Simultaneous Bleeding and Thrombosis in Superwarfarin Poisoning

Thrombosis Research (2009) 123, 637–639

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BRIEF COMMUNICATION Simultaneous bleeding and thrombosis in superwarfarin poisoning

Erich Vinicius De Paula a,⁎, Silmara Aparecida Lima Montalvao a, Paulo Roberto Madureira b, Ronan Jose Vieira b, Joyce Maria Annichino-Bizzacchi b, Margareth Castro Ozelo a a Hematology and Hemotherapy Center, State University of Campinas, Brazil b School of Medical Sciences, State University of Campinas, Campinas, SP, Brazil

Received 23 December 2007; received in revised form 29 January 2008; accepted 5 February 2008 Available online 18 April 2008

Superwarfarin poisoning causes a severe acquired Case report coagulation disorder that, despite its frequency, severity and specific therapeutic implications, still A 24-year-old male presented to the emergency goes largely unrecognized by physicians. Hematol- room with gross hematuria and a 20-day long history ogists are often called to evaluate these patients, of melena and gingival bleeding. The patient also but unawareness of the specificities of the problem presented pain and swelling in the left knee which, often precludes adequate diagnosis and treatment. given the initial laboratory results, was interpreted Superwarfarin poisoning differs from coumarin over- as a hemarthrosis. He had a history of heavy alco- dose in that the former is resistant to reversal with hol consumption and had been taking disulfiram standard doses of vitamin K, and that anticoagulant 250 mg/day for 6 months to support treatment of effects can last for weeks after drug discontinuation. chronic alcoholism. Laboratory workup revealed Here we report a case of superwarfarin poisoning with prolonged prothrombin time (PTN300 s) and acti- a previously unreported clinical presentation, in which vated partial thromboplastin time (APTT=88.1 s), diffuse bleeding and venous thrombosis were simulta- which were both corrected on mixing studies. neously present at diagnosis. The diagnostic implica- Factors II, VII, IX and X activities were very low tions and the therapeutic dilemmas raised by this new (5.8%, 2.5%, 3.8% and 1.3% respectively), where- presentation are discussed. as factors V and VIII levels were normal, indicating a deficiency of vitamin K (VK) dependent factors. However, screening for warfarin in urine was negative. Protein S and protein C (PC) activities were ⁎ Corresponding author. Hematology and Hemotherapy Center, 44.6% and 3.9% respectively. Shortly after admission, State University of Campinas, Rua Carlos Chagas 480, 13081-878 Campinas, SP, Brazil. Tel.: +55 19 3521 8756; fax: +55 19 3521 knee edema revealed to be caused by deep venous 8600. thrombosis (DVT) of popliteal and femoral veins by E-mail address: [email protected] (E.V. De Paula). ultrasound. Because of the high bleeding risks, and the

Figure 1 Time course of superwarfarin-induced coagulopathy. Treatment strategies used since admission (day 0) when the patient presented with simultaneous bleeding and thrombosis are shown (a). The activities of coagulation factors II, V, VII, and PC (b) demonstrate the severe deficiency on day 0, followed by a slow rise towards normal values, which were only detected after 3 months of treatment. Prothrombin time (PT) (c) reached normal values earlier, but up to day 40, short-term withdrawal of vitamin K treatment were promptly followed by significant prolongation of the PT. Increased levels of Pivka-II (above 30 ng/ml) were present for as long as 9 months after superwarfarin withdrawal.

reduced levels of VK-dependent factors, anticoagula- VK-dependent factors, including PC returned to tion with heparin was not initiated. normal. After discharge, he was referred to psy- Treatment with fresh frozen plasma (FFP), as- chiatric follow-up, and admitted intentional in- sociated with intravenous VK (30 mg/day) was gestion of rodenticides (difethialone) during the initiated shortly after the initial laboratory results 30 days preceding admission. A diagnosis of schyzo- (Fig. 1). On this regimen bleeding stopped, PT and phrenia was made, and continuous ingestion of APTT decreased, but levels of factors II, VII, IX and X difethialone ruled out based on the psychiatric and PC (19.5%) persisted below normal. The patient evaluation, since specific tests to detect difethia- was discharged after 10 days with oral VK, which lone were not available. Residual sub-clinical antic- was gradually tapered down during the following oagulant effect of difethialone persisted for as 4 months. During the first 3 months of follow-up, late as 9 months after admission as evidenced withdrawal of VK was invariably associated with by high levels of descarboxyprothrombin (PIVKA-II). rapid-onset prolongation of the PT, and it was not The patient provided written informed consent for until the 4th month after admission that levels of this report.

Figure 2 Effects of superwarfarin poisoning on the hemostatic balance. Superwarfarins cause deficiencies of both pro- coagulant and anti-coagulant proteins. The net impact on the hemostatic balance, which can be influenced by use of hemostatic agents to control bleeding and pre-existent risk factors, will result in bleeding, thrombosis or both. Simultaneous bleeding and thrombosis in superwarfarin poisoning 639

Discussion during the first weeks of follow-up, despite VK sup- plementation (PT around 1.5 to 2-fold higher than Superwarfarins are long-acting anticoagulants that normal up to the 3rd month after DVT). Below-knee like warfarin, exert their anticoagulant effect by elastic compression stockings were prescribed after inhibiting the vitamin K (VK) epoxide reductase en- 10 days of the initial event, and the patient did not zyme [1]. Mainly represented by brodifacoum and develop post-thrombotic syndrome. difethialone, superwarfarins are available without In conclusion, one must keep in mind that im- restrictions and are used with increased frequency balances between pro and anti-coagulant factors in as home rodenticides. In 2004, poisoning with super- these patients can result in both bleeding and throm- warfarins affected at least 16,000 persons in the US, bosis, and that the risk of life-threatening thrombo- mostly children [2]. embolic complications may be further aggravated by The usual clinical presentation of superwarfarin initial treatment with VK or other haemostatic agents poisoning is bleeding. In contrast to warfarin over- such as prothrombin complex concentrates (Fig. 2). dose, VK administration, even at high doses, fails to reverse the anticoagulant effects of superwarfarins, Summary which may persist for months after exposure [3]. Laboratory findings include: (1) prolonged PT and Superwarfarin-associated coagulopathy is a severe APTT that correct on mixing studies with normal and potentially fatal condition which, despite its plasma, (2) reduced activity of factors II, VII, IX, X, frequency, severity and specific therapeutic char- PC and S, (3) elevated PIVKA-II levels, (4) a very high acteristics, still goes largely unrecognized. Hema- ratio of VK1 epoxide to reduced VK1, and (5) un- tologists are often called to evaluate these patients, detectable levels of warfarin [4]. In addition, super- and unawareness of these specificities can preclude warfarin levels can be measured in serum by high adequate diagnosis ant treatment. We present a performance liquid chromatography, allowing a more case of superwarfarin poisoning in which bleeding, precise monitoring of drug clearance [5]. associated with severe depletion of coagulation fac- This report reinforces both the long-lasting an- tors II, VII, IX and X, occurred simultaneously to ticoagulant effects of superwarfarins, and the re- venous thromboembolism, associated with severe quirement of VK doses that are much higher than protein C deficiency. The diagnostic and therapeutic those conventionally used in warfarin overdose, two dilemmas raised by this previously unreported pre- aspects with important therapeutic implications [6]. sentation of superwarfarin poisoning are discussed. However, the most interesting feature of our case is that it describes an additional complication of References superwarfarin poisoning, which is a severe acquired deficiency of natural anticoagulant PC associated [1] Chua JD, Friedenberg WR. Superwarfarin poisoning. Arch with clinical venous thromboembolism (VTE). In fact, Intern Med 1998;158:1929–32. thrombosis in the setting of superwarfarin poisoning [2] Watson WA, Litovitz TL, Rodgers Jr GC, Klein-Schwartz W, has been recently described after the use of pro- Reid N, Youniss J, et al. 2004 annual report of the American Association of Poison Control Centers Toxic Exposure Surveil- coagulant agents to control bleeding, which repre- lance System. Am J Emerg Med 2005;23:589–666. sents per se a risk factor for thrombosis [7].Thefact [3] Sarin S, Mukhtar H, Mirza MA. Prolonged coagulopathy related that in our patient VTE occurred spontaneously has to superwarfarin overdose. Ann Intern Med 2005;142:156. important implications not only for the diagnosis of [4] Pavlu J, Harrington DJ, Voong K, Savidge GF, Jan-Mohamed R, superwarfarin poisoning, but mainly for its initial Kaczmarski R. Superwarfarin poisoning. Lancet 2005;365:628. [5] Kuijpers EA, den Hartigh J, Savelkoul TJ, de Wolff FA. A treatment, which is usually aimed to control life- method for the simultaneous identification and quantitation threatening bleeding. Treatment of VTE in these pa- of five superwarfarin rodenticides in human serum. J Anal tients is further complicated by the question wheth- Toxicol 1995;19:557–62. er additional anticoagulation should be initiated in [6] Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long- the setting of VK-dependent factors and high bleed- acting anticoagulant overdose: brodifacoum kinetics and op- timal vitamin K dosing. Ann Emerg Med 2000;36:262–7. ing risk on one side, and the risk of untreated VTE on [7] Laposata M, Van Cott EM, Lev MH. Case records of the the other side. In our case, the decision not to start Massachusetts General Hospital. Case 1-2007. A 40-year-old additional anticoagulation was based on the assump- woman with epistaxis, hematemesis, and altered mental tion of an unfavorable risk:benefit ratio due to per- status. N Engl J Med 2007;356:174–82. sistent low levels of VK-dependent factors observed