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

Abstract

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.

Comparison of Tinzaparin™ and Unfractionated Heparin as Anticoagulation on Haemodialysis: Equal Safety, Efficacy and Economical Parity

“…Although monitoring of anti-factor Xa activity has failed to show any significant accumulation of LMWH with recurrent use on haemodialysis [7, 9, 22, 23], it is important to acknowledge that there is poor correlation between anti-Xa levels and the risk of haemorrhage [24, 25]. Additionally, the changing paradigms of haemostasis [26,27,28] point to reduced clot elastic module and platelet contractile force (i.e.…”

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

“…It also increased the template bleeding time consistent with several reports on the antihemostatic effects of LMWH. [29][30][31][32][33][34] The bleeding time test, which remains the most reliable global marker of treatment-induced hemostasis impairment, [22][23][24][35][36][37] was therefore used for the safety assessment of PCA treatment infusion in the equiefficacious dose range. While the absence of significant increase in the bleeding time during PCA infusion does not exclude the possibility of bleeding side effects, 38 the direct comparison between LMWH and PCA strongly suggested that the latter was considerably safer.…”

Differences Among Low-Molecular-Weight Heparins: Evidence in Patients With Acute Coronary Syndromes

“…26 In terms of clinical correlates, some studies have suggested that the ratio of anti-Xa to anti-IIa activity for any given LMWH may impact clinical outcomes. 27,28 Experimental studies suggest that LMWHs with lower anti-Xa to anti-IIa ratios may increase the risk of hemorrhage, whereas those with higher anti-Xa to anti-IIa ratios may be associated with a lower bleeding risk. These observations are biologically plausible when considering the physiology of hemostasis.…”