Monocyte-bound PF4 in the pathogenis of heparin induced thrombocytopenia

Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Blood (Impact Factor: 10.45). 12/2010; 116(23):5021-31. DOI: 10.1182/blood-2010-03-276964
Source: PubMed


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.

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    • "Yet studies using antibodies isolated from HIT patients soon demonstrated that PF4 bound to other glycosaminoglycan drugs could also be targeted by PF4/heparin antibodies [116]. These antibodies also bind to PF4 on endothelial cells [13], monocytes [77] or platelets [78,117], or to PF4 immobilized on anionic surfaces [94]. While the conformational neoepitope can be exposed by other PF4 binding partners, none are as immunogenic as unfractionated heparin. "
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    ABSTRACT: Heparin Induced Thrombocytopenia (HIT) is caused by antibodies that recognize platelet factor 4 (PF4) associated with polyanionic glycosaminoglycan drugs or displayed on vascular cell membranes. These antibodies are elicited by multimolecular complexes that can occur when heparin is administered in clinical settings associated with abundant PF4. Heparin binding alters native PF4 and elicits immune recognition and response. While the presence of heparin is integral to immunogenesis, the HIT antibody binding site is within PF4. Thus HIT antibodies develop and function to cause thrombocytopenia and/or thrombosis only in the presence of PF4. Future emphasis on understanding the biology, turnover and regulation of PF4 may lead to insights into the prevention and treatment of HIT.
    Thrombosis Journal 04/2013; 11(1):7. DOI:10.1186/1477-9560-11-7 · 1.31 Impact Factor
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a prothrombotic and potentially devastating complication of heparin therapy due to formation of platelet-activating antibodies against complexes of platelet factor 4 and heparin. Over the last several decades, great advances in our understanding of HIT have elevated a once enigmatic syndrome, the mere existence of which was doubted by the medical community, to a well-characterized disorder. Nevertheless, critical questions remain unanswered. The objective of this review is to examine our current understanding of the epidemiology, pathophysiology, diagnosis, and management of HIT and to highlight areas of future inquiry.
    Journal of Thrombosis and Thrombolysis 02/2011; 31(3):353-66. DOI:10.1007/s11239-011-0569-6 · 2.17 Impact Factor
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    ABSTRACT: Blood contains microparticles (MPs) derived from a variety of cell types, including platelets, monocytes, and endothelial cells. In addition, tumors release MPs into the circulation. MPs are formed from membrane blebs that are released from the cell surface by proteolytic cleavage of the cytoskeleton. All MPs are procoagulant because they provide a membrane surface for the assembly of components of the coagulation protease cascade. Importantly, procoagulant activity is increased by the presence of anionic phospholipids, particularly phosphatidylserine (PS), and the procoagulant protein tissue factor (TF), which is the major cellular activator of the clotting cascade. High levels of platelet-derived PS(+) MPs are present in healthy individuals, whereas the number of TF(+), PS(+) MPs is undetectable or very low. However, levels of PS(+), TF(+) MPs are readily detected in a variety of diseases, and monocytes appear to be the primary cellular source. In cancer, PS(+), TF(+) MPs are derived from tumors and may serve as a useful biomarker to identify patients at risk for venous thrombosis. This review will summarize our current knowledge of the role of procoagulant MPs in hemostasis and thrombosis.
    Circulation Research 05/2011; 108(10):1284-97. DOI:10.1161/CIRCRESAHA.110.233056 · 11.02 Impact Factor
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