CONTINUING MEDICAL EDUCATION

Blue (or purple) toe syndrome

Jan V. Hirschmann, MD,
a
and Gregory J. Raugi, MD, PhD
b
Seattle, Washington
The blue (or purple) toe syndrome consists of the development of blue or violaceous discoloration of one
or more toes in the absence of obvious trauma, serious cold-induced injury, or disorders producing
generalized cyanosis. The major general categories are: (1) decreased arterial ow, (2) impaired venous
outow, and (3) abnormal circulating blood. Depending on its pathogenesis, the discoloration may be
blanching or nonblanching. An accurate diagnosis is critical, because many of the causes threaten life and
limb, but the patients medical history, accompanying nondermatologic ndings on physical examination,
and a discriminating use of laboratory tests are usually more important than the nature of the cutaneous
abnormalities in determining the cause. ( J Am Acad Dermatol 2009;60:1-20.)
Learning objectives: After completing this learning activity, participants should be able to dene the blue
(or purple) toe syndrome, categorize the causes, and recognize the important historical, clinical, and
laboratory ndings that differentiate the causes and lead to the correct diagnosis.
I
n 1961, a report described six patients who
developed painful, tender purple toes 3 to 8
weeks after beginning oral anticoagulation.
1
Their prothrombin times were in the therapeutic
range, and in all patients the bluish-purple color
blanched completely on moderate pressure and
faded with leg elevation. Biopsies were unrevealing,
and the pathogenesis remained mysterious. Fifteen
years later, the term blue toe syndrome (BTS) first
appeared in a publication that defined the entity as
the sudden onset of acute pain and cyanosis in one or
more toes.
2
The report described 31 patients, all with
angiographic evidence of a proximal source of em-
boli in the vascular tree, primarily in the femoral or
popliteal arteries, but also in aortic aneurysms and
iliac vessels. The authors urged prompt excision of
the vascular site of origin and restoration of arterial
continuity, because among five untreated patients,
four suffered further embolization within the subse-
quent 6 weeks, causing substantial ischemic loss of
the forefoot in three cases.
Since then, numerous reports of BTS have ap-
peared, and, although emboli remain a common
source, other mechanisms occur, indicating that
carefully delineating the cause is necessary to deter-
mine the appropriate management. BTS may be
dened as the development of blue or violaceous
discoloration in one or more toes in the absence of
obvious trauma, serious cold-induced injury, or
disorders that produce generalized cyanosis, such
as hypoxemia or methemoglobinemia. The affected
digits are often painful. In many cases, the cyanosis
blanches with pressure or leg elevation initially,
indicating that in the rst stages of the disorder the
primary problem is often not hemorrhage, but slug-
gish ow of desaturated blood. In some of these
patients, vascular damage occurs later, red cells leak
into the surrounding tissues, and the discoloration
becomes nonblanchable. In others, vascular injury is
present from the beginning, and the bluish or pur-
plish color represents nonblanchable cutaneous
hemorrhage. Whatever the initial mechanism, once
ischemia becomes pronounced, ulceration, tissue
loss, infection, and gangrene can develop, some-
times necessitating amputation.
The general conditions leading to the sluggish
blood ow or vascular damage that causes BTS are:
(1) decreased arterial perfusion, (2) impaired venous
outow, and (3) abnormal circulating blood (Table
I). This scheme assigns a cause according to the
primary mechanism involved, but the categories are
not mutually exclusive. The presence of cryoglobu-
lins (abnormal circulating blood) for example, can
induce vasculitis and subsequent thrombosis of the
arterioles and capillaries supplying blood to the toes
(decreased arterial flow). Knowing the extracutane-
ous clinical features, pathogenesis, and laboratory
findings of the various disorders in these categories is
From the Medical Service, Puget Sound Veterans Affairs Medical
Center,
a
and the Department of Medicine,
b
University of
Washington.
Funding sources: None.
Conflicts of interest: None declared.
Reprints not available from the authors.
Correspondence to: Jan V. Hirschmann, MD, Puget Sound Veterans
Affairs Medical Center, Medical Service (111), 1660 S Columbian
Way, Seattle, WA 98108. E-mail: pepsi@u.washington.edu.
0190-9622/$36.00
2008 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2008.09.038
1
crucial, because they often suggest or establish the
diagnosis, rather than the dermatologic aspects,
which are frequently nonspecific.
BLUE TOE SYNDROME FROM DECREASED
ARTERIAL PERFUSION
Emboli
Emboli fromatheroscleroticplaque(atherom-
atous or cholesterol crystal emboli). Material
dislodged from ulcerated atheromatous plaques in
the aorta and arteries of the lower extremities can
occlude the small vessels of the feet, leading to BTS.
Depending upon their site of origin, the emboli may
affect other areas, including the eye, central nervous
system, kidney, muscle, and gastrointestinal (GI)
organs.
Predisposing factors, incidence, and
pathogenesis
Atheromatous plaques (Fig 1) contain a necrotic
core within the arterial intima, consisting of foam
cells, debris, and lipids, including cholesterol crys-
tals, all covered by a fibrous cap comprising endo-
thelial cells, smooth muscle cells, and connective
tissue. Spontaneous plaque hemorrhage or shear
forces of the circulating blood can disrupt this
protective cap and cause embolization of the cho-
lesterol crystals. More commonly, however, such
atheroemboli are iatrogenic complications, espe-
cially those caused by mechanical damage to the
arterial walls from vascular surgery or invasive per-
cutaneous procedures, such as angiography and
angioplasty. Another predisposing factor is antico-
agulant or fibrinolytic therapy, which can weaken
the thrombi that, by overlying ulcerated plaques,
help prevent the release of cholesterol crystals.
Inroutine autopsies, the incidence of spontaneous
atheroembolism has ranged from 0.3% to 3.5%.
3-6
In
an examination of the skin and skeletal muscle of the
lower extremities in 100 consecutive autopsies, the
frequency was 4%.
6
When advanced atherosclerosis
is present, the incidence is between4.3%and31%.
7-11
As expected, the frequency of atheromatous emboli
found during routine postmortem examinations in-
creases with the patients age.
3,4
In one study exam-
ining atheroemboli to the kidneys, for example, the
incidence in patients between 80 and 90 years of age
was 11.8%.
9
After vascular procedures, the risk of atheroem-
bolization is substantial. In patients dying shortly
after cardiac surgery for valve operations or my-
ocardial revascularization, 22% had atheroembo-
lism, almost exclusively in those with severe
atherosclerosis of the ascending aorta.
12
Among
71 autopsies of patients who had recently under-
gone angiography, the frequency of atheroembo-
lization was 30% following aortograms and 25.5%
Table I. Causes of blue toe syndrome
Decreased arterial flow
Embolism
Atheroemboli
Cardiac or aortic tumor
Myxoma
Intimal aortic angiosarcoma
Cardiac vegetations
Infective endocarditis
Nonbacterial thrombotic endocarditis
Thrombosis
Antiphospholipid syndrome
Malignancy (paraneoplastic acral vascular syndrome)
Thrombotic thrombocytopenic purpura
Disseminated intravascular coagulation
Warfarin skin necrosis
Vasoconstrictive disorders
Acrocyanosis
Perniosis
Chilblain lupus erythematosus
Medication-induced vasoconstriction
Infectious and noninfectious inflammation
Syphilis
Pyogenic infection
Behcets disease
Other forms of vasculitis
Other vascular obstruction
Calcific vasculopathy (calciphylaxis)
Impaired venous outflow
Extensive venous thrombosis
Phlegmasia cerulea dolens and venous gangrene
Abnormal circulating blood
Paraproteinemia with hyperviscosity
Myeloproliferative disorders
Polycythemia vera
Essential thrombocythemia
Cryofibrinogenemia
Cryoglobulinemia
Cold agglutinins
Fig 1. Distal aorta and iliac bifurcation in a patient with
extensive atherosclerosis and calcication.
J AM ACAD DERMATOL
JANUARY 2009
2 Hirschmann and Raugi
after cardiac catheterization and coronary angio-
grams.
7
Postmortem examinations of patients dy-
ing shortly after surgery for abdominal aortic
aneurysms disclosed atheroemboli to the kidneys
in 77.3%.
10
In 1000 percutaneous catheterizations
for coronary interventions, blood retrieved from
the lumen of the guiding catheter, which scrapes
the aorta during insertion, revealed atheromatous
debris in 24% to 65% of the procedures, depend-
ing upon the catheter shape.
13
Clinically apparent atheroemboli, however, are
much less common. Retrospective studies of patients
undergoing cardiac catheterization or aortic angio-
grams suggestedincidences of about 0.1%to0.2%.
14-16
In a prospective study of 1786 patients 40 years of age
or older undergoing cardiac catheterization, however,
25 (1.4%) had clinical evidence of cholesterol
emboli.
17
Clinical features
Skin ndings. Cutaneous abnormalities are
usually the earliest,
18,19
and often the only, clinical
findings of atheromatous emboli and may appear the
very day of the provoking event
14
or, more often, a
few days later, but sometimes only after many
weeks.
14,20
A common finding, BTS, may affect
only a single digit, but usually involves several and
is typically bilateral if the origin of the atheroemboli
is proximal to the bifurcation of the abdominal aorta.
Peripheral pulses are characteristically well pre-
served, but if the small vessels become occluded,
digital infarcts, ulceration, and gangrene may
develop.
Another common cutaneous nding is livedo
reticularis, which consists of macular reddish, blue,
or violaceous connecting rings in a net-like pat-
tern
21,22
(Fig 2). This discoloration occurs when the
cutaneous venous plexus becomes visible because
of increased amounts of desaturated venous blood
or because of venodilation. Its presence in athe-
roembolization arises when cholesterol crystals ob-
struct small arteries, decreasing vascular flowinto the
venous plexus and causing the blood there to stag-
nate and deoxygenate. Livedo reticularis blanches
with pressure and disappears or fades with elevating
the affected area, which explains why it is sometimes
visible only when the patient is in the upright
position.
23,24
In atheroembolization, livedo reticula-
ris is usually bilateral, is often quite extensive, and is
most commonly seen on the feet and legs, but it may
appear on the buttocks, trunk, or upper extremities,
depending upon the origin of the cholesterol
crystals.
25,26
Additional cutaneous ndings include purpura,
cyanosis, gangrene, and ulcerations in areas other
than the feet, such as the leg,
18
scrotum,
25
and
penis.
27
An inflammatory reaction to the atheroem-
boli can cause nodules, which are typically firm,
erythematous, and localized to the lower extremities.
Splinter hemorrhages in the nail bed may also be a
manifestation.
28
Renal involvement. Clinical kidney disease oc-
curs in about 50% of reported cases of atheroembo-
lism.
19
In one series of 354 patients, iatrogenic
causes, such as invasive vascular procedures, were
responsible for about 75% of those with renal
involvement, while approximately 25% occurred
spontaneously.
29
Nearly all the iatrogenic cases
had at least a 50% reduction in glomerular filtration
rate that was either acute or subacute, defined as an
onset within 1 week or 2 to 6 weeks after the inciting
event, respectively. These patterns suggest a sudden
large shower of atheroemboli or repeated episodes
of intense embolization over a short period of time,
the latter probably explaining the stepwise decrease
in renal function (periods of worsening alternating
with periods of stability) often seen during the
subsequent weeks of observation. Oliguria is un-
common. The spontaneous cases typically pre-
sented as stable chronic renal failure, with the
pathogenesis probably being slow or intermittent
release of fewer cholesterol crystals over a pro-
longed period of time. About half of all patients with
renal involvement have severe, accelerated, or labile
hypertension.
30
Urinalysis may disclose hematuria, casts (usually
hyaline or granular), and pyuria. With the Hansel
stain, eosinophiluria (eosinophils constituting $ 1%
of the white cells in the spun urine), was present in
89% of nine patients.
31
Proteinuria of [11 on dip-
stick occurs in about 60% of cases,
32,33
but only in a
fewhas it been severe enough to cause the nephrotic
syndrome.
33,34
Hypocomplementemia develops in
about 40% of patients.
30
Approximately 35% require
dialysis,
15,29,33
and of these, only 20% to 30% im-
prove enough to discontinue it.
20,29,35,36
Fig 2. Blue toes and livedo reticularis from atheroemboli
following coronary angiography.
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Hirschmann and Raugi 3
Gastrointestinal involvement. About 15% to
20% of patients with systemic atheroemboli have
involvement of one or more digestive organs.
5,37
The
most common features are abdominal pain, diarrhea,
and GI blood loss.
37
The mechanism of diarrhea is
unclear, but probably arises from mucosal inflam-
mation, malabsorption, and the purgative effect of
blood in the gut.
37
GI bleeding presumably develops
from mucosal damage (including erosions, ulcera-
tions, and infarcts) caused by bowel ischemia, which
can also be a mechanism for the abdominal pain.
Occasionally, bowel infarction and perforation
occur.
Pancreatitis is a common complication. In one
series of 16 cases, serum amylase levels were in-
creased in 44% of patients,
38
which is about the
frequency of pancreatic involvement discovered at
autopsy.
32
Most patients are asymptomatic, but some
develop clinically overt disease, which is occasion-
ally fatal.
39
Similarly, hepatic involvement is frequent
on postmortem examination,
32
and liver enzymes
are often elevated, but patients rarely have
symptoms.
Neurologic ndings. Atheroemboli originating
from the proximal aorta may travel to the eye and
brain. They are sometimes visible on fundoscopy as
bright yellow, orange, or copper-colored fragments
lodged at bifurcations of the retinal arterioles. Called
Hollenhorst plaques after the ophthalmologist who
described them,
40
these lesions more often arise
from carotid arteries, but when bilateral, multiple, or
associated with atheroemboli elsewhere, they are
virtually diagnostic of the cholesterol crystal embo-
lization syndrome
41
(Fig 3). They usually produce no
symptoms but do occasionally occlude vessels,
resulting in visual loss. Emboli to the brain can cause
transient ischemic attacks, strokes, confusional
states, seizures, and gradual deterioration in cerebral
function.
29
Atheroemboli may travel to the spinal
cord, but rarely cause symptoms.
42
A peripheral
neuropathy caused by cholesterol crystal emboli to
peripheral nerves is also uncommon.
43
Other clinical features. Atheroemboli to the
pulmonary vessels can cause diffuse alveolar hem-
orrhage with hemoptysis.
44
Weight loss and fever
may occur, probably from inflammation provoked
by the cholesterol crystals. Myalgia is another non-
specific symptom, caused by vessel occlusion within
the muscles.
26
The combination of constitutional
features, multiorgan involvement, and skin lesions
can suggest a systemic vasculitis.
45
Some commonly
abnormal laboratory results may contribute to that
impression, including elevated erythrocyte sedimen-
tation rates in almost all patients, anemia, and
leukocytosis. A particularly important finding is
blood eosinophilia, which occurs in about 60% to
80% of cases.
29,46
Diagnosis. The clinical features may be suf-
ciently compelling to allow a presumptive diagnosis
of cholesterol crystal syndrome, but denitive evi-
dence depends upon histologic examination of a
sample from an affected organ. Premortem diagnosis
has usually come from specimens of the skin,
kidney, or muscle. Skin biopsies of a wide variety
of lesions, including livedo reticularis, purpura, and
cyanotic areas, have been positive in about 90% of
cases.
25
In paraffin-fixed biopsy or autopsy speci-
mens, cholesterol crystals are dissolved and leave
diagnostic acicular (needle-shaped) clefts within the
lumen of blood vessels, most commonly in small
arterioles with diameters of 100 m to 200 m.
26,47,48
The atheroemboli initiate a thrombotic process, and,
by irritating the vessel wall, provoke a foreign
bodyetype giant cell reaction or inflammation that
resembles vasculitis and includes neutrophils, eosin-
ophils, and mononuclear cells. Within the involved
vessels, hyperplastic intimal proliferation occurs
with variable fibrosis. The occluded vessel may
recanalize but the cholesterol crystals seem perma-
nent because they are insoluble in body fluids and
impervious to phagocytosis.
47
Emboli from coral reef aorta
An unusual form of atherosclerosis consists of
large, discrete, rock-hard, andgritty calcic intraaortic
masses that resemble a coral reef.
49-51
Pathologic
examination of the masses demonstrates fibrosis of
the intima and media, with a loss of the internal elastic
lamina, focal intraplaquehemorrhage, anddystrophic
calcification, sometimes with hyperplastic bone for-
mation. The masses are most common in the supra-
renal aorta alone or in both suprarenal and infrarenal
locations, often primarily on the posterior vessel wall.
Fig 3. A Hollenhorst plaque (a bright yellow, orange, or
copper-colored atheroembolus) is lodged at a bifurcation
of the retinal artery.
J AM ACAD DERMATOL
JANUARY 2009
4 Hirschmann and Raugi
The disease is more frequent in women than men.
Patients are usually in their fifties, most are smokers,
and many have hyperlipidemia.
49-51
The main man-
ifestations are renovascular hypertension and lower
extremity ischemia causing claudication or rest pain.
A few have intestinal angina with postprandial pain
andweight loss. In one case, a 45-year-oldfemale had
intermittently painful blue toes over the course of 3
months, at one time or another affecting all the
digits.
51
After undergoing an endarterectomy of an
infrarenal coral reef aorta, no further episodes oc-
curred. Presumably, she had emboli from the calcific
mass.
Emboli from cardiovascular tumors
Myxomas. The most common primary heart ne-
oplasm, a myxoma, arises in the left cardiac cham-
bers in nearly 80% of casesin the left atrium in
about 75%, in the left ventricle in about 3%and,
from these locations, fragments of the tumor can
embolize to various arterial vessels, including those
of the foot.
52
More common in females than males,
they are most frequently discovered between the
third and sixth decades of life. Most symptomatic
patients have one or more of the classic triad of
clinical features: (1) obstructive cardiac findings, (2)
emboli, and (3) constitutional symptoms. When a left
atrial myxoma occludes the mitral valve, patients
may develop dyspnea from increased pulmonary
venous pressure, syncope from impaired left ven-
tricular filling and subsequent inadequate cerebral
perfusion, or arrhythmias, which can be life threat-
ening. Constitutional symptoms include fatigue, fe-
ver, weight loss, arthralgias, and myalgias. The
myxomas may have a smooth surface or one that
consists of fragile, gelatinous projections that tend to
fragment, causing emboli, which occur in about 30%
to 40% of patients. Clinically apparent emboli from
the left side of the heart most frequently involve the
cerebral vessels, including the retinal arteries, caus-
ing transient or permanent visual or neurologic
findings. Less commonly, they produce symptoms
by obstructing peripheral, visceral, and renal arter-
ies. Occasionally, the tumor fragments cause skin
lesions, and biopsies may reveal myxomatous mate-
rial obstructing a vessel.
53,54
Cutaneous findings are
acrocyanosis, including blue toes
54,55
; erythematous,
often tender, and usually acral macules and papules;
petechiae; splinter hemorrhages; livedo reticularis;
ulcers; reddish-violet malar flush; Raynaud phenom-
enon; and serpiginous and annular, violaceous non-
blanching lesions.
53
Intimal angiosarcoma of the aorta. Intimal
angiosarcoma of the aorta, a rare malignant tumor of
endothelial origin arising in the vessel lumen, can
affect the aorta at the arch, the upper abdominal
portion, or, most frequently, the infrarenal segment
56
(Fig 4). Its most common manifestation is an embo-
lus to a peripheral or mesenteric artery. In one case, it
caused bilateral foot pain, mottled purplish discol-
oration of both lower extremities, and cyanotic or
gangrenous toes.
57
Multiple erythematous macules
also occurred on the legs and feet.
Emboli from cardiac vegetations
Infective endocarditis. In infective endocardi-
tis of any duration, diverse cutaneous lesions can
develop, including erythematous or purplish mac-
ules, papules, or nodules. They most commonly
appear on the hands and feet, including the pads of
the ngers or toes (Fig 5). Edward Janeway in 1899
and William Osler in 1909 described some of these
skin findings,
58
which are now commonly called
Janeway lesions and Osler nodes, but with differing
and often conflicting definitions.
59,60
Perhaps the
most widely adopted distinction characterizes Osler
nodes as painful papules on the tips of the fingers
and toes and Janeway lesions as painless macules on
Fig 4. Intimal aortic angiosarcoma is visible in the inferior
aortic arch on the sagittal view of a computed tomography
angiogram. The tumor emboli caused left arm ischemia,
right homonymous hemianopsia, and blue toe syndrome.
Fig 5. Osler nodes in patient with bacterial endocarditis
caused by Staphylococcus aureus.
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Hirschmann and Raugi 5
the palms and soles. Skin biopsies or aspirates from
several of these lesions have disclosed such features
as neutrophilic inflammation (sometimes forming
microabscesses), vascular occlusion, septic vasculi-
tis, microemboli, and evidence of the infecting
organism on stains and/or culture of the speci-
mens.
60-65
These findings indicate that at least some
of the cutaneous manifestations of endocarditis rep-
resent infectious, rather than immunologic, compli-
cations and are probably caused by emboli from an
infected valve.
Nonbacterial thrombotic (marantic)
endocarditis
Nonbacterial thrombotic endocarditis consists of
sterile platelet-brin thrombi on cardiac valves. The
term is partly a misnomer, because inammation is
absent. Its prevalence at autopsy is about 1%, being
present about three times more commonly in pa-
tients with malignancies than in benign disorders.
66
The cancer is most frequently an adenocarcinoma of
the lung, pancreas, or alimentary canal, but virtually
any malignancy, including hematologic ones, can be
present.
66
Other associated disorders comprise a
wide variety of illnesses, including acute infections
and chronic, often debilitating, diseases, which led to
the name of marantic (from Latin, marasmus:
wasting) endocarditis. Patients may have dissemi-
nated intravascular coagulation or antiphospholipid
syndrome. When associated with systemic lupus
erythematosus (SLE), the valvular lesions are called
LibmaneSachs endocarditis, but they do not differ
histologically from other kinds of nonbacterial
thrombotic endocarditis.
67
These cardiac vegetations
may be much more common than autopsy data
suggest: echocardiograms have identified lesions
compatible with nonbacterial thrombotic endocar-
ditis in 32% of patients with primary antiphospholi-
pid antibody syndrome, 63% with myeloproliferative
diseases, 19% with solid tumors, and 43% with
SLE.
68,69
The vegetations are present on the mitral valve
(on the atrial surface) in about 45% of cases, on the
aortic valve (on the ventricular surface) in 35%, on
both in 15%, and on the right-sided valves (tricuspid
much more often than the pulmonic) in less than 5%
of cases. They rarely alter valve function or produce
cardiac murmurs. Most are less than 3 mm in diam-
eter, and several vegetations can occupy a single
valve. Because of their size, emboli usually occlude
small arteries, most commonly in the spleen, kidney,
and extremities, where they typically produce no
symptoms or signs. Emboli become clinically evident
most commonly in the cerebral vessels, causing focal
ndings (eg, aphasia or hemiparesis) or, with several
emboli, either multifocal features (eg, left hemipare-
sis and focal seizures of the right arm) or diffuse
cerebral dysfunction (eg, confusion or coma).
Coronary artery occlusion can cause an acute myo-
cardial infarction. Less common ndings are hema-
turia from emboli to the kidneys, bowel infarction
from occlusion of GI vessels, left upper quadrant
pain from splenic infarct, and myalgia or weakness
from obstruction of arteries to the muscles.
Occasionally, emboli from nonbacterial thrombotic
endocarditis can cause BTS.
70
THROMBOSIS
Hypercoagulable states
Antiphospholipidsyndrome. Antiphospholipid
syndrome is an autoimmune disorder whose diagnosis
requires both clinical and laboratory ndings.
71
The
clinical features include: (1) thrombosis anywhere in
the arterial or venous vessels confirmed by imaging
techniques or histopathology and/or (2) pregnancy
morbidity. The latter is defined by: (1) one or more
unexplained deaths of a morphologically normal fetus
at or beyond the tenth week of gestation; (2) one or
more premature deaths at or before the thirty-fourth
week of gestation because of severe preeclampsia,
eclampsia, or placental insufficiency; or (3) three or
more unexplained consecutive abortions before the
tenth week of gestation. The laboratory abnormalities
must include the presence of one or more of the
following: (1) lupus anticoagulant, (2) immunoglobu-
lin G (IgG) or IgM anticardiolipin antibodies in me-
dium or high titers, or (3) antieb2-glycoprotein I of
IgG or IgM isotype at a titer more than the 99th
percentile for the testing laboratory when assessed
according to recommended procedures. These find-
ings must be present on two or more occasions at least
12 weeks apart, because these antibodies can appear
transiently in some healthy people and with certain
illnesses, especially infections, but in those situations,
the tests are rarely positive when repeated after 3
months or longer.
71
Antiphospholipid syndrome may occur in the
absence of other diseases or be associated with
some disorders, especially SLE. The most common
clinical feature of the syndrome is venous thrombo-
sis, which can affect supercial vessels but more
frequently involves deep veins, especially in the legs,
often accompanied by pulmonary emboli.
72
Neurologic manifestations are also common, most
frequently in the form of ischemic strokes and
transient ischemic attacks from occlusion of the
cerebral arteries. Arthritis or arthralgias occur in
more than half of patients.
72
Cardiac manifestations
include myocardial infarction, stenosis or regurgita-
tion of the mitral or aortic valves, and the presence of
J AM ACAD DERMATOL
JANUARY 2009
6 Hirschmann and Raugi
leaflet thickening or vegetations. Renal disease con-
sists of acute or chronic renal failure, hypertension,
proteinuria, and hematuria that result from either
thrombosis of large veins or arteries or thrombotic
microangiopathy affecting both arterioles and glo-
merular capillaries. Thrombocytopenia occurs in
about 50% of cases, and hemolytic anemia in ap-
proximately 20% of cases.
72
When sought carefully, dermatologic ndings are
detectable in about 50% of patients and are the
presenting feature in approximately 30% of pa-
tients.
73
Livedo reticularis is the most common cuta-
neous manifestation. In their criteria for diagnosing
antiphospholipid syndrome, an international con-
sensus group
71
defined it as violaceous, red or blue,
reticular or mottled pattern [. . .] that may consist of
regular unbroken circles (regular livedo reticularis)
or irregular-broken circles (livedo racemosa [from
Latin, racemus: grape bunch]). The width of the
branching lines can be large ( $10 mm) or small
(\10 mm). The most frequent appearance is a fine,
widespread, and irregular network in several areas,
including the limbs, trunk, and buttocks. Other
cutaneous findings include skin necrosis or gan-
grene, especially affecting the digits; superficial
thrombophlebitis; leg ulcers, often consisting of
painful, stellate lesions around the ankle; thrombo-
cytopenic purpura; and anetoderma (circumscribed
round or oval atrophic, wrinkled areas of slack skin,
either bulging or depressed, caused by loss of elastic
tissue). Patients can have blue toes from: acrocya-
nosis,
74
purplish macules apparently provoked by
systemic corticosteroid therapy,
75
digital ische-
mia,
76,77
nonblanching dusky network (unfading
acral microlivedo),
78
or nodules resembling pernio
(chilblains)
79
(Fig 6).
An uncommon subset of the disease, character-
ized by rapidly progressive multiorgan failure pri-
marily caused by small vessel thrombi, is
catastrophic antiphospholipid syndrome.
80
About
one-half of patients have antiphospholipid syn-
drome alone, 40% SLE, and the remainder have
other rheumatic diseases. Approximately 50% of
patients have had no previous evidence of antiphos-
pholipid syndrome. The female to male ratio is[2:1.
Specific inciting eventsincluding infections (most
commonly, cutaneous), neoplasias, exacerbations of
SLE, interrupted anticoagulation, medications, or
obstetric problemsoccur in about 50% of cases.
The distribution of organ involvement is about 70%
kidney (usually renal failure), 60% cerebral (primar-
ily strokes), 65% lung (mostly pulmonary emboli and
acute respiratory distress syndrome [ARDS]), 50%
cardiac (heart failure, mitral or aortic valve defects,
or myocardial infarction), and 50% skin.
81
The
cutaneous findings include livedo reticularis, ulcers,
digital gangrene, purpura, multiple ecchymoses, and
acrocyanosis.
81
The last four conditions can cause
blue toes.
The diagnosis of catastrophic antiphospholipid
syndrome employs four criteria: (1) evidence of
involvement of 3 or more organs, systems, or tissues;
(2) development of manifestations simultaneously or
in less than 1 week; (3) conrmation by histopathol-
ogy of small-vessel occlusion in 1 or more organs or
tissue; and (4) laboratory demonstration of antiphos-
pholipid antibodies on 2 or more occasions 6 or
more weeks apart. A denite diagnosis requires all
four criteria, while a probable diagnosis entails: (a)
all four criteria, but only two organs or tissues
involved; (b) all four criteria, but the absence of at
least two positive serologic tests; (c) 1, 2, and 4
above; or (d) 1, 3, and 4 above and the development
of a third event between 1 week and 1 month after
onset despite anticoagulation.
82
Malignancy (paraneoplastic acral vascular
syndrome)
The association of Raynaud phenomenon, gan-
grene, or acrocyanosis of the ngers and toes with
neoplasias is called paraneoplastic acral vascular
syndrome.
83
About 60% of the reported underlying
malignancies have been carcinomas of various his-
tologies, most commonly adenocarcinomas affecting
diverse organs, especially the lungs, ovaries, and
stomach. About 20% have been hematologic malig-
nancies, including leukemias, lymphomas, and plas-
macytomas. The remaining 20% were sarcomas or
cancers of unknown types. The cutaneous abnor-
malities appeared simultaneously with cancer detec-
tion in about 50% of patients, preceded the diagnosis
in about 45% by a median interval of 3.5 months, and
developed after discovery of malignancy in about 5%
of patients.
Fig 6. Violaceous discoloration of the toes in a patient
with antiphospholipid syndrome.
J AM ACAD DERMATOL
VOLUME 60, NUMBER 1
Hirschmann and Raugi 7
The most common skin nding was acute digital
gangrene in about 60% of cases, preceded by
Raynaud phenomenon in about 50% of cases
(Fig 7). Acrocyanosis occurred in about 25% of
patients and Raynaud phenomenon alone in about
20% of patients. The fingers were affected in about
95% of patients, both fingers and toes in 30% of
patients, and the toes alone in approximately 5% of
patients. The histologic examinations of skin biop-
sies from 10 patients revealed fibrinoid necrosis of
the vessels, intimal proliferation, and inflammatory
cells in five cases and tissue necrosis with venous
and/or arterial thromboses in the other five cases. In
about 50% of cases, the digital ischemia regressed
with successful treatment of the malignancy.
83
Thrombotic thrombocytopenic purpura
In thrombotic thrombocytopenic purpura (TTP),
which is primarily a disease of previously healthy
adults, the major histologic feature is widespread
occlusion of small arterioles by platelet plugs con-
taining variable quantities of von Willebrand factor. It
is clinically dened by the presence of thrombocy-
topenia and a microangiopathic hemolytic anemia
without another cause, such as disseminated intra-
vascular coagulation, malignant hypertension, ma-
lignancy, or severe preeclampsia.
84,85
As in other
forms of microangiopathic hemolytic anemia, the
erythrocyte damage is not immune-relatedthe di-
rect antiglobulin (or Coombs) test is negativebut
instead is caused by the shearing of erythrocytes
passing through vasculature partially occluded by
microthrombi. The resulting fragmented red cells
(schistocytes) are visible on a peripheral blood
smear (Fig 8).
TTP affects women more than men, with an
average age at onset of about 40 years. It has a
nine-fold increased incidence among blacks. Most
cases are idiopathic, but some have been associated
with medications (eg, ticlopidine, clopidogrel, qui-
nine, cyclosporine, or tacrolimus), infection with
HIV, pregnancy or the postpartum period, and
bloody diarrhea caused by enterohemorrhagic
Escherichia coli.
85
The earliest clinical manifestations are often non-
specic symptoms, such as weakness, malaise, nau-
sea, abdominal pain, and fatigue. Most patients
develop neurologic ndings that are typically tran-
sient or uctuating, including confusion, headaches,
focal motor or sensory abnormalities, seizures, visual
symptoms, and coma. Fever is common but is often
low-grade (\1028F [38.98C]). Renal involvement is
frequent, with proteinuria, microscopic hematuria,
and mild to moderate depression of renal function
being the predominant features. Clinically apparent
bleeding is often the earliest sign, and the skin is, by
far, the most common site of hemorrhage, evidenced
primarily by petechiae and purpura. Digital ischemia
occurs in some patients with TTP and begins with
mottling of the ngers and toes that evolves into
bluish discoloration and, eventually, gangrene
86
(Fig 9).
The laboratory evidence for microangiopathic
hemolysis includes markedly elevated serum lactate
dehydrogenase (LDH), increased indirect bilirubin,
decreased haptoglobin, elevated reticulocyte count,
and anemia with the peripheral blood smear re-
vealing increased polychromatophilic erythrocytes
and fragmented red cells (schistocytes) representing
more than 1% of the red cell population (usually
$2 per microscopic eld at 3100 magnication).
85
Thrombocytopenia is usually severe, with average
platelet counts being about 25,000 per L.
A large percentage of patients with TTP unasso-
ciated with other disorders have a severe deciency
of ADAMTS 13 (the thirteenth of a group of proteases
named by the acronym a disintegrin and
Fig 7. Blue toes progressing to distal gangrene as a result
of multiple arterial thrombi (paraneoplastic acral vascular
syndrome) in a patient with lung cancer.
Fig 8. Peripheral blood smear in patient with thrombotic
thrombocytopenic purpura demonstrates numerous irreg-
ularly-shaped, fragmented red cells (schistocytes).
J AM ACAD DERMATOL
JANUARY 2009
8 Hirschmann and Raugi
metalloprotease with thrombospondin-1-like do-
mains). This substance cleaves the large von
Willebrand factors produced by vascular endothelial
cells, and, when its levels are diminished, von
Willebrand factor multimers accumulate and react
with platelets, causing the disseminated platelet
thrombi that are characteristic of TTP. The ADAMTS
13 levels are less than 5% to 10% of normal in many
patients with TTP, depending on the definition of the
disease, and usually the cause is an ADAMTS
13ebinding IgG. Rarely, there is a hereditary defi-
ciency of ADAMTS 13.
85
Disseminated intravascular coagulation
In disseminated intravascular coagulation (DIC),
widespread activation of the clotting cascade and
generation of excess thrombin results in intravascular
brin formation and thrombotic occlusion of small
and larger vessels, often causing organ failure.
87
The
consumption of clotting factors and platelets in the
diffuse thrombotic process may deplete these hemo-
static substances, leading to hemorrhage fromvarious
sites. The compensatory actions of natural anticoagu-
lants, such as protein C and antithrombin, are de-
creased because of consumption, impaired synthesis,
and increased degradation; fibrinolysis, although ac-
tivated and resulting in increased fibrin degradation
products, is inadequate to halt the clotting.
DIC is always secondary to another illness, most
commonly the following: (1) diverse infections, but
especially those with bacteremia; (2) severe trauma;
(3) malignancy, including myeloproliferative and
lymphoproliferative disorders, promyelocytic leuke-
mia, and solid tumors; (4) obstetric complications,
such as abruption placentae and amniotic uid
emboli; (5) severe immunologic or toxic reactions,
such as snakebites, transplant rejection, and transfu-
sion reactions; and (6) fulminant hepatic failure.
The major clinical features may relate to the
underlying disorder, but DIC, when acute, tends to
cause bleeding, tissue ischemia, and a microangio-
pathic hemolytic anemia similar to that seen with
TTP. Acute renal failure and hepatic dysfunction are
common. Neurologic features, caused by thrombi,
hemorrhage, or hypoperfusion, include delirium,
coma, and transient focal signs.
The bleeding of DIC may be from mucosal sur-
faces, but most commonly involves the skin. The
cutaneous ndings include petechiae, macular or
palpable purpura, hemorrhagic bullae, subcutane-
ous hematomas, and bleeding from areas of trauma,
such as venipuncture sites or surgical wounds.
88
Acrocyanosis in DIC is a gun-metal gray to purplish,
sharply demarcated and symmetrical discoloration of
the tips of the fingers or toes that may progress to
gangrene. A distinctive finding, purpura fulminans,
tends to occur with infections and consists of an
extensive confluent purpura of explosive onset, fre-
quently associatedwithhemorrhagic bullae andfocal
gangrene (Fig 10). The lesions can occur diffusely
and anywhere on the body, but are usually symmet-
rical and involve the distal upper and lower extrem-
ities, tip of the nose, and genitalia.
89
The critical steps in diagnosis are to identify the
underlying disorder that provoked the problem and
to conrm the presence of DIC by laboratory studies
that demonstrate evidence of both thrombin gener-
ation (eg, decreased brinogen) and compensatory
brinolysis (eg, elevated brin-related markers). No
single test establishes the diagnosis of DIC, but
suggestive ndings are: (1) thrombocytopenia; (2)
elevated brin-related markers (eg, brin degrada-
tion products, D-dimer); (3) prolonged prothrombin
time (PT); and (4) decreased brinogen. Often, serial
coagulation tests are more helpful than single
measurements.
87
Warfarin-induced skin necrosis. Skinnecrosis
occurs in an estimated 0.01% to 0.1% of patients
taking warfarin, and the indication for anticoagula-
tion in these cases is usually venous thrombosis
rather than cardiac conditions, such as atrial brilla-
tion.
90
It typically occurs in middle-aged, obese
women, with the first cutaneous symptoms
Fig 9. Blue toes in thrombotic thrombocytopenic purpura
have progressed to gangrene and tissue loss.
Fig 10. Blue toes from purpura fulminans in patient with
pneumococcal bacteremia.
J AM ACAD DERMATOL
VOLUME 60, NUMBER 1
Hirschmann and Raugi 9
appearing 1 to 10 days (usually 3-6 days) after
initiation of warfarin, although occasionally they
develop more than 2 weeks later.
91
Paresthesias, a
sensation of pressure, and an evanescent flush may
occur at the sites of involvement before the appear-
ance of the skinlesions, whichare usually painful and
tender, well demarcated red or hemorrhagic plaques
with an erythematous rim. They may have an edem-
atous dimpled surface (peau dorange). Hemorrhagic
bullae develop within the lesions, and underlying
necrosis thenoccurs. The most commonlocations are
the breast, buttocks, and thighs, but the process can
involvethe feet, causingblue toes.
91,92
Biopsies of the
lesions demonstrate extensive occlusion of the der-
mal and subcutaneous capillaries with fibrin thrombi.
The pathogenesis of warfarin skin necrosis remains
unclear, but deficiency of protein C, a natural antico-
agulant, is a major risk factor. In some cases, at least,
the rapid decrease in protein C that normally occurs
after warfarin initiation may remove an important
anticoagulant in patients with low levels already,
thereby encouraging thrombosis in the small cutane-
ous vessels.
VASOCONSTRICTION
Acrocyanosis
Acrocyanosis is transient or persistent bluish dis-
coloration of the ngers and/or toes that may also
involve the proximal surfaces of the hands or feet. It
tends to lessen with elevation and become redder
with dependency. Exposure to cold often intensies
the cyanosis, and warming the area can decrease or
eliminate the discoloration. Its mechanism appears
to be vasoconstriction of the small cutaneous arteries
and arterioles, causing diminished blood ow, with
engorgement of the capillaries and subpapillary
venules.
93
Sometimes, it is episodic. For unclear reasons, it
occurs in patients with anorexia nervosa, especially
those who are more severely ill, and improves with
weight gain.
94
Perniosis (chilblains) and chilblain lupus
erythematosus
Perniosis or chilblains (Anglo-Saxon for cold
sores) are red-purple patches, papules, or plaques
that develop on acral areas in nonfreezing cold,
damp conditions.
95,96
They typically occur on the
toes, fingers, and ears, usually bilaterally. Both acute
and chronic forms exist. In the acute type, the lesions
appear a few hours after exposure, causing intense
pruritus, and often produce a burning sensation,
especially after warming. Blisters, erosions, and
ulcers may develop, but the lesions tend to resolve
in 1 to 3 weeks.
In the chronic type, recurrent cyanotic papules,
macules, plaques, or nodules form on the toes and
ngers after repeated exposures to cold. Sometimes,
the only manifestation is cyanotic toes.
97
Most
patients are women between 20 and 40 years of
age, in whomthese lesions develop each year during
the cold months and typically resolve when the
weather becomes warmer. In many patients, the
disorder is idiopathic, but those with severe, pro-
tracted lesions often have clinical symptoms or
laboratory findings of a concomitant rheumatologic
disease.
98
Occasionally, it is Sjogren syndrome, but
usually SLE or cutaneous lupus erythematosus (dis-
coid lupus) is present. The lesions commonly persist
throughout the year, and in some of the patients,
biopsies of the lesions do not reveal the features of
usual chilblains (described below) but instead show
the histopathologic and direct immunofluorescence
findings typical of lupus erythematosus. This disor-
der, originally described by Hutchinson in 1888,
99
has
beencalledchilblainlupus erythematosus.
100
Other
cutaneous findings are often present, including
Raynaud phenomenon, malar rash, photosensitivity,
and discoid lupus.
98,100-103
Serologic testing com-
monly reveals antinuclear antibodies, less frequently
anticardiolipin antibodies, or antieSS-Aor antieSS-B.
Proposed diagnostic criteria for chilblain lupus eryth-
ematosus are divided into two categories as follows:
major criteria(1) skin lesions in acral locations
inducedby exposure tocoldor a dropintemperature;
(2) evidence of lupus erythematosus in the skin
lesions by histopathologic examination or direct im-
munofluorescence; and minor criteria(1) the coex-
istence of SLE or skin lesions of discoid lupus
erythematosus; (2) response to antielupus erythema-
tosus therapy; and(3) negative results of cryoglobulin
and cold agglutinin studies. Diagnosis requires ful-
filling both major and one or more of the minor
criteria.
101
The pathogenesis of chilblains is unsettled, but
the usual explanation is that intermittent or pro-
tracted cold-induced vasoconstriction causes ische-
mia and inammation of vessels and surrounding
tissue. The major histopathologic ndings are dermal
edema, keratinocyte necrosis, and a deep dermal
lymphocytic inltrate, which are especially prom-
inent around vessels and eccrine glands.
98,104,105
Vascular thrombi are sometimes present.
Angiography in one patient disclosed narrowing
and occlusion of several vessels.
95
Medication-induced vasoconstriction
Some medications, such as amphotericin B deox-
ycholate
106
and imipramine,
107
can cause acrocya-
nosis. A similar phenomenon occurs when local
J AM ACAD DERMATOL
JANUARY 2009
10 Hirschmann and Raugi
anesthetic combinedwithepinephrine is injectedas a
nerve block for toe surgery.
108
Systemic vasopressors
also produce cutaneous vasoconstriction, which can
lead to acrocyanosis, ischemia, and even gangrene.
Such ischemic skin lesions occurred in 30% of 63
patients receiving continuous arginine vasopressin
infusion for catecholamine-resistant vasodilatory
shock
109
and have developed from the intravenous
administrations of dopamine,
110
norepineph-
rine,
111,112
and phenylephrine.
113
Another cause is
ergotism, now most commonly associated with ergot
medications taken for migraines.
114
INFECTIOUS AND NONINFECTIOUS
INFLAMMATION, INCLUDING VASCULITIS
A patient with syphilis developed painful blue
toes that on biopsy demonstrated a supercial and
deep, tightly cuffed perivascular lymphohistiocytic
and plasma cell inltrate with endothelial cell
swelling.
115
The findings resolved with penicillin
therapy.
Patients with localized pyogenic infection of the
foot can develop blue toes, presumably from im-
paired arterial ow because of the pressure of
accumulating pus compressing the vessels and/or
from vasculitis causing vessel narrowing or occlu-
sion (Fig 11).
A young girl with Behcet disease developed
tender, purpuric papulondodular lesions on her
toes and ngertips.
116
A skin biopsy demonstrated
a lymphocytic interface dermatitis and perivascular
and intramural lymphohistiocytic infiltrates associ-
ated with endothelial prominence, mural edema,
and erythrocyte extravasation. Other vasculitides can
also cause BTS, but they have not been the subjects
of reports (Fig 12).
OTHER VASCULAR OBSTRUCTION
Calcic vasculopathy (calciphylaxis)
Ischemic skin lesions can develop when calci-
cation of the small cutaneous vessels and intimal
brosis cause narrowing or occlusion of the vascu-
lature. It is most common in patients with end-stage
renal disease, including kidney transplant recipients
and those undergoing chronic peritoneal or hemo-
dialysis.
117-119
They often have evidence of second-
ary or tertiary hyperparathyroidism with an elevated
serum calcium-phosphate product. It has also oc-
curred, however, without end-stage renal disease in
such disorders as cancer, autoimmune hepatitis,
inflammatory bowel disease, rheumatoid arthritis,
sarcoidosis, SLE, alcoholic liver disease, and primary
hyperparathyroidism.
117,118
In one series of 64 pa-
tients, for example, 23% were not undergoing
dialysis, although most had some degree of renal
insufficiency.
118
Risk factors include obesity, liver
disease, systemic corticosteroid use, and a calcium-
phosphate product of greater than 70 mg
2
/dL
2
.
118
Called calciphylaxis, based on the dubious as-
sumption that it is caused by a hypersensitivity
reaction, this disorder has also been labeled calcific
uremic arteriolopathy, calcifying panniculitis,
metastatic calcinosis cutis, and necrotizing pan-
niculitis.
117
A more accurate name would be cal-
cific vasculopathy.
Cutaneous lesions usually occur on either or both:
(1) the distal extremities (below the elbow or, much
more commonly, the knee) and (2) the proximal
extremities, trunk, and buttocks.
117,118
The skin ab-
normalities on the distal lower extremities may begin
as livedo reticularis or acral cyanosis, including blue
toes,
120
but typically progress rapidly to ulceration
and gangrene. In the proximal form, the cutaneous
lesions tend to overlie thick adipose tissues of the
abdomen, thigh, and buttocks and begin as erythema
Fig 11. A diabetic with a foot ulcer and infected distal foot
developed a blue fourth toe. An amputation specimen of
toe revealed purulence and extensive tissue necrosis,
presumably from pus compressing the vessels and/or
vascular inammation occluding the vessel lumen.
Fig 12. Focal violaceous cutaneous infarcts and splinter
hemorrhages in a patient with leukocytoclastic vasculitis.
J AM ACAD DERMATOL
VOLUME 60, NUMBER 1
Hirschmann and Raugi 11
that evolves into violaceous, indurated nodules or
plaques. Hemorrhagic bullae may form, commonly
followed by ulceration or necrosis with eschar for-
mation. When the process involves both inner
thighs, they are often in a symmetrical kissing
pattern where the surfaces of the skin appose.
Unusual sites include the neck, breast, and genitals.
In all forms, intense cutaneous pain is common.
The diagnosis is often readily apparent in patients
with chronic renal failure who have characteristic
lesions. When the condition is atypical or occurs in
the absence of end-stage renal disease, the diagnosis
can be suggested by skin biopsy, although the
biopsy site may heal poorly. The characteristic nd-
ings are calcication of the media, intimal prolifer-
ation, and endovascular brosis of the small vessels
of dermis and subcutaneous fat. Vascular occlusion
by thrombus or calcic obliteration of the lumen is
often, but not necessarily, present.
118,119
Acute and
chronic panniculitis, with a predominantly septal
pattern, may occur, and collagenous degeneration is
frequent in early lesions. In advanced cases, dermal
and subcutaneous necrosis with mixed acute and
chronic inflammation is common.
121
BLUE TOE SYNDROME FROM IMPAIRED
VENOUS OUTFLOW
Ischemic venous thrombosis (phlegmasia
cerulea dolens and venous gangrene)
Occasionally, extensive occlusion of the veins in
an extremity causes tissue ischemia. Sometimes
called phlegmasia cerulean dolens (painful blue
inammation) to distinguish it from the much more
common nonischemic venous thrombosis phlegma-
sia alba dolens (painful white inammation), it
nearly always involves the legs.
122
Many patients
have predisposing factors for venous thrombosis,
such as immobility, clotting disorders, pregnancy,
and leg trauma. The most frequent underlying con-
dition, however, is a malignancy, which is present in
about 40%of cases. The most common cancer, by far,
is bronchogenic, but others tumors have arisen from
such sites as the pancreas, alimentary canal, gall-
bladder, ovary, and uterus. The left leg is more
commonly involved than the right, probably because
the right iliac artery normally compresses the left iliac
vein as it crosses over it, predisposing it to clotting in
the presence of another condition promoting
thrombosis.
Typically, the clots in phlegmasia cerulea dolens
obstruct nearly the entire venous system of the
affected extremity, inhibiting venous outow and
substantially elevating venous hydrostatic pressure.
Marked edema forms from extravasation of uid and
its impaired absorption. The excessive uid in-
creases tissue pressure and diminishes arterial ow,
to the point that it may cease, even though the
arterial lumens remain patent. Cyanosis develops
from the supercial venules becoming engorged
with stagnant, desaturated blood.
The major clinical ndings are unilateral pain,
edema, and cyanosis, which begins in the toes but
can ascend the leg and is sometimes associated with
rubor. Hemorrhagic bullae may form over the toes,
and gangrene develops in 40% to 60% of cases (Fig
13). Pulmonary emboli occur in about 15% to 40%
of cases.
123
The diagnosis is apparent on duplex
Doppler ultrasonography.
124
BLUE TOE SYNDROME FROM ABNORMAL
CIRCULATING BLOOD
Paraproteinemia causing hyperviscosity
syndrome
Viscosity is a measure of a uids resistance to
deformation, and in whole blood its major determi-
nants are the plasma and the erythrocytes, whose
viscosity depends upon their concentration (hemat-
ocrit), mechanical properties, and reversible aggre-
gation.
125,126
White cells contribute significantly only
with marked leukocytosis. The primary factors af-
fecting plasma viscosity are the levels of fibrinogen,
albumin, and globulins. In adults, the most common
cause of clinically significant increased viscosity
(hyperviscosity syndrome) is substantially elevated
serum globulins in the form of monoclonal immu-
noglobulins (paraproteins), whose viscosity de-
pends upon their quantity, shape, and size.
Because of its size, IgM increases viscosity the
most, and in Waldenstrom macroglobulinemia, the
hyperviscosity syndrome is fairly frequent, occurring
Fig 13. Blue toes in a patient with venous gangrene
resulting from prostate cancer. The foot is edematous, and
hemorrhagic bullae have formed.
J AM ACAD DERMATOL
JANUARY 2009
12 Hirschmann and Raugi
in 8% to 39% of patients.
125
Because polymerization
of the paraprotein commonly occurs in IgA mye-
lomas, they are the second most common cause of
the hyperviscosity syndrome. With multiple mye-
lomas associated with an IgGparaprotein, symptoms
of hyperviscosity arise in about 4% of cases.
125
Less
frequent causes of hyperviscosity syndrome are
polyclonal hyperglobulinemia, erythrocytosis from
polycythemia vera, and leukocytosis caused by acute
or chronic leukemias. On peripheral blood smears,
rouleau formation (red cells arranged in a row like a
stack of coins; Fig 14) can be visible with multiple
myeloma or Waldenstrom macroglobulinemia,
which can also cause red cell agglutination (clump-
ing of erythrocytes; Fig 15).
The major clinical manifestations of hyperviscos-
ity syndrome are: (1) mucosal hemorrhage, from
gingival, nasal, GI, or postoperative sites; (2) oph-
thalmic abnormalities, such as blurring, visual loss,
and fundoscopic ndings of retinal hemorrhages and
exudates, retinal vein thrombosis, and papilledema;
and (3) neurologic abnormalities, such as headache,
dizziness, hearing loss, and confusion. Some patients
develop congestive heart failure. The main cutane-
ous ndings, which arise from stasis of blood and
vascular occlusion in the supercial vessels, include
livedo reticularis, acrocyanosis, and digital ischemia,
which can progress to gangrene.
127
Myeloproliferative neoplasms
Chronic myeloproliferative neoplasms are clonal
hematopoietic stem cell disorders with bone marrow
proliferation of one or more myeloid lineages (ie,
granulocytic, erythroid, or megakaryocytic).
128
Effective maturation of the cells leads to increased
numbers of circulating erythrocytes, granulocytes,
and/or platelets. The resultant diseases include pol-
ycythemia vera, chronic myelogenous leukemia,
chronic neutrophilic leukemia, chronic eosinophilic
leukemia, hypereosinophilic syndrome, primary my-
elofibrosis, mast cell disease, and essential thrombo-
cythemia. Two of thesepolycythemia vera and
essential thrombocythemiacan cause BTS. The
World Health Organization diagnosis of essential
thrombocythemia requires fulfilling all four of the
following criteria: (1) a sustained platelet count
equal to or greater than 450 3 10
9
/L; (2) a bone
marrow biopsy whose major abnormality is in-
creased numbers of enlarged, mature megakaryo-
cytes; (3) the exclusion of other disorders that can
cause thrombocytosis, such as chronic inflammation,
previous splenectomy, underlying neoplasm, and
other myeloproliferative diseases; and (4) demon-
stration of JAK2V617F or another clonal marker.
128
The diagnosis of polycythemia vera requires meeting
two major criteria and one minor one or the first
major criterion and two minor ones. The major
criteria are: (1) an elevated red cell mass more than
25% above the mean normal predicted value or a
hemoglobin value greater than 18.5 g/dl in men or
greater than 16.5 g/dl in women; (2) the presence of
JAK2V617F or similar mutation. The minor criteria
are: (1) bone marrow demonstrating proliferation of
erythroid, megakaryocyte, and granulocyte precur-
sors; (2) a subnormal serumerythropoietin level; and
(3) endogenous erythroid colony growth in vitro.
12
When patients with these disorders develop BTS,
the main initial feature is erythromelalgia, a burning
erythema and swelling of the extremities that is
exacerbated by heat, relieved by cold, and usually
preceded by paresthesias. Without treatment, cya-
nosis and coldness of the toes may develop and
progress to ulceration or gangrene. With aspirin, the
symptoms and signs usually resolve within hours. In
others, the normalization of platelet counts by
cytoreductive therapy may be necessary to relieve
Fig 14. Rouleaux formation in a patient with multiple
myeloma. The presence of positively-charged parapro-
teins causes the negatively-charged erythrocytes to ad-
here, forming rows of red cells.
Fig 15. Red cell agglutination in a patient with cold-
agglutinin disease. The high levels of immunoglobulin M
cause the red cells to form clumps of adherent
erythrocytes.
J AM ACAD DERMATOL
VOLUME 60, NUMBER 1
Hirschmann and Raugi 13
the symptoms. The mechanism of erythromelalgia
appears to be spontaneous platelet aggregation to
form platelet thrombi in the microvasculature, a
feature visible on histopathologic studies, which
also reveal swollen endothelial cells and bromus-
cular intimal proliferation.
129
When platelet counts
are less than 400 3 10
9
/L, erythromelalgia does not
occur. Because it does not develop with reactive
thrombocytosis, such as in chronic inflammation, a
qualitative abnormality of the platelets must be
present in addition to their sheer number to cause
this disorder.
These diseases can also cause blue toes through
mechanisms other than erythromelalgia. In essential
thrombocythemia, cutaneous hemorrhage causing
purpura or ecchymoses is the most common derma-
tologic nding,
130
perhaps from bleeding caused by
an acquired von Willebrand syndrome that occurs
with very high platelet counts.
129
In polycythemia
vera, the markedly increased number of circulating
erythrocytes may cause hyperviscosity, producing
stagnant blood flow and consequent cyanosis.
125,131
Cryobrinogenemia
Cryobrinogens are complexes present in the
plasma, but not the serum, which precipitate when
the plasma is cooled to 48C and dissolve at 378C.
They consist of brinogen, brin, bronectin, and
smaller amounts of other proteins. In some cases, no
underlying disease coexistsprimary or essential
cryofibrinogenemiabut most patients have the
secondary form, associated with such illnesses as
infections, rheumatologic disorders, or cancer.
132,133
Some patients have concomitant cryoglobulins, and
they usually have an underlying disease. Although
Raynaud phenomenon, arthralgias, fever, glomeru-
lonephritis, and arterial or venous thromboses can
occur, the main clinical features in symptomatic
cryofibrinogenemia are cutaneous and include li-
vedo reticularis, purpura or ecchymoses, ischemia,
ulcers, necrosis, and gangrene. Blue toes from vio-
laceous nodules or purpura are one manifesta-
tion.
134-136
The various skin findings can occur
anywhere, but tend to develop in areas where the
body temperature is low, including the hands, feet,
ears, nose, and buttocks.
137
Cooling these areas may
provoke skin lesions. Biopsies of the cutaneous
abnormalities reveal thrombi in the superficial and
deep dermal vasculature that are eosinophilic with
hematoxylineeosin stain and purple-red with the
periodic acideSchiff preparation. They may partially
or completely occlude the vessels. These findings are
nonspecific, occurring in several thrombotic dis-
eases, including TTP, DIC, monoclonal cryoglobu-
linemia, and antiphospholipid syndrome.
138
Other
abnormalities include dermal and epidermal necro-
sis and leukocytoclastic vasculitis.
Cryoglobulinemia
Unlike cryobrinogens, which precipitate when
the plasma is cooled, cryoglobulins precipitate with
cooling of the serum. Blood is allowed to clot
completely at 378C for 30 to 60 minutes before
centrifugation, and the supernatant is then stored at
48C for the 1 to 7 days required for the cryoprecip-
itate to appear.
139,140
Cryoglobulins are immuno-
globulins of three major types. Type I consists of
isolated monoclonal immunoglobulins, usually IgM
or IgG. Types II and III are mixed cryoglobulins,
composed of two immunoglobulins, one of which,
usually IgM, has either monoclonal (type II) or
polyclonal (type III) rheumatoid factor activity
(anti-Fc) against a polyclonal component, usually
IgG. In a fewcases, there is an oligoclonal IgGor IgM
and polyclonal IgG, and these have been called type
II-III cryoglobulins.
Type I cryoglobulinemia occurs most commonly
with lymphoproliferative diseases, such as
Waldenstrom macroglobulinemia, chronic lympho-
cytic leukemia, or multiple myeloma. Most cases of
type II and III cryoglobulinemia have underlying
hepatitis C infectionin many series, the frequency
is higher than 80%.
141,142
Conversely, about 20% to
60% of patients with hepatitis C infection have cryo-
globulinemia, although it causes symptoms in only
about 10% to 30% of these.
140
In some patients with
cryoglobulinemia, no other disease is present (es-
sential cryoglobulinemia), but inthesecondarycases,
other causes besides lymphoproliferative disorders
and hepatitis C infection include: (1) rheumatologic
diseases, suchas SLE, rheumatoidarthritis, andSjogren
syndrome; (2) other inflammatory disorders, such as
sarcoidosis, thyroiditis, and inflammatory bowel dis-
ease; and (3) viral, bacterial, fungal, or parasitic
infections, suchas HIV, Qfever, bacterial endocarditis,
coccidioidomycosis, toxoplasmosis, and malaria.
139
The major clinical manifestations of the cryoglob-
ulinemias involve the skin, kidney, peripheral
nerves, and the liver. In type I, the prominent
ndings are cutaneous and tend to be acrocyanosis,
purpura, ulcers, and gangrene, which are sometimes
precipitated by cold exposure. Extracutaneous fea-
tures are much less common and include arthralgias,
renal disease, and peripheral neuropathy.
In the mixed cryoglobulinemias, characteristic
features are purpura, weakness, and arthralgias
(also known as the Melzer triad). Purpura is present
in most patients and may be preceded by a burning or
itchingsensation, most oftenonthelower extremities.
The purpura may have an erythematous and papular
J AM ACAD DERMATOL
JANUARY 2009
14 Hirschmann and Raugi
component, reecting the presence of leukocytoclas-
tic vasculitis or nonvasculitic inammationcommonly
seen in skin biopsies.
143
Showers of purpura lasting
for 1 to 2 weeks may occur once or twice a month,
witha minority of attacks provokedby coldexposure.
Postinflammatory sequelae include hyperpigmenta-
tion, especially on the legs; ulcers, which character-
istically appear above the malleoli; hemorrhagic
crusts; and scarring.
140,143
Raynaud phenomenon is
common and may lead to digital necrosis. Livedo
reticularis may also occur. Bullous or vesicular lesions
are unusual.
Blue toes, which may be the major dermatologic
nding of cryoglobulinemia,
144
can develop from
several mechanisms: acrocyanosis caused by vaso-
constriction, vascular thrombosis, purpura from vas-
culitis or nonvasculitic inflammation, and ischemia.
About 20% to 30% of patients with mixed cryo-
globulinemia have renal involvement, but it usually
follows the onset of purpura by about 4 years.
139
The
major manifestations are proteinuria, sometimes
leading to nephrotic syndrome, hematuria, and acute
nephritic syndrome (hematuria, proteinuria, and
rapid deterioration in renal function). The most
common histologic pattern, present in about 80%
of cases, is type I membranoproliferative glomeru-
lonephritis. Most of the remaining patients have mild
mesangial proliferative glomerulonephropathy.
139
Peripheral neuropathy occurs in about 20% to 60%
of patients and usually begins with symmetric or
asymmetric sensory ndings, including numbness
and painful paresthesias in the distal extremities.
Later, motor involvement may develop. Mononeuritis
(mononeuropathy) multiplex, the discrete involve-
ment of two or more individual nerves, can also occur.
Other common ndings include hepatomegaly,
splenomegaly, and increased liver enzymes. Many
patients have arthralgias, which usually involve the
small distal joints symmetrically and may follow cold
exposure. Frank arthritis, however, is rare.
Cold agglutinins
Cold agglutinins are immunoglobulins, usually
IgM, that agglutinate erythrocytes at temperatures
below 378C. They can be present in healthy people,
but with titers less than 1:64 at 48C and no activity at
higher temperatures. Pathologic cold agglutinins
occur in high titers at 48C and frequently react at
288C to 318C.
145
In primary cold agglutinin disease, in which no
other systemic disease is present, the responsible
immunoglobulins are usually monoclonal IgMk par-
aproteins, and the disease is typically a chronic, low-
grade lymphoproliferative disorder occurring in
older adults. Transformation to a clinically overt B-
cell lymphoma is rare. In secondary cold agglutinin
disease, the associated illness is usually an infection,
especially from Mycoplasma pneumoniae or
EpsteineBarr virus (infectious mononucleosis) in
children or young adults, and the IgM antibodies
are polyclonal. The IgM in either situation fixes
serum complement to the red cell surface, causing
hemolysis when the mononuclear phagocytic system
destroys the erythrocytes, mostly in the liver. The
IgM is usually directed against the I antigen on the
red cell surface with chronic cold agglutinin disease
and against the i antigen with the acute, self-limited,
postinfectious disorder. In addition to markedly
elevated cold agglutinin titers, the laboratory find-
ings include increased serum lactate dehydrogenase,
elevated indirect bilirubin, and a positive Coombs
test when employing polyspecific and anticomple-
ment antisera, but usually negative with anti-IgG.
In patients with chronic cold agglutinin disease,
cold-induced circulatory symptoms are common,
primarily acrocyanosis or Raynaud phenomenon,
which are often precipitated by even very slight cold
exposure.
145,146
Rarely, gangrene can occur.
147
EVALUATING PATIENTS WITH THE BLUE
TOE SYNDROME
History
A critical component in determining the cause of
BTS is a thorough history, which should particularly
elicit informationabout several issues whosepresence
suggests certain specic diagnoses (listed in paren-
theses): (1) cold-induced skin lesions (perniosis, cry-
oglobulinemia, cryobrinogenemia, cold agglutinin
disease, and acrocyanosis); (2) a recent invasive pro-
cedure involving the heart or a peripheral arterial
vessel (atheroembolism); (3) the recent initiation of
warfarin (atheroembolism and warfarin skin necro-
sis); (4) previous arterial or venous thromboses and/or
pregnancy morbidity (antiphospholipid syndrome);
(5) neurologic symptoms involving the brain (myx-
oma, aortic tumor, infective endocarditis, nonbacterial
thrombotic endocarditis, antiphospholipid syndrome,
TTP, hyperviscosity syndrome, essential thrombocy-
themia, polycythemia vera, and DIC); and (6) the
presence of malignancy (nonbacterial thrombotic en-
docarditis, paraneoplastic acral vascular syndrome,
phlegmasia cerulea dolens, hyperviscosity syndrome,
cryoglobulinemia, cryobrinogenemia, and DIC).
Physical examination
As with the history, the physical examination
should be meticulous and specically seek the follow-
ing ndings, whose presence suggests certain condi-
tions (listed in parentheses): (1) fever (atheroemboli,
infective endocarditis, myxoma, TTP, and DIC); (2)
J AM ACAD DERMATOL
VOLUME 60, NUMBER 1
Hirschmann and Raugi 15
cardiac murmur (infective endocarditis and atrial
myxoma); (3) livedo reticularis (atheroemboli, myx-
oma, antiphospholipid syndrome, hyperviscosity
syndrome, cryobrinogenemia, cryoglobulinemia,
and calcic vasculopathy); (4) extensive edema in
the ipsilateral leg (phlegmasia cerulea dolens); (5)
retinal examination demonstrating Hollenhorst
plaques (atheroemboli); and (6) a retinal examination
revealing dilated veins, hemorrhages, and exudates
(hyperviscosity syndrome).
Laboratory and imaging studies
Table II summarizes the pertinent laboratory and
imaging studies for evaluating BTS. One of the most
rewarding investigations is a complete blood count
with white cell differential and a peripheral blood
smear. Certain findings suggest various diagnoses
(listed in parentheses): (1) erythrocytosis (polycythe-
mia vera); (2) thrombocytosis (essential thrombocy-
themia); (3) thrombocytopenia (antiphospholipid
syndrome, TTP, and DIC); (4) eosinophilia (athe-
roemboli); (5) rouleaux on the blood smear (multiple
myeloma causing cryoglobulinemia, and Walden-
strom macroglobulinemia causing hyperviscosity or
hyperviscosity from other causes); (6) red cell agglu-
tination on the blood smear (increased IgMassociated
with cold agglutinin disease, and Waldenstrom mac-
roglobulinemia causing hyperviscosity or cryoglobu-
linemia); and (7) schistocytes, polychromatophilia,
and nucleated red cells on the blood smear (TTP and
DIC).
Abnormal renal function tests and urinalyses
commonly occur with cholesterol emboli, cryoglob-
ulinemia, calcic vasculopathy, TTP, and DIC. Liver
tests are frequently abnormal in cryoglobulinemia,
atheroemboli, DIC, and catastrophic antiphospholi-
pid syndrome. Specic tests are required to detect
cryobrinogenemia, cryoglobulinemia, and cold ag-
glutinin disease. Laboratory conrmation of para-
proteinemia generally depends upon serum and
urine protein electrophoresis and immunoxation.
Imaging techniques that may be productive in-
clude a chest radiograph to seek an underlying lung
cancer in malignancy-associated conditions, venous
duplex to detect deep venous thrombosis in phleg-
masia cerulea dolens or antiphospholipid syndrome,
computed tomographic angiogram to discover an
aortic tumor or the source of atheromatous emboli,
and echocardiogram to reveal cardiac tumors or
vegetations from endocarditis. Thoracic and abdom-
inal computed tomographic scans may be useful in
detecting a suspected malignancy.
Skin biopsies are often nonspecic, but they are
especially helpful in atheroemboli, myxoma, aortic
malignancy, calcic vasculopathy, and vasculitis
from cryoglobulinemia, Behcet disease, or syphilis.
CONCLUSIONS
BTS consists of the presence of blue or purplish
toes in the absence of a history of trauma, serious
cold exposure, or disorders producing generalized
cyanosis. The diverse causes can be divided into the
following categories: (1) decreased arterial ow, (2)
impaired venous outow, and (3) abnormal circu-
lating blood. Careful history, a thorough physical
examination, and a thoughtful laboratory evaluation
should reveal the diagnosis.
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