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2018年05月20日 时讯速递, 进展交流 暂无评论

Intravenous Immune Globulin to Prevent Heparin-Induced Thrombocytopenia

Theodore E. Warkentin, Troy H. Climans, Pierre-Aurèle Morin

N Engl J Med 2018; 378:1845-1848

DOI: 10.1056/NEJMc1801799

TO THE EDITOR:

Heparin-induced thrombocytopenia is a prothrombotic drug reaction caused by anti–platelet factor 4 (PF4)–heparin antibodies of the IgG class that activate platelets through platelet Fcγ receptors.1 Although treatment with nonheparin anticoagulation is emphasized, recent attention has focused on treating severe or persisting heparin-induced thrombocytopenia with high-dose intravenous immune globulin (IVIG), since IgG competitively inhibits antibody-induced Fcγ receptor–mediated platelet activation.2,3

Heparin-dependent antibodies are transient; thus, reexposure to heparin is appropriate in patients with a history of heparin-induced thrombocytopenia (and who no longer have detectable platelet-activating antibodies) in procedures for which there is a strong indication for heparin, such as vascular surgery.4 However, a problem arises when surgery is urgent and antibodies remain detectable. We report the preoperative administration of high-dose IVIG to permit reexposure to heparin for urgent vascular surgery in such a patient with persisting platelet-activating heparin-dependent antibodies.

Figure 1. High-Dose Intravenous Immune Globulin for Prevention of Recurrent Heparin-Induced Thrombocytopenia in the Patient.

Heparin-induced thrombocytopenia developed in a 59-year-old man while he was receiving heparin for symptomatic atherothrombosis involving both superficial femoral arteries (Figure 1A). The diagnosis was based on a decrease in the platelet count to 34,000 per cubic millimeter after right femoral–popliteal bypass surgery, and an anti–PF4–heparin immunoassay and a serotonin-release assay5were strongly positive for heparin-induced thrombocytopenia antibodies (100% serotonin release at 0.1 and 0.3 U per milliliter of heparin; normal value, <20%). Vascular surgery in the left femoral artery was postponed pending disappearance of the platelet-activating antibodies.

After 13 weeks, progressive ischemic necrosis of the distal left lower limb occurred, and urgent revascularization was recommended. However, the patient’s serum still showed 100% heparin-dependent serotonin release (Figure 1B), which could be inhibited by the addition of IVIG (Figure 1C). Accordingly, the patient received IVIG, at a dose of 90 g, beginning 9 hours before surgery, and a second 90-g dose given during surgery. He received 7000 units of heparin during surgery; the platelet count, which was 130,000 per cubic millimeter immediately before the administration of heparin, was unchanged 2 hours after the heparin bolus. The surgery was successful, without thrombotic complications, and the subsequent decrease in the platelet count to 112,000 per cubic millimeter was consistent with the administration of 3 liters of fluid perioperatively.

Testing of serial serum samples obtained from the patient showed that IVIG treatment resulted in a negative serotonin-release assay (Figure 1D); this proved that the strategy successfully interrupted platelet activation by heparin-dependent antibodies. The platelet-inhibitory effects of IVIG were transient, with return to a strongly positive serotonin-release assay within 1 week. Our observations show that high-dose IVIG inhibited heparin-dependent antibody–induced platelet activation in a dose-dependent fashion. Moreover, the enzyme-linked immunosorbent assay for IgG reactivity remained strongly positive throughout (>2.00 optical-density units), indicating that IVIG did not block antibody binding to target antigen, but rather probably inhibited platelet activation through platelet Fcγ receptors.2,3 This finding offers a potential new approach for treating patients with recent heparin-induced thrombocytopenia and residual platelet-activating antibodies who require urgent surgery in which heparin is used. Although IVIG predictably inhibits heparin-dependent platelet activation in vitro, patient-dependent differences in treatment efficacy remain to be established.

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