Open access peer-reviewed chapter
Abstract
Hepatic and extrahepatic factors contribute to mortality related to liver cirrhosis and therefore much research is still to be done in order to understand the condition thoroughly and to possibly intervene in the process. It is considered that the currently applied prognostic scores are not ideal mortality predictors. On the other hand, recent scientific concepts have revealed the significant contributing role of endothelial dysfunction and of systemic inflammation in the pathogenesis of portal hypertension. Consequently, these concepts are inevitably leading towards proposing and validating new prognostic indicators in cirrhotic patients. Von-Willebrand factor as an indicator of endothelial dysfunction and C-reactive protein as a surrogate marker of systemic inflammation and several other parameters and biological markers have been emerging as a relevant and potentially useful prognostic indicators. Also, the coagulopathy associated to liver disease is in close relation with these entities and still an important research topic. Despite the promising data regarding their prognostic potential, additional research is needed in order to define and validate their value more precisely in clinical and prognostic settings.
Keywords
- cirrhosis
- portal hypertension
- endothelial dysfunction
- systemic inflammation
- von-Willebrand factor
- CRP
- coagulopathy
1. Introduction
Liver cirrhosis represents the final stage of chronic liver disease which denotes reduced hepatic cell mass, formation of regenerative nodules and progressive fibrosis. The altered hepatic architecture leads to an impaired hepatic haemodynamics that manifests with portal hypertension (PH) and gradually leads to development of liver failure [1, 2]. PH is an accompanying condition of the natural course of chronic liver disease and a key factor underlying most of the complications that often determine the prognosis in these patients [3]. Although the development of PH has been mainly attributed to the elevated hydrostatic pressure due to increased vascular resistance, different perspectives have recently emerged regarding this topic. Endothelial dysfunction (ED), a state that indicates irregular function of the endothelial cell (EC), seems to have an important role in the increased vascular tone of the hepatic microcirculation [4, 5] and is an important factor involved in the development of PH [6]. It is also considered that elevated von Willebrand factor (vWF) contributes to the presence of a subtle hypercoagulable state that worsens the PH [7]. Chronic liver disease has also been related to many complex abnormalities in all segments of the haemostatic process. Moreover, the simultaneous impairment in the procoagulant and anticoagulant activity and the increased vWF concentration transform liver cirrhosis into a condition that is characterized by a globally rebalanced hemostasis [8].
2. Portal hypertension: definition, diagnostic criteria, clinical and prognostic significance
PH is an entity that indicates elevated hydrostatic pressure in the portal vein that initially occurs as a result of the structural abnormalities in the hepatic vasculature [6]. The increased vascular inflow which develops as a consequence of the splanchnic vasodilation and of the increased cardiac “output” also contribute in the progressivon of PH [9]. The main diagnostic criterion for PH is the presence of elevated hepatic venous pressure gradient (HVPG). HVPG denotes the pressure gradient between the so-called “wedged” pressure and the free pressure of the hepatic veins, which actually reflects the pressure gradient between the portal vein and the inferior vena cava. The HVPG value correlates with PH-related complications [10] and the HVPG measurement is used in therapeutic as well as in prognostic purposes [11]. Clinically significant portal hypertension is defined as the presence of HVPG ≥10 mmHg and it indicates an increased risk of complications and death associated with liver disease and an increased risk of hepatocellular carcinoma [12, 13, 14, 15]. HVPG ≥12 mmHg carries an increased risk of variceal bleeding, and HVPG ≥20 mmHg is associated with poor clinical outcomes in cirrhotic patients [12, 13, 14, 15]. The PH-related complications are often life-threatening conditions associated with high morbidity and mortality [3] and hence early diagnosis and appropriate treatment is essential for improving the prognosis in these patients [16]. Although HVPG measurement is the gold standard for determining the presence and extent of PH, this diagnostic procedure is not widely used in the everyday clinical practice. It is invasive, expensive and due to technical reasons in about 4% of patients it could be unsuccessful [17]. Consequently, these limitations also preclude the widespread use of the diagnostic and therapeutic algorithms that rely on pressure-based diagnostics. Therefore, the Baveno V Consensus for portal hypertension encourages research towards defining new, non-invasive indicators of PH with better sensitivity and specificity than the ones that are currently used [16, 18].
The natural course of chronic liver disease is characterized by two phases. The first compensated phase is followed by a rapidly progressing, decompensated phase characterized by the presence of complications of PH and/or hepatic dysfunction [1]. As the disease progresses, portal pressure increases and liver function decreases, leading to development of ascites, hypertensive gastrointestinal bleeding, encephalopathy, and jaundice [1]. The occurrence of any complication of PH defines the transition from a compensated to a decompensated phase [1]. The occurrence of ascites is the most common initial complication of PH in cirrhotic patients [19] and it is usually considered a hallmark of the decompensated phase [1]. By combining data from two large studies involving 1649 patients that analyzed the natural course of the disease [19, 20], four clinical stages of cirrhosis were defined, each with a different clinical presentation and a significantly different prognosis [1]. Stage 1 is characterized by the absence of esophageal varices and ascites (mortality rate about 1% per year); stage 2 is characterized by the presence of esophageal varices but without bleeding or ascites (mortality rate 3.4% per year); stage 3 is characterized by the presence of ascites with or without varices in a patient who has never bleed (mortality rate 20% per year) and stage 4 is characterized by gastrointestinal bleeding with or without ascites (mortality rate 57% per year). Stages 1 and 2 correspond to compensated and stages 3 and 4 to decompensated cirrhosis [1]. The transition from compensated to decompensated phase occurs at a rate of 5–7% per year [21, 22] and with the onset of the first episode of decompensation the life expectancy of patients is significantly shortened [1]. Median survival is significantly shorter in patients with decompensated than in patients with compensated cirrhosis (approximately 2 years versus over 12 years) [1]. Consequently, the prognostic indicators used in both stages are different and have different prognostic significance [23, 24].
3. The role of endothelial dysfunction in the pathogenesis of portal hypertension
EC has a potential for producing many different mediators that are crucial for proper regulation of the vascular homeostasis, the vasomotor tone and for many inflammatory, metabolic and hemostatic processes in the body [25]. EC regulates the vascular tone by its ability to release vasoactive substances, including vasodilators such as nitric oxide (NO) and prostacyclin and vasoconstrictors such as thromboxane A2 (TXA2) [9]. Endothelial activation is a broad term implying EC function changes occurring as a response to a number of different stimuli. As a response to vascular stress, infections or hypoxia, the EC undergoes certain changes that lead to an imbalance in the release of vasoactive mediators predisposing development of a pro-inflammatory and pro-coagulant state [26, 27, 28, 29, 30, 31, 32]. As a response to chronic, continuous exposure of the EC to various physical or chemical stimuli a disturbance in the function of the EC occurs, a state defined as ED. [25]. ED is a condition of imbalanced release of vasoconstrictors and vasodilators, stimulators and inhibitors of growth, proatherogenic and antiatherogenic, and pro-coagulant and anticoagulant mediators [4, 25]. It has been established that ED is an early key event in many vascular diseases [5] and its presence is generally associated with a poor prognosis [7]. Also, ED is an early event that has been involved in the pathogenesis of PH [6]. ED as part of the liver disease occurs in the liver microcirculation and in the EC in the systemic and splanchnic circulation. Hepatic inflammation in early cirrhosis is the primary trigger that causes damage to the hepatic reticuloendothelial system and leads to intrahepatic ED [33, 34, 35, 36, 37, 38, 39, 40, 41]. This ED is manifested by an increased release of vasoconstrictive substances leading to impaired flow-associated endothelial-dependent vascular relaxation, i.e., to inadequate postprandial vasodilation. Intrahepatic ED is considered to be the primary disorder that leads to increased intrahepatic vascular resistance and progressive PH [4, 5, 9, 42], and later, to a consequent arterial vasodilation in the splanchnic circulation [4, 43, 44, 45]. On the contrary, in advanced disease, endotoxemia is considered to be the main factor responsible for the development of ED in the systemic circulation. The systemic ED is manifested by an increased production of vasodilator molecules, mainly NO [46, 47], a vasodilator that is secreted by the endothelial and vascular smooth muscle cells [48] and that also has certain anti-inflammatory and antithrombotic properties [7]. The increased vasodilator tone in the systemic circulation leads to increased endothelial-dependent relaxation and increased blood flow, which consequently leads to the development of hyperdynamic circulation (HC) [49, 50, 51].
As a result of the vascular stress and increased concentration of some circulatory factors such as catecholamines, estrogens, and substance P that stimulate the endothelial synthetic activity [52, 53] several typical hemodynamic disorders occur in cirrhotic patients. The HC is one of the main and most typical hemodynamic features of patients with liver cirrhosis and PH [54, 55, 56, 57]. It occurs as a result of a specific combination of several hemodynamic abnormalities, but the increased NO production is considered to be the major factor in the development of HC [54, 55, 56, 57]. In this context, some studies have confirmed a significant correlation between the level of vWF and the NO production which may suggest a common activation mechanism [27]. HC is characterized by increased intrahepatic vascular resistance as a result of intrahepatic vasoconstriction and increased systemic vasodilation leading to an increased portal flow. The presence of HC in patients with liver cirrhosis is manifested by hypotension, low vascular resistance, and increased cardiac output, which develops as a compensation of the systemic vasodilation [9, 58]. Additionally, increased portal systemic shunting and reduced renal flow also occur [3, 59]. The severity of the HC has been significantly associated with the degree of PH, that is, by activating the NO synthetase, the portal pressure is an important factor that regulates the vasodilation in the splanchnic circulation [60]. Hence, in patients with liver cirrhosis, in addition to the endotoxemia, PH is thought to act as a factor of increased endothelial stress and stimulates additional NO production [52], i.e., the PH indirectly emphasizes the vasodilation in the splanchnic circulation.
4. Von-willebrand factor as an indicator of endothelial dysfunction and factor of PH progression
Some mediators secreted by the activated EC such as NO, vWF, P-selectin and Isoprostran are used as indicators of ED [26, 29, 61, 62, 63]. The important role of vWF in the process of angiogenesis, inflammation, cell proliferation and tumor growth has recently been increasingly emphasized [64]. Considering the fact that liver cirrhosis is closely related to ED, vWF as an indicator of ED causes considerable attention in cirrhotic patients. Since vWF is also involved in the pathogenesis and progression of PH, its value as a prognostic indicator in these patients becomes even more important.
vWF is a large multimeric glycoprotein released by the megakaryocytes and the activated vascular EC that plays a role in the process of primary hemostasis and coagulation [65]. In a coordinated manner, the function of vWF is regulated by two platelet membrane receptors, glycoprotein Ib (GPIb/IX/V) and glycoprotein IIb/IIIa [16, 66]. During primary hemostasis, vWF participates in both platelet adhesion and platelet aggregation. In case of endothelial damage, circulating vWF binds to exposed collagen in subendothelial structures and interacts with the platelet receptor GPIb/IX/V. This transient interaction enables subsequent stable interaction between platelets and collagen through the collagen receptor α2ẞ1 and glycoprotein VI [67]. This is followed by the exposure and activation of the receptor GP IIb/IIIa resulting in the release of platelet activating mediators such as
Human EC has the capacity to synthesize vWF multimers with a higher molecular weight called ultra-large molecular weight multimers (ULMWM) [70]. After secretion by the EC, ULMWM usually undergo a process of fractionation to smaller vWF forms that are normally present in the circulation [70, 71, 72]. vWF is continuously secreted by the EC and megakaryocytes, while the ULMWM are stored in the cytoplasmic granules and are released after their degranulation as a response to a significant endothelial damage [73]. Contrary to the small vWG multimers, ULMWMs are the most haemostatically active forms of vWF that have the property of spontaneous binding to platelets and subendothelial structures, and are considered prothrombotic [74]. The multimeric composition of vWF is regulated by its protease ADAMTS13 [67], a clearance metalloprotease synthesized in hepatic stellate cells [75, 76] that processes ULMWM into smaller vWF forms [67, 75, 76]. The vWF activity is strictly regulated by ADAMTS13 and the vWF reactivity towards platelets is proportional to the size of the vWF multimers [9]. Since ADAMTS13 is synthesized in the liver [77], as expected, some studies have confirmed a markedly reduced concentration of ADAMTS13 in patients with liver disease [78]. In some patients Lisman et al. also confirmed reduced ADAMTS13 concentration, but in others the concentration and activity of ADAMTS13 has been elevated [67]. This may be due to its reduced clearance of ADAMTS13 or its reduced release from platelets [79] as a consequence of platelet activation secondary to disseminated intravascular coagulation (DIC). Although in advanced liver disease the synthesis function of the hepatocytes is generally reduced, the stellate cells tend to have an increased synthetic activity [80, 81] which may also explain the increased synthesis of ADAMTS13 registered in some patients.
It has been established that intrahepatic and systemic ED is involved in the pathogenesis and progression of PH. Since vWF is an indicator of ED, vWF recently has gained an important role as a prognostic indicator in cirrhotic patients. There are many mechanisms that are related to the increased vWF production in cirrhotic patients. The intrahepatic production of vWF as a result of the intrahepatic ED has been confirmed by the positive immune staining of vWF in sinusoidal endothelial cells in these patients [82, 83]. Also, the presence of endotoxemia and bacterial products, especially in advanced diseases appear to be the most important cause of increased endothelial secretion of vWF [58, 67], which has been confirmed by the linear increase in vWF concentration with the increase of endotoxemia [58, 84]. In addition to the increased endothelial production of vWF, there are other mechanisms that contribute to the increase in vWF such as increased shear stress, bacterial infections [58, 85], neoplastic processes, physical activity, or interferon-based therapy [86, 87]. Decreased expression or activity of ADAMTS13 recorded in some cirrhotic patients may also result in reduced clearance and increased vWF concentration [79]. It is also considered that increased vWF values may be related to the hyperfibrinolysis found in some patients, but on the other hand increased vWF has been also registered in patients without evidence of an increased proteolysis [58], which means that this is probably not a dominant mechanism.
Not only vWF is an indicator of ED, but the clinical and prognostic relevance of vWF is more pronounced because vWF is involved in the progression of PH. Since vWF is a large multimeric molecule, its increased concentration along with other abnormalities that favor procoagulant tendency in cirrhotic patients often results in occurrence of thrombosis in the hepatic microcirculation. If this is a long-term and continuous process, then it progressively obliterates and increases the resistance in the portal vasculature [67, 88] that leads to additional worsening of the PH. Additionally, it is assumed that when these thrombotic events are localized in the intestinal microcirculation they favor enterocytic ischemia and consequent intestinal bacterial translocation causing endotoxemia, which is crucial for the development of the majority of PH-related complications [9]. The literature data confirm a correlation between the concentration of vWF and the HVPG values [7, 16] suggesting that vWF level reflects the degree of PH. Also, vWF level has been related to some complications of PH such as hepatopulmonary syndrome and esopgaheal varices [89, 90].
The presence of PH is related to most of the complications in cirrhotic patients that define the course of the disease and more importantly the prognosis in these patients. Since vWF reflects PH, recent evidence emphasizes the importance of vWF as a predictor of mortality. Most studies that have analyzed the association between vWF and chronic liver disease have reported that vWF concentration correlates with the stage of liver disease assessed by Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) score [7, 27, 91], that vWF can predict acute decompensation [16], occurrence of clinical events and PH-related complication [7, 92] and that vWF is an independent predictor of mortality that equals MELD score [7, 16, 91].
5. The relation between systemic inflammation and adverse outcomes in cirrhotic patients and the prognostic role of C-reactive protein
It has been established that systemic inflammation (SI) is common in patients with advanced liver disease and PH [93] and that the presence of SI in these patients has been associated with adverse outcomes [94, 95, 96] and a poor prognosis [95, 97, 98, 99]. The negative impact of SI on liver disease is reflected mainly through the increase in the portal pressure and in the reduction of the hepatic blood flow i.e. through deterioration of PH and liver disease progression [100].
SI is defined as a state of persistent and inadequate stimulation of the immune system, which is manifested by the presence of elevated inflammatory cytokines and activated immune cells [101]. The presence of SI is usually assessed by the presence of systemic inflammatory response syndrome (SIRS), a set of hemodynamic alteration that develops as a response to SI. The presence of SIRS is usually confirmed by specific diagnostic criteria. Sepsis is a condition of a systemic inflammatory response to infection, which involves a characteristic range of pathological changes in many host systems. The pathophysiological sequence involves release of cytokines and endothelial and neutrophil activation, which initiates a cascade of leukocyte-endothelial interaction and adhesion. This is followed by transendothelial migration and subsequent microvascular and tissue damage, consequently leading to a multiple organ failure [102]. It has been reported that endothelial and tissue damage correlates with the intensity of the inflammatory response and leukocyte sequestration in tissues [103].
It is known that SIRS most commonly develops in the context of acute bacterial infection. In patients with liver cirrhosis acute bacterial infection (respiratory, urinary etc.) can often cause an acute deterioration of liver function, which is mainly due to the effects of the SIRS. This may be a result of some specific features of the liver sinusoidal endothelial cells (SEC) that are not typical for the endothelial cells at other locations in the body. The liver SEC are fenestrated allowing inflammatory cells to pass through easily and come into direct contact with hepatocytes [104]. Additionally, the inflammatory cytokines within SI stimulate release of vWF from the EC [105, 106] and suppress the synthesis of ADAMTS13 in the stellate cells [105, 107] which may also contribute to the vWF rise and reflect the relation between SI and ED in cirrhotic patients. It has been also established that SI is underlying many of the PH-related complications and acute events in cirrhotic patients [93]. It is considered that in critically ill patients with liver cirrhosis, these acute events are better taken into account by the use of the general prognostic scores [Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score (SAPS)], which provide better short-term mortality prediction than the prognostic scores specifically designed for patients with liver cirrhosis such as CTP and MELD score [9, 108]. On the other hand, some disorders related to liver disease, PH or HC may modify the clinical and biochemical parameters included in the SIRS scores which decreases their value as SIRS indicators [95]. Hypersplenism may mask leukocytosis or exacerbate leucopenia; subclinical encephalopathy may increase the respiratory rate and favor hypercapnia; hyperkinetic circulatory syndrome may increase the heart rate, and beta blockers may mask the tachycardia. This means that the presence of SIRS in patients with liver cirrhosis may often be underestimated by the scores and criteria for SIRS [93, 109]. Considering all the above, many researchers have focused on identifying new biological variables that would be more accurate indicators of SIRS than the currently used criteria. In this context, the value of serum C-reactive protein (CRP) as a surrogate marker of SIRS has recently been increasingly recognized [9].
CRP is an acute-phase inflammation protein that is synthesized in the liver mainly by interleukin 6. Moreover, it has been shown that CRP synthesis is preserved even in advanced liver disease [110, 111], which makes CRP a reliable SIRS indicator in this category of patients. Many researchers evaluated the predictive value of CRP in the general population and also in patients with liver cirrhosis. In the everyday clinical practice elevated CRP has been mainly used as an indicator of bacterial infection and many researchers have confirmed this relation [112, 113, 114]. Lazzarotto et al. defined that CRP value of 29.5 mg/L (sensitivity 82% and specificity 81%) is a reliable indicator of bacterial infection in cirrhotic patients [112]. Moreover, recent evidence suggests that the significant prognostic value of CRP in cirrhotic patients comes from the fact that in advanced liver cirrhosis, elevated CRP may persist after a bacterial infection has resolved [9] or it may also reflect the presence of a low grade SI that is not directly related to bacterial infection [108]. This is probably related to the endotoxemia and the bacterial products reaching systemic circulation.
The presence of SI in cirrhotic patients has the potential to trigger several serious complications and acute events related to PH and liver disease such as encephalopathy [68], renal failure [65, 70] or infection [108] and it has been related to negative outcomes during acute [115, 116, 117] or chronic [94, 95, 96] liver failure. Also, elevated CRP has been related to the organ failure and liver disease-related mortality [93, 112, 118]. Lazzarotto et al. confirmed that in patients with liver cirrhosis higher initial CRP values were associated with death before the ninetieth day of hospitalization [112]. Cervoni et al. demonstrated that mortality in liver cirrhosis was independently associated with CRP, MELD score, and extrahepatic comorbidities. They defined a CRP cut-off value of 29 mg/L persisting for 15 days after hospitalization to have the best sensitivity and specificity for predicting mortality in cirrhotic patients [93]. By using the variables found to be independent predictors of a six-month mortality (variations in CRP, MELD score and extrahepatic comorbidities) in the previous research [93], Di Martino et al. developed a prognostic model in order to predict the three-month mortality in patients with advanced liver cirrhosis and in a subgroup of patients with acute decompensation. They found that the MELD score [HR1.10; 95% CI, (1.05–1.14); P < 0.001] and mean CRP above 32 mg/L at baseline or 15 days after hospitalization [HR 2.21; 95% CI (1.03–4.76), P = 0.042) were independent predictors of the three-month mortality. Moreover, the study showed better diagnostic efficacy of the prognostic model than the diagnostic efficacy of the MELD score (AUROC, 0.789 vs. 0.734; P = 0.043) [118]. Also, a positive correlation was registered between CRP and MELD score in the whole population, but such correlation was not registered in the subgroup of patients with end-stage liver disease. These findings suggested that the presence of SI was clinically more significant in patients with advanced liver disease, that the prognostic significance of the CRP variations as indicators of SI was greater in more severe patients and that the presence of SI could not be adequately assessed by using the MELD score. These findings once again emphasize the significant role of CRP as a prognostic indicator in patients with liver cirrhosis, especially in advanced disease.
6. The relation between endothelial dysfunction, systemic inflammation and haemostatic abnormalities in chronic liver disease
The haemostatic process is a strictly regulated system in which the process of conversion of fibrinogen into fibrin is consequently followed by its subsequent degradation [119]. Since most coagulation factors and fibrinolytic proteins are synthesized in the liver, a proper hepatic function is of particular importance for the perfectly synchronized function of the haemostatic process. Hence, acute and chronic liver conditions often have an intense influence on the process of hemostasis [120] and advanced liver disease is associated with many complex abnormalities in all three parts of the haemostatic process. In patients with liver cirrhosis the haemostatic dysfunction is related to several mechanisms, such as quantitative and qualitative platelet abnormalities, quantitative and qualitative abnormalities in the coagulation factors and fibrinolytic proteins, reduced clearance of activated coagulation factors, abnormalities in the process of fibrinolysis, as well as to the presence of intensified fibrinolysis and low grade intravascular coagulation [121, 122, 123].
The primary hemostasis reflects the interaction between the platelets and the blood vessel and it is mediated by the action of vWF. Thrombocytopenia and the variable thrombocytopathy are the two most common abnormalities in cirrhotic patients within the primary hemostasis [124]. Thrombocytopenia occurs as a result of the increased sequestration due to splenomegaly, decreased thrombopoietin level and myelosuppression, increased systemic immune activation due to portosystemic shunting, impaired intestinal barrier and increased endotoxemia, immune-mediated platelet destruction and due to the platelet consumption within low grade intravascular coagulation [125, 126, 127, 128, 129]. The platelet dysfunction is presented as a reduced transmembrane signaling and progressive inability for platelet activation as a response to several stimuli such as adenosine diphosphate, thrombin, collagen, epinephrine or rhizocetine. This dysfunction results in insufficient production of thromboxane and serotonin and precipitates cascade abnormalities in the process of platelet aggregation [130, 131].
The central part of the haemostatic process is the process of coagulation, also called secondary homeostasis or thrombin generation. Most coagulation factors, such as fibrinogen, factor V, VII, VIII, IX, X, XI, XII are synthesized in the liver, which means if the liver synthetic function is impaired, their level inevitably decreases [132]. On the other hand, in patients with liver cirrhosis the synthesis of the anticoagulant proteins, such as protein C, protein S, and antithrombin is also reduced which partially compensate for the procoagulant deficiency. Despite the decreased concentration of most coagulation factors, in cirrhotic patients there is an increased concentration of factor VIII and vWF, two coagulation factors that are considered acute phase reactants [133, 134, 135, 136, 137]. Due to the reduced synthesis of the coagulation factors of the external pathway (mainly factor VII) prolonged prothrombin time (PT) is usually registered, while the reduced synthesis of the coagulation factors of the internal pathway results in prolongation of the activated partial thromboplastin time (aPTT). Thrombin time (TT) reflects the final step of the coagulation cascade, the conversion of fibrinogen into fibrin. TT reflects quantitative and qualitative fibrinogen abnormalities, a state called dysfibrinogenemia. Fibrinogen is also an acute phase reactant and in patients with mild or moderate liver cirrhosis it can be normal or slightly elevated [138, 139]. On the contrary, in advanced, severe cirrhosis fibrinogen concentration is usually decreased [139] resulting in prolongation of the TT. Fibrinogen is almost exclusively synthesized in the liver and hypofibrinogenemia in these patients could be a consequence of the reduced synthetic liver capacity, the increased metabolism, the abnormal fibrinolytic activity or the consumption as part of the DIC [140].
The final phase of the haemostatic process is fibrinolysis, the process of thrombus dissolution that limits the coagulation cascade. The fibrinolytic impulse is generated by the tissue plasminogen activator (t-PA), uricinase plasminogen activator and activated factor XII. They induce the conversion of plasminogen to plasmin, which then acts on fibrin to produce the fibrin degradation products (FDP). Deviations in the fibrinolysis in cirrhotic patients occur as a result of the decreased hepatocyte function, vitamin K deficiency and presence of hyperfibrinolysis [48, 141] which has been registered in about one third of the cirrhotic patients [48, 142, 143, 144]. The presence of hyperfibrinolysis and DIC in patients with liver cirrhosis is still the subject of a wide debate [145]. According to some studies, the abnormalities in the hyperfibrinolitic process correlate with the CTP score and are more prevalent in the elderly and in patients with decompensated cirrhosis [146, 147]. Primary hyperfibrinolysis occurs due to the increased concentration of t-PA (as a consequence of impaired hepatic clearance) and decreased concentration or functionality of antiplasmin and other plasminogen activator inhibitors [148, 149, 150, 151], which leads to an increased conversion of plasminogen to plasmin [152]. The secondary hyperfibrinolysis develops as a continuum of an emphasized coagulation, most commonly within DIC. Although DIC has been registered in a small number of patients with hyperfibrinolysis, it rarely has a significant clinical impact [152].
An important perspective of the hyperfibrinolysis in cirrhotic patients is its relation to the increased bleeding risk and to the increased incidence of portal vein thrombosis (PVT). FDP created during hyperfibrinolysis interfere with the process of fibrin polymerization by inhibiting the platelet aggregation and thus increasing the risk of bleeding. As the measurement of individual components of the fibrinolytic pathway is of little use in the assessment of this tendency, the role of hyperfibrinolysis in the pathogenesis of bleeding in patients with liver cirrhosis is still not completely clear [142]. On the other hand, the relation between elevated D-dimers and PVT in cirrhotic patients has also been evaluated. Most studies that analyzed the relation and prognostic role of D-dimers in these patients confirmed significant association between the elevated D-dimers and the occurrence of PVT [153, 154]. One study suggested that the risk of developing PVT in patients with liver cirrhosis was significantly higher in case of a significant postoperative rise in the D-dimers concentration that exceeded 16,000 ng/ml [153]. Zhang et al. confirmed significant association between the elevated D-dimers and the occurrence of PVT independent of the CTP score [154]. Additionally, a meta-analysis of 21 studies found that increased concentration of D-dimers was associated with an increased risk of PVT not related to surgery, suggesting that D-dimers could be used as a diagnostic marker for PVT in cirrhotic patients [155]. However, not all studies confirmed this relation. A retrospective observational study of 66 patients did not find any significant difference in the D-dimers level between cirrhotic patients with and without PVT [156]. Most studies suggest that elevated D-dimers in cirrhotic patients correlate with the degree of liver dysfunction which is probably related to the increased hyperfibrinolysis in advanced liver disease [144, 157, 158]. More importantly, it has also been established that in patients with liver cirrhosis elevated D-dimers were related to poor outcomes [144, 154, 157, 158] and that they were significant predictor of short-term mortality [157, 158]. These findings suggest that in critically ill cirrhotic patients or in some specific clinical settings monitoring of the D-dimers concentration may have some useful clinical and prognostic implication.
It is well established that the significantly reduced synthetic liver function in advanced disease is responsible for the reduced synthesis of the coagulation factors. But, since this occurs late in the stage of the disease, several other mechanisms might be responsible for many complex abnormalities in the coagulation process in cirrhotic patients. In this context, the ED in patients with liver cirrhosis seems to be largely involved in this process through several mechanisms [48]. The process of ED by itself among other disturbances implies an imbalance in the secretion of pro-coagulants, anticoagulants, and also fibrinolytic substances, which can be responsible for some of the haemostatic abnormalities. Also, some evidence suggests that in patients with liver cirrhosis there is a direct relation between the endotoxemia and coagulation activity i.e. that endotoxemia can directly activates the coagulation and fibrinolytic pathway in patients with liver cirrhosis [159]. In this context, some researchers have demonstrated a strong association between endotoxemia and high levels of prothrombin fragments F1 + 2, which are markers of thrombin generation [159, 160], and also between endotoxemia and elevated D-dimers, which are markers of hyperfibrinolysis [159]. This is confirmed by the fact that in cirrhotic patients with elevated F1 + 2 and D-dimers a reduction in the coagulation and fibrinolytic activity has been registered after reduction of endotoxemia [159]. Some data also confirm a direct association between endotoxin and a thrombin-antithrombin complex [160]. Endothelial activation may also explain the relationship between the synchronized rise of vWF and D-dimers as part of secondary hyperfibrinolysis. Lisman et al. extensively analyzed the qualitative and quantitative deviations of vWF in patients with liver cirrhosis and found elevated levels of propeptide indicating an acute endothelial damage, presumably associated to the presence of low grade DIC [67]. It is considered that the increased plasma proteolysis in these patients leads to increased concentrations of vWF as well as highly reactive vWF multimers [161, 162]. The endotoxin also has a potential to induce increased expression of tissue factor (TF) on the surface of the macrophages and to stimulate synthesis of tumor necrotic factor (TNF), which activates the external coagulation pathway [118, 163, 164, 165]. The presence of SI in cirrhotic patients also has an influence on the coagulation process. In terms of severe inflammation, the inflammatory cytokines activate the endothelial cells, inhibit the liver synthesis of protein C [166] and can stimulate degranulation of the cytoplasmic granules and release of ULMWM [105, 107], the most prothrombotic vWF multimers. Among other complex haemostatic abnormalities in cirrhotic patients, the increased concentration of ULMWM confirmed in some patients with acute decompensation [167] is considered to be related to the increased prothrombotic tendency.
7. Conclusion
All the above suggests a close relation between SI, ED, and liver disease-related coagulopathy in cirrhotic patients and emphasizes their important role in the pathogenesis of majority of manifestations and complications of PH. It also explains the crucial role of endotoxemia as a central initiating factor in their pathogenesis. Elevated vWF reflecting ED and significant and prolonged CRP rise reflecting SI should be routinely used in the everyday clinical practice. Additional research is needed in order to insert more deeply into the patogenesis of these entities and to propose new variables that would reflect their presence and significance more precisely.
References
- 1.
D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis:a systematic review of 118 studies. J Hepatol. 2006;44(1):217-231. - 2.
Kamegaya K. Definition and classification of liver cirrhosis. Nihon Rinsho. 1994 Jan;52(1):11-8. Japanese. PMID: 8114278. - 3.
Bosch J, Garcia-Pagan JC. Complications of cirrhosis. I. Portal hypertension. J Hepatol 2000;32(1 Suppl):141-56. - 4.
Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007;46:927-934. - 5.
Matei V, Rodriguez-Vilarrupla A, Deulofeu R, et al. The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis. Hepatology 2006;44:44-52. - 6.
Gracia-Sancho J, Lavina B, Rodriguez-Vilarrupla A, et al. Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 2008;47:1248-56. - 7.
La Mura V, Reverter JC, Flores-Arroyo A, Raffa S, Reverter E, Seijo S, et al. Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension. Gut 2011;60:1133-1138 - 8.
Tripodi A. Liver Disease and Hemostatic (Dys)function. Semin Thromb Hemost. 2015; 41(5):462-7 - 9.
Di Martino V, Weil D, Cervoni JP, Thevenot T. New prognostic markers in liver cirrhosis. World J Hepatol. 2015 May 28;7(9):1244-50. - 10.
Bosch J, Abraldes JG, Berzigotti A, Garcia-Pagan JC. The clinical use of HVPG measurements in chronic liver disease. Nature reviews Gastroenterology & hepatology. 2009; 6(10):573-82. - 11.
Hametner S, Ferlitsch A, Ferlitsch M, et al. The VITRO Score (Von Willebrand Factor Antigen/Thrombocyte Ratio) as a New Marker for Clinically Significant Portal Hypertension in Comparison to Other Non-Invasive Parameters of Fibrosis Including ELF Test. PLoS One. 2016;11(2):e0149230. - 12.
Bosch J, Garcia-Pagan JC, Berzigotti A, Abraldes JG. Measurement of portal pressure and its role in the management of chronic liver disease. Seminars in liver disease. 2006; 26(4):348-62. Epub 2006/10/20. - 13.
de Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010; 53 (4):762-8. - 14.
Ripoll C, Groszmann RJ, Garcia-Tsao G, Bosch J, Grace N, Burroughs A, et al. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol 2009; 50(5):923-8. - 15.
Peck-Radosavljevic M, Angermayr B, Datz C, Ferlitsch A, Ferlitsch M, Fuhrmann V, et al. Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II). Wieneklinische Wochenschrift. 2013; 125(7-8):200-19 - 16.
Ferlitsch M, Reiberger T, Hoke M, Salzl P, Schwengerer B, Ulbrich G, Payer BA, Trauner M, Peck-Radosavljevic M, Ferlitsch A. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology 2012; 56: 1439-1447 - 17.
Reiberger T, Ferlitsch A, Payer BA, Pinter M, Homoncik M, Peck-Radosavljevic M. Non-selective beta-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis. Journal of gastroenterology. 2012; 47(5):561-8. - 18.
de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015. - 19.
D’Amico G, Morabito A, Pagliaro L, Marubini E. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 1986;31:468-475 - 20.
D’Amico G, Pasta L, Madonia S, Tarantino G, Mancuso A, Malizia G, et al. The incidence of esophageal varices in cirrhosis. Gastroenterology 2001;120:A2. - 21.
D’Amico G. Natural history of compensated cirrhosis and varices. In: Boyer TD, Groszmann RJ, editors. Complications of cirrhosis: pathogenesis, consequences and therapy. American Association for the Study of Liver Diseases; 2001. p. 118-123 - 22.
Samonakis DN, Koulentaki M, Coucoutsi C, et al. Clinical outcomes of compensated and decompensated cirrhosis: A long term study. World J Hepatol. 2014;6(7):504-512. - 23.
D’Amico G, Garcia–Tsao G, Abraldes J, Gine’s P, Kim WR, Schepis F, et al. Prognostic indicators in cirrhosis. In: de Franchis R, editor. Portal Hypertension IV. Proceedings of the Fourth Baveno International Consensus Workshop on Definitions, Methodology and Therapeutic Strategies. Blackwell, 2005 - 24.
Cabre E, Abad-Lacruz A, Nunez MC, Gonzalez-Huix F, Fernandez- Banares F, Gil A, et al. The relationship of plasma polyunsaturated fatty acid deficiency with survival in advanced liver cirrhosis: multivariate analysis. Am J Gastroenterol 1993;88:718-722 - 25.
Caballero AE. Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes Res 2003;11:1278-1289 - 26.
van Mourik JA, Boertjes R, Huisveld IA, et al. von Willebrand factor propeptide in vascular disorders: A tool to distinguish between acute and chronic endothelial cell perturbation. Blood. 1999;94(1):179-185. - 27.
Albornoz L, Alvarez D, Otaso JC, et al. Von Willebrand factor could be an index of endothelial dysfunction in patients with cirrhosis: relationship to degree of liver failure and nitric oxide levels. J Hepatol 1999;30:451-5 - 28.
Blann A. Von Willebrand factor and the endothelium in vascular disease. Br J Biomed Sci 1993;50:125-134. - 29.
Spiel AO, Gilbert JC, Jilma B. Von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008;117:1449-1459. - 30.
Lip GY, Blann A. Von Willebrand factor: a marker of endothelial dysfunction in vascular disorders? Cardiovasc Res 1997;34:255-265. - 31.
Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation: part I. Circulation 2003;108:1917-1923. - 32.
Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159-165 - 33.
Albillos A, Hera Ad Ade L, Reyes E, Monserrat J, Munoz L, Nieto M, et al. Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin. J Hepatol 2004;40:624-631. - 34.
Genesca J, Marti R, Gonzalez A, Torregrosa M, Segura R. Soluble interleukin- 6 receptor levels in liver cirrhosis. Am J Gastroenterol 1999;94:3074-3075. - 35.
Lopez-Talavera JC, Levitzki A, Martinez M, Gazit A, Esteban R, Guardia J. Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites. J Clin Invest 1997;100:664-670. - 36.
Giron-Gonzalez JA, Martinez-Sierra C, Rodriguez-Ramos C, Rendon P, Macias MA, Fernandez-Gutierrez C, et al. Adhesion molecules as a prognostic marker of liver cirrhosis. Scand J Gastroenterol 2005;40: 217-224. - 37.
Buck M, Garcia-Tsao G, Groszmann RJ, Stalling C, Grace ND, Burroughs AK, et al. Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients. Hepatology 2014;59:1052-1059 - 38.
Wiese S, Mortensen C, Gotze JP, Christensen E, Andersen O, Bendtsen F, et al. Cardiac and proinflammatory markers predict prognosis in cirrhosis. Liver Int 2013;34:e19-30. - 39.
Guarner C, Soriano G, Tomas A, Bulbena O, Novella MT, Balanzo J, et al. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology 1993;18:1139-1143. - 40.
Campillo B, Bories PN, Benvenuti C, Dupeyron C. Serum and urinary nitrate levels in liver cirrhosis: endotoxemia, renal function and hyperdynamic circulation. J Hepatol 1996;25:707-714. - 41.
Tazi KA, Moreau R, Herve P, Dauvergne A, Cazals-Hatem D, Bert F, et al. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up- regulation in cirrhotic rats: role of Akt signaling. Gastroenterology 2005;129:303-314. - 42.
Bellis L, Berzigotti A, Abraldes JG, Moitinho E, Garcia-Pagan JC, Bosch J, et al. Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis. Hepatology 2003;37:378-384 - 43.
Groszmann RJ, Abraldes JG. Portal hypertension: from bedside to bench. J Clin Gastroenterol 2005;39:S125–S130. - 44.
Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002;35:478-491. - 45.
Groszmann RJ, Loureiro-Silva M, Tsai MH. The biology of portal hypertension. 4 ed. New York: Lippincott Williams and Wilkins; 2001, 679-97. - 46.
Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide. Lancet 1991;337:776-778. - 47.
Bomzon A, Blendis LM. The nitric oxide hypothesis and the hyperdynamic circulation in cirrhosis. Hepatology 1994;20:1343-1350 - 48.
Ferro D, Quintarelli C, Saliola M, Alessandri C, Basili S, Bonavita MS, Violi F. Prevalence of hyperfibrinolysis in patients with liver cirrhosis. Fibrinolysis 1993;7:59-62 - 49.
Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, Sessa WC, Groszmann RJ. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 1999; 117: 1222-1228 - 50.
Tsai MH, Iwakiri Y, Cadelina G, Sessa WC, Groszmann RJ. Mesenteric vasoconstriction triggers nitric oxide overproduction in the superior mesenteric artery of portal hypertensive rats. Gastroenterology 2003;125:1452-1461. - 51.
Wiest R, Shah V, Sessa WC, Groszmann RJ. NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. Am J Physiol 1999;276:G1043–G1051. - 52.
Sterling R, Sanyal A, Schubert M. Nitric oxide and portal hypertension Gastroenterology, 112 (1997), pp. 1767-1768 - 53.
Blann AD, Naqvi T, Waite M, McCollum CN. Von Willebrand factor and endothelial damage in essential hypertension o J Hum Hypertens, 7 (1993), pp. 107-111 - 54.
Pizcucta MP, Piqué JM, Bosch J, Whittle BJR, Moncada S. Effeets of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension. Br J Pharmacol, 105 (1992), pp. 184-190 - 55.
Claria J, Jiménez W, Ros J, Rigol M, Angeli P, Arroyo V, et al. Increased nitric oxide-dependent vasorelaxation in aortic rings of cirrhotic rats with ascites. Hepatology, 20 (1994), pp. 1615-1621. - 56.
Sieber CC, Groszmann RJ. Nitric oxide mediates in vitro hyporeactivity to vasopressors in mesenteric vessels of portal hypertensive rats Gastroenterology, 103 (1992), pp. 235-239. - 57.
Castro A, Jiménez W, Claria J, Ros J, Martinez JM, Bosch M, et al. Impaired responsiveness to angiotensin II in experimental cirrhosis: role of nitric oxide. Hepatology, 18 (1993), pp. 367-372. - 58.
Ferro D, Quintarelli C, Lattuada A, Leo R, Alessandroni M, Mannucci PM, et al. High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia. Hepatology 1996;23:1377-1383 - 59.
Newby DE, Jalan R, Masumori S, Hayes PC, Boon NA, Webb DJ. Peripheral vascular tone in patients with cirrhosis: role of the renin-angiotensin and sympathetic nervous systems. Cardiovasc Res 1998;38:221-228. - 60.
Abraldes JG, Iwakiri Y, Loureiro-Silva M, Haq O, Sessa WC, Groszmann RJ. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 2006;290:G980–G987. - 61.
Leon DA, McCambridge J. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet 2006;367:52-6 - 62.
Smyth SS, McEver RP, Weyrich AS, et al. Platelet functions beyond hemostasis. J Thromb Haemost 2009;7:1759-66. - 63.
Lavi S, Yang EH, Prasad A, et al. The interaction between coronary endothelial dysfunction, local oxidative stress, and endogenous nitric oxide in humans. Hypertension 2008;51:127-33. - 64.
Lenting PJ, Casari C, Christophe OD, Denis CV (2012) von Willebrand factor: the old, the new and the unknown. J Thromb Haemost 10: 2428-2437. - 65.
Maieron A, Salzl P, Peck-Radosavljevic M, et al. Von Willebrand Factor as a new marker for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2014;39(3):331-338 - 66.
Iannacone M, Sitia G, Isogawa M, et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med 2005; 11: 1167-9 - 67.
Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44(1):53-61 - 68.
Brinkhous KM, Sandberg H, Garris JB, et al. Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci U S A 1985; 82:8752. - 69.
De Meyer SF, Deckmyn H, Vanhoorelbeke K. von Willebrand factor to the rescue. Blood 2009; 113:5049. - 70.
Moake, J. L., C. K. Rudy, J. H. Troll, M. J. Weinstein, N. M. Colannino, J. Azocar, R. H. Seder, S. L. Hong, and D. Deykin. 1982. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. New Engl. J. Med. 307:1432-1435. - 71.
Moake, J. L., J. J. Byrnes, J. H. Troll, C. K. Rudy, S. L. Hong, M. J. Weinstein, and N. M. Colannino. 1985. Effects of fresh frozen plasma and its cryosupernatant fraction on von Willebrand factor multimer forms in chronic relapsing thrombotic thrombocytopenic purpura. Blood. 65:1232-1236. - 72.
Frangos, J., J. L. Moake, L. Nolasco, and L. McIntire. 1986. Evidence for an unusually large factor VIII: vWF depolymerase in normal plasma cryosupernatant. Clin. Res. 34:656A. - 73.
Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest. 1986;78(6):1456-1461 - 74.
Chow TW, Turner NA, Chintagumpala M, et al. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol 1998; 57:293. - 75.
Zhou W, Inada M, Lee TP, et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 2005;85(06):780-788 - 76.
Uemura M, Tatsumi K, Matsumoto M, et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood 2005;106 (03):922-924 - 77.
Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276: 41059-41063. - 78.
Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001;98(09):2730-2735 - 79.
Suzuki M, Murata M, Matsubara Y, Uchida T, Ishihara H, Shibano T, et al. Detection of von Willebrand factor-cleaving protease (ADAMTS13) in human platelets. Biochem Biophys Res Commun 2004;313: 212-216 - 80.
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-218. - 81.
Atzori L, Poli G, Perra A. Hepatic stellate cell: a star cell in the liver. Int J Biochem Cell Biol 2009;41(8-9):1639-1642 - 82.
Knittel T, Neubauer K, Armbrust T, Ramadori G. Expression of von Willebrand factor in normal and diseased rat livers and in cultivated liver cells. Hepatology 1995;21:470-476. - 83.
Wu H, Yan S, Wang G, Cui S, Zhang C, Zhu Q . Von Willebrand factor as a novel noninvasive predictor of portal hypertension and esophageal varices in hepatitis B patients with cirrhosis. Scand J Gastroenterol 2015;16:1-10 - 84.
Yilmaz VT, Dincer D, Avci AB, Cetinkaya R. Significant Association between Serum Levels of Von Willebrand Factor (vWF) Antigen with Stages of Cirrhosis. Eurasian J Med. 2015;47(1):21-25 - 85.
Gulley D, Teal E, Suvannasanka A, Chalasani N, Liangpusankul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci 2008;53:3012-3017 - 86.
Pramhas S, Homoncik M, Ferenci P, Ferlitsch A, Scherzer T, Gangl A, et al. von Willebrand factor antigen: a novel on-treatment predictor of response to antiviral therapy in chronic hepatitis C genotypes 1 and 4. Antiviral therapy. 2010; 15(6):831-9. - 87.
Homoncik M, Ferlitsch A, Ferenci P, Formann E, Jilma B, Gangl A, et al. Short- and long-term effects of therapy with interferon-alpha and pegylated interferon-alpha/ribavirin on platelet plug formation and von Willebrand factor release in patients with chronic hepatitis C. Alimentary pharmacology & therapeutics. 2005; 21(1):49-55. - 88.
Wannhoff A, Müller OJ, Friedrich K, et al. Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis. PLoS One. 2014;9(11):e112583. Published 2014 Nov 14. - 89.
Horvatits T, Drolz A, Roedl K, Herkner H, Ferlitsch A, Perkmann T, Müller C, Trauner M, Schenk P, Fuhrmann V. Von Willebrand factor antigen for detection of hepatopulmonary sundrome in patients with cirrhosis. J Hepatol. 2014 Sep;61(3):544-9. - 90.
Mahmoud HS, Ghweil AA, Bazeed SE, Fayed HM, Meguid MMA: Reliability of Plasma Von Willebrand Factor Antigen in Prediction of Esophageal Varices in Patients with Liver Cirrhosis. Open Journal of Gastroenterology, 2015; 5, 49-57. - 91.
Curakova Ristovska E, Genadieva-Dimitrova M, Caloska-Ivanova V, Misevski J. Von-Willebrand factor as a predictor of three-month mortality in patients with liver cirrhosis compared to MELD score. Acta Gastroenterol Belg. 2019 Oct-Dec;82(4):487-493. PMID: 31950803. - 92.
Kalambokis GN, Oikonomou A, Christou L, et al. von Willebrand factor and procoagulant imbalance predict outcome in patients with cirrhosis and thrombocytopenia. J Hepatol. 2016;65(5):921-928. - 93.
Cervoni JP, Thévenot T, Weil D, Muel E, Barbot O, Sheppard F, Monnet E, Di Martino V. C-reactive protein predicts short-term mortality in patients with cirrhosis. J Hepatol 2012; 56: 1299-1304 - 94.
Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254. - 95.
Cazzaniga M, Dionigi E, Gobbo G, Fioretti A, Monti V, Salerno F. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol 2009;51:475-482. - 96.
Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E, et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology 2007;46:1872-1882 - 97.
Dirchwolf M, Ruf AE. Role of systemic inflammation in cirrhosis: From pathogenesis to prognosis. World J Hepatol. 2015 Aug 8;7(16):1974-81. - 98.
Abdel-Khalek EE, El-Fakhry A, Helaly M, Hamed M, Elbaz O. Systemic inflammatory response syndrome in patients with liver cirrhosis. Arab J Gastroenterol 2011; 12: 173-177. - 99.
Behroozian R, Bayazidchi M, Rasooli J. Systemic Inflammatory Response Syndrome and MELD Score in Hospital Outcome of Patients with Liver Cirrhosis. Middle East J Dig Dis 2012; 4: 168-172. - 100.
Jalan R, MookerjeeR. Systemic hemodynamic, hepatic blood flow and portal pressure in patients with cirrhosis and multiorgan failure: the role of sympathetic activation. Hepatology 2008: 48:1077A - 101.
Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: Distinct features and clinical relevance. J Hepatol 2014;61: 1385-1396 - 102.
Parrillo, J. E. 1993. Pathogenetic mechanisms of septic shock. N. Engl. J. Med. 328:1471-1477. - 103.
Weiss, S. J. 1989. Tissue destruction by neutrophils. N. Engl. J. Med. 320:365-376. - 104.
Braet F, Wisse E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol 2002;1:1. - 105.
Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultra large vWF multimers under flow. Blood 2004;104: 100-106. - 106.
Schorer AE, Moldow CF, Rick ME. Interleukin 1 or endotoxin increases the release of von Willebrand factor from human endothelial cells. Br J Haematol 1987;67:193-197. - 107.
Cao WJ, Niiya M, Zheng XW, Shang DZ, Zheng XL. Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells. J Thromb Haemost 2008;6:1233-1235. - 108.
Malik R, Mookerjee RP, Jalan R. Infection and inflammation in liver failure: two sides of the same coin. J Hepatol 2009;51:426-429. - 109.
Curakova Ristovska E, Genadieva-Dimitrova M, Caloska-Ivanova V, Nikolovska E, Joksimovic N, Todorovska B, Isahi U, Milichevik I. The SIRS score relevance for assessment of systemic inflammation compared to C-reactive protein in patients with liver cirrhosis. Macedonian Medical Review. 2019; 73(1): 24-30 - 110.
Bota DP, Van Nuffelen M, Zakariah AN, Vincent JL. Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med 2005; 146: 347-351 - 111.
Park WB, Lee KD, Lee CS, Jang HC, Kim HB, Lee HS, Oh MD, Choe KW. Production of C-reactive protein in Escherichia coli-infected patients with liver dysfunction due to liver cirrhosis. Diagn Microbiol Infect Dis 2005; 51: 227-230 - 112.
Lazzarotto C, Ronsoni MF, Fayad L, et al. Acute phase proteins for the diagnosis of bacterial infection and prediction of mortality in acute complications of cirrhosis. Ann Hepatol. 2013;12(4):599-607. - 113.
Papp M, Vitalis Z, Altorjay I, Tornai I, Udvardy M, Harsfalvi J, Vida A, et al. Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infections. Liver Int 2012; 32: 603-11. - 114.
Tsiakalos A, Karatzaferis A, Ziakas P, Hatzis G. Acute- phase proteins as indicators of bacterial infection in patients with cirrhosis. Liver Int 2009; 29: 1538-42. - 115.
Leithead JA, Ferguson JW, Bates CM, Davidson JS, Lee A, Bathgate AJ, et al. The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure. Gut 2009;58:443-449. - 116.
Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000;32:734-739. - 117.
Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology 2003;125:755-764. - 118.
Di Martino V, Coutris C, Cervoni JP, et al. Prognostic value of C-reactive protein levels in patients with cirrhosis. Liver Transpl. 2015;21(6):753-760. - 119.
Michie HR, Manogue KR, Spriggs DR, Roux-Lombard P, J5 Study Group, Lambert PH. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318:1481-1486. - 120.
Lisman T, Leebeek FWG, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol. 2002;37(2):280-87 - 121.
Vukovich T, Teufelsbauer H, Fritzer M, Kreuzer S, Knoflach P. Hemostasis activation in patients with liver cirrhosis. Thromb Res. 1995 Feb 1;77(3):271-8. - 122.
Tang Z. Zhou JG., Huang WF., Yang MQ . Detection of platelet ca2+ (i), CD62P, CD63 and plasma CD62 P in cirrhosis patients. Chin. J. Hepatol., 2003, 11: 412-414 - 123.
Violi F, Leo R, Vezza E, Basili S, Cordova C, Balsano F. Bleeding time in patients with cirrhosis-relation with degree of liver failure and clotting abnormalities. C.A.L.C. Group. Coagulation Abnormalities in Cirrhosis Study Group. J. Hepatol., 1994, 20: 531-536 - 124.
Caldwell SH, Hoffman M, Lisman T, et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006; 44: 1039-1046 - 125.
Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?. J Hepatol. 2011;55(6):1415-1427. - 126.
Monroe DM, Hoffman M. The coagulation cascade in cirrhosis. Clin Liver Dis 2009; 13: 1-9. - 127.
Goulis J, Chau TN, Jordan S, Mehta AB, Watkinson A, Rolles K, Burroughs AK. Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia are restored after orthotopic liver transplantation. Gut 1999; 44: 754-8. - 128.
Kajihara M, Okazaki Y, Kato S, Ishii H, Kawakami Y, Ikeda Y, Kuwana M. Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura. J Gastroenterol Hepatol 2007; 22: 112. - 129.
Hugenholtz GG, Porte RJ, Lisman T. The platelet and platelet function testing in liver. Disease Clin Liver Dis 2009; 13: 11-20 - 130.
Thomas DP, Ream VJ, Stuart RK. Platelet aggregation in patients with Laennec’s cirrhosis of the liver. N Engl J Med. 1967;276:1344-1348. - 131.
Witters P, Freson K, Verslype C, Peerlinck K, Hoylaerts M, Nevens F, et al., Review article: blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther. 2008;27:1017-1029 - 132.
Muciño-Bermejo J, Carrillo-Esper R, Uribe M, Méndez-Sánchez N. Coagulation abnormalities in the cirrhotic patient. Ann Hepatol. 2013;12(5):713-724. - 133.
Tripodi A. Hemostasis abnormalities in chronic liver failure. In: Gines P, Kamath PS, Arroyo V, eds. Chronic liver failure: mechanisms and management. New York: Springer, 2010:289-303 - 134.
Hollestelle MJ, Thinnes T, Crain K, Stiko A, Kruijt JK, van Berkel TJ, et al. Tissue distribution of factor VIII gene expression in vivo – a closer look. Thromb Haemost 2001;86:855-861. - 135.
Wion K, Kelly D, Summerfield JA, Tuddenham EG, Lawn RM. Distribution of factor VIII mRNA and antigen in human liver and other tissues. Nature 1985; 317: 726-9. - 136.
Shovlin CL, Angus G, Manning RA, Okoli GN, Govani FS, El- derfield K, Birdsey GM, et al. Endothelial cell processing and alternatively spliced transcripts of factor VIII: poten- tial implications for coagulation cascades and pulmonary hypertension. PLoS ONE 2010; 5: 9154. - 137.
Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6: 217-46. - 138.
Al Ghumlas AK, Abdel Gader AG, Al Faleh FZ. Haemostatic abnormalities in liver disease: could some haemostatic tests be useful as liver function tests? Blood Coagulation and Fibrinolysis. 2005;16:329-35. - 139.
de Maat MP, Nieuwenhuizen W, Knot EA, van Buuren HR, Swart GR. Measuring plasma fibrinogen levels in patients with liver cirrhosis. The occurrence of proteolytic fibrin(ogen) degradation products and their influence on several fibrinogen assays. Thromb Res. 1995 May 15;78(4):353-62. doi: 10.1016/0049-3848(95)91463-u. PMID: 7631315 - 140.
Amitrano L, Guardascione MA, Brancac-cio V, Balzano A. Coagulation disorders in liver disease. Semin Liver Dis. 2002;22(1):83-96. - 141.
Ng VL. Liver disease, coagulation testing, and hemostasis. Clin Lab Med 2009; 29: 265-82. - 142.
Dahlback B. Progress in the understanding of the protein C anticoagulant pathway. Int J Hematol 2004;79:109-116 - 143.
Francis RB Jr, Feinstein DI.Clinical significance of accelerated fibrinolysis in liver disease.Haemostasis. 1984; 14(6): 460-465. - 144.
Violi F, Ferro D, Basili S, Quintarelli C, Musca A, Cordova C Balsano F, et al. Hyperfibrinolysis resulting from clotting activation in patients with different degrees of cirrhosis. Hepatology 1993;17:78-83. - 145.
Ben Ari Z, Osman E, Hutton RA, Burroughs AK. Disseminated intravascular coagulation in liver cirrhosis: fact or fiction? Am J Gastroenterol 1999;94:2977-2982 - 146.
Hu KQ , Yu AS, Tiyyagura L, Redeker AG, Reynolds TB. Hyperfibrinolytic activity in hospitalized cirrhotic patients in a referral liver unit. Am J Gastroenterol. 2001 ; 96(5): 1581-1586 - 147.
Cioni G, Cristani A, Vignoli A, Ventura E. High D-dimer levels: a possible index of risk of overt disseminated intravascular coagulation and/or digestive bleeding in advanced liver cirrhosis?. Recenti Prog Med. 1994;85(4):230-234. - 148.
Nilsson T, Wallen P, Mellbring G. In vivo metabolism of human tissue type ptasminogen activator. Scand J Haematol 1984;33: 49-53. - 149.
Knot EAR, Drilfhout HR, ten Cate JW, De Jong E, Iburg AHC, Kahle LH, Grijm R. ~2-plasmin inhibitor mechanism in patients with liver cirrhosis. J Lab Clin Med 1985;105:353-358. - 150.
Leebeek FWG, Kluft C, Knot EAR, de Maat MPM, Wilson SPH. A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis. Gastroenterology 1991; 101:1382-1390. - 151.
Rai V, Dhameja N, Kumar S, Shukla J, Singh R, Dixit VK. Haemostatic Profile of Patients with Chronic Liver Disease- its Correlation with Severity and Outcome. J Clin Diagn Res. 2017;11(8) - 152.
Mammen EF. Coagulation abnormalities in liver disease. Haematol Oncol Clin North Am. 1992;6:1247-57. - 153.
Deng MH, Liu B, Fang HP, et al. Predictive value of D-dimer for portal vein thrombosis after portal hypertension surgery in hepatitis B virus-related cirrhosis. World J Gastroenterol. 2007;13(48):6588-6592. - 154.
Zhang D, Hao J, Yang N. Protein C and D-dimer are related to portal vein thrombosis in pa- tients with liver cirrhosis. J Gastroenterol Hepatol 2010; 25: 116-21. - 155.
Dai J, Qi X, Li H, Guo X. Role of D-dimer in the Development of Portal Vein Thrombosis in Liver Cirrhosis: A Meta-analysis. Saudi J Gastroenterol. 2015;21(3):165-174. - 156.
Dai J, Qi X, Peng Y, Hou Y, Chen J, Li H, Guo X. Association between D-dimer level and portal venous system thrombosis in liver cirrhosis: a retrospective observational study. Int J Clin Exp Med. 2015 Sep 15;8(9):15296-301. PMID: 26629017; PMCID: PMC4658906. - 157.
Primignani M, Dell’Era A, Bucciarelli P, Bottasso B, Bajetta MT, de Franchis R, Cattaneo M. High-D-dimer plasma levels predict poor out-come in esophageal variceal bleeding. Dig Liver Dis 2008; 40: 874-81. - 158.
Li Y, Qi X, Li H, Dai J, Deng H, Li J, Peng Y, Liu X, Sun X, Guo X. D-dimer level for predicting the in-hospital mortality in liver cirrhosis: A retrospective study. Exp Ther Med. 2017 Jan;13(1):285-289. doi: 10.3892/etm.2016.3930. Epub 2016 Nov 28. PMID: 28123503; PMCID: PMC5245161. - 159.
Violi F, Ferro D, Basili S, et al. Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology. 1995;109(2):531-539. - 160.
Van Deventer SJH, Butler HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990;12:2520-2526. - 161.
Federici AB, Berkowitz SD, Zimmerman TS, Mannucci PM. Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction. Blood 1992;79:38-44. - 162.
Atichartarn V, Marder V, Kirby EP, Budzynski AZ. Effects of enzymatic degradation on the subunit composition and biologic properties of human factor VIII. Blood 1978;51:281-292 - 163.
Semeraro N, Biondi A, Lorenzet R, Locati D, Mantovani A, Donati MB. Direct induction of tissue factor synthesis by endotoxin in human macrophages from diverse anatomical sites. Immunology 1983;50:529-535. - 164.
Colucci M, Balconi G, Lorenzet R, Pietra A, Locati D. Cultured human endothelial cells generate tissue factor in response to endotoxins. J Ciin Invest 1983; 71:1893-1896. - 165.
Van der Poll T, Buller HR, ten Cate H, Wortel CH, Bauer KA, Van Deventer SJH, Hack E, Sauerwein HP, Rosemberg RD, ten Cate JW. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990;322:1622-1627 - 166.
Yamamoto K, Shimokawa T, Kojima T, Loskutoff DJ, Saito H. Regulation of murine protein C gene expression in vivo: effects of tumor necrosis factor- alpha, interleukin-1, and transforming growth factor-beta. Thromb Haemost 1999;82:1297-1301. - 167.
Palyu E, Harsfalvi J, Tornai T, et al. Major Changes of von Willebrand Factor Multimer Distribution in Cirrhotic Patients with Stable Disease or Acute Decompensation. Thromb Haemost. 2018;118(8):1397-1408