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

Abstract

Key Points Warfarin-induced venous gangrene in cancer affects limb with DVT and features platelet fall after stopping heparin and supratherapeutic INR. Persisting thrombin generation occurs despite elevated INR, indicating severe PC depletion that occurs in parallel with reduced factor VII.

Ischemic Limb Gangrene with Pulses

“…9,10 Venous limb gangrene and symmetric peripheral gangrene (with or without purpura fulminans) are cutaneous manifestations of disseminated intravascular coagulation that are modified and aggravated by interacting clinical factors such as warfarin therapy, deep-vein thrombosis, hypotension, and vasopressor therapy. [1][2][3][4] Associated failure of the natural anticoagulant systems, both the protein C system (crucial for down-regulating thrombin generation in the microvasculature 11 ) and the antithrombin system (catalyzed by circulating pharmacologic heparin and endogenous endothelial-bound heparan sulfate), helps to explain why risk factors for microthrombosis include the use of warfarin (a vitamin K antagonist) and hepatic dysfunction or failure, since the liver synthesizes protein C (a vitamin K-dependent anticoagulant) and antithrombin (Fig. 1C).…”

“…12,13 However, in recent years, patients with venous gangrene have often been reported with underlying acquired hypercoagulability states, such as cancer-associated consumptive coagulopathy, 1,14 heparin-induced thrombocytopenia, 2,15 and the antiphospholipid syndrome, 16,17 with associated macrovascular and microvascular thrombosis that is frequently exacerbated by protein C depletion associated with the administration of warfarin or other coumarin derivatives. 1,2,[14][15][16] The characteristic laboratory picture includes thrombocytopenia and an international normalized ratio (INR) that typically exceeds 4.0; a supratherapeutic INR is a proxy for a severely reduced protein C level. 1,2,14 …”

Coumarin Induced and Spontaneous Hemorrhagic Skin Necrosis

“…In retrospect, the strongly prolonged INR and the very low protein C (PC) levels at time of strongly prolonged INR were very low, 0.10 and 0.05 U/mL, and pathgnomonically diagnostic for coumarin necrosis as the cause of phlegmasia alba dolens (episode 1) and gangrene of the skin (episode 2) in (Figure 5). In the second ilustrated case of Warkentin shown in Figure 5, warfarin 5 mg/day induced within 4 to 5 days after start a strongly prolonged INR associated with gangrene of the skin and extremely low protein C (PC) level of 0.05 and 0.02, which could be corrected by vitamin k supplementation on the basis of which the only diagnosis possible is coumarin necrosis [16,17]. The recently described warfarin-induced venous limb ischemia/gangrene complicating cancer by Warkentin et al [17] is not a novel syndrome but has all features of coumarininduced thrombo hemorrhagic skin necrosis and ischemia.…”

“…Purpura fulminans and skin necrosis in neonates with homozygous protein C deficiency is caused by diffuse thrombosis in the microcirculation of capilaries and venules [16], similar as seen as in the early stages of coumarin induced skin necrosis [14]. Lewandowski oberved that intravenous protein C concentrate induced a rapid cure of coumarin induced skin necrosis in a patient with heterozygous protein C deficiency [17].…”

How I treat catastrophic thrombotic syndromes

“…47 Warfarin may be ineffective in patients with severe Trousseau syndrome, 48 and has been associated with venous limb gangrene in patients with cancer and thrombosis, similar to patients with HIT. [49][50][51] Rivaroxaban has also been associated with venous limb gangrene in a patient with acute cancer-associated thrombosis. 52 Patients with malignancy who develop catastrophic APS have been reported, 53 and 9% of patients reported in the CAPS Registry had cancer.…”