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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 228-236

Von willebrand factor level and activity in correlation with D-dimer level among COVID-19 patients in Saudi Arabia


1 Hematology Unit; Department of Internal Medicine, King Fahad Military Medical Complex, Dhahran, Saudi Arabia
2 Department of Medical Laboratory, King Fahad Military Medical Complex, Dhahran, Saudi Arabia
3 Department of Clinical Laboratory Sciences, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia
4 Pathology Department, King Fahd Hospital of the University; Imam Abdulrahman Bin Faisal University, AlKhobar, Saudi Arabia
5 Department of Internal Medicine, King Fahad Military Medical Complex, Dhahran, Saudi Arabia
6 Vice Deanship of Postgraduate Studies and Research, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia

Date of Submission09-Jan-2022
Date of Decision25-May-2022
Date of Acceptance13-Jun-2022
Date of Web Publication18-Oct-2022

Correspondence Address:
Dr. Rehab Yusuf Al-Ansari
Department of Internal Medicine, Adult Hematology Unit, King Fahad Military Medical Complex, Dhahran
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_2_22

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  Abstract 

BACKGROUND: Thrombosis and acute respiratory failure are among the leading causes of mortality in COVID-19 patients. The von Willebrand factor (VWF) is one of the main components in the blood coagulation system. It has been hypothesized that the increased VWF level results from vascular damage because VWF is stored in endothelial cells. Infection of endothelial cells with SARS-CoV-2 can stimulate the release of VWF. This study aimed to determine the level of VWF activity among the Saudi population affected by COVID-19 and investigate the correlation between VWF level and D-dimer level.
MATERIALS AND METHODS: This is an analytical, retrospective, observational study conducted in a single-center tertiary hospital at King Fahad Military Medical Complex (KFMMC). A study sample of 80 hospitalized patients (aged ≥18 years) diagnosed with COVID-19 confirmed by nasopharyngeal SARS-COV was randomly included in this study. Frozen blood samples were used to measure VWF antigen (Ag) level and activity for all patients. Historical data on hemostasis markers such as platelets (PLTS), fibrinogen, and D-dimer were obtained retrospectively, as well as demographic and clinical data.
RESULTS: Data of 80 patients were analyzed to assess VWF Ag level and activity in correlation to D-dimer level. The mean age of the patients was 58.3 (standard deviation 16.18), with nearly two-thirds being females (62.6%). The most common comorbidities were arterial hypertension (67.5%), diabetes (56.3%), and dyslipidemia (22.5%). Only 10% of patients were obese. The mean values of were 3.25 for D-dimer, 3.55 for fibrinogen, 226.4 for PLTS, 9.88 for white blood cell, 237.04 for VWF Ag, 253.21 for VWF activity, and 70.45 for C-reactive protein. Pearson's correlation coefficient revealed that the correlation between D-dimer and VWF Ag and D-dimer and VWF activity was statistically insignificant (P > 0.05). Only six patients had overt thrombosis, but this has no significant correlation with VWF Ag, activity, D-dimer, or platelet count. VWF Ag and activity were higher in intensive care unit (ICU) than non-ICU patients. However, it is not significant statistically. VWF Ag and activity were significantly higher in deceased patients than in survivors.
CONCLUSIONS: The results of this study showed that there was no significant correlation between VWF Ag and activity with D-dimer among Saudi patients with confirmed COVID-19.

Keywords: COVID-19, D-dimer level, thrombosis, von Willebrand factor activity, von Willebrand factor level/antigen


How to cite this article:
Al-Ansari RY, AL-Yami FS, Al-Jamea LH, Osman Abdalla LM, Halawi AH, AlShehri AM, Zakary N, Jebakumar AZ, Woodman A. Von willebrand factor level and activity in correlation with D-dimer level among COVID-19 patients in Saudi Arabia. J Appl Hematol 2022;13:228-36

How to cite this URL:
Al-Ansari RY, AL-Yami FS, Al-Jamea LH, Osman Abdalla LM, Halawi AH, AlShehri AM, Zakary N, Jebakumar AZ, Woodman A. Von willebrand factor level and activity in correlation with D-dimer level among COVID-19 patients in Saudi Arabia. J Appl Hematol [serial online] 2022 [cited 2022 Dec 3];13:228-36. Available from: https://www.jahjournal.org/text.asp?2022/13/4/228/358706


  Introduction Top


The von Willebrand factor (VWF) is a multimeric adhesive glycoprotein, important for hemostatic interactions of platelets (PLTS) and platelet vessels, i.e., mediating platelet–platelet or platelet–vessel interaction.[1],[2] VWF is an acute phase reagent that can be elevated by inflammation and stress. The importance of VWF in hemostasis is supported by the fact that hereditary deficiencies or dysfunctions of this protein cause a bleeding disorder called von Willebrand disease, which is relatively common in humans and animals. In addition, VWF plays a role in thrombosis.[1],[3] Several clinical studies have shown that people with cardiovascular disease and high plasma VWF are at risk of subsequent clinical outcomes such as mortality and myocardial infarction.[1],[3],[4]

The evidence in the current literature suggests a possible relationship between VWF and the severity of COVID-19. As VWF is an important factor in the blood coagulation system, the virus replication stimulates the development of micro damages on the walls of blood vessels.[5],[6] In response to this, the body releases VWF into the blood, trying to cover possible holes. As a result, the risk of thrombosis increases, and up to 25% of COVID-19 patients develop thromboembolic complications, especially those with severe cases.[5],[7]

Several factors may support the hypothesis of the severity of COVID-19 being associated with increased level or activity of VWF.[3],[5],[6] The risk of developing COVID-19 is slightly reduced in people with blood Group O, which is characterized by a lower level of VWF. Furthermore, the level of VWF in children is lower than in adults and higher in males compared to females.[8],[9],[10],[11]

COVID-19 patients were discovered to have coagulopathies with different etiologies. Thus, it has been suggested that COVID-19 may lead to hypercoagulation and the development of disseminated intravascular coagulation (DIC). D-dimer and VWF have a predominant role in coagulopathies, where a D-dimer greater than 2.0 μg/mL is associated with a higher mortality rate. At the same time, a low platelet count is associated with an increased risk of severe disease and mortality. One of the findings associated with thrombocytopenia is an increase in circulating biomarkers such as VWF and D-dimer.[2],[3],[5]

A number of international studies have been carried out to confirm the relationship of the above factors with COVID-19. Thus, in their cohort study, Philippe et al. reported that circulating VWF levels strongly correlate with clinical severity and are the most reliable endothelial markers for predicting inhospital mortality. In addition, Ruberto et al. (2021) reported that VWF antigen (Ag) and the active form of VWF binding to PLTS were markedly elevated in patients with COVID-19.[6] Lopez-Castaneda et al. reported significantly higher concentrations of VWF both in the severe COVID-19 group that included patients requiring support with high flow nasal cannula and the mortality groups. These results are consistent with those found by Rauch et al., who stated that high plasma concentrations of VWF are independent predictors of increased oxygen requirements and poor outcomes in COVID-19.[12] Furthermore, Lopez-Castaneda et al. estimated the D-dimer concentrations using two independent methods: coagulometry and flow cytometry using antibody-coated beads. The results confirmed existing evidence, according to which the level of D-dimer is significantly higher among patients with severe COVID-19 cases and death groups compared to those in the nonsevere groups.[13]

Furthermore, existing data suggest that elevated VWF level and activity play an important role in the complication of COVID-19 and may be an important predictor of the severity and mortality of COVID-19.[2],[3],[5],[13],[14] Considering this evidence and hypothesis proposed by several international studies, the current research was the first in the Kingdom of Saudi Arabia to determine the level of VWF activity among the Saudi population affected by COVID-19 and investigate the correlation between VWF level and D-dimer level.


  Materials and Methods Top


Study design and sample

This is an analytical, retrospective, observational study conducted in a single-center tertiary hospital at King Fahad Military Medical Complex (KFMMC). A study sample of n = 80 hospitalized patients (aged ≥18 years) diagnosed with COVID-19, confirmed by nasopharyngeal SARS-COV, was randomly included in this study.

Patients receiving hormone therapy or having DIC condition, autoimmunity, vasculitis, liver disease, positive familial type, or acquired bleeding disorder, as well as pregnant women were excluded.

Methods

Frozen blood samples were used to measure VWF Ag level and activity for all the included participants. In addition, historical data on hemostasis markers such as PLTS, fibrinogen, and D-dimer were obtained in retrospect. The level and activity of VWF Ag were determined in two groups of patients with a low platelet count and a normal platelet count. The level of D-dimer was correlated with the level and activity of VWF.

Procedures

  • Specimen type: citrated platelet-poor human plasma
  • 1 part of sodium citrate solution (0.11 mol/L) with 9 parts of venous blood was carefully mixed, avoiding foam formation, to obtain plasma
  • The blood tube was centrifuged immediately for at least 15 min at ≥1 at 4000 rpm
  • Plasma was frozen for >8 h after blood collection, at a temperature of ≤− 20°C. Frozen plasma was thawed for 10 min at 37°C and homogenized by carefully mixing to avoid foam formation.


There was no expected harm or danger as the blood sample was taken from the peripheral line during routine blood collection. Additional blood tests were not performed because the sample was used in a frozen form. After analysis, the blood samples were discarded following the safety policy procedure of the Ministry of Health of Saudi Arabia and the hospital to prevent the spread of infection to other health-care workers and laboratory staff.

Instrumentation and statistical analysis

The distribution of the sample values of qualitative variables (i.e., close-ended) was examined using frequency tables, including the demographic characteristics of the sample. The D-dimer level was correlated to the VWF level using Pearson's correlation coefficient under the low platelet group and normal platelet group of COVID-19 cases.

VWF Ag and VWF activity were evaluated using an automated immunoassay protocol standard package (Dade Behring, Siemens Healthcare Diagnostics). VWF Ag and VWF activity level was determined on automated coagulation analyzers (Sysmex, 5100). Additional parameters between the low platelet group and the normal platelet group were compared using nonparametric tests, such as the Mann–Whitney U-test, to determine the difference between them. P ≤ 0.05 was considered for statistical significance.


  Results Top


The data of n = 80 hospitalized patients (≥18 years) diagnosed with COVID-19, confirmed by nasopharyngeal SARS-COV, were analyzed to assess the level and activity of VWF in correlation with the level of D-dimer. The mean age of the patients was 58.3 (standard deviation [SD] 16.18). Approximately two-thirds of the patients were female (62.6%) [Table 1]. The most common comorbidities were arterial hypertension (67.5%), diabetes (56.3%), and dyslipidemia (22.5%). Only 10% of the patients were obese. Furthermore, [Table 1] shows the mean values of D-dimer (3.25), fibrinogen (3.55), Hg (11.57), PLTS (226.4), white blood cell (9.88), VWF Ag (237.04), VWF activity (253.21), C-reactive protein CRP (70.45), and lactate dehydrogenase (504.67).
Table 1: Sociodemographic characteristics, clinical characteristics, and laboratory parameters of patients with COVID-19 (n=80)

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Ladikou et al. published a study to explore the markers of coagulopathy in patients with COVID-19, which could indicate or explain a tendency for venous thromboembolism.[15] Since the current research had patients with similar demographic characteristics as Ladikou et al., a comparison of two studies was made [Table 2]. In addition, the current research compared data on VWF activity with a study by Philippe et al. (2021) [Table 2].[3]
Table 2: Comparison of clinical characteristics and laboratory parameters of patients with COVID-19 this study with the study by Eleni E Ladikou et al. and Philippe et al.

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[Table 2] shows the clinical characteristics and laboratory parameters of patients with COVID-19 compared to the studies mentioned above. The comparison shows that the mean values of PLTS (P = 0.02), VWF Ag (P = 0.0001), and fibrinogen (P = 0.001) were statistically significantly higher in the data of Ladikou et al. compared to this study. At the same time, the mean VWF activity was statistically significantly higher in the data of Philippe et al. than in this study (P = 0.0001).[3],[15]

The mean VWF Ag values were higher among patients who did not survive [Figure 1]. This pattern was also observed in VWF activity, as it was higher among patients who did not survive compared to those who survived [Figure 2].
Figure 1: von Willebrand factor Ag in relation to the outcome of the COVID-19 patients

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Figure 2: von Willebrand factor Activity in relation to the outcome of the COVID-19 patients

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The Mann–Whitney U-test showed that the mean VWF level depending on age (P = 0.02), male gender (P < 0.001), and length of stay (P < 0.001) were statistically significantly higher in critically ill patients [Table 3]. The mean VWF mortality (P < 0.001) and blood group O (P < 0.001) were statistically significantly higher among intensive care unit (ICU) patients.. In contrast, the mean VWF level of people with a blood group different from O was statistically higher among non-ICU patients (P < 0.001) [Table 3].
Table 3: A comparison of clinical characteristics and laboratory parameters between intensive care unit and nonintensive care unit patients affected by COVID-19

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VWF Ag, VWF activity, PLTS, and D-dimer value (mean and SD) for thrombosis in COVID-19 patients were analyzed using the Mann–Whitney U-test. The results showed that the mean values of VWF Ag, VWF activity, platelet, and D-dimer activities did not differ significantly in thrombosis (P > 0.05) [Table 4].
Table 4: Von Willebrand factor antigen, von Willebrand factor activity, platelets and D-dimer value (mean and standard deviation) in relation to thrombosis in COVID-19 patients

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Pearson's correlation coefficient was used to measure the correlation between D-dimer and VWF Ag. The correlation between D-dimer and VWF Ag and D-Dimer and VWF activity was not statistically significant (P > 0.05) [Table 5].
Table 5: Correlation between D-dimer and von Willebrand factor antigen as well as activity in relation to co-morbid condition

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Further statistical tests revealed that patients with dyslipidemia had significantly high VWF Ag (P = 0.03), while patients with diabetes exhibited significantly high VWF activity (P = 0.04). Among patients with heart disease, D-dimer was significantly low (P = 0.02) [Table 6].
Table 6: Comorbidities in relation to von Willebrand factor antigen, von Willebrand factor activity and D-dimer in COVID-19 patients

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Analysis for D-dimer, VWF Ag, and activity in relation to platelet count showed significantly high D-dimer in the low platelet group, but no significant relation to VWF Ag and activity [Table 7].
Table 7: Von Willebrand factor antigen, von Willebrand factor activity and D-dimer in COVID-19 patients in relation to platelet count

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  Discussion Top


Saudi Arabia is one of the largest Middle Eastern countries that has been affected by the COVID-19 pandemic. COVID-19 patients were discovered to have coagulopathies with different etiologies. Fibrinogen, D-dimer, VWF, and P-selectin are central in the development of coagulopathies. Existing data suggest that elevated VWF level and activity play an important role in the complication of COVID-19 and may be an important predictor of COVID-19 severity and mortality.[2],[3],[5],[13],[14] The current research became the first in Saudi Arabia to assess the relation between COVID-19 and VWF level and activity. In addition, the study looked into differences in blood group types and ethnicity, allowing comparisons with previous and future studies.

The most common comorbidities were arterial hypertension (67.5%), diabetes (56.3%), and dyslipidemia (22.5%). Only 10% of patients were obese. These results are consistent with the meta-analysis by Sanyaolu et al. and Ng et al. As such, cancer, chronic kidney disease, diabetes, and hypertension have been independently associated with mortality in COVID-19 patients.[16],[17] However, despite its high prevalence, obesity was not significantly associated with mortality in COVID-19 patients. Reported comorbidities have been associated with high VWF level. For instance, dyslipidemic patients had significantly higher VWF Ag level compared to nondyslipidemic patients. This pattern was also true for diabetic patients who had higher VWF activity compared to nondiabetic COVID-19 patients. Despite comorbidities with higher VWF level, the D-dimer level was not significantly associated with comorbidities. In addition, diabetes has been linked to abnormalities in the vascular endothelium, which explains the high activity of VWF even in non-COVID-19 patients. This is a risk factor for the development of microvascular complications and the progression of cardiovascular complications.[18],[19]

Further analysis showed that n = 46 patients (57.5%) required ICU hospitalization. Of these, 23.9% required intubation and mechanical ventilation. Moreover, 60.86% were male, and about 70% were non-O blood types. These findings support the previous data that males with A/AB blood type have a higher risk for intubation of hospitalization, intubation, or mortality, compared to males with O blood type. Similarly, in a study of ABO blood group distribution in 2173 COVID-19 patients by Zhao et al. (2021), people in Group A were more likely to have COVID-19, while people in Group O were less likely to have COVID-19.[20] Moreover, a genome-wide association study involving 1980 patients in Europe showed that the 9q34.2 locus (including the ABO glycosyltransferase gene) is associated with severe COVID-19 and respiratory failure. This study also confirmed a higher risk in blood group A than in other blood groups and a protective effect in blood Group O compared to other blood groups.[21] However, this association is not universal. Thus, Latz et al. did not correlate ABO type and intubation or mortality associated with COVID-19. Still, they confirmed that people in Group O are the least likely to test positive for SARS-CoV-2. These findings may be associated with elevated VWF level in non-O individuals, predisposing them to thromboembolic events and hence a severer course of disease.[22],[23]

The analysis showed that VWF Ag and VWF activity were higher in ICU patients than in non-ICU patients. These findings are consistent with a study by Jothimani et al. (2021), where ICU patients had significantly higher VWF Ag level (P = 0.006), fibrinogen (P = 0.037), and D-dimer (P = 0.043).[24]

Additional findings of the current research showed that the mortality rate in the ICU was 30%, which is significantly higher than non-ICU patients. Similarly, Jothimani et al. found a clear association between elevated VWF Ag and COVID-19 patients with complications.[24] Thus, the mortality rate in patients with elevated VWF Ag level was 11.4%, slightly lower than in a study by Ladikou et al., where the mortality rate was 16.7%.[15] The correlation between VWF Ag and activity level was higher among nonsurvivors. These results are consistent with those obtained by Philippe et al. (2021).[3] Similarly, Marco and Marco (2021) reported that Ag VWF was higher in non-survivors of COVID-19 (370.2% (312–400%)) compared with survivors (143.5% (104.5–218.9%)) (P < 0.05).[25]

Microvascular and macrovascular thromboembolic lesions are the leading cause of mortality or morbidity in patients with COVID-19.[26] At the same time, severe endothelial injury was the most important autopsy finding.[27],[28],[29],[30] This allows the hypothesis that if the endothelium is damaged, more VWF Ag or activity will stimulate binding to PLTS, collagen, and glycoprotein Ib. This will result in thrombocytopenia, as well as the formation of thrombosis.[31]

In this study, six out of eighty patients developed thromboembolic events with an insignificant P value between those who developed thrombosis and not in relation to VWF Ag (P = 0.77), VWF activity (P = 0.93), PLTS count (P = 0.62), and D-dimer (P = 0.18). Moreover, five of these six patients required ICU hospitalization (P = 0.08), which is consistent with other studies showing that the risk of thrombosis is higher in cases of COVID-19 admitted to ICU.[32],[33],[34],[35] Compared to Ladikou et al., where the mean platelet count was 284, this study showed a lower mean of 212 with statistical significance (P = 0.02).[15] Furthermore, in this research, the thrombotic events were not related to platelet count, VWF Ag, VWF activity, and level of D-dimer, which contradicts some studies.[3],[5],[6] Thus, Aksenova noted that infection-induced endothelial cells dysfunction could result in a hypercoagulable state. This condition is characterized by excessive thrombin levels, elevated D-dimer levels, and problems with fibrinolysis along with hypoxia, which can stimulate thrombus formation in severely infected COVID-19 patients.[5]

D-dimer is an indicative marker of COVID-19 severity and mortality. During the early onset of the condition, the D-dimer is within normal limits or increases only slightly. Still, as the severity of the disease progresses in the patient, the D-dimer level rises significantly. It has also been suggested that early assessment and continuous monitoring of D-dimer level after hospitalization may identify patients with cardiac injury and predict further complications of COVID-19.[8],[31],[36],[37],[38] In addition, a COVID-19 patient has a two-to-threefold increase in VWF Ag level and activity.[37],[39],[40] In this study, the mean D-dimer was 3.25 with a SD of 9.52 and a median of 1.09, slightly lower than in the study by Ladikou et al. In addition, the mean Ag and VWF activity were 237.04 and 253.21 (SD 212.18 and 246.1), respectively. These data represent a significantly lower value of both VWF Ag and activity compared to Philippe et al. and Ladikou et al.[3],[15]

Our data showed that, out of 80 cases, 26 (32.5%) have low platelet and 54 (67.5%) have normal or high platelet count. The relation between platelet level and VWF Ag/activity was statistically insignificant (P = 0.91 and P = 0.50, respectively). On the other hand, D-dimer was higher in the low platelet group, which is statistically significant (P = 0.00). These data were consistent with Xu et al.'s result, which showed that D-dimer was negatively related to platelet count in COVID-19 patients.[41] Moreover, the data showed that COVID-19-induced thrombocytopenia is associated with an increase in circulating biomarkers such as VWF and D-dimer, which is somehow different than our findings.[2],[3],[5] However, the degree of increment in D-Dimer level or reduction in the platelet count as well as increasing in VWF activity/Ag depends on the severity of the COVID-19 infection and reflecting worse prognosis.[42],[43],[44],[45]

A research by Philippe et al. (2021) emphasizes the importance of VWF Ag, as well as the usefulness of this parameter in supporting anticoagulation and as a detector of premature thrombosis and severity of COVID-19. This gives a comparable prediction and a possible correlation between D-dimer and VWF activity. The high level of D-dimer, VWF Ag, and activity in COVID-19 patients evident in this study supports much of the previous study. However, VWF Ag (0.436) and activity toward D-dimer (0.495) were insignificant. This finding contradicts the findings by Agbuduwe and Basu and Grobler et al. Although the current study results did not show a significant correlation between D-dimer, VWF Ag, and activity, this could be due to the small sample size as a limitation that warrants a further, larger study.[46],[47]


  Conclusions Top


The evidence in the current literature suggests a possible relationship between VWF and the severity of COVID-19. As VWF is an important factor in the blood coagulation system, the virus replication stimulates the development of microdamages on the walls of blood vessels. Therefore, D-dimer and VWF are of predominant role in coagulopathies, where a D-dimer level >2.0 μg/mL is associated with a higher mortality rate. Considering this evidence and hypotheses proposed by several international studies, the current research became the first in Saudi Arabia to determine the level of VWF activity among the Saudi population affected by COVID-19 and investigate the correlation between VWF level and D-dimer level. The results of this study showed that there was no significant correlation between VWF Ag and activity with D-dimer among Saudi patients with confirmed COVID-19. Further studies with a larger sample size are required to make a comparison with the findings of the current research.

Limitations

This study is observational in nature and has explored retrospective data with limited information. The study setting was conducted in a military hospital with a restricted eligibility for admission. Furthermore, the sample size of this research was small. Finally, frozen blood samples used in this research might affect the accuracy of the results.

Compliance with ethical standards

Ethical Approval was Obtained from Armed Forces Hospitals Eastern Province Institutional Review Board (IRB), with IRB Protocol No.AFHER-IRB-2020-037.

Effective: October 27, 2020.

Expiration: October 26, 2021.

Author contributions

R. Al-A. proposal, IRB and discussion; A. W. introduction, discussion, editing, review; A. H. H. and A. M. A. data collection and review; F. Al-Y. and L. Al-J. results and review; L. A. review; Z. J. A. statistics; N. Z. data supervision and final review.

Data availability

The authors declare that data supporting the findings of this study are available within the article.

Acknowledgments

The authors would like to acknowledge Al Kamal Importing Office-Siemens Healthineers Partners for providing VWF test/reagent and Jenifer Vecina Quiambao for her assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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