The relationship among the clinical expression of HIT (thrombocytopenia with or without thrombosis), the type of heparin used, and the antibodies that cause HIT. This can be conceptualized as an “iceberg.” The visible component of the iceberg (the portion above the waterline) represents clinically evident features of HIT, such as thrombocytopenia and/or thrombosis. The mass of the iceberg corresponds to the entire spectrum of anti-PF4/heparin antibodies generated. Some of these antibodies will be biologically active (platelet-activating), and others will be nonplatelet-activating which may make them unlikely to cause clinical consequences. The type of heparin given to the patient determines the overall size of the iceberg, with unfractionated heparin (UFH) being the largest (most immunogenic), and low-molecular-weight heparin and fondaparinux have lesser immunogenicity. Also illustrated in this figure is the vivo cross-reactivity. UFH forms antigens which are readily recognized by HIT antibodies. In contrast, fondaparinux forms poorly recognized antigens. LMWH is intermediate. Illustration by A.Y. Chen.