Danaparoid

Danaparoid sodium (Orgaran) is an anticoagulant[1] with an antithrombotic action due to inhibition of thrombin generation (TGI) by two mechanisms: indirect inactivation of Factor Xa via AT and direct inhibition of thrombin activation of Factor IX (an important feedback loop for thrombin generation). It also possesses a minor anti-thrombin activity, mediated equally via AT and Heparin Co-factor II producing a ratio of anti-Xa:IIa activity >22. [Meuleman DG. Haemostasis 1992;22:58-65 and Ofosu FA Haemostasis 1992;22:66-72]

Danaparoid
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Trade namesOrgaran
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MedlinePlusa602007
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Danaparoid is a low molecular weight heparinoid devoid of heparin. It consists of a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate.[2] It is chemically distinct from heparin, has different protein-binding properties because of its low degree of sulphation and low surface charge density and thus has little cross-reactivity in heparin-intolerant patients.

The TGI activity, considered by Fernandes et al. [Thromb Haemostas 1987;57/3:286-93] to provide an index of antithrombotic potential, of danaparoid has a half-life of 6.7 hours.

Uses

It is used to prevent deep venous clots, particularly in situations with a high risk of clot formation, such as after hip surgery.

It is also used as a heparin substitute in heparin-induced thrombocytopenia[3][4] (HIT) which may otherwise cause paradoxical thrombosis. Danaparoid is used for thrombosis prophylaxis and treatment in heparin-induced thrombocytopenia patients. Although pre-treatment serological cross-reactivity with heparin-induced antibodies can occur in 5.2% of the patients it bears no systematic relationship with clinical cross-reactivity, 3.2% in the same study of 1478 patients with acute HIT [Magnani & Gallus Thromb Haemost 2006;95:967-81] (ESRA).

It is also approved for the treatment of DIC in Japan and although not approved for the following it has shown efficacy and safety in 406 case reports of paediatric use [Bidlingmaier et al. Acta Haematologica 2006;115:237-247], pregnancy [see Magnani HN. Thromb Res 2010;125:297-302] 197 cases & 81 additional uses to protect cesarian section, patients in renal failure requiring intermittent [Magnani HN. Thromb Res 2010;125:e171-e176] or continuous (CVVRT) [Magnani HN & Wester JPJ. Open access Scientific Reports 2012;1/9:423-9] renal replacement therapy and in patients with hepatic disorders associated with cirrhosis such as portal vein thrombosis [Fujiyama et al. BMC Gatsroenterol 2017;17:112-20] and the sinusoidal obstruction syndrome [Kato et al. Pediatr Transplant 2017;e13099] and thrombotic micro-angiopathy [Machida et al. Bone Marrow Transplant 2016;1-3 Doi:10.1038/bmt.2016.270] that occur after haemopoietic stem-cell transplantation in patients with haematogenous and solid malignancies.

It has also been used in Kasabach–Merritt syndrome in 3 cases.[5]

Discontinuation

On August 14, 2002, this drug was withdrawn by Organon International.[6] from the US market, due to a shortage in drug substance. The manufacturer has continued providing the medication in all other locales where it is approved for marketing.[7]

The drug is now owned and distributed by Aspen Pharma.

Administration

IV and SC

Side effects
  • Bleeding (solely restricted to patients undergoing cardio-pulmonmary surgery with by pass)<Magnani HN, Gallus AG. Heparin-induced thrombocytopenia (HIT) A report of 1478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid 2004." Thromb Haemost 2006; 95: 967-871> found in 4.6% of medical patients, 6.1% after major general and vascular surgery, but 42.3% after CPBS (due to lack of an effective antidote) for which it is now contraindicated.
  • Low platelets, due to a low level of structural similarity between danaparoid and heparin, i.e.only in some patients sensitive to heparin or a LMWH but to date never developed spontaneously. Platelet count recovery was more frequent than in the control group in 2 comparative studies in patients with HIT [Chong et al. Thromb Haemost 2001;86:1170-1175 and Lubenow et al. Thromb Res 2006;117:507-15]
  • Possibly Asthma exacerbations, due to allergies to sulfites contained within the medicine (no case has been reported to date).

References
  1. Hagiwara S, Iwasaka H, Hidaka S, Hishiyama S, Noguchi T (2008). "Danaparoid sodium inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats". Crit Care. 12 (2): R43. doi:10.1186/cc6851. PMC 2447588. PMID 18380908.
  2. de Pont AC, Hofstra JJ, Pik DR, Meijers JC, Schultz MJ (2007). "Pharmacokinetics and pharmacodynamics of danaparoid during continuous venovenous hemofiltration: a pilot study". Crit Care. 11 (5): R102. doi:10.1186/cc6119. PMC 2556745. PMID 17854496.
  3. Schindewolf M, Magnani HN, Lindhoff-Last E (May 2007). "[Danaparoid in pregnancy in cases of heparin intolerance - use in 59 cases]". Hamostaseologie (in German). 27 (2): 89–97. PMID 17479171.
  4. Magnani HN, Gallus A (June 2006). "Heparin-induced thrombocytopenia (HIT). A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004". Thromb. Haemost. 95 (6): 967–81. doi:10.1160/TH05-07-0489. PMID 16732376.
  5. Ontachi Y, Asakura H, Omote M, Yoshida T, Matsui O, Nakao S (November 2005). "Kasabach-Merritt syndrome associated with giant liver hemangioma: the effect of combined therapy with danaparoid sodium and tranexamic acid". Haematologica. 90 Suppl: ECR29. PMID 16266920.
  6. "Danaparoid (Subcutaneous Route) - MayoClinic.com". Retrieved 2007-08-23.
  7. "Heparin Induced Thrombocytopenia" Uptodate www.uptodate.com retrieved on 2/6/2009
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