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ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 839-844

Study of von Willebrand factor as a risk for thrombotic cerebrovascular stroke in cirrhotic patients


1 Tropical Medicine Department,Faculty of Medicine, Menoufia University, Shebin El-kom, Egypt
2 Neurology Department, Faculty of Medicine, Menoufia University, Shebin El-kom, Egypt
3 Clinical pathology Department,Faculty of Medicine, Menoufia University, Shebin El-kom, Egypt
4 Public Health and Community Medicine, Faculty of Medicine, Menoufia University, Shebin El-kom, Egypt

Date of Submission30-Oct-2020
Date of Decision24-Feb-2021
Date of Acceptance02-Mar-2021
Date of Web Publication18-Oct-2021

Correspondence Address:
Ayman A Sakr
Gamal Abd El-Nasr St., Shebin El-kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_403_20

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  Abstract 


Objective
This work aimed to assess the risk of von Willebrand factor (vWF) in ischemic stroke (IS) among cirrhotic versus noncirrhotic patients and its relation to IS severity and outcome.
Background
Liver cirrhosis is complicated by extensive hemostatic dysfunctions. vWF is found to be elevated and may expose these patients to thrombosis. Therefore, cirrhosis may be associated with bleeding or thrombotic events.
Patients and methods
This study included 22 cirrhotic patients without IS, 18 noncirrhotic patients with IS, 33 cirrhotic patients with IS (mixed group), and 20 healthy control. They were subjected to vWF measurement by ELISA, imaging (abdominal ultrasonography, computed tomography, and/or MRI brain, echocardiography, and duplex Doppler ultrasound on carotid arteries), National Institute of Health Stroke Scale (NIHSS), and modified Rankin Scale (MRS).
Results
Serum vWF levels were highly significantly increased in IS (94.6 ± 6.3) and mixed groups (115.9 ± 42.1) compared with other groups (P < 0.001). vWF was statistically significant in correlation with NIHSS and Child's score (P = 0.016 and 0.041, respectively). There was no significant correlation between Child's score and NIHSS (P = 0.558) or MRS (P = 0.526) or between vWF and MRS (P = 0.194), IS subtypes, or outcome (P > 0.05). Longer hospital stay was reported in mixed (14.8 ± 3.3) compared with IS group (8.5 ± 1.7) (P < 0.001).
Mixed group encountered a higher morbidity and mortality (44.4 and 22.22%, respectively) than IS group (51.5 and 24.24%, respectively), though was nonsignificant. Hypertension was the only highly significant risk factor for stroke among IS group.
Conclusion
Serum vWF was higher in cirrhosis and mixed groups than in IS, but had no role in increased morbidity and mortality in all groups. There was no significant correlation between the severity of liver cirrhosis and the severity of IS.

Keywords: ischemic stroke, liver cirrhosis, outcome, thrombosis, von Willebrand factor


How to cite this article:
Mohammed HI, Afifi KH, El Zaiat RS, Alghalban YA, El khalek MK, Sakr AA. Study of von Willebrand factor as a risk for thrombotic cerebrovascular stroke in cirrhotic patients. Menoufia Med J 2021;34:839-44

How to cite this URL:
Mohammed HI, Afifi KH, El Zaiat RS, Alghalban YA, El khalek MK, Sakr AA. Study of von Willebrand factor as a risk for thrombotic cerebrovascular stroke in cirrhotic patients. Menoufia Med J [serial online] 2021 [cited 2024 Mar 28];34:839-44. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/839/328336




  Introduction Top


Ischemic stroke (IS) is a sudden interruption in brain blood supply lasting more than 24 h. It may be thrombotic or embolic. The thrombotic stroke has two subtypes: large or small vessel disease [1].

The liver plays a central role in hemostasis. It may be altered in a complex manner in cirrhosis to extent that one cannot rely on simplified tests of hemostasis; however, a complex overview is required to clarify the hemostatic status in these patients [2].

Cirrhosis affects many organ systems including the hematological system. Previous studies reported high rates of bleeding tendency in cirrhotic patients; however, further studies suggested a tendency toward thrombotic events as well [3].

von Willebrand factor (vWF) synthesized in endothelial cells and megakaryocytes mediates initial platelet adhesion at sites of vascular injury. Low plasma levels of vWF can cause bleeding; however, its elevation may increase thrombosis risk. vWF is elevated in cirrhosis as a result of increase synthesis secondary to endothelial damage [4], reduced hepatic clearance, or reduced vWF cleaving protease [5].

Several studies identified that high plasma levels of vWF strongly predicts IS and stroke-related mortality [6],[7]. Hypercoagulability encountered in advanced cirrhosis might increase the risk of IS [8].

The aim of the present study was to assess the risk of vWF in IS among cirrhotic versus noncirrhotic patients and its relation to IS severity and outcome.


  Patients and methods Top


This cross-section case–control study was conducted on 73 patients who were selected from the inpatient and outpatients clinic of Tropical and Neuropsychiatry Departments, Menoufia University Hospital, in the period from February 2019 to February 2020. There were 41 (56.16%) males and 32 (43.84%) females, and their ages ranged between 47 and 82 years, with a mean value of 61.15 ± 6.06 years. They were classified into three groups: GI (cirrhosis group) included 22 cirrhotic patients, GII (IS group) included 18 patients with new-onset acute IS, and GIII (mixed group) included 33 cirrhotic patients with new-onset acute IS. Moreover, 20 healthy persons of matched age and sex were included as a control (GIV).

Inclusion criteria were as follows: cirrhotic patients were selected based on the presence of clinical, laboratory, and imaging evidence of cirrhosis; however, patients with IS were selected based on the presence of acute episodes of focal neurologic deficit of new-onset lasting more than 24 h.

Informed consents were obtained from all patients and controls included in the study, approved by the local ethical committee of the Faculty of Medicine, Menoufia University.

Exclusion criteria were as follows: patients were excluded from the study if they had a stroke of any cause other than ischemic etiology, myocardial infarction, major surgery, severe trauma or massive hemorrhage within the preceding 3 months, vasculitis, malignancy, known bleeding or clotting diathesis other than those associated with cirrhosis, current infection and if they were on NSAIDs, antiplatelet, coagulant, or anticoagulant medication.

All patients and controls were subjected to the following: full clinical assessment; sample collection, and laboratory tests, where aseptic withdrawal of 10 ml of venous blood after overnight fasting was done from each patient and control and divided into five tubes. In tube 1, 2 ml of blood was allowed to clot at 37°C, centrifugated, and the separated serum was used for assaying blood sugar, liver enzymes (ALT and AST) and liver function tests (serum bilirubin, albumin, and INR), renal function test, serum electrolytes, lipid profile (AU480; Beckman coulter, Brea, California, USA), CRP by turbidimetry (USA), and viral markers (COBAS; Basel, Switzerland, Germany). With respect to tube 2, 2 ml of blood was collected in an EDTA tube for assaying CBC (Sysmex XN 1000, Kobe, Japan). Regarding tube 3, 2 ml of blood was collected on a citrate blue tube for assaying prothrombin time (Stago, Chaoyang, China). With respect to tube 4, 2 ml of blood was collected on a citrate black tube for assaying ESR. With respect to tube 5, 2 ml of blood was prepared as tube 1 and kept at −20°C for vWF measurement by ELISA kit based on Sandwich-ELISA technique (Shanghai, China.). Imaging included abdominal ultrasonography, computed tomography, and/or MRI brain, two-dimensional transthoracic echocardiography, and color duplex Doppler ultrasound on carotid and vertebrobasilar arteries. Child–Pugh grading was done for all studied cirrhotic patients. Assessment of IS severity was done using National Institute of Health Stroke Scale (NIHSS) and neurologic outcome using modified Rankin Scale (MRS)-IS subtyping, as was defined by Trial of Org10172 in Acute Stroke Treatment (TOAST) [9]. Patients' follow-up was done to determine in-hospital outcome; however, patients with stroke were assessed by MRS 3 months after stroke.

Statistical analysis

Data were collected, tabulated, and statistically analyzed using an IBM personal computer with Statistical Package of Social Science (SPSS), version 22 (SPSS Inc., Chicago, Illinois, USA), where the following statistics were applied.

Descriptive statistics: in which quantitative data were presented in the form of mean, SD, and range, and qualitative data were presented in the form numbers and percentages.

Analytical statistics were used to find out the possible association between studied factors and the targeted disease. The used tests of significance included the following:

  1. χ2 test was used to study the association between two qualitative variables.
  2. Mann–Whitney test (nonparametric test) is a test of significance used for comparison between two groups not normally distributed having quantitative variables.
  3. A two-sided P value less than 0.05 means null hypothesis was rejected.



  Results Top


This study included 73 patients admitted at Menoufia University hospitals in Tropical Medicine and Neurology Department complaining of acute IS which was defined as a focal neurological insult occurred suddenly owing to a vascular cause with no clinical or radiological evidence of cerebral hemorrhage. They were classified into four groups: GI included 22 cirrhotic patients without IS; GII included 18 noncirrhotic patients with IS, GIII (mixed group) included 33 cirrhotic patients with IS, and GIV included 20 healthy control. Of 73 included patients, 41 (56.16%) were males and 32 (43.84%) were females; their ages ranged from 47 to 82 years, with a mean value of 61.15 ± 6.06 years.

Mean serum vWF levels were highly statistically significant among the four groups, being higher in cirrhosis and mixed groups than IS and control groups (P = 0.00), but there was no statistically significant difference between mixed and IS groups (P = 0.9) [Table 1].
Table 1: Mean von Willebrand factor serum levels among the studied groups

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Regarding Child–Pugh grading for liver cirrhosis in both cirrhosis and mixed groups, there was a statistically significant difference between both groups (P = 0.008) and Child's grade B showed significantly higher values in mixed compared with cirrhosis groups. Additionally, mean Child score was significantly higher in cirrhosis compared with mixed group (P = 0.004) [Table 2].
Table 2: Child-Pugh grading and score among GI and GIII

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MRS score more than 3 was significantly higher in mixed compared with stroke group (48.5 vs. 44.6%, respectively, P = 0.003) [Table 3].
Table 3: Modified Rankin score on admission and after 3 months and National Institutes of Health Stroke Scale among GII and GIII on admission

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Mean MRS score in mixed group measured 3 months after stroke onset was higher in mixed compared with stroke group, though was statistically nonsignificant (2.2 ± 1.2 vs. 1.6 ± 0.64, respectively), and scores 3 and 4; 3 months after stroke were higher among mixed patients compared with stroke group, though nonsignificant (11.5 and 19.2% vs. 7.1 and 0.0%, respectively) [Table 3].

There was no statistically significant correlation between Child's score in cirrhosis and mixed groups and both NIHSS and MRS scores either on admission or 3 months after admission in IS and mixed groups (P = 0.55, 0.5, and 0.8, respectively). On the contrary, serum vWF showed a statistically significant positive correlation with NIHSS and Child's score (P = 0.04 and 0.01, respectively) and nonsignificant correlation with MRS, length of hospital stay, or IS subtypes [Table 4].
Table 4: Correlation of Child's score and von Willebrand factor with different parameters

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There was longer hospital stay with a highly statistically significant in the mixed group compared with the stroke group (P = 0.00), and a statistically significant increase in mixed compared with cirrhosis group, and in cirrhosis compared with stroke group (P = 0.037 and 0.002, respectively) [Table 1].

During follow-up of the patients, we reported related complications such as hepatic decompensation progression, sepsis, and pneumonia in six of 22 patients in cirrhosis group, 8/18 in in IS group, and 17/18 in the mixed group, albeit no statistically significant difference between the studied groups (P = 0.08). Additionally, no statistically significant relation between serum level of vWF and patients' outcomes in all groups was reported [Table 5].
Table 5: Morbidity and mortality outcomes among the studied groups and their relation to von Willebrand factor

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Logistic regression model for determination of risk factors for morbidity and mortality could not be performed because of the small sample size.


  Discussion Top


Elevated vWF levels in our cirrhotic patients and their significant relation to the severity of cirrhosis agreed with the results of Yilmaz et al. [10], Maher et al. [11], and Ristovska et al.[12] Moreover, Lisman et al.[2] reported that elevated serum vWF levels were related to endotoxemia, and intestinal bacterial decontamination significantly decreased both endotoxin and vWF levels. Moreover, Li et al.[13] found that endotoxemia was closely related to procoagulant activity in liver disease. So, we can conclude that the significant increase in mean Child's score in our cirrhosis group might explain the significant increase of vWF.

Although vWF was highly significantly elevated in all IS subtypes compared with control, there was no significant difference among these subtypes and vWF. Hanson et al.[14] demonstrated a significant increase of vWF in all IS subtypes at the acute phase (agreed with our results), whereas 3 months after stroke, levels (not assessed in our study) were increased in large artery disease, cardioembolic, and cryptogenic subtype. Samai et al.[15] reported a high risk of recurrent stroke in patients with persistently elevated vWF 7 days after discharge (vWF follow up was not assessed in our study), and they proposed the therapeutic value of vWF targeting in the prevention of IS recurrence. Siegler et al.[16] found that patients with higher vWF were at twice the risk of stroke even if they were asymptomatic. Menih et al.[17] reported the association between high levels of vWF and stroke severity (agreed with our results).

The nonsignificant relation of vWF elevation with neurologic outcome assessed by MRS, morbidity, or mortality of our stroke patients disagreed with previous results. The elevated vWF was an independent risk factor for mortality[18] and significantly related to worse functional outcomes of patients with stroke [19]. Samai et al.[20] and Menih et al.[17] reported a significant relation of increased vWF with stroke severity (agreed with our results), neuro-worsening, and inpatient infectious complications (disagreed with our results) as well as stroke recurrence (not assessed in our study). La Mura et al.[4] and Ferlitsch et al.[21] reported that, although vWF was significantly correlated with Child's score (agreed with our results), hepatic venous pressure gradient, and model for end-stage liver disease (MELD) score (not assessed in our study), it was a significant predictor of mortality in cirrhotic patients (disagreed with our results), independent of MELD score, and its marked elevation increased the prothrombotic potential in cirrhotic patients. Similarly, Kalambokis et al.[22] reported a significant correlation of vWF with mortality in cirrhotic patients (disagreed with our results). Ristovska et al.[12] found that vWF not only correlated with Child's score (agreed with our results) and MELD score but also was significantly associated with 3-month mortality (not assessed in our study), with no significant difference between vWF and MELD score in the diagnostic performance.

Although there was no significant correlation between Child's score and either NIHSS or MRS scores, moderately severe and severe NIHSS scores were higher in the mixed compared with the stroke group, though nonsignificant, and neuro-worsening (MRS scores > 3) was significantly higher in the mixed group compared with stroke group at the acute phase. The mean MRS score in mixed group 3 months after stroke was higher compared with IS group, though nonsignificant. Moreover, cirrhosis highly significantly increased the hospital stay of patients with IS and exposed them to higher mortality and morbidity compared with noncirrhotics, though was nonsignificant. In comparison with previous studies, heterogeneous results were reported.

Goyal et al.[23] reported that despite IS was less likely in cirrhosis, liver-related mortality and morbidity were significantly higher compared with IS noncirrhotics. Parikh et al.[24] and Wu et al.[25] found that cirrhotic patients were at higher risk of IS, as well as poststroke morbidity and mortality. Zhang et al.[8] reported that the high mortality in IS cirrhotics was significantly related to older age, systemic hypertension, and hypertriglyceridemia (disagreed with our results).

Systemic hypertension was the only significant risk factor for stroke in the IS group but not among the mixed group. Our results agreed with Hornsten and Weidung[26] but disagreed with Willey et al. [27]. The highly significant decrease in blood pressure in cirrhosis might be related to progressive splanchnic and systemic vasodilatation mediated via nitric oxide and other vasodilator substances with a subsequent decrease in effective blood volume and mean arterial blood pressure [28].


  Conclusion Top


vWF elevation was significantly positively correlated with the severity of IS, irrespective of cirrhosis. There was no significant correlation between the severity of liver cirrhosis and the severity of IS. The presence of cirrhosis exposed patients with acute IS to a prolonged hospital stay and higher morbidity and mortality compared with noncirrhotic patient. Hypertension was a highly significant risk factor for IS noncirrhotic patients.

Financial support and sponsorship

Nil.

Conflicts of interest

None.



 
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