In this issue of Blood, Krauel and colleagues identify two potential off-label treatments (rivaroxaban, dabigatran) for heparin-induced thrombocytopenia (HIT), and also outline a HIT prevention strategy through disrupting PF4/heparin complexes with low-sulfated heparin; the former approach will be easy to implement, the latter much harder—but potentially more worthwhile.1
HIT is a highly prothrombotic adverse drug reaction caused by strong platelet-activating antibodies that amplify coagulation reactions. In about half of all patients with HIT confirmed by laboratory detection of heparin-dependent, platelet-activating antibodies, the patient is found to have thrombosis at the time that of HIT diagnosis.2,3 These presenting HIT-associated thromboses include disabling stroke, critical limb ischemia, or fatal pulmonary embolism.
For more than a decade, treatment of HIT in the US has focused on parenterally administered direct thrombin inhibitors (DTIs), lepirudin and argatroban. However, these are “niche” agents that did not obtain approvals for any other non-HIT indication. Moreover, they require frequent monitoring (usually by activated partial thromboplastin time [aPTT]), cause serious bleeding (∼ 1% major bleed rate per treatment day),4 and are expensive—not only because of drug costs but also because their parenteral administration mandates prolonged hospitalization. Recently, even their “advantage” of simple aPTT monitoring has come under scrutiny, as it has been recognized that patients with severe HIT-associated consumptive coagulopathy can fail DTI treatment due to difficulty monitoring treatment with the aPTT.5,6 This problem should not occur with agents such as fondaparinux, rivaroxaban, or dabigatran that do not require active laboratory monitoring (although they will have their own drawbacks; eg, potential for accumulation in renal insufficiency).
It is also now recognized that, at most, only 10% of patients suspected of having HIT ultimately are proven to have this disorder.3,6 So, what is needed to treat HIT are easy-to-apply anticoagulant regimes effective for both HIT and non-HIT settings of thrombosis treatment and prevention. In this regard, agents such as fondaparinux, rivaroxaban, and dabigatran are likely to be welcomed by practitioners. The studies of Krauel et al, together with a previous study by Walenga and colleagues,7 indicate that there is no reason why the direct Xa inhibitor, rivaroxaban, should not be effective for thromboprophylaxis in patients with a history of HIT or, more provocatively, for the treatment of acute HIT itself. Krauel and colleagues further extended these studies to dabigatran, an orally active DTI now approved for the prevention of stroke in atrial fibrillation. No doubt these new agents will be tried in some patients with clinically suspected HIT, and some of this experience will be reported in the medical literature, as has occurred with fondaparinux.8-10 For example, in a summary of 52 patients who received fondaparinux for treatment of acute HIT, none (0%) developed new, progressive, or recurrent thrombosis.3 As “off-label” use of approved medications is permitted, experience treating HIT with rivaroxaban and dabigatran will likely emerge quickly.
Why should we care about prevention of HIT when there are effective therapies for HIT? The answer is that HIT still harms many patients, usually as a result of serious thrombotic events that occur soon after this drug reaction begins. For example, the study described above also noted that 34 of the 52 fondaparinux-treated patients (65%) had already developed HIT-associated thrombosis before this alternative anticoagulant was started.3 Three of these patients (6% overall) required limb amputation; another patient (patient no. 3 in the McMaster study10 ) had a disabling stroke (aphasia), which occurred at the very onset of the platelet count fall indicating HIT, and which therefore was unlikely to have been pre-empted by any platelet count monitoring protocol. So while fondaparinux therapy of HIT yielded “successful” outcomes (ie, platelet count recovery, no new thrombosis, infrequent major bleeding),3 the inescapable conclusion is that HIT will still harm many patients in a devastating fashion before the hypercoagulability state can be controlled by an alternative anticoagulant (see figure).
Krauel et al now describe a possible prevention strategy for HIT.1 They report that a low-sulfated heparin, called 2-O, 3-O desulfated heparin (ODSH), has several properties that would be expected to reduce the immunogenicity of heparin: (1) it inhibited formation of PF4/heparin complexes; (2) it disrupted PF4/heparin complexes on platelets and other cells; and (3) it inhibited HIT antibody-induced platelet activation.
These are intriguing observations and imply that ODSH could prevent HIT if given to the appropriate patient population at the appropriate time point. As ODSH has only minimal anticoagulant effect, one approach would be to coadminister ODSH with heparin in a study of postoperative thromboprophylaxis. Antibody formation could be used as a “surrogate” marker for HIT. Most likely, ODSH would only need to be given for the first day or 2 (because HIT is believed to represent a “point immunization” syndrome6 related to perioperative PF4 release and surgery-associated proinflammatory factors). Indeed, the therapeutic combination of heparin and ODSH would mirror somewhat the composition of danaparoid—a mixture of both high- and low-sulfated anticoagulant glycosaminoglycans, and a compound which (to my knowledge) has never been implicated as causing HIT when given for postoperative thromboprophylaxis.
If such a proof-of-principle study was successful, definitive trials with HIT as a key study end point could be performed, also combining ODSH with intraoperative heparin use (ie, for cardiac or vascular surgery). Such studies would not be easy; the frequency of HIT is approximately 1% in situations of intra- and/or postoperative unfractionated heparin administration, and performing appropriately powered clinical trials would be challenging. But reducing the scourge of HIT is a worthwhile goal, and could have a cost-effective benefit of making an inexpensive anticoagulant—unfractionated heparin—much safer.
Conflict-of interest disclosure: The author has received lecture honoraria from Pfizer Canada and Sanofi-Aventis, has provided consulting services to, and/or has received research funding from, Canyon Pharmaceuticals, Gen-Probe GTI Diagnostics, GlaxoSmithKline, and Paringenix, and has provided expert witness testimony relating to heparin-induced thrombocytopenia. ■