practice
Skin necrosis due to fluindione treatment: a rare but serious complication In the setting of protein C deficiency, skin necrosis, which occurs most often at the initial phase of oral anticoagulants therapy, is a rare side effect. Six cases have previously been reported in the literature. In this case report, we present a protein C deficient 42-year-old woman who was being treated for venous thrombosis. Five days after the initiation of oral anticoagulant treatment, she developed extensive skin necrosis on her left calf, followed by a painful leg ulcer. The pathogenesis underlying skin necrosis caused by anticoagulation therapy is still not clear. Despite only a few cases being reported in the literature, it is important to recognise this complication since adequate therapeutic approaches leading to a stable anticoagulation state may prevent it. protein C deficiency; skin necrosis; leg ulcer; oral anticoagulants; vitamin K antagonists
S16
Case report A 42 year old woman was referred to the dermatologic department at Cochin hospital for a large and deep skin ulceration of the left calf in October 2008. The patient’s past medical history brought important information about her. She was a non-smoker, married and worked as a social assistant. She underwent two uneventful pregnancies. She first experienced a venous superficial thrombotic episode at the age of 26 years, 6 months after the initiation of a contraceptive estrogen-progestin treatment, treated only with low molecular weight heparin (LMWH) injection. An assessment of family history revealed that severe homozygote protein C deficiency was first detected in the patient’s sister, who developed a proximal deep vein thrombosis during pregnancy (15% protein C activity; normal range is 70–130%). Her sister was treated successfully after the pregnancy with a combination of LMWH and warfarin over an extended period of time. The same severe protein C deficiency was detected in our patient, who exhibited 11% protein C activity levels and protein C antigen levels of 27%. Platelet count (196000/mm3) and other blood coagulation factors were within normal range. Gene analysis of protein C identified a homozygote point mutation at R220Q (178). Our patient was treated in 2005 at the age of 37 years for a breast carcinoma by mastectomy and
ltd
P
rotein C is an important vitamin-Kdependent protein that has anticoagulant activity. Low levels of this protein leads to a hypercoagulable state and thromboembolic manifestations. Congenital protein C deficiency was first described in 1981, and occurs in about 0.2–0.4% of the general population.1-2 This hereditary coagulation disorder is transmitted in an autosomal dominant manner. The gene encoding protein C is localised on chromosome 2 (2q13-q14), contains 8 exons and spans approximately 11kb. Several mutations of this gene has been reported.1-2 Heterozygous patients have decreased blood levels of normal protein C (approximately 50%) and are presented with venous thrombosis episodes, whereas homozygous patients usually have very low protein C activity and develop, soon after birth, a neonatal purpura and extensive thrombosis incompatible with survival. Homozygote adults with asymptomatic or late onset thromboembolic events are exceptional. At the initiation of oral anticoagulant treatment, 3% of these patients may develop skin necrosis. We describe in this case report a skin necrotic ulcer of the leg, which developed following the initiation of oral anticoagulant therapy in a female patient affected by homozygous protein C deficiency.
© 2014 MA Healthcare
K. Beqqal, MD, Dermatologist; M.H. Horellou,3 MD, Biologist; A. Philippe,1 Nurse, M. Alhene Gelas,4 MD, Geneticist; C. Flaujac,3 MD, Biologist; I. Gorin,1 MD, Dermatologist; S. Jacobelli,1 MD, Dermatologist; N. Dupin,1 MD, Dermatologist; B. Hassam,2 MD, Dermatologist; M.F. Avril,1 MD, Dermatologist; 1 APHP, Department of Dermatology, Hospital Cochin, Paris Descartes University, Paris, France. 2 Department of Dermatology, Ibn Sina Hospital, University of Mohammed V-Souissi, Rabat, Morocco; Continued on page S17 1,2
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
practice radiotherapy. Thereafter, she received tamoxifene treatment until the end of July 2008. At the age of 42 years, on the 2nd of August 2008, she was presented with a second episode of superficial venous thrombosis confirmed par Doppler ultra-sonography. She received treatment with LMWH. This thrombosis occurred after a long journey by car. Extension of the superficial deep vein thrombosis to the left femoral vein occurred after 4 days of LMWH treatment. She was referred to the emergency department of Orléans hospital on 6 August 2008 and was treated with a combination of LMWH and oral vitamin K antagonists (VKA) (i.e. fluindione 2 tablets/day i.e. 40 mg/day) for 5 days. On August 16, an oval ecchymotic area appeared on the left calf (Fig 1), and the treatment by LMWH was interrupted on the next day when INR of 4 was obtained. She continued to receive fluindione tablets until the 18th of September. The diagnosis of necrosis-related to VKA was suspected by the dermatologist 1 month after the initial cutaneous symptoms. The clinicians decided to cease VKA therapy and to restart heparin treatment. Phlebitis resolution was confirmed by ultrasonography. The large ecchymotic area had evolved into skin necrosis (Fig 2) and thereafter into an extensive leg ulcer (Fig 3). The patient was subsequently referred to the wound care unit in the dermatology department of the hospital for treatment of the leg ulcer. At the first visit, the leg ulceration was very painful, requiring morphine treatment. It was localised on the left calf and measured 14.5 cm x 10 cm in diameter, and 2 cm in depth. The fibrincovered surface was bleeding when wound care was performed (Fig 3). Wound care consisted of an initial alginate dressing and silicone gel dressing thereafter, which was changed every 2 days (Fig 4 and 5). For local care, autolytic and mechanical cleaning was initiated, and a saline-saturated hydrofiber dressing was used as the patient did not tolerate hydrogel dressing. When the ulceration was at fibrinous stage, an alginate dressing was applied. At the end of the healing process, foam dressing was used. The follow-up period until complete healing of the ulceration lasted 94 days (Fig 6). The resulting scar was atrophic and measured 15cm x 9cm. Heparin treatment was stopped in June 2010, after 20 months of treatment.
3 APHP, Department of Haematology and Biology, Cochin Hospital, Paris Descartes University, Paris, France; 4 APHP, Department of Haematology and Biology, Georges Pompidou European Hospital, Paris, France. Email: kawtarbeqqal@ yahoo.fr
Fig 1. August 16: Large ecchymotic area of the left calf
Fig 2. Skin necrosis and ulceration developed in the following days.
Skin necrosis is a rare complication of oral anticoagulant treatment in adults carrying a protein C deficiency. This complication was reported in adults with homozygous deficiency of protein C which results in very low levels of protein C activity, as was the case with our patient. She had a severe deficiency, with protein C activity at 15% of the normal value and a homozygous point mutation of PROC
Fig 3. October 2: Extensive ulcer on the left calf, covered by fibrin and bleeding.
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
Declaration of interest: There were no external sources of funding for this study. The author has no conflicts of interest to declare with regard to the manuscript or its content.
s
© 2014 MA Healthcare
ltd
Discussion
S17
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
practice Table 1. Characteristics of the reported cases PC activity
Age at Dg of PC deficiency (y)
Delay to SN and IT (days)
Size of ulceration or necrosis area
Delay to healing
[1]
F/70
40%
N/A
730
N/A
N/A
[2]
F/20
NA
20
NA
N/A
N/A
[3]
F/57
19%
45
3
10cm
N/A
[4]
M/17
16%
N/A
2
N/A
[5]
F/33
17%
21
120
12cmX14cm
NA (skin graft)
[6]
M/31
N/A
31
8
NA
NA
Present case
F/42
11%
26
5
14.5 X 10 cm
94 days
PC = protein C, Dg = diagnosis, SN= skin necrosis, IT= initiation of VKA treatment y= years, N/A= not available
gene R220Q (178). It may also happen in patients with either an heterozygote protein C deficiency or even an acquired protein C deficiency. More than 300 cases of skin necrosis related to anticoagulant treatment have been reported in the literature.1 We identified only six cases in adults with congenital severe protein C deficiency after oral fluindione treatment (Table 1). Necrosis usually appears during the first 10 days after initiation of oral anticoagulant treatment and most often between the third and the sixth day, according to published case reports. Only two patients developed skin necrosis after a longer period of time, 6 months2 and 2 years1 after initiation of treatment with fluindione. In all patients, the initial cutaneous manifestations were ecchymotic plaques, hematomas, or skin necrosis of the lower limbs, especially of the calf. These occured after 2–4 days of VKA treatment and developed into a necrotic leg ulcer.1,3,4,5,8 Our patient had a similar ecchymotic plaque that shortly developed into skin necrosis and leg ulceration on the fifth day of treatment with fluindione. All reported cases had protein C activity approximately 16–20%.3–5,7,8 Similar complications were not apparent when protein C activity was higher than 20%. In one case, skin necrosis preceded the diagnosis of protein C deficiency.3 Therefore, assessment of coagulation factors is necessary in adults with skin necrosis after anticoagulation treatment for phlebitis. Other anticoagulant treatments may also be associated with skin necrosis, such as warfarin and other coumarin derivates. This has been reported in 0.010.1% of patients receiving warfarin. It has been suggested that early in the course of warfarin therapy, there may be procoagulant effects because of the inhibition of protein C, leading to venous limb gangrene.9 Warfarin predisposes and increases the risk of this complication in coagulation deficiencies such as reduced levels of protein S, protein C or other coagulation factors.10-15 S18
Fig 4. October 12th: after daily dressings with alginate dressing.
Fig 5. October 26th: dressings with silicone gel every 2 days.
Fig 6. Complete healing of skin necrosis after 94 days: atrophic scar
The pathogenesis underlying skin necrosis caused by anticoagulants is still not clear. Many hypotheses have been proposed. The most likely hypothesis is that a procoagulant-anticoagulant unbalance occurs during the initial phase of oral anticoagulant treatment, usually during the first ten days following the initiation of the treatment.4,5,15,16 VKAs block protein C synthesis and induces a rapid decrease, whereas
ltd
Sex/ age
© 2014 MA Healthcare
Reference
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
practice procoagulant factors (II, X, IX) are less rapidly affected. When PC deficiency is severe, this unbalance will be amplified, leading to a transient hypercoagulability state and the occurrence of skin vessels microthrombus, which induces skin necrosis and ulceration. Adequate therapeutic approaches could lead to stable anticoagulation. The development of skin necrosis may be prevented by treatment with either heparin alone, or if oral therapy adheres to the following rules: (1) low doses of VKA are mandatory in phlebitis treatment; (2) a combination of heparin and VKA should be prescribed and maintained at least 5 days before the interruption of heparin. 2,4,18,20 When skin necrosis occurs, oral anticoagulant therapy must be discontinued, and instead be treated with heparin. In our patient, skin necrosis occurred even though she was treated by a combination of heparin and VKA for 5 days. We proposed that in our patient, a combination of severe protein C deficiency and the interruption of heparin while doses of VKA were higher lead to a transient hypercoagulability state, which induced skin vessel microthrombus and skin necrosis. A long-term anticoagulant treatment is indicated in the case of recurrent thrombosis. In our patient, the anticoagulant treatment was stopped after 20
months of treatment after the deep vein thrombotic episode. When administering general anaesthesia to patients with protein C deficiency, careful attention is required because of increased thrombotic risk and possible skin necrosis. Strict control of blood coagulation and administration of recombinant humanactivated protein C concentrates or fresh plasma has previously shown to be effective.3,5,19 Skin necrosis may also be the earliest manifestation of heparin-induced thrombocytopenia (HIT) and is not always accompanied by lowered platelets count. Because of the presence of heparin platelet factor 4 (PF4) antibodies, thrombocytopenia occurs rapidly, leading to hematoma formation.10-11 An increased risk of skin necrosis is reported in the setting of HIT at the initiation of warfarin.9
References 1 Merklen-Djafri, C., Mazurier, I., Samama, M.M. et al. Skin necrosis during long-term fluindione treatment revealing protein C deficiency. Ann Dermatol Venereol 2012; 139: 3, 199–203. 2 Funes, C., Fernández, M.L., Alberola, C. et al. Necrotic ulcers during oral anticoagulant treatment in protein C deficiency. Med Clin (Barc) 1992; 98: 16, 639. 3 Pescatore, P., Horellou, H.M., Conard, J. et al. Problems of oral anticoagulation in an adult with homozygous protein C deficiency and late onset of thrombosis. Thromb Haemost 1993; 69: 4, 311–315. 4 Samama, M., Horellou, M.H., Soria, J. et al. Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulant treatment. Thromb Haemost 1984; 51: 1, 132–133. 5 Orimo, H.,Yamamoto, O., Yasuda, H. et al. A leg ulcer due to
10 Abdel-Wahab, O.I., Rosovsky, R.P., Warth, J.A. Warfarin-induced skin necrosis in a patient with heparin-induced thrombocytopenia: two diseases or one? Acta Haematol 2008; 120: 2, 117–122. 11 Martinez Del Pero, M.,Verma, S., Espeso, A. et al. An unusual case of warfarin-induced pinna skin necrosis. J Laryngol Otol 2009; 123: 6, 685–688. 12 Anderson, D.R., Brill-Edwards, P., Walker, I. Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy. Haemostasis 1992; 22: 3, 124–128. 13 Oz, B.S., Asgun, F., Oz, K. et al. Warfarin-induced skin necrosis after open heart surgery due to protein S and C deficiency. Heart Vessels 2007; 22: 1, 64–66. 14 Ward, C.T., Chavalitanonda, N. Atypical warfarin-induced skin necrosis. Pharmacotherapy 2006; 26: 8, 1175–1179. 15 Essex, D.W., Wynn, S.S., Jin, D.K. Late-onset warfarin-induced
The present case report shows that skin necrosis may occur in adults with homozygous protein C deficiency early after initiation of an oral anticoagulant treatment. Although only a few cases have been reported in the literature, it is worth taking note of this complication, since adequate therapeutic approaches leading to stable anticoagulation state may prevent it. n skin necrosis: case report and review of the literature. Am J Hematol 1998; 57: 3, 233–237. 16 Essex, D.W., Wynn, S.S., Jin, D.K. Late-onset warfarin-induced skin necrosis: case report and review of the literature. Am J Hematol 1998; 57: 3, 233–237. 17 Conard, J., Horellou, M.H.,Van Dreden, P. et al. Protein C. Rev Med Int 1986; 7: 4, 391–404. 18 Pigatto, P.D., Fumagalli, M., Polenghi, M. et al. Medicament dermatitis around leg ulcers due to lack of protein C. Contact Dermatitis 1987; 17: 2, 116–117. 19 Rosenzweig, N., Strauss, T., Rubinstein, M. et al. Activated protein C concentrate treatment for skin necrosis under warfarin treatment in severe genetic protein C deficiency combined with prothrombin mutation and factor V Leiden. Thromb Haemost 2009; 101: 2, 405–407. 20 Melissari, E., Kabbar,V.V. Congenital severe protein C deficiency in adults. Br J Haematol 1989; 72: 2, 222–228.
Find out more about the JWC at:
www.journalofwoundcare.com s
© 2014 MA Healthcare
ltd
protein C deficiency: successful treatment with split thickness skin graft after protein C supplementation. J Dermatol 2001; 28: 9, 511–513. 6 Roth, B., Debarbieux, S., Causeret, A.S. et al. A necrotic plaque on the thigh. Ann Dermatol Venereol 2003; 130: 11, 1061–1063. 7 Griffin, J.H., Evatt, B., Zimmerman, T.S. et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 5, 1370–1373. 8 Piffoux, M., Tcherakian, F., Tcherakian, S. et al. Cutaneous necrosis at the initiation of antivitamin K treatment disclosing hereditary protein C deficiency. Rev Pneumol Clin 1990; 46: 3, 125–127. 9 Srinavasan, A.F., Rice, L., Bartholomew, J.R. et al. Warfarin induced skin necrosis and venous limb gangrene in the setting of heparin induced thrombopenia. Arch Intern Med 2004, 164: 1, 66–70.
Conclusion
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
S19
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
Skin necrosis due to fluindione treatment: a rare but serious complication In the setting of protein C deficiency, skin necrosis, which occurs most often at the initial phase of oral anticoagulants therapy, is a rare side effect. Six cases have previously been reported in the literature. In this case report, we present a protein C deficient 42-year-old woman who was being treated for venous thrombosis. Five days after the initiation of oral anticoagulant treatment, she developed extensive skin necrosis on her left calf, followed by a painful leg ulcer. The pathogenesis underlying skin necrosis caused by anticoagulation therapy is still not clear. Despite only a few cases being reported in the literature, it is important to recognise this complication since adequate therapeutic approaches leading to a stable anticoagulation state may prevent it. protein C deficiency; skin necrosis; leg ulcer; oral anticoagulants; vitamin K antagonists
S16
Case report A 42 year old woman was referred to the dermatologic department at Cochin hospital for a large and deep skin ulceration of the left calf in October 2008. The patient’s past medical history brought important information about her. She was a non-smoker, married and worked as a social assistant. She underwent two uneventful pregnancies. She first experienced a venous superficial thrombotic episode at the age of 26 years, 6 months after the initiation of a contraceptive estrogen-progestin treatment, treated only with low molecular weight heparin (LMWH) injection. An assessment of family history revealed that severe homozygote protein C deficiency was first detected in the patient’s sister, who developed a proximal deep vein thrombosis during pregnancy (15% protein C activity; normal range is 70–130%). Her sister was treated successfully after the pregnancy with a combination of LMWH and warfarin over an extended period of time. The same severe protein C deficiency was detected in our patient, who exhibited 11% protein C activity levels and protein C antigen levels of 27%. Platelet count (196000/mm3) and other blood coagulation factors were within normal range. Gene analysis of protein C identified a homozygote point mutation at R220Q (178). Our patient was treated in 2005 at the age of 37 years for a breast carcinoma by mastectomy and
ltd
P
rotein C is an important vitamin-Kdependent protein that has anticoagulant activity. Low levels of this protein leads to a hypercoagulable state and thromboembolic manifestations. Congenital protein C deficiency was first described in 1981, and occurs in about 0.2–0.4% of the general population.1-2 This hereditary coagulation disorder is transmitted in an autosomal dominant manner. The gene encoding protein C is localised on chromosome 2 (2q13-q14), contains 8 exons and spans approximately 11kb. Several mutations of this gene has been reported.1-2 Heterozygous patients have decreased blood levels of normal protein C (approximately 50%) and are presented with venous thrombosis episodes, whereas homozygous patients usually have very low protein C activity and develop, soon after birth, a neonatal purpura and extensive thrombosis incompatible with survival. Homozygote adults with asymptomatic or late onset thromboembolic events are exceptional. At the initiation of oral anticoagulant treatment, 3% of these patients may develop skin necrosis. We describe in this case report a skin necrotic ulcer of the leg, which developed following the initiation of oral anticoagulant therapy in a female patient affected by homozygous protein C deficiency.
© 2014 MA Healthcare
K. Beqqal, MD, Dermatologist; M.H. Horellou,3 MD, Biologist; A. Philippe,1 Nurse, M. Alhene Gelas,4 MD, Geneticist; C. Flaujac,3 MD, Biologist; I. Gorin,1 MD, Dermatologist; S. Jacobelli,1 MD, Dermatologist; N. Dupin,1 MD, Dermatologist; B. Hassam,2 MD, Dermatologist; M.F. Avril,1 MD, Dermatologist; 1 APHP, Department of Dermatology, Hospital Cochin, Paris Descartes University, Paris, France. 2 Department of Dermatology, Ibn Sina Hospital, University of Mohammed V-Souissi, Rabat, Morocco; Continued on page S17 1,2
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
practice radiotherapy. Thereafter, she received tamoxifene treatment until the end of July 2008. At the age of 42 years, on the 2nd of August 2008, she was presented with a second episode of superficial venous thrombosis confirmed par Doppler ultra-sonography. She received treatment with LMWH. This thrombosis occurred after a long journey by car. Extension of the superficial deep vein thrombosis to the left femoral vein occurred after 4 days of LMWH treatment. She was referred to the emergency department of Orléans hospital on 6 August 2008 and was treated with a combination of LMWH and oral vitamin K antagonists (VKA) (i.e. fluindione 2 tablets/day i.e. 40 mg/day) for 5 days. On August 16, an oval ecchymotic area appeared on the left calf (Fig 1), and the treatment by LMWH was interrupted on the next day when INR of 4 was obtained. She continued to receive fluindione tablets until the 18th of September. The diagnosis of necrosis-related to VKA was suspected by the dermatologist 1 month after the initial cutaneous symptoms. The clinicians decided to cease VKA therapy and to restart heparin treatment. Phlebitis resolution was confirmed by ultrasonography. The large ecchymotic area had evolved into skin necrosis (Fig 2) and thereafter into an extensive leg ulcer (Fig 3). The patient was subsequently referred to the wound care unit in the dermatology department of the hospital for treatment of the leg ulcer. At the first visit, the leg ulceration was very painful, requiring morphine treatment. It was localised on the left calf and measured 14.5 cm x 10 cm in diameter, and 2 cm in depth. The fibrincovered surface was bleeding when wound care was performed (Fig 3). Wound care consisted of an initial alginate dressing and silicone gel dressing thereafter, which was changed every 2 days (Fig 4 and 5). For local care, autolytic and mechanical cleaning was initiated, and a saline-saturated hydrofiber dressing was used as the patient did not tolerate hydrogel dressing. When the ulceration was at fibrinous stage, an alginate dressing was applied. At the end of the healing process, foam dressing was used. The follow-up period until complete healing of the ulceration lasted 94 days (Fig 6). The resulting scar was atrophic and measured 15cm x 9cm. Heparin treatment was stopped in June 2010, after 20 months of treatment.
3 APHP, Department of Haematology and Biology, Cochin Hospital, Paris Descartes University, Paris, France; 4 APHP, Department of Haematology and Biology, Georges Pompidou European Hospital, Paris, France. Email: kawtarbeqqal@ yahoo.fr
Fig 1. August 16: Large ecchymotic area of the left calf
Fig 2. Skin necrosis and ulceration developed in the following days.
Skin necrosis is a rare complication of oral anticoagulant treatment in adults carrying a protein C deficiency. This complication was reported in adults with homozygous deficiency of protein C which results in very low levels of protein C activity, as was the case with our patient. She had a severe deficiency, with protein C activity at 15% of the normal value and a homozygous point mutation of PROC
Fig 3. October 2: Extensive ulcer on the left calf, covered by fibrin and bleeding.
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
Declaration of interest: There were no external sources of funding for this study. The author has no conflicts of interest to declare with regard to the manuscript or its content.
s
© 2014 MA Healthcare
ltd
Discussion
S17
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
practice Table 1. Characteristics of the reported cases PC activity
Age at Dg of PC deficiency (y)
Delay to SN and IT (days)
Size of ulceration or necrosis area
Delay to healing
[1]
F/70
40%
N/A
730
N/A
N/A
[2]
F/20
NA
20
NA
N/A
N/A
[3]
F/57
19%
45
3
10cm
N/A
[4]
M/17
16%
N/A
2
N/A
[5]
F/33
17%
21
120
12cmX14cm
NA (skin graft)
[6]
M/31
N/A
31
8
NA
NA
Present case
F/42
11%
26
5
14.5 X 10 cm
94 days
PC = protein C, Dg = diagnosis, SN= skin necrosis, IT= initiation of VKA treatment y= years, N/A= not available
gene R220Q (178). It may also happen in patients with either an heterozygote protein C deficiency or even an acquired protein C deficiency. More than 300 cases of skin necrosis related to anticoagulant treatment have been reported in the literature.1 We identified only six cases in adults with congenital severe protein C deficiency after oral fluindione treatment (Table 1). Necrosis usually appears during the first 10 days after initiation of oral anticoagulant treatment and most often between the third and the sixth day, according to published case reports. Only two patients developed skin necrosis after a longer period of time, 6 months2 and 2 years1 after initiation of treatment with fluindione. In all patients, the initial cutaneous manifestations were ecchymotic plaques, hematomas, or skin necrosis of the lower limbs, especially of the calf. These occured after 2–4 days of VKA treatment and developed into a necrotic leg ulcer.1,3,4,5,8 Our patient had a similar ecchymotic plaque that shortly developed into skin necrosis and leg ulceration on the fifth day of treatment with fluindione. All reported cases had protein C activity approximately 16–20%.3–5,7,8 Similar complications were not apparent when protein C activity was higher than 20%. In one case, skin necrosis preceded the diagnosis of protein C deficiency.3 Therefore, assessment of coagulation factors is necessary in adults with skin necrosis after anticoagulation treatment for phlebitis. Other anticoagulant treatments may also be associated with skin necrosis, such as warfarin and other coumarin derivates. This has been reported in 0.010.1% of patients receiving warfarin. It has been suggested that early in the course of warfarin therapy, there may be procoagulant effects because of the inhibition of protein C, leading to venous limb gangrene.9 Warfarin predisposes and increases the risk of this complication in coagulation deficiencies such as reduced levels of protein S, protein C or other coagulation factors.10-15 S18
Fig 4. October 12th: after daily dressings with alginate dressing.
Fig 5. October 26th: dressings with silicone gel every 2 days.
Fig 6. Complete healing of skin necrosis after 94 days: atrophic scar
The pathogenesis underlying skin necrosis caused by anticoagulants is still not clear. Many hypotheses have been proposed. The most likely hypothesis is that a procoagulant-anticoagulant unbalance occurs during the initial phase of oral anticoagulant treatment, usually during the first ten days following the initiation of the treatment.4,5,15,16 VKAs block protein C synthesis and induces a rapid decrease, whereas
ltd
Sex/ age
© 2014 MA Healthcare
Reference
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
practice procoagulant factors (II, X, IX) are less rapidly affected. When PC deficiency is severe, this unbalance will be amplified, leading to a transient hypercoagulability state and the occurrence of skin vessels microthrombus, which induces skin necrosis and ulceration. Adequate therapeutic approaches could lead to stable anticoagulation. The development of skin necrosis may be prevented by treatment with either heparin alone, or if oral therapy adheres to the following rules: (1) low doses of VKA are mandatory in phlebitis treatment; (2) a combination of heparin and VKA should be prescribed and maintained at least 5 days before the interruption of heparin. 2,4,18,20 When skin necrosis occurs, oral anticoagulant therapy must be discontinued, and instead be treated with heparin. In our patient, skin necrosis occurred even though she was treated by a combination of heparin and VKA for 5 days. We proposed that in our patient, a combination of severe protein C deficiency and the interruption of heparin while doses of VKA were higher lead to a transient hypercoagulability state, which induced skin vessel microthrombus and skin necrosis. A long-term anticoagulant treatment is indicated in the case of recurrent thrombosis. In our patient, the anticoagulant treatment was stopped after 20
months of treatment after the deep vein thrombotic episode. When administering general anaesthesia to patients with protein C deficiency, careful attention is required because of increased thrombotic risk and possible skin necrosis. Strict control of blood coagulation and administration of recombinant humanactivated protein C concentrates or fresh plasma has previously shown to be effective.3,5,19 Skin necrosis may also be the earliest manifestation of heparin-induced thrombocytopenia (HIT) and is not always accompanied by lowered platelets count. Because of the presence of heparin platelet factor 4 (PF4) antibodies, thrombocytopenia occurs rapidly, leading to hematoma formation.10-11 An increased risk of skin necrosis is reported in the setting of HIT at the initiation of warfarin.9
References 1 Merklen-Djafri, C., Mazurier, I., Samama, M.M. et al. Skin necrosis during long-term fluindione treatment revealing protein C deficiency. Ann Dermatol Venereol 2012; 139: 3, 199–203. 2 Funes, C., Fernández, M.L., Alberola, C. et al. Necrotic ulcers during oral anticoagulant treatment in protein C deficiency. Med Clin (Barc) 1992; 98: 16, 639. 3 Pescatore, P., Horellou, H.M., Conard, J. et al. Problems of oral anticoagulation in an adult with homozygous protein C deficiency and late onset of thrombosis. Thromb Haemost 1993; 69: 4, 311–315. 4 Samama, M., Horellou, M.H., Soria, J. et al. Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulant treatment. Thromb Haemost 1984; 51: 1, 132–133. 5 Orimo, H.,Yamamoto, O., Yasuda, H. et al. A leg ulcer due to
10 Abdel-Wahab, O.I., Rosovsky, R.P., Warth, J.A. Warfarin-induced skin necrosis in a patient with heparin-induced thrombocytopenia: two diseases or one? Acta Haematol 2008; 120: 2, 117–122. 11 Martinez Del Pero, M.,Verma, S., Espeso, A. et al. An unusual case of warfarin-induced pinna skin necrosis. J Laryngol Otol 2009; 123: 6, 685–688. 12 Anderson, D.R., Brill-Edwards, P., Walker, I. Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy. Haemostasis 1992; 22: 3, 124–128. 13 Oz, B.S., Asgun, F., Oz, K. et al. Warfarin-induced skin necrosis after open heart surgery due to protein S and C deficiency. Heart Vessels 2007; 22: 1, 64–66. 14 Ward, C.T., Chavalitanonda, N. Atypical warfarin-induced skin necrosis. Pharmacotherapy 2006; 26: 8, 1175–1179. 15 Essex, D.W., Wynn, S.S., Jin, D.K. Late-onset warfarin-induced
The present case report shows that skin necrosis may occur in adults with homozygous protein C deficiency early after initiation of an oral anticoagulant treatment. Although only a few cases have been reported in the literature, it is worth taking note of this complication, since adequate therapeutic approaches leading to stable anticoagulation state may prevent it. n skin necrosis: case report and review of the literature. Am J Hematol 1998; 57: 3, 233–237. 16 Essex, D.W., Wynn, S.S., Jin, D.K. Late-onset warfarin-induced skin necrosis: case report and review of the literature. Am J Hematol 1998; 57: 3, 233–237. 17 Conard, J., Horellou, M.H.,Van Dreden, P. et al. Protein C. Rev Med Int 1986; 7: 4, 391–404. 18 Pigatto, P.D., Fumagalli, M., Polenghi, M. et al. Medicament dermatitis around leg ulcers due to lack of protein C. Contact Dermatitis 1987; 17: 2, 116–117. 19 Rosenzweig, N., Strauss, T., Rubinstein, M. et al. Activated protein C concentrate treatment for skin necrosis under warfarin treatment in severe genetic protein C deficiency combined with prothrombin mutation and factor V Leiden. Thromb Haemost 2009; 101: 2, 405–407. 20 Melissari, E., Kabbar,V.V. Congenital severe protein C deficiency in adults. Br J Haematol 1989; 72: 2, 222–228.
Find out more about the JWC at:
www.journalofwoundcare.com s
© 2014 MA Healthcare
ltd
protein C deficiency: successful treatment with split thickness skin graft after protein C supplementation. J Dermatol 2001; 28: 9, 511–513. 6 Roth, B., Debarbieux, S., Causeret, A.S. et al. A necrotic plaque on the thigh. Ann Dermatol Venereol 2003; 130: 11, 1061–1063. 7 Griffin, J.H., Evatt, B., Zimmerman, T.S. et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 5, 1370–1373. 8 Piffoux, M., Tcherakian, F., Tcherakian, S. et al. Cutaneous necrosis at the initiation of antivitamin K treatment disclosing hereditary protein C deficiency. Rev Pneumol Clin 1990; 46: 3, 125–127. 9 Srinavasan, A.F., Rice, L., Bartholomew, J.R. et al. Warfarin induced skin necrosis and venous limb gangrene in the setting of heparin induced thrombopenia. Arch Intern Med 2004, 164: 1, 66–70.
Conclusion
J O U R N A L O F WO U N D C A R E C A S E S S U P P L E M E N T V O L 2 3 , N O 2 , 2 0 1 4
S19
ournal of Wound Care. Downloaded from magonlinelibrary.com by 130.179.016.201 on November 19, 2015. For personal use only. No other uses without permission. . All rights reserved
