Anticoagulation in critical illness

Contents

VTE Prophylaxis in the ICU

Critically ill patients are at high risk of venous thromboembolism (VTE): immobility, venous cannulae, systemic inflammation, altered coagulation, and haemoconcentration all contribute.

Pharmacological Prophylaxis

  • Low molecular weight heparin (LMWH): first-line; enoxaparin 40 mg SC once daily (reduce dose in severe renal failure — eGFR <30: enoxaparin 20 mg daily; consider unfractionated heparin (UFH) instead which is renally cleared safely)
  • Unfractionated heparin (UFH): 5000 units SC 8–12-hourly; alternative in severe renal failure or if anti-Xa monitoring not available; more predictable reversal
  • Timing: start as soon as safely possible (post-op: 12–24h; head injury: per neurosurgical guidance; active haemorrhage: contraindicated)

Mechanical Prophylaxis

  • Graduated compression stockings (GCS) and/or intermittent pneumatic compression devices (IPC)

PREVENT Trial

The PREVENT trial (Al-Hameed, NEJM 2019, n=2003) randomised ICU patients already receiving pharmacological thromboprophylaxis to adjunctive IPC or sham. Adding IPC did not reduce proximal DVT rates (3.9% vs 4.2%, p=0.74). Current guidance: IPC is not required in ICU patients already on pharmacological prophylaxis; use IPC when pharmacological prophylaxis is contraindicated.

When to Withhold Pharmacological Prophylaxis

  • Active, uncontrolled haemorrhage
  • Platelet count <50 ×10⁹/L (relative; assess bleeding vs thrombotic risk)
  • Within 12–24h of major surgery or epidural catheter placement
  • Severe thrombocytopenia from HIT (see below)
  • Intracranial haemorrhage, spinal haematoma (per neurosurgical/neurology guidance)

Treatment Anticoagulation in ICU

Pulmonary Embolism

  • Massive PE (haemodynamic compromise): systemic thrombolysis (alteplase 100 mg over 2 hours IV) vs surgical or catheter-directed embolectomy; anticoagulate after
  • Submassive PE (RV dysfunction without shock): heparin anticoagulation; consider thrombolysis if clinical deterioration
  • Non-massive PE: therapeutic LMWH or UFH; transition to oral anticoagulant (DOAC preferred over warfarin in most)
  • UFH infusion preferred over LMWH in ICU PE: allows rapid dose titration; reversible with protamine; no drug accumulation in renal failure
  • UFH target: APTT ratio 2.0–3.0 (or anti-Xa 0.3–0.7 IU/mL)

Atrial Fibrillation

  • New-onset AF in ICU: treat underlying cause first; anticoagulation decision based on CHA₂DS₂-VASc score and bleeding risk
  • Therapeutic anticoagulation for AF in ICU generally reserved for haemodynamic instability with AF or confirmed intracardiac thrombus

Catheter-Associated DVT

  • Therapeutic anticoagulation for proximal DVT; LMWH preferred; remove central line if feasible
  • Upper limb DVT from PICC/CVC: treat if symptomatic

Extracorporeal Circuits (CRRT, ECMO)

  • CRRT: regional citrate anticoagulation is preferred (chelates ionised Ca²⁺ in circuit → anticoagulation localised to circuit; negligible systemic effect); if contraindicated: UFH; prostacyclin as alternative
  • ECMO: UFH infusion titrated to anti-Xa 0.2–0.4 IU/mL; ACT monitoring in some centres

Heparin-Induced Thrombocytopenia (HIT)

Pathophysiology

HIT is a drug-induced immune thrombocytopenia mediated by antibodies against PF4-heparin complexes:

  1. Heparin binds platelet factor 4 (PF4) → forms antigenic complex
  2. Anti-PF4/heparin IgG antibodies (HIT antibodies) bind to the complex
  3. Fc receptor engagement on platelets → platelet activation → thrombosis + thrombocytopenia
  4. Endothelial activation → further thrombotic risk

Key point: HIT is paradoxically a prothrombotic condition despite thrombocytopenia — do not transfuse platelets (worsens thrombosis).

Diagnosis

4T Score: pre-test probability assessment:

Variable 2 points 1 point 0 points
Thrombocytopenia >50% fall to nadir ≥20 30–50% fall or nadir 10–19 <30% fall or nadir <10
Timing Day 5–10 or ≤1 day if prior heparin within 30d Day 5–10 but unclear ≤4 days without prior exposure
Thrombosis New thrombosis, skin necrosis, anaphylaxis Progressive or recurrent thrombosis None
Other cause of thrombocytopenia None apparent Possible Definite
  • 4T ≥6: high probability → stop all heparin, start alternative anticoagulant, send anti-PF4 antibody and HIT ELISA
  • 4T 4–5: intermediate; anti-PF4 testing
  • 4T 0–3: low; unlikely HIT

Confirmatory testing: anti-PF4/heparin ELISA (sensitive but not specific); functional assay (serotonin release assay — SRA; gold standard)

Management

  1. Stop all heparin immediately (including heparin flushes, LMWH prophylaxis, heparin-coated catheters)
  2. Start alternative anticoagulant at therapeutic dose (HIT is prothrombotic — anticoagulation must continue):
    • Argatroban (direct thrombin inhibitor): preferred in renal failure (hepatically metabolised); dose 0.5–2 mcg/kg/min; titrate APTT to 1.5–3× baseline; available IV; monitor LFTs
    • Danaparoid: alternative; cross-reactivity with HIT antibodies rare; renally cleared (reduce dose in AKI)
    • Fondaparinux: off-label; anti-Xa; renally cleared; avoid in severe AKI
  3. Do NOT transfuse platelets (worsens thrombotic risk)
  4. Do NOT use warfarin in acute HIT (causes paradoxical thrombosis — protein C inhibition before therapeutic INR reached → skin necrosis)
  5. Transition to warfarin or DOAC only once platelet count >150 and argatroban dose stable

Reversal of Anticoagulation

Unfractionated Heparin

  • Protamine sulfate: 1 mg neutralises 100 units UFH; give over 10 minutes (risk of hypotension, bradycardia, anaphylaxis); check ACT/APTT post-administration
  • Dose: based on weight of heparin given in last 2–2.5 hours (adjust for heparin half-life ~60–90 min)

LMWH

  • Protamine partially reverses LMWH (~60–80% anti-Xa reversal — complete reversal not achievable)
  • Dose: 1 mg protamine per 1 mg enoxaparin given in last 8 hours

Warfarin

  • Vitamin K 5–10 mg IV: gradual reversal over 6–12 hours (synthesises new clotting factors)
  • Prothrombin complex concentrate (PCC): 4-factor PCC (Beriplex/Octaplex) replaces factors II, VII, IX, X; rapid reversal within minutes; dose based on INR and weight; preferred for life-threatening haemorrhage
  • FFP: large volumes needed (10–15 mL/kg); delayed reversal; fluid load; reserved if PCC unavailable

Direct Oral Anticoagulants (DOACs)

DOAC Reversal agent
Dabigatran (direct thrombin inhibitor) Idarucizumab (Praxbind) 5 g IV — complete, rapid reversal
Rivaroxaban, Apixaban, Edoxaban (factor Xa inhibitors) Andexanet alfa — recombinant FXa decoy; reverses FXa inhibition; licensed in UK for rivaroxaban/apixaban; high cost
Any DOAC (life-threatening bleed, no specific reversal available) 4-factor PCC 50 IU/kg IV — partial reversal; off-label but commonly used

Bridging and Peri-Procedure Anticoagulation

For patients on long-term anticoagulation requiring ICU procedures or surgery:

Warfarin

  • Stop warfarin 5 days before elective surgery (target INR <1.5)
  • Bridging LMWH: required only in high-risk patients (mechanical heart valves, recent VTE <3 months, AF with high CHA₂DS₂-VASc); not required for most patients on warfarin for AF (BRIDGE trial, 2015: no bridging non-inferior for peri-operative outcomes in AF)
  • Restart post-op once haemostasis achieved (typically 12–24h)

DOACs

  • Stop 24–48h before low-bleeding-risk procedure; 48–72h (or 4+ days for renal impairment with dabigatran) before high-risk surgery
  • No bridging required; restart 24–48h post-procedure

Viva Questions

1. What is HIT, how do you diagnose it, and how does management differ from other causes of thrombocytopenia?

HIT (heparin-induced thrombocytopenia) is a drug-induced immune thrombocytopenia paradoxically associated with high thrombotic risk. It is caused by IgG antibodies against PF4-heparin complexes, which bind to platelet Fc receptors, activating platelets and triggering a hypercoagulable state. Clinically: platelet count falls ≥30–50% from baseline, typically on days 5–10 of heparin exposure (or within 24 hours in re-exposure with prior sensitisation). Diagnosis is clinical-first using the 4T score. High pre-test probability (≥6 points): stop all heparin immediately and start alternative anticoagulation without waiting for laboratory confirmation. Confirmatory testing: anti-PF4/heparin ELISA (sensitive) and serotonin release assay (specific, gold standard). Management differs fundamentally from other thrombocytopenias: (1) stop heparin — LMWH, UFH, heparin flushes, heparin-coated catheters all cause HIT; (2) start therapeutic alternative anticoagulation immediately (argatroban preferred in renal failure; danaparoid or fondaparinux alternatives); (3) do NOT transfuse platelets — platelet transfusion in HIT worsens thrombosis risk; (4) do NOT give warfarin in the acute phase — paradoxical protein C depletion → thrombosis and skin necrosis.

2. Describe the evidence from the PREVENT trial and its implications for your practice.

The PREVENT trial (see Journal Club) randomised 2003 ICU patients already receiving pharmacological thromboprophylaxis (LMWH or UFH) to adjunctive intermittent pneumatic compression (IPC) or sham IPC. The primary outcome was proximal DVT (detected by twice-weekly lower-limb compression ultrasound). There was no significant difference: proximal DVT 3.9% (IPC) vs 4.2% (sham), p=0.74. The trial was well-powered and methodologically rigorous. The implication is clear: adding IPC to pharmacological prophylaxis in ICU patients does not reduce DVT rates. This changed the standard practice of routinely combining both modalities. Current evidence-based approach: pharmacological prophylaxis (LMWH as first-line) is the primary intervention; IPC should be reserved for patients in whom pharmacological prophylaxis is contraindicated (active haemorrhage, thrombocytopenia, anticipated surgical procedure). IPC alone remains appropriate when anticoagulation is contraindicated.

3. A patient on warfarin for a mechanical heart valve presents with a subarachnoid haemorrhage. How do you manage their anticoagulation?

This is a critical conflict: the patient requires reversal for the haemorrhage, but stopping anticoagulation in a mechanical valve risks catastrophic thrombosis. Immediate priority: reverse anticoagulation urgently — subarachnoid haemorrhage with ongoing anticoagulation is immediately life-threatening. Give vitamin K 10 mg IV AND 4-factor prothrombin complex concentrate (PCC) at the appropriate dose for their INR (typically 25–50 IU/kg). This achieves rapid reversal within minutes; monitor INR after 15–30 minutes. Contact haematology and neurosurgery simultaneously. Do NOT use FFP as primary reversal — too slow and insufficient volume for this emergency. Once haemorrhage is controlled (imaging and neurosurgical assessment): restart anticoagulation is a high-stakes decision. For mechanical mitral valve: prothrombotic risk is very high — aim to restart therapeutic anticoagulation at 48–72h if haemostasis is confirmed. For mechanical aortic valve (lower risk): 3–5 days may be safe. This should be a multidisciplinary decision involving haematology, cardiology/cardiac surgery, neurosurgery, and the ICU team. No reversal agent for warfarin corrects the underlying prothrombotic risk, so ongoing monitoring and close collaboration are essential.