The coumarins are a group of naturally occurring lactones that are produced by a number of plants and microbes. Ironically, the least complex member, coumarin (1,2-benzopyrone), has no anticoagulant action despite its synonymous designation for those chemically related molecules that possess anticoagulant activity.¹² Warfarin (Coumadin), a 4-hydroxycoumarin derivative, is the most widely used oral anticoagulant in North America and worldwide.² Therefore, most instances of CISN in North America are warfarin induced. However, the syndrome can be caused by other coumarin congeners (e.g., phenprocoumon, acenocoumarol, and nicoumalone), as well as by the rarely used phenindione group of oral anticoagulants.¹³, ¹⁴ Phenprocoumon (Marcumar) is widely used in continental Europe. Because its half-life is longer than that of warfarin (6 vs. 1.5 days), relatively large loading doses are often given; however, whether these differences result in a lesser or greater frequency of CISN, compared with warfarin, is unknown. The coumarins interfere with vitamin K epoxide reductase,¹⁵ producing posttranslational modifications of four procoagulant and two anticoagulant vitamin K-dependent factors¹⁶ (see Chapter 106).

Several observations suggest that the fundamental pathobiology of coumarin necrosis is a transient disturbance in procoagulant/anticoagulant balance that leads to microthrombosis in susceptible tissue sites. First, coumarin necrosis has a characteristic temporal profile, usually occurring within 1 week of initiating oral anticoagulant therapy.⁵, ⁶, ⁷, ⁹, ¹⁷, ¹⁸, ¹⁹, ²⁰ During this interval, functional levels of protein C decline much more quickly than the major procoagulant factor, prothrombin,²¹, ²² because of differences in their half-lives¹⁶ (see Table 109.1); given that prothrombin inhibits the ability of activated protein C to inactivate factor Va,²³ this early discrepancy in prothrombin versus protein C concentrations— (low-)normal and very low, respectively—can impair the protein C anticoagulant system. Second, the pathology is that of noninflammatory, small-vessel thrombosis affecting the dermal and subcutaneous postcapillary venules and small veins.⁵, ¹⁹ This is consistent with the role of the protein C anticoagulant pathway in preventing thrombosis of these small vessels.²⁴ Third, a relatively high proportion of patients with CISN (although not with venous limb gangrene) have a hereditary abnormality of the protein C anticoagulant pathway, which predisposes such patients to further, potentially dangerous reductions in protein C during the first few days of oral anticoagulant treatment. Fourth, the clinical and pathologic appearance of CISN resembles that of neonatal purpura fulminans caused by severe congenital protein C deficiency.²⁵ Fifth, skin necrosis can be a feature of acquired deficiency of protein C or protein S due to infection, autoimmunity, or the antiphospholipid syndrome²⁶, ²⁷, ²⁸ or functional inhibition of protein C or protein S by antiphospholipid antibodies.²⁹, ³⁰ Sixth, coumarin necrosis (particularly venous limb gangrene) is associated with markedly increased thrombin generation.⁴, ⁵, ⁶, ³¹

CISN refers to central (nonacral) necrosis of skin and subcutaneous tissues (see FIGURE 109.1) (4); it occurs more often in women (3:1 ratio), with mean age being 50 to 55 years, and most commonly involves sites with substantial underlying fatty tissues, such as the breast, anterior abdomen, buttocks, hips, thighs, and calves and less commonly, the flank, back, penis (ischemic priapism, necrosis), legs, arms, and face (e.g., cheeks, nose, eyelids, pinnae).³, ¹³, ¹⁷, ¹⁸, ¹⁹, ²⁰, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹ Multiple (sometimes symmetric) lesions are observed in about one-third of patients. CISN is rare (estimated frequency, 0.01% to 0.1%).³, ¹⁸

The typical temporal onset between 3 and 6 days of oral anticoagulant therapy occurs in 90% of patients,¹³, ¹⁷, ¹⁸, ¹⁹, ²⁰, ⁴⁰ although late onset after weeks or months has been reported.⁴¹, ⁴², ⁴³ Localized pain, induration, and erythema progress over hours to central purplish black skin discoloration, usually with blistering, and ultimately evolving to well-demarcated, full-thickness necrosis of the skin and subdermal tissues (see FIGURE 109.2). With or without surgical debridement, there usually is a permanent region of depressed skin that reflects the loss of underlying tissues. The necrotic skin also presents the real possibility of secondary fatal sepsis.⁴⁰, ⁴², ⁴⁴

The earliest stages of CISN can resemble subcutaneous hemorrhage. Incipient skin necrosis is suggested by (a) recent initiation of coumarin, (b) typical location of lesions, (c) absence of trauma, and (d) an international normalized ratio (INR) that is within (in 33% to 60% of patients) or above the therapeutic range.¹⁷, ¹⁸ CISN that occurs when the INR is within the therapeutic range suggests that the patient has a preexisting abnormality of the protein C natural anticoagulant pathway, as noted in four family members with hereditary protein S deficiency.⁴⁵ In contrast, when warfarin-induced venous limb gangrene complicates disorders associated with disseminated intravascular coagulation (DIC), such as HIT or adenocarcinoma, there typically is a supratherapeutic INR (>3.5). This reflects the special susceptibility of factor VII and protein C to severe depletion during coumarin therapy in DIC. In such patients, congenital abnormalities of the protein C natural anticoagulant pathway are usually not present.⁵, ⁶, ¹⁰, ⁴⁴

Often, multiple risk factors can be identified in individual patients (see Table 109.2).⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ³¹, ³², ³³, ³⁴, ⁴⁰, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³, ⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴, ⁷⁵, ⁷⁶ An example is the concurrence of postpartum DVT, antiphospholipid syndrome, “loading doses” of warfarin, and premature discontinuation of heparin in one patient⁵⁰; another is the concurrence of pulmonary embolism, factor V_Leiden, “loading doses” of warfarin, and premature discontinuation of heparin in another.⁴⁶

Abnormalities of the protein C natural anticoagulant pathway are a relatively common finding in patients with CISN. Indeed, congenital deficiency of protein C was the first hemostatic abnormality identified in some patients with CISN (although reports do not always distinguish hereditary deficiency from the reversible reduction expected in a patient receiving coumarin).⁶⁸, ⁶⁹, ⁷⁰ Congenital deficiency of protein S⁴⁵, ⁴⁸, ⁴⁹, ⁵¹, ⁵², ⁶⁴, ⁷¹ and of antithrombin⁷⁴ also has been observed, as has been the presence of factor V_Leiden,⁴⁶, ⁴⁹, ⁵³, ⁶³, ⁷², ⁷³ a common mutation that renders factor V less susceptible to proteolytic degradation by activated protein C. Most patients with CISN have acute DVT (rather than a nonthrombotic indication such as atrial fibrillation)⁵⁵ as their indication for oral anticoagulants,³ suggesting
that associated clinical factors (perhaps thrombin generation related to an acute thrombus) are relevant in CISN pathogenesis.