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See also Greinacher A. Immunogenic but effective: the HIT-fondaparinux brain puzzler. This issue, pp 2386–8; Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparin-induced thrombocytopenia: confirmed by the serotonin-release assay: a 30-month, 16-patient case series. This issue, pp 2389–96.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated drug reaction caused by platelet-activating IgG antibodies that recognize complexes of platelet factor 4 (PF4) and heparin leading to thrombocytopenia and predisposing to both venous and arterial thrombosis. There are currently three direct thrombin inhibitors (DTIs; lepirudin, argatroban and bivalirudin) and one factor Xa inhibitor (danaparoid) therapeutically used for HIT. More recently, a new antithrombin-dependent factor Xa inhibitor, fondaparinux, has emerged as a new potential agent for the treatment for HIT.
Fondaparinux is a non-heparinoid pentasaccharide that has 100:1 times more selectivity for factor Xa than for thrombin (vs. 20:1 for danaparoid) . Fondaparinux usually lacks cross-reactivity with anti-PF4 antibodies and thus has a very low likelihood of causing, or exacerbating, HIT. However, there have been three reported isolated cases of fondaparinux-induced HIT [2–4] and one putative case of fondaparinux-worsened thrombocytopenia . There is an increasing body of observational evidence supporting the use of fondaparinux in HIT. There have been four case series totalling 47 patients who received fondaparinux for HIT, none of whom had any major bleeding or thrombotic events (although two of 36 [5.6%] had limb amputation due to irreversible limb necrosis prior to fondaparinux) [6–9]. For comparison, the thrombotic rates seen in the prospective cohort studies used to approve lepirudin and argatroban for the treatment of HIT were 7% and 16%, respectively .
The factor Xa inhibitors share some key advantages over the DTIs, such as long half-lives preventing rebound hypercoaguability, ability to monitor drug levels directly using anti-FXa (factor Xa) assays (although not widely available), no effect on the protein C pathway and no interference with the INR, which makes the initiation of warfarin simpler. In addition, fondaparinux has some additional benefits over danaparoid, such as lower cost and lower frequency of ‘cross-reactivity’ with HIT antibodies. The removal of danaparoid from the Canadian market and the increasing evidence for the safety and efficacy of fondaparinux led our institution to adopt fondaparinux as a treatment for suspected and confirmed HIT in non-critically ill patients with good renal function. We report eight cases of confirmed HIT treated with fondaparinux at a single institution.
Pharmacy records at the Jewish General Hospital (JGH), a McGill University teaching hospital in Montreal, Canada, were used to identify all patients who received fondaparinux from 1 April 2009 to 1 May 2011. The laboratory database was then used to identify patients with a positive HIT Enzyme Immunosorbent Assay (EIA). The HIT assay is a polyspecific PF4-dependent EIA (Gen-Probe GTI Diagnostics, Waukesha, WI, USA). The serotonin release assay (SRA) was performed, as described , at the McMaster Platelet Immunology Laboratory in Hamilton, Ontario. The electronic medical records of confirmed HIT-positive patients were reviewed to obtain clinical information. One-month outcomes after administration of fondaparinux were recorded from the patient’s medical record. This retrospective study was approved by the Director of Professional Services on behalf of the Research Ethics Committee at the Jewish General Hospital.
A definite case of HIT consisted of a 4T score of > 4 , combined with a peak % serotonin-release of 0.1 and 0.3 U mL−1 unfractionated heparin (UFH) of > 20%  or an EIA optical density (OD) > 2.0 U. A HIT EIA ≥ 2.0 U has been shown to have a high likelihood (> 90%) of a corresponding positive SRA > 90% .
Table 1 shows the results of the eight patients who were diagnosed with HIT. The median age of patients was 76 years old. There were five females and three males. Five patients were on surgical services (two cardiac surgery, two orthopedic surgery, one general surgery) and three were on medical wards. The trigger for HIT was intravenous therapeutic unfractionated heparin in five patients and low-molecular-weight heparin (two therapeutic, one prophylactic) in three patients.
Table 1. Clinical data of eight patients with heparin-induced thrombocytopenia treated with fondaparinux
|Patient number||Age and gender||4T score||Thrombosis||HIT EIA||Peak SRA||Platelet nadir (× 109 L−1)||Complications (at 30 days)|
|1||81M||8||Yes||+ 2.201||Not sent||30||No|
|2||84F||8||Yes||+ 2.888||Not sent||23||No|
|3||74M||6||Yes||+ 2.868||Not sent||58||No|
|4||96F||6||Yes||+ 2.230||Not sent||59||No|
All eight cases had 4T scores > 6. All patients were SRA positive or had a HIT EIA OD >2.0. The median EIA was 2.77 U. The four SRA-positive samples had a mean peak % serotonin-release (at 0.3 U mL−1 UFH) of 97%, with a range of 93–100%. There were no other patients who met our criteria for HIT during the study period who were started on other anticoagulants.
In six patients (75% of cases), there was a venous thrombosis identified at the time of HIT diagnosis, including one patient with a transverse sinus and splenic vein thrombosis. Six patients had a platelet drop occurring between 5 and 10 days of starting heparin. Two patients who had recently received heparin had a platelet drop after the first day. The median platelet count nadir was 56 × 109 L−1. All patients had an absolute platelet nadir between 20 and 99 (× 109 L−1). Six patients had relative platelet decreases of > 50% and two patients had a platelet decrease between 30% and 50%. Except for Case 8, in which sepsis was considered in the differential diagnosis for thrombocytopenia, there were no alternate explanations for the platelet drop identified in these patients.
All patients had good renal function (creatinine clearance ≥ 50 ml min−1) and were started on fondaparinux 7.5 mg injected subcutaneously once daily. Anti-FXa levels were not drawn and there was no adjustment of dosing. The median duration of treatment with fondaparinux was 8.9 days and coumadin was initiated in all patients while receiving fondaparinux, without complications during overlap. The time to platelet recovery (defined as the lower limit of normal, 150(× 109 L−1)) ranged from 2 to 7 days, with the mean 3.8 days. At the 1-month follow-up visit, there were no new, progressive or recurrent thromboses. There were no major bleeds, limb amputations or mortalities recorded at 30 days. Additional clinical detail is available in the supplemental table online (Table S1).
The most recent ACCP guidelines for the treatment of HIT hesitate to recommend fondaparinux as an anticoagulant in the setting of HIT, despite its theoretical efficacy, because of the limited evidence . At our institution, fondaparinux was introduced for the off-label treatment of both suspected and confirmed HIT after the removal of danaparoid from the Canadian market in February 2009. Argatroban is reserved for critically ill patients requiring frequent interventions and in patients with renal insufficiency. Of note, < 1% of thrombocytopenic patients in the ICU have HIT, and over 2.5 years no ICU patients met our criteria for HIT.
Including this study and the companion article by Warkentin et al.  there are now six case series totaling 71 patients demonstrating that fondaparinux is not only an effective anticoagulant in the setting of HIT but it appears to have a low risk of overall complications, particularly new thromboses, as compared with the DTIs and danaparoid. The benefits of using fondaparinux, such as its ease of administration, long half-life (reducing risk of rebound hypercoaguability), availability of monitoring and low cost, must be balanced against the lack of an established loading dose, a risk of inadequate dosing in the first 24–48 h, an increased bleeding risk from accumulation in renal failure and lack of an antidote for reversal . Anti-FXa levels were not monitored in this study. It is unclear at this time whether anti-FXa levels need to be followed regularly in patients with normal renal function. There is also a lack of data concerning the use of fondaparinux in patients with renal insufficiency. In conclusion, this study further supports the observational evidence that fondaparinux is a safe and effective option in non-critically ill patients with normal renal function in the setting of suspected or confirmed HIT.