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Coagulopathy as a risk factor in warfarinised head injury patients

Three Part Question

In [elderly warfarinised head injury (WHI) patients] does the [International Normalised Ratio (INR)] influence the likelihood of [intracranial haemorrhage (ICH)]?

Clinical Scenario

A 72-year-old woman presents with a minor head injury (MHI). Her INR was 2, and she has no amnesia or loss of consciousness, therefore not strictly fulfilling the National Institute for Health and Care Excellence (NICE) criteria for a scan. The radiologist on call does not want to scan the patient unless her INR had been >2.5, and so the request is denied.

You wonder why the radiologist had chosen an INR of 2.5 and want to find out more about relevance of the INR in the WHI patient, and specifically to question the reassurance that a therapeutic or even subtherapeutic INR could bring for the otherwise asymptomatic MHI.

Search Strategy

MEDLINE 1946 to August Week 4 2013 using the OVID interface
[(exp Craniocerebral trauma/ OR head injur$.mp) AND (exp Warfarin/ OR OR exp Coumarins/ OR exp Anticoagulants/ OR anticoagula$.mp OR OR OR OR OR OR OR] LIMIT to humans AND english language.

Search Outcome

In total, 796 papers were found, of which 778 were irrelevant. The remaining 18 were directly relevant to the three-part question and are summarised in the table. The references of these papers were also searched but yielded no additional relevant papers.

Relevant papers were those looking at warfarinised head injuries, together with assessment of the presenting INR and a CT scan for assessment of ICH to give an indicator for bleeding.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Menditto et al
97 prospectively enrolled consecutive warfarinised (for at least 1/52) patients ≥14 years old in Level 2 trauma centre without ICH on 1st CT after minor head injury (any head trauma, other than superficial injury to face, presenting with GCS 14 or 15), regardless of presence of absence of LOC, within 48 h of injury, with ISS <15 between Jan 2007–Mar 2010. Structured clinical pathway implemented, comprising 24-h period of observation and 2nd CT prior to discharge Case seriesImmediate TICH19/97 (16%) +ve initial CT scanNone had GCS 14 or received concomitant antiplatelet therapy. Only 5 developed ICH by 2nd CT—therefore lacking statistical power to analyse multivariate predictors of such haemorrhage. Not designed to investigate optimal period of observation before repeat CT
DeathNo deaths reported
DICH5/97 (6%) (95% CI 1% to 11%). Only 1 showed signs of neurological deterioration during observation period, 2/5 were discharged anyway as ICH regarded as minimal. 2 discharged after completing study protocol with –ve CT admitted 2/7 and 8/7 later with symptomatic SDH; neither required surgery. 2/5 with DICH at 24 h had initial INR >3 as did both beyond 24 h (RR DICH with INR >3 was 14 (95% CI 4 to 49)). 10 refused 2nd CT and were well during 30/7 follow-up
Admission3 hospitalised
Neurosurgery1 craniotomy
Claudia et al
Medical records of 1554 adult patients with MHI evaluated by a University Hospital ED between Jan 2007 & Feb 2008 analysed retrospectively. 1410 patients (mean age 57) had at least 1 risk factor & so underwent CTB. 75 patients (5.2%) on warfarinCase-control study ICH89 patients in total (12 warfarinised)Small sample size – 12/75 with ICH. Retrospective
Risk factors significantly associated with ICHAnticoagulation (OR=2.69, 95% CI 1.36-5.3, p<0.005) multiple linear regression: coefficient beta 0.078, t=2.841, p=0.005
INRMean INR for warfarinised patient 2.371.04 & was significantly associated with ICH after head injury (r=0.37, p<0.005). INR values analysed using ROC curve, AUC 0.76 (95% CI 0.62-0.91), p<0.05. Showed that most effective INR cut off value was 2.43, with sensitivity of 92%, specificity of 66%, & PPV & NPV of 33% & 97% respectively
Brewer et al
Retrospective review of trauma registry at level II trauma centre. All trauma registry patients with MHI registered between 2004 & 2006 who were taking clopidogrel or warfarin, GCS 15 and had CTB included. Trauma registry includes all patients admitted to or consulted by the trauma service. 141 patients (mean age 79, range 36-101)Case-control study ICH41 patients (29%) diagnosed with ICH. 23/84 (27%) on warfarin. Mean presenting INR with ICH 1.97+/-0.92 compared with 2.3+/-1.2 without ICH (p=0.0987). 15/36 (41%) on clopidogrel, 3/21 (14%) on combination therapy. 39 (95%) of patients with ICH underwent reversal +/- discontinuation of clopidogrel +/- warfarin. 5 patients required surgical evacuation of ICH. 4 patients died. LOC (Wald=7.468, beta=1.179, p=0.008) predicted a +ve CT. Type of medication (warfarin, clopidogrel or aspirin) did not reach statistical significance as a predictor of a +ve CTPatient population only includes those from trauma registry & may explain a selection bias. Relatively small numbers & retrospective design
Major & Reed
399 patients presenting to University Hospital ED with head injury & coexistent anticoagulant (warfarin) or antiplatelet (aspirin, clopidogrel or dipyridamole) therapy who were admitted to the hospital over a 3-year period (Jan 2005-Dec 2007), identified through search of electronic patient recordsCohort studyICH110 patients (28% had CTB, of which 24 showed ICH. 4 died & 2 had neurosurgical intervention, but none of these were warfarinised. Of 89 patients on warfarin (including 5 also on aspirin), 27 (30%) underwent CTB, with 4 of these (15%) having ICH. There were 63 patients on warfarin who had an INR <3 (2/17 +ve scans) & 26 who had an INR >3 (2/10 +ve scans). The RR of a patient having a +ve CTB with an INR >3 compared with an INR <3 was 1.7 (95% CI 0.3-10.3)Patients discharged from ED excluded leading to a selection bias. Retrospective. Only 44/110 patients scanned had the indication recorded. No information as to whether those with +ve scans were the ones with indications for scanning. May suggest that a significant proportion of this cohort was low risk
Grandhi et al
Retrospective review of all patients evaluated at level I trauma centre between Jan 2000 & Dec 2006, to include patients >/=65 coded with a closed head injury. 52/491 (11%) were documented as taking warfarin (AC) & subsequently compared with those not anticoagulated (NAC) by 1:3 propensity matching. Mean admission INR in AC group 2.4+/-1.2Case-control studyVentilator LOS (days)2.8+/-7.9 AC vs 1.5+/-5.8 NAC, p=0.08Numbers too small to determine if there was a certain level of anticoagulation for which outcomes significantly worsened ?type II error. Analysis of association between degree of anticoagulation & various measures of morbidity & mortality with larger sample populations may be able to determine a “cut-off” INR value for which the benefits of anticoagulation are outweighed by its potential complications. Retrospective
ICU LOS (days)6.4+/-11.8 AC vs 4.4+/-7.3 NAC, p=0.19
Hospital LOS (days)10.5+/-13.6 AC vs 9.1+/-12.1 NAC, p=0.97
Mortality19/49 (38.8%) AC vs 34/147 (23.1%) NAC, p=0.04
Pieracci et al
Retrospective study (2004-2006) of all trauma patients aged >/=65 (n=275) evaluated by a trauma service at a level I trauma centre who had a CTB following a head injury, including 40 WHI. 3 cohorts compared: (1) WHI with INR >/=2 (therapeutic group [TG]), n=22, 11 of whom had INR >3. Mean INR 3.33, range 2.12-7.28. (2) WHI with INR <2 (nontherapeutic group [NT]), n=18. Mean INR 1.51, range 1.00-1.96. (3) Warfarin non-users (NU), n=235. Mean INR 1.11, range 0.87-4.01Case-control studyAdmission GCS TG 9 patients (40.9%), p=0.001; NT 2 patients (11.1%); NU 22 patients (11.9%). OR=5.13, 95% CI 1.97-13.39, p=0.001 comparing TG to NU groupRelatively small sample size, therefore, unable to fully compare warfarin users with INR 2-3 with those with INR >3. Results suggest threshold rather than a linear relationship between level of anticoagulation & risk of ICH, which is consistent with exponential scale of INR. However, both a small number of therapeutic users & a relatively narrow range of INRs among them preclude more detailed analysis. Retrospective
ICHTG 17 patients (77.2%), p=0.10; NT 9 patients (50.0%); NU 105 (56.8%). OR=2.59, 95% CI 0.92-7.32, p=0.07 comparing TG to NU group. Subgroup analysis revealed no difference in likelihood of ICH between those with INR 2-3 (9/11, 81.8%) & INR >3 (8/11, 72.7%)
Overall mortalityTG 7 patients (31.8%), p=0.009; NT 2 patients (11.8%); NU 17 patients (9.4%). OR=4.48, 95% CI 1.60-12.50, p=0.004 comparing TG to NU group
Mortality after ICHTG 6 patients (35.3%), p=0.01; NT 1 patient (12.5%); NU 14 patients (13.7%). OR=3.42, 95% CI 1.09-10.76, p=0.03 comparing TG to NU group
Cohen et al
77 patients from 2 trauma databases over 3-year period on warfarin with minor head inury (GCS 13-15). Average age 68. INR obtained in 57% with average 4.4 & values >3 in 47%, range 1.8-9.5. (There was another group of 49 patients who had GCS <8, average age 65. Average INR 6.5, 50% >5. Mortality 87.8%)Cohort studyMortality20 evaluated & sent home from ED. Of these, 35% had CT & all were normal. 18 returned & subsequently diagnosed with significant ICH. 2 patients died at home, 1 with autopsy-confirmed acute SDH. Overall mortality in these 20 patients was 88.8%. 45 patients admitted for observation for head injury +/- treatment of other injuries. CT obtained before admission in 70%, with only 4 showing any ICH. Within 8-18hrs of injury (mean 12hrs), 80% deteriorated to GCS <10 with ICH. Mortality in this group 84%. 12 patients presented within hours or days of injury with ICH. All underwent emergent craniotomy with a resultant mortality of 83.3%No matched control group. Majority of patients supratherapeutically anticoagulated &, of those undergoing CT on initial presentation, only slightly >30% had any evidence of ICH. Retrospective
Franko et al
Retrospective analysis of consecutive series of 1493 adult blunt head injury patients between Jan 2001 & May 2005. 159 warfarinised patients identified and were significantly older, with average age 78+/-10 & average INR 2.4+/-1.06 Case-control study ISSSignificantly greater 14.5+/-8.4 WHI vs 12.4+/-9.4 control, p<0.01They site a selection bias through education of anticoagulated patients, encouraging the seeking of early medical attention, even after seemingly minimal trauma, and so more of these patients present for evaluation. It is suggested that nontherapeutic users and non-users had similar results, but they were not compared directly. Retrospective
LOSSignificantly longer 6.7+/-11.1 WHI vs 4.1+/-6.3 control, p<0.001
ICHSignificantly more likely 96/159 (60.4%) WHI vs 536/1334 (40.2%) control, p<0.001, OR=2.2, 95% CI 1.6-3.1
MortalitySignificantly higher 38/159 (23.9%) WHI vs 66/1334 (4.9%) control, p<0.001, OR=6.0, 95% CI 3.8-9.3
Mortality in those with ICH (n=632)Significantly higher 36/96 (37.5%) WHI vs 61/536 (11.4%) control, p<0.001, OR=4.6, 95% CI 2.8-7.6
Effect of pre-injury anticoagulant levelMortality & occurrence of ICH both significantly increased with increasing INR (Cochran’s linear trend p<0.001)
Age-dependent mortalityMortality of patients >70 significantly higher than that of younger patients (p<0.001). In control group mortality significantly higher with age >70 (38/465, 8.2% vs 28/869, 3.2%) p<0.001. In WHI group mortality significantly higher with age >70 (34/133, 25.6% vs 4/26, 16.4%) p<0.001
Ivascu et al
82 WHI patients identified prospectively between Feb 2003 & April 2007, of which 19 (23%) had evidence of ICH on CTB. Compared with 2 control groups: a group identified during this protocol & a group of historic controls treated before implementation of this protocol to fast-track anticoagulation reversalCohort studyAge, sex, MOI, presenting GCSNot statistically significant between groups with ICH & those withoutThe validity of comparing the median INR is questionable, as opposed to the comparison of mean INR. There are minimal details given of the level of coagulopathies, such as range, from which more informed conclusions could be drawn
INRAll patients with ICH had therapeutic INR, & there was not a statistically significant difference in degree of anticoagulation between groups. Median INR 2.7 (with ICH) vs 2.5 (without), p=0.350
ICH63 patients without ICH on initial CTB were admitted for 23 hours of observation. None subsequently developed ICH, including 12 patients with an INR >3.5
Protocol implementationImproved time from hospital presentation to physician evaluation, 50% less time in triage, significant reduction in time to obtain CTB, full anticoagulation reversal with FFP, significant reduction in rates of ICH progression & mortality
Gittleman et al
89 patients being treated with heparin or coumadin who had a head injury & underwent a CTB at a level I trauma centre identified over a 4-year period (April 1997-Jan 2002) using hospital information database & neuroradiology case log. 77 taking coumadin, 8 taking heparin and 4 taking bothCohort studyICH7 patients with ICH & all had GCS <15. Included 3 cerebellar haemorrhages that were more suggestive of hypertensive rather than traumatic aetiology. No significant difference found between those with ICH & those without with respect to coagulation profile (INR 2.2+/-1.1 with ICH vs 2.5+/-1.2 without ICH)Relatively small numbers & failed to meet sample size required by pre-test power calculation. Selection bias from only including those who had CTB. Retrospective. No breakdown of ICH patients to say who was on coumadin or heparin & presumably this could skew the mean INR values of the groups. No mortality data or follow-up data either regarding the possibility of DICH
Mina et al
Prospective evaluation of all WHI patients seen in ED of level I trauma centre between Jan 2001 & Feb 2002 via a “Coumadin protocol” & compared with a group of age-matched patients over the same time period admitted with head injury but not on warfarin. 94 WHIs, mean age 77+/-11. Control group mean age 75+/-12 with normal INR values (mean 1.1+/-0.1)Case-control studyDemographicsWHI group: no significant differences between those with & those without ICH in terms of age, gender, INR (3.2+/-1.9 with ICH vs 3.2+/-2.5 without, p=0.914), or MOI. ISS significantly higher (21.3+/-8.2 vs 3.4+/-7.1, p<0.001) & GCS significantly lower (12.0+/-4.2 vs 14.7+/-1.6, p<0.001) for patients with ICH. Control group: GCS not significantly different from WHI group but significantly higher ISS than WHI groupWell designed but no mention of impact of level of anticoagulation with regards to mortality. Apparently, most patients were therapeutic though
ICH25/94 (27%) WHI group. 47/70 (67%) control group. No significant differences in age, gender, ISS, GCS or MOI
MortalitySignificantly higher WHI group 12/25 (48%) vs 5/47 (10%) control group, p<0.001. WHI group: INR similar (3.3+/-1.6 dead vs 3.0+/-2.1 survivors, p=0.585). ISS significantly lower & GCS significantly higher in survivors. Control group: ISS not significantly different but GCS significantly higher in survivors
Reynolds et al
32 WHI patients over 7-year period identified from trauma registry database at level II trauma centre. Group 1 – 24 patients (mean age 82.5). All GCS 15. 8 had INR checked (mean 2.45, range 1.6-3.6). Group 2a – 4 patients. All GCS 15. Mean INR 2 (range 1.5-2.6). Group 2b – 4 patients. All GCS 15 but all became comatose within 6 hours. Mean INR 2.5 (range 2.3-3.1)Cohort studyICHFailed to observe a statistically significant difference in mean INR between groups 1 & 2 (p=0.59) although only 8/24 patients from group 1 tested. No statistical difference between subgroups 2a & 2b (p=0.12). GROUP 1: Only 3 had CTB (all normal). All discharged home from ED. 22 alive 6/12 post-injury without evidence of DICH. 2 patients lost to follow-up. GROUP 2a: All had evidence of ICH on CTB. 2 had FFP & vitamin K. All treated conservatively & survived to return to their location of origin. GROUP 2b: All had evidence of ICH on CTB. All had FFP+/-vitamin K. 3 had craniotomy with decompression (2 died; 1 discharged to nursing/rehab facility) and the 4th declined intervention and subsequently diedSmall observational study really with only 8 patients with ICH in 7 years. Retrospective. Would have been more informative if all of group 1 had an INR and CTB. Note that delay to reversal occurred from failure to send appropriate blood samples from patients who appeared neurologically normal after arrival in ED
Karni et al
Retrospective review of approx 2000 patients admitted to trauma service of regional trauma centre between Sept 1998 & May 2000. 278 patients >65 years old with CT-documented TICH. 21 warfarinised but 5 excluded as thought more likely spontaneous ICH. Average age 78, average GCS 11, average INR 3.0Case-control studyMortalityUse of FFP & cryoprecipitate to reverse coagulopathy did not impact on mortality. Nearly ˝ of patients studied underwent craniotomy with 67% 30-day mortality. Overall mortality rate in WHI patients was 50% (8/16) compared with 20% (51/256) in those without coagulopathy (p=0.011). In subgroup of patients with INR >3.5, the mortality rate approached 75%Really no data displayed to appreciate. Inadequate sample size for those with INR >3 (n approx 8) from which to draw meaningful conclusions. Retrospective
Li et al
Retrospective chart review from 2 centres, May 1996-May 2000 from 1 & Jan-Dec 1998 from another. 144 WHI patients identified that had CTB. Excluded those with high-risk & moderate-risk findings. Median (IQR) age 83 (77-87)Cohort studyClinically important CT injury that results in change in disposition10 patients found to have such injuries (7%, 95% CI 3-11). No significant demographic or case-characteristic differences between groups with & without CT-identified injuries. Median (IQR) INR 2.1 (1.8-3.0) CT abnormal vs 2.1 (1.6-2.7) CT normal (p=0.6)Retrospective design using different time periods from 2 centres for an unexplained reason. Selection bias from including only those who had CTB and no follow-up data to ensure no DICH
Garra et al
65 anticoagulated patients suffering minor head injury without LOC or acute neurological abnormality identified from retrospective chart review of electronic records from 6 community hospital EDs, including 1 trauma centre over 2-year period. Only 38 patients had PT assessment (range 12-30.7 secs)Cohort studyClinically significant intracranial injuryNo intracranial injury found in any of the 39 patients who had a CT. Telephone follow-up of the remaining 26 patients revealed no evidence of complications related to their head injuriesTheir computer system may not have identified all eligible patients leading to a selection bias. Retrospective. In the 38 patients in whom PT was checked, none was >30 secs and almost 1/3 were <14 secs, indicating that even though these patients were on warfarin, few were actually anticoagulated
Nishijima et al,
Secondary aims from previously published study data (see below). Those without initial CT however excluded, leaving 982 patients on warfarin (72.7%) or clopidogrel. Mean age 75 with almost equal sex distribution. 83.6% were ground level falls and 89.5% were GCS 15 Cohort study Immediate TICH60 patients (6.1%; 95% CI 4.7% to 7.8%). None of 65 without initial CT were later diagnosed with TICH although 2 were lost to follow-up. 31/60 warfarinised. RR of warfarin 0.40 (95% CI 0.25 to 0.65) In addition to comments for the previous paper, there were relatively few patients meeting primary outcome of immediate TICH, however, including more patients with TICH would not resolve the fact that many patients with immediate TICH appeared to have no risk factors for TICH beyond age and anticoagulant use. Also limited ability to conduct subgroup analyses by medication type (warfarin or clopidogrel) or by INR level
In-hospital mortality after immediate TICH10/60 (16.7%; 95% CI 8.3% to 28.5%)
Neurosurgical intervention after immediate TICH12/60 (20%; 95% CI 8.3% to 28.5%)
Factors associated with immediate TICH identified by multivariate logistic regressionVomiting (aOR 3.68; 95% CI 1.55 to 8.96) and abnormal mental status (aOR 3.08; 95% CI 1.60 to 5.4.) However, these 2 variables were absent in a substantial number of those with TICH
Rendell and Batchelor,
82 WHI patients identified from 3338 CT scans requested by the ED over 2-year period (Jan 2008–Dec 2009) 72/82 (88%) patients had their INR checked Cohort studyICH 12/82 (15%). RR of ICH for INR subgroups calculated: INR <2 (RR 1.89; 95% CI 0.65 to 5.55); INR 2–3 (RR 0.84; 95% CI 0.27 to 2.64); and INR >3 (RR 0.53; 95% CI 0.13 to 2.29). The greatest proportion of those with ICH (42%) had a sub-therapeutic INR. 2/12 (17%) found to have ICH despite not meeting criteria for a CT scan according to NICE. Results of INR subgroup analysis suggest that a sub-therapeutic INR may not be protective against ICH following a minor head injury Retrospective review so never easy to capture all patients. However, a random trawl of notes over a 2-month period coded as head injury revealed no further patients. Small, but comparatively equivalent sample size, did not allow statistically significant conclusions, but did, however, yield interesting conclusions
Neurosurgical intervention4/12


There were no randomised controlled trials, but a mixture of case-controlled studies and cohort studies to give grade B recommendations for our emergency department population. There is good evidence here to demonstrate the deleterious effects of a supra-therapeutic INR (Menditto et al, 2012; Major and Reed, 2009; Pieracci et al, 2007; Cohen et al, 2006; Franko et al, 2006), but you would also expect this to accompany clinical signs, a reduced Glasgow Coma Score (GCS) and an increased mortality. It is of more use, though, to examine the impact of the INR in the low risk patient: one who is asymptomatic with GCS 15. Cohen et al (2006) highlight significant inconsistencies in the management of this group of patients even in a single centre, particularly with respect to measuring the INR, obtaining a CT scan and indeed the timing of this scan. They suggest routine measurement of the INR in all those warfarinised and consideration of routine CT scanning. There is much to suggest, though, that there is not a great causal significance in the level of coagulopathy in the low-risk WHI patient (Rendell and Batchelor, 2013; Nishijima et al, 2012). Nishijima et al (2013), Nishijima et al (2012), Gittleman et al (2005) and Li et al (2001) demonstrate the high incidence of ICH in anticoagulated patients following seemingly trivial injury without high-risk features. Furthermore, Rendell and Batchelor (2013), Brewer et al (2011) and Reynolds et al (2003) found no statistical difference in INR between those with positive compared with negative scans, Mina et al (2003) between those that died compared with survivors and Reynolds et al (2003) between those with ICH who remained stable compared with those who subsequently deteriorated. Rendell and Batchelor (2013) and Ivascu et al (2005) conclude that neither the GCS nor the level of anticoagulation can reliably predict the presence of ICH, even that a sub-therapeutic INR appears to offer no protection, and that urgent scanning combined with prompt reversal can reduce ICH progression and improve mortality. Therefore, both the clinical picture and the INR have not shown to be effective at ruling out ICH in the asymptomatic WHI patient. It is, nevertheless, an important investigation in this setting, as an early check has been shown to allow rapid time to reversal of the INR with ICH. Importantly, Nishijima et al (2013) and Rendell and Batchelor (2013) found that there was no ‘low-risk group’ of warfarinised head injury patients safely managed without CT despite their apparent well-being. In the presence of a normal CT scan, it would appear to be prudent to admit a patient with a supra-therapeutic INR for at least a period of observation, and perhaps consideration given to short-term reversal of anticoagulation, as advocated by Cohen et al (2006).

Editor Comment

Key: MHI = minor head injury; ED = emergency department; OR = odds ratio; CI = confidence interval; ICH = intracranial haemorrhage; ROC = receiver operator curve; AUC = area under the curve; PPV = positive predictive value; NPV = negative predictive value; GCS = Glasgow coma score; LOC = loss of consciousness; RR = relative risk; LOS = length of stay; WHI = warfarinised head injury; ISS = injury severity score; MOI = mechanism of injury; DICH = delayed intracranial haemorrhage; FFP = fresh frozen plasma; TICH = traumatic intracranial haemorrhage; IQR = interquartile range.

Clinical Bottom Line

With the low-risk patient, the level of coagulopathy does not seem to confer an obvious causal significance, although the risk is clearly greater than those not anticoagulated. Cranial imaging would therefore appear to be an urgent and necessary tool in the evaluation of the anticoagulated minor head injury patient, even if asymptomatic, especially given the apparent lack of protection from a sub-therapeutic International Normalised Ratio.


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