Venous Limb Gangrene Complicating Adenocarcinoma

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The venous thrombotic events complicating adenocarcinoma include DVT, phleg-masia cerulea dolens, and even venous limb gangrene (Everett and Jones, 1986; Adamson and Currie, 1993). Clinical and laboratory parallels between HIT and adenocarcinoma suggest that, paradoxically, coumarin treatment could contribute to the pathogenesis of venous gangrene in these patients through a disturbance in procoagulant-anticoagulant balance (Warkentin, 1996, 2001; Klein et al., 2004; Ng and Crowther, 2006). Figure 2 summarizes the proposed pathogenesis of this syndrome from the perspective of the characteristic clinical triad of venous limb gangrene: (1) thrombocytopenia caused by HIT or adenocarcinoma-associated DIC;

(2) acute DVT with acral (distal) microvascular thrombosis; and (3) a suprathera-peutic international normalized ratio (INR) associated with coumarin therapy.

Venous limb gangrene appears to result from failure of the protein C anticoagulant pathway to down-regulate thrombin generation within the microvascu-lature (Warkentin 1996; Warkentin et al., 1997; see Chapter 2). Here, the elevated INR represents a surrogate marker for marked reduction in functional protein C levels (by a parallel reduction in factor VII); the thrombocytopenia is a surrogate marker for uncontrolled thrombin generation associated either with HIT or adenocarcinoma (Fig. 2). As venous limb gangrene occurs in a limb with preceding active DVT, this suggests that local factors, such as direct extension of thrombosis, as well as exacerbation of distal thrombosis by venous stasis, contribute to large- and small-vessel thrombosis characteristic of this syndrome.

Venous thrombosis complicating adenocarcinoma, especially when complicated by DIC or severe venous ischemia or necrosis, should be treated with heparin, rather than warfarin or other coumarin anticoagulants. Reversal of warfarin anticoagulation (intravenous vitamin K, with or without plasma infusion) and prompt control of DIC with heparin could salvage a limb with severe phlegmasia, or limit damage in a patient with venous gangrene. An effective agent often is LMWH (Prandoni, 1997; Lee et al., 2003). I recommend monitoring using antifactor Xa levels, because some patients with heparin resistance require high doses of heparin to achieve therapeutic anticoagulation.

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