Abstract
Background
Liver disease is any condition that affects the liver cells and their function. It is directly linked to coagulation disorders since most coagulation factors are produced by the liver. Therefore, this study aimed to assess the magnitude and associated factors of coagulation abnormalities among liver disease patients.
Methods
A cross-sectional study was conducted from August to October 2022 among 307 consecutively selected study participants at the University of Gondar Comprehensive Specialized Hospital. Sociodemographic and clinical data were collected using a structured questionnaire and data extraction sheet, respectively. About 2.7 mL of venous blood were collected and analyzed by the Genrui CA51 coagulation analyzer. Data were entered into Epi-data and exported to STATA version 14 software for analysis. The finding was described in terms of frequencies and proportions. Factors associated with coagulation abnormalities were analyzed by bivariable and multivariable logistic regression.
Result
In this study, a total of 307 study participants were included. Of them the magnitude of prolonged Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) were 68.08% and 63.51%, respectively. The presence of anaemia (AOR = 2.97, 95% CI: 1.26, 7.03), a lack of a vegetable feeding habit (AOR = 2.98, 95% CI: 1.42, 6.24), no history of blood transfusion (AOR = 3.72, 95% CI: 1.78, 7.78), and lack of physical exercise (AOR = 3.23, 95% CI: 1.60, 6.52) were significantly associated with prolonged PT. While the presence of anaemia (AOR = 3.02; 95% CI: 1.34, 6.76), lack of vegetable feeding habit (AOR = 2.64; 95% CI: 1.34, 5.20), no history of blood transfusion (AOR = 2.28; 95% CI: 1.09, 4.79), and a lack of physical exercise (AOR = 2.35; 95% CI: 1.16, 4.78) were significantly associated with abnormal APTT.
Conclusion
Patients with liver disease had substantial coagulation problems. Being anemic, having a transfusion history, lack of physical activity, and lack of vegetables showed significant association with coagulopathy. Therefore, early detection and management of coagulation abnormalities in liver disease patients are critical.
Keywords: Activated Partial Thrombin Time, Prothrombin Time, Liver disease, Gondar, Ethiopia
Background
Liver diseases are various disorders that can affect liver cells and impair normal liver function [1]. It is one of the world's most critical public health problems. The most common causes of the rising burden of liver disease are chronic viral hepatitis, mainly hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic fatty liver disease, caused by obesity, diabetes, autoimmunity, and hemochromatosis, damage from medication or chemicals are the other most common causes and types of liver disease [2, 3]. The liver has more than 5,000 separate bodily functions, including the synthesis of coagulation factor proteins to control bleeding within a damaged blood vessel and the production of blood coagulation inhibitors to prevent blood clots in normal circulation. Furthermore, the liver is involved in the reticuloendothelial system, which plays an important role in the clearance of active coagulation products. Liver disease affects both primary and secondary hemostasis by impairing the synthesis of all blood coagulation factors, activators, and inhibitors; which are essential to the blood coagulation pathway and fibrinolytic systems [4]. Consequently, patients with liver disease will suffer from the consequences of prolonged coagulation time, decreased clearance of activated factors, low platelet count, hyperfibrinolysis, and accelerated intravascular coagulation [5].
The PT and the APTT are both affected by cirrhosis because in liver disease there is reduced production of clotting factors and anticoagulants that are dependent on and independent of vitamin K [6]. The laboratory values of several coagulation tests are used to manage the bleeding problem in liver disease patients [7]. Up to 60% of chronic and active liver disease patients have prolonged PT, an independent predictor of poor survival in individuals with advanced cirrhosis [8]. In patients with cirrhosis, considerable amounts of fresh frozen plasma are necessary to enhance clotting factor levels [9]. Additionally, for patients with cirrhosis and abnormal coagulation screening tests, supplementation of vitamin K also corrects abnormal coagulation results [10].
Hemorrhagic complications due to liver disease patients are a major consequence and significant reason for intensive care unit admission, which varies from 15 to 61%, with 17–20% of cirrhotic patients experiencing a new commencement of substantial bleeding [11]. Around one‐third of patients with acute liver failure died from bleeding consequences [12]. Liver disease primarily causes upper gastrointestinal bleeding, portal hypertension caused by coagulation defects results in death in up to 2–6.7% of cases. Acute upper gastrointestinal bleeding is still a major cause of death in liver disease, accounting for up to 48% of cases [13]. Despite its consequences, there is a scarcity of information on the magnitude and associated factors of coagulation abnormalities among liver disease patients in the study area. Therefore, the current study aimed to assess the magnitude and associated factors of coagulation abnormalities among liver disease patients.
Methods and materials
Study design, area, and period
A hospital-based cross-sectional study was conducted from August to October 2022 at the University of Gondar Comprehensive Specialized Hospital (UoG-CSH). The hospital is located in Gondar town. Gondar is found at a distance of 727 km from Addis Ababa, the capital city of Ethiopia, in the northwest direction, and at a distance of 175 km from Bahir Dar, the capital city of the Amhara National Regional State. According to the 2015 report of the central statistical agency of Ethiopia, Gondar has a population of 323,900 [14]. The town has one public comprehensive specialized hospital, which is one of the oldest teaching hospitals in the country and provides health services for more than 7 million people in Gondar town and surrounding catchment areas [15].
Operational definitions
Habit of drinking tea or coffee
Habitual tea/coffee drinkers are defined by tea/coffee consumption of 120 mL/day or more for at least 1 year [16].
Physical exercise
Participant who performs the daily active exercise for about 30 min a day [17, 18].
Habit of feeding vegetables
It is a consistent action to integrate a variety of vegetables into one's diet or meal plan [19].
Habit of feeding meat
It is the consumption of animal-derived proteins such as beef, poultry, pork, fish, or other meats as a primary source of nutrition in one's daily diet [20].
Population, variables, and sampling techniques
Liver disease patients who were attending the UoG-CSH during the data collection period and who fulfilled the inclusion criteria were considered as a study population. Although the coagulation parameters (PT and APTT) were taken as dependent variables, the socio-demographic variables (age, gender, marital status, educational level, and residence), clinical variables (comorbidity, nutritional characteristics, blood transfusion history, smoking, habit of alcohol consumption, types of liver disease, and habit of physical exercise), and behavioural related variables (smoking, habit of alcohol consumption, and habit of physical exercise) were taken as independent variables. A total of 307 consecutively selected liver disease patients were included in this study. Study participants with a history of hereditary coagulation disease, critically ill patients, pregnant women, patients who took oral contraceptives, and patients who took drugs such as aspirin, heparin, and warfarin were excluded from the study.
Data collection methods and data quality management
The socio-demographic, lifestyle, and nutritional data were collected using a pretested structured questionnaire through a face-to-face interview, and the clinical data were collected using a data extraction sheet from the patient’s medical charts. Coagulation tests were carried out by a Genrui CA51 coagulation analyzer. To maintain the quality of the data, quality control testing was performed for each procedure. Furthermore, standard operating procedures were strictly followed. Training was given to all data collectors prior to the actual data collection. During the data collection period, there was close supervision by the investigators.
Statistical analysis
Epidata version 3.1 software was used to enter, code, clean, and sort data. The data were then exported to STATA version 14.0 software for analysis. Frequencies, proportions, and summary statistics were used to summarize the data. Pearson rank chi-square assumption fulfillment was checked for categorical variables. Bivariable and multivariable logistic regression were used to determine factors associated with coagulation abnormalities. The Hosmer–Lemeshow goodness of fit test with a p-value greater than 0.5 was used to validate the model fitness assumption. Finally, the odds ratio with a 95% confidence interval was used to express the strength of the association. Variables with a p-value < 0.05 from the multivariable analysis were considered to have a significant association with the outcome.
Results
Socio-demographic and clinical characteristics of study participants
In this study, a total of 307 study participants were included. Of them, 220 (71.66%), 213 (69.38%), 181 (59.28%), and 143 (46.58%) were males, from rural residences, married, and unable to read and write, respectively. Besides, the mean age of the study participants was 38.38 ± 15.13 years, ranging from 6 to 82 years (Table 1).
Table 1.
Socio demographic of Liver disease patients at UoG-CSH, Northwest Ethiopia, 2022. (n = 307)
| Variable | Category | Frequency | Percent (%) |
|---|---|---|---|
| Sex | Male | 220 | 71.66 |
| Female | 87 | 28.34 | |
| Age | < 18 (children) | 28 | 9.12 |
| 18–45 (young adult) | 188 | 61.24 | |
| > 45 (old adult) | 91 | 29.64 | |
| Residence | Rural | 213 | 69.38 |
| Urban | 94 | 30.62 | |
| Educational level | Unable to read and write | 143 | 46.58 |
| Primary school | 119 | 38.76 | |
| Secondary school | 26 | 8.47 | |
| College &University | 19 | 6.19 | |
| Marital status | Married | 223 | 72.67 |
| Unmarried | 84 | 27.36 | |
| Occupation | Farmer | 177 | 57.65 |
| Housewife | 33 | 10.75 | |
| Merchant | 23 | 7.49 | |
| Government employee | 21 | 6.84 | |
| Private employee | 19 | 6.19 | |
| Other | 34 | 11.70 | |
| Religion | Orthodox | 284 | 92.51 |
| Muslim | 17 | 5.54 | |
| Protestant | 6 | 1.95 |
From a total of study participants, 157 (51.14%), 37 (12.05%), 87 (28.34%), and 26 (8.47%) of study participants had chronic liver disease (CLD), acute liver disease, viral hepatitis, and ALD, respectively. Among viral hepatitis study participants, about 62/87 (71.26%) and 25/87 (28.74%) had HBV and HCV, respectively. On the other hand, about 86 (28.01%) of the study participants had taken medication rather than liver disease drugs. About 51 (16.61%), 39 (12.70%), and 33 (10.75%) were anemic, had a history of blood transfusions, and had heart disease, respectively (Table 2).
Table 2.
Clinical characteristics of liver disease patients at UoG-CSH Northwest, Ethiopia, 2022 (n = 307)
| Variable | Category | Frequency | Percent (%) |
|---|---|---|---|
| Use of medication other than liver disease | Yes | 86 | 28.01 |
| No | 221 | 71.99 | |
| History of anemia | Yes | 51 | 16.61 |
| No | 256 | 83.61 | |
| History of tuberculosis | Yes | 12 | 3.90 |
| No | 295 | 96.10 | |
| Presence of DM | Yes | 13 | 4.20 |
| No | 294 | 95.80 | |
| Presence of cardiac disease | Yes | 31 | 10.10 |
| No | 276 | 89.90 | |
| History of blood transfusion | Yes | 39 | 12.70 |
| No | 268 | 87.30 | |
| History of surgery | Yes | 10 | 3.30 |
| No | 297 | 96.70 | |
| Presence of cancer | Yes | 8 | 2.60 |
| No | 299 | 97.40 | |
| Presence of hypertension | Yes | 21 | 6.80 |
| No | 286 | 93.2 | |
| Presence of HIV/AIDS | Yes | 6 | 2.0 |
| No | 301 | 98.0 | |
| Types of liver disease | Acute liver disease | 37 | 12.05 |
| CLD | 157 | 51.14 | |
| ALD | 26 | 8.47 | |
| Viral hepatitis | 87 | 28.34 | |
| Presence of viral hepatitis | Yes | 87 | 28.34 |
| No | 220 | 71.66 |
Abbreviations: ALD Alcoholic Liver Disease, CLD Chronic Liver Disease, HIV Human Immunodeficiency Virus, DM Diabetes Miletus
Nutritional and life style characteristics of study participants
About 269 (87.91%), 287 (93.49%), and 237 (77.1%) of the study participants had a habit of drinking tea/coffee, habit of feeding meat, and habit of vegetable, respectively. However, most of the study participants 262 (85.34%) had no habit of physical exercise, and about 11 (3.58%) had a smoking habit (Table 3).
Table 3.
Lifestyle characteristics of liver disease patients at UoG-CSH Northwest, Ethiopia, 2022 (n = 307)
| Variable | Category | Frequency | Percent (%) |
|---|---|---|---|
| Tea or coffee drinking habit | Yes | 270 | 88.24 |
| No | 37 | 11.76 | |
| Meat feeding habit | Yes | 284 | 92.51 |
| No | 23 | 7.49 | |
| Vegetable feeding habit | Yes | 237 | 7.2 |
| No | 70 | 22.8 | |
| Alcohol drinking habit | Yes | 205 | 66.8 |
| No | 102 | 33.2 | |
| Cigarette smoking habit | Yes | 11 | 3.58 |
| No | 296 | 96.42 | |
| Physical exercise habit | Yes | 45 | 14.66 |
| No | 262 | 85.34 |
Magnitude of coagulation abnormalities
From the total study participants, 209 (68.08%, 95% CI: 62.8%, 73.3%) had a prolonged PT. On the other hand, 195 (63.51%; 95% CI: 58.1%, 68.9%) of the study participants had abnormal APTT. From the abnormal APTT, 184 (94.4%) patients had prolonged APTTs, and 11 (5.6%) had shorter APTTs. Furthermore, 161 (52.44%) study participants had both prolonged PT and abnormal APTT (Table 4, Fig. 1).
Table 4.
Coagulation abnormalities tabulated with PT and APTT among liver diseased study participants at the UoG-CSH, Northwest Ethiopia, 2022 (n = 307)
| Variable | Category | Prolonged PT | APTT | ||
|---|---|---|---|---|---|
| Yes | No | Abnormal | Normal | ||
| Sex | Male | 146 | 74 | 138 | 82 |
| Female | 63 | 24 | 57 | 30 | |
| Age | < 18 (children) | 14 | 14 | 12 | 16 |
| 18–45 (young adult) | 131 | 57 | 120 | 68 | |
| > 45 (old adult) | 64 | 27 | 63 | 28 | |
| Residence | Urban | 62 | 32 | 59 | 35 |
| Rural | 147 | 66 | 136 | 77 | |
| Occupation | Farmer | 127 | 50 | 115 | 62 |
| Housewife | 23 | 10 | 22 | 11 | |
| Merchant | 11 | 12 | 17 | 6 | |
| Government employee | 13 | 8 | 10 | 11 | |
| Private employee | 14 | 5 | 12 | 7 | |
| Other | 21 | 13 | 19 | 15 | |
| Educational level | No education | 101 | 44 | 93 | 50 |
| Primary school | 76 | 42 | 76 | 43 | |
| High school | 20 | 6 | 16 | 10 | |
| University & College | 12 | 6 | 10 | 9 | |
| Marital status | Married | 119 | 62 | 115 | 66 |
| Unmarried | 90 | 36 | 80 | 46 | |
| Use of medication other than liver disease | Yes | 58 | 28 | 57 | 29 |
| No | 151 | 70 | 138 | 83 | |
| History of anemia | Yes | 43 | 8 | 42 | 9 |
| No | 166 | 90 | 153 | 102 | |
| History of tuberculosis | Yes | 8 | 4 | 8 | 4 |
| No | 201 | 94 | 187 | 108 | |
| Presence of DM | Yes | 8 | 5 | 8 | 5 |
| No | 201 | 94 | 187 | 107 | |
| Presence of cardiac disease | Yes | 25 | 6 | 23 | 8 |
| No | 184 | 92 | 172 | 104 | |
| History of blood transfusion | Yes | 17 | 22 | 18 | 21 |
| No | 192 | 76 | 177 | 91 | |
| Have a history of surgery | Yes | 7 | 3 | 7 | 3 |
| No | 202 | 95 | 188 | 109 | |
| Presence of cancer | Yes | 6 | 2 | 4 | 4 |
| No | 203 | 96 | 371 | 108 | |
| Presence of hypertension | Yes | 15 | 6 | 12 | 9 |
| No | 194 | 92 | 183 | 103 | |
| Presence of HIV disease | Yes | 4 | 2 | 4 | 2 |
| No | 205 | 96 | 202 | 110 | |
| Consumption of tea or coffee | Yes | 183 | 87 | 171 | 99 |
| No | 26 | 11 | 24 | 13 | |
| Meat feeding habit | Yes | 192 | 92 | 179 | 105 |
| No | 17 | 6 | 16 | 7 | |
| Vegetable feeding habit | Yes | 151 | 86 | 140 | 97 |
| No | 58 | 12 | 55 | 15 | |
| Alcohol drinking habit | Yes | 139 | 66 | 126 | 79 |
| No | 70 | 32 | 69 | 33 | |
| Cigarette smoking habit | Yes | 7 | 4 | 6 | 5 |
| No | 202 | 94 | 189 | 107 | |
| Physical exercise habit | Yes | 22 | 23 | 22 | 23 |
| No | 187 | 75 | 173 | 89 | |
| Types of liver disease | Acute liver disease | 17 | 20 | 21 | 16 |
| CLD | 108 | 49 | 92 | 65 | |
| ALD | 20 | 6 | 19 | 7 | |
| Viral hepatitis | 64 | 23 | 63 | 24 | |
| Presence of virus hepatitis (HBV and HCV) | Yes | 53 | 34 | 50 | 37 |
| No | 156 | 64 | 145 | 75 | |
Abbreviations: ALD Alcoholic Liver Disease, CLD Chronic Liver Disease, HIV Human Immunodeficiency Virus, DM Diabetes Miletus, Other includes student and no jobs
Fig. 1.
Magnitude of coagulation abnormalities among liver disease patients at the UoG-CSH, Northwest Ethiopia, 2022 (n = 307)
Factors associated with coagulation abnormalities
Bivariable and multivariable logistic regressions were performed to determine the association between PT abnormality and independent variables. Bivariable and multivariable logistic regressions were done for variables that fulfilled the chi-square assumption. The presence of anemia, physical exercise, a history of blood transfusion, the type of liver disease, the habit of feeding vegetables, and the frequency of feeding vegetables were associated with prolonged PT in bivariable analysis. Variables with a p-value of less than 0.25 in the bivariable analysis were selected for multivariable logistic regression. After multivariable logistic regression analysis, the history of anaemia (AOR = 2.97; 95% CI: 1.26, 7.03), the absence of a history of blood transfusion (AOR = 3.72; 95% CI: 1.78, 7.78), the absence of a vegetable feeding habit (AOR = 2.98; 95% CI: 1.42, 6.24), and the lack of physical exercise (AOR = 3.23; 95% CI: 1.60, 6.52) are significantly associated with prolonged PT (Table 5).
Table 5.
Bivariable and multivariable logistic regression of PT among liver disease patients attending at the UoG-CSH, Northwest, Ethiopia, 2022 (n = 307)
| Variables | Category | PT | Bivariable analysis | Multivariable | ||
|---|---|---|---|---|---|---|
| Prolonged PT (%) | Normal PT (%) | COR (95%CI) | P-value | AOR (95%CI) | ||
| Sex | Male | 146 (66.36) | 74 (33.64) | 0.75 (0.43, 1.29) | .306 | - |
| Female | 63 (72.41) | 24 (27.59) | 1 | |||
| Age | < 18 (children) | 14(50.00) | 14(50.00) | 1 | 1 | |
| 18–45 (young adult) | 131 (69.68) | 57(30.32) | 2.29(1.02, 5.13) | 0.042 | 1.09(0.35, 3.38) | |
| > 45 (old adult) | 64 (70.33) | 27(29.67) | 2.37(0.99, 5.63) | 0.051 | 0.85(0.25, 2.84) | |
| Residence | Rural | 147(69.01) | 66(30.99) | 1.15(0.68, 1.92) | 0.597 | - |
| Urban | 62(65.96) | 32(34.04) | 1 | |||
| Occupation of study participants | Farmer | 127(71.75) | 50(28.25) | 1.56(0.61, 3.99) | 0.351 | - |
| Housewife | 23(69.70) | 10(30.30) | 1.41(0.44, 4.47) | 0.554 | ||
| Merchant | 11(47.83) | 12(52.17) | 0.56(0.16, 1.87) | 0.351 | ||
| Private employee | 14(73.68) | 5(26.32) | 1.72(0.44, 6.63) | 0.429 | ||
| Other | 21(61.76) | 13(38.24) | 0.99(0.32, 3.04) | 0.992 | ||
| Government employee | 13(61.90) | 8(38.10) | 1 | |||
| Educational level | No education | 101(69.23) | 44(30.77) | 1.03(0.37, 2.91) | 0.943 | - |
| Primary school | 76(64.71) | 42(35.29) | 0.84(0.29, 2.38) | 0.752 | ||
| High school | 20(76.92) | 6(23.08) | 1.53(0.40, 5.81) | 0.525 | ||
| University & college | 12(68.42) | 6(31.58) | 1 | |||
| Marital status | Unmarried | 90(71.43) | 36(28.57) | 1.30(0.79, 2.13) | 0.294 | - |
| Married | 119(65.75) | 62(34.25) | 1 | |||
| Use of medication other than liver disease | Yes | 58(67.44) | 28(32.56) | 0.96(0.56, 1.63) | 0.881 | - |
| No | 151(68.33) | 70(31.67) | 1 | |||
| History of anemia | Yes | 43(84.31) | 8(15.69) | 2.91(1.31, 6.46) | 0.009 | 2.97(1.26, 7.03) |
| No | 166(64.84) | 90(35.16) | 1 | 1 | ||
| Presence of DM | Yes | 9(69.23) | 4(30.77) | 1.05(0.31, 3.52) | 0.927 | - |
| No | 200(68.03) | 94(31.97) | 1 | |||
| Presence of cardiac disease | Yes | 25(80.65) | 6(19.35) | 2.08(0.82, 5.25) | 0.120 | 1.87(0.68, 5.15) |
| No | 184(66.67) | 92(33.33) | 1 | 1 | ||
| History of blood transfusion | No | 192(71.64) | 76(28.36) | 3.26(1.64, 6.49) | 0.003 | 3.72(1.78, 7.78) |
| Yes | 17(43.59) | 22(56.41) | 1 | 1 | ||
| Presence of hypertension | Yes | 15(71.43) | 6(28.57) | 1.18(0.44, 3.15) | 0.733 | - |
| No | 194(67.83) | 92(32.17) | 1 | |||
| Tea or coffee drinking habit | No | 26(70.27) | 11(29.73) | 0.97(0.46, 2.04) | 0.955 | - |
| Yes | 183(67.78) | 87(32.22) | 1 | |||
| Meat feeding habit | Yes | 192(67.61) | 92(32.39) | 0.73(0.28, 1.93) | 0.534 | - |
| No | 17(73.91) | 6(26.09) | 1 | |||
| Vegetable feeding habit | No | 58(82.86) | 12(17.14) | 2.75(1.40, 5.40) | 0.003 | 2.98(1.42, 6.24) |
| Yes | 151(63.71) | 86(36.29) | 1 | 1 | ||
| Alcohol drinking habit | Yes | 139(67.80) | 66(32.20) | 0.96(0.57, 1.60) | 0.884 | - |
| No | 70(68.63) | 32(31.37) | 1 | |||
| Cigarette smoking habit | Yes | 7(63.64) | 4(36.36) | 0.81(0.23, 2.84) | 0.748 | - |
| No | 202(68.24) | 94(31.76) | 1 | |||
| Physical exercise habit | No | 187(71.37) | 75(28.63) | 2.60(1.37, 4.95) | 0.003 | 3.23(1.60, 6.52) |
| Yes | 22(48.89) | 23(51.11) | 1 | 1 | ||
| Types of liver disease | CLD | 108(68.79) | 49(31.21) | 2.59(1.25, 5.37) | 0.010 | 3.01(1.10, 8.21) |
| ALD | 20(76.92) | 6(23.08) | 3.92(1.28, 11.99) | 0.017 | 4.97(1.27, 17.41) | |
| Viral hepatitis | 64(73.56) | 23(26.44) | 3.27(1.46, 7.30) | 0.004 | 3.56(1.19, 10.63) | |
| Acute liver disease | 17(45.95) | 20(54.05) | 1 | 1 | ||
| Presence of virus hepatitis (HBV and HCV) | Yes | 53(60.92) | 34(39.08) | 0.63(0.38, 1.07) | 0.092 | 0.74(0.42, 1.33) |
| No | 156(70.91) | 64(29.09) | 1 | 1 | ||
Abbreviation: * = Significant Variable, ALD Alcoholic Liver Disease, APTT Activated Partial Thromboplastin Time, CLD Chronic Liver Disease, DMDiabetes millets, AOR, Adjusted odds ratio, CORCrude Odd Ratio, CI Confidence Interval, 1 reference group other includes student and have no jobs
To determine the association between APTT abnormality and independent variables, both bi-variable and multi-variable binary logistic regression were done. The analysis includes independent variables that satisfy the chi square assumption. The presence of anemia, physical exercise, a history of blood transfusion, a type of liver disease, the feeding habits of vegetables, and age group were associated with APTT abnormalities in bivariable analysis. Variables with a p-value of less than 0.25 in the bivariable analysis were selected for multivariable logistic regression. After multivariable logistic regression analysis, young adult (18–45) (AOR = 5.22; 95%CI: 1.26, 21.63), old adult (> 45) (AOR = 5.49; 95%CI: 1.21, 24.82), presence of anemia (AOR = 3.02; 95% CI: 1.34, 6.76), lack of blood transfusion history (AOR = 2.28; 95%CI: 1.09, 4.79), lack of vegetable feeding habit (AOR = 2.64; 95%CI: 1.34, 5.20), and not doing physical exercise (AOR = 2.35; 95%CI: 1.16, 4.78) remained significantly associated with APTT abnormality ( \* MERGEFORMAT Table 6).
Table 6.
Bivariable and multivariable logistic regression of abnormal APTT among liver disease patients attending at the UoG-CSH, Northwest, Ethiopia, 2022 (n = 307)
| Variable | Category | APTT | Bivariable analysis | Multivariable analysis | ||
|---|---|---|---|---|---|---|
| Abnormal (%) | Normal (%) | P-value | COR (95%CI) | AOR (95%CI) | ||
| Sex | Male | 138(62.73) | 82(37.27) | 0.567 | 0.85 (0.50, 1.44) | - |
| Female | 57(65.52) | 30(34.48) | 1 | |||
| Age | < 18 (children) | 12(42.86) | 16(57.14) | 1 | 1 | |
| 18–45 (young adult) | 120(63.83) | 68(36.17) | 0.037 | 2.35(1.05, 5.2) | 5.22(1.26, 21.63) | |
| > 45 (old adult) | 63(69.23) | 28(30.77) | 0.013 | 3 (1.25, 7.16) | 5.49(1.21, 24.82) | |
| Residence | Rural | 136(63.85) | 77(36.15) | 0.856 | 1.03(0.62, 1.72) | - |
| Urban | 59(62.77) | 35(37.23) | 1 | |||
| Occupation | Farmer | 115(64.97) | 62(35.03) | 0.125 | 2.04(0.82, 5.07) | 1.84(0.66, 5.12) |
| Housewife | 22(66.67) | 11(33.33) | 0.168 | 2.20(0.71, 6.75) | 1.59(0.46, 5.50) | |
| Merchant | 17(73.91) | 6(26.09) | 0.078 | 3.11(0.87, 11.03) | 3.61(0.94, 13.92) | |
| Private employee | 12(63.16) | 7(36.84) | 0.326 | 1.88(0.53, 6.68) | 1.63(0.41, 6.41) | |
| Other | 19(55.88) | 15(44.12) | 0.551 | 1.39(0.46, 4.15) | 3.21(0.74, 13.77) | |
| Government employee | 10(47.62) | 11(52.38) | 1 | 1 | ||
| Educational level | No education | 93(65.03) | 50(34.97) | 0.295 | 1.67(0.63, 4.38) | - |
| Primary school | 76(63.87) | 43(36.13) | 0.351 | 1.59(0.59, 4.21) | ||
| High school | 16(61.54) | 10(38.46) | 0.551 | 1.44(0.43, 4.77) | ||
| University& College | 10(52.63) | 9(47.37) | 1 | |||
| Marital status | Unmarried | 80(63.49) | 46(36.51) | 0.994 | 0.99(0.62, 1.60) | - |
| Married | 115(63.54) | 66(36.46) | 1 | |||
| Use of medication other than liver disease | Yes | 57(66.28) | 29(33.72) | 0.531 | 1.18(0.70,1.99) | |
| No | 138(62.44) | 83(37.56) | 1 | |||
| History of anemia | Yes | 42(82.35) | 9(17.65) | 0.003 | 3.14(1.46, 6.73) | 3.02(1.34, 6.76) |
| No | 153(59.77) | 102(40.23) | 1 | 1 | ||
| Presence of DM | Yes | 8(61.54) | 5(38.46) | 0.880 | 0.91(0.29, 2.86) | - |
| No | 187(63.61) | 107()36.39 | 1 | |||
| Presence of heart disease | Yes | 23(74.19) | 8(25.81) | 0.197 | 1.73(0.75, 4.02) | 1.48(0.61, 3.62) |
| No | 172(62.32) | 104(37.68) | 1 | 1 | ||
| History of blood transfusion | No | 177(66.04) | 91(33.96) | 0.018 | 2.26(1.15, 4.47) | 2.28(1.09, 4.79) |
| Yes | 18(46.15) | 21(53.85) | 1 | 1 | ||
| Presence of hypertension | Yes | 12(57.14) | 9(42.86) | 0.531 | 0.75(0.30, 1.84) | - |
| No | 183(63.99) | 103(36.01) | 1 | |||
| Tea or coffee drinking habit | No | 24(64.86) | 13(35.14) | 0.878 | 1.05(0.15, 2.17) | - |
| Yes | 171(63.33) | 99(36.67) | 1 | |||
| Meat feeding habit | Yes | 179(63.03) | 105(36.97) | 0.532 | 0.74(0.29, 1.87) | - |
| No | 16(69.57) | 7(30.43) | 1 | |||
| Vegetable feeding habit | No | 55(78.57) | 15(21.43) | 0.004 | 2.54(1.35, 4.75) | 2.64(1.34, 5.20) |
| Yes | 140(59.07) | 97(40.93) | 1 | 1 | ||
| Alcohol drinking habit | Yes | 126(61.46) | 79(38.54) | 0.289 | 0.76(0.46, 1.25) | - |
| No | 69(67.65) | 33(32.35) | 1 | |||
| Cigarette smoking habit | Yes | 6(54.55) | 5(45.45) | 0.531 | 0.67(0.20, 2.27) | - |
| No | 189(63.85) | 107(36.15) | 1 | |||
| Physical exercise habit | No | 173(66.03) | 89(33.97) | 0.029 | 2.03(1.07, 3.84) | 2.35(1.16, 4.78) |
| Yes | 22(48.89) | 23(51.11) | 1 | 1 | ||
| Type of liver disease | CLD | 92(58.60) | 65(41.40) | 0.838 | 1.07(0.52, 2.22) | 0.53(0.18, 1.53) |
| ALD | 19(73.08) | 7(26.92) | 0.189 | 2.06(0.69, 6.11) | 1.17(0.28, 4.81) | |
| Viral hepatitis | 63(72.41) | 24(27.59) | 0.090 | 2(0.89, 4.46) | 0.94(0.30, 2.95) | |
| Acute liver disease | 21(56.76) | 16(43.24) | 1 | 1 | ||
| Presence of virus hepatitis (HBV and HCV) | Yes | 50(57.47) | 37(42.53) | 0.167 | 0.69(0.42, 1.16) | 0.88(0.50, 1.55) |
| No | 145(65.91) | 75(34.09) | 1 | 1 | ||
Abbreviation: * = Significant Variable, ALD Alcoholic Liver Disease, APTT Activated Partial Thromboplastin Time, CLD Chronic Liver Disease DM Diabetes millets, AOR Adjusted odds ratio, COR Crude Odd Ratio, CI Confidence Interval, 1 the reference group, other Includes student and have no jobs
Discussion
Liver disease is a global public health problem that results in mortality and morbidity. It is one of the main causes of coagulopathy both in developed and developing countries [21]. Thus, the magnitude and associated factors of coagulation abnormalities in liver disease patients attending UoG-CSH were investigated in this study.
The findings of this study showed that the overall prevalence of prolonged PT and abnormal APTT test results was 68.08% (95% CI: 62.8%, 73.3%) and 63.51% (95% CI: 58.1%, 68.9%), respectively. This value represents a high public health problem for patients with liver disease. The magnitude of abnormal PT and APTT in this study is significant. This high result is due to liver disease, which reduces the production of clotting factors, particularly vitamin K-dependent factors. Hence, patients with liver disease experience a range of hemostatic problems, including reduced production of clotting factors and coagulation inhibitor proteins [5, 6]. In contrast, the shorter APTT finding might be associated with inflammation, which may initiate clotting and decrease the activity of natural anticoagulant mechanisms. Additionally, inflammatory cytokines are also the major mediators involved in coagulation activation [22]. The prolonged PT in this study was consistent with a study reported by Bohania N et al. 68.33% [23], and Yatish PA et al. 63% [24]. In contrast, the finding of this study was lower than a study by Chetali Rupela et al. 86.6% [25], Parashat Patel et al. 85% [26], and Siddiqui SA et al. 88% [27]. The differences could be due to the variety of the study population or the way the tests were done. However, it is higher than that of Garg RP et al. 4.90% [28], Shobhaha P et al. 42.22% [29], Bhatia G et al. 62% [30]. The possible reason for the high coagulation abnormality in this study may be associated with the presence of other comorbidities in this study; mainly, 16.61% were anaemic and 10.75% had cardiac disease; additionally, 86 (28.01%) patients had treatment other than liver disease drugs.
The magnitude of abnormal APTT in this study was 63.51% (95% CI: 58.1%, 68.9%); it was in line with a study conducted by Bohania et al., which found a 61.67% prevalence of abnormal APTT [23]. In contrast, the magnitude of the abnormal APTT was lower than that of Chetali R. et al. (82.2%) [25], Siddiqui SA et al. (71%) [27]. The differences could be in the study population or the way the tests were done, but this study finding was higher than a study reported by Shobhaha. P et al. (26.66%) [29], Bhatia G et al. (39.3%) [30], Yatish PA et al. (56%) [24], Parashat P. et al., (52%) [26]. The possible reason may be associated with the presence of other comorbidities; mainly, 51 (16.61%) patients were anaemic and 33 (10.75%) had heart disease; additionally, 86 (28.01%) patients had treatment other than liver disease drugs. Additionally, possible reasons for the difference might be associated with differences in the study population, geographical variability, or the way the test was done.
Anemia was statistically associated with prolonged PT and abnormal APTT. In the current study, study participants has history of anaemia were 2.97 times (95% CI: 1.26, 7.03) more likely to have prolonged PT and 3.02 times (95% CI: 1.34, 6.76) more likely to have APTT abnormalities when compared with those without anemia. This is due to an anaemic patients' delayed response in the initiation of the coagulation cascade [31].
Types of liver disease were statistically associated with prolonged PT. Study participants with CLD had a 3.01-fold (95% CI: 1.10, 8.21) higher likelihood of being associated with prolonged PT; study participants with ALD had a 4.97-fold (95% CI: 1.27, 17.41) higher likelihood of being associated with prolonged PT; and study participants with viral hepatitis had a 3.56-fold (95% CI: 1.19, 10.63) higher likelihood of being associated with prolonged PT when compared to acute liver disease. Scientific explanations suggest that the liver plays a central role in the clotting process and is invariably associated with coagulation disorders due to decreased synthesis of clotting and inhibitory factors. Additionally, liver disease causes decreased synthesis of clotting factors, mainly vitamin K-dependent factors [6].
In this study, the young adult age (18–45) class has a 5.22-fold (95% CI: 1.26, 21.63) higher likelihood of being associated with abnormal APTT, whereas study participants in the old adult (> 45) age class have a 5.49-fold (95% CI: 1.21, 24.82) higher likelihood of being associated with abnormal APTT when compared with children (< 18). According to research, as one gets older, the liver's proliferative and metabolic functions may decline [32]. Since the regenerative capacity of the liver correlates with liver function [33].
Physical exercise was statistically associated with coagulation abnormalities. Study participants who did not do physical exercise had 3.23 times (95% CI: 1.60, 6.52) more likely associations with prolonged PT and 2.35 times (95% CI: 1.16, 4.78) more likely associations with APTT abnormalities when compared with those who did. This is due to the fact that physical exercise enhances the activation of both the coagulation and fibrinolytic cascades and increases the activity of several components of the coagulation cascades [34]. Additionally, it is suggested that short-term exercise activates blood coagulation, enhances blood fibrinolysis, and maintains the delicate balance between clot formation and clot dissolution [35].
The history of blood transfusion has been statistically associated with coagulation abnormalities. A study participant without a history of blood transfusion has a 3.72-fold (95% CI: 1.78, 7.78) more likely association with prolonged PT and a 2.28-fold (95% CI: 1.09, 4.79) more likely association with an APTT abnormality when compared with a participant with a history of blood transfusion. A scientific explanation suggests blood transfusions reintroduce blood clotting elements into the patient's blood. Additionally, whole blood contains approximately 150 mL of plasma, which provides the patient with non-labile clotting factors [36].
Vegetable feeding habits were statistically associated with coagulation abnormalities. Study participants with a lack of vegetable feeding habits had 2.98 times (95% CI: 1.42, 6.24) more likely associated with prolonged PT and 2.64 times (95% CI: 1.34, 5.20) more likely associated with APTT abnormality when compared with study participants who have a vegetable feeding habit. Scientific suggestions are that vitamin K and dependent coagulation factors such as FII, FVII, FIX, and FX are essential for regulating blood coagulation and comprise the coagulation factors. Vitamin K is found in the diet in two bioactive forms: phylloquinone (vitamin K1) and menaquinones (vitamin K2), both of which are abundant in leafy green vegetables [37, 38].
Strength and limitation of the study
This study has its strengths and limitations. The strength of this study is that it is the first study on the determination of the magnitude and associated factors of coagulation abnormalities in liver disease patients in Ethiopia. However, the limitation of this study was that we could not perform parasitic infection screening, which may interfere with the finding of the study.
Conclusion on recommendation
Coagulation abnormalities in liver disease were identified as a major public health issue. About half of liver disease patients had coagulation abnormalities (prolonged PT and abnormal APTT). Prolonged PT was associated with the presence of anemia, an absence of transfusion history, a habit of physical exercise, types of liver disease, and vegetable feeding habits. Abnormal APTT was associated with the presence of anemia, the absence of transfusion history, a habit of physical exercise, increased age, and vegetable feeding habits. Based on the high prevalence of coagulation abnormalities in patients with liver disease, it is recommended that healthcare providers should regularly monitor and assess coagulation function in these patients. This can help identify any potential bleeding and allow for timely intervention to prevent complications.
Acknowledgements
We would like to thank the Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, and the University of Gondar. We also wish to extend our sincere thanks and gratitude to the University of Gondar Hospital for their willingness and efforts during this data collection. Finally, many thanks are given to all study participants for their willingness to participate and for providing the necessary information during the data collection.
Abbreviations
- ALD
Alcoholic Liver Disease
- APTT
Activated Partial Thromboplastin Time
- CLD
Chronic Liver Disease
- HBV
Hepatitis B virus
- HCV
Hepatitis C virus
- PT
Prothrombin Time
- UoG-CSH
University of Gondar Comprehensive Specialized Hospital
Authors’ contributions
All authors participated in the data collection, feeding, performing the statistical analysis, drafting the manuscript, and reading and editing the manuscript. All authors read and approved the final manuscript.
Funding
The authors did not receive any funding for this work.
Availability of data and materials
All the data supporting these findings are contained within the manuscript.
Declarations
Ethics approval and consent to participate
An ethical clearance was obtained from the Ethics Review Committee of the School of Biomedical and Laboratory Science, College of Medicine and Health Science, University of Gondar Research, with reference number SBMLS/384/2022. Then, a permission letter was secured from the UoG-CSH medical director. Before starting data collection, the data collectors were informed to ask permission, explain the purpose of the study and its importance and benefits, and offer to answer all the participants' questions to confirm their willingness. Then, written informed consent, or assent, was obtained. Participation in the study and refusals were possible. To ensure confidentiality of data, study participants were identified using codes, and unauthorised persons had no access to the data. All abnormal laboratory findings were linked to health professionals for proper management and treatment of patients.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Abateneh Melkamu, Email: abatenehmelkamu@gmail.com.
Berhanu Woldu, Email: britishwoldu25@gmail.com.
Chomaw Sitotaw, Email: chomaw2007sitotaw@gmail.com.
Masresha Seyoum, Email: masreshaseyoum0001@gmail.com.
Melak Aynalem, Email: melak.aynalem1234@gmail.com.
References
- 1.Krishnan S. Liver diseases-an overview. World J Pharm Pharmaceutical Sci. 2019;8:1385–1395. [Google Scholar]
- 2.Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic liver failure: part I. Am Fam Physician. 2006;74(5):756–762. [PubMed] [Google Scholar]
- 3.Rifai N. Tietz textbook of clinical chemistry and molecular diagnostics. 7 ed: Elsevier Health Sciences; 2017. 1637 p.
- 4.Monroe D, Hoffman M, Roberts H. Williams hematology. New York NY: McGraw-Hill Professional Publishing; 2010. p. 2191. [Google Scholar]
- 5.Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Coagulation disorders in liver disease. Semin Liver Dis. 2002;22(1):83–96. doi: 10.1055/s-2002-23205. [DOI] [PubMed] [Google Scholar]
- 6.Tripodi A. Hemostasis abnormalities in cirrhosis. Curr Opin Hematol. 2015;22(5):406–412. doi: 10.1097/MOH.0000000000000164. [DOI] [PubMed] [Google Scholar]
- 7.Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth. 2014;58(5):515–523. doi: 10.4103/0019-5049.144643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Peck-Radosavljevic M. Review article: coagulation disorders in chronic liver disease. Aliment Pharmacol Ther. 2007;26(Suppl 1):21–28. doi: 10.1111/j.1365-2036.2007.03509.x. [DOI] [PubMed] [Google Scholar]
- 9.Kujovich JL. Coagulopathy in liver disease: a balancing act. Hematology. 2015;2015(1):243–249. doi: 10.1182/asheducation-2015.1.243. [DOI] [PubMed] [Google Scholar]
- 10.Saja MFAA, Sanai FM, Shaikh SA, Gader AGT. The coagulopathy of liver disease: does vitamin K help? Blood Coagul Fibrinolysis. 2013;24(1):10–17. doi: 10.1097/MBC.0b013e32835975ed. [DOI] [PubMed] [Google Scholar]
- 11.Drolz A, Horvatits T, Roedl K, Rutter K, Staufer K, Kneidinger N, et al. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology. 2016;64(2):556–568. doi: 10.1002/hep.28628. [DOI] [PubMed] [Google Scholar]
- 12.Munoz SJ, Stravitz RT, Gabriel DA. Coagulopathy of acute liver failure. Clin Liver Dis. 2009;13(1):95–107. doi: 10.1016/j.cld.2008.10.001. [DOI] [PubMed] [Google Scholar]
- 13.Fondu P, Thijs O. Haemostatic failure in liver disease: Springer Science & Business Media; 2012. 192 p.
- 14.Atsede D. Tegegne MAN MKD, Kumela G. Nedessa, Hone M. Belaye https://mdl.donau-uni.ac.at/ses/pluginfile.php/314/mod_page/content/4/CITY%20PROFILE%20GONDAR.pdf. City profile Gondar ( 29 October 2022).
- 15.Woldekidan NA, Mohammed AS. Clinical Knowledge and Practice of “Ketofol” at University of Gondar Comprehensive Specialized Hospital. Frontiers in Medicine. 2021:1518. [DOI] [PMC free article] [PubMed]
- 16.Dong X-X, Wang R-R, Liu J-Y, Ma Q-H, Pan C-W. Habitual tea consumption and 5-year incident metabolic syndrome among older adults: a community-based cohort study. BMC Geriatr. 2021;21(1):728. doi: 10.1186/s12877-021-02707-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Diaz KM, Shimbo D. Physical activity and the prevention of hypertension. Curr Hypertens Rep. 2013;15(6):659–668. doi: 10.1007/s11906-013-0386-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Diaz KMSD. Physical activity and the prevention of hypertension. Curr Hypertens Rep. 2013;15(6):659–668. doi: 10.1007/s11906-013-0386-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Pem D, Jeewon R. Fruit and Vegetable Intake: Benefits and Progress of Nutrition Education Interventions- Narrative Review Article. Iran J Public Health. 2015;44(10):1309–1321. [PMC free article] [PubMed] [Google Scholar]
- 20.Lofgren PA. Meat, Poultry, and Meat Products: Nutritional Value. In: Caballero B, editor. Encyclopedia of Human Nutrition. 3. Waltham: Academic Press; 2013. pp. 160–167. [Google Scholar]
- 21.Mijač D, Krstić MN, Marković AP, Popović DD, Krstić JM, Milosavljević T. Abnormal Liver blood tests: Primary care approach. Dig Dis. 2022;40(2):215–222. doi: 10.1159/000517016. [DOI] [PubMed] [Google Scholar]
- 22.Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005;131(4):417–430. doi: 10.1111/j.1365-2141.2005.05753.x. [DOI] [PubMed] [Google Scholar]
- 23.Bohania N, Agrawal A, Prakash A, Nangia A, Kumar A. Coagulation Profile and its Correlation with Severity of Liver Dysfunction and Gastrointestinal Bleed in Alcoholic Liver Disease Patients. J Assoc Physicians India. 2021;69(6):11–12. [PubMed] [Google Scholar]
- 24.Yatish PA, Mudholkar Vishal G. The study of coagulation profile in patients of liver disease. Indian Journal of Pathology: Research and Practice. 2020;9(2 Part I).
- 25.Chetali Rupela BV, Hansa Goswami. Coagulation profile in liver disease. International Journal of Current Research and Review. 2020;12(11).
- 26.Patel P, Mangar U, Patel R. Comparative study of coagulation profile in liver disease in tertiary care hospital. Indian J Pathol Oncol. 2018;5(4):554–557. [Google Scholar]
- 27.Siddiqui SA, Ahmed M, Ghani MH, Memon MA, Mustafa G, Ghori MA. Coagulation abnormalities in patients with chronic liver disease in Pakistan. J Pak Med Assoc. 2011;61(4):363–367. [PubMed] [Google Scholar]
- 28.Garg RP, Agrawal A, Bhake AS, Vagha S. Correlation study of coagulation profile in spectrum of liver diseases. J Evol Med Dent Sci. 2020;9(8):549–555. doi: 10.14260/jemds/2020/123. [DOI] [Google Scholar]
- 29.Dr Shobhana Prajapati D, Manisha M Shah, Dr. Roopam K Gidwani, , Dr. Falguni Goswami DNVS, Dr. Ashok Prajapati and , Prajapati A. Coagulation profile in liver diseases: A study of 250 cases in a tertiary care hospital. international jounral of clinical and diagnostic pathology. 2020;3(3):185–8.
- 30.Bhatia G, Kaushik S, Kumar R, Kishore S, Bhatia U. Coagulation profile in liver diseases: a study of 300 cases in a tertiary care Hospital in Uttarakhand, India. Int J Adv Integr Med Sci. 2017;2:61–64. [Google Scholar]
- 31.Roeloffzen WW, Kluin-Nelemans HC, Bosman L, de Wolf JT. Effects of red blood cells on hemostasis. Transfusion. 2010;50(7):1536–1544. doi: 10.1111/j.1537-2995.2010.02586.x. [DOI] [PubMed] [Google Scholar]
- 32.Baiocchi L, Glaser S, Francis H, Kennedy L, Felli E, Alpini G, et al. Impact of Aging on Liver Cells and Liver Disease: Focus on the Biliary and Vascular Compartments. Hepatol Commun. 2021;5(7):1125–1137. doi: 10.1002/hep4.1725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Cieslak KP, Baur O, Verheij J, Bennink RJ, van Gulik TM. Liver function declines with increased age. HPB (Oxford) 2016;18(8):691–696. doi: 10.1016/j.hpb.2016.05.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Smith JE. Effects of strenuous exercise on haemostasis. Br J Sports Med. 2003;37(5):433. doi: 10.1136/bjsm.37.5.433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.El-Sayed MS. Effects of exercise on blood coagulation, fibrinolysis and platelet aggregation. Sports Med. 1996;22(5):282–298. doi: 10.2165/00007256-199622050-00002. [DOI] [PubMed] [Google Scholar]
- 36.Association for the advancement of blood biotherapies. Whole blood and red blood cell components 2022 [cited 2022 /28/10]. Available from: https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/regulatory-for-blood/whole-blood-and-red-blood-cell-components.
- 37.Booth SL. Vitamin K: food composition and dietary intakes. Food Nutr Res. 2012;56. [DOI] [PMC free article] [PubMed]
- 38.Hoffbrand AV, Higgs DR, Keeling DM, Mehta AB. Postgraduate haematology: John Wiley & Sons; 2016.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All the data supporting these findings are contained within the manuscript.