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ABO and Rh blood groups, demographics, and comorbidities in COVID-19 related deaths: A retrospective study in Split-Dalmatia County, Croatia

      Abstract

      Background

      Blood group phenotypes have been associated with COVID-19 susceptibility and severity. This study aimed to examine ABO/Rh blood group distribution in COVID-19-related deaths considering demographics and pathological conditions.

      Methods

      We conducted a retrospective study at the University Hospital Center Split, Croatia, that included 245 COVID-19 positive individuals that died from April 8, 2020, to January 25, 2021. We extracted data on their blood groups, demographics, and pre-existing comorbidities and compared findings with general population data from blood group donations (n = 101,357) and non-COVID-19 deaths from 2019 (n = 4968).

      Results

      The proportion of dead males was significantly higher than in non-COVID-19 cases (63.7% vs. 48.9%, P < 0.001), while the proportion of older individuals did not differ. The prevailing pre-existing diseases were hypertension (59.6%), diabetes (37.1%), heart failure (28.8%), digestive disorder (26.5%), and solid tumor (21.6%). The ABO distribution in the deceased and donors' group showed significant differences, with the higher prevalence of A/AB group and lower prevalence of 0, but with individual differences significant only for AB and non-AB groups. There was a reduced proportion of females within the deceased with group 0 (P = 0.014) and a higher proportion of AB individuals with coronary heart disease (P = 0.024).

      Conclusion

      The study confirmed a higher risk of death in males. The lower proportion of type 0 in deceased individuals was greater in females, implying that group 0 is not necessarily an independent protective factor. Coronary heart disease was identified as a potential risk factor for AB individuals.

      Keywords

      1. Introduction

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      Besides numerous clinical, environmental, and lifestyle factors that have been considered, ABO phenotypes have also been identified to play a possible role in COVID-19 susceptibility and disease severity [
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      Genomewide association study of severe covid-19 with respiratory failure.
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      Reduced prevalence of SARS-CoV-2 infection in ABO blood group O.
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      Association between ABO blood groups and risk of SARS-CoV-2 pneumonia.
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      ], have been related to the increased risk for contracting SARS-CoV-2 infection and/or disease severity. A similar relationship was also explored for the risk of death, but yielded even more different results. Zhao et al. [
      • Zhao J.
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      Relationship between the ABO blood group and the coronavirus disease 2019 ( COVID-19) susceptibility.
      ] have associated group 0 with a lower and group A with a higher risk of death. Ray et al. [
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      Association between ABO and Rh blood groups and SARS-CoV-2 infection or severe COVID-19 illness: a population-based cohort study.
      ] also showed a lower risk of death for type O blood group, Takagi [
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      Down the rabbit‐hole of blood groups and COVID‐19.
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      Associations between blood type and COVID-19.
      ] reported increased risk of death in AB group. In contrast, several studies have failed to confirm any association between ABO blood types and COVID-19 related mortality [
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      • Haunstrup T.M.
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      • Hansen M.B.
      • et al.
      Reduced prevalence of SARS-CoV-2 infection in ABO blood group O.
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      The recent systematic review and meta-analysis that considered prevalence of 0 vs non-0 blood types, demonstrated limited evidence of lower disease susceptibility in group 0 individuals and no evidence of an effect on disease severity. However, authors highlighted the low quality of evidence provided in the studies, that primarily stemmed from their designs [
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      Pronounced discrepancies in results could also stem from population differences, sampling strategies, type of control group, and many other factors like sex, age, as well as comorbidities that are not always equally considered and controlled for in these types of studies [
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      ].
      Since pre-existing comorbidities and ABO phenotypes have been less extensively studied in the COVID-19 deceased individuals, this study aimed to examine differences of the ABO and Rh blood groups distribution in the COVID-19 related deaths and their association to the chronic diseases and individuals' demographic characteristics. The secondary aim was to reveal potential specificities in the Croatian population, as it has not been regarded in such type of studies.

      2. Materials and methods

      We conducted a retrospective study between March 1, 2021, and May 15, 2021, at the University Hospital Center Split, Split, Croatia. The study comprised individuals with diagnosed COVID-19 that died in Split-Dalmatia County, Croatia, from April 8, 2020, to January 25, 2021. Using the information from the hospital database, we included only individuals with known ABO blood groups and available information on chronic diseases.
      To examine potential demographic differences between the general population of deceased and COVID-19 related deaths, we extracted the data from the statistical report Natural Change in Population for 2019 (n = 4968) [
      Croatian Bureau of Statistics
      Statistical Report: Natural Change in Population, 2019.
      ]. For estimating blood group distribution in the general population, we used information from collected blood group donations (n = 101,357) from January 1, 2016, to April 26, 2021, provided by the Department of Transfusion Medicine of the University Hospital Center Split, Croatia.

      2.1 Statistical analysis

      Continuous variables were described as mean, standard deviation (SD), and range, while for categorical variables, we provided counts and proportions (%). To examine differences in categorical variables, we used a Pearson's Chi-squared with Yates's correction. When test assumptions were not fully met, we approximated P-values using Monte-Carlo simulation with 2000 replicates. All analyses were performed in R statistical software version 3.6.2 and RStudio version 1.2.1335. The statistical significance level was set at P ≤ 0.05.

      2.2 Ethical approval

      The study was approved by the ethical committee of University Hospital Center Split on June 15, 2020 (500–03/20–01/09; 2181–147–01/06/M.S.–20–12).

      3. Results

      3.1 Participants' characteristics

      From a total of 393 COVID-19 related deaths in the analyzed period, we included 248 patients for which data on ABO blood groups was available. After excluding from the study individuals with no available clinical data in the database (n = 3), the final sample consisted of 245 individuals, 165 (67.3%) male and 80 (32.7%) female subjects. The mean age of male subjects was 74.2 ( ± 11.3), with a range of 30 – 93, while the mean age of female subjects was 78.8 ( ± 10.3) with an age range of 48 – 96.
      Sex ratio of the COVID-19 group (2.1:1) statistically significantly differed from non-COVID-19 mortality data from 2019 [
      Croatian Bureau of Statistics
      Statistical Report: Natural Change in Population, 2019.
      ] (χ2 = 30.935, P < 0.001), in which proportion of male and female subjects was almost the same (48.9% males and 51.1% females, 0.96:1). When proportion of subjects younger and older than 60 years was considered, no statistically significant differences were noted in either the males (87% vs 86%; χ2 = 0.062, P = 0.803), or the females (95% vs 94%; χ2 = 0.065, P = 0.800).

      3.2 Frequency of chronic diseases

      Table 1 shows the frequencies of pre-existing chronic diseases in the COVID-19 group. The most common condition in the analyzed individuals was hypertension and diabetes identified in 60% and 37% of the subjects studied, respectively. Heart failure, digestive disorder, and solid tumor were recorded for 20–30% of individuals, while other conditions were represented in less than 20% of subjects. Among analyzed conditions, the sex differences were statistically significant only for hypothyroidism (P = 0.047), where a proportion of the disease in female subjects was remarkably higher (64% vs. 36%).
      Table 1Frequency of chronic diseases in COVID-19 related deaths.
      n (%)n (%)n (%)Sex differences
      DiseaseTotal (n = 245)Males (n = 165)Females (n = 80)χ2P
      Cerebrovascular disease24 (9.8)16 (66.7)8 (33.3)< 0.0011.000
      Coronary heart disease45 (18.4)35 (77.8)10 (22.2)2.1770.140
      Heart failure69 (28.8)48 (69.6)21 (30.4)0.0970.755
      Hypertension146 (59.6)95 (65.1)51 (34.9)0.6160.433
      Diabetes91 (37.1)62 (68.1)29 (31.9)0.0040.952
      Digestive disorder65 (26.5)43 (66.2)22 (33.8)0.0070.932
      COPD33 (13.5)23 (69.7)10 (30.3)0.0120.913
      Solid tumor53 (21.6)34 (64.2)19 (35.8)0.1560.693
      Chronic renal disease20 (8.2)16 (80.0)4 (20.0)1.0210.312
      Hepatitis2 (0.8)2 (100.0)0 (0)
      Atrial fibrillation41 (16.7)30 (73.2)11 (26.8)0.4750.491
      Gout19 (7.8)15 (78.9)4 (21.1)0.7530.385
      Hypothyroidism11 (4.5)4 (36.4)7 (63.6)5.0280.047 *
      Rheumatic diseases6 (2.5)4 (66.7)2 (33.3)0.0011.000
      *Statistically significant.
      † RA, Arthritis, and Morbus Bechterew

      3.3 ABO blood group distribution

      ABO blood groups distribution showed statistically significant differences in blood donors' and COVID-19 deceased group (χ2 = 8.204, P = 0.042). However, when blood groups were separately compared (e. g., AB and non-AB group in donors and deceased individuals) the difference was statistically significant only for the AB group (P = 0.034), which was more represented in the deceased individuals. The proportion of Rh-positive and Rh-negative subjects was not significantly different in the donor sample and deceased subjects (P = 0.396).
      After considering ABO-Rh blood types, we found no statistically significant differences between groups (χ2 = 11.227, P = 0.135). A separate comparison of blood types revealed significant differences for AB- blood type (P = 0.034; Table 3), which was more represented in the group of COVID-19 positive deceased individuals. Due to the small proportion of Rh-negative individuals, we included only ABO blood groups in further analyses.
      Table 2ABO blood group and Rh distribution in donors and deceased subjects.
      Blood groupRh
      ABAB0+-
      Donors (n = 101,343), %39,251 (38.7)17,599 (17.4)7046 (7.0)37,457 (37.0)82,599 (81.5)18,754 (18.5)
      Deceased (n = 245), %104 (42.4)39 (15.9)26 (10.6)76 (31.0)194 (79.2)51 (20.8)
      χ21.2740.2624.5073.4470.720
      P0.2590.6090.034*0.0630.396
      *Statistically significant.
      Table 3ABO-Rh blood group distribution in donors and deceased subjects.
      Blood group
      A+B+AB+0 +A-B-AB-0-
      Donors (n = 101,343), %31,984 (31.6)14,246 (14.1)5816

      (5.7)
      30,553

      (30.1)
      7267

      (7.2)
      3353

      (3.3)
      1230

      (1.2)
      6904

      (6.8)
      Deceased (n = 245), %82

      (33.5)
      31

      (12.7)
      19

      (7.8)
      62

      (25.3)
      22

      (9.0)
      8

      (3.3)
      7

      (2.9)
      14

      (5.7)
      χ20.3300.2911.4832.4930.945<0.0015.4890.307
      P0.5660.5900.2230.1140.3311.0000.034*0.579
      *Statistically significant.

      3.4 Diseases and blood group distribution

      When we analyzed blood groups according to the sex of subjects within the deceased group, overall differences were not statistically significant (Table 4). Nonetheless, when blood groups were separately considered, there was a statistically significantly smaller proportion of females in group 0 (P = 0.014). Among all diseases recorded in the studied subjects, differences in blood group distributions were only statistically significant for coronary heart disease (P = 0.033). This difference was mainly expressed in the AB group, in which more than a third of subjects suffered from coronary heart disease (P = 0.024). Interestingly, the proportion of blood group 0 was twice as higher in participants without disease but with no statistical significance (P = 0.052).
      Table 4ABO blood group distribution and pre-existing chronic diseases in COVID-19-related deaths.
      Blood group
      ABAB0χ2P
      Sex distribution (n = 245), %
      Males (n = 165), %65 (39.4)23 (13.9)17 (10.3)60 (36.4)7.0510.070
      Females (n = 80), %39 (48.8)16 (20)9 (11.2)16 (20)
      χ21.5671.060< 0.0015.999
      P0.2110.3030.9960.014*
      Cerebrovascular disease
      Yes (n = 24)12 (50.0)4 (16.7)1 (4.2)7 (29.2)1.4740.730
      No (n = 221)92 (41.6)35 (15.8)25 (11.3)69 (31.2)
      χ20.3260.0111.165< 0.001
      P0.5681.0000.3621.000
      Coronary heart disease
      Yes (n = 45)22 (48.9)6 (13.3)9 (20.0)8 (17.8)8.4640.033*
      No (n = 200)82 (41.0)33 (16.5)17 (8.5)68 (34.0)
      χ20.6400.0895.1213.792
      P0.4230.7650.024 *0.052
      Heart failure
      Yes (n = 69)31 (44.9)11 (15.9)6 (8.7)21 (30.4)0.4820.923
      No (n = 200)73 (41.5)28 (15.9)20 (11.4)55 (31.2)
      χ20.121< 0.0010.144< 0.001
      P0.7281.0000.7051.000
      Hypertension
      Yes (n = 146)69 (47.3)18 (12.3)16 (11.0)43 (29.5)5.2220.156
      No (n = 99)35 (35.4)21 (21.2)10 (10.1)33 (33.3)
      χ22.9532.846< 0.0010.254
      P0.0860.0920.9980.614
      Diabetes
      Yes (n = 91)38 (41.8)12 (13.2)9 (9.9)32 (35.2)1.5670.667
      No (n = 154)66 (42.9)27 (17.5)17 (11.0)44 (28.6)
      χ20.0010.5150.0050.874
      P0.9730.4730.9460.350
      Digestive disorder
      Yes (n = 65)30 (46.2)9 (13.8)4 (6.2)22 (33.8)2.4100.492
      No (n = 180)74 (41.1)30 (16.7)22 (12.2)54 (30.0)
      χ20.3120.1121.2690.175
      P0.5760.7380.2600.676
      COPD
      Yes (n = 33)14 (42.4)6 (18.2)3 (9.1)10 (30.3)0.2120.971
      No (n = 212)90 (42.5)33 (15.6)23 (10.8)66 (31.1)
      χ2< 0.0010.0160.093< 0.001
      P1.0000.9000.8081.000
      Solid tumor
      Yes (n = 53)18 (34.0)9 (17.0)6 (11.3)20 (37.7)2.2110.530
      No (n = 192)86 (44.8)30 (15.6)20 (10.4)56 (29.2)
      χ21.5750.001< 0.0011.053
      P0.2090.9791.0000.305
      Chronic renal disease
      Yes (n = 20)10 (50.0)3 (15.0)3 (15.0)4 (20.0)1.5520.685
      No (n = 225)94 (41.8)36 (16.0)23 (10.2)72 (32.0)
      χ20.2270.0140.4420.739
      P0.6331.0000.7310.390
      Atrial fibrillation
      Yes (n = 41)14 (34.1)8 (19.5)5 (12.2)14 (34.1)1.4710.710
      No (n = 204)90 (44.1)31 (15.2)21 (10.3)62 (30.4)
      χ21.0110.2070.1300.084
      P0.3150.6490.8040.772
      Gout
      Yes (n = 19)11 (57.9)2 (10.5)1 (5.3)5 (26.3)2.2360.553
      No (n = 226)93 (41.2)37 (16.4)25 (11.1)71 (31.4)
      χ21.3840.4470.6210.041
      P0.2390.5720.5250.839
      Hypothyroidism
      Yes (n = 11)2 (18.2)4 (36.4)0 (0)5 (45.5)6.6180.082
      No (n = 234)102 (43.6)35 (15.0)26 (11.1)71 (30.3)
      χ22.7763.5971.3671.121
      P0.1220.0940.4030.352
      Rheumatic diseases
      Yes (n = 6)4 (66.7)0 (0)0 (0)2 (33.3)2.4920.413
      No (n = 239)100 (41.8)39 (16.3)26 (10.9)74 (31.0)
      χ21.4771.1640.7300.015
      P0.4240.6140.6561.000
      *Statistically significant.

      4. Discussion

      Along with ABO blood groups, this is the first study in the Croatian population that analyzed demographic and pathological conditions in COVID-19 positive deceased individuals. We showed that the distribution of the ABO blood groups could be associated with the structure of the COVID-19 related deaths in the analyzed Croatian population sample, but to a limited extent. Blood group AB was significantly more represented in the COVID-19 group than in the group of donors, which is why it might be treated as a potential risk factor in the analyzed population. As expected, blood group 0 was less represented in deceased individuals, but this difference was significant only in females, implying that ABO differences could be masked by the sex of individuals or conditions more frequent in one sex.
      Compared to the non-COVID-19 deaths from 2019, where the proportion of males and females was almost equal, the proportion of males was more than twice higher in our study. This result is in line with previous studies that showed significantly higher mortality in male individuals, notwithstanding the approximately equal susceptibility to the disease [
      • Elmore R.
      • Schmidt L.
      • Lam J.
      • Howard B.E.
      • Tandon A.
      • Taxman D.J.
      • et al.
      Risk and protective factors in the COVID-19 pandemic: a rapid evidence map.
      ,
      • Gebhard C.
      • Regitz-Zagrosek V.
      • Neuhauser H.K.
      • Morgan R.
      • Klein S.L.
      Impact of sex and gender on COVID-19 outcomes in Europe.
      ]. Unexpectedly, the proportion of older individuals (>60) was almost equal in COVID-19 and non-COVID-19 related deaths from 2019, thus not reflecting the increased risk of death for older individuals recognized in the previous studies [
      • Elmore R.
      • Schmidt L.
      • Lam J.
      • Howard B.E.
      • Tandon A.
      • Taxman D.J.
      • et al.
      Risk and protective factors in the COVID-19 pandemic: a rapid evidence map.
      ,
      • Parohan M.
      • Yaghoubi S.
      • Seraji A.
      • Javanbakht M.H.
      • Sarraf P.
      • Djalali M.
      Risk factors for mortality in patients with Coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of observational studies.
      ]. The most frequent diseases observed in the analyzed subjects mainly were those previously identified to increase odds of death in COVID-19 cases, such as hypertension, cardiovascular diseases, and diabetes [
      • Parohan M.
      • Yaghoubi S.
      • Seraji A.
      • Javanbakht M.H.
      • Sarraf P.
      • Djalali M.
      Risk factors for mortality in patients with Coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of observational studies.
      ,
      • Deng G.
      • Yin M.
      • Chen X.
      • Zeng F.
      Clinical determinants for fatality of 44,672 patients with COVID-19.
      ,
      • Williamson E.J.
      • Walker A.J.
      • Bhaskaran K.
      • Bacon S.
      • Bates C.
      • Morton C.E.
      • et al.
      Factors associated with COVID-19-related death using OpenSAFELY.
      ]. Sex distribution of nearly all diseases did not significantly differ except from hypothyroidism, commonly more frequently diagnosed in females [
      • Pearce E.N.
      The presence of hypothyroid symptoms is more reliable in diagnosing hypothyroidism in men than in women.
      ]. Although not statistically significant, coronary heart diseases were almost twice as common in male than female individuals, which was not expected considering that proportion of females that died with diagnosed coronary heart disease in 2019 was slightly higher [
      Croatian Bureau of Statistics
      Statistical Report: Mortality Report According to the List of Selected Causes of Death in 2019.
      ]. This finding could point out to the additional risk for male individuals with coronary heart diseases.
      ABO blood groups distribution showed statistically significant differences in COVID-19 positive deceased individuals and donors' group, with higher prevalence of A and AB groups and lower prevalence of group 0 in the deceased individuals. Increased proportion of A group and reduced proportion of group 0 in our study was consistent with general findings of disease susceptibility, but also with the disease severity reported in some studies [
      • Zhao J.
      • Yang Y.
      • Huang H.
      • Li D.
      • Gu D.
      • Lu X.
      Relationship between the ABO blood group and the coronavirus disease 2019 ( COVID-19) susceptibility.
      ,
      • Wu Y.
      • Feng Z.
      • Li P.
      • Yu Q.
      Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19.
      ,
      • The Severe Covid-19 GWAS Group
      Genomewide association study of severe covid-19 with respiratory failure.
      ,
      • Li J.
      • Wang X.
      • Chen J.
      • Cai Y.
      • Deng A.
      • Yang M.
      Association between ABO blood groups and risk of SARS-CoV-2 pneumonia.
      ,
      • Göker H.
      • Aladağ Karakulak E.
      • Demiroğlu H.
      • Ayaz Ceylan Ç.M.
      • Büyükaşik Y.
      • Inkaya A.Ç.
      • et al.
      The effects of blood group types on the risk of COVID-19 infection and its clinical outcome.
      ,
      • Hoiland R.L.
      • Fergusson N.A.
      • Mitra A.R.
      • Griesdale D.E.G.
      • Devine D.V.
      • Stukas S.
      • et al.
      The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19.
      ,
      • Latz C.A.
      • DeCarlo C.
      • Boitano L.
      • Png C.Y.M.
      • Patell R.
      • Conrad M.F.
      • et al.
      Blood type and outcomes in patients with COVID-19.
      ]. However, in our study, only AB group was significantly more represented in the group of deceased. This finding is partly in line with meta-analysis that, although statistically non-significant, reported the greatest odds ratio for death in AB group individuals [
      • Pourali F.
      • Afshari M.
      • Alizadeh-Navaei R.
      • Javidnia J.
      • Moosazadeh M.
      • Hessami A.
      Relationship between blood group and risk of infection and death in COVID-19: a live meta-analysis.
      ] and the results reported by Zietz et al. [
      • Zietz M.
      • Zucker J.
      • Tatonetti N.P.
      Associations between blood type and COVID-19.
      ]. One of the possible reasons for this outcome could be biding SARS-CoV-2 to the carbohydrates responsible for the blood group. As those carbohydrates are vastly represented at the respiratory tract mucous membrane, this results in the greatest contact with virus for AB blood type [
      • Pourali F.
      • Afshari M.
      • Alizadeh-Navaei R.
      • Javidnia J.
      • Moosazadeh M.
      • Hessami A.
      Relationship between blood group and risk of infection and death in COVID-19: a live meta-analysis.
      ].
      The distribution of Rh+ and Rh blood group in donors and COVID-19 deceased individuals did not differ significantly when analyzed separately neither within ABO Rh groups. This result concurs with the study by Solmaz and Araç [
      • Solmaz İ.
      • Araç S.
      ABO blood groups in COVID-19 patients; Cross-sectional study.
      ], who found no associations of Rh groups with disease susceptibility, severity or risk of death. However, several studies showed that Rh+ individuals are more likely to test positive [
      • Latz C.A.
      • DeCarlo C.
      • Boitano L.
      • Png C.Y.M.
      • Patell R.
      • Conrad M.F.
      • et al.
      Blood type and outcomes in patients with COVID-19.
      ] and associated Rh- individuals with decreased risk for severe disease or death [
      • Ray J.G.
      • Schull M.J.
      • Vermeulen M.J.
      • Park A.L.
      Association between ABO and Rh blood groups and SARS-CoV-2 infection or severe COVID-19 illness: a population-based cohort study.
      ,
      • Zietz M.
      • Zucker J.
      • Tatonetti N.P.
      Associations between blood type and COVID-19.
      ]. Due to the mentioned inconsistencies and a limited number of studies, more research is needed to reveal if Rh groups could be related to the risk or resistance to the disease.
      We did not find statistically significant differences in sex and ABO blood group distribution within deceased individuals, but when we considered the distribution of 0 and non-0 individuals, there was a significantly lower proportion of females with blood group 0. It is unlikely that this difference is directly linked to the sex and blood group distribution differences, but it might result from sex-specific frequencies of diseases and the blood group-specific susceptibility to a particular disease.
      Namely, it has been assumed that anti-A antibodies inhibit the interaction between SARS-CoV-1 and ACE2 receptors [
      • Guillon P.
      • Clément M.
      • Sébille V.
      • Rivain J.G.
      • Chou C.F.
      • Ruvoën-Clouet N.
      • et al.
      Inhibition of the interaction between the SARS-CoV Spike protein and its cellular receptor by anti-histo-blood group antibodies.
      ]; a similar process probably takes place in SARS-CoV-2 infection [
      • Zhao J.
      • Yang Y.
      • Huang H.
      • Li D.
      • Gu D.
      • Lu X.
      Relationship between the ABO blood group and the coronavirus disease 2019 ( COVID-19) susceptibility.
      ]. This effect probably also depends on the level of the anti-A antibody [
      • Deleers M.
      • Breiman A.
      • Daubie V.
      • Maggetto C.
      • Barreau I.
      • Besse T.
      • et al.
      Covid-19 and blood groups: ABO antibody levels may also matter.
      ]. McVey et al. [
      • McVey J.
      • Baker D.
      • Parti R.
      • Berg R.
      • Gudino M.
      • Teschner W.
      Anti-A and anti-B titers in donor plasma, plasma pools, and immunoglobulin final products.
      ] showed that among persons with blood group 0, a larger number of women than men have a higher titer of anti-A-antibodies and anti-B antibodies, and a significantly higher number of women have anti-A-antibodies, which corresponds to other similar works. This could be one of the reasons for the lower proportion of deceased females with blood group 0.
      Among considered pre-existing chronic conditions, the statistically significant difference in ABO group distributions was observed for coronary heart disease (CHD) that exhibited a higher prevalence of group A and AB and a lower prevalence of group 0. The differences were mostly expressed and statistically significant for AB group, in which more than third of individuals suffered from CHD. This could be explained by generally greater risk in non-O blood type individuals for contracting CHD, particularly group AB, which in some studies showed the highest hazard ratio [
      • He M.
      • Wolpin B.
      • Rexrode K.
      • Manson J.E.
      • Rimm E.
      • Hu F.B.
      • et al.
      ABO blood group and risk of coronary heart disease in two prospective cohort studies.
      ]. Nonetheless, it is challenging to explain why a similar trend was not observed for heart failure, which exhibited the second smallest differences between ABO blood group distribution according to the χ2 and P-value.
      In contrast to the known association between ABO blood groups and CHD, data on the possible association between ABO blood groups and heart failure are lacking. Gotsman et al. [
      • Gotsman I.
      • Keren A.
      • Zwas D.R.
      • Lotan C.
      • Admon D.
      Clinical impact of ABO and rhesus D blood type groups in patients with chronic heart failure.
      ] demonstrated the distribution of blood groups in HF patients similar to that in the general population. The results of this study suggest that the ABO blood group does not play a significant role in the development of HF. However, they show an association between the non-O blood group and poorer prognosis in patients with nonischemic cardiomyopathy. Individuals with non-O blood groups have an increased risk of thrombosis due to elevated levels of von Willebrand factor and factor VIII, with a significantly higher risk of myocardial infarction, peripheral vascular disease, and venous thromboembolism [
      • Wu O.
      • Bayoumi N.
      • Vickers M.A.
      • Clark P.
      ABO (H) blood groups and vascular disease: a systematic review and meta‐analysis.
      ].
      One of the study restrictions are somewhat smaller sample size in deceased sample and structure of blood donor population that might not accurately represent the general population. This could reflect not only in blood group distribution but also in age distribution (unknown in the present case) that could be biased towards younger individuals and constrain conclusion drawn from comparisons, especially because of higher mortality among elderly patients with comorbidities. So, the major limitation is the unavailability of appropriate control groups that would allow us to draw stronger conclusions. Control groups of COVID-19 negative individuals with data on ABO blood groups and chronic conditions or the same data for individuals that were infected but survived the disease would have enabled more robust analyses regarding the risk factors for disease severity and death in analyzed individuals. For the same reasons, despite sufficient donors' sample size, we could not exclude the possibility that the general bias of collecting more samples from universal donors (group 0) and less from AB group affected results to some extent. However, since population differences reflect not only in blood types but also in many other genetic and environmental factors, we believe that the present and future studies of this type conducted in various population samples will contribute to creating a clearer and more complete picture of COVID-19 and ABO groups association.

      Funding

      This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

      CRediT authorship Contribution Statement

      Ivan Brdar: Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Ivan Jerković: Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Željana Bašić: Conceptualization, Formal analysis, Investigation, Writing – review & editing. Nenad Kunac: Conceptualization, Investigation, Writing – review & editing. Deny Anđelinović: Conceptualization, Investigation, Writing – review & editing. Joško Bezić: Conceptualization, Investigation, Writing – review & editing. Ivana Kružić: Conceptualization, Investigation Writing – review & editing. Arijana Vuko: Conceptualization, Investigation, Writing – review & editing. Šimun Anđelinović: Conceptualization, Investigation, Writing – review & editing, Supervision.

      Data availability

      The data that support the findings of this study are available on request from the corresponding author.

      Declaration of Competing Interest

      Authors declare no conflict of interest.

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