Lauzier et al 2013: Heparin Thromboprophylaxis and Major Bleeding

Journal Club 004

Authors: Shriya Gupta
Chris Nickson

Lauzier F, et al. Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis. Intensive Care Med. 2013 Dec;39(12):2135-43. doi:10.1007/s00134-013-3044-3. Epub 2013 Aug 14. PubMed PMID: 23942857.


What is the incidence, timing, and anatomical locations of major bleeding in critically ill patients?

What are the risk factors for major bleeding in these patients?

Is there an association between major bleeding and blood product transfusion, duration of mechanical ventilation, ICU and hospital length of stay, and mortality?



  • prospective cohort study involving patients from the PROTECT study


  • n=3,746 patients receiving heparin thromboprophylaxis
  • patients were enrolled between May 2006 and June 2010
  • involved 67 centers in 6 countries (including Australasia)

Inclusion criteria:

  • >18 years of age
  • >45 kg
  • expected to remain in the ICU >72 h

Exclusion criteria:

  • trauma, neurosurgery or orthopedic surgery
  • therapeutic anticoagulation at baseline
  • prophylactic or therapeutic heparin for at least 72 h prior to ICU admission
  • contraindication to heparin or blood products
  • pregnancy
  • limitation of life support
  • platelet count <75 x10E9/L or abnormal coagulation testing (INR or aPTT greater than twice the upper normal limit), or enrollment in a related trial


  • unfractionated heparin (UFH) 5,000 units SC bd versus dalteparin 5,000 units SC daily


Incidence of haemorrhage (as a proportion)

  • Haemorrhage (major or minor) 13.1 % ( 95 % CI 12.1–14.2 %)
  • Minor haemorrhage 7.6 % (95 % CI 6.8–8.4 %)
  • Major haemorrhage 5.6 % (95 % CI 4.9–6.3 %)


  • GI tract 2.9% (95 % CI 2.4–3.5) (this accounted for 51% of patients with major bleeding)
  • surgical site (including CVC site) 1.7% (95 % CI 1.3–2.1)
  • respiratory tract 0.9% (95 % CI 0.6–1.2)
  • retroperitioneal space  0.5% (95 % CI 0.3–0.7)
  • intracranial haemorrhage 0.2 % (95 % CI 0.1–0.4)
  • pericardial 0.1% (95 % CI 0.03–0.2)
  • other 0.5% (95 % CI 0.3–0.8)

Complications of major haemorrhage

  • >1 major haemorrhage episode 0.8 %, 95 % CI 0.6–1.2 %
  • hypovolemic shock 17.3%
  • bleeding at a critical site 17.8%
  • required invasive intervention 35.1%
  • clinically important bleeding 88.0%

Independent predictors of major bleeding (all in the preceding 3 days unless otherwise stated):

  • RRT
  • surgical procedures
  • therapeutic anticoagulation
  • prolonged aPTT
  • thrombocytopaenia
  • antiplatelet therapy in the preceding 7 days
  • No difference between unfractionated heparin and LMWH

Patients with major bleeding associated with increased:

  • blood transfusion
  • duration of mechanical ventilation
  • hospital LOS
  • ICU mortality (HR 1.64, 1.27–2.10)
  • hospital mortality (HR 2.09, 1.69–2.57)
  • median time from ICU admission to first major bleeding was 9.5 days (6–15.5 days)


  • Bleeding was defined as ‘ major’ if, in the absence of another cause, the patient fulfilled one of the following criteria:
    1. hypovolemic shock
    2. bleeding into critical sites
    3. invasive intervention requirement, or
    4. need for transfusion of 2 or more units of red blood cells, or was associated with a decrease of >20 mmHg in systolic blood pressure or an increase of at least 20 beats/min in heart rate without another explanation.
  • bleeding events were adjucated using a standardised pretested measurement tool by assessors who were blinded to center and allocation
  • multivariable Cox proportional hazards regression analysis was used to identify independent risk factors, using baseline charateristics selected according to a priori plans and time-dependent covariates
  • 6,034 patients fulfilled the inclusion criteria, only 3,764 were randomised (82.3% consent rate) for the study, 18 were lost to followup – thus a large number of patients who met the inclusion criteria were not included, this may be a source of bias
  • all management decisions apart from VTE prophylaxis were at the discretion of the treating clinicians, hence the results may be affected by unknown confounders
  • No baseline patient characteristics were independent predictors of major haemorrhage, but there was some baseline imbalance. for instance, 34.1% of patients with major bleeding had respiratory admitting diagnoses compaired to 46.3% of those without. Conversely, 24.5% of patients with major bleeding had sepsis as an admitting diagnosis compaired to 14.2% of those without.
  • The adjudicators of bleeding events were blinded to centre and and treatment allocation. Furthermore, the bleeding events were measured using a standardized pretested measurement tool.
  • 86.6% of patients were enrolled from Canada, UK or Australia suggesting good external validity to the Australasian setting, but this is limited by important exclusions such as trauma, neurosurgical and orthopaedic patients
  • incidence of major bleeding consistent with previous ICU studies, which is much higher than in non-ICU medical patients


This study defines the incidence, sites and impact of major bleeding associated with VTE prophylaxis in ICU patients (but not trauma, neurosurgery or othopaedic patients).

Based on this the authors provide these suggestions for clinical practice:

  • Close monitoring of aPTT levels to ensure they are within therapeutic range
  • Daily measurement of patients at risk of thrombocytopaenia to ensure that platelet levels do not drop too low
  • Witholding anti-platelet agents in those patients in whom the risk of major bleeding outweighs the risk associated with not continuiing on anti-platelet agent
  • Close monitoring of patients post invasive procedures to ensure any major bleeding is detected early
  • Close monitoring of patients on renal replacement therapy
  • Deferral of non-urgent surgical procedures

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