Bleeding from gastro-oesophageal varices is the most serious and life-threatening complication of cirrhosis and accounts for 10% of all cases of bleeding from the upper GI (gastrointestinal) tract. Despite the advances in treatment of variceal bleeding, mortality remains high at around 40%, being closely related to the severity of un- derlying liver disease as assessed by child’s class and impairment of renal function [1] .

Clinical factors associated with an increased risk of a first variceal hemorrhage include continued alcohol use and poor liver function. Endoscopic predictors of bleeding include endoscopic red signs on the variceal wall and large varices [2] .

Thrombocytopenia, ascites and splenomegaly are useful non invasive parameters to predict bleeding from esophageal varices [3] . Factor (F)V and factor VII (FVII) levels are sensitive indicators of hepatic protein syn- thesis often used to assess the severity of disease [4] [5] . FVII is the first clotting factor level to fall, because of its short half-life of 6 hours. FVII deficiency develops in 75% - 85% of patients, and levels range from 23% to 74% of normal in compensated cirrhosis [4] - [7] . FVII levels are significantly lower in decompensated cirrhosis, but 30% of normal ones are in most patients with stable disease [4] [5] [8] .

The elevated levels of vWF (von Willebrand factor) in cirrhosis may be a consequence of endothelial perturbation, possibly caused by bacterial infection [5] . Another possible mechanism of elevated vWF in cirrhosis is induction of synthesis of vWF in the liver with cirrhosis itself [8] or reduced liver-mediated clearance. Although it is established that vWF antigen levels are increased in patients with cirrhosis, relatively little is known on the relation between it and the bleeding from esophageal varices [9] [10] so we aimed in this study to determine the clinical predictors of bleeding esophageal varices and study the role of FVII and vWF in predicting bleeding in patients with eosphogeal varices.

All patients with a clinical diagnosis of liver cirrhosis who underwent endoscopy at Qena and Sohag faculty of medicine hospitals from January 2012 to August 2013 were divided into 2 groups. Group A consisted of patients with a history and clinical presentation of bleeding esophageal varices and Group B were those patients with esophageal varices on endoscopy but with no history of variceal bleeding. The diagnosis of cirrhosis was based on a combination of clinical, laboratory and radiographic criteria.

Bleeding esophageal varices is defined as those patients who presented with upper gastrointestinal bleeding manifested by hematemesis, melena and/or hematochezia with endoscopic confirmation of esophageal variceal bleeding and no other bleeding lesion seen on endoscopy. Patients with a clinical diagnosis of upper gastrointestinal bleeding due to acquired coagulopathy, gastric ulcers, duodenal ulcers or gastric varices were excluded. All patients underwent complete clinical examination, abdominal sonography laboratory investigations and upper GIT endoscopy.

Forty patients from each group A and B are randomly selected and Factor VII and vWF are estimated.

Data were analyzed utilizing the STATA SOFTWARE. Continuous variables were expressed as means ± standard deviation and nominal variables were recorded as frequencies. Student’s unpaired t test or Mann–Whitney test were used to compare continuous variables. The Chi2 test was used to identify differences between categorical variables. P values less than 0.05 was considered to indicate statistical significance.

From January 2012 to August 2013, three hundred liver cirrhotic patients underwent endoscopy. One hundred and sixty patients with esophageal variceal hemorrhage made up the study group and one hundred and forty patients with esophageal varices but no history of variceal hemorrhage comprised the negative control group. Two hundred and Forty (80%) had Hepatitis C, Fifty Six (18%) had hepatitis B, Six patients 2% had both hepatitis B and C, 2% of all patients had HCC per biopsy factors for their liver disease. Male compromised 86% of the study population with a mean age of 42 years. The Physical examination are listed in Table 1, laboratory findings are listed in Table 2, there is significant decrease of hemoglobin level and platelet count in bleeding group when compared with non bleeding group. Also Table 2 shows significant increase in von Willebrand factor and significant decrease in FVII in bleeding group when compared with non bleeding group

No significant difference between both groups as regard splenomegaly, presence of ascites and presence of splenic or hepatic collaterals as shown in Table 3.

Endoscopic findings are listed in Table 4. High grade of varices, presence of red color sign [RC], number of columns of EV, presence of gastric varices and presence of portal gastropathy were significantly correlated with increased risk of bleeding from esophageal varices. RC sign is the most sensitive and specific sign for bleeding as shown in Table 5.

Table 5 shows the sensitivity, specificity and accuracy of various predictors of bleeding including the

NS: non significant.

NS: non significant.

sensitivity and specificity of low FVII (<28.2%) and high vWF (>187.1 IU/dl) to predict bleeding in patients having esophageal varices. The sensitivity of FVII and vWF were 75% and 82.5% respectively while the specificity were 85% and 65% respectively. We found no significant difference between patients with HCV infection and patients with HBV infections as regard the previous predictors of bleeding.

Variceal hemorrhage is a major source of mortality of patients with portal hypertension [11] , gastroesophageal varices are present in 50% - 60% of cirrhotic patients. The natural history of liver cirrhosis shows that 30% of patients with liver cirrhosis will experience an episode of variceal hemorrhage within one year of diagnosis of varices [12] . Endoscopy proved to be a powerful tool for the determination of bleeding risks. Higher grade esophageal varices, red color sign, portal gastropathy and presence of fundal varices are other predictors of bleeding in esophageal varices. Our study has shown that large varices are more likely to bleed than small ones. Bleeding

was present in 61.3% of our patients with grade 3 and in 18.1% with grade 4 varices. Wall tension is a factor of diameter and wall thickness, and it is not surprising that larger varices are more likely to rupture. Variceal size has been investigated by many researchers [13] [14] . All of them have documented the fact that larger varices bleed more often than smaller varices. The only exception to this is only one study found that 35% of patients with small varices bled, while only 20% of patients with large varices also bled [15] .

Another endoscopic finding of value in predicting variceal bleeding is the appearance of the vessel wall. The color of varices is thought to predict impending hemorrhage. Our study has shown that endoscopic finding of “red signs” is related to the variceal bleeding. The “red signs” were found in 90% of varices with bleeding. The red color signs are the result of microteleangioectasia of the varix. This agrees with many previous studies [16] [17] . In addition, the presence of concomitant gastric varices could be added as a further criterion for the prediction of bleeding from esophageal varices.

In agreement with previous, the presence of gastric varices in predicting bleeding from esophageal varices is noteworthy. Close anatomical connections have been demonstrated between the veins of the stomach and the distal esophagus. Furthermore, the presence of the varices in the gastric fundus indicates a particularly high venous blood pressure in that area thus offering an explanation for the increased bleeding risk [16] - [18] .

In our study we found another criterion in predicting bleeding from esophageal varices is the presence of portal gastropathy on endoscopy. Prevalence of hypertensive gastropathy parallels the severity of portal hypertension and liver dysfunction. A high portal pressure [>12 mmHg] can explain the snake skin appearance of gastric mucosa on endoscopy and positively correlates with the risk of bleeding this agree with previous studies [16] . We also found that increase the number of varices predicting bleeding from esophageal varices.

In patients with liver cirrhosis elevated levels of von Willebrand factor antigen are found frequently but the clinical significance is unclear. VWF-Ag plays an important role in primary haemostasis and development of thrombotic vascular obliteration is discussed as a possible mechanism leading to portal hypertension [19] . Endothelial dysfunction is a major determinant of the increased hepatic vascular tone of cirrhotic livers. Von Willebrand factor [vWF], surrogate markers of endothelial dysfunction, is increased in patients with cirrhosis. So the vWF is increased in bleeding patients as increase of portal hypertension [20] .

In our study we found that the increase of vWF correlates with the increased risk of bleeding form oesophageal varices as it significantly higher in patient with bleeding so it is significant predictor of bleeding.

Factor [F]V and FVII levels are sensitive indicators of hepatic protein synthesis often used to assess the severity of disease [4] [5] . FVII is the first clotting factor level to fall, because of its short half-life of 6 hours. FVII deficiency develops in 75% - 85% of patients, and levels range from 23% to 74% of normal in compensated cirrhosis [4] [6] [7] . FVII levels are significantly lower in decompensated cirrhosiss.

In our study significant decrease in FVII in bleeding group. Clinical trials are needed to better define the role of recombinant activated factor VII in the treatment of bleeding complications of liver disorder [21] .

Our study concludes that vWF and FVII could be used as predictors for bleeding in patients having esophageal varices but further additional work should be done to study their roles in management.