Protein C and the Development of Skin Necrosis During Anticoagulant Therapy

Abstract

Protein C and'the Development of Skin Necrosis During Anticoagulant Therapy Dear Sir, Coumarin skin necrosis is thought to be the consequence of diffuse thrombosis of the small venules in the lesions with secondary bleeding due to the coumarin-induced hypocoagulability (1, 2). The report by one of us (V. H.) of a patient who developed skin necrosis not only during the initial phase of oral anticoagulant therapy, but also at the onset of cholestatic vitamin K deficiency (3), questions the proposed pathogenic mechanisms such as toxic influences of oral anticoagulants and hypersensitivity vasculitis due to the coumarin drug. In the report it was suggested that PIVKAs might play a role in the development of skin necrosis. Recently it has been recognized that during the initial phase of oral anticoagulant therapy-there is a rapid drop not-only of factor VII but also of protein C, their biological half-lives being very similar. Protein C is a vitamin K dependent protein (4) Thrombotest (sec) 36 35.5 S 3 9

Coumarin Induced and Spontaneous Hemorrhagic Skin Necrosis

“…This observation is diagnostic for severe vitamin K deficiency as the cause of spontaneous hemorrhagic skin necrosis in this case. (Figure 2 ) [14,15].…”

“…Based on personal observations on the curative effect of Vitamin K supplementation at time of strongly prolonged prothrombin time (INR), Loeliger hypothesized between 1975 and 1977 that severe factor VII deficiency was an obligate prerequisite for the development of severe coumarin induced hemorrhagic skin necrosis [10,11]. With the discovery of hereditary protein C deficiency as cause of congenital thrombophila it became clear that protein C is a natural anticoagulant at the level of vessel wall endothelium in the microcirculation [12][13][14]. Two studies of Loeliger et al incontrovertible demonstrated that severe protein C and factor VII deficiency as compared to the vitamin K dependent procoagulant appeared to be a good explanation for the etiology of coumarin induced hemorrhagic skin necrosis [11,14].…”

“…With the discovery of hereditary protein C deficiency as cause of congenital thrombophila it became clear that protein C is a natural anticoagulant at the level of vessel wall endothelium in the microcirculation [12][13][14]. Two studies of Loeliger et al incontrovertible demonstrated that severe protein C and factor VII deficiency as compared to the vitamin K dependent procoagulant appeared to be a good explanation for the etiology of coumarin induced hemorrhagic skin necrosis [11,14]. Vitamin K supplementation and short discontinuation of coumarin treatment for a few days in the early stage of swollen skin purpura could prevent the progression into blister formation and hemorrhagic skin necrosis [14,15].…”

“…Two studies of Loeliger et al incontrovertible demonstrated that severe protein C and factor VII deficiency as compared to the vitamin K dependent procoagulant appeared to be a good explanation for the etiology of coumarin induced hemorrhagic skin necrosis [11,14]. Vitamin K supplementation and short discontinuation of coumarin treatment for a few days in the early stage of swollen skin purpura could prevent the progression into blister formation and hemorrhagic skin necrosis [14,15]. 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].…”

“…Vitamin K supplementation and short discontinuation of coumarin treatment for a few days in the early stage of swollen skin purpura could prevent the progression into blister formation and hemorrhagic skin necrosis [14,15]. 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].…”