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Danaparoid

A Review of its Pharmacology and Clinical Use in the Management of Heparin-Induced Thrombocytopenia

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An Erratum to this article was published on 01 April 1998

Summary

Synopsis

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 ≈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.

Pathophysiology of Heparin-Induced Thrombocytopenia

Immune-mediated heparin-induced thrombocytopenia (HIT; type II) is characterised by mild to moderate, delayed-onset reductions in platelet count, the presence of heparin-associated antibodies (predominandy IgG), and the paratioxical but frequent occurrence of serious venous and/or arterial thromboembolic events (HITT).

The pathogenesis of HIT involves platelet activation induced by conjugates of heparin, platelet proteins [usually platelet factor 4 (PF4)] and heparin-associated antibodies. Binding of excess PF4 to endothelial cells and the generation of platelet-derived microparticles that have procoagulant activity are involved in the pathogenesis of HITT.

The antibody responsible for platelet activation in patients with HIT does not appear to be heparin specific; highly sulphated nonheparin polysaccharides that are negatively charged can produce HIT-associated antibodies.

Pharmacodynamic Properties

Danaparoid, a low molecular weight heparinoid derived from porcine gut mucosa, contains a mixture of heparan sulfate (≈84%), dermatan sulfate (≈12%) and chondroitin sulfate (≈4%).

The exact antithrombotic mechanism of action of danaparoid is not clear but is thought to involve a complex interaction between its 2 major components. Danaparoid exerts its antithrombotic effect principally through antithrombin III-mediated inhibition of factor Xa; factor IIa is inactivated to a much lesser extent. This action results in inhibition of thrombin generation and consequent inhibition of fibrin generation and thrombus formation. The high ratio of antifactor Xa to antifactor IIa activity (≥20: 1) contrasts with that for low molecular weight heparins (LMWHs; 1.9 to 3.2: 1) and unfractionated heparin (UFH; 1:1). The simultaneous inhibition of factors IX and X may also contribute to the antithrombotic activity of danaparoid.

Danaparoid was at least as effective as UFH in inhibiting the formation of thrombi and preventing the extension of established venous thrombi in animal models of thrombosis. However, unlike UFH, danaparoid has minimal or no effects on platelet function, minimal effects on activated partial thromboplastin time, thrombin time and prothrombin time, and a low tendency to promote bleeding.

A major advantage of danaparoid over LMWHs is its low rate of cross-reactivity with heparin-associated antibodies from patients with HIT [0 to 20% (mean ≈10%)vs 25.5 to 100%].

Danaparoid appears to have no clinically significant effects on individual components of the fibrinolytic system and has less lipolytic activity than UFH.

Pharmacokinetic Properties

Pharmacokinetic studies of danaparoid have been based on the kinetics of its anticoagulant activities. Available data are limited to those from healthy volunteers. Wide interindividual variation in the pharmacokinetic parameters of the anticoagulant activities of danaparoid has been observed.

The absolute bioavailability of danaparoid after subcutaneous administration approaches 100%. The antifactor Xa activity of danaparoid exhibits biexponential pharmacokinetic characteristics after intravenous administration, whereas plasma antifactor IIa activity exhibits monoexponential kinetics.

A linear relationship between plasma antifactor Xa activity and increasing danaparoid dose occurs after intravenous administration. After subcutaneous administration, maximum plasma antifactor Xa activity (150 U/L after a dose of 750 antifactor Xa units) occurs after approximately 2 to 5 hours; maximum plasma antifactor IIa and factor IIa generation-inhibiting (IlaGI) activities occur earlier. Steady-state plasma antifactor Xa and IlaGI activities are usually reached within 4 to 5 days and 1 to 2 days, respectively.

No antifactor Xa activity was demonstrated in cord blood in 4 pregnant women who received danaparoid.

Danaparoid is excreted predominantly by the kidney. There is no evidence of hepatic metabolism. The elimination half-life (t½β) of antifactor Xa activity (19.2 to 24.5 hours; range of mean values) is longer than that for antifactor IIa (1.8 to 4.3 hours) and IIaGI acdvides (6.2 to 6.7 hours).

In patients with renal failure, the renal clearance of danaparoid is reduced and the t½β of plasma andfactor Xa activity may be prolonged. Dosage adjustments are recommended in these patients (see Dosage and Administration summary). The pharmacokinetics of danaparoid do not appear to be altered by changes in hepadc function, age or bodyweight.

Clinical Use

At present, efficacy data on danaparoid in patients with HIT are limited to those from a compassionate-use programme, case series, individual case reports and 2 comparative trials; some data are available in abstract form only.

In the worldwide compassionate-use programme of danaparoid, involving a total of 667 patients with HIT to date, 93% of evaluable treatment episodes were considered to be successful. Successful treatment was defined as resolution of thrombocytopenia or no development of thrombocytopenia in a patient with a previously normal count, and either no (further) thromboembolic events or no clinically significant problems after a surgical or intravascular procedure. Thrombocytopenia resolved in 91% of treatment episodes. Treatment outcome was similar irrespective of whether HIT was confirmed and whether patients had acute, subacute or past HIT.

In other case series and individual case reports of specific subgroups of patients with HIT, treatment was considered to be successful in 80 to 100% of patients with present or past HIT undergoing haemodialysis (total n = 14); in all of 5 intensive care patients with HIT; in all of 11 patients with HITT and normal platelet counts; and in 87% of 47 evaluable patients who underwent cardiopulmonary bypass surgery.

In patients with HITT, thrombosis resolved in significantly more danaparoid than dextran recipients, and danaparoid achieved an effective clinical response in significantly more patients than dextran. Significantly fewer new or progressive thromboses occurred with danaparoid than with ancrod in patients with HITT

Tolerability and Drug Interactions

Mortality rates of 10.4% (during danaparoid treatment) and 7.8% (during the 3-month follow-up period) were reported in the worldwide danaparoid compassionate-use programme involving 677 patients with HIT. 14 of the 114 deaths during the 3-month follow-up period were considered to be related to danaparoid therapy. Mortality rates were similar irrespective of the type of HIT or whether HIT had been confirmed. Danaparoid (7%), ancrod (11%) and dextran (12%) were associated with similar mortality rates in the 2 available comparative trials.

Of the patients in the compassionate-use programme, severe bleeding occurred in 3.1% of patients, persistent or recurrent thrombocytopenia in 2.6% or a new thromboembolic event/extension of existing thrombosis in 1.7%.

No bleeding events were reported in the comparative trial of danaparoid and dextran. The incidence of bleeding was not reported in the report of danaparoid versus ancrod.

Delayed-type hypersensitivity reactions may occur in patients receiving danaparoid. No clinically significant changes in laboratory parameters with danaparoid have been reported.

No adverse pharmacodynamic changes have been observed with the concomitant administration of danaparoid and oral anticoagulants, agents that interfere with platelet function or haemostasis, potentially ulcerogenic agents, chlorthalidone or digoxin. The overall kinetics of antipyrine (phenazone) were unaffected by danaparoid. However, the clinical relevance of a large increase (86%) in the volume of distribution of antifactor IIa activity of danaparoid by chlorthalidone requires further investigation.

Dosage and Administration

Danaparoid may be administered to patients with HIT (clinically suspected, preferably confirmed) requiring further anticoagulation once all sources of heparin have been discontinued.

The drug may be administered subcutaneously or intravenously. Oral anticoagulants may replace danaparoid once adequate antithrombotic control has been achieved. In vitro cross-reactivity to HIT-associated antibodies is not always predictive of clinical cross-reactivity. However, it is currently recommended that cross-reactivity should be excluded, when possible, before initiation of danaparoid therapy.

Dosage recommendations for danaparoid vary greatly according to the reason for further anticoagulation, underlying diseases, coexistent haemostatic disorders, bodyweight and age. Therefore, the reader is referred to the main text for specific dosage recommendations (section 7).

In patients with renal failure undergoing haemodialysis, maintenance dosages should be reduced and titrated according to predialysis plasma antifactor Xa activity.

Platelet counts should be monitored periodically during danaparoid therapy. The activity of danaparoid can be monitored by measuring plasma antifactor Xa levels. If serious bleeding events occur during danaparoid administration, the drug should be discontinued and bleeding controlled by supportive means; protamine does not reverse the effects of danaparoid.

Danaparoid is contraindicated in patients with severe haemorrhagic diathesis, active major bleeding, hypersensitivity to danaparoid, sulfite or pork products, or a positive in vitro test for antiplatelet antibody in the presence of danaparoid. Extreme caution is advised in patients with disease states in which there is an increased risk of haemorrhage. Caution is also advised in patients with severe renal impairment. Danaparoid should be used in pregnant or lactating women only when no alternative antithrombotic agent is available.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Michelle I. Wilde & Anthony Markham

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  1. Michelle I. Wilde
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  2. Anthony Markham
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Correspondence to Michelle I. Wilde.

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Various sections of the manuscript reviewed by: M. Danhof, Center for Bio-Pharmaceutical Sciences, Division of Pharmacology, University of Leiden, Leiden, The Netherlands; A. Greinacher, Institute for Immunology and Transfusion Medicine, Sauerbruchstrasse, Greifswald, Germany; S.R. Insler, Department of Cardiothoracic Anesthesia, Cleveland Clinic Foundation, Cleveland, Ohio, USA; I.A. Jagroop, Department of Chemical Pathology and Human Metabolism, Royal Free Hospital, London, England; M.C. Kappers-Klunne, Department of Haematology, University Hospital Rotterdam Dijkzigt, Rotterdam, The Netherlands; D.P. Mikhailidis, Department of Chemical Pathology and Human Metabolism, Royal Free Hospital, London, England; H. ten Cate, Division of Haemostasis and Thrombosis, Department of Haematology, Academic Medical Center, Amsterdam, The Netherlands; T.E. Warkentin, Department of Laboratory Medicine, Hamilton General Hospital, Hamilton, Ontario, Canada.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259986.

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Wilde, M.I., Markham, A. Danaparoid. Drugs 54, 903–924 (1997). https://doi.org/10.2165/00003495-199754060-00008

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