Biology Reference
In-Depth Information
physiological conditions. It requires the action of Factors VIII, IX, X, XI, XII, and high
molecular weight kininogen, prekallikrein, Ca
2
as well as platelet-derived phospholipids.
The intrinsic pathway is initiated through exposure of several factors (prekallikrein, Factor XI,
and Factor XII) to a negatively charged surface (“contact phase”). Exposure of these factors to
phospholipids with a net negative charge (e.g., phosphatidylethanolamine) present on circulating
lipids can initiate this pathway, and this partly accounts for the prothrombotic tendencies of
hyperlipidemic states. The extrinsic pathway begins at the site of tissue (endothelial) injury,
and the cascade is initiated by the release from the site of injury of Factor III (“tissue factor”).
Factor III participates in the activated Factor V-activation of Factor X [forming activated Factor
X (Factor Xa), the beginning of the common pathway that links the intrinsic and extrinsic
cascades]. Factor Xa in turn proteolytically activates prothrombin to thrombin (Factor IIa), and
this occurs on the surface of activated platelets. Factor IIa then proteolytically cleaves fibrinogen
(which is comprised of three pairs of polypeptides that are covalently linked) to form fibrin
through the aggregation of monomers produced via the digestion of the fibrinogen. The fibrin
acts as a mesh-like lattice that stabilizes the forming platelet aggregate (fibrin clot). Factors VIII
and V can be inactivated (regulated) by proteins C and S, and these regulatory components are
activated by thrombin. Inhibition of several factors is accomplished by antithrombin.
As shown in the figure, hazard level 1 colubrid venom toxins may act on these clotting
mechanisms by activating Factor X, thereby producing indirect activation of prothrombin,
or by directly activating prothrombin. These toxins will thereby cause a coagulopathy that
will rapidly consume the available clotting factors. As these venoms also contain proteolytic
toxins that cause damage to blood vessel endothelium, massive hemorrhage may occur. In
addition, the consumptive coagulopathy causes microthrombi that may lodge in the renal
vasculature and result in mini-infarcts. The envenomated victim may hemorrhage extensively
and develop hypovolemia, anemia, severe ecchymoses, hemorrhagic infarcts, and acute
kidney injury. Bleeding may be brisk and life threatening. In addition,
P. olfersii
Duvernoy's
secretion contains a fibrinogenolytic toxin that may prevent formation of a stable fibrin clot,
and therefore could act as an anticoagulant. However, unlike the well-documented correlation
between the pharmacology of hazard level 1 colubrid venom toxins and the pathophysiology
of envenomation, there has been no clinically documented or confirmed coagulopathy from an
envenomation by
P. olfersii
. Figure copyright to Julian White.
4.2.2.3 Summary of Experimental Pathophysiological Effects of Duvernoy's
Secretion from
P. patagoniensis
Peichoto et al. (2006) investigated the pathophysiological changes induced in rats by
s.c, i.m., or i.v. administration of
P. patagoniensis
Duvernoy's secretions. Intravenously
administered doses between 0.23 and 0.90 mg of secretion resulted in reported multifo-
cal hemorrhage involving the cerebellum, cerebrum, and lungs. Noted also were renal
peritubular capillary congestion and hepatic hydropic degeneration (Peichoto et al.,
2006). The s.c. and i.m. routes exhibited similar effects aside from a lack of cerebel-
lar and/or cerebral hemorrhage, while i.v. and s.c. administration were associated
with elevated hepatic enzymes [aspartate aminotransferase (AST) and alanine amino-
transferase (ALT); Peichoto et al., 2006]. The authors concluded that
P. patagoniensis
Duvernoy's secretion induced moderate histopathological changes in the vital organs
of rats shortly after administration. They opined that the observed changes might be
associated with functional abnormalities of the affected organs during envenoming
(Peichoto et al., 2006).
