**4. Conclusions**

*Free Radical Medicine and Biology*

ROS/RNS (O2

*RBC biomarkers*

*Platelet biomarkers*

potential

externalization

PS externalization and loss of mitochondrial membrane

Mitochondrial membrane hyperpolarization without PS

*Biomarkers of oxidative stress in KD.*

*ROS/RNS, oxygen- and nitrogen-derived species; O2*

*RBC, red blood cell; PS, phosphatidylserine; NOS, nitric oxide synthase.*

H2O2)

•−, • OH, • NO,

been hypothesized that in KD patients, oxidative stress can alter platelet functions and platelet apoptosis program resulting in thrombocytosis that can exert a pathogenetic role in the cardiovascular complications [47]. This hypothesis is supported by the detection of markers of platelet activation, such as P-selectin shedding and PS externalization. P-selectin is a cell-adhesion molecule constitutively expressed in the α-granules of resting platelet. It translocates at the surface during platelet activation and subsequently released by a shedding phenomenon. Its release modulates leucocyte adhesion to both platelets and endothelial cells during inflammatory responses and thrombus formation [73]. PS externalization in platelets is usually associated with a sort of programmed cell death and correlated with their hyper-activation. In KD patients, before treatment with IVIG and aspirin, two different sub-populations of platelets have been identified: (i) annexin V positive platelets, characterized by a decreased mitochondrial membrane potential and

**Plasmatic biomarkers Specificity Clinical findings** 

NOS. Regulates the NO bioavailability

death when externalized to the outer leaflet

leucocyte adhesion to both platelets and endothelial cells during inflammatory responses and thrombus formation

Biomarkers of potentially pro-coagulant

*, superoxide anion; •*

*H2O2, hydrogen peroxide; MDA, malondialdehyde; ADMA, asymmetric dimethylarginine; MPO, myeloperoxidase;* 

Biomarkers of pro-coagulant platelets Detected

fatty acids peroxidation

pro-inflammatory state

of the plasma membrane

MDA Specific marker of omega-3 and omega-6

Protein 3-nitrotyrosine End-product of modification of tyrosine residues

ADMA Endogenous inhibitor of the endothelial

MPO Pro-oxidant enzyme that can promote the

Glycophorin A Glycoprotein downregulated during RBC senescence

CD47 Thrombospondin receptor that acts as a

Band 3 Ion exchanger involved in RBC adhesion to endothelium

PS externalization Phospholipid, marker of RBC aging and

P-selectin A cell-adhesion molecule that modulates

platelets

*•*

marker of self

Generates in blood a pro-oxidant status Increased levels

**in KD**

Increased levels

Increased levels

Decreased levels

Increased levels

Down-regulated

Down-regulated

Down-regulated

Shedding

Detected

*NO, nitric oxide;* 

*OH, hydroxyl radicals; •*

Increased percentage of RBCs with externalized PS

**44**

**Table 3.**

In this chapter, a complex framework of events contributing to the etiology of KD has been described. These include some type of bacterial or viral infection, genetic determinants, immune system as well as hematological alterations. Although epidemiological and clinical data suggest that KD may arise from an abnormal response to infectious diseases in genetically susceptible individuals, there are still many controversies about the etiology of KD. There is no agreement on KD-related infectious agents, and the immune mechanisms behind KD remaining only partially known. Only the basic research evaluating the pathogenic mechanisms of this disease will probably find new targets for identifying diseasemodifying agents or therapies that are more specific. Moreover, in this chapter, we provided new lines of evidence supporting the hypothesis that systemic oxidative stress together with premature aging of RBCs and platelets could play a critical role in the cardiovascular risk observed in patients with KD.
