*2.1.6.1. FXIIIa inhibitors*

Factor XIIIa promotes the covalent crosslinking of fibrin polymers and incorporation of proteins into the fibrin network and thus the thrombus can be stable and relative resistance to plasmin-mediated degradation. Besides, FXIIIa is involved in other processes such as wound healing and arteriosclerosis. Therefore, selective FXIIIa inhibitors may be a valuable tool for evaluation of the various functions of FXIIIa and their pharmacological control [112]. In this field, a potent FXIIIa inhibitor was found in leeches. Tridegin was discovered in salivary glands of blood-sucking leech, *Haementeria ghilianii*. It is a highly specific inhibitor of factor XIIIa with about 7 kDa, this inhibitor works with effective concentrations in the nanomolar range [113]. It was also related the presence of transcripts similar to tridegin in some transcriptome analysis of other leeches specie [12], but the obtaining of new molecules from leeches with this function was not yet published. Some tridegin analog peptides have been synthesized and analyzed for their action improvement, but so far, nothing very relevant has been exposed [114]. Although not used in clinical trials on its recombinant form (T087), a derivative of tridegin is being marketed by more than one company for use in laboratory research.

and is a unique representative of invertebrate lysozymes. This molecule combines the properties of endo-s-lysyl-y-glutamyl isopeptidase (D-dimer monomerase), lysozyme, and chitinase and simultaneously is also a non-enzymatic antimicrobial agent. Its ability to hydrolyze endoisopeptide bonds formed by transglutaminases, which are involved in many pathological conditions, including thrombosis, causes this enzyme to become a focus to seek its use in

Anticoagulants from Hematophagous http://dx.doi.org/10.5772/intechopen.78025 49

The substrate of destabilase is the D-D-dimer, a protein of 190 kDa that contains fragments of all three chains of monomer fibrin (alpha, beta, and gamma) and there is a nonlinear dependence of the reaction rate on substrate concentration. The crosslinked fibrin is also a substrate of destabilase, which catalyzes hydrolysis of isopeptide bonds connecting gamma-gamma

Recently, a study demonstrated an optimization procedures related to the expression, isolation, and purification of active destabilase isoforms (mlDL-Ds1, 2, 3) using an *Escherichia coli* expression system, where their muramidase, lytic, isopeptidase and antimicrobial activities were detected and compared. Analyses of the tested activities revealed that all isoforms had almost identical patterns of pH and ionic strength effects. It was determined that three isoforms possessed nonenzymatic antibacterial activity independent of their muramidase activity. It was also demonstrated, for the first time, the fibrinolytic activity of the recombinant destabilase and showed that only intact proteins possessed this activity, suggesting being an enzymatic property [126].

Most anticoagulants from ticks are produced for the salivary glands and play essential functions during feeding. Ticks inject the saliva into the skin of a wide range of terrestrial vertebrates and absorb it along with the blood of the animal. Faced with an injury inflicted by tick bite, the animal respond by activating blood coagulation, vasoconstriction, inflammation, and tissue remodeling related to wound healing. However, these ectoparasites have a complex and potent pharmacological mechanism to overcome the host defenses, blocking pain and

Differences in the composition of tick saliva are reflected in the co-evolution between ticks and their host, the feeding strategies, the tick developmental stage, the process of penetration of the host skin, and the duration of the feeding. This can be observed between the two major families, Argasidae and Ixodidae. The first family (family Argasidae) is called soft ticks. They feed fast, less than 1 h, for multiple times causing profound damage to the host skin due the deep mouthparts penetration, while hard ticks (family Ixodidae) feed for a prolonged period (days to weeks) in each developmental stage. Hard ticks have strategies to firmly attach to its host, producing large amount of cement or glue to penetrate the host skin and cause a superficial damage (Metastriata ticks, e.g., *Dermacentor* or *Rhipicephalus* genera), or by attaching more deeply to the host skin by physical mechanisms using longer, barbed mouthparts. Females hard tick feed only once and may ingest more blood than 100-times their initial body weight to die later after

oviposition (Prostriata, e.g., *Ixodes*, *Metastriata*, and *Amblyomma* genera) [127, 129–131].

practice [123], on the other hand, none was presented after that.

itch and facilitating blood flow to allow the feeding [25, 127, 128].

and alpha-alpha-chains of this protein [124, 125].

**3. Anticoagulants from ticks**
