Warfarin‐induced limb gangrene in the setting of lung adenocarcinoma

Abstract

A 53-year-old man with lung adenocarcinoma developed pulmonary embolism and bilateral popliteal venous thrombosis. Treated with intravenous unfractionated heparin and discharged home on warfarin, he returned a week later with extending thrombosis. Treatment with heparin followed by warfarin was reinitiated. Twenty-four hours following the readministration of warfarin, the patient's INR increased to 14.5. The platelet count dropped by more than 50%, and he developed venous limb gangrene of the left leg and skin necrosis of the right leg. Heparin-induced thrombocytopenia was ruled out, and coagulation studies showed a severe depletion of protein C as well as increased thrombin generation. The patient was transfused with fresh frozen plasma, and vitamin K was given. Heparin was continued, and after 4 weeks, the patient improved markedly showing only minimal necrosis of the toes. Venous limb gangrene is a major complication associated with warfarin therapy. Its pathogenesis is explained by a transient hypercoagulable state produced by protein C depletion that leads to microvascular thrombi progressing to venous limb gangrene. The present case emphasizes the importance of careful anticoagulation with heparin followed by slow initiation of low-dose warfarin, in order to minimize thrombotic complications. Am.

Warfarin-induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome

“…4,5 There are also case reports of warfarin-induced VLG complicating metastatic cancer, usually adenocarcinoma. [6][7][8][9][10] The clinical features and pathogenesis of this syndrome are obscure, although 2 reports 7,8 provided laboratory data (increased TAT to PC activity ratio) suggesting a model of disturbed procoagulant-anticoagulant balance mimicking that seen in HIT/warfarin-induced venous limb ischemia. We now report 10 patients with cancer-associated severe venous limb ischemia/gangrene allowing us to characterize the clinical and laboratory picture.…”

Warfarin-Induced Penile Necrosis in a Patient with Heparin-Induced Thrombocytopenia

“…However, despite the elevated INRs, these patients had higher levels of thrombin-antithrombin complexes simultaneously. Coagulation factor studies have revealed that these patients have severe depletion of factor VII (the coagulation factor most rapidly affected by vitamin K antagonists) as well as protein C. These observations suggest that patients with hypercoagulable disorders are predisposed to skin necrosis during anticoagulation administration due to an increase in the ratio of thrombin-antithrombin complexes to protein C activity (10, 11). …”

Warfarin-Induced Skin Necrosis in a Patient with Heparin-Induced Thrombocytopenia: Two Diseases or One?

“…However, despite the elevated INRs, these patients simultaneously had higher levels of thrombin-antithrombin complexes (a marker of in vivo thrombin generation). Coagulation factor studies revealed that these patients experienced severe depletions of factor VII (the coagulation factor most rapidly affected by vitamin K antagonists) [15] as well as protein C. These observations suggest that patients with hypercoagulable disorders are predisposed to skin necrosis during anticoagulation administration due to an increase in the ratio of thrombin-antithrombin complexes to protein C activity [14, 16, 17]. …”

“…The alternative anticoagulant should not be stopped until the platelet count reaches a stable plateau and until there is at least 5 days of overlap with the INR >2 for 2 consecutive days [19]. In addition, excessive levels of warfarin anticoagulation should be avoided in hopes of preventing precipitous decrements in protein C levels [16, 17]. As was mentioned earlier, a supratherapeutic INR during warfarin initiation in a thrombophilic patient does not necessarily guarantee protection against thrombin generation.…”