Pathophysiological Consequences of Protein N-Homocysteinylation - Homocysteine in Protein Structure/Function and Human Disease - page 114

N-Hcy

Fibrinogen

Hcy-thiolactone

N-Glucose

NH 2

Altered
fibrin
clot
structure

Glucose

Thrombosis

Fibrinogen

Fibrinogen

N-Ox-lipid

Ox-Lipids

Fibrinogen

Fig. 6.4 Fibrinogen modifications affect fibrin clot structure and lead to enhanced thrombosis
(Reproduced from [143])

in vivo. The in vivo relevance of fibrinogen N-homocysteinylation in humans is
further supported by findings showing that elevated plasma tHcy decreases perme-
ability, and increases resistance to lysis, of fibrin clots from plasma of coronary
artery disease (CAD) patients and healthy subjects [174]. Moreover, fibrin clot
structure is more compact and less permeable in CAD patients than in controls.
These detrimental effects of elevated plasma tHcy on fibrin clot structure are
consistent with a mechanism involving fibrinogen modification by Hcy-thiolactone
(Fig. 6.4 ) [174]. Furthermore, prothrombotic N-Hcy-fibrinogen levels are signifi-
cantly elevated in CBS-deficient patients (Table 5.10 ) known to have increased
susceptibility to thrombosis [115].
In patients with diabetes and hypercholesterolemia, the fibrin clot structure is
less permeable and less susceptible to lysis by plasmin, i.e., thrombogenic, com-
pared with CAD patients or healthy subjects. However, the influence of Hcy on the
clot structure in patients with diabetes and hypercholesterolemia is obscured by the
dominant effects of glucose and cholesterol, respectively. These findings suggest
that fibrinogen modifications by glucose and products of lipid oxidation, like the
modification by Hcy-thiolactone, are detrimental and that these modifications
predominate over the modification by Hcy-thiolactone in patients with diabetes
and hypercholesterolemia (Fig. 6.3 ) [174].
Lowering plasma tHcy by folic acid supplementation improves clot structure
(increases permeability and susceptibility to lysis) in asymptomatic human
subjects. This finding suggests that Hcy-lowering therapy by vitamin supplementa-
tion can have beneficial antithrombotic effects [174]. Taken together, these results
support a hypothesis that fibrinogen N-homocysteinylation by Hcy-thiolactone
leads to abnormal resistance of fibrin clots to lysis in vivo and thus contributes to
increased risk of thrombosis [174, 175]. In addition to N-homocysteinylation, other
fibrinogen modifications, such as those occurring in hypercholesterolemia and
hyperglycemia, can also increase the risk of thrombosis (Fig. 6.3 ) [174].