What is the definition of major bleeding according to the International Society on Thrombosis and Haemostasis (ISTH)?

ISTH Definition of Major Bleeding

According to the most recent 2022 ISTH update, major bleeding is defined as a composite of five criteria: (1) fatal bleeding, (2) clinically overt bleeding with hemoglobin decrease ≥20 g/L (2 g/dL) in 24 hours, (3) critical site bleeding (retroperitoneal, pulmonary, pericardial, intracranial, or CNS involvement), (4) bleeding requiring invasive intervention (surgery, interventional radiology, or endoscopy), or (5) overt bleeding requiring reversal agent administration. 1

Core Criteria for Major Bleeding

The ISTH definition identifies major bleeding through any ONE of the following five components:

1. Fatal Bleeding

• Any bleeding event that directly results in death 1

2. Hemodynamically Significant Bleeding

• Clinically overt bleeding associated with a hemoglobin decrease of at least 20 g/L (2 g/dL) within a 24-hour period 1
• This represents a quantifiable marker of bleeding severity that can be objectively measured 2

3. Critical Site Bleeding

• The 2022 update emphasizes "critical" bleeding at specific anatomical locations to distinguish significant from trivial bleeding at these sites 1
• Included critical sites:
  • Retroperitoneal
  • Pulmonary
  • Pericardial (newly added in 2022 update) 1
  • Intracranial
  • Central nervous system involvement 1

4. Bleeding Requiring Invasive Intervention

• The 2022 update expanded beyond operating suite procedures to include: 1
  • Surgery in an operating suite
  • Interventional radiology procedures (new addition)
  • Endoscopic interventions (new addition) 1

5. Bleeding Requiring Reversal Agent Administration

• This is a completely new criterion added in the 2022 update 1
• Includes administration of:
  • Vitamin K
  • Plasma
  • Prothrombin complex concentrate
  • Protamine
  • Andexanet alfa
  • Idarucizumab 1

Important Updates and Nuances

Menstrual Bleeding

• Menstrual bleeding can now qualify as major bleeding if it meets any of the above criteria 1
• This represents an important inclusion for accurate bleeding assessment in women of reproductive age 1

Prognostic Subcategorization

• The ISTH recommends considering sub-categorization of major bleeding based on development of disability or significant sequelae 1
• Research demonstrates that not all ISTH-defined major bleeds carry equal mortality risk—intracranial hemorrhage with Glasgow Coma Scale <14 or non-ICH bleeding with shock represent "life-threatening" major bleeds with highest 30-day mortality 3

Clinical Application Considerations

Strengths of the ISTH Definition

• The ISTH criteria show substantial agreement with BARC criteria (Cohen's κ = 0.69) and similar prognostic utility for mortality prediction 4
• Both ISTH and BARC definitions identify patients with approximately 3.3-fold increased risk of 30-day mortality compared to clinically relevant non-major bleeds 4
• The definition is objective and standardized, reducing underreporting that occurs with subjective definitions (which missed 31 major bleeding events in one study) 2

Common Pitfalls to Avoid

• Do not rely solely on hospitalization as a criterion—the 2022 update removed this as a standalone major bleeding criterion (it now falls under clinically relevant non-major bleeding) 1
• Isolated ocular or articular bleeding rarely meets major bleeding criteria and carries minimal mortality risk 3
• Blood product transfusion alone without meeting other criteria does not automatically qualify as major bleeding in the updated definition 1

Comparison with Other Definitions

• TIMI criteria identify a higher-risk subset of patients (5.9-fold increased mortality risk) but show poor agreement with ISTH (low Cohen's κ) 4
• The 2005 original ISTH definition has been widely adopted but the 2022 update provides more granular and clinically relevant categorization 5