Anticoagulant Accumulation/Toxicity

warfarin use

• better than DOACs in these populations:

  • Mechanical heart valves (DOACs CI in these pts**) → reduced stroke and valve thrombosis

  • rheumatic mitral stenosis + atrial fibrillation (= valvular atrial fibrillation) → reduced mortality and stroke

  • Antiphospholipid aby syndrome → reduces strokes

  • frail elderly stable on warfarin → reduces bleeding

  • Break through events during DOAC therapy

• used much less in clinical practice

• clinician comfort declining

• increasing role for Anticoagulation Clinic

• shift in clinician’s minds re: DOAC use: DOACs for all vs DOACs w/ some nuances

balancing risk: thrombosis vs bleeding

• implications of thrombosis dependent on indication:

  • Mechanical heart valves → valve thrombosis/stroke

  • Afib → stroke

  • VTE → PE

  • diff pt populations (contrast VTE vs AF)

• Bleeding

  • minor - trivial

  • major bleeding - in critical organ and or decline in hgb 20g/L

    • transfusion (1 pack blood ~10g/L)

    • CBCs annually in those on anticoagulants

  • bleeding risk

bleeding risk

• indication dependent, reflecting diff pt populations

• high bleeding risk score is NOT a reason to avoid anticoagulation

  • in AF, thrombotic and bleeding risk often rise in parallel

  • in VTE, implications w/ extended (secondary prevention) therapy - proph dose vs cessation of therapy

• Benefit: awareness of bleeding risk for front line clinician

major bleeding: intracranial

• most feared complication; uncommon

• diff types:

  • epidural or subdural hematoma - trauma, elderly - generally do well

  • subarachnoid or intracerebral hemorrhage - more likely to do less well

• fixed space (w/i skull), concern w/ initial volume and expansion of bleeding

• once hemorrhage occurs on anticoagulants, initial volume, risk of expansion, severity and probability of death is higher

  • overall mortality rate 40-67%

• DOACs reduce risk of ICH by 30-70% compared to warfarin, w/ intracranial hemorrhage reported:

  • smaller volumes of blood

  • less severe strokes (more having fxnal recovery)

  • fewer deaths

major bleeding: extracranial

• most common site is GI but could be anywhere; more GI bleeds w/ DOACs - counsel*

• majority result in full recovery w/ approp medical attention

• req reversal or interruption of therapy

  • predisposes to risk of thrombosis, depending on duration of held anticoagulant

  • identification of reason/source of bleeding - tx vs no txed

assessment of bleeding

• bleeding - location

  • major (extra/intracranial)

  • minor

• timing of blood loss

  • when did it start/stop?

  • freq?

  • had this in past?

• qualify and quantify blood loss:

  • color, amount, explanation? hgb drop? sx of anemia?

• immediate management

  • monitor (CBC, s/s)

  • refer to physician vs emergency department

• future management

  • tx of source vs not?

  • mitigate other risk factors?

  • educate pts that they would rather have bleeding event than clotting bc once resolved tend to recover well

• impact of major bleed vs clotting event

  • error of commission vs omission

  • most pts would prefer to be over-anticoagulated

factors impacting (elevating) INR - areas to target for pt assessment

1. deterioration in health

   • acute changes (flu, COVID, fever, diarrhea etc)

   • chronic medical condition changes

     • exacerbation of HF

2. changes to meds

   • rx, non-rx, herbals

   • drug interactions: CYP450 (major: 2C9; minor: 3A4, 1A2)

3. changes to lifestyle

   • vitK intake

   • EtOH consumption

   • level of activity

4. administration of too much warfarin

   • inadvertent dose doubling

   • tab strength mix up

assess timing of impact and chronicity of change**

ambulatory critical INR (>5) management

• s/s of bleeding/unusual bruising or smn more concerning ongoing

  • medical attention vs ambulatory management

• clot vs bleed risk

  • immediate critical INR management: hold warf ± administer vitK

• factor(s) contributing to critical INR:

  • maintenance dosing post-critical INR management

vitamin K in critical INR management: ambulatory, non-bleeding pt

• INR 4.5-10.0: omit 1-2 warf doses, consider vitK PO 1-2.5mg and reassess INR

• INR >10.0: hold warfarin, vitK PO 2-5mg and reassess INR

• supra-therapeutic INR 3.5-5.0, non bleeding: typically will not hold warfarin, reduce as per dosing chart and assess INR w/i 7-14d

antidotes for warfarin

• VitK

  • po: works w/i 16-24h

  • IV: works in ~12h

  • SC and IM not recommended

• Prothrombin Complex Concentrate = PCC (factors II, VII, IX, X)

  • TEMPORARY reversal of INR (w/i mins); must also admin vitK - used for urgent bleeding cases

pt counselling w/ critical INR

• specific to warf dosing/holding timing instructions (ensure understanding)

• specific to vitk admin (if applicable)

• specific to increased risk of bleeding

• general precautions to mitigate bleeding:

  • restful evening/day

  • general avoidance of exposure to high risk situations that may result in cutting oneself or injuring oneself

  • avoid EtOH if applicable (for at least 24h)

• ongoing monitoring for s/s of bleeding

  • overview of what to look for

  • head to ER if concerning bleeding occurs

post-critical INR management INR now <4 or therapeutic

Situation:

• acute, reversible cause

  • likely resume prior warf dosing (assuming stable)

  • check INR in 2-4wks

• change that is ongoing

  • empiric reduction in maintenance dosing based on experience/literature

  • check INR in 4d to a week to 2 wks based on reason (if delayed DDI may wait 1-2 wks vs non-delayed would assess w/i 3-5d

• no identifiable reason

  • empiric reduction in maintenance dosing (~10%) guided largely based on clot vs bleed risk

  • check INR ~7d

PCC

• contained factors II, VII, IX, X, protein C and S

• reduces INR w/i mins, effects not sustained (6-12h)

  • must also admin vitK to sustain reversal in INR

• Indications:

  • serious or life-threatening bleeding

  • req urgent (<6h) interventions w/ risk of bleeding

• aPCC (activated PCC) - contains activated FVIIa (approved for those w/ hemophilia)

• PCC use to reverse DOACs

  • use antidotes first if available bc PCCs are blood products

anticoagulant MOAs

• DOACs: act directly on clotting factors in circulation

  • don’t req a co-factor

  • act quickly

• LMWH req a co-factor

• warfarin: acts indirectly via vitK

DOACs

• apix, riva, edox - metabolized via 3A4

• accumulation if:

  • renal dysfxn OD (dabig»edox>riva>apix)

  • apix and riva: strong Pgp and 3A4 inh

  • edox and dabig: strong Pgp inh

• peak @ 2-4h and have shorter half lives (7-14h) - timing of last dose and adherence important

• need for “reversal” if:

  • major bleeding or urgent need for procedure

  • acute ischemic stroke (or if want to reverse so we can effectively tx them w/ smn else)

• assessment of DOAC [ ] (quantifiable - may not be readily available) vs presence (qualitative)

  • correlate these w/ timing of dosing

• lab tests for DOACs unhelpful altogether

idarucizumab (Praxbind)

• antidote specific for ONLY dabigatran

• engineered aby fragment (fab) that binds non-competitively to dabig w/ ~350 stronger affinity than thrombin; half life 4.5-9h

• indicated for adult pts tx w/ dabig when rapid reversal of anticoagulant effect is req for:

  • emergency surgery/urgent procedures

  • life-threatening or uncontrolled bleeding

• $$$

andexanet alfa (Ondexxya)

• antidote for Factor Xa inh (apix and riva)

• factor Xa molecule that acts as a decoy to target and sequester both PO and inj FXa inh - competitive binding

  • inh of tissue factor pathway inh (TFPI) may increase thrombin generation, increasing risk of thrombosis

• indicated: for rapid reversal of anticoagulation (apix or riva) due to life threatening or uncontrolled bleeding

• will cause unresponsiveness to heparin

  • antiXa assays unsuitable after admin - erroneous elevation

• not yet available in AB

• short half life 3.8-4.2h

tranexamic acid, aminocaproic acid

• anti-fibrinolytics: inh fibrinolysis by preventing conversion of plasminogen to plasmin

• not antidotes, rather blocks the breakdown of blood clots

• arrest/mitigate bleeding if other components of hemostasis system are intact

• practical uses: topical if dental/nasal bleeding, PO if heavy menstruation or IV in an operating room

management of severe bleeding

• urgent resuscitation if hemodynamic stability (resting tachycardia, postural hypotension, postural pulse increment of >30bpm) or end organ damage (altered mentation, decreased urinary output)

• varies based on:

  • bleeding characteristics: severity, source and source txed vs not

  • thrombotic risk (indication based)

  • other factors: overall prognosis, adherence/stability of INRs, etc

• generalities of timing to restart:

  • <2wks - increased risk of bleeding (unless cause identified and rectified - then w/i a wk)

  • 2-8wks - conservative approach to restart

• observational data shows:

  • post GIB: restarting decreases risk of thrombosis and mortality and does not increase risk of recurrence

  • post ICH: restarting reduces risk of ischemic events and mortality and had no difference in major bleeding

• med management:

  • antiplatelet agents/NSAIDs

  • approp anticoagulant

    • if warf, INR target/control

  • DDI that enhance anticoagulant

• control/management of modifiable risk factors:

  • BP, EtOH consumption, fall risk/stability, age, renal dysfxn, hepatic dysfxn