A career in solving clinical‐pathological conundrums: Heyde syndrome, anti‐platelet factor 4 disorders, and microvascular limb ischemic necrosis

Abstract

AbstractHematology is a clinical specialty with strong roots in the laboratory; accordingly, the lab can help solve perplexing clinical problems. This review highlights clinical‐pathological conundrums addressed during my 35‐year hematology career at McMaster University. 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‐molecular‐weight (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‐induced thrombocytopenia (HIT)—a highly prothrombotic, antibody‐mediated, anti‐platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin‐dependent platelet‐activating antibodies—permitted 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‐independent anti‐PF4 antibodies, now recognized as the explanation for vaccine‐induced immune thrombotic thrombocytopenia (VITT), as well as VITT‐like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep‐vein/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT‐ and cancer‐associated 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 “shock liver” (impaired hepatic synthesis of natural anticoagulants).