**5.3 Von Willebrand factor and ADAMTS 13 effect on ALF and ACLF**

The Von Willebrand factor (VWF) is formed by endothelial cells, megakaryocytes, and hepatocytes in the latter when the hepatic injury occurs [21]. This factor is cleared by macrophages and stored in endothelial cells, in Weibel-Palade bodies, and in the alpha granules of megariocytes.

VWF has MW 10,000 KD and is released at sites of vascular damage in response to secretion stimuli, such as thrombin, endothelial stress, vasopressin, or its synthetic analog desmopressin.

In ALF and ACLF, it generates damage to the endothelial cells of the liver sinusoids and releases VWF multimers, which bind to Domain A1, Glycoprotein IB Alpha (GPIbα), and GPIIb/IIa of platelets, and subendothelial collagen, allowing adhesion, platelet aggregation, and sequestration, giving rise to the formation of microthrombi

and generating intrahepatic hemodynamic changes and liver ischemia, cell necrosis, worsening of liver function, activating innate immunity, and contributing to the development of multi-organ dysfunction [22].

Basic experimentation studies in mice with ALF by paracetamol show an increase in VWF and platelet aggregation after 48 hours after drug exposure [21, 23]. In a prospective study of patients with ACLF, increased VWF was correlated with higher MELD and SOFA scores [22].

Damage to stellate cells determines a lower release of ADAMTS 13. Under normal conditions, this disintegrin metalloproteinase cleaves the TYr 1605-Met 1606 bond of the VWF A2 domain, degrading the VWF multimers. In ALF and ACLF, low levels of ADAMTS 13 [24, 25] are identified, causing less cleavage of the VWF multimeters. These new links require further studies on the use of VWF inhibitors, ADAMTS 13 supplementation, or the use of extracorporeal liver support therapies for the removal of VWF multimers [25] and limiting liver damage.

#### **5.4 Macrophage activation**

When hepatocyte damage is generated, Kupffer cells express two phenotypes: proinflammatory where Kupffer cells release cytokines (IL-1β, tumor necrosis factor (TNF)-α and Ccl2), the chemokine Ccl2 and the activity of plasmin during liver tissue damage, stimulating the chemotaxis of monocyte-derived macrophages from the systemic circulation to the liver at sites of injury, in order to control intrahepatic trafficking, endocytosis, phagocytosis, and phenotype switching to one of repair with dedifferentiation of macrophages to fibroblasts [26].

Under healthy conditions, macrophages constitutively present CD163 and CD206 receptors. During the proinflammatory phase of ALF and ACLF, a detachment of soluble sCD163 and sCD206 is generated, and the severity of ALF, ACLF, and mortality is considered biomarkers [27], which may play a role in making early medical or transplant decisions.

Macrophages are persistently activated in the presence of VWF and these cells are located in low-pressure sinusoids, being the parking residence of activated macrophages and which, together with microthrombi, alter hepatic hemodynamics.

The lines of study in inhibitors of macrophage chemotaxis, the use of extracorporeal liver purification therapies in the elimination of cytokines and chemokines, and achieving immunomodulation that allows limiting the migration of mononuclear cells to the liver and mitigates the damage may be promising.

#### **5.5 Extracorporeal liver support therapy**

Liver support therapies have been used with the aim of trying to replace the loss of important functions of the liver, and these systems are limited to detoxification and to reduce the inflammatory response.

#### *5.5.1 Types of extracorporeal liver support therapy*

They are divided into artificial and biological [28]. In this review, the description of artificial therapies will be made (**Table 4**).

The artificial liver support system allows the removal of water-soluble toxins, such as ammonium, urea, creatinine, iron, aromatic amino acids, trypophan, and also fatsoluble toxins, such as bile acids, conjugated and unconjugated bilirubin, short and


#### **Table 4.**

*Classification of liver support systems.*

medium chain fatty acids, benzoadiazepines endogenous, mercaptans, copper, nitric oxide, indoyxisulfate, and protoporphyrin [29].

We consider that the removal of the mentioned toxicants with detoxification-only approach does not generate the clear benefit due to the extensive mechanisms of perpetuation of liver damage, it is possible that the traditional MARS, Prometheus techniques are not good enough due to the smaller diameter of the beads, smaller pore diameter, smaller amount of resin, and smaller adsorbent surface in the first two and that the concentration of albumin used in MARS and SPAD is not sufficient, and these details will be reviewed in each of the techniques extracorporeal support.
