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Heyde syndrome is the association between aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia where the bleeding is usually cured by aortic valve replacement; the chance reading of a neonatal study showing reversible deficiency of high\u2010molecular\u2010weight (HMW) multimers of von Willebrand factor (vWF) following surgical correction of congenital heart disease provided the key insight that a subtle deficiency of HMW multimers of vWF explains Heyde syndrome. The unusual immunobiology of heparin\u2010induced thrombocytopenia (HIT)\u2014a highly prothrombotic, antibody\u2010mediated, anti\u2010platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin\u2010dependent platelet\u2010activating antibodies\u2014permitted identification of key clinical features that informed development of a scoring system (4Ts) to aid in HIT diagnosis. Atypical clinical presentations of HIT prompted identification of heparin\u2010<jats:italic>independent<\/jats:italic> anti\u2010PF4 antibodies, now recognized as the explanation for vaccine\u2010induced immune thrombotic thrombocytopenia (VITT), as well as VITT\u2010like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep\u2010vein\/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT\u2010 and cancer\u2010associated venous limb gangrene provided insight into disturbed procoagulant\/anticoagulant balance; these concepts are relevant to microvascular thrombosis in critical illness (symmetrical peripheral gangrene), including a pathophysiological role for proximate \u201cshock liver\u201d (impaired hepatic synthesis of natural anticoagulants).<\/jats:p>","DOI":"10.1111\/ijlh.14261","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:30:21Z","timestamp":1709512221000},"page":"12-26","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A career in solving clinical\u2010pathological conundrums: <scp>Heyde syndrome<\/scp>, anti\u2010platelet factor 4 disorders, and microvascular limb ischemic 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