Clinical Study Am J Nephrol 2001;21:289–293 Received: September 20, 2000 Accepted: May 7, 2001 Heparin-Induced Skin Necrosis in a Patient with End-Stage Renal Failure and Functional Protein S Deficiency Mark D. Denton a Shamilla Mauiyyedi b Hasan Bazari a a Renal Division, Department of Medicine and b Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass., USA Abstract Skin ulceration is a well-characterized thrombotic complication of the heparin-induced thrombocytopenia (HIT) syndrome. We present the case of a 73-year-old diabetic woman nearing end-stage renal failure who developed extensive upper thigh, abdominal and buttock ulceration following initiation of subcutaneous heparin for prophylaxis against deep vein thrombosis. A preliminary diagnosis of calciphylaxis was made based on the classical distribution and macroscopic appearance of the ulceration in a patient with end-stage renal failure and secondary hyperparathyroidism. However skin biopsy showed complete absence of calcium deposits in the dermal microvasculature. The presence of extensive microthrombi within dermal vessels prompted serologic testing to detect a prothrombotic state. We identified the combined presence of heparin-dependent platelet activating (HIT) antibodies and functional protein S deficiency. To our knowledge this is the first reported case of a ABC © 2001 S. Karger AG, Basel 0250–8095/01/0214–0289$17.50/0 Fax + 41 61 306 12 34 E-Mail email@example.com www.karger.com Accessible online at: www.karger.com/journals/ajn dialysis patient presenting with skin ulceration induced by heparin and protein S deficiency. This case highlights the importance of a skin biopsy and testing for a hypercoaguable state in patients with end-stage renal disease and skin ulceration. We suggest that HIT antibodies should be requested in all dialysis patients presenting with skin ulceration. Copyright © 2001 S. Karger AG, Basel Introduction Heparin is widely administered to patients with endstage renal disease both on hemodialysis and during acute hospital admission. Adverse side effects of heparin include thrombocytopenia, paradoxical thrombosis and skin necrosis. Recently these clinical features have become recognized as components of the heparin-induced thrombocytopenia (HIT) syndrome ; an immunological response induced by heparin complexed to platelet factor 4 and characterized by the presence of platelet-activating antibodies in the serum (HIT antibodies). The incidence of the HIT syndrome varies considerably among different patient populations and is dependent on the type Mark Denton Renal Division, Brigham and Women’s Hospital 75 Francis Street Boston, MA 02116 (USA) Tel. +1 617 525 5708, Fax +1 617 732 5254, E-Mail firstname.lastname@example.org Downloaded by: University of Florida, Gainesville and Jacksonville 126.96.36.199 - 10/26/2017 4:27:59 AM Key Words Calciphylaxis W Heparin W Skin W Protein S W Renal failure, chronic Fig. 1. Skin lesions. Extensive black necrotic indurated plaques with adjacent ulcerations distributed over the thighs, abdomen and buttocks. Case Report A 73-year-old woman was transferred to our institution for management of end-stage renal disease and skin ulceration over the upper thighs, abdomen and buttocks. She had a 20-year history of insulindependent diabetes mellitus and hypertension. Over the previous 3 years she had progressive chronic renal failure associated with significant proteinuria secondary to diabetic nephropathy. Her past medical history included: (1) deep vein thrombosis and pulmonary embolism in 1975 managed by inferior vena caval clipping; (2) coronary artery bypass and porcine aortic valve replacement in 1995; (3) complete heart block requiring permanent pacemaker insertion, and (4) colonic polyps and recurrent lower gastrointestinal bleeding. Her 290 Am J Nephrol 2001;21:289–293 past surgical history included a cholecystectomy and hysterectomy. In November 1999 she was admitted to another institution with confusion and dyspnea. She was obese, edematous and had clinical and radiological evidence of pulmonary edema and was near end-stage renal failure (blood urea nitrogen, BUN 100 and creatinine 5.2). Medications were calcium acetate, amlodipine, frusemide and insulin. She was initially managed conservatively with intravenous diuretics with improvement of her pulmonary edema. However, she remained confused and was unable to mobilize, and low molecular weight heparin was initiated for prophylaxis of deep vein thrombosis. Approximately 5 days later she developed symmetrical painful violaceous lesions on the top of the thighs. These progressed to painful necrotic ulcerations and similar lesions developed on the abdomen (in a kissing distribution) followed by lesions on the buttocks. She was initiated on hemodialysis with heparin anticoagulation and transferred to our institution for further management. Her skin lesions were extensive as shown in figure 1. A preliminary diagnosis of calciphylaxis was made. She was initiated on broad-spectrum antibiotic therapy (vancomycin per levels; gentamicin post-hemodialysis). Routine laboratory testing showed; sodium 138; potassium 4.4; chloride 98; HCO3 23; BUN 75; creatinine 4.1; albumin 1.9; hemoglobin 9; WCC 23, and platelets 410. There was no significant change in the platelet count throughout her admission. She was noted to be hypercalcemic (corrected total calcium 11.8, ionized calcium 1.33, phosphate 6.0) associated with a raised parathyroid hormone (PTH, 748). She was on calcium acetate 667 mg t.i.d. with meals but had not received vitamin D analogs. Calcium acetate was replaced by aluminum hydroxide and she was dialyzed against a low calcium dialysate with normalization of her calcium and calcium/phosphate product. At this point oral calcitriol was started with good response (decrease in PTH to 255). Despite these measures her skin ulcerations deteriorated. A skin biopsy taken from the margin of the thigh ulcer showed multiple fibrin thrombi in the dermal microvasculature and subcutaneous vessels with ischemic necrosis of the overlying epider- Denton/Mauiyyedi/Bazari Downloaded by: University of Florida, Gainesville and Jacksonville 188.8.131.52 - 10/26/2017 4:27:59 AM of heparin administered . Approximately 5% of patients receiving unfractionated heparin develop HIT antibodies and thrombocytopenia of which 50% develop thrombotic complications such as deep vein thrombosis and pulmonary embolism. Skin necrosis is also observed in 10–20% of patients with HIT syndrome, occurs both at the site of heparin injection and at distant sites and, interestingly, frequently occurs in the absence of thrombocytopenia making the clinical association of skin ulceration with the HIT syndrome less apparent . We present the case of an obese diabetic woman with end-stage renal disease and hyperparathyroidism who was transferred to our institution with a provisional diagnosis of calciphylaxis and, on further investigation, was found to have HIT syndrome and functional protein S deficiency. Fig. 2. Skin biopsy, right thigh at the edge of the ulcer. A Ischemic necrosis of the epidermis (arrow). HE. !120. B Capillary venule in the upper dermis containing fibrin thrombus (arrow), entrapped inflammatory cells and red blood cells. HE. !210. C Small vessels of the deep reticular dermis containing fibrin thrombi (arrows) without vasculitis or calcifications. HE. !210. D A mediumsized subcutaneous vessel occluded by fibrin thrombus containing entrapped inflammatory cells. There are no perivascular infiltrates, vessel wall inflammation or medial calcification. HE. !210. The differential diagnosis of skin ulceration in patients with end-stage renal disease is broad (table 1). Although the clinical picture in this case was highly suggestive of calciphylaxis, this diagnosis was excluded by the absence of calcification in the dermal and subcutaneous microvasculature. Furthermore there was no evidence of vasculitis or bacterial invasion in the skin biopsy. The finding of extensive microvascular thrombosis prompted a panel of prothrombotic studies. Cryoglobulins and antiphospholipid antibodies were negative and there were no hematological parameters indicative of disseminated intravascular coagulation. The patient had never received coumadin in the past. A diagnosis of heparin-induced skin necrosis was made, based on the temporal association of ulceration with heparin administration, and the presence of HIT antibodies. Heparin-induced skin necrosis has become a wellestablished complication of heparin therapy and the HIT syndrome, and over 100 cases have been described in the literature [1, 2]. It is a thrombotic manifestation of the HIT syndrome and is characterized by the presence of platelet thrombi within the dermal microvasculature. It occurs in approximately 10–20% of patients with HIT antibodies and interestingly, as in this case, generally occurs in the absence of thrombocytopenia [2, 3]. Other thrombotic manifestations such as deep vein thrombosis, pulmonary embolism and adrenal infarction are also seen in patients with heparin-induced skin necrosis . Highmolecular weight heparins and those of bovine lung sources may cause these complications more frequently than lower molecular weight heparins and those of porcine gut sources [1, 5]. Skin necrosis may be seen at sites of heparin injection  or occur at distant sites such as thighs, abdomen and buttocks particularly in obese dia- Heparin-Induced Skin Necrosis Am J Nephrol 2001;21:289–293 Discussion 291 Downloaded by: University of Florida, Gainesville and Jacksonville 184.108.40.206 - 10/26/2017 4:27:59 AM mis (fig. 2), indicative of a coagulopathy. Calcification of the vessel walls (calciphylaxis) was not found; special stains for calcium (Alizarin red) and phosphate (Von Kossa) were also negative. There was no evidence of vasculitis, or bacterial invasion. Cryoglobulins, ANA, anti-dsDNA were all negative. Coagulation studies showed prothrombin time 14.7, partial thromboplastin time 22, fibrinogen 1261, d-dimer mildly raised, IgG and IgM antiphospholipid antibodies negative, Antithrombin III function was reduced 70 (80–130) reflecting heparin exposure on dialysis. Factor VIII levels were mildly elevated: 280. Protein C function was normal and there was no activated protein C resistance. In contrast, we found protein S function to be reduced: 37% (70–140%) with normal protein S antigen levels (heterozygous protein S deficiency type II), and antibody to platelet factor 4 (HIT antibody) was positive. All forms of heparin therapy were stopped. Hemodialysis was performed heparin free and her dialysis catheter was instilled with hirudin to maintain patency. In view of previous lower gastrointestinal bleeding and a severe ulcerative esophagitis found on endoscopy, it was decided not to fully anticoagulate her with hirudin. Despite these measures, her condition deteriorated and she died 3 weeks later. Permission for a postmortem examination was refused. Table 1. Conditions that can cause skin ulceration in a patient with ESRD Condition Pathology/diagnosis Calciphylaxis Systemic vasculitis, e.g. SLE, Wegener’s granulomatosus, cryoglobulinemia Heparin-induced thrombosis and skin necrosis ‘white thrombus syndrome’ Warfarin-induced skin necrosis Disseminated intravascular coagulation Antiphospholipid syndrome Cryofibrinogenemia Pancreatic panniculitis Necrotizing fascitis Infected emboli Pyoderma gangrenosum Microvascular calcification, paniculitis Fibrinoid necrosis, dsDNA, ANCA, cryoglobulins Microvascular thrombosis, HIT antibodies (anti-PF4) Microvascular thrombosis, Warfarin exposure, protein C deficiency Microvascular thrombosis, thrombocytopenia, low fibrinogen, raised d-dimers Microvascular thrombosis, lupus anticoagulant, antiphospholipid antibodies Cold-induced vasculitic purpura, plasma cryofibrinogen precipitates Panniculitis, raised amylase, abdominal pain Necrosis along fascial planes, group-A ß-hemolytic streptococcus Bacterial endocarditis Neutrophilic dermatosis, papulopustules, ulcerating folliculitis 292 Am J Nephrol 2001;21:289–293 caused in part by differences in the half lives of the key anticoagulant (protein C) and procoagulant (prothrombin) factors (9 and 60 h, respectively). However, since most patients who receive warfarin therapy have also received heparin it may be argued that heparin alone is responsible for inducing the hypercoaguable state responsible for skin necrosis in these cases. Recent reports have demonstrated the presence of anti-PF4 antibodies in patients previously diagnosed with warfarin-induced skin necrosis . The term ‘anticoagulant-induced skin necrosis’ has evolved to envelop this clinical overlap. Given that the majority of hemodialysis patients regularly receive heparin, it is somewhat surprising that only a handful of cases of heparin-induced skin ulceration have been reported in this patient population [7–9]. We speculate that this is because many cases of heparin-induced skin necrosis are misdiagnosed as calciphylaxis. Indeed the clinical features of heparin-induced skin necrosis and calciphylaxis are strikingly similar: both conditions present with painful echymoses or levido reticularis followed by ulceration and eschar formation often in a symmetrical distribution involving the upper thighs, adjacent abdomen and buttocks, and commonly in obese diabetic women [16, 17]. In a recent large case series of end-stage renal disease patients diagnosed with calciphylaxis 7 of 12 skin biopsies showed microvascular thrombi, suggesting an underlying thrombotic state in these cases . Indeed, prothrombotic states such as protein C and S deficiencies have been described in calciphylaxis [18, 19]. To date no studies have actually examined the incidence of HIT antibodies in patients diagnosed with calciphylaxis. Differentiation between calciphylaxis and heparin-induced skin Denton/Mauiyyedi/Bazari Downloaded by: University of Florida, Gainesville and Jacksonville 220.127.116.11 - 10/26/2017 4:27:59 AM betic women [6–9]. Onset of skin necrosis usually occurs 5–10 days after initiating heparin but lesion formation may be delayed several months as reported in 1 hemodialysis patient . HIT antibodies are present in almost all cases of heparin-induced skin necrosis and are likely directly involved in the pathogenesis of these lesions. HIT antibodies are generated following B lymphocyte recognition of ‘neoantigens’ created by the physical interaction between heparin with platelet factor 4 (PF4) . The resulting antibodies interact with heparin-bound PF4 to form immune complexes that bind specific Fc receptors on platelets and promote platelet activation. In addition it is speculated that HIT antibodies interact with PF4 bound to glycosaminoglycans on endothelial cells resulting in antibodymediated endothelial cell injury, and thrombosis . Since only a minority of patients with HIT antibodies develop overt thrombotic complications or skin necrosis it is likely that additional procoagulant conditions may be crucial for this condition to manifest clinically. Our patient had heterozygous protein S deficiency type II and a prior history of venous thromboembolism. Indeed heparin-induced skin necrosis has been previously associated with heterozygous protein S deficiency [11, 12]. To our knowledge this is the first report describing the coexistence of HIT antibodies and protein S deficiency leading to skin necrosis in a dialysis patient. Warfarin-induced skin necrosis is clinically similar to heparin-induced skin necrosis and is associated with congenital deficiencies of both protein C  and protein S . During initiation of warfarin therapy, a disturbance in procoagulant/anticoagulant balance can develop, necrosis is clearly important given that distinct treatment options exist for both conditions. Management of the HIT syndrome involves discontinuation of heparin and anticoagulation with agents that rapidly control thrombin generation such as the thrombin inhibitor, hirudin . Normalization of calcium, phosphate and PTH levels are the goals of therapy in calciphylaxis. In summary, we present the case of patient with endstage renal failure and presumed calciphylaxis who on further investigation was found to have heparin-induced skin necrosis and functional protein S deficiency. This case highlights the importance of skin biopsy and assessment of a prothrombotic state in dialysis patients presenting with skin ulceration. References Heparin-Induced Skin Necrosis 8 Humphries JE, Kaplan DM, Bolton WK: Heparin skin necrosis: Delayed occurrence in a patient on hemodialysis. Am J Kidney Dis 1991;17:233–236. 9 Leblanc M, Roy LF, Legault L, Dufresne LR, Morin C, Thuot C: Severe skin necrosis associated with heparin in hemodialysis. Nephron 1994;68:133–137. 10 Viscentin GP: Heparin-induced thrombocytopenia: molecular pathogenesis. Thromb Haemost 1999;82:448–456. 11 Libow LF, DiPreta EA, Dyksterhouse DL: Cutaneous heparin necrosis in patient with heterozygous protein S deficiency. Cutis 1997;59: 242–244. 12 Gailani D, Reese EP Jr: Anticoagulant-induced skin necrosis in a patient with hereditary deficiency of protein S. Am J Hematol 1999;60: 231–236. 13 Goldberg SL, Orthner CL, Yalisove BL, Elgart ML, Kessler CM: Skin necrosis following prolonged administration of coumarin in a patient with inherited protein S deficiency. Am J Hematol 1991;38:64–66. 14 Sallah S, Abdallah JM, Gagnon GA: Recurrent warfarin-induced skin necrosis in kindreds with protein S deficiency. Haemostasis 1998; 28:25–30. 15 Warkentin TE, Sikov WM, Lillicrap DP: Milticentric warfarin-induced skin necrosis complicating heparin-induced thrombocytopenia. Am J Hematol 1999;62:44–48. 16 Coates T, Kirkland GS, Dymock RB, Murphy BF, Brealey JK, Mathew TH, Disney AP: Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis 1998;32:384–391. 17 Ruggian JC, Maesaka JK, Fishbane S: Proximal calciphylaxis in four insulin-requiring diabetic hemodialysis patients. Am J Kidney Dis 1996;28:409–414. 18 Mehta RL, Scott G, Sloand JA, Francis CW: Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med 1990;88:252–257. 19 Perez-Mijares R, Guzman-Zamudio JL, Payan-Lopez J, Rodriguez-Fernandez A, Gomez-Fernandez P, Almaraz-Jimenez M: Calciphylaxis in a haemodialysis patient: Functional protein S deficiency? Nephrol Dial Transplant 1996;11:1856–1859. 20 Greinacher A: Treatment of heparin-induced thrombocytopenia. Thromb Haemost 1999;82: 457–467. Am J Nephrol 2001;21:289–293 293 Downloaded by: University of Florida, Gainesville and Jacksonville 18.104.22.168 - 10/26/2017 4:27:59 AM 1 Warkentin T: Heparin-induced thrombocytopenia: A clinicopathologic syndrome. Thromb Haemost 1999;82:439–447. 2 Warkentin TE: Heparin-induced skin lesions. Br J Haematol 1996;92:494–497. 3 Tuneu A, Moreno A, de Moragas JM: Cutaneous reactions secondary to heparin injections. J Am Acad Dermatol 1985;12:1072– 1077. 4 Harenberg J, Huhle G, Wang L, Hoffmann U, Bayerl C, Kerowgan M: Association of heparininduced skin lesions, intracutaneous tests, and heparin-induced IgG. Allergy 1999;54:473– 477. 5 Fureder W, Kyrle PA, Gisslinger H, Lechner K: Low-molecular-weight heparin-induced skin necrosis. Ann Hematol 1998;77:127–130. 6 Amiral J, Bridey F, Wolf M, Boyer-Neumann C, Fressinaud E, Vissac AM, Peynaud-Debayle E, Dreyfus M, Meyer D: Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: A study of 44 cases. Thromb Haemost 1995;73:21–28. 7 Carrozza P, Gabutti L, Gilliet F, Marone C: Heparin-induced systemic inflammatory response syndrome with progressive skin necrosis in haemodialysis. Nephrol Dial Transplant 1997;12:2424–2427.