Heparin-induced Thrombocytopenia Associated with Fondaparinux
Beng H. Chong, MBBS, PhD, FRACP1 and James J.H. Chong, MBBS, FRACP2
1Haematology Department, St George Hospital; Department of Medicine, St George Clinical School, University of New South Wales; 2Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
Introduction
Fondaparinux (Arixtra, GlaxoSmithKline) is a new indirect anti-factor Xa anticoagulant of the heparin family. Unlike unfractionated heparin (UFH) and low molecular weight heparin (LMWH), which are proteoglycans isolated from animal tissues, fondaparinux is a synthetic compound. It comprises the 5 sugar moieties that mediate the anticoagulant activity of UFH and LMWH.
Recently, a few cases of thrombocytopenia associated with the use of fondaparinux have been reported.1-4 In most of these cases2-4 the thrombocytopenia was induced initially by prior administration of UFH or LMWH. Therefore, it remains unclear in these patients whether fondaparinux actually caused the thrombocytopenia. For fondaparinux to be implicated as the cause of the thrombocytopenia, certain conditions must be met.
Fondaparinux-associated Thrombocytopenia Pathophysiology
Since fondaparinux is a heparin-like drug, an interesting question is, “Can fondaparinux cause HIT?” HIT is a clinical syndrome that is quite different from other drug-induced thrombocytopenias (DITs) such as thrombocytopenia induced by quinine.5 The thrombocytopenia in HIT is not severe compared with other DITs,6 and thrombosis, but not bleeding, is a prominent feature.7
Pathophysiologically, HIT differs from other DITs in that the immunoglobulin (Ig) G antibody in HIT reacts with a drug/plasma protein complex (ie, heparin/platelet factor 4 [PF4] complex).6,7 The antibody/antigen complex is bound by the IgG Fc domain7 to Fc gamma RIIa receptors on platelets, cross-linking the Fc receptors and inducing platelet activation, platelet microparticle formation, and thrombin generation,6 leading to thromboembolic complications in patients with HIT. The thromboembolism is frequently severe, extensive, and potentially disabling or fatal. The antibody in other DITs rarely causes platelet activation and seldom leads to thromboembolism.5
The only other drug that can cause a clinical syndrome like HIT is LMWH, although it does so less frequently than UFH.6 This is not unexpected, as LMWH has a chemical structure similar to UFH except it consists of proteoglycans with shorter chain lengths. Like UFH, LMWH is capable of forming with HIT IgG and PF4 large molecular proteoglycan/PF4/antibody complexes,8 which can induce, and are necessary for, platelet activation and consequently thromboembolism in HIT. In contrast, fondaparinux is a small (or short-chain) molecule and is probably unable to form the large proteoglycan/ PF4/antibody complexes8 necessary for inducing platelet activation and causing the clinical syndrome of HIT. Interestingly, both LMWH and fondaparinux are equally able to induce the formation of anti-PF4/heparin antibodies as demonstrated by Warkentin and colleagues9 in a cohort of orthopedic surgery patients receiving LMWH or fondaparinux for thromboprophylaxis. However, the anti-PF4/heparin antibodies in patients receiving fondaparinux did not cross-react with fondaparinux in vitro and the patients did not progress to develop HIT or HIT-like syndrome probably because the antibody and small size (or very short chain) of fondaparinux molecules do not form the large immune complexes necessary for causing platelet activation. Consistent with these findings, antibodies in patients with HIT cross-react strongly with LMWH10 but do not cross-react with fondaparinux.11
Given the above immunopathologic data, it would be very rare for fondaparinux to cause HIT or a syndrome like HIT. To date, clinical evidence also suggests that fondaparinux does not usually cause HIT except in very rare cases. In most of the reported cases of fondaparinuxassociated thrombocytopenia, there was prior exposure to UFH or LMWH that induced the development of HIT.2-4 With subsequent administration of fondaparinux, thrombocytopenia occurred or recurred (if the thrombocytopenia had resolved following UFH or LMW withdrawal). In the case reported by Alsaleh and associates,4 the patient had delayed-onset HIT and the patient’s thrombocytopenia was not initiated nor caused by fondaparinux; the onset of thrombocytopenia simply coincided temporally with the administration of fondaparinux. In delayedonset HIT, thrombocytopenia occurs even in the absence of continuing UFH or LMWH, once heparin has initiated the immune reaction as the induced antibody reacts with platelets independently of heparin. It is possible that the previously reported cases of fondaparinux-associated thrombocytopenia with prior UFH or LMWH exposure2-4 were patients with delayed-onset HIT, and the onset of thrombocytopenia merely coincided with fondaparinux administration. It is only in the patient reported by Warkentin and colleagues1 that there was compelling evidence that fondaparinux might have directly induced the thrombocytopenia, as there was no prior exposure to UFH or LMWH. Even in this case, the authors were unable to demonstrate the presence of a fondaparinuxdependent antibody in the serotonin-release assay, as the patient antibody reacted with platelets in the absence of heparin or fondaparinux. Ratuapli and colleagues12 describe a patient who was treated with enoxaparin and warfarin for bilateral lower limb vein thrombosis and pulmonary embolism.
Two days after discharge from hospital, she developed digital gangrene of the right foot; the platelet count had dropped from 148 x 109/L to 22 x 109/L. Upon cessation of enoxaparin, the platelet count rose to 138 x 109/L but fell again to 86 x 109/L when fondaparinux was given for one day. Thrombocytopenia resolved when fondaparinux was replaced by lepirudin (Refludan, Bayer Healthcare). In this patient, the evidence for fondaparinux causing the thrombocytopenia would have been stronger if (1) the fall in platelet level was verified by a repeat blood count, (2) a laboratory artifact such as in vitro platelet clumping was excluded by blood smear examination, and (3) cross-reaction of the antibody with fondaparinux was demonstrated by an in vitro assay.
Diagnosis
Similar to the diagnosis of HIT caused by UFH or LMWH, diagnosis of fondaparinux-induced or -associated thrombocytopenia should be based on the following criteria:
• Thrombocytopenia (platelet count <150 x 109/L) or a fall in platelets to a level 50% or less from baseline6 occurring with administration of fondaparinux 5–14 days after its commencement, unless there is prior exposure to fondaparinux, UFH, or LMWH
• Other causes of thrombocytopenia are excluded7
• Demonstration of an anti-PF4/fondaparinux antibody or anti-PF4/heparin antibody6 that cross-reacts with fondaparinux
• Resolution of thrombocytopenia or a return of platelet count to baseline after cessation of fondaparinux, UFH, or LMWH6 (this criterion may not be applicable if the diagnosis is initially made when the patient is still receiving fondaparinux, but it is helpful in confirming the diagnosis retrospectively)
If there is prior exposure to UFH or LMWH and the patient has a clinical picture consistent with delayed-onset HIT and a heparin-independent antibody, it is not possible to implicate fondaparinux confidently as the cause of the thrombocytopenia (as discussed above).4 The onset of thrombocytopenia may merely coincide with or at best be encouraged by fondaparinux administration. Technically speaking, the diagnosis of these patients is fondaparinuxassociated thrombocytopenia. The term fondaparinuxinduced thrombocytopenia should be reserved for patients in whom fondaparinux can be clearly implicated as the cause of their thrombocytopenia using the above diagnostic criteria.
Management
There are little or no clinical data to guide treatment of patients with fondaparinux-associated thrombocytopenia. The suggested treatment approach below is based on lessons we have learned from the treatment of HIT. With or without prior exposure to UFH or LMWH, when the platelet count drops by more than 50% from baseline or to less than 150 x 109/L during fondaparinux administration, the offending drug should be promptly ceased. The patient should not be treated with UFH or LMWH, as the antibody is likely to cross-react with UFH or LMWH.10 Even if a subsequent laboratory test shows no antibody cross-reaction with fondaparinux, it may not be safe to recommence fondaparinux until safety data from further research become available.
Patients who have fondaparinux-induced or fondaparinux-associated thrombocytopenia, with or without a clinical overt thrombosis, should be treated with an alternative anticoagulant used in the treatment of HIT6 eg, lepirudin, argatroban [Pfizer], or danaparoid13). The alternative anticoagulant should be continued until the platelet count returns to normal, at which time it would be safe to commence warfarin.6 Warfarin should be continued for 3 or more months as is deemed appropriate for the thrombosis that the patient has. From clinical experience with HIT, it would seem likely that patients without clinically overt thrombosis will probably develop a thrombotic event in the next 30 days. These patients may benefit from a short course of lepirudin, argatroban, or danaparoid, which should be continued until resolution of thrombocytopenia without commencing warfarin thereafter.6
Conclusion
Immunopathologic data suggest that fondaparinux is unlikely to directly cause HIT. Clinical evidence to date shows that fondaparinux usually does not cause thrombocytopenia, except perhaps in one previously reported patient. In several other patients who had prior UFH or LMWH exposure, the onset of thrombocytopenia probably coincided with fondaparinux administration. When fondaparinux-induced or fondaparinux associated thrombocytopenia is suspected, every effort should be made clinically and by laboratory testing to establish that fondaparinux is the cause of the patient’s thrombocytopenia.
If the onset of thrombocytopenia is temporally related to fondaparinux administration, even if fondaparinux could not be established as its cause, the patient should be treated as if he or she has HIT, and should be given lepirudin, argatroban, or danaparoid.6,13
References
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