Warfarin necrosis is a rare but severe complication of treatment with warfarin or related anticoagulants.[2] The typical patient appears to be an obese, middle aged woman (median age 54 years, male to female ratio 1:3).[1][3]: 122–3 This drug eruption usually occurs between the third and tenth days of therapy with warfarin derivatives.[1] The first symptoms are pain and redness in the affected area. As they progress, lesions develop a sharp border and become petechial, then hard and purpuric. They may then resolve or progress to form large, irregular, bloody bullae with eventual necrosis and slow-healing eschar formation. Favored sites are breasts, thighs, buttocks and penis,[1] all areas with subcutaneous fat.[3]: 122 In rare cases, the fascia and muscle are involved.[4]
Development of the syndrome is associated with the use of large loading doses at the start of treatment.[5]
Warfarin necrosis usually occurs three to five days after drug therapy is begun, and a high initial dose increases the risk of its development.[3]: 122 Warfarin-induced necrosis can develop both at sites of local injection and - when infused intravenously - in a widespread pattern.[3]: 123
In warfarin's initial stages of action, inhibition of protein C and Factor VII is stronger than inhibition of the other vitamin K-dependent coagulation factorsII, IX, and X. This results from the fact that these proteins have different half-lives: 1.5 to six hours for factor VII and eight hours for protein C, versus one day for factor IX, two days for factor X and two to five days for factor II. The larger the initial dose of vitamin K-antagonist, the more pronounced these differences are. This coagulation factor imbalance leads to paradoxical activation of coagulation, resulting in a hypercoagulable state and thrombosis. The blood clots interrupt the blood supply to the skin, causing necrosis. Protein C is an innate anticoagulant, and as warfarin further decreases protein C levels, it can lead to massive thrombosis with necrosis and gangrene of limbs.
Notably, the prothrombin time (or international normalized ratio, INR) used to test the effect of warfarin is highly dependent on factor VII, which explains why patients can have a therapeutic INR (indicating good anticoagulant effect) but still be in a hypercoagulable state.[1]
In one third of cases, warfarin necrosis occurs in patients with an underlying, innate and previously unknown deficiency of protein C. The condition is related to purpura fulminans, a complication in infants with sepsis which also involves skin necrosis. These infants often have protein C deficiency as well. There have also been cases in patients with other deficiency, including protein S deficiency,[6][7]activated protein C resistance (Factor V Leiden)[8] and antithrombin III deficiency.[9]
Although the above hypothesis is the most commonly accepted, others believe that it is a hypersensitivity reaction or a direct toxic effect.[1]
DiagnosisEdit
Differential diagnosisEdit
Many conditions mimic or may be mistaken for warfarin necrosis, including pyoderma gangrenosum or necrotizing fasciitis. Warfarin necrosis is also different from another drug eruption associated with warfarin, purple toe syndrome, which usually occurs three to eight weeks after the start of anticoagulation therapy. No report has described this disorder in the immediate postpartum period in patients with protein S deficiency.[10]
PreventionEdit
Vitamin K1 can be used to reverse the effects of warfarin, and heparin or its low molecular weight heparin (LMWH) can be used in an attempt to prevent further clotting. None of these suggested therapies have been studied in clinical trials.
Heparin and LMWH act by a different mechanism than warfarin, so these drugs can also be used to prevent clotting during the first few days of warfarin therapy and thus prevent warfarin necrosis (this is called 'bridging').
TreatmentEdit
The first element of treatment is usually to discontinue the offending drug, although there have been reports describing how the eruption evolved little after it had established in spite of continuing the medication.[11][12]
Based on the assumption that low levels of protein C are involved in the underlying mechanism, common treatments in this setting include fresh frozen plasma or pure activated protein C.[13]
Since the clot-promoting effects of starting administration of 4-hydroxycoumarins are transitory, patients with protein C deficiency or previous warfarin necrosis can still be restarted on these drugs if appropriate measures are taken.[14] These include gradual increase starting from low doses and supplemental administration of protein C (pure or from fresh frozen plasma).[15]
The necrotic skin areas are treated as in other conditions, sometimes healing spontaneously with or without scarring, sometimes going on to require surgical debridement or skin grafting.[1]
HistoryEdit
While skin necrosis in patients had been previously described, Verhagen was the first to publish a paper on this relationship in the medical literature, in 1954.[12]
^Sallah S, Abdallah JM, Gagnon GA (1998). "Recurrent warfarin-induced skin necrosis in kindreds with protein S deficiency". Haemostasis. 28 (1): 25–30. doi:10.1159/000022380. PMID 9885367. S2CID 46762929.
^Grimaudo V, Gueissaz F, Hauert J, Sarraj A, Kruithof EK, Bachmann F (January 1989). "Necrosis of skin induced by coumadin in a patient deficient in protein S". BMJ. 298 (6668): 233–4. doi:10.1136/bmj.298.6668.233. PMC1835547. PMID 2522326.
^Makris M, Bardhan G, Preston FE (March 1996). "Warfarin induced skin necrosis associated with activated protein C resistance". Thromb. Haemost. 75 (3): 523–4. doi:10.1055/s-0038-1650312. PMID 8701423. S2CID 30576117.
^Kiehl R, Hellstern P, Wenzel E (January 1987). "Hereditary antithrombin III (AT III) deficiency and atypical localization of a coumadin necrosis". Thromb. Res. 45 (2): 191–3. doi:10.1016/0049-3848(87)90173-3. PMID 3563984.
^Cheng, A; Scheinfeld, NS; McDowell, B; Dokras, AA (1997). "Warfarin skin necrosis in a postpartum woman with protein S deficiency". Obstetrics and Gynecology. 90 (4 Pt 2): 671–2. doi:10.1016/S0029-7844(97)00393-1. PMID 11770590. S2CID 20764940.
^Nalbandian RM, Mader IJ, Barrett JL, Pearce JF, Rupp EC (May 1965). "Petechiae, ecchymoses, and necrosis of skin induced by coumadin congeners: rare, occasionally lethal complication of anticoagulant therapy". JAMA. 192: 603–8. doi:10.1001/jama.1965.03080200021006. PMID 14284863.
^ abVerhagen H (1954). "Local haemorrhage and necrosis of the skin and underlying tissues, during anti-coagulant therapy with dicumarol or dicumacyl". Acta Med Scand. 148 (6): 453–67. doi:10.1111/j.0954-6820.1954.tb01741.x. PMID 13171021.
^Schramm W, Spannagl M, Bauer KA, et al. (June 1993). "Treatment of coumadin-induced skin necrosis with a monoclonal antibody purified protein C concentrate". Arch Dermatol. 129 (6): 753–6. doi:10.1001/archderm.129.6.753. PMID 8507079.
^Zauber NP, Stark MW (May 1986). "Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis". Ann. Intern. Med. 104 (5): 659–60. doi:10.7326/0003-4819-104-5-659. PMID 3754407.
^De Stefano V, Mastrangelo S, Schwarz HP, et al. (August 1993). "Replacement therapy with a purified protein C concentrate during initiation of oral anticoagulation in severe protein C congenital deficiency". Thromb. Haemost. 70 (2): 247–9. doi:10.1055/s-0038-1649478. PMID 8236128. S2CID 28480921.
August 25, 2023
warfarin, necrosis, warfarin, induced, skin, necrosis, condition, which, skin, subcutaneous, tissue, necrosis, tissue, death, occurs, acquired, protein, deficiency, following, treatment, with, anti, vitamin, anticoagulants, hydroxycoumarins, such, warfarin, ot. Warfarin induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis tissue death occurs due to acquired protein C deficiency following treatment with anti vitamin K anticoagulants 4 hydroxycoumarins such as warfarin 1 Warfarin necrosisOther namesAnticoagulant induced skin necrosisRight leg affected by warfarin necrosis Warfarin necrosis is a rare but severe complication of treatment with warfarin or related anticoagulants 2 The typical patient appears to be an obese middle aged woman median age 54 years male to female ratio 1 3 1 3 122 3 This drug eruption usually occurs between the third and tenth days of therapy with warfarin derivatives 1 The first symptoms are pain and redness in the affected area As they progress lesions develop a sharp border and become petechial then hard and purpuric They may then resolve or progress to form large irregular bloody bullae with eventual necrosis and slow healing eschar formation Favored sites are breasts thighs buttocks and penis 1 all areas with subcutaneous fat 3 122 In rare cases the fascia and muscle are involved 4 Development of the syndrome is associated with the use of large loading doses at the start of treatment 5 Contents 1 Mechanism 2 Diagnosis 2 1 Differential diagnosis 3 Prevention 4 Treatment 5 History 6 See also 7 ReferencesMechanism Edit The coagulation cascade Warfarin necrosis usually occurs three to five days after drug therapy is begun and a high initial dose increases the risk of its development 3 122 Warfarin induced necrosis can develop both at sites of local injection and when infused intravenously in a widespread pattern 3 123 In warfarin s initial stages of action inhibition of protein C and Factor VII is stronger than inhibition of the other vitamin K dependent coagulation factors II IX and X This results from the fact that these proteins have different half lives 1 5 to six hours for factor VII and eight hours for protein C versus one day for factor IX two days for factor X and two to five days for factor II The larger the initial dose of vitamin K antagonist the more pronounced these differences are This coagulation factor imbalance leads to paradoxical activation of coagulation resulting in a hypercoagulable state and thrombosis The blood clots interrupt the blood supply to the skin causing necrosis Protein C is an innate anticoagulant and as warfarin further decreases protein C levels it can lead to massive thrombosis with necrosis and gangrene of limbs Notably the prothrombin time or international normalized ratio INR used to test the effect of warfarin is highly dependent on factor VII which explains why patients can have a therapeutic INR indicating good anticoagulant effect but still be in a hypercoagulable state 1 In one third of cases warfarin necrosis occurs in patients with an underlying innate and previously unknown deficiency of protein C The condition is related to purpura fulminans a complication in infants with sepsis which also involves skin necrosis These infants often have protein C deficiency as well There have also been cases in patients with other deficiency including protein S deficiency 6 7 activated protein C resistance Factor V Leiden 8 and antithrombin III deficiency 9 Although the above hypothesis is the most commonly accepted others believe that it is a hypersensitivity reaction or a direct toxic effect 1 Diagnosis EditDifferential diagnosis Edit Many conditions mimic or may be mistaken for warfarin necrosis including pyoderma gangrenosum or necrotizing fasciitis Warfarin necrosis is also different from another drug eruption associated with warfarin purple toe syndrome which usually occurs three to eight weeks after the start of anticoagulation therapy No report has described this disorder in the immediate postpartum period in patients with protein S deficiency 10 Prevention EditVitamin K1 can be used to reverse the effects of warfarin and heparin or its low molecular weight heparin LMWH can be used in an attempt to prevent further clotting None of these suggested therapies have been studied in clinical trials Heparin and LMWH act by a different mechanism than warfarin so these drugs can also be used to prevent clotting during the first few days of warfarin therapy and thus prevent warfarin necrosis this is called bridging Treatment EditThe first element of treatment is usually to discontinue the offending drug although there have been reports describing how the eruption evolved little after it had established in spite of continuing the medication 11 12 Based on the assumption that low levels of protein C are involved in the underlying mechanism common treatments in this setting include fresh frozen plasma or pure activated protein C 13 Since the clot promoting effects of starting administration of 4 hydroxycoumarins are transitory patients with protein C deficiency or previous warfarin necrosis can still be restarted on these drugs if appropriate measures are taken 14 These include gradual increase starting from low doses and supplemental administration of protein C pure or from fresh frozen plasma 15 The necrotic skin areas are treated as in other conditions sometimes healing spontaneously with or without scarring sometimes going on to require surgical debridement or skin grafting 1 History EditWhile skin necrosis in patients had been previously described Verhagen was the first to publish a paper on this relationship in the medical literature in 1954 12 See also EditList of cutaneous conditionsReferences Edit a b c d e f g McKnight JT Maxwell AJ Anderson RL 1992 Warfarin necrosis Arch Fam Med 1 1 105 8 doi 10 1001 archfami 1 1 105 PMID 1341581 Rapini Ronald P Bolognia Jean L Jorizzo Joseph L 2007 Dermatology 2 Volume Set St Louis Mosby pp 331 340 ISBN 978 1 4160 2999 1 a b c d James William Berger Timothy Elston Dirk 2005 Andrews Diseases of the Skin Clinical Dermatology 10th ed Saunders ISBN 0 7216 2921 0 Schleicher SM Fricker MP April 1980 Coumadin necrosis Arch Dermatol 116 4 444 5 doi 10 1001 archderm 116 4 444 PMID 7369776 Chan YC Valenti D Mansfield AO Stansby G March 2000 Warfarin induced skin necrosis Br J Surg 87 3 266 72 doi 10 1046 j 1365 2168 2000 01352 x PMC 4928566 PMID 10718793 Sallah S Abdallah JM Gagnon GA 1998 Recurrent warfarin induced skin necrosis in kindreds with protein S deficiency Haemostasis 28 1 25 30 doi 10 1159 000022380 PMID 9885367 S2CID 46762929 Grimaudo V Gueissaz F Hauert J Sarraj A Kruithof EK Bachmann F January 1989 Necrosis of skin induced by coumadin in a patient deficient in protein S BMJ 298 6668 233 4 doi 10 1136 bmj 298 6668 233 PMC 1835547 PMID 2522326 Makris M Bardhan G Preston FE March 1996 Warfarin induced skin necrosis associated with activated protein C resistance Thromb Haemost 75 3 523 4 doi 10 1055 s 0038 1650312 PMID 8701423 S2CID 30576117 Kiehl R Hellstern P Wenzel E January 1987 Hereditary antithrombin III AT III deficiency and atypical localization of a coumadin necrosis Thromb Res 45 2 191 3 doi 10 1016 0049 3848 87 90173 3 PMID 3563984 Cheng A Scheinfeld NS McDowell B Dokras AA 1997 Warfarin skin necrosis in a postpartum woman with protein S deficiency Obstetrics and Gynecology 90 4 Pt 2 671 2 doi 10 1016 S0029 7844 97 00393 1 PMID 11770590 S2CID 20764940 Nalbandian RM Mader IJ Barrett JL Pearce JF Rupp EC May 1965 Petechiae ecchymoses and necrosis of skin induced by coumadin congeners rare occasionally lethal complication of anticoagulant therapy JAMA 192 603 8 doi 10 1001 jama 1965 03080200021006 PMID 14284863 a b Verhagen H 1954 Local haemorrhage and necrosis of the skin and underlying tissues during anti coagulant therapy with dicumarol or dicumacyl Acta Med Scand 148 6 453 67 doi 10 1111 j 0954 6820 1954 tb01741 x PMID 13171021 Schramm W Spannagl M Bauer KA et al June 1993 Treatment of coumadin induced skin necrosis with a monoclonal antibody purified protein C concentrate Arch Dermatol 129 6 753 6 doi 10 1001 archderm 129 6 753 PMID 8507079 Zauber NP Stark MW May 1986 Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis Ann Intern Med 104 5 659 60 doi 10 7326 0003 4819 104 5 659 PMID 3754407 De Stefano V Mastrangelo S Schwarz HP et al August 1993 Replacement therapy with a purified protein C concentrate during initiation of oral anticoagulation in severe protein C congenital deficiency Thromb Haemost 70 2 247 9 doi 10 1055 s 0038 1649478 PMID 8236128 S2CID 28480921 Retrieved from https en wikipedia org w index php title Warfarin necrosis amp oldid 1144079763, wikipedia, wiki, book, books, library,
