title: Warfarin-induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome.
abstract: Venous limb gangrene (VLG) can occur in cancer patients, but the clinical picture and pathogenesis remain uncertain. We identified 10 patients with metastatic cancer (7 pathologically proven) who developed severe venous limb ischemia (phlegmasia/VLG) after initiating treatment of deep-vein thrombosis (DVT); in 8 patients, cancer was not known or suspected at presentation. The patients exhibited a novel, clinically distinct syndrome: warfarin-associated supratherapeutic international normalized ratio (INR; median, 6.5) at onset of limb ischemia, rising platelet count during heparin anticoagulation, and platelet fall after stopping heparin. Despite supratherapeutic INRs, patient plasma contained markedly elevated thrombin-antithrombin (TAT) complex levels (indicating uncontrolled thrombin generation) and protein C (PC) depletion; this profile resembles the greatly elevated TAT/PC activity ratios reported in patients with warfarin-associated VLG complicating heparin-induced thrombocytopenia. Analyses of vitamin K-dependent factors in 6 cancer patients with available serial plasma samples showed that variations in the INR corresponded most closely with changes in factor VII, with a highly collinear relationship between VII and PC. We conclude that venous limb ischemia/gangrene is explained in some cancer patients by profoundly disturbed procoagulant-anticoagulant balance, whereby warfarin fails to block cancer-associated hypercoagulability while nonetheless contributing to severe PC depletion, manifest as a characteristic supratherapeutic INR caused by parallel severe factor VII depletion.
authors.affiliation: Department of Pathology and Molecular Medicine, and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada;
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Warkentin
authors.affiliation: Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON, Canada; and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cook
authors.affiliation: Transfusion Medicine and Hemostasis, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Ravi
authors.initials: R
authors.lastname: Sarode
authors.affiliation: Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada;
authors.forename: Debi A
authors.initials: DA
authors.lastname: Sloane
authors.affiliation: Department of Pathology and Molecular Medicine, and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Crowther
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D000990:Antithrombin III / Q000378:metabolism; D001779:Blood Coagulation Factors / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005734:Gangrene / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006493:Heparin / Q000009:adverse effects; D006801:Humans; D019934:International Normalized Ratio; D007511:Ischemia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007866:Leg / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000503:physiopathology*; D010447:Peptide Hydrolases / Q000378:metabolism; D011379:Prognosis; D020151:Protein C Deficiency / Q000139:chemically induced; D013577:Syndrome; D020246:Venous Thrombosis / Q000150:complications* / Q000188:drug therapy; D014812:Vitamin K / Q000008:administration & dosage; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D001779:Blood Coagulation Factors; C046193:antithrombin III-protease complex; D014812:Vitamin K; D014859:Warfarin; D000990:Antithrombin III; D006493:Heparin; D010447:Peptide Hydrolases