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.

journal_name

Blood

journal_title

Blood

authors

Warkentin TE,Cook RJ,Sarode R,Sloane DA,Crowther MA

doi

10.1182/blood-2015-01-622787

subject

Has Abstract

pub_date

2015-07-23 00:00:00

pages

486-93

issue

4

eissn

0006-4971

issn

1528-0020

pii

blood-2015-01-622787

journal_volume

126

pub_type

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