Correspondence
Heparin-Induced Thrombocytopenia Associated with Fondaparinux
N Engl J Med 2007; 356:2653-2655June 21, 2007
- Article
To the Editor:
Heparin-induced thrombocytopenia is a transient disorder in which thrombocytopenia appears about 1 week after exposure to heparin.1 Often there is also arterial or venous thrombosis, including adrenal necrosis due to adrenal-vein thrombosis. Heparin-induced thrombocytopenia is caused by platelet-activating antibodies against platelet factor 4 (PF4)–heparin complexes. Its frequency is reduced by a factor of about 10 with low-molecular-weight heparin as compared with unfractionated heparin. The risk of heparin-induced thrombocytopenia is believed to be even lower — perhaps negligible — with fondaparinux (Arixtra),2 a factor Xa inhibitor modeled after a critical heparin pentasaccharide sequence. To our knowledge, a causal association between fondaparinux therapy and the occurrence of heparin-induced thrombocytopenia has not been established.
We report on a 48-year-old woman who underwent bilateral knee replacement without apparent perioperative or postoperative exposure to heparin. (A thorough search of hospital records revealed no use of intraarterial or central venous catheters and showed that a cell-saver device had been flushed with saline rather than heparin.) Prophylaxis against thrombosis with fondaparinux (2.5 mg given subcutaneously once daily) was initiated on postoperative day 1 (Figure 1Figure 1
Clinical Course of a Patient with Fondaparinux-Associated Thrombocytopenia, Bilateral Adrenal Infarction, and Deep-Vein Thrombosis.). On day 7, she reported abdominal and flank pain, which was found to be due to a bilateral adrenal infarction. The platelet count was 39,000 per cubic millimeter. Ultrasonography revealed asymptomatic deep-vein thrombosis. Argatroban and warfarin were given, with full recovery except for adrenocortical insufficiency requiring long-term replacement therapy with adrenal hormones.The platelet serotonin-release assay of the patient's serum was strongly positive for heparin-induced thrombocytopenia antibodies (90% release with no added drug; 96% release with 0.2 U of heparin per milliliter [normal value, <20%], reduced to 0% release with 100 U of heparin per milliliter). The anti-PF4–polyanion enzyme immunoassay was also positive, at 1.871 units (normal value, <0.40).
Fondaparinux is occasionally associated with platelet-activating anti-PF4–heparin antibodies that are indistinguishable from those associated with heparin-induced thrombocytopenia,2 but a heparin-induced thrombocytopenia syndrome does not develop in these cases. The failure of these antibodies to cause heparin-induced thrombocytopenia has been attributed to the inability of fondaparinux to react with PF4 in a way that reveals sites for antibody binding.2
In our patient, strong serum-induced platelet activation in the absence of heparin — a serologic feature of delayed-onset heparin-induced thrombocytopenia3 — was a prominent finding. Our observations suggest that on rare occasions, fondaparinux can cause a disorder resembling heparin-induced thrombocytopenia, perhaps through mechanisms similar to those seen in delayed-onset heparin-induced thrombocytopenia. In this condition, antibodies triggered by heparin cause thrombocytopenia and thrombosis even after the discontinuation of heparin therapy,3,4 perhaps because the antibodies recognize PF4 bound to endogenous platelet-associated chondroitin sulfate.5
Theodore E. Warkentin, M.D.
McMaster University, Hamilton, ON L8N3Z5, Canada
twarken@mcmaster.ca Brian T. Maurer, M.D.
Orthopedic Institute of Illinois, Peoria, IL 61605Richard H. Aster, M.D.
Blood Center of Wisconsin, Milwaukee, WI 53233Dr. Warkentin reports receiving consulting and speaker fees and research grants from GlaxoSmithKline, speaker fees from Sanofi-Aventis and Oryx Pharmaceuticals, consulting fees from GTI, and consulting and speaker fees from Organon. Dr. Aster reports receiving royalties from GTI. No other potential conflict of interest relevant to this letter was reported.
5 References1
Warkentin TE. Think of HIT. Hematol Am Soc Hematol Educ Program 2006:404-14.
2
Warkentin TE ,Cook RJ ,Marder VJ , et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005;106:3791-3796
CrossRef | Web of Science | Medline3
Warkentin TE ,Bernstein RA . Delayed-onset heparin-induced thrombocytopenia and cerebral thrombosis after a single administration of unfractionated heparin. N Engl J Med 2003;348:1067-1069
Full Text | Web of Science | Medline4
Rice L ,Attisha WK ,Drexler A ,Francis JL . Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med 2002;136:210-215
Web of Science | Medline5
Rauova L ,Zhai L ,Kowalska MA ,Arepally GM ,Cines DB ,Poncz M . Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood 2006;107:2346-2353
CrossRef | Web of Science | Medline
Author/Editor Response
The above letter was referred to GlaxoSmithKline, the manufacturer of fondaparinux, which offers the following reply:
To the Editor: Warkentin and colleagues describe a 48-year-old woman in whom a syndrome resembling heparin-induced thrombocytopenia developed after bilateral knee replacement while she was receiving fondaparinux (Arixtra), a selective factor Xa inhibitor. This case report highlights the complex pathophysiology of this serious clinical syndrome. Warkentin and colleagues raise an interesting hypothesis regarding a potential mechanism of delayed heparin-induced thrombocytopenia in association with fondaparinux.
Since it was first approved for use in the United States in December 2001, more than 1 million patients globally have received fondaparinux for the prevention or treatment of thromboembolic events in various clinical settings. Rare events of heparin-induced thrombocytopenia in patients treated with fondaparinux have been reported to GlaxoSmithKline. However, because of the use of heparin or low-molecular-weight heparin (which are agents known to be causally associated with heparin-induced thrombocytopenia), insufficient information to definitively assess a possible causal relationship between fondaparinux and heparin-induced thrombocytopenia, or both, interpretation of these reports is often difficult. The case described in the letter by Warkentin and colleagues was initially reported to GlaxoSmithKline and was shared with the Food and Drug Administration and regulatory authorities in other countries where fondaparinux is registered according to local regulations. As a result of a review of all available data, GlaxoSmithKline is considering an update to fondaparinux prescribing information.
Joseph Soffer, M.D.
Jai Patel, M.D.
Robin Saltzman, M.D.
GlaxoSmithKline, Philadelphia, PA 19102- Citing Articles (70)
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