Fondaparinux: does it cause HIT? can it treat HIT?

Abstract

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated prothrombotic disorder triggered by PF4-binding polyanions, usually heparin. The pentasaccharide anticoagulant, fondaparinux, despite its negative charge and structural similarity to heparin, does not usually promote antibody binding to PF4 (owing to absent/weak ‘cross-reactivity’). Thus, despite its ability to trigger anti-PF4/heparin antibodies (‘immunogenicity’), fondaparinux has low – but not zero – risk of inducing HIT de novo, or of exacerbating HIT when antibodies are already present. Indeed, despite rare reports of fondaparinux-induced HIT, this ‘dissociation’ between immunogenicity and cross-reactivity suggests that fondaparinux should be effective in treating HIT, as supported by several observational studies. An emerging issue: will clinicians accept this favorable experience of fondaparinux for treating HIT when a lack of randomized trials will hinder regulatory approval for this indication?

Keywords::

• antithrombotic agents
• fondaparinux
• heparin
• heparinoid
• low-molecular-weight heparin
• thrombocytopenia
• unfractionated heparin

Acknowledgements

The author thanks Dr Roman Jaeschke for translation of non-English language publications reviewed, and also Dr John W Eikelboom and Dr Menaka Pai for providing comments onBox 1.

Financial & competing interests disclosure

Theodore E Warkentin (last 12 months): research support from GlaxoSmithKline and GTI Inc.; Consultant to GTI Inc. and Canyon Pharmaceuticals; Speaker’s honoraria from Sanofi-Aventis and Pfizer Canada; Medicolegal testimony; Royalties for editing book, ‘Heparin-induced thrombocytopenia (Informa Healthcare USA).’ Some of the studies cited[4,5,7,8,10,14,16,17,20,24–26,29,34,35,37,39,65,66,82,89]were funded by the Heart and Stroke Foundation of Ontario (Theodore Warkentin: from 1993 until the present, operating grants A2449, T2967, B3763, T4502, T5207, T6157, T6950). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes

^†HIT is often diagnosed by platelet count monitoring and thus treatment is frequently started in the afternoon or evening.

^‡10 mg, rather than 7.5 mg, may be appropriate even for a 50–100 kg patient if HIT is judged to be very severe (e.g., with overt DIC), or if the initial dose is given in the morning and therefore a 20–24 h interval before the next (morning) dose is anticipated.

^§Intravenous injection can be considered if immediate anticoagulation is desired. If given intravenously, flush the line afterwards, or administer the fondaparinux in 25–50 ml normal saline over 3–5 min.

^¶5 mg if bodyweight is under 50 kg and 10 mg if bodyweight is more than 100 kg.

^#The rationale for administering second and subsequent doses in the morning – even if the first dose was given in the preceding afternoon or evening – is that it will help to achieve early therapeutic levels of anticoagulation (since there will usually be <20 h interval between the first two doses); in addition, it will facilitate determining plasma anticoagulant levels (trough) by the morning blood draw, using anti-Xa levels, if desired.

^††A target drug (trough) level of 0.6–1.0 anti-Xa U/ml is currently being used by the author.

^‡‡The author frequently follows serial markers of hemostasis activation, especially in patients with severe HIT-associated DIC, where effective anticoagulation should result in increase in fibrinogen levels, decrease in fibrin D-dimer/fibrin monomer levels, and decrease in LD levels (marker of intravascular hemolysis).

^§§Low-dose (prophylactic-dose) fondaparinux regimen may be appropriate if: (a) patient has low (or intermediate) probability for acute HIT and (b) no thrombosis; or (c) for various other typical settings of prophylactic-dose anticoagulation, for example, patient with history of previous HIT who requires postoperative prophylaxis.

^¶¶Assumes normal renal function.

APTT: Activated partial thromboplastin time; DIC: Disseminated intravascular coagulation; LD: Lactate dehydrogenase; PT (INR): Prothrombin time (international normalized ratio); s.c.: Subcutaneous.