Curr Derm Rep (2017) 6:55–62

DOI 10.1007/s13671-017-0184-7

HOSPITAL-BASED DERMATOLOGY (D KROSHINSKY, SECTION EDITOR)

Updates in the Approach to the Patient with Purpura

Ryan Arakaki 1 & Lindy Fox 1

Published online: 15 May 2017

# Springer Science+Business Media New York 2017

Abstract Keywords Purpura . Cutaneous morphology . Clinical

Purpose of Review This review aims to provide an updated approach . Workup . Vasculitis . Vasculopathy
clinical framework for how to approach the patient with a
purpuric eruption. The approach outlined within is focused
on the identification of the primary cutaneous morphology Introduction
from which one can then generate a focused differential diag-
nosis and initiate an appropriate workup. The approach to the patient with purpura is primarily driven by
Recent Findings The primary morphologies of purpura in- the identification and classification of the cutaneous morpholog-
clude petechiae, macular purpura, palpable purpura, and ic findings [1]. Once the primary morphology has been identi-
retiform purpura. Each of these morphologies is associated fied, a hypothesis regarding the underlying pathophysiology
with a specific underlying pathophysiology. Identifying the accounting for the clinical presentation and a differential diag-
morphology and pathophysiology that is present is especially nosis can be generated. Using the primary morphology to guide
important in purpuric eruptions as they may be associated with the differential helps to provide the clinician with a systematic
underlying systemic illness such as malignancy, infection, method of evaluating the patient who presents with purpura. The
vasculitis, or autoimmune disease. goal of this paper is to outline the approach to the evaluation of
Summary The approach to purpura starts with identifying the purpura when purpura is the primary morphologic finding.
suspected primary cutaneous morphology. This allows the cli- The primary cutaneous morphologies of purpura that can be
nician to generate a hypothesis regarding the pathophysiology observed include petechiae, macular purpura, palpable purpura,
causing a patient’s eruption. Based on the pathophysiology and retiform purpura. Each of these findings implies a specific
that is suspected, a differential diagnosis can be generated pathophysiology as the cause of purpura and a more focused
and an appropriate workup can be initiated. This is especially differential diagnosis can then be generated. Depending on the
important in purpuric eruptions as they can be a manifestation ultimate diagnosis, there may at times be multiple morphol-
of many types of internal diseases. ogies present at one time. This is typically seen in eruptions
that have palpable purpura “plus” an additional morphology.
While this morphologic-based approach provides the clinician
This article is part of the Topical Collection on Hospital-based with a systematic method of evaluation, it can have limitations
Dermatology
as not all processes will strictly adhere to these patterns, espe-
cially infections in immunocompromised patients.
* Lindy Fox
Lindy.Fox@ucsf.edu
Ryan Arakaki
Ryan.Arakaki@ucsf.edu
Petechiae (Fig. 1)

1
Department of Dermatology, University of California—San
Petechiae are defined as non-blanching purpuric small mac-
Francisco, 1701 Divisadero, 4th Floor, San Francisco, CA 94115, ules, usually 4 mm or less in diameter [2]. The underlying
USA causes of petechiae can be divided into conditions related to
56 Curr Derm Rep (2017) 6:55–62

coagulation studies. Further studies should be sent depending

on the clinical scenario. If a disorder of platelet function is
under consideration, further workup with platelet function
testing should be performed. This may include evaluation of
a peripheral blood smear as well as more specific testing such
as a platelet function assay. Although traditionally a bleeding
time was the test of choice, technical factors lead to wide
variability in results; thus, the platelet function analyzer
(PFA-100) is preferred as it has greater sensitivity and repro-
ducibility than the bleeding time test [5]. It is recommended
that workup for a platelet function disorder be performed with
assistance from hematology to ensure that the proper testing is
performed and interpreted correctly. While not always re-
quired, if a biopsy is performed, it should be taken from a
Fig. 1 Petechiae. Credit to the UCSF Dermatology Department teaching discrete individual lesion.
files

Macular Purpura (Fig. 2)

platelet anomalies versus those that are not. When considering
platelet-related causes, etiologies are related to either low
Macular purpura is defined as purpuric macules or patches
platelet number or abnormal platelet function. There are many
larger than petechiae, usually 5 mm or more [2]. In many
potential causes of thrombocytopenia including malignancy,
ways, the causes of macular purpura overlap significantly with
autoimmune disease, medications, and liver disease (Table 1).
those of petechiae. Many of the causes of macular purpura
Petechiae may also occur when platelet levels are normal but
involve multiple factors occurring at once. Examples include
functioning abnormally. This can be a result of renal disease,
trauma, infection, or inflammation occurring in a patient with
medications, hypocoagulable states (often medication-in-
underlying abnormal coagulation due to low or dysfunctional
duced), or by inherited causes of abnormal platelet function.
platelets. Tissue fragility can also be a factor (Table 3). Other
There are numerous causes of non-platelet-related petechi-
causes include leukocytoclastic vasculitis and emboli to the
ae. In terms of categories, one can consider diseases that lead
skin. Biopsy should be performed from the center of an in-
to tissue fragility such as scurvy, actinic damage, amyloidosis,
volved area in most cases, such as in a febrile or systemically
steroid (topical or systemic)-induced atrophy, and inherited
unwell patient. Biopsy for culture should also be also be con-
diseases such as Ehlers–Danlos syndrome. Petechiae may also
sidered if an infectious process is suspected.
be a result of trauma or increased pressure (e.g., valsalva). In
addition, early leukocytoclastic vasculitis and some infections
(e.g., Rocky Mountain spotted fever, parvovirus, and Epstein–
Barr virus) may result in petechiae (Table 2) [3, 4]. Palpable Purpura (Fig. 3)
Evaluation of a patient with petechiae should include re-
view of pertinent medical history and medication exposures. Palpable purpura is defined as round non-blanching papules,
Laboratory evaluation should start by obtaining a platelet lev- usually with a component of erythema [2]. When it is a pri-
el, assessing kidney and liver function, and checking mary process, this finding is most commonly due to cutaneous

Table 1 Platelet-related causes

of petechiae Thrombocytopenia Abnormal platelet function

•Idiopathic thrombocytopenic purpura •Congenital/hereditary defects

•Leukemia/bone marrow failure •Medications (aspirin, NSAIDs)
•Heparin-induced thrombocytopenia •Thrombocytosis
•Thrombotic thrombocytopenic purpura •Renal insufficiency
•Hemolytic uremic syndrome
•Disseminated intravascular coagulation
•Medication-induced
•Cirrhosis
Curr Derm Rep (2017) 6:55–62 57

Table 2 Non-platelet-related causes of petechiae Table 3 Macular purpura

•Valsalva (retching, childbirth) •Thrombocytopenia + infection/inflammation/trauma

•Trauma •Abnormal platelet function + infection/inflammation/trauma
•Scurvy •Infection
•Actinic damage •Abnormal coagulation + trauma
•Amyloid Disseminated intravascular coagulation
Renal or hepatic dysfunction
•Steroid (topical or systemic)-induced atrophy
Anticoagulant medications
•Fragility syndromes (such as Ehlers–Danlos) Vitamin K deficiency
•Hypergammaglobulinemic purpura of Waldenström •Poor dermal support + trauma
•Infection Actinic damage
Early Rocky Mountain spotted fever Amyloid
Parvovirus Steroid atrophy
Epstein–Barr virus Fragility syndromes
•Early leukocytoclastic vasculitis Trauma
Scurvy
•Pigmented purpuric dermatosis
•Other
•Graft-versus-host disease Leukocytoclastic vasculitis
Hypergammaglobulinemic purpura of Waldenström
Emboli
small vessel vasculitis with histopathologic findings of Contact dermatitis
leukocytoclasia. Also to include in the differential diagnosis
are conditions that predispose to bleeding in the setting of a
primary papular process (e.g., bleeding into a morbilliform group of antineutrophil cytoplasmic autoantibody (ANCA)
eruption in a patient who has both thrombocytopenia and a vasculitides, microscopic polyangiitis, granulomatosis with
morbilliform drug eruption). There is also a shorter list of polyangiitis, and eosinophilic granulomatosis with polyangii-
conditions that are not due to vasculitis but where the primary tis. In these diseases, ANCAs bind to activated neutrophils
lesion is a purpuric papule (Table 4). and the ANCA-bound neutrophils mediate direct blood vessel
The underlying pathology of vasculitis in the skin can be damage [2]. Other diseases in the category of pauci-immune
divided into immune complex-related vasculitis versus pauci- vasculitis include levamisole-associated purpura, which at
immune complex vasculitis (Table 4). Most types of cutane- least in part is thought to be due to ANCA positivity induced
ous vasculitis are immune complex mediated, which, although by levamisole exposure [8•]. Rarely, leukemia cutis may pres-
most often idiopathic (45–55% of cases), may be due to un- ent as a vasculitis, presenting with palpable purpura [9]. In
derlying causes including infections (15–20%), inflammatory some cases of Sweet’s syndrome, the neutrophilic infiltrate
diseases (15–20%), medications (10–15%), and malignancy in the dermis is so intense that vessel damage indistinguish-
(<5%) [7]. able from vasculitis may occur [10].
Pauci-immune vasculitis is defined as vasculitis not medi- When evaluating a patient with palpable purpura, a skin
ated via immune complexes. The prototypic example is the biopsy can be used to help confirm a vasculitis as the under-
lying etiology of a patient’s cutaneous findings. As

Fig. 2 Macular purpura due to prednisone, actinic damage, and trauma

(compression device) in a heart transplant patient Fig. 3 Palpable purpura of leukocytoclastic vasculitis
58 Curr Derm Rep (2017) 6:55–62

Table 4 Palpable purpura [12]. In patients who have accompanying fever, blood cultures
Immune complex vasculitis and an echocardiogram should be considered.
•Idiopathic (45–55%), infection (15–20%), inflammatory diseases As mentioned above, DIF testing is suggested for patients
(15–20%), drug (10–15%), malignancy (5%) presenting with palpable purpura. While non-specific findings
•IgA vasculitis, Henoch–Schönlein purpura such as Complement 3 and IgM may be found in cases of
•Urticarial vasculitis leukocytoclastic vasculitis, the presence of IgA deposition may
•Hypergammaglobulinemic purpura of Waldenström also be found. It is well described that IgA deposition can be
•Bowel-bypass syndrome seen on DIF in the setting of leukocytoclastic vasculitis (LCV)
•Mixed cryoglobulinemia not associated with a specific disease. In cases of LCV, a range
•Connective tissue disease of 31–49% of patients have been shown to have IgA deposition
•Behcet’s disease on DIF [13–15]; however, perivascular IgA deposition is typi-
•Serum sickness cally present in both Henoch–Schönlein purpura (HSP) and
adult-onset IgA vasculitis (adult HSP). In a small retrospective
Pauci-immune complex vasculitis study of 32 patients with adult HSP, DIF was demonstrated to
•ANCA-associated vasculitides have a sensitivity of 81% and specificity of 83% [16•].
Granulomatosis with polyangiitis In the correct clinical setting, the presence of IgA deposi-
Eosinophilic granulomatosis with polyangitis tion in adult patients is a significant finding as IgA vasculitis
Microscopic polyangiitis
has important clinical and prognostic significance. IgA vascu-
•Levamisole vasculitis (can also be a vasculopathy)
•Sweet’s syndrome
litis in adults, especially older adult males, is associated with
•Leukemic vasculitis long-term renal complications and the potential for underlying
malignancies [17]. When malignancy occurs, it is more likely
Palpable purpura (not vasculitis) to be a solid tumor malignancy than a hematologic malignan-
•Papular and purpuric eruption due to cytarabine cy. Of the cases of IgA vasculitis reported in association with a
•Parvovirus B-19 infection (follicular and purpuric papules, papular malignancy, 61% are associated with a solid organ tumor, with
and purpuric gloves and socks) [6]
non-small cell lung cancer and prostate cancer being the most
frequently reported malignancies [17]. Of the hematologic
malignancies, myeloma is most commonly associated follow-
ed by non-Hodgkin’s and Hodgkin’s lymphoma. IgA vasculi-
histopathologic confirmation of leukocytoclastic vasculitis tis in adults is also associated with a more severe course than
does not reveal the etiology of the clinical presentation, addi- what is observed in children, with an increase in joint symp-
tional testing is recommended to determine the underlying toms, more severe acute renal disease, more severe chronic
cause of vasculitis. Sending a biopsy for direct immunofluo- renal disease (30% of cases), and increased risk of end-stage
rescence (DIF) testing can be helpful in confirming the diag- renal disease [18].
nosis of leukocytoclastic vasculitis and is most important for
identifying the presence of IgA deposition (see below).
Biopsy should be performed of an individual lesion that is Palpable Purpura Found Concomitantly with Other
ideally less than 48 h old as this is when immunoglobulin Morphologies
deposition will be highest [11].
Laboratory testing varies depending on the clinical scenar- Palpable purpura in the presence of other morphologies asso-
io given the numerous possible causes of vasculitis. That said, ciated with vasculitis, specifically nodules, ulcers, livedo
most hospitalized patients with vasculitis are extremely ill and racemosa, and retiform purpura, clues the clinician to the size
have complex medical conditions, justifying a very thorough of the vessels involved and helps to narrow the differential
evaluation for all potential etiologies. General labs that are diagnosis. Palpable purpura is considered a sign of vasculitis
typically checked in the setting of a small vessel vasculitis involving small blood vessels in the skin. The presence of
include a complete blood count, urinalysis with microscopy, palpable purpura in addition to findings such as dermal or
and assessment of renal function. Additional laboratory tests subcutaneous nodules, ulcerations, livedo racemosa, and/or
looking for specific underlying causes including antinuclear retiform purpura indicates involvement of larger medium-
antibody (ANA), ANCA, serum protein electrophoresis, hep- sized blood vessels [2]. The differential of processes that in-
atitis B & C serologies, blood cultures, antistreptolysin O, volve both small- and medium-sized vessels is more limited
urine toxicology screen, rheumatoid factor, and cryoglobulins and includes septic vasculitis, ANCA-associated vasculitis,
should be performed. Of note when testing for cryoglobulins, mixed cryoglobulinemia, IgA vasculitis, vasculitis associated
it is useful to order a rheumatoid factor as it has a sensitivity of with connective tissue disease, levamisole-associated vasculi-
approximately 70% in patients with mixed cryoglobulinemia tis, and leukemic vasculitis (Table 5).
Curr Derm Rep (2017) 6:55–62 59

Table 5 Palpable purpura in addition to other cutaneous findings infiltration and obstruction of blood vessels, their presentation
(nodules, ulcers, livedo racemosa, and retiform purpura)
can be varied and may present with multiple primary
•Septic vasculitis morphologies.
•ANCA-associated vasculitis Diseases that lead to intravascular occlusion can be either
•Mixed cryoglobulinemia thrombotic or embolic in nature. When embolic, the clinic
•IgA vasculitis presentation typically includes fewer lesions with an acral or
•Connective tissue disease-associated vasculitis distal predominance. Clinical history of a recent procedure
•Leukemic vasculitis may also be helpful in suggesting emboli as an etiology.
There are multiple types of emboli that can be considered,
and their likelihood will depend on the clinical context. In
Retiform Purpura (Fig. 4) terms of thrombotic causes of retiform purpura, the broad
categories of diseases that can be considered include coagula-
Retiform purpura is defined as purpura in the skin in a tion disorders, vasculopathies, platelet plugging, cold-related
branching or net-like pattern that is due to alteration in blood diseases such as cryoglobulinemia, and diseases of red cell
flow through the dermal and subcutaneous vasculature. This occlusion (Table 7).
finding can occur in a range of vessel size from millimeters to Given the numerous causes of retiform purpura and the
several centimeters. Once this morphology is observed, a cli- severity of the diseases that lead to this finding, workup should
nician must then evaluate for the presence of erythema. generally include skin biopsy. This should include sending
Prominent early erythema, i.e., so-called “inflammatory tissue for hematoxylin and eosin (H&E) as well as for tissue
retiform purpura”, suggests an infectious or inflammatory dis- culture. It is recommended that biopsies should be taken from
order [2]. The presence of minimal erythema is more sugges- both the edge of an individual lesion and the purpuric center
tive of an occlusive disorder. The classic teaching is that pur- [19]. In the case of livedo racemosa, it is ideal to sample both a
pura or necrosis should account for greater than two thirds of a purpuric portion and a white portion when possible. This can
lesion in occlusion syndromes as opposed to infectious or be accomplished via a large wedge biopsy or two 4 or 5 mm
inflammatory disorders, where lesions will have a larger ery- biopsies that sample each morphology. A general laboratory
thematous component. Presence of fever also favors infectious
or inflammatory causes. Table 6 Retiform purpura—infiltration in blood vessel wall
Causes of retiform purpura can be divided into diseases that
affect the blood vessel wall versus those that are intravascular Infection
in nature. Diseases that affect the blood vessel wall include •Bacterial
Meningococcemia
infections, vasculitis, and deposition diseases (Table 6). Gonococcemia
Patients with an infectious cause can have overlapping fea- Staphylococcus
tures as they may have a vasculitis affecting the small and/or E. coli
medium vessels in addition to thrombosis from the infectious Klebsiella
Pseudomonas
organism causing obstruction. As infections can cause both
•Fungal
Mucor/Rhizopus
Aspergillus
Candida
Fusarium
•Other
Strongyloidiasis
Lucio’s (leprosy)
Vasculitis
•IgA vasculitis
•Connective tissue disease vasculitis
•Mixed cryoglobulinemia
•Microscopic polyangiitis
•Granulomatosis with polyangiitis
•Eosinophilic granulomatosis with polyangiitis
•Polyarteritis nodosa
•Septic vasculitis
•Levamisole
Depositional
•Calciphylaxis
Fig. 4 Retiform purpura in the setting of antiphospholipid antibody •Oxalosis
syndrome
60 Curr Derm Rep (2017) 6:55–62

Table 7 Retiform purpura—intravascular Regarding other entities in the differential diagnosis, a blood
Embolic smear can assess for microangiopathy and elevated calcium
•Atrial myxoma and phosphate or parathyroid hormone levels. In addition,
•Cardiac
renal dysfunction or surrounding subcutaneous induration
•Marantic endocarditis
may be suggestive of calciphylaxis.
•Septic endocarditis
•Cholesterol
•Libman–Sacks endocarditis
Purpura as a Sign of Systemic Infection
•Air
When evaluating a patient with a purpuric morphology, care-
Thrombotic
ful consideration should be given to the possibility of an in-
•Abnormal coagulation
fectious etiology as infections may affect the skin through
Protein C, S deficiency
multiple types of pathophysiology including vasculitis with-
Antiphospholipid antibody syndrome
out organisms present, septic emboli, and localized small ves-
Coumadin necrosis
sel thrombosis. This variability in pathophysiology is
Purpura fulminans
highlighted by the cutaneous findings seen in patients with
•Thrombotic vasculopathy
endocarditis. Traditionally, a clinical distinction is made be-
Livedoid vasculopathy
tween Osler’s nodes, which are painful, and Janeway lesions,
Sneddon’s syndrome
which are painless. Despite the supposed differences between
Malignant atrophic papulosis
these clinical findings, on biopsy in some patients they have
Thromboangiitis obliterans both been shown to stain positive for microorganisms as well
•Phlegmasia as to demonstrate findings of vasculitis [21–23]. In the setting
•Calciphylaxis of systemic bacterial infection and cutaneous purpuric lesions,
•Platelet plugging the histopathologic findings and ability to detect an organism
Heparin-induced thrombocytopenia are thought to depend more on the virulence of the infectious
Thrombotic thrombocytopenia purpura, hemolytic uremic syndrome organism involved rather than whether or not a patient clini-
Paroxysmal nocturnal hemoglobinuria cally has an Osler node or Janeway lesion. More virulent
Essential thrombocythemia, polycythemia vera infections such as Staphylococcus aureus in acute endocardi-
Hyperviscosity tis tend to cause skin lesions that will stain positive for organ-
•Cold-related isms or grow organisms on skin biopsy for culture. Less vir-
•Red cell occlusion ulent organisms, for example those seen in the setting of sub-
Sickle cell disease acute endocarditis such as Viridans Streptococci, tend to lead
Hemolytic anemia to findings of leukocytoclastic vasculitis without identification
of an underlying organism in the skin (although blood cultures
and echocardiogram might be diagnostic). Given that in the
workup may include many of the same tests that are sent when setting of acute infections associated with purpuric skin le-
evaluating palpable purpura in a patient with suspected vascu- sions it may be possible to find microorganisms in the skin,
litis, including complete blood count with differential, urinal- we recommend sending biopsy specimens for both H&E sec-
ysis with microscopy, renal function, toxicology screen, ANA, tions as well as for tissue culture in all patients presenting with
ANCA, rheumatoid factor, cryoglobulins, hepatitis serologies, palpable and/or retiform purpura, as this is a clinical scenario
and antistreptolysin O [19]. Evaluation of retiform purpura where the morphology cannot reliably help to distinguish be-
differs in that the differential also includes microvascular oc- tween the different possible pathophysiologies.
clusion syndromes, emboli, and hypercoagulable disorders.
Given this expanded differential, a workup should include co-
agulation studies, blood cultures, blood smear, as well as cal- Conclusions
cium and phosphate levels.
Special considerations in the laboratory workup of retiform We have attempted to outline a systematic approach to
purpura include assessing for the presence of eosinophilia evaluating a patient with purpura that is driven by a pa-
which may be seen both in eosinophilic granulomatosis with tient’s primary cutaneous morphology (Fig. 5). This article
polyangiitis and in the setting of cholesterol emboli. Some was not meant to exhaustively list every diagnostic possi-
studies report up to 80% of patients with cholesterol emboli bility, but rather to provide clinicians with guidance for
will have a transient eosinophilia, thus this can be an impor- how they can appropriately use the tests at their disposal
tant laboratory marker in a post-procedural setting [20]. to workup patients with purpuric eruptions. It is important
Curr Derm Rep (2017) 6:55–62 61

Fig. 5 Overview of the approach to the patient with purpura in the hospital setting

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Conflict of Interest The authors declare that they have no conflict of antineutrophil cytoplasmic antibodies associated with levamisole
interest. adulterated cocaine. Arthritis & Rheumatism. 2011;63(12):3998–
4001. This study noted the presence of antineutrophil cytoplas-
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Human and Animal Rights and Informed Consent This article does used levamisole-adultered cocaine.
not contain any studies with human or animal subjects performed by any
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