (above)
Trivial bleeding: Continue DAPT
Mild bleeding (No hospitalisation): Consider reducing duration of DAPT
Moderate bleeding (hospitalisation, no CVS compromise): Stop DAPT, continue single agent
Severe (Major blood loss): Stop DAPT, treat source of bleeding, continue single agent unless bleeding source cannot be controlled
Life-threatening: Stop anti-platelets, treat source of bleeding
Trial data to consider:
- ATACAS 2017: TXA vs placebo in cardiac surgery. No increase in thrombotic complications
- PATCH 2016: Non-traumatic ICH on anti-platelets, not fit for urgent surgery. Platelet transfusion vs standard of care. Primary outcome: increased mortality/disability at 3 months in platelet arm. Surprising finding, lead to further analysis in 2020 but still no evidence for platelet benefit.
- Zakko et al 2017: case-control trial. Platelets for GI bleeding on anti-platelets. No benefit but also no harm.
- RESTART 2019: Re-starting anti-platelets after ICH. Small trial. Larger trials in progress.

Prasugrel

Thienopyridine drug class (same as clopidogrel)

Mechanism:

Binds to P2Y12 preventing ADP-induced platelet aggregation
Prodrug. Converted to active drug by CYP450. Metabolised more efficiently than clopidogrel resulting in a greater antiplatelet effect.

Perioperative

Emergency surgery with high bleed risk
- Consider 2-4 units platelets >12-24 hours since last dose (based on little evidence)

Half-life: 7 hours

Onset of action: 2-4 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 16-18 hours

Time to normal platelet function after discontinuation: 5-7 days

Dipyridamole

Mechanism:

Inhibits phosphodiesterase --> accumulation of cAMP --> Intracellular Ca2+ falls --> blocks response to ADP --> reduced thromboxane A2 production preventing plt aggregation.
Also prevents cellular uptake of adenosine

Alpha half-life: 40 min, Beta half-life: 10 hours

Onset of action: 1 hour

Time from drug admin during which platelet transfusion will have reduced efficacy: 5-7 hours

Time to normal platelet function after discontinuation: 24 hours

GPIIb/IIIa Inhibitors

Abciximab

Mechanism

Human-murine antibody to GpIIb/IIIa, close to FGN binding site

SE: Thrombocytopenia in 0.5%. Onset in hours to days. Risk increases with repeated exposure

Half-life: 30 minutes

Time from drug admin during which platelet transfusion will have reduced efficacy: 1-2 hours

Time to normal platelet function after discontinuation: 24-48 hours

Tirofibran

SE: Thrombocytopenia in 0.5%

Half-life 2 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 4 hours

Time to normal platelet function after discontinuation: 4-8 hours

Eptifibatide

Half-life 2.5 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 4 hours

Time to normal platelet function after discontinuation: 4-8 hours

Significant Others

Ticagrelor

Mechanism

Reversible binding of ADP receptors
50-60% inhibition of ADP-induced plt aggregation (>clopidogrel)

Perioperative

Emergency surgery with high bleed risk
- Consider 4 units platelets >24 hours since last dose (based on little evidence)

Half-life: 6-13 hours

Onset of action: 1-2 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 18-26 hours

Time to normal platelet function after discontinuation: 3-5 days

Cangrelor

IV reversible ADP P2Y12 inhibitor

Continuous infusion

Half-life 90 min

Plt return to normal after 60 minutes

Vorapaxar & Atopaxar

Reversible PAR-1 inhibitors

PAR1 and PAR4 receptors are activated by thrombin leading to plt aggregation.

Fibrinolytics

Streptokinase

IV infusion

Enzyme produced by Group C haemolytic streptococcus

Binds to plasminogen activating it to plasmin independently of fibrin

Hyperfibrinolytic effect lasts a few hours after stopping infusion, but TT remains prolonged for 24 hours.

Tissue Plasminogen Activator (t-PA)

Human recombinant protein

Causes fibrinolysis only at the site of vascular injury

Reteplase

Non-glycosylated t-PA —> longer half-life

Tenecteplase

Modified t-PA —> longer half-life

Urokinase

Half-life: 12 minutes

IV infusion

Obtained from human neonatal kidney cells

Emergency reversal of Fibrinolytics

For cerebral bleeding within 48 hours of administration

FFP + TXA +/- FGN replacement