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Case Report *Corresponding author Arun Kannan, Internal Medicine, Canton Medical Education Foundation, 1501 N Campbell Ave PO BOX Sepsis as a Cause of Acquired 245212 Tucson AZ 85712, USA, Tel: 3304121641; Fax: 5206265721; Email: Submitted: 14 December 2014 Protein C and Protein S Accepted: 30 December 2013 Published: 31 December 2013 Deficiency- a Case Report and Copyright © 2014 Kannan et al. Literature Review OPEN ACCESS Arun Kannan*, Sweta Chandra, Jose Lizcano, Christie Murphy Keywords Internal Medicine, Canton Medical Education Foundation, USA • Sepsis • Warfarin • Skin necrosis Abstract • Protein C, Protein S Warfarin Induced Skin Necrosis is a well-known and dreaded complication in patients who is being started on warfarin without adequate bridging with other anticoagulants. The mechanism is thought to be due to protein C deficiency acquired after initial exposure to warfarin. We present a rather unusual cause of protein C deficiency due to sepsis resulting in warfarin induced skin necrosis. 43 year old lady who has been on chronic warfarin therapy secondary to anti phospholipid syndrome was admitted to the hospital for acute ischemic cerebellar stroke. Warfarin was held due to acute thrombocytopenia. She was discharged to a facility after restarting the warfarin at the same dose. She presented back to the hospital with septic shock due to pneumonia. She was found to have multiple necrotic areas consistent with skin necrosis. Unfortunately, patient died due to multi organ failure despite goal directed therapy. This case demonstrates the importance of recognizing the sepsis as an acquired cause of protein C deficiency.

ABBREVIATIONS therapy for 10 years was admitted to the hospital. Recently patient was admitted to the hospital for ischemic cerebellar APS: Antiphospholipid Syndrome; DVT: Deep Vein stroke and Warfarin was held due to acute thrombocytopenia. Thrombosis; PE: Pulmonary Embolism; WISN: Warfarin-Induced Warfarin was restarted again on the same dose (7.5 mg) with Skin Necrosis adequate bridging and sent to Nursing Home. About 10 days INTRODUCTION later patient was brought again with fever, hypotension. She was found to be in septic shock likely secondary to pneumonia and Warfarin-induced skin necrosis is a rare (prevalence of 0.01- admitted to Intensive Care Unit. She also complained of black 0.1% of warfarin treated patients) but potentially life threatening eschar lesions under inframammary and groin area. Upon further complication of anticoagulant therapy with an associated questioning it was revealed that lesion was of recent onset about morbidity and mortality requiring immediate drug cessation. 5-6 days after restarting Warfarin. It started as an erythematous Warfarin is a highly effective anticoagulant widely used for the lesion and within 48 hours it progressed to painful black lesions. primary and secondary prevention of thromboembolic disorders It was 6cm by 15 cm underneath the left breast and 7cm by 12cm in current medical practice. The drug is administered orally, in the left groin. Considering the septic shock, necrotizing fasciitis absorbed in the gastrointestinal tract, bound to serum albumin, was considered but it was ruled out by a surgeon. Warfarin metabolized by the hepatic CYP2C9 enzyme, and excreted as an was held and patient was put on heparin intravenously .Biopsy inactive metabolite into bile. Adverse effects associated with the use of warfarin include bleeding, hepatitis, priapism, alopecia, pruritic macular and papular eruption, purple toe syndrome werewas done consistent and it with revealed Warfarin skin Induced with superficial Skin Necrosis dermal (WISN). fibrin (cholesterol microembolization), and cutaneous necrosis. Unfortunatelythrombi, hemorrhage despite treatment and ischemic patient changes. died due These to multi-organ findings failure. CASE PRESENTATION DISCUSSION 43 year old Caucasian female with a history of antiphospholipid syndrome (APLS), multiple DVTs and PEs on chronic Warfarin So far, in literature approximately 300 cases of (WISN) have

Cite this article: Kannan A, Chandra S, Lizcano J, Murphy C (2014) Sepsis as a Cause of Acquired Protein C and Protein S Deficiency- a Case Report and Literature Review. JSM Clin Case Rep 2(2): 1028. Kannan et al. (2014) Email: Central been reported. The earliest symptoms of WISN appeared within multifactorial etiology. Recent reintroduction of warfarin and 10 days of restarting the warfarin with the peak incidence also coexistence of septic shock which is known to be one of the between days 3 and 6 (83-90% of cases) [1,2] (Figure 1). patient was already started on heparin by weight to bridge the WISN is a potentially catastrophic complication of warfarin therapycauses of as transient she had aacquired history ofprotein antiphospholipid C deficiency. syndrome Unfortunately with therapy that arises as a consequence of different half lives of multiple episodes of thrombosis in the past and level of protein different vitamin K dependent proteins. One day after initiation C and S could not be accessed. Patient was also started on broad of the usual doses of warfarin, the level of protein C almost spectrum antibiotics on admission due to being in septic shock, decreases by 50 %( same as factor VII). Rest of the vitamin K which could have further contributed to the acquired protein C dependent clotting factors have half life longer than that (48-60 hrs) and declines more slowly in the serum leading to a transient thus reducing vitamin K levels. imbalance in the proteins of the procoagulant-anticoagulant deficiency by reducing gut flora, intestinal malabsorption and system occurring during the initial phase of anticoagulation Our literature search has so far exposed only two cases of which creates a hypercoagulable state. This leads to thrombotic occlusions of the microvasculature causing the necrosis as seen had similar catastrophic outcome as our patient- Death from in our patient. The effect is more pronounced when a higher dose multiorganacquired protein failure. C deficiency [13,14]. One of these patients of warfarin is administered. REFERENCES The commonest cause has been attributed to hereditary 1. Nalbandian RM, Mader IJ, Barrett JL, Pearce JF, Rupp EC. Petechiae, ecchymoses, and Necrosis of skin induced by coumarin congeners: protein C deficiency. [3-5]. Other condition causing WISN is rare, occasionally lethal complication of anticoagulant therapy. Jama. 1965; 192: 603-608. disseminatedacquired causes intravascular of protein coagulation, C deficiency chemotherapeutic like acute thrombosis, agents forwarfarin breast therapy, cancer [6,7 vitamin ], sepsis K [8,9], deficiency primary [5], antiphospholipid liver disease, 2. Horn JR, Danziger LH, Davis RJ. Warfarin-induced skin necrosis: report of four cases. Am J Hosp Pharm. 1981; 38: 1763-1768. syndrome [10], acute exacerbation of ulcerative colitis [11], protein C auto-antibody formation[12] (Figure 2). 3. McGehee WG, Klotz TA, Epstein DJ, Rapaport SI. Coumarin necrosis

In our patient, the appearance of necrotic skin lesion which 1984; 101: 59-60. appeared on the 6-th day of reintroduction of warfarin therapy associated with hereditary protein C deficiency. Ann Intern Med. and later, on biopsy was proven to be WISN is speculated to have 4. Rose VL, Kwaan HC, Williamson K, Hoppensteadt D, Walenga J, Fareed

1986; 86: 653-655. J. Protein C antigen deficiency and warfarin necrosis. Am J Clin Pathol. 5. Presgrave P, Ma D. Genetic predisposition to venous thromboembolism: moleculer basis and a practical guide to management.Aust.NZ J. Phleb. 2000; 4: 39-45

6. Taher A, Shamsseddine A, Saghir N, Seoud M, Mourad F, Dabajah B,

administration for locally advanced breast cancer. Case report. Eur J et al. Acquired protein C deficiency following cisplatinum-navelbine Gynaecol Oncol. 1999; 20: 323-324.

7. in patients with breast cancer receiving cyclophosphamide, Feffer SE, Carmosino LS, Fox RL. Acquired protein C deficiency Figure 1 Skin necrosis seen underneath her left breast thought to be due to depletion of Protein C and S. 8. methotrexate,Fisher CJ Jr, Yan and SB.5-fluorouracil. Protein C levelsCancer. as 1989; a prognostic 63: 1303-1307. indicator of outcome in sepsis and related diseases. Crit Care Med. 2000; 28: S49- 56.

9. Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GR. Low levels of protein C are associated with poor outcome in severe sepsis. Chest. 2001; 120: 915-922.

10. Ruiz-Arguelles GJ, Ruiz-Arguelles A, Deleze M, Alarcón-Segovia

antiphospholipid syndrome. Relationship to reactivity of D. Acquired protein C deficiency in a patient with primary anticardiolipin antibody with thrombomodulin. J Rheumatol. 1989; 16: 381-383.

11. The cause of thromboembolic complications]. Dtsch Med Wochenschr. Korsten S, Reis HE. [Acquired protein C deficiency in ulcerative colitis. Figure 2 1992; 117: 419-424. consistent with warfarin induced skin necrosis. Histopathological stain revealed dermal fibrin thrombi 12. Mitchell CA, Rowell JA, Hau L, Young JP, Salem HH. A fatal thrombotic

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disorder associated with an acquired inhibitor of protein C. N Engl J 14. Parsi K, Younger I, Gallo J. Warfarin-induced skin necrosis associated Med. 1987; 317: 1638-1642. 57-61. 13. Argaud L, Guerin C, Thomas L, Fournier G. Extensive coumarin- with acquired protein C deficiency. Australas J Dermatol. 2003; 44:

Intensive Care Med. 2001; 27: 1555. induced skin necrosis in a patient with acquired protein C deficiency.

Cite this article Kannan A, Chandra S, Lizcano J, Murphy C (2014) Sepsis as a Cause of Acquired Protein C and Protein S Deficiency- a Case Report and Literature Review. JSM Clin Case Rep 2(2): 1028.

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