ORTHOPAEDIC SURGERY Ann R Coll Surg Engl 2014; 96: 442–445 doi 10.1308/003588414X13946184902604
Association of ABO blood group with fracture pattern and mortality in hip fracture patients CE Uzoigwe, RP Smith, A Khan, D Aghedo, M Venkatesan University Hospitals of Leicester NHS Trust, UK ABSTRACT INTRODUCTION
The mechanism of falling has been proposed as the exclusive explanation for hip fracture pattern. Evidence exists that other genetic factors also influence proximal femoral fracture configuration. The ABO blood group serotype has been associated with other pathologies but any role in hip fracture has yet to be definitively characterised. METHODS Our National Hip Fracture Database was interrogated over a four-year period. All patients had their blood group retrieved, and this was compared with hip fracture pattern and mortality rates. Confounding factors were accounted for using logistic regression and the Cox proportional hazards model. RESULTS A total of 2,987 consecutive patients presented to our institution. Those with blood group A were significantly more likely to sustain intracapsular fractures than ‘non-A’ individuals (p=0.009). The blood group distribution of patients with intracapsular fractures was identical to that of the national population of England. However, blood group A was less common in patients with intertrochanteric fractures than in the general population (p=0.0002). Even after correction for age and sex, blood group A was associated with a decrease in the odds of suffering an intertrochanteric fracture to 80% (p=0.002). Blood group A had inferior survivorship correcting for age, sex and hip fracture pattern (hazard ratio: 1.14, p=0.035). This may be due to associated increased prevalence of co-morbid disease in this cohort. CONCLUSIONS Blood group is an independent predictor of hip fracture pattern, with group A patients more likely to sustain an intracapsular fracture and non-A individuals more likely to sustain an intertrochanteric fracture. The determinants of fracture pattern are likely to be related to complex interactions at a molecular level based on genetic susceptibility. The mechanism of fall may not be the only aetiological determinant of proximal femoral fracture configuration.
KEYWORDS
Hip fracture – ABO blood group – Mortality – Fracture pattern Accepted 4 April 2014 CORRESPONENCE TO Chika Uzoigwe, E: [email protected]
The hip fracture remains clinically the most important fracture because of its high incidence, poor survivorship and the need for expeditious surgery. Understanding of the mechanisms of disease has not developed significantly in 50 years. Fracture pattern was thought traditionally to be a biomechanical lottery. Recent insights have challenged this assumption. Tanner et al reported that increasing age is associated with an increasing intertrochanteric fracture incidence in women but an increasing intracapsular fracture incidence in men.1 Similarly, in contradiction to the mechanical model, Fisher et al observed that parathyroid hormone sensitivity in the calcium–parathyroid hormone–vitamin D axis dictates whether the fall will result in an intracapsular or extracapsular (intertrochanteric) fracture.2 They reported that the majority of patients with hip fractures were vitamin D deficient. However, those with an elevated parathyroid hormone level, in response to hypovitaminosis D, tended to suffer extracapsular fractures. Those with a muted parathyroid hormone response presented with intracapsular fractures. Certain individuals are at increased risk of one fracture type over another. Carriers of 3 or 4 of the rs7116604 or
442
Ann R Coll Surg Engl 2014; 96: 442–445
rs3781600 LRP5 alleles have a 7.5-fold increase in the odds of intertrochanteric fractures compared with non-carriers.3 This is independent of neck morphology. Despite this, these alleles are rare. We therefore considered whether there was any association between the most common human polymorphism (ABO blood group) and hip fracture. The work of Fisher et al2 is just the latest part of a 21st century movement, which has seen vitamin D emerge from its traditional role as calcium regulator to becoming one of the most promiscuous endocrine factors. The clinical perception of the ABO blood group system is undergoing a similar transformation. Familiarity with the system is germane to safe transfusion medicine. However, this is clearly not the reason the antigens exist. Their origin may be related to host immunity although there is no definitive explanation.4 In recent years, ABO antigens have been linked strongly to cerebrovascular and cardiovascular disease, visceral neoplasia and infections.5–7 This suggests that genes and enzymes in the ABO system have pleiotropic roles. Alternatively, ABO genes may be linked and coinherited with other alleles involved in pathological
UZOIGWE SMITH KHAN AGHEDO VENKATESAN
Table 1
ASSOCIATION OF ABO BLOOD GROUP WITH FRACTURE PATTERN AND MORTALITY IN HIP FRACTURE PATIENTS
Features of the various blood groups p-value
A (n=1,242)
B (n=274)
O (n=1,281)
AB (n=99)
Mean age
81
80
81
82
Male : female
5:2
5:2
5:2
5:2
0.8
ASA grade 3/4 : 1/2
2:1
2:1
2:1
13:1
0.08
30-day mortality
8.8%
8.4%
8.4%
8.1%
0.99
Intracapsular fracture
59%
54%
55%
47%
Intertrochanteric fracture
36%
43%
40%
49%
Ratio of intracapsular to intertrochanteric fractures
1.7
1.3
1.4
1.0
0.009
ASA = American Society of Anesthesiologists
processes. Hip fractures engender an equivalent mortality and financial challenge for healthcare systems to that of both cardiovascular and neoplastic disease.8 Nevertheless, no previous studies have sought to correlate ABO blood group with survivorship or as an independent determinant of fracture pattern in patients with hip fractures. We sought specifically to determine the following: Do patients of different blood groups suffer different hip fracture patterns? Do patients with intracapsular and intertrochanteric fractures have different blood group distributions? Is there any association between blood group and fracture pattern, independent of the potential confounders of age and sex? Is there any association with blood group and mortality in hip fracture patients?
Methods The National Hip Fracture Database was interrogated for all patients presenting to our institution with a hip fracture between 2009 and 2013. Patient demographics and clinical features including fracture pattern and survivorship are recorded in the database. Fracture pattern is determined and recorded following the daily trauma and orthopaedic consultant-led trauma meeting. All hip fracture patients have their blood group determined in preparation for theatre. These data were retrieved. The ABO distribution for intracapsular and intertrochanteric fractures was compared with the national average for the UK.9
Statistical methods
group, the mean age was 81 years. The female-to-male ratio was 5:2. Blood group O (44%) and A (43%) were the most common types. Fewer patients displayed B (10%) and AB (3%) antigens. Of the fracture patterns recorded, intracapsular (56%) and intertrochanteric (39%) fractures were the most common. Fewer fractures fell within the subtrochanteric (4%) or the other (basicervical 1%) categories. When the different blood groups were compared, they differed significantly with regard to fracture pattern prevalence. Patients with blood group A had a much higher frequency of intracapsular fractures and a lower frequency of intertrochanteric fractures than ‘non-A’ individuals. The ratio of intracapsular to intertrochanteric fractures was much higher for individuals with blood group A than for non-A patients (p=0.009) (Table 1). However, each serotype was similar with regard to age, unadjusted 30-day mortality and, to a lesser extent, ASA (American Society of Anesthesiologists) grade. The distribution of blood groups among patients with intracapsular fractures was identical (p=1.0) to the national mean for blood group distribution in England9 but the segregation of blood groups for the intertrochanteric cohort was considerably different (p=0.0002). Among this fracture pattern population, blood group A was significantly underrepresented and non-A groups were overrepresented compared with their prevalence among those suffering intracapsular fractures (Table 2). It has been suggested that fracture pattern varies with age and sex.1 Multivariate analysis was therefore used to adjust for these two potential confounders to determine
Categorical data were compared with the chi-squared test. Normal continuous data were analysed with the t-test. Nonnormal continuous data were examined with the Mann– Whitney U test. Logistic regression was used to compare any relationship with blood group correcting for age and sex. The Cox proportional hazards model was employed to produce adjusted estimates of long-term survivorship.
Table 2 Fracture pattern blood group distribution compared with national average9
A
45%
45% (n=734) 39% (n=442)
50% (n=52)
Results
B
9%
9% (n=149)
3% (n=3)
During the relevant time period, 2,987 consecutive patients presented to our institution with hip fractures. Of these, the blood group was retrievable in 2,896 (97%). For this
O
43%
43% (n=705) 46% (n=514)
45% (n=46)
3% (n=47)
2% (n=2)
National Intracapsular average (n=1,635)
AB 3%
Intertrochanteric Subtrochanteric (n=1,125) (n=103) 11% (n=119)
4% (n=49)
Ann R Coll Surg Engl 2014; 96: 442–445
443
UZOIGWE SMITH KHAN AGHEDO VENKATESAN
ASSOCIATION OF ABO BLOOD GROUP WITH FRACTURE PATTERN AND MORTALITY IN HIP FRACTURE PATIENTS
Table 3 Logistic regression model used to determine predictors of suffering an intertrochanteric fracture in a cohort of patients with proximal femoral fractures Odds ratio
95% confidence interval
p-value
Blood group A vs ‘non-A’
0.8
0.68–0.91
0.002
Female vs male
1.2
1.04–1.46
0.018
Age
1.0
0.99–1.01
0.180
any independent association between blood group and fracture type. In the analysis, any link was sought between blood group and intertrochanteric fracture. In patients with hip fractures, those of blood group A had a decrease in the odds of an intertrochanteric fracture to 80% compared with non-A individuals (95% confidence interval: 0.68–0.91, p=0.002). Female sex was associated with an increase in the odds of an intertrochanteric fracture by a factor of 1.2 (Table 3). In our study, age had no effect on fracture pattern. We next evaluated the impact of blood group on longterm mortality. A total of 2,882 patients were included in this analysis. Fourteen were excluded as there was no age recorded. Adjusting for age, sex and fracture type (intracapsular vs extracapsular) in a Cox proportional hazards analysis, we found that A serotype increased the risk of death by 10% (p=0.035) at any given time (Table 4). We then looked at only those who underwent surgery and had a recorded ASA grade. This involved 2,717 patients. When ASA grade was included in multivariate analysis in the cohort undergoing surgery, the effect of blood group on mortality (ie type A having a higher risk) was extinguished (Table 5). This result suggests that the increased long-term mortality associated with group A may be due to a greater burden of co-morbid disease.
Discussion Austrian physician Karl Landsteiner and Czech psychologist Jan Janský independently and coevally discovered the basis of the ABO blood group system in the first decade of the 20th
Table 4 Cox proportional hazard analysis to determine the effect of various factors on survivorship in 2,882 hip fracture patients
Blood group A vs ‘non-A’
Risk ratio
95% confidence interval
p-value
1.1
1.05–1.29
0.035
Female vs male
0.6
0.47–0.61
Association of ABO blood group with fracture pattern and mortality in hip fracture patients CE Uzoigwe, RP Smith, A Khan, D Aghedo, M Venkatesan University Hospitals of Leicester NHS Trust, UK ABSTRACT INTRODUCTION
The mechanism of falling has been proposed as the exclusive explanation for hip fracture pattern. Evidence exists that other genetic factors also influence proximal femoral fracture configuration. The ABO blood group serotype has been associated with other pathologies but any role in hip fracture has yet to be definitively characterised. METHODS Our National Hip Fracture Database was interrogated over a four-year period. All patients had their blood group retrieved, and this was compared with hip fracture pattern and mortality rates. Confounding factors were accounted for using logistic regression and the Cox proportional hazards model. RESULTS A total of 2,987 consecutive patients presented to our institution. Those with blood group A were significantly more likely to sustain intracapsular fractures than ‘non-A’ individuals (p=0.009). The blood group distribution of patients with intracapsular fractures was identical to that of the national population of England. However, blood group A was less common in patients with intertrochanteric fractures than in the general population (p=0.0002). Even after correction for age and sex, blood group A was associated with a decrease in the odds of suffering an intertrochanteric fracture to 80% (p=0.002). Blood group A had inferior survivorship correcting for age, sex and hip fracture pattern (hazard ratio: 1.14, p=0.035). This may be due to associated increased prevalence of co-morbid disease in this cohort. CONCLUSIONS Blood group is an independent predictor of hip fracture pattern, with group A patients more likely to sustain an intracapsular fracture and non-A individuals more likely to sustain an intertrochanteric fracture. The determinants of fracture pattern are likely to be related to complex interactions at a molecular level based on genetic susceptibility. The mechanism of fall may not be the only aetiological determinant of proximal femoral fracture configuration.
KEYWORDS
Hip fracture – ABO blood group – Mortality – Fracture pattern Accepted 4 April 2014 CORRESPONENCE TO Chika Uzoigwe, E: [email protected]
The hip fracture remains clinically the most important fracture because of its high incidence, poor survivorship and the need for expeditious surgery. Understanding of the mechanisms of disease has not developed significantly in 50 years. Fracture pattern was thought traditionally to be a biomechanical lottery. Recent insights have challenged this assumption. Tanner et al reported that increasing age is associated with an increasing intertrochanteric fracture incidence in women but an increasing intracapsular fracture incidence in men.1 Similarly, in contradiction to the mechanical model, Fisher et al observed that parathyroid hormone sensitivity in the calcium–parathyroid hormone–vitamin D axis dictates whether the fall will result in an intracapsular or extracapsular (intertrochanteric) fracture.2 They reported that the majority of patients with hip fractures were vitamin D deficient. However, those with an elevated parathyroid hormone level, in response to hypovitaminosis D, tended to suffer extracapsular fractures. Those with a muted parathyroid hormone response presented with intracapsular fractures. Certain individuals are at increased risk of one fracture type over another. Carriers of 3 or 4 of the rs7116604 or
442
Ann R Coll Surg Engl 2014; 96: 442–445
rs3781600 LRP5 alleles have a 7.5-fold increase in the odds of intertrochanteric fractures compared with non-carriers.3 This is independent of neck morphology. Despite this, these alleles are rare. We therefore considered whether there was any association between the most common human polymorphism (ABO blood group) and hip fracture. The work of Fisher et al2 is just the latest part of a 21st century movement, which has seen vitamin D emerge from its traditional role as calcium regulator to becoming one of the most promiscuous endocrine factors. The clinical perception of the ABO blood group system is undergoing a similar transformation. Familiarity with the system is germane to safe transfusion medicine. However, this is clearly not the reason the antigens exist. Their origin may be related to host immunity although there is no definitive explanation.4 In recent years, ABO antigens have been linked strongly to cerebrovascular and cardiovascular disease, visceral neoplasia and infections.5–7 This suggests that genes and enzymes in the ABO system have pleiotropic roles. Alternatively, ABO genes may be linked and coinherited with other alleles involved in pathological
UZOIGWE SMITH KHAN AGHEDO VENKATESAN
Table 1
ASSOCIATION OF ABO BLOOD GROUP WITH FRACTURE PATTERN AND MORTALITY IN HIP FRACTURE PATIENTS
Features of the various blood groups p-value
A (n=1,242)
B (n=274)
O (n=1,281)
AB (n=99)
Mean age
81
80
81
82
Male : female
5:2
5:2
5:2
5:2
0.8
ASA grade 3/4 : 1/2
2:1
2:1
2:1
13:1
0.08
30-day mortality
8.8%
8.4%
8.4%
8.1%
0.99
Intracapsular fracture
59%
54%
55%
47%
Intertrochanteric fracture
36%
43%
40%
49%
Ratio of intracapsular to intertrochanteric fractures
1.7
1.3
1.4
1.0
0.009
ASA = American Society of Anesthesiologists
processes. Hip fractures engender an equivalent mortality and financial challenge for healthcare systems to that of both cardiovascular and neoplastic disease.8 Nevertheless, no previous studies have sought to correlate ABO blood group with survivorship or as an independent determinant of fracture pattern in patients with hip fractures. We sought specifically to determine the following: Do patients of different blood groups suffer different hip fracture patterns? Do patients with intracapsular and intertrochanteric fractures have different blood group distributions? Is there any association between blood group and fracture pattern, independent of the potential confounders of age and sex? Is there any association with blood group and mortality in hip fracture patients?
Methods The National Hip Fracture Database was interrogated for all patients presenting to our institution with a hip fracture between 2009 and 2013. Patient demographics and clinical features including fracture pattern and survivorship are recorded in the database. Fracture pattern is determined and recorded following the daily trauma and orthopaedic consultant-led trauma meeting. All hip fracture patients have their blood group determined in preparation for theatre. These data were retrieved. The ABO distribution for intracapsular and intertrochanteric fractures was compared with the national average for the UK.9
Statistical methods
group, the mean age was 81 years. The female-to-male ratio was 5:2. Blood group O (44%) and A (43%) were the most common types. Fewer patients displayed B (10%) and AB (3%) antigens. Of the fracture patterns recorded, intracapsular (56%) and intertrochanteric (39%) fractures were the most common. Fewer fractures fell within the subtrochanteric (4%) or the other (basicervical 1%) categories. When the different blood groups were compared, they differed significantly with regard to fracture pattern prevalence. Patients with blood group A had a much higher frequency of intracapsular fractures and a lower frequency of intertrochanteric fractures than ‘non-A’ individuals. The ratio of intracapsular to intertrochanteric fractures was much higher for individuals with blood group A than for non-A patients (p=0.009) (Table 1). However, each serotype was similar with regard to age, unadjusted 30-day mortality and, to a lesser extent, ASA (American Society of Anesthesiologists) grade. The distribution of blood groups among patients with intracapsular fractures was identical (p=1.0) to the national mean for blood group distribution in England9 but the segregation of blood groups for the intertrochanteric cohort was considerably different (p=0.0002). Among this fracture pattern population, blood group A was significantly underrepresented and non-A groups were overrepresented compared with their prevalence among those suffering intracapsular fractures (Table 2). It has been suggested that fracture pattern varies with age and sex.1 Multivariate analysis was therefore used to adjust for these two potential confounders to determine
Categorical data were compared with the chi-squared test. Normal continuous data were analysed with the t-test. Nonnormal continuous data were examined with the Mann– Whitney U test. Logistic regression was used to compare any relationship with blood group correcting for age and sex. The Cox proportional hazards model was employed to produce adjusted estimates of long-term survivorship.
Table 2 Fracture pattern blood group distribution compared with national average9
A
45%
45% (n=734) 39% (n=442)
50% (n=52)
Results
B
9%
9% (n=149)
3% (n=3)
During the relevant time period, 2,987 consecutive patients presented to our institution with hip fractures. Of these, the blood group was retrievable in 2,896 (97%). For this
O
43%
43% (n=705) 46% (n=514)
45% (n=46)
3% (n=47)
2% (n=2)
National Intracapsular average (n=1,635)
AB 3%
Intertrochanteric Subtrochanteric (n=1,125) (n=103) 11% (n=119)
4% (n=49)
Ann R Coll Surg Engl 2014; 96: 442–445
443
UZOIGWE SMITH KHAN AGHEDO VENKATESAN
ASSOCIATION OF ABO BLOOD GROUP WITH FRACTURE PATTERN AND MORTALITY IN HIP FRACTURE PATIENTS
Table 3 Logistic regression model used to determine predictors of suffering an intertrochanteric fracture in a cohort of patients with proximal femoral fractures Odds ratio
95% confidence interval
p-value
Blood group A vs ‘non-A’
0.8
0.68–0.91
0.002
Female vs male
1.2
1.04–1.46
0.018
Age
1.0
0.99–1.01
0.180
any independent association between blood group and fracture type. In the analysis, any link was sought between blood group and intertrochanteric fracture. In patients with hip fractures, those of blood group A had a decrease in the odds of an intertrochanteric fracture to 80% compared with non-A individuals (95% confidence interval: 0.68–0.91, p=0.002). Female sex was associated with an increase in the odds of an intertrochanteric fracture by a factor of 1.2 (Table 3). In our study, age had no effect on fracture pattern. We next evaluated the impact of blood group on longterm mortality. A total of 2,882 patients were included in this analysis. Fourteen were excluded as there was no age recorded. Adjusting for age, sex and fracture type (intracapsular vs extracapsular) in a Cox proportional hazards analysis, we found that A serotype increased the risk of death by 10% (p=0.035) at any given time (Table 4). We then looked at only those who underwent surgery and had a recorded ASA grade. This involved 2,717 patients. When ASA grade was included in multivariate analysis in the cohort undergoing surgery, the effect of blood group on mortality (ie type A having a higher risk) was extinguished (Table 5). This result suggests that the increased long-term mortality associated with group A may be due to a greater burden of co-morbid disease.
Discussion Austrian physician Karl Landsteiner and Czech psychologist Jan Janský independently and coevally discovered the basis of the ABO blood group system in the first decade of the 20th
Table 4 Cox proportional hazard analysis to determine the effect of various factors on survivorship in 2,882 hip fracture patients
Blood group A vs ‘non-A’
Risk ratio
95% confidence interval
p-value
1.1
1.05–1.29
0.035
Female vs male
0.6
0.47–0.61
