**2.2 COVID-19-associated coagulopathy (CAC)**

Most critically ill patients with COVID-19 present with isolated respiratory failure, usually acute respiratory distress syndrome (ARDS). In COVID-19 deaths, the predominant lung damage is diffuse alveolar damage, which includes hyaline membrane formation, capillary congestion, inflammation and pneumocyte necrosis [4, 11]. In addition, fibrin-platelet thrombi in small arterial vessels are also identified in many of these cases [4]. However, about 20–30% of these patients have multiorgan involvement. Among the extra respiratory complications present in COVID-19 are vascular alterations, among which coagulopathies are of great relevance [2]. In general, COVID-19-associated coagulopathy (CAC) is characterised by moderate thrombocytopenia, mildly increased prothrombin time (PT), elevated D-dimer and fibrinogen levels [4].

## *2.2.1 Chronic reactive endotheliitis and von Willebrand factor*

There are different prothrombotic mechanisms in SARS-CoV-2 infection. It has been established that the virus induces oxidative stress at the endothelial level, causing the release of von Willebrand factor (vWF) multimers causing hypercoagulability, despite the thrombopenia caused by the virus, leading to a state of prothrombosis through increased thrombin and D-dimer levels [4, 12–14]. Thus, vWF may be implicated in CAC, due to its direct relationship with homeostasis, inflammation and endothelial cell activation and damage [4]. vWF is a large multimeric glycoprotein whose gene is located on the short arm of chromosome 12 at position 13.3 and has a length of 180 kb and 52 exons [15]. The VWF gene belongs to the endogenous ligand gene family and genetic differences between individuals are associated with vWF

#### *COVID-19 and Thrombosis: Pathophysiological Mechanisms and Therapeutic Update DOI: http://dx.doi.org/10.5772/intechopen.102834*

levels. This includes polymorphisms in the 5′ homeostatic factor regulatory region, which contributes to the level of vWF present in plasma and, consequently, to the risk of thrombotic events [15]. This protein is present in blood plasma, platelet-α-granules, subendothelial connective tissue and endothelium [4, 15]. vWF is synthesised and stored primarily in endothelial cells, megakaryocytes and platelet precursors in the bone marrow [15]. Upon synthesis in endothelial cells, the sequence of the vWF propeptide acts by aligning the 2 units of the molecule to ensure optimal multimerisation. Post-translational modifications involve the removal of the propeptide, glycosylation and the addition of blood group determinants, and then, a multitude of ultra-long vWF (UL-vWF) molecules are synthesised. When endothelial cells are activated, UL-vWF molecules are released and can remain free in plasma or bound to the endothelial surface. UL-vWF molecules exhibit greater prothrombotic activity than smaller vWF multiples. Simultaneously to the release of UL-vWF molecules, ADAMTS-13 (thrombospondin type 1 metalloprotease, member 13) cleaves these molecules into smaller multimers, to stop unwanted thrombus formation [4, 15]. This protein has a functional duality, as it is involved in both homeostasis and thrombosis [4, 15].

vWF plays a major role in primary haemostasis. When damage to the vascular wall occurs, the subendothelium to which vWF is bound is exposed. This protein interacts with platelets and promotes the recruitment of circulating platelets to the site of damage. Platelet-vWF binding is an adhesive interaction capable of binding platelets to the endothelial surface. Although the binding between platelets and vWF is unstable, it promotes a stronger and prolonged adhesion to the endothelium, which is mediated primarily by vWF [4, 15]. As for the process of secondary haemostasis, vWF also plays an important role and that process involves coagulation factors and the coagulation cascade to produce fibrin networks in areas of vascular damage. vWF promotes the process of secondary haemostasis by two mechanisms: Firstly, vWF acts as a transporter of coagulation factor VIII, stabilising it and extending its half-life in plasma. Secondly, it releases and concentrates factor VIII at the site of endothelial damage. Factor VIII is a coagulation factor that, when activated, complements other factors to generate fibrin [4].

During the inflammatory process, different mediators are released as inflammatory molecules activate endothelial cells to release their contents, such as vWF. UL-vWF molecules that remain attached to the cell surface will bind to platelets and serve as a surface to interact with leukocytes. Inflammation also promotes association between vWF molecules, leading to an increase in platelet adhesiveness and a decrease in ADAMTS-13 cleavage. In addition, high-density lipoprotein (HDL) levels decrease during the inflammatory process. HDL plays a key role in preventing the association of vWF molecules with inflammation, as well as decreasing the risk of thrombus under normal circumstances. Increased release of vWF can induce a prothrombotic state [4], which is a pathological state of the haemostatic process. Thrombi are composed of numerous elements including endothelial cells, plasma, proteins and alterations in haemodynamic stress [15]. There is evidence of an association between increased levels of vWF and increased risk of thrombosis [4, 16]; therefore during the inflammatory process, there is an increased risk of thrombosis due to the imbalance in which vWF level and activity are elevated due to over-activation of endothelial cells.

The increase in vWF levels in COVID-19 could be due to the release of this molecule from pulmonary endothelial cells as a result of the pathophysiological process of COVID-19 itself. Infection of endothelial cells by SARS-CoV-2 or their activation in response to inflammatory mediators results in the release of prothrombotic factors, such as vWF. vWF either binds to endothelial cells or circulates in plasma to promote platelet aggregation and thrombus formation (**Figure 1**) [4].

#### **Figure 1.**

*Adapted from Mei et al., J. Appl. Lab. Med. 2021: Mechanism and characteristics of CAC in mild and severe cases. (A) CAC in mild cases. Localised infection and minimal systemic inflammation increase endothelial cell activation. Infection and inflammation remain well regulated. HDL and ADAMTS-13 mechanisms remain largely unchanged, with only a slight increase in thrombotic events. (B) CAC in severe cases. Infection and inflammation are deregulated, leading to an extremely high level of activated endothelial cells. In addition, HDL and ADAMTS-13 levels are decreased, leading to a much greater increase in thrombotic events. (C) Thrombotic thrombocytopenic Purpura (TTP). In TTP, ADAMTS-13 activity levels are significantly lower than in CAC. TTP leads to the elevated levels of UL-vWF. Consequently, platelet-binding levels increase and, consequently, the risk of thrombosis increases. Addendum: In the NIH COVID-19 treatment guidelines panel's statement on anticoagulation in hospitalized patients with COVID-19, last updated the 5th of January 2022, the panel recommends using therapeutic-dose heparin for patients who have a D-dimer above the upper limit of normal, require low-flow oxygen, and have no increased bleeding risk. They recommend continue therapeutic-dose heparin treatment for 14 days or until hospital discharge, whichever comes first [17].*
