Research Notes: Chondroitin Sulfate

See also: Hematological

Alcohol. 2006 Jun.
The effect of acetaldehyde-glycosaminoglycan mixtures upon Factor IXa and Factor IX-Deficient Plasma.
Brecher AS, Moon AR, Gray KD.
Department of Chemistry, Bowling Green State University, Bowling Green, OH, USA.

Earlier studies have shown that acetaldehyde, the primary intermediate in the biological degradation of ethanol, interacts with enzymes and zymogens of the common coagulation pathway, prolonging prothrombin time and activated partial thromboplastin time (APTT), and that acetaldehyde-glycosaminoglycans (GAGs) mixtures synergistically prolong clotting times (Brecher, A. S. (2005). In Comprehensive Handbook of Alcohol Related Pathology. Vol. 3(93), pp. 1223-1244). In this study, the effect of acetaldehyde and GAGs upon Factor IXa, an intrinsic pathway enzyme, has been investigated. Individually, acetaldehyde, heparins of various molecular weights, dermatan sulfate, and chondroitin sulfates A and C affect Factor IXa, prolonging clotting time as measured by APTT. Pre-incubation of Factor IXa with a mixture of 22.3 mM acetaldehyde and heparin(17k), heparin(6k), dermatan sulfate, or chondroitin sulfate A additively prolongs clotting times, reflecting individual, unrelated molecular mechanistic effects. In contrast, a synergistic effect is observed at the 44.7 mM acetaldehyde level with heparin(17k), heparin(3k), chondroitin sulfates A and C, and dermatan sulfate, suggesting that acetaldehyde may cross-link with the enzyme and the GAGs, forming tertiary complexes, further influencing coagulopathy. These observations upon Factor IXa present a deeper dimension to the anticoagulation effect of alcohol on the coagulation cascade.

Can J Physiol Pharmacol. 2005 May.
The effect of glycosaminoglycans with acetaldehyde on the activation of prothrombin.
Brecher AS, Adamu MT.
Department of Chemistry, Bowling Green State University, OH, USA.

Heparin17-19k, (25, 50, and 100 ng), heparin6k (50 and 100 ng), heparin3k (50, 100, and 200 microg), chondroitin sulfates B (dermatan sulfate) (0.25, 0.5, and 1.0 microg), C (1 and 10 microg), and A (1 and 10 microg) each prolong the activated partial thromboplastin time (APTT) when preincubated with prothrombin to a greater extent than when preincubated with Factor II-deficient plasma prior to their mixing and subsequent additions of APTT reagent and Ca2+. In all cases statistical significance (p < or = 0.05) was observed except with the 2 lower levels of heparin3k. These results suggest that the glycosaminoglycans (GAGs) may exert a direct effect upon prothrombin (FII) in their anticoagulant activity. Pre mix tures of [(FII/25 ng H17-19k) + 447 mmol acetaldehyde (AcH)/L] as well as [(AcH/H) + FII] and [(FII/AcH) + H] each exert a synergistic anticoagulant effect upon APTT. At low AcH concentrations (44.7 mmol/L), neither a synergistic nor an additive effect is seen. H6k and H3k, on premixing with 447 mmol AcH/L, exhibit an additive effect on APTT prolongation but no synergism. Similarly, premixtures of CSB/447 mmol AcH/L/FII show a greater anticoagulant effect than do [(CSB/AcH) + FII] or [(FII/AcH) + CSB] premixtures. CSC-AcH and CSA-AcH patterns are analogous to those of CSB (DS). These data suggest the possibility that AcH, the primary product of ethanol metabolism, may serve as a crosslinking adduct with proteins, in this case, prothrombin, as well as GAGs. Thus ternary complexes between the zymogen form of coagulation factors, GAGs, and AcH are possible, further influencing coagulopathy.

Dig Dis Sci. 2001 Sep.
Coagulation protein function: enhancement of the anticoagulant effect of acetaldehyde by sulfated glycosaminoglycans.
Brecher AS, Adamu MT.
Department of Chemistry, Bowling Green State University, Ohio, USA.

In view of the increased anticoagulant effect of acetaldehyde-treated heparin, other glycosaminoglycans (GAGs) such as chondroitin sulfates A and C, dermatan sulfate (chondroitin sulfate B), heparan sulfate, and hyaluronic acid were tested for anticoagulant activity before and after exposure to acetaldehyde. Clotting times of human plasma Ci-Trol coagulation control, level I (Baxter Healthcare Corp.), were tested in the presence of 1.8, 3.0, 3.6, or 4.5 microg heparin (0.32, 0.54, 0.64, 0.81 units heparin). Additionally, 9, 27, or 90 microg of chondroitin sulfates A, B, or C was utilized in lieu of heparin. The effects of 2 microg heparin (0.36 units), chondroitin sulfates A, B, and C, (20 microg each), 2 microg heparan sulfate, and 2 microg hyaluronic acid, respectively, in the presence of 44.7 mM acetaldehyde on the clotting time of plasma were studied. It was observed that chondroitin sulfate B (dermatan sulfate) prolonged the clotting time of plasma, although to a lesser extent than heparin. Chondroitin sulfates A and C, heparan sulfate, and hyaluronic acid did not prolong clotting time. However, pretreatment of all the sulfated GAGs with acetaldehyde gave products that enhanced the anticoagulant effect of acetaldehyde, notwithstanding the lack of anticoagulant effect of the GAGs. In contrast, hyaluronic acid exhibited no effect upon clotting time nor did its acetaldehyde-treated product. Furthermore, ethanol exhibited no effect upon the clotting times of the GAG-plasma mixtures. These results suggest that sulfated GAGs may be modified by acetaldehyde, a component of plasma in chronic alcoholics, and that the resultant products may contribute to the prolonged clotting times.