Skip to main content


Log in

Clinical outcomes following early versus late pharmacologic thromboprophylaxis in patients with traumatic intracranial hemorrhage: a systematic review and meta-analysis

  • Review
  • Published:
Neurosurgical Review Aims and scope Submit manuscript


Venous thromboembolism (VTE) after traumatic brain injury (TBI) with intracranial hemorrhage (ICH) presents a serious yet manageable morbidity and mortality risk. This systematic review and meta-analysis aimed to pool the current literature to evaluate whether or not pharmacologic thromboprophylaxis (PTP) administered early after traumatic ICH significantly changes incidence of VTE or hemorrhagic progression when compared to late administration. Systematic searches of seven electronic databases from their inception to July 2018 were conducted following the appropriate guidelines. One thousand four hundred ninety articles were identified for screening. Outcomes of interest were pooled as odd ratios (ORs) and analyzed using a random-effects model. Eleven comparative studies satisfied selection criteria, yielding a total of 5036 cases. Overall, mean age was 47.6 years and 36% patients were female. PTP was administered early (≤ 72 h from admission) in 2106 (42%) patients and late (> 72 h from admission) in 2922 (58%) cases. There was no statistically significant difference in the incidence of hemorrhagic progression (OR, 0.86; P = 0.450) or all-cause mortality (OR, 0.83; P = 0.347) between the early versus late PTP patient groups. However, incidence of VTE was significantly less in the early PTP patient group (OR, 0.58; P = 0.008). The early administration of PTP after traumatic ICH does not appear to confer a worse prognosis in terms of hemorrhagic progression. However, it seems to confer superior VTE prophylaxis, when compared to late PTP administration. We suggest that early PTP should not be prematurely discounted for patients with ICH in TBI on the assumption of aggravating hemorrhagic progression alone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others


  1. Abdel-Aziz H, Dunham CM, Malik RJ, Hileman BM (2015) Timing for deep vein thrombosis chemoprophylaxis in traumatic brain injury: an evidence-based review. Crit Care (London, England) 19:96.

    Article  Google Scholar 

  2. Acosta JA, Yang JC, Winchell RJ, Simons RK, Fortlage DA, Hollingsworth-Fridlund P, Hoyt DB (1998) Lethal injuries and time to death in a level I trauma center. J Am Coll Surg 186:528–533

    Article  CAS  PubMed  Google Scholar 

  3. Adams H, Donnelly J, Czosnyka M, Kolias AG, Helmy A, Menon DK, Smielewski P, Hutchinson PJ (2017) Temporal profile of intracranial pressure and cerebrovascular reactivity in severe traumatic brain injury and association with fatal outcome: an observational study. PLoS Med 14:e1002353.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Al-Mufti F, Thabet AM, Singh T, El-Ghanem M, Amuluru K, Gandhi CD (2018) Clinical and radiographic predictors of intracerebral hemorrhage outcome. Interv Neurol 7:118–136

    Article  PubMed  PubMed Central  Google Scholar 

  5. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O'Connell D, Oxman AD, Phillips B, Schunemann HJ, Edejer T, Varonen H, Vist GE, Williams JW Jr, Zaza S (2004) Grading quality of evidence and strength of recommendations. BMJ (Clin Res Ed) 328:1490.

    Article  Google Scholar 

  6. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  7. Beitland S, Sandven I, Kjaervik LK, Sandset PM, Sunde K, Eken T (2015) Thromboprophylaxis with low molecular weight heparin versus unfractionated heparin in intensive care patients: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 41:1209–1219.

    Article  CAS  PubMed  Google Scholar 

  8. Boeer A, Voth E, Henze T, Prange HW (1991) Early heparin therapy in patients with spontaneous intracerebral haemorrhage. J Neurol Neurosurg Psychiatry 54:466–467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Byrne JP, Mason SA, Gomez D, Hoeft C, Subacius H, Xiong W, Neal M, Pirouzmand F, Nathens AB (2016) Timing of pharmacologic venous thromboembolism prophylaxis in severe traumatic brain injury: a propensity-matched cohort study. J Am Coll Surg 223:621–631.e625.

    Article  PubMed  Google Scholar 

  10. Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GWJ, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J (2017) Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery 80:6–15.

    Article  PubMed  Google Scholar 

  11. Dengler BA, Mendez-Gomez P, Chavez A, Avila L, Michalek J, Hernandez B, Grandhi R, Seifi A (2016) Safety of chemical DVT prophylaxis in severe traumatic brain injury with invasive monitoring devices. Neurocrit Care 25:215–223.

    Article  CAS  PubMed  Google Scholar 

  12. Denson K, Morgan D, Cunningham R, Nigliazzo A, Brackett D, Lane M, Smith B, Albrecht R (2007) Incidence of venous thromboembolism in patients with traumatic brain injury. Am J Surg 193:380–383; discussion 383-384.

    Article  PubMed  Google Scholar 

  13. Depew AJ, Hu CK, Nguyen AC, Driessen N (2008) Thromboembolic prophylaxis in blunt traumatic intracranial hemorrhage: a retrospective review. Am Surg 74:906–911

    PubMed  Google Scholar 

  14. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  15. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ (Clin Res Ed) 315:629–634

    Article  CAS  Google Scholar 

  16. Farooqui A, Hiser B, Barnes SL, Litofsky NS (2013) Safety and efficacy of early thromboembolism chemoprophylaxis after intracranial hemorrhage from traumatic brain injury. J Neurosurg 119:1576–1582.

    Article  PubMed  Google Scholar 

  17. Faul M, Xu L, Wald M, Coronado V (2010) Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths 2002–2006. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Atlanta

    Book  Google Scholar 

  18. Faust AC, Finch CK, Hurdle AC, Elijovich L (2017) Early versus delayed initiation of pharmacological venous thromboembolism prophylaxis after an intracranial hemorrhage. Neurologist 22:166–170.

    Article  PubMed  Google Scholar 

  19. Frisoli FA, Shinseki M, Nwabuobi L, Zeng XL, Adrados M, Kanter C, Frangos SG, Huang PP (2017) Early venous thromboembolism chemoprophylaxis after traumatic intracranial hemorrhage. Neurosurgery 81:1016–1020.

    Article  PubMed  Google Scholar 

  20. Geerts WH, Code KI, Jay RM, Chen E, Szalai JP (1994) A prospective study of venous thromboembolism after major trauma. N Engl J Med 331:1601–1606.

    Article  CAS  PubMed  Google Scholar 

  21. Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ: Br Med J 327:557–560

    Article  Google Scholar 

  22. Jamjoom AA, Jamjoom AB (2013) Safety and efficacy of early pharmacological thromboprophylaxis in traumatic brain injury: systematic review and meta-analysis. J Neurotrauma 30:503–511.

    Article  PubMed  Google Scholar 

  23. Kim J, Gearhart MM, Zuccarello M, James L, Luchette FA (2002) Preliminary report on the safety of heparin for deep venous thrombosis prophylaxis after severe head injury. J Trauma 53:38–43.

    Article  PubMed  Google Scholar 

  24. Kim L, Schuster J, Holena DN, Sims CA, Levine J, Pascual JL (2014) Early initiation of prophylactic heparin in severe traumatic brain injury is associated with accelerated improvement on brain imaging. J Emergencies, Trauma Shock 7:141–148.

    Article  Google Scholar 

  25. Knudson MM, Ikossi DG, Khaw L, Morabito D, Speetzen LS (2004) Thromboembolism after trauma: an analysis of 1602 episodes from the American College of Surgeons National Trauma Data Bank. Ann Surg 240:490–496 discussion 496-498

    Article  PubMed  PubMed Central  Google Scholar 

  26. Koehler DM, Shipman J, Davidson MA, Guillamondegui O (2011) Is early venous thromboembolism prophylaxis safe in trauma patients with intracranial hemorrhage. J Trauma 70:324–329.

    Article  PubMed  Google Scholar 

  27. Mesa Galan LA, Egea-Guerrero JJ, Quintana Diaz M, Vilches-Arenas A (2016) The effectiveness and safety of pharmacological prophylaxis against venous thromboembolism in patients with moderate to severe traumatic brain injury: a systematic review and meta-analysis. J Trauma Acute Care Surg 81:567–574.

    Article  CAS  PubMed  Google Scholar 

  28. Minshall CT, Eriksson EA, Leon SM, Doben AR, McKinzie BP, Fakhry SM (2011) Safety and efficacy of heparin or enoxaparin prophylaxis in blunt trauma patients with a head abbreviated injury severity score >2. J Trauma 71:396–399; discussion 399-400.

    Article  CAS  PubMed  Google Scholar 

  29. Moher D, Liberati A, Tetzlaff J, Althman D (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Morgenstern LB, Hemphill Iii JC, Anderson C, Becker K, Broderick JP, Connolly ES Jr, Greenberg SM, Huang JN, MacDonald RL, Messé SR, Mitchell PH, Selim M, Tamargo RJ (2010) Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 41:2108–2129.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Oertel M, Kelly DF, McArthur D, Boscardin WJ, Glenn TC, Lee JH, Gravori T, Obukhov D, McBride DQ, Martin NA (2002) Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg 96:109–116.

    Article  PubMed  Google Scholar 

  32. Orken DN, Kenangil G, Ozkurt H, Guner C, Gundogdu L, Basak M, Forta H (2009) Prevention of deep venous thrombosis and pulmonary embolism in patients with acute intracerebral hemorrhage. Neurologist 15:329–331.

    Article  PubMed  Google Scholar 

  33. Reiff DA, Haricharan RN, Bullington NM, Griffin RL, McGwin G Jr, Rue LW III (2009) Traumatic brain injury is associated with the development of deep vein thrombosis independent of pharmacological prophylaxis. J Trauma 66:1436–1440.

    Article  CAS  PubMed  Google Scholar 

  34. Saadeh Y, Gohil K, Bill C, Smith C, Morrison C, Mosher B, Schneider P, Stevens P, Kepros JP (2012) Chemical venous thromboembolic prophylaxis is safe and effective for patients with traumatic brain injury when started 24 hours after the absence of hemorrhage progression on head CT. J Trauma Acute Care Surg 73:426–430.

    Article  CAS  PubMed  Google Scholar 

  35. Salottolo K, Offner P, Levy AS, Mains CW, Slone DS, Bar-Or D (2011) Interrupted pharmocologic thromboprophylaxis increases venous thromboembolism in traumatic brain injury. J Trauma 70:19–24; discussion 25-16.

    Article  CAS  PubMed  Google Scholar 

  36. Schardt C, Adams MB, Owens T, Keitz S, Fontelo P (2007) Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inf Decis Making 7:16.

    Article  Google Scholar 

  37. Tanweer O, Boah A, Huang PP (2013) Risks for hemorrhagic complications after placement of external ventricular drains with early chemical prophylaxis against venous thromboembolisms. J Neurosurg 119:1309–1313.

    Article  PubMed  Google Scholar 

  38. Tetri S, Hakala J, Juvela S, Saloheimo P, Pyhtinen J, Rusanen H, Savolainen ER, Hillbom M (2008) Safety of low-dose subcutaneous enoxaparin for the prevention of venous thromboembolism after primary intracerebral haemorrhage. Thromb Res 123:206–212.

    Article  CAS  PubMed  Google Scholar 

  39. Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, Tugwell P (2016) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute, Ottawa (ON) 2009. Available in March

    Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Victor M. Lu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not required.

Informed consent

Not required.


The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Electronic supplementary material


(DOCX 563 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, V.M., Alvi, M.A., Rovin, R.A. et al. Clinical outcomes following early versus late pharmacologic thromboprophylaxis in patients with traumatic intracranial hemorrhage: a systematic review and meta-analysis. Neurosurg Rev 43, 861–872 (2020).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: