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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
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E-Mail karger@karger.ch
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Accessible online at:
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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 [1]; 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 dentonmd@gis.net
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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
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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-
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of heparin administered [1]. 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 [2]. 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 [4]. 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 [2] 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
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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
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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 [15]. 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 [16]. 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
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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 [8].
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) [10]. 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 [10].
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 [13] and protein S
[14]. 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 [20].
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.
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