title: The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.
abstract: BACKGROUND
  Platelet-mediated arterial occlusion is a well-recognized cause of limb loss in patients with heparin-induced thrombocytopenia. However, the syndrome of distal ischemic necrosis complicating the deep venous thrombosis (venous limb gangrene) sometimes associated with heparin-induced thrombocytopenia has not been well characterized.
  
  
  OBJECTIVE
  To study the pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.
  
  
  METHODS
  Characterization (based on descriptive and case-control studies) of a novel syndrome of limb loss and hypothesis testing by analysis of plasma samples.
  
  
  METHODS
  Five university-associated hospitals in one medical community.
  
  
  METHODS
  Clinical and laboratory records of 158 patients with heparin-induced thrombocytopenia were reviewed to identify patients with venous limb gangrene (n = 8), limb arterial thrombosis (n = 10), and uncomplicated deep venous thrombosis (n = 58).
  
  
  METHODS
  Clinical and laboratory factors associated with venous limb gangrene, including thrombin-antithrombin complexes and vitamin K-dependent procoagulant and anticoagulant factors.
  
  
  RESULTS
  Warfarin treatment was more frequently associated with venous limb gangrene than with limb arterial thrombosis (8 of 8 patients compared with 3 of 10 patients; P = 0.004). The anticoagulant effect of warfarin seemed greater in the 8 patients with venous limb gangrene than in the 58 patients who did not develop gangrene (median International normalized ratio, 5.8 compared with 3.1; P < 0.001). Compared with plasma from controls, plasma from patients with venous limb gangrene had a higher ratio of thrombin-antithrombin complex to protein C activity during warfarin treatment. No hereditable abnormalities of the protein C anticoagulant pathway were seen in any patient.
  
  
  CONCLUSIONS
  Warfarin treatment of deep venous thrombosis associated with heparin-induced thrombocytopenia is a possible cause of venous limb gangrene, perhaps because of acquired failure of the protein C anticoagulant pathway to regulate thrombin generation.
authors.affiliation: McMaster University, Hamilton Health Sciences Corporation, Ontario, Canada.
authors.forename: T E
authors.initials: TE
authors.lastname: Warkentin
authors.forename: L J
authors.initials: LJ
authors.lastname: Elavathil
authors.forename: C P
authors.initials: CP
authors.lastname: Hayward
authors.forename: M A
authors.initials: MA
authors.lastname: Johnston
authors.forename: J I
authors.initials: JI
authors.lastname: Russett
authors.forename: J G
authors.initials: JG
authors.lastname: Kelton
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects*; D016022:Case-Control Studies; D005260:Female; D005734:Gangrene / Q000139:chemically induced*; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced*; D013924:Thrombophlebitis / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D011486:Protein C; D014859:Warfarin; D006493:Heparin; D013917:Thrombin