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• W2068992029 abstract "We thank Drs Elalamy and Tribout for their detailed comments relating to the case of putative fondaparinux-associated HIT that we reported in 2007 [1]. Given previous space limitations, we welcome the opportunity to respond, as well as to discuss several key implications of this case. We will also note two additional examples of HIT associated with fondaparinux treatment that have been recently recognized, including one that we will newly describe in this communication. Drs Elalamy and Tribout are skeptical that fondaparinux can induce HIT, in part because the anti-PF4/heparin antibodies that have been associated with use of fondaparinux do not usually react with PF4 in a way that leads to platelet activation [2]. Moreover, they state that in the patient we reported, the platelet serotonin-release assay was ‘positive in the absence of heparin but negative in the presence of fondaparinux’, thereby arguing that other non-HIT platelet-activating antibodies might have been present, such as other anti-chemokine antibodies, or that thrombin could be responsible for causing a false-positive test result, or perhaps the antiphospholipid syndrome could explain this unusual disorder characterized by thrombocytopenia, adrenal hemorrhagic infarction, and deep venous thrombosis. Furthermore, they take exception to the use of the term ‘delayed-onset HIT’, asking how this designation can apply when preceding heparin use was not documented, and no subsequent heparin challenge was performed. Conceptually, HIT is defined as the presence of thrombocytopenia with or without complicating thrombosis (or other characteristic features, such as adrenal hemorrhagic necrosis) and the presence of heparin-dependent platelet-activating antibodies that recognize PF4 bound to heparin or certain other polyanions [3]. Although the syndrome is almost always ‘induced’ by heparin (unfractionated heparin [UFH] more often than low-molecular-weight heparin [LMWH] [4]), it is important to note that there are well-documented examples of an identical clinical syndrome, including an identical serological profile (positive heparin-dependent platelet activation assays and PF4-dependent EIAs), being triggered by certain non-heparin polyanions, such as polysulfated chondroitin sulfate [5], pentosan polysulfate [6], and the anti-angiogenesis agent, PI-88 [7]. Thus, the concept that a syndrome essentially identical to severe HIT could be triggered by a non-heparin agent with strong negative charge, such as the polysulfated pentasaccharide, fondaparinux, is plausible. Indeed, as fondaparinux thromboprophylaxis has been associated with formation of anti-PF4/heparin antibodies, including some with platelet-activating properties, at a frequency similar to that observed with LMWH [2], the prospect of fondaparinux itself inducing HIT under certain circumstances should be carefully considered. We believe that the reaction profile produced by the serum obtained from the patient case in question, and in this particular clinical context, is diagnostic of HIT. We observed that the patient serum caused strong platelet activation (91.6% serotonin release using buffer control) in the absence of any anticoagulant, but was inhibited (to <10% serotonin release) by the addition of high (supratherapeutic) concentrations of heparin (100 IU mL−1) or fondaparinux (100 μg mL−1) (all reactions performed in duplicate). The former property of strong serum-induced platelet activation in the absence of heparin is observed with many HIT sera [8], particularly those obtained from patients with the syndrome of delayed-onset HIT (discussed subsequently) [9], and the latter property of inhibition of platelet activation by supratherapeutic heparin or fondaparinux concentrations is a characteristic feature of HIT sera more generally [2]. We excluded an effect of thrombin by using patient serum that was heat-inactivated, and also by observing that the addition of pharmacologic doses of LMWH (0.2 anti-Xa U mL−1) increased the patient serum-induced platelet activation from 91.6% mean serotonin release (buffer control) to 97.7%, a feature consistent with HIT antibodies but not with thrombin. In contrast, two pharmacologic concentrations of fondaparinux (0.4 and 1.2 μg mL−1) resulted in mean serotonin release of 91.8%, a value virtually identical to that of buffer control. Thus, patient serum-induced platelet activation was by no means ‘negative’ in the presence of pharmacologic levels of fondaparinux, but rather was substantial (>90% serotonin release), and, although the serum-induced platelet activation was not appreciably enhanced by fondaparinux in vitro, the degree of platelet activation was much stronger than is usually seen even in patients with delayed-onset HIT [9]. Our reference to the term, ‘delayed-onset HIT’, does not necessarily imply that heparin itself must be the cause of the HIT syndrome; rather, it indicates that the antibodies associated with delayed-onset HIT, whatever their trigger, are able to cause strong platelet activation without the need for pharmacologic heparin to be present (this is why these antibodies cause thrombocytopenia and thrombosis many days after the inciting heparin exposure). In theory, such antibodies could be caused by non-heparin anticoagulants, such as fondaparinux, and perhaps even ‘spontaneously’ in settings of acute inflammation, thus producing an illness resembling HIT even in the absence of any preceding heparin exposure, a phenomenon we have recently reported [10]. The patient also had strong positive reactions for PF4-dependent antibodies, by immunoassay (including >50% inhibition by high-dose UFH), both in the commercial EIA from GTI Inc (Waukesha, WI, USA) [1.87 units (normal, <0.40 units)], as well as in an in-house EIA that detects only IgG class antibodies [2.70 units (normal, <0.45 units)]. The limited amount of patient serum (and unavailability of presurgery specimens) precluded before/after testing for anti-chemokine antibodies or antiphospholipid antibodies. Given the presence of the strong HIT antibodies we detected, however, the clinical relevance of any other kinds of putative antibodies, or the presence of an underlying rheumatic disorder (which has not been identified in this patient), would not negate the diagnosis of HIT. Although Elalamy and Tribout ask about the ‘evolution of the anti-PF4/H EIA results’, this would not be helpful, because levels of HIT antibodies can wane whether or not heparin is continued. Also, we disagree with the contention that the onset of thrombocytopenia occurred ‘too early’ to be due to fondaparinux: antibodies associated with post-surgical administration of LMWH or fondaparinux are detectable as early as 5 days after injection [2], and in our studies of HIT during clinical trials of heparin therapy (in which daily platelet counts were available, and daily blood samples for documenting the detectability of HIT antibodies), the onset of the platelet count fall indicating HIT began at a median of 6 days among three patients proven to have HIT associated with LMWH (T. E. Warkentin, unpublished observations). Elalamy and Tribout have suggested that the term ‘pseudo-HIT’ be applied to our patient with fondaparinux-associated HIT. However, this designation is inappropriate, as the term ‘pseudo-HIT’ was coined to indicate patients whose clinical course resembles HIT in certain respects, but in whom the pathogenic HIT antibodies cannot be detected [11]. As summarized above, the patient we described had strongly-reacting HIT antibodies. Moreover, the clinical course (onset of thrombocytopenia at day 6, the transient nature of the thrombocytopenia, bilateral adrenal necrosis, and deep-vein thrombosis) is highly characteristic of HIT. We agree with Elalamy and Tribout that fondaparinux in the prophylactic doses administered to our patient failed to suppress the HIT-associated hypercoagulability state, as it did not prevent adrenal vein thrombosis (the presumed cause of adrenal hemorrhagic necrosis) and deep-vein thrombosis. This is an intriguing aspect of this case, and while one should be hesitant to over-interpret a single case observation, it is consistent with the view that therapeutic, rather than prophylactic, doses of alternative anticoagulation are usually required for management of HIT [12]. Indeed, an analogous situation exists for danaparoid (which, like fondaparinux, exhibits predominant anti-factor Xa activity), where the evidence indicates that therapeutic doses are more effective than prophylactic doses when used to prevent thrombosis in patients with HIT [13]. If fondaparinux really can cause HIT, our 2007 report will not remain an isolated one. In this regard, Rota and colleagues [14] recently reported an elderly woman who developed an illness resembling HIT (with strong positive antibodies by PF4-dependent EIA) during exclusive anticoagulant therapy with fondaparinux administered following elective hip replacement surgery. A noteworthy aspect of this report was that the patient had a previous history of HIT (due to the LMWH, nadroparin) 3 years earlier, and thus special care was taken to avoid exposure to heparin during/after the hip replacement surgery. Unfortunately, functional (platelet activation) assays were not performed in this case, and thus whether or not the serological features of delayed-onset HIT (as seen in our case) were present is not known. Within the past month, one of us (W.L.) identified a patient in a local hospital with evidence for a pathogenic role of fondaparinux in producing HIT (Fig. 1). Although this patient received a single preoperative 5000-unit subcutaneous dose of UFH, the thrombocytopenia began 5 days later, and while the patient was receiving prophylactic-dose fondaparinux. Of interest, the serological profile associated with delayed-onset HIT was not observed; rather, the patient’s serum caused negligible platelet activation with buffer control, but produced substantial platelet activation in the presence of either UFH or fondaparinux (Fig. 1 inset). This suggests that some HIT antibodies may indeed ‘cross-react’ with fondaparinux, with clinical consequences including thrombocytopenia. Further, comparing this case with our previous report [1] indicates that there are likely to be at least two mechanisms by which fondaparinux might be linked to HIT, either through triggering strong PF4-reactive antibodies that will cause thrombocytopenia with or without any polysaccharide anticoagulant subsequently being present (i.e. the ‘delayed-onset HIT’ mechanism we reported in 2007 [1]), or by enhancing the ability of HIT antibodies (however they might arise) to bind to PF4 in a fondaparinux-dependent manner (Fig. 1 inset). A new case of fondaparinux-associated HIT. An 87-year-old woman underwent hip replacement surgery for traumatic hip fracture. She received a single preoperative 5000-unit dose of unfractionated heparin (UFH), administered by subcutaneous (s.c.) injection. She received postoperative thromboprophylaxis with fondaparinux 2.5 mg s.c. once-daily. The platelet count fell by 67.6% (from 225 to 73 × 109 L−1), beginning 5 days after the UFH injection, and while the patient was receiving fondaparinux. No thrombotic events occurred. The serological investigations (inset) showed UFH- and fondaparinux-dependent platelet activation, which was inhibited by Fc receptor-blocking monoclonal antibody (not shown). An in-house EIA that detects IgG class antibodies against PF4/heparin complexes (EIA-G) was strongly positive (1.91 od units; normal <0.45 units), as was a commercial EIA from GTI (Waukesha, WI; 2.63 od units; normal <0.40 units); reactions in both EIA’s were inhibited >80% by addition of high concentrations of UFH (100 IU mL−1). The inset shows the reactivity in the SRA using patient sera obtained at three different time points, corresponding to baseline (A) and postoperative day 8 (B) and day 15 (C). Finally, the larger public health question that cannot be answered by these individual patient cases is whether the risk of HIT with fondaparinux differs from that of LMWH. In our view, the combination of a relatively low risk of fondaparinux for inducing clinically-significant HIT antibodies (approximately the same as LMWH) together with a substantially reduced risk (vis-à-vis UFH and LMWH) of ‘cross-reacting’ with HIT antibodies (whether these antibodies are induced by fondaparinux or some other more conventional trigger) infers that the risk of HIT is likely to be less than that caused by LMWH [2]. Thus, the appreciation that on rare occasions, disorders resembling HIT might result from fondaparinux use, should not dissuade from its use to reduce the frequency of this important adverse effect of heparin [2] or to evaluate its potential as a therapeutic option for patients with acute HIT [15]. The authors thank C. A. Smith, J. C. Moore and J.-A. I. Sheppard for technical assistance, and also J.-A. I. Sheppard for preparing the Figure. Supported by the Heart and Stroke Foundation of Ontario (operating grant #T6157 [T.E. Warkentin]). T. E. Warkentin has received research support from GlaxoSmithKline, has consulted for GTI Inc., and has received support for lectures given on behalf of GlaxoSmithKline, Sanofi-Aventis, and Organon Inc. W. Lim states that she has no conflict of interest." @default.
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• W2068992029 title "Can heparin‐induced thrombocytopenia be associated with fondaparinux use? Reply to a rebuttal" @default.
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