Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.

Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Blood (Impact Factor: 9.78). 12/2010; 116(23):5021-31. DOI: 10.1182/blood-2010-03-276964
Source: PubMed

ABSTRACT Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia. We now show that platelet factor 4 binds to monocytes and forms antigenic complexes with their surface GAG side chains more efficiently than on platelets likely due to differences in GAG composition. Binding to monocytes is enhanced when the cells are activated by endotoxin. Monocyte accumulation within developing arteriolar thrombi was visualized by situ microscopy. Monocyte depletion or inactivation in vivo attenuates thrombus formation induced by photochemical injury of the carotid artery in a modified murine model of HIT while paradoxically exacerbating thrombocytopenia. These studies demonstrate a previously unappreciated role for monocytes in the pathogenesis of arterial thrombosis in HIT and suggest that therapies targeting these cells might provide an alternative approach to help limit thrombosis in this and possibly other thrombotic disorders that occur in the setting of inflammation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Heparin, the standard perioperative anticoagulant for prevention of graft vessel thrombosis in patients undergoing liver transplantation (LT), binds to the chemokine platelet factor 4 (PF4). Antibodies which are formed against the resulting PF4/heparin complexes can induce heparin-induced thrombocytopenia (HIT). LT is a clinical situation, which allows to study T-cell-dependency of immune responses as T-cell function are largely suppressed pharmacologically in these patients to prevent graft rejection.Objectives To investigate the immune response against PF4/heparin complexes in patients undergoing LT.Patients/Methods In this prospective cohort study, 38 consecutive patients undergoing LT were systematically screened for anti-PF4/heparin antibodies (enzyme immunoassay [EIA] and functional assay [HIPA]), platelet count, liver function, and engraftment.ResultsAt baseline, 5/38 (13%) patients tested positive for anti-PF4/heparin IgG (non-platelet-activating) antibodies. By day 20, additional 5/33 patients (15%) seroconverted for IgG (two platelet-activating) antibodies. No patient developed clinical HIT. Two of six patients with graft function failure had anti-PF4/heparin IgG antibodies at the time of graft function failure. Graft liver biopsies in these patients showed thrombotic occlusions of the microcirculation.Conclusions As anti-PF4/heparin IgG antibodies are generated despite strong pharmacologic suppression of T-cells indicating that T-cells have likely a limited role in the immune response to PF4/heparin complexes in humans.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 03/2014; · 6.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite less frequent, heparin-induced thrombocytopenia (HIT) remains a severe complication of treatment with heparin, and is important to diagnose and manage appropriately. HIT results from an atypical immune response to heparin, with the synthesis of IgG antibodies specific to heparin-modified platelet factor 4 (PF4) which activate platelets, leukocytes and the endothelium. This activation explains that low platelet count is associated with thrombotic events in 50% of patients. The diagnosis of HIT is sometimes evoked because of atypical manifestations (i.e. cutaneous necrosis, amnesia, hypotension or dyspnea following intravenous injection of heparin). Biological assays are always necessary to confirm HIT in case of clinical suspicion, and specific rapid tests are now available for detecting anti-PF4 antibodies. However, their specificity is poor and functional assays such as serotonin release assay or platelet aggregation test are often necessary. Argatroban that is a direct antithrombin drug can be used in patients with severe renal failure and will be preferred to danaparoid sodium in this situation. Fondaparinux is not licensed for treating confirmed HIT and can only be used in case of suspicion. The early detection of HIT is based on the monitoring of platelet count recommended in surgical patients receiving a low molecular weight heparin and in all patients treated with unfractionated heparin.
    La Revue de Médecine Interne 03/2014; 35(3):174–182. · 1.32 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To review the recent developments in understanding the pathophysiology of heparin-induced thrombocytopenia (HIT) and in applying this knowledge to the treatment of patients with suspected and proven HIT.
    Current Opinion in Hematology 07/2014; · 4.05 Impact Factor