Comparative Antithrombotic and Hemorrhagic Effects of Dermatan Sulfate, Heparan Sulfate, and Heparin

Hoppensteadt, Debra; Racanelli, A.; Walenga, Jeanine M.; Fareed, Jawed

doi:10.1055/s-2007-1002734

Cited by 19 publications

(12 citation statements)

References 11 publications

(17 reference statements)

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“…The tested dose of DS appears to be potentially suitable for antithrombotic use [7] but as seen in the present study there is a risk for bleeding complications similar to that of the tested LMWHs. These results are in line with results from a various experimental haemostasis model (Cade ear bleeding model) where doses up to 5.0 mg/kg only slightly increased blood loss [30],…”

Section: Discussionsupporting

confidence: 90%

The Haemorrhagic Effect of Low Molecular Weight Heparins, Dermatan Sulphate and Hirudin

Matthíasson

Lindblad²,

Stjernquist³

et al. 1995

Pathophysiol Haemos Thromb

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In a randomized, blind study the primary effect on haemostasis after intravenous administration of dermatan sulphate (DS), recombinant hirudin (r-hirudin) and four commercial low molecular weight heparins (LMWHs) (nadroparine, enoxaparin, dalteparin and tinzaparin) was investigated in rats and compared with saline (control). The tail bleeding time, the bleeding from the gastric mucosa [the mucosal bleeding time (min) and the mucosal bleeding (μ1)] as well as changes in activated partial thromboplastin time, antifactor IIa and Xa activities were investigated. DS and r-hirudin were investigated in a dose potentially suitable in thomboprophylaxis and the LMWHs in doses recommended by the manufacturers for thromboprophylaxis, adjusted to body weight. All substances significantly prolonged the mucosal bleeding time. Dalteparin, tinzaparin, DS and r-hirudin increased the mucosal bleeding when compared with controls whereas nadroparine and enoxaparin did not. The effect of r-hirudin was also significantly more pronounced compared with other treatments. Moreover, r-hirudin prolonged the tail bleeding time significantly whereas the other substances did not. The antifactor Xa activity in plasma correlated well with the given dose of the LMWHs (r_s = 0.7). However, the monitored bleeding parameters in the LMWH groups did not correlate with the plasma activities of antifactor IIa or Xa. The results indicate that the tested LMWHs are not equipotent in their effect on haemostasis in this model and that antifactor Ha or Xa activities do not directly correlate with their effect on haemostasis although increased haemorrhage was observed in the LMWHs with lower antifactor Xa/antifactor IIa ratios. Our findings indicate that the different commercial LMWHs may differ in their haemorrhagic effect when given in recommended clinical doses adjusted to body weight. DS (3.0 mg/kg) did not cause more bleeding than the tested LMWHs but r-hirudin (2.0 mg/kg) caused considerable bleeding.

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Section: Discussionsupporting

confidence: 90%

The Haemorrhagic Effect of Low Molecular Weight Heparins, Dermatan Sulphate and Hirudin

Matthíasson

Lindblad²,

Stjernquist³

et al. 1995

Pathophysiol Haemos Thromb

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“…Naroparcil exerted its antithrombotic effect without enhancing bleeding, even at high oral doses ( 400 mg/kg). Whilst it is difficult to extrapolate experimental (animal) data to possible effects in man, using the same type of model, the bleeding enhancing effects of heparin have been clearly demonstrated (19, 30-32, present study) and no or little effect on bleeding time has been observed with dermatan sulfate and the heparinoid Org 10172 (31)(32)(33). These experimental observations coincide with those obtained in man (see Introduction}, hence it is possible that naroparcil could have an excellent safety profile (antithrombotic effect compared to bleeding risk).…”

Section: Discussionmentioning

confidence: 66%

The Venous Antithrombotic Profile of Naroparcil in the Rabbit

1994

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SummaryThe venous antithrombotic profile of naroparcil or (4-[4-cyanoben-zoyl]-phenyl)-1.5-dithio-β-D-xylopyranoside was investigated in the rabbit following single i. v. and oral administration. Naroparcil attenuated thrombus development in a Wessler stasis model of venous thrombosis (jugular vein) employing bovine factor Xa as a thrombogenic stimulus giving ED50 values of 21.9 mg/kg and 36.0 mg/kg after respectively i. v. and oral administration. Venous antithrombotic activity was maximal 2-3 h after i. v. administration and 4-8 h after oral administration. Four hours after the oral administration of maximal antithrombotic (Wessler model, factor Xa) doses (100 and 400 mg/kg), naroparcil had no significant effect on bleeding time. In platelet poor plasma obtained from animals treated 4 h previously with various doses (25 to 400 mg/kg) of naroparcil, there was no detectable anti-factor Xa nor antithrombin activity. Similarly, naroparcil had no effect on APTT nor on thrombin time. A sensitized thrombin time (to about 35 s) was modestly but significantly increased following oral administration of the compound at 400 mg/kg. However, thrombin generation by the intrinsic pathway was reduced in a dose-related manner, maximal reduction being 65% at 400 mg/kg. The same doses of naroparcil enhanced the formation of thrombin/heparin cofactor II complexes at the expense of thrombin/antithrombin III complexes in plasma incubated with (125I)-human a-thrombin and induced the appearance of dermatan sulfate-like material in the plasma of treated rabbits, as measured by a heparin cofactor II-mediated thrombin inhibition assay. The results suggest that naroparcil could have a safe venous antithrombotic profile following oral administration (antithrombotic effect compared to bleeding risk). It is probable that part of the mechanism of action of the β-D-xyloside, naroparcil, is due to the induction of chondroitin sulfate-like glycosaminoglycan biosynthesis, this material being detectable in the plasma.

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“…The selected dose of DS is high but known to have minimal effect on bleeding [18] and therefore to be potentially suitable for throm boprophylaxis. One might expect that r-hiru din in the tested dose would be capable of completely preventing occlusive thrombosis and even reducing the frequency of thombosis, especially when administered by intrave nous route that generates high initial plasma activity.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike heparin DS does not inhibit factor Xa and is virtually inactive as an anticoagulant in conventional in vitro clotting assays [15]. It has also been suggested that DS has a profibrinolytic effect probably due to plasminogen activation [16], although recent data do not support this theo ry [17], Experimental data from rabbits show that 5-10 times higher doses of DS are re quired to gain a similar antithrombotic effect as UH (Wessler model) and doses up to 5.0 mg/kg only slightly increase blood loss (Cade ear bleeding model) [18], The aim of this study was to evaluate in an in vivo experimental venous thrombosis model in rabbits the individual thrombopro phylactic effect of four commercially avail able LMWHs in doses clinically recom mended by the manufacturer and compare the efficacy to that of recombinant hirudin (rhirudin, CGP 39393) and DS (MF 701).…”

Section: ]mentioning

confidence: 99%

Prevention of Experimental Venous Thrombosis in Rabbits with Different Low Molecular Weight Heparins, Dermatan Sulphate and Hirudin

Matthíasson

Lindblad²,

Bergqvist³

1995

Pathophysiol Haemos Thromb

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In a randomized, blind study the antithrombotic efficacy of dermatan sulphate (DS), recombinant hirudin (r-hirudin) and four commercially available low molecular weight heparins (LMWHs) was investigated after intravenous administration in a jugular vein thrombus model in rabbits utilizing a combination of endothelial damage and flow reduction. The parameters observed were the frequency of visible thrombosis, the frequency of occlusive thrombosis and thrombus weights. DS and r-hirudin were investigated in one fixed dose and the LMWHs in prophylactic doses, adjusted to body weight, recommended in high-risk situations by the manufacturers. All substances effectively reduced the three observed parameters. DS and r-hirudin were equally or even more effective than the LMWHs. Although significant differences were not found between the individual LMWH treatments a visible trend cannot be overlooked in all three observed parameters. This cannot solely be explained by the different antifactor Xa activity doses given but increased antithrombotic activity was observed with declining antifactor Xa/antifactor Ila ratio. Our findings indicate that the different commercial LMWHs may differ in their antithrombotic activity when given in recommended doses adjusted to body weight in this experimental model. Dose range studies are required to clarify the thrombo-prophylactic efficacy of DS and r-hirudin in relation to the tested LMWHs.

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Comparative Antithrombotic and Hemorrhagic Effects of Dermatan Sulfate, Heparan Sulfate, and Heparin

Cited by 19 publications

References 11 publications

The Haemorrhagic Effect of Low Molecular Weight Heparins, Dermatan Sulphate and Hirudin

The Haemorrhagic Effect of Low Molecular Weight Heparins, Dermatan Sulphate and Hirudin

The Venous Antithrombotic Profile of Naroparcil in the Rabbit

Prevention of Experimental Venous Thrombosis in Rabbits with Different Low Molecular Weight Heparins, Dermatan Sulphate and Hirudin

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