Heparin-Induced Thrombocytopenia: A Focus on Thrombosis

Abstract

Heparin-induced thrombocytopenia is an immune-mediated disorder caused by antibodies that recognize complexes of platelet factor 4 and heparin. Thrombosis is a central and unpredictable feature of this syndrome. Despite optimal management, disease morbidity and mortality from thrombosis remain high. The hypercoagulable state in heparin-induced thrombocytopenia is biologically distinct from other thrombophilic disorders in that clinical complications are directly attributable to circulating ultra-large immune complexes. In some individuals, ultra-large immune complexes elicit unchecked cellular procoagulant responses that culminate in thrombosis. To date, the clinical and biologic risk factors associated with thrombotic risk in heparin-induced thrombocytopenia remain elusive. This review will summarize our current understanding of thrombosis in heparin-induced thrombocytopenia with attention to its clinical features, cellular mechanisms, and its management.

Keywords: antibodies; heparin; platelets; thrombocytopenia; thrombosis.

Figure 1.. Platelet contributions to thrombosis:

Binding of HIT ULICs to platelet FcγRIIA (1) initiates phosphorylation of ITAM motifs and downstream signaling via Syk kinase(2) leading to degranulation of alpha and dense granules leading to release of additional PF4, polyphosphate (PO4⁻_n), ADP, and release of soluble P-selectin and microparticles (3). Released ADP binds to G-coupled receptors, P2Y₁₂ initiating Gi-dependent intracellular signaling (4) resulting in further activation signals to generate “coated” platelets. Negative regulators include increased expression of TULA-2 and polymorphisms of the tyrosine phosphatase CD148 (5).

Figure 2.. Monocyte contributions to thrombosis:

PF4 bound to cell-surface GAGs serves as an important physiologic reservoir for binding HIT antibodies (1). Circulating ULICs also engage cellular FcγRIIA (2) initiating downstream signaling via Syk kinase(3) leading to upregulation of cell surface TF and release of TF-bearing microparticles that promote thrombin (IIa) generation (4) which then activates platelet protease activated receptor-1 to generate coated-platelets. Activated monocytes upregulate CD11b/Mac-1 which binds to circulating platelets to form leukocyte-platelet aggregates (5).

Figure 3.. Neutrophil contributions to thrombosis:

Circulating ULICs engage cellular FcγRIIA (1) initiating neutrophil activation, degranulation (2) upregulation of L-selectin and CD11b/Mac-1 to promote adhesion and formation of leukocyte platelet aggregates (3). Activated neutrophils extrude NETs which bind PF4 and HIT ULICs (4).

Figure 4.. Endothelial cell contributions to thrombosis:

Circulating ULICs or HIT antibodies bind to endothelial cell GAGs (1) triggering complement activation, deposition and EC activation(2). ECs express TF (3), and in the presence of activated platelets, upregulate cell-surface adhesive markers, E-selectin, ICAM-1 and VCAM (4). Activated ECs release vWF strings that bind PF4 to serve as new antigenic targets for HIT antibodies(5).