Anticoagulants, antiplatelets and fibrinolytics

Warfarin

• Close to 100% BA reaching peak blood concentrations in 90 minutes
• Circulating half-life 36-42 hours
• Bound to albumin, metabolised by liver and excreted in urine
• Protein C has short half-life (8 hours) and levels drop rapidly after starting warfarin
• Factor VII half-life is 7 hours and Factor II (thrombin) half-life of 60 hours
• Thus get transient thrombogenic state for 24-36 hours before predominant anticoagulant effect seen
• Crossover anticoagulation with heparin/LMWH should not be ceased until INR in therapeutic range for at least 2 days
• Prothrombotic rebound during warfarin withdrawal
  • In first 4 days, Factors VII and IX increase more rapidly than Protein C and S
  • Does NOT correlate with clinically increased thrombosis

warfarin

• Absolute contraindications
  • Known large oesophageal varices
  • Pregnant or 2 days post-partum
  • Platelets <50
  • Within 72 hours of major surgery
  • Previous hypersensitivity e.g. priapism or ischaemic skin necrosis
  • Acute bleeding
  • Decompensated liver disease or deranged baseline clotting with INR >1.5

warfarin

• Relative contraindications
  • Previous ICH
  • Recent major extracranial bleed within 6 months where cause has not been identified and treated
  • Peptic ulcer within last 3 months
  • HASBLED >= 3
  • Dementia or marked cognitive impairment with poor medicine adherence
  • Chronic alcohol abuse (esp. if binge drinking)
  • Untreated or poorly controlled HTN >160/90
• Can be used in breastfeeding up to 12mg per day (if higher, consider INR testing of infant)

warfarin

• Target INR
  • Most indications 2.0-3.0
  • 2.5-3.5 if mechanical mitral valve or mechanical aortic valve + risk factor (AF, previous VTE, hypercoagulable state, LV dysfunction or older generation AVR)
• Initiation
  • Post-operative patients can be re-started on previously stable dose without re-loading or parenteral anticoagulant cover
  • Low-risk patients (e.g. AF) can have warfarin started without anticoagulant cover
    • 3mg daily then re-check at Day 8 and day 15 with dose modification as required
  • High-risk patients (e.g. DVT) need therapeutic heparin cover with minimum 5 days overlap and cessation of heparin only once INR therapeutic for 2 days
    • 5mg daily with daily INR for minimum of 5 days is recommended
  • INR change of 0.5 over 3 days or 1.0 over seven days = unstable and need ongoing INR checks every 3-4 days at minimum

warfarin

• Complications
  • Bleeding
    • Risk of clinically significant bleeding rises when INR 3.0-4.5 and exponential increase if INR >5
    • 50% of bleeding episodes occur while INR <4.0
    • Risk factors for bleeding
      • Age
      • Previous bleeding episodes
      • Hypertension
      • Anaemia
      • Prior cerebrovascular disease
      • GI lesions
      • Renal disease
      • Antiplatelets
      • Drug/diet interactions
      • Fluctuations in INR
      • Antibiotic use

warfarin

• Complications
  • Skin necrosis
    • Mostly in those with Protein C deficiency on day 3-8 after initiation of therapy due to thrombosis of small cutaneous vessels
    • Treatment – Discontinue warfarin, LMWH/UFH, Vitamin K administration and screening for Protein C and S deficiency

warfarin

• Interactions
  • Warfarin is a racemin mixture of R and S isomers. S isomer is 5x more potent than R isomer
  • S isomer metabolised by CytP450 2C9
    • Potent inhibitors: Amiodarone, fluconazole, fluoxetine, metronidazole, sulfamethoxazole (raised INR)
    • Potent inducers: Carbamazepine, phenobarbital, phenytoin, rifampicin
  • R isomer metabolised by CytP450 3A4
    • Potent inhibitors: Clarithromycin, diltiazem, erythromycin, grapefruit juice, itraconazole, ketoconazole, verapamil (raised INR)
    • Potent inducers: Carbamazepine, St John’s Wort, phenobarbital, phenytoin, rifampicin (reduced INR)
  • Pharmacodynamic interactions occur with agents that increase bleeding risk without changing INR (e.g. aspirin/NSAID) Vitamin K malabsorption or dietary Insufficiency (increased INR)
  • Excessive dietary vitamin K (reduced INR)
  • Reduced gut bacteria from antibiotics (increased INR)
  • Reduced warfarin absorption (reduced INR)
  • Check INR every 2-3 days while interacting drugs initiated to ensure dose adjustments made

warfarin

• Reversal
  • No bleeding (always consider why and if alternative drug may be better)
    • INR high but <4.5: Reduce or withold next dose then resume lower dose once INR therapeutic 
    • INR 4.5-10: Cease warfarin. Consider reason for raised INR. If high risk of bleeding given Vitamin K 1-2mg PO or 0.5-1mg IV. Recheck INR within 24 hours and resume warfarin at lower dose once approaching therapeutic range
      • High risk of bleeding = Major bleed in last 4 weeks, known liver disease, concomitant antiplatelet therapy
    • INR >10: Cease warfarin. Vitamin K 3-5mg PO or 0.5-1mg IV. If high risk of bleeding, give prothrombinex 15-30IU/kg IV
      • Recheck INR in 12-24 hours and monitor every 1-2 days
      • Resume lower dose warfarin once INR approaches therapeutic range

warfarin

• Reversal
  • Bleeding
    • Life-threatening and INR >1.5: Cease warfarin, vitamin K 5-10mg IV, prothrombinex 50IU/kg, FFP 150-300mL
    • INR >2 with clinically significant but non-life-threatening bleed: Cease warfarin, Vitamin K 5-10mg IV, prothrombinex 35-50U/kg
    • Any INR with minor bleeding: Omit warfarin. Repeat INR and adjust warfarin to ensure therapeutic range. If bleeding risk is high or INR >4.5, consider vitamin K 1-2mg PO or 0.5-1mg IV 

warfarin

• Urgent surgery
  • INR < 1.5 – No intervention required
  • INR >1.5 – Prothrombinex 15-30IU/kg
• Vitamin K
  • In asymptomatic patients with INR 5-9, vitamin K 1-2.5mg PO will measurably reduce INR within 16 hours
  • If INR >10, reduction in INR takes longer
  • IV Vitamin K carries rare but serious, non-dose dependent risk of anaphylaxis and should NOT be used for routine reduction in INR. Also carries risk of overcorrection not seen with PO use
    • Should be restricted to INR >20, life-threatening bleeding, suicidal overdose

rivaroxaban

• Direct Factor Xa inhibitor
• Rapid oral absorption
• Plasma protein bound 95%
• 2/3 metabolised by liver
• 1/3 renally excreted unchanged (half-life 5-9 hrs; 11-13hrs in elderly)
• Anticoagulant effect lasts 12 hours
• Coag profile
  • PT using thromboplastin that is rivaroxaban sensitive is the most sensitive test for detecting activity
  • Normal PT makes high levels unlikely
  • APTT/PT and thrombin clotting time cannot estimate level of activity
  • Anti-Factor Xa level is sensitive for quantitative measure if drug-specific assay available

rivaroxaban

• Management of bleeding
  • Mild bleeding – Stop rivaroxaban and re-start based on severity of bleeding, ongoing risk factors and original indication
  • Moderate-severe bleeding (non-trivial with Hb drop of <20 or requiring <2U of PRBC)
    • Activated charcoal 50g if last dose <2 hours ago and no airway compromise
    • Plt transfusion if <50 or <100 and on anti-platelet agents
  • Life-threatening bleeding
    • TXA 1g IV then 1mg/kg/hr infusion
    • Prothrombinex 50IU/kg IV
    • Consider recombinant Factor VII 50mcg/kg if critical
  • Factor replacement is of limited utility as rivaroxaban directly inhibits them as opposed to reduces their number (as in warfarin)

apixiban

• Another direct Factor Xa inhibitor
• 66% bioavailability
• Half-life 8-13 hours
• 25% renal elimination, 75% faecal
• Management is the same as for rivaroxaban

dabigatran

• Dilute thrombin clotting time assay (TCT) such as Haemoclot Thrombin Inhibitor (HTI) is recommended assay to determine drug levels
• Thrombin time is very sensitive and normal TT excludes presence of significant amounts of drug
• APTT is moderately sensitive to dabigatran
• INR is not recommended
• Moderate bleeding
  • Oral charcoal if within 2 hours of dose
  • Blood product resuscitation with FFP if evidence of coagulopathy e.g. DIC/dilutional
  • Consider platelets if <50 or <100 on antiplatelets
• Severe/life-threatening bleeding
  • As above + idarucizumab 5g IV over 10-20 min

dabigatran

• Idarucizumab lasts 24 hours and effect is immediate
• Crucial to maintain urine output as up to 85% is renally excreted unchanged
• Haemodialysis removes 60% or more of drug within 2 hours
• Recombinant Factor VIIa and Prothrombin concentrate are both effective at reversing effect (FFP is NOT)

Heparins

• Unfractionated heparin
  • Heterogenous mixture of polysaccharides 3-50kD
  • Heterogenous chain sizes results in unpredictable clinical effect
  • Binds to antithrombin III, the complex of which inhibits Factors Xa, IXa, XIa, XIIa and thrombin
  • Primary anticoagulant effect is indirect inhibition of Factors Xa and thrombin
  • Shorter chains are more Factor Xa specific
  • Weight-based IV UFH dosing protocols are the most reliable approach for achieving therapeutic anticoagulation and preventing further thrombosis
  • SC UFH can be used for prophylactic therapy but not for therapeutic anticoagulation as bioavailability ranges from 10-90%
  • Neither UFH nor LMWH cross the placenta
  • UFH actually activates platelets via PF4 membrane receptor

heparins

• LMWH
  • Also binds to antithrombin III but Factor Xa specific (as opposed to UFH thrombin:Factor Xa 1:1)
  • Cleared by kidneys and thus in severe impairment may be half-dosed or UFH used instead
  • Weight-based dosing in obese patients appears to be safe and preferred over fixed dosing
  • Advantages over UFH
    • Rapid and predictable SC absorption – more reliable levels of anticoagulation
    • More stable dose response – far less monitoring
    • Resistance to inhibition by PF4 – decreased incidence of thrombocytopaenia
    • Decreased antiheparin antibody formation – Greater antithrombotic effects
    • Greater Factor Xa specificity – Potential for reduced bleeding
    • Less anti-thrombin activity – Absence of rebound
    • Ease of administration – Outpatient therapy

heparins

• Minor bleeding
  • Cease heparin therapy
  • Anticoagulation effect lasts 3 hours from last dose (UFH) and 24 hours from LMWH
  • Observation with serial APTT or Anti-Factor Xa assays may be sufficient
• Major bleeding
  • UFH
    • Protamine 1mg per 100IU of total IV dose given over last 3 hours
      • Maximum 50mg over any 10 minute period
  • Enoxaparin
    • 1mg per 1mg of enoxaparin given in last 8 hours
    • 0.5mg per 1mg of enoxaparin given 8-24 hours ago
  • Dalteparin
    • 1mg per 100 units of dalteparin in last 8 hours
    • 0.5mg per 100 units of dalteparin in last 8-24 hours

heparins

• 1/3 of patients on UFH suffer some bleeding complication (2-6% major bleeding)
• Increased risk of up to 20% for major bleeding in presence of UFH +
  • Recent surgery or trauma
  • Liver disease
  • Renal disease
  • Malignancy
  • Alcoholism
  • GI bleeding
  • Concurrent antiplatelet/anticoagulant use
• Heparin rebound can occur due to short half-life of protamine, necessitating second dose
• Protamine carries a 0.2% anaphylaxis rate with high case fatality so only for major bleeding

heparins

• Heparin-associated thrombocytopaenia
  • Platelet count falls 10-20% on day 2-3 of therapy with UFH due to non-immunological platelet aggregation
  • Nadir is 100 and it carries no risk for associated thrombosis and platelet count should recover within 4 days despite ongoing UFH therapy

heparins

• Heparin-induced thrombocytopaenia (HIT)
  • Reserved for process by which IgG or IgM antibodies to heparin and PF4 results in platelet activation, thrombocytopaenia, and tendency for thrombosis
  • Skin necrosis, ischaemic limbs or VTE may result
  • Usually occurs 5-10 days into therapy but can be sooner if previous heparin exposure
  • One of the earliest signs is an anaphylactoid reaction within 30 minutes of IV bolus dose – obtain immediate platelet count as often get transient drop in platelets at the time and this confirms diagnosis and necessity for alternative agent
  • Occurs in 1-3% of post-operative patients on UFH vs. 0.1-1% of medical patients on UFH
  • 10x less frequent with LMWH
  • Platelet nadir 20 to 150 usually
  • Drop of 50% from baseline is considered evidence of HIT, even if still in normal range
  • Need to cease all heparin exposure including heparin ‘locks’
  • Platelet count contraindicated as minimal risk of bleeding but serious risk of thrombosis
  • During recovery phase (platelet count usually returns to normal over 4-6 days), significant thrombosis risk so need non-heparin anticoagulant cover, even if no symptomatic thrombosis

fondaparinux

• Synthetic pentasaccharide that binds antithrombin III and enhances its anti-Factor Xa activity only
• SC injection

hirudins

• Direct thrombin inhibitors
• Inhibit both clot-bound and circulating thrombin, do not require antithrombin III as a cofactor, do not interact with PF4 and do not inhibit other coagulation pathways
• More predictable anticoagulant effect than UFH
• Hirudin, lepirudin and argatroban are all indicated for anticoagulation in HIT
• Bivalirudin and argatroban are synthetic analogues used for PCI
• Half-lives <2 hours so no antidote currently available
  Can use FFP or prothrombin concentrate in the event of severe bleeding

Antiplatelet agents

• Aspirin
  • Irreversible COX-2 inhibitor, thus inhibiting arachidonic acid conversion to thromboxane A2 in platelets and inhibiting prostacyclin synthesis in endothelium
  • Rapidly absorbed, half-life 3-4 hours (but 7 days antiplatelet effect)
• NSAID’s reversibly inhibit cycloxygenase and can reduce the antiplatelet effect of aspirin through competition
• STEMI patients on NSAID’s have higher mortality
• Severe haemorrhage in setting of aspirin requires platelet administration to raise count by 50 and may have to repeat this given ongoing aspirin effect for 7 days from last dose

Antiplatelet agents

• Clopidogrel
  • Selective irreversible ADP inhibitor, causing fibrinogen receptor to be ineffective due to membrane deformation
  • Full antiplatelet effect within 2 hours of 600mg dose
  • Effect lasts 5-7 days
  • Delivered as a prodrug and requires activation by CytP450 2C19 (thus patients with limited activity of this enzyme have less antiplatelet effect; seen in up to 14% of Chinese people)
  • Omeprazole inhibits this enzyme if given within 12 hours of clopidogrel dose

Antiplatelet agents

• Ticagrelor
  • Alternative ADP receptor inhibitor but is reversible
  • 2-3 hrs to peak effect and half-life 7-9 hours
  • Antiplatelet effect 3-5 days
  • Not a prodrug
  • V.s clopidogrel, reduces all cause cardiovascular mortality and MI with modest increase in major bleeding and a trend towards more intracranial bleeding
  • Associated with heart block and dyspnoea
• Ticlopidine
  • Alternative ADP receptor inhibitor but associated with neutropaenia and TTP so rarely used now

Antiplatelet agents

• Prasugrel
  • Alternative irreversible ADP inhibitor
  • Also a prodrug requiring hepatic activation
  • Compared to clopidogrel has higher risk of major bleeding and less effective in those with previous stroke/TIA, >75yo and body weight <60kg

Antiplatelet agents

• Dipyramidole
  • Vasodilator and antiplatelet effect through reversible phosphodiesterase inhibition
  • Used in combination with aspirin for stroke or TIA secondary prevention
  • Common adverse effects include headache, dizziness, flushing and abdominal pain
• Cliostazol
  • Strong reversible PDE inhibitor
  • Used to increase walking distance in PVD and reduces incidence of stroke in cerebrovascular disease

Antiplatelet agents

• GP IIb/IIIa inhibitors
  • Fibrinogen binds to glycoprotein Iib/IIIa receptors in platelet aggregation
  • All given by IV loading dose then continuous infusion
  • Mainly indicated for patients undergoing PCI
  • Delayed until time of PCI as reduces bleeding with similar outcomes
  • Abciximab, epitifibatide and tirofiban all effective

fibrinolytics

• Streptokinase
  • Binds to and activates circulating plasminogen to plasmin
  • Given as slow infusion with serum half-life of 23 minutes with fibrinolytic effect lasting 24 hours
  • Antigenic with allergic reactions in 6% of patients
  • Re-treatment within 6 months carries high risk of allergy and should not be used within 12 months of a streptococcal infection
• Alteplase
  • Tissue plasminogen activator is a naturally occurring enzyme in endothelial cells that cleaves peptide bond in plasminogen to active plasmin
  • Alteplase has binding sites for fibrin, suggesting specificity for thrombus vs. systemic fibrinolysis
  • Clinical effects do not show this specificity however
  • Serum half-life 4-8 minutes and shorter fibrinolytic state than streptokinase
  • Heparin can be administered shortly afterwards if required
  • Not antigenic
  • 0.9mg/kg – 10% bolus and 90% over 60 minutes

fibrinolytics

• Tenecteplase
  • Alteplase with amino acid substitutions at four sites with longer half-life, high fibrin specificity and extended duration of effect
  • Serum half-life of 20 minutes (2x) allows for weight-tiered bolus dosing
  • 14-fold greater fibrin specificity and reduced systemic plasmin production
  • Plasminogen activator inhibitor 1 resistance 80x greater than alteplase allowing for longer association of tenecteplase with fibrin-rich clot
  • Theoretical reduced bleeding complications due to less thrombin-antithrombin complex induction
  • No absolute mortality or safety benefit in STEMI vs. alteplase
  • Less medication errors due to bolus dosing but this has not translated into improved patient outcomes

fibrinolytics

• Bleeding complications
  • Avoid all needle sticks
  • Avoid any arterial punctures
  • Limit venous acce to easily compressible sites
  • Avoid any central venous access
  • Avoid NG tubes and nasotracheal intubation
• Significant bleeding requires: 
  • Cessation of fibrinolytic/heparin/antiplatelets
  • Protamine for heparin reversal if required
  • Platelets +- desmopressin if Plt <50 or <100 with antiplatelets
  • Empiric cryo 10IU or FFP 300mL
  • TXA 1g + 15mg/kg/hr infusion

Antifibrinolytic agents

• TXA and e-aminocaproic acid are both derivatives of lysine, with LMW and administered both orally and IV
• Attach to sites on plasminogen to prevent its binding to fibrin
• Minimally metabolised
• Excreted by kidney
• TXA has 8x the antifibrinolytic activity of ACA
• CRASH-2 trial showed TXA 1g over 10 min then 1g over 8 hours reduced death due to bleeding and all-cause mortality if provided within 3 hours with no increase in thrombosis
• Limb ischaemia and MI rate is <1%
• In adult trauma, VTE risk was not significantly increased but does increase if provided for SAH (up to 2-3%)
• STAAMP trial of prehospital bolus of 2g TXA vs. 1g bolus + 1g infusion over 8 hours showed equal benefit without an increase in adverse events

Antifibrinolytics

• Indications
  • Trauma within 3 hours of event
  • PPH (WOMEN trial)
  • Haemoptysis
  • Dental bleeding in haemophilia (mouthwash 500mg tab in 10mL water)
  • Prevent bleeding in haemophilia patients during surgery
  • Traumatic hyphaema (decreases rates of rebleeding)
  • Menorrhagia
    • 1g q6h for 3-4 days
  • When fibrinolysis contributes to bleeding (post-thrombolytics)
  • Epistaxis (gauze soaked in IV solution)

Last Updated on August 4, 2021 by Andrew Crofton