Danaparoid

Abstract

Danaparoid, a low molecular weight heparinoid consisting of a mixture of heparan, dermatan and chondroitin sulfates, has well established antithrombotic activity. The drug has a high antifactor Xa to antifactor IIa (thrombin) activity ratio, a low tendency to cause bleeding and minimal effects on the fibrinolytic system. Danaparoid has a low cross-reactivity rate with heparin-associated antiplatelet antibodies (0 to 20%; mean approximately 10%). This represents a significant advantage over low molecular weight heparins (LMWHs) as a potential replacement agent for unfractionated heparin (UFH) in patients with immune-mediated (type II) heparin-induced thrombocytopenia (HIT). In a worldwide compassionate-use programme involving a total of 667 patients with HIT to date, 93% of danaparoid treatment courses were considered to be successful. Thrombocytopenia resolved in 91% of episodes. In a multicentre randomised comparative trial of danaparoid and dextran in patients with HIT plus thrombosis (HITT), significantly more danaparoid than dextran recipients had resolution of thromboses, and an effective clinical response was achieved in significantly more danaparoid recipients. Results of a retrospective case-controlled study of danaparoid and ancrod in patients with HITT showed significantly fewer new or progressive thromboses with danaparoid. In the compassionate-use programme, danaparoid was associated with a mortality rate of 10.4% during treatment (up to 3.5 years) and 7.8% during the follow-up period (3 months). 14 of 114 deaths during the follow-up period were considered to be related to danaparoid therapy. A mortality rate of 23.5% was reported in patients accepted for but not treated with, danaparoid. Mortality rates with danaparoid, ancrod and dextran in the comparative studies were similar (7, 11 and 12%, respectively). Severe bleeding was reported in 3.1% of patients in the compassionate-use programme, persistent or recurrent thrombocytopenia in 2.6% and new thromboembolic events/extension of existing thrombosis in 1.7%. The incidence of bleeding was similar with danaparoid and dextran in a comparative trial. Although in vitro cross-reactivity does not always translate into clinical cross-reactivity, testing is currently recommended, when possible, before initiation of danaparoid therapy. Thus, danaparoid appears to be an effective and well tolerated replacement agent for UFH in many patients with HIT who require further anticoagulation. The drug has low cross-reactivity with HIT-associated antibodies. Further comparative trials are needed to confirm these promising findings.

Effect of Factor X Inhibition on Coagulation Activation and Cytokine Induction in Human Systemic Inflammation

“…We used 6400 U of danaparoid in the present trial, which is currently only recommended in the setting of cardiac bypass surgery. Although we have not fully reached the initial anti-FXa activities of the UFH trial, anti-FXa activities were in the "supratherapeutic range" for any standard indication of danaparoid [28], up to 6 h after administration. Hence, even very high doses of a relatively selective anti-FXa anticoagulant cannot fully suppress thrombin generation during endotoxemia.…”

“…Danaparoid was chosen because of its predominant anti-FXa activity. Although the precise at Kainan University on March 30, 2015 http://jid.oxfordjournals.org/ Downloaded from mechanism of action is not clear, its high ratio of anti-FXa: anti-FIIa activity (120:1) is assumed to be related to the differences in half-lives of anti-FXa and anti-FIIa activities (20 h and 90 min, respectively) [28].…”

Glycosaminoglycan Neutralization in Coagulation Control

“… 5 Another drug, danaparoid is a mixture of HS, DS, and chondroitin sulfate and is used in some countries for the treatment of heparin-induced thrombocytopenia. 24 …”

By-Products of Heparin Production Provide a Diverse Source of Heparin-like and Heparan Sulfate Glycosaminoglycans

“…They are thus quite distinct from Hp in terms of both structure and activity, and represent a relatively untapped resource for production of Hp-like and HS polysaccharides. Although some mixed GAG preparations such as sulodexide, a mixture of LMWH and dermatan sulfate; 5 and danaparoid, a mixture of HS, DS and CS 35 ; have been prepared from crude mammalian mucosa extracts for pharmaceutical use 5,6 details of their structural characterisation have been largely lacking until recently 36 . HS GAGs from crude porcine mucosal Hp preparations have been previously described 4 , and recent work has also highlighted the need for careful structural characterisation of such preparations to avoid potential production artefacts such as de-N-sulfated glucosamine 32 .…”