A major potential side effect of heparin is immunogenicity, eliciting antibody development to a protein complex comprised of platelet factor 4 and heparin. Nevertheless, the clinical implications of heparin antibody positive patients remain broad, ranging from no apparent clinical consequences to life-threatening arterial and venous thromboemboli. The “Iceberg Model” has been proposed to depict this spectrum, with a relatively large population of antibody-positive patients forming the base of the iceberg, a smaller population of thrombocytopenic patients in the middle and a limited number of patients with thrombocytopenia and thrombosis comprising the apex. An underlying assumption of this model is that thrombosis occurs only in settings of relative or absolute thrombocytopenia. However, several recent studies suggest that antibody formation to platelet factor 4/heparin complexes, even in the absence of thrombocytopenia, may be associated with thrombotic events. In this review, we summarize these data, consider potential mechanisms for thrombosis, and suggest recommendations for testing and management of antibody-positive patients.