Thrombosis of lienal vein and acute consumptive coagulopathy following warfarin administration in a patientwith severe protein C deficiency

To the Editor: The frequency of homozygous protein C (PC) de®ciency has been estimated as 1:160,000 to 1:360,000, and the de®ciency is associated with peculiar phenotypic and clinical expression (1). In patients with undetectable PC activity purpura fulminans may occur soon after birth or in the ®rst year of life (2). Patients with very low but measurable PC (5±20%) usually develop thromboembolic complications in childhood or in early adult life (3). Management of these patients is often problematic because administration of warfarin may be associated with occurrence of skin necrosis, consumptive coagulopathy and recurrence of thrombosis (4). We recently had the rare opportunity to follow various haemostatic parameters in a patient with severe protein C de®ciency who developed lienal vein thrombosis and consumptive coagulopathy during initiation of warfarin therapy. An 11-yr-old patient presented in 1992 with spontaneous left iliaco-femoral vein thrombosis. Four years later he sustained thrombosis of the same localization and was initially treated with i.v. heparin followed by warfarin. Five days after introduction of warfarin therapy he developed an area of skin necrosis on his left leg. Warfarin was stopped and treatment with LMW heparin (Fraxiparine 7500 anti-Xa U, once daily) and fresh frozen plasma (FFP) was commenced. Three days later patient developed allergic reaction and plasma transfusion was discontinued. Protein C activity determined by chromogenic method 30 d after ceasing warfarin was 6% (normal 70±140%), and protein C:Ag was <10% (normal 70±140%). Activity of AT III was 101%, protein S 84% and plasminogen 98%. Sensitivity to activated protein C was normal (4.3, normal 2.1±7.3). In February 1997 the patient developed thrombosis of the left axillar vein and the Fraxiparine dose was increased to 7500 anti-Xa U, twice daily. Two months later due to economic reasons warfarin 1 mg/d was started, overlapped with Fraxiparine therapy (7500 anti-Xa U, three times daily). On the fourth day after commencement of warfarin, when INR reached 2.3, the patient started to complain of dull abdominal pain. ECHO-Doppler examination of the patient's abdomen revealed the presence of the lienal vein thrombosis. At that time PC activity was 1% and other laboratory investigations revealed occurrence of acute consumptive coagulopathy (Table 1). Warfarin was ceased and intravenous heparin with fresh frozen plasma administered. Protein C activity increased up to 10% and all investigated parameters normalized in the next few days. Fraxiparine (7500 anti-Xa U, twice daily) was recommenced, and there have been no further episodes of thrombosis. The patient's mother experienced several episodes of deep vein thrombosis, and protein C activity in her plasma was 48%. His father was not available for investigation, having died in a car accident. Only 16 recently published reports on patients with severe PC de®ciency provide details of their treatment. While receiving therapeutic amounts of warfarin, 3 (19%) developed recurrent thrombosis and 6 (38%) developed skin necrosis (5). Many of the patients who experience skin necrosis or rethrombosis need long-term anticoagulation, but the safety of warfarin re-administration is still an unresolved issue. Although our patient had previously experienced skin necrosis, we re-instituted warfarin in a low dose overlapped with LMW heparin, but lienal vein thrombosis occurred concomitantly with acute consumptive coagulopathy when the PC level fell to 1%. Interestingly, the rapid increase of prothrombin fragment F 1+2, and ®brin monomer (FM) levels was observed only when manifest consumptive coagulopathy developed, and did not precede to a fall in the ®brinogen and platelet count. This suggests that activation of coagulation in severe PC-de®cient patients receiving Eur J Haematol 2000: 64: 130±131 Printed in UK. All rights reserved Copyright # Munksgaard 2000