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REVIEWS

FB 930.1309

The skin and hypercoagulable states


Laura A. Thornsberry, MD, Kristen I. LoSicco, MD, and Joseph C. English III, MD
Pittsburgh, Pennsylvania
Hypercoagulable states (HS) are inherited or acquired conditions that predispose an individual to venous
and/or arterial thrombosis. The dermatologist can play a vital role in diagnosing a patients HS by
recognizing the associated cutaneous manifestations, such as purpura, purpura fulminans, livedo
reticularis, livedo vasculopathy (atrophie blanche), anetoderma, chronic venous ulcers, and superficial
venous thrombosis. The cutaneous manifestations of HS are generally nonspecific, but identification of an
abnormal finding can warrant a further workup for an underlying thrombophilic disorder. This review will
focus on the basic science of hemostasis, the evaluation of HS, the skin manifestations associated with
hypercoagulability, and the use of antiplatelet and anticoagulant therapy in dermatology. ( J Am Acad
Dermatol 2013;69:450-62.)
Key words: anetoderma; antiphospholipid antibody syndrome; chronic venous ulcer; hemostasis;
hypercoagulable states; livedo reticularis; livedo vasculopathy; purpura; superficial venous thrombosis;
thrombosis.

HEMOSTASIS

Abbreviations used:

Hemostasis is the physiologic response that minimizes blood loss while maintaining blood flow after an
injury to a vessel. Endothelial injury triggers immediate
vasoconstriction and exposes tissue factor (TF) and
collagen in the subendothelial matrix, providing a
surface for platelet adherence and plug formation.
Traditionally, coagulation has been described as a
cascade of enzyme reactions, consisting of the extrinsic and intrinsic pathways converging on the common
pathway to produce an insoluble fibrin clot.1-3
Although the extrinsic and intrinsic pathways correlate
with the laboratory values of prothrombin time and
partial thromboplastin time, respectively, this model
has shortcomings and fails to describe the importance
of cells during the coagulation process.3 Thus, a cellbased model of coagulation has been proposed,
which consists of 3 phases: initiation, amplification,
and propagation (Fig 1), and results in platelet activation and fibrin clot production.3 TF, a cell membrane
glycoprotein, is responsible for the initiation of coagulation, which occurs on the surface of a TF-bearing
cell and results in the production of small amounts of
thrombin (activated [a] factor [F] II).3 During amplification, thrombin generated in the initiation phase
activates factors V, VIII, and XI on the negatively
charged phospholipid surface of a platelet leading to
platelet activation.3 Finally, in the propagation phase,

Venous and arterial thromboses are major causes of


morbidity and mortality. Venous thromboembolism
(VTE) includes deep venous thrombosis (DVT) and
pulmonary embolism (PE). Hypercoagulability, in
addition to stasis (slow flow) and endothelial injury,

From the Department of Dermatology, University of Pittsburgh.


Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication January 25, 2013.
Reprint requests: Joseph C. English III, MD, Department of
Dermatology, University of Pittsburgh, 200 Lothrop St, Presby

South Tower, Suite 3880, Pittsburgh, PA 15213. E-mail:


englishjc@upmc.edu.
Published online April 11, 2013.
0190-9622/$36.00
2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.01.043

450

APC:
APLA:
APLS:
CVU:
DIC:
DVT:
HIT:
HS:
LMWH:
LR:
LV:
PE:
PF:
SVT:
TF:
TTP:
VTE:

activated protein C
antiphospholipid antibody
antiphospholipid antibody syndrome
chronic venous ulceration
disseminated intravascular coagulation
deep venous thrombosis
heparin-induced thrombocytopenia
hypercoagulable states
low-molecular-weight heparin
livedo reticularis
livedo vasculopathy
pulmonary embolism
purpura fulminans
superficial venous thrombosis
tissue factor
thrombotic thrombocytopenic purpura
venous thromboembolism

significant amounts of thrombin are generated on the


surface of an activated platelet, resulting in the conversion of fibrinogen into insoluble fibrin.3-5

HYPERCOAGULABLE STATES

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Thornsberry, LoSicco, and English 451

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compose the Virchow triad of risk factors for venous


with their initial episode of VTE have a FV Leiden
thrombosis.6 Several components can contribute to a
mutation.8 A point mutation in the FV gene switches
thrombophilic state, including genetic and acquired
guanine (G) to adenine (A) at nucleotide 1691 and
risk factors (Table I), triggering factors, and/or a lack
codes for glutamine instead of arginine. FV is usually
of appropriate pharmacologic or nonpharmacologic
inactivated by activated protein C (APC) by cleavage
prophylaxis. Arterial thrombosis results in an ischemic
at 3 sites, however, the FV Leiden mutant is resistant
event, such as acute coronary syndrome, stroke, or
to degradation by APC.9,10 The FV Leiden mutation
accounts for over 90% of APC
limb ischemia. These events
resistance.11
are often the consequence of
CAPSULE
SUMMARY
Prothrombin
a ruptured atherosclerotic
G20210A. Prothrombin G2plaque that provides a surface
Venous and arterial thrombosis often
0210A mutation is the second
for platelet aggregation that
develop in the setting of a
7
most common primary HS,
can lead to vessel occlusion.
hypercoagulable state and cause
In these high-flow vessels,
present in approximately 5%
significant patient morbidity and
platelets are the primary meof the population, and also
mortality.
diators of thrombosis.
inherited in an autosomal
Hypercoagulable states can present with
Hypercoagulable states
dominant pattern.11 This mua wide variety of cutaneous
tation is present in approxi(HS) can be divided into primanifestations.
mately 10% of patients
mary (inherited) or secondpresenting with their initial
ary (acquired) conditions
Recognizing the cutaneous
episode of VTE.8 A mutation
(Table I) and are associated
manifestations of hypercoagulable states
at nucleotide 20210 in the
with increased risk of venous
can improve patient safety and
3-untranslated region of the
thrombosis or both venous
outcomes.
prothrombin gene causes a
and arterial thrombosis
guanine (G) to adenine (A)
(Table II). The cutaneous
substitution.12 This mutation is associated with elemanifestations of HS are generally not specific for a
vated plasma levels of prothrombin and increased
certain condition, but recognition of an abnormal
thrombin formation.13
finding can warrant a further workup for an underMethyltetrahydrofolate
reductase
and
lying thrombophilic condition or VTE.
hyperhomocysteinemia. Homocysteine is an
The evaluation of HS begins with a thorough
amino acid, with elevated serum levels leading to
history and physical examination. The dermatologist
increased risk of both venous and arterial thrombosis
can recognize cutaneous findings that are associated
through an unknown mechanism. Inherited causes
with underlying HS and perform a skin biopsy and
are secondary to mutation of the enzyme methyltetlaboratory tests to further evaluate. The preliminary
rahydrofolate reductase, or less commonly cystalaboratory tests used to evaluate for HS are listed in
thione-b-synthase; the enzyme deficiency in
Table III, and include gene mutations, antiphosphocongenital homocystinuria.11 Patients with a homolipid antibodies (APLAs), and anticoagulant activity
zygous methyltetrahydrofolate reductase mutation
levels. In addition to blood work, compression ultraare at increased risk of VTE.14 Acquired hypersonography can be used to evaluate the deep venous
homocysteinemia can be secondary to renal or
system if a patient has a suspected DVT or superficial
thyroid disease, smoking, aging, or a vitamin defivenous thrombosis (SVT). If there are symptoms to
ciency (B12, B6, or folate).
suggest PE, imaging studies such as a high-resolution
Antithrombin III. Antithrombin III deficiency
computed tomography scan of the chest with contrast
was the first primary thrombophilic state identified,
or ventilation perfusion scan may be obtained. For
inherited in an autosomal dominant pattern and
arterial thrombosis, Doppler studies, angiography, or
occurring in less than 0.02% of the population.11,15
magnetic resonance angiography can be performed.
Antithrombin III degrades thrombin (IIa) and multiple
Appropriate referral to specialists should be considother activated coagulation factors (IXa, FXa, XIa, and
ered, including the hematologist, internist, or intenXIIa), thus a deficiency leads to a thrombophilic state
sivist, depending on the clinical scenario.
because of increased levels of these activated factors.
The heterozygous deficiency can be quantitative (type
Primary HS
I) or qualitative (type II). The homozygous condition
Factor V Leiden. Factor V Leiden is the most
is usually fatal in the neonatal period. Antithrombin III
common primary HS, occurring in 5% to 15% of the
deficiency, and protein C and S deficiency, can be
population and inherited in an autosomal dominant
acquired secondary to consumption (infection, sepsis,
pattern.6 Approximately 20% of patients presenting
d

452 Thornsberry, LoSicco, and English

disseminated intravascular coagulation [DIC]), decreased production (hepatic failure), or excess loss
(nephrotic syndrome).
Protein C or protein S deficiency. Heterozygous
protein C deficiency is an autosomal dominant condition present in 0.2% of the population and heterozygous protein S deficiency is an autosomal dominant
condition present in less than 0.1% of the population.11
Homozygous protein C or protein S deficiency often
results in neonatal purpura fulminans (PF) and is
usually fatal.16 There have been numerous mutations
of the protein C gene identified. The deficiency can
either be quantitative (type I) or qualitative (type II).
APC, in conjunction with its cofactor, protein S, inactivates FVa and FVIIIa, thus protein C or protein S
deficiency leads to unbalanced activation of these
factors and increased production of thrombin.9 Protein
C or protein S deficiency can also be acquired
secondary to consumption, decreased production, or
excess loss, by similar mechanisms as acquired antithrombin III deficiency.
Secondary HS
Hospitalization, trauma, and surgery. Hospitalization is a risk factor for VTE, likely as a result of
immobilization, with the severity of the illness also
contributing to the risk.17 Patients admitted with major
trauma are at an exceptionally high risk of DVT. A
prospective study of 349 patients with major trauma
identified at least 1 DVT present in 58% of the
patients.18 Patients undergoing surgical procedures
are also at increased risk of VTE, with numerous
associated risk factors, including patient age, a history
of VTE, the type and duration of the surgery, and
comorbid conditions.
Obesity. The cause of venous and arterial hypercoagulability in obese patients is multifactorial.19,20
Increased levels of fibrinogen, FVII, FVIII, von
Willebrand factor, and plasminogen activator inhibitor have been described, however the exact mechanisms predisposing to thrombosis are unclear.19
The body mass index (kg/m2) correlates with risk of
VTE, and increased fat deposition around the abdomen and upper body is associated with arterial
thrombosis.21 In addition, elevated levels of leptin,
a hormone produced by adipocytes, has been shown
to increase the risk of arterial thrombosis.22
Cancer. Patients with cancer are at a higher risk
of VTE and arterial thrombosis, with venous thrombosis as the second leading cause of mortality.23
Venous or arterial thrombosis occurs in 15% to 20%
of patients with cancer.24 The risk of thrombosis is
related to the actual disease and to the associated
treatments and procedures. Elevated levels of fibrinogen, FV, FVIII, FIX, FX, fibrin degradation products,

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and platelets have been reported with malignancy.25


In addition, TF is expressed at higher levels on the
surfaces of tumor cells.26 Surgery, chemotherapy,
indwelling catheters, immobilization, and infections
are other common risk factors leading to an increased risk of thrombosis in patients with cancer.27,28 The most common malignancies associated
with thrombosis include pancreas, stomach, uterus,
kidney, lung, and primary brain tumors.29 Stomach
and pancreas cancer are at very high risk for chemotherapy-associated VTE.29
Medications. Medications can be associated
with HS. Hormonal medications, including oral
contraceptive pills, estrogen replacement therapy,
and selective estrogen receptor modulations are
associated with increased risk of thrombosis.
Chemotherapeutic agents, including bevacizumab,
thalidomide, lenalidomide, cyclophosphamide,
chlorambucil, and nitrogen mustard contribute to
hypercoagulability in patients with cancer.
Commonly used anticoagulants, including heparin
and warfarin, can paradoxically be associated with
thrombosis, as discussed later.
Pregnancy. Women are at an increased risk of
VTE during pregnancy and the postpartum period,
with VTE occurring in 0.5 to 2.2 of 1000 pregnancies.30,31 Women are at the highest risk of DVT
during the third trimester, whereas the risk of PE is
highest during the postpartum period.31 There are
several mechanisms contributing to hypercoagulability in pregnancy, including venous stasis, alterations in coagulation factors, and damage to the
venous system.32 During pregnancy, there is increased production of thrombin33 and increased
levels of factors VII, VIII, and X; fibrinogen; and von
Willebrand factor.32 In addition, there are decreased
levels of protein S and resistance to APC.31 Pregnant
women should be assessed for thrombophilic risk
factors, especially a history of VTE, with lowmolecular-weight heparin (LMWH) as the treatment
of choice if prophylaxis or treatment of VTE if
indicated.32

SKIN MANIFESTATIONS AND


SYNDROMES
Purpura and associated conditions
Purpura. Purpura consists of 5- to 20-mm nonblanching erythematous to violaceous macules, often located on the lower extremities. Many HS
produce noninflammatory purpura with microvascular occlusion (Fig 2, A) and the associated conditions include: PF, thrombotic thrombocytopenic
purpura (TTP), warfarin (Coumadin) necrosis,
heparin-induced thrombotic thrombocytopenia, calciphylaxis, and catastrophic APLA syndrome (APLS).

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Thornsberry, LoSicco, and English 453

Fig 1. Simplified cell-based model of coagulation. A, Initiation and amplification. On surface


of tissue factor (TF )-bearing cell, such as fibroblast, TF complexes with activated factor VII
(FVIIa) to activate FIX and FX, ultimately resulting in thrombin (FIIa) generation via FVa and
FXa prothrombinase complex.3,4 Amplification occurs on platelet, and thrombin formed during
initiation phase activates FV, FVIII, and FXI, leading to activated platelet. B, Propagation.
During propagation, significant amounts of thrombin are formed on surface of activated
platelet via prothrombinase complex and tenase complex (FIXa and FVIIIa).5 Thrombin
cleaves soluble fibrinogen to insoluble fibrin, which polymerizes and is cross-linked by FXIIIa.
Plasmin, activated by tissue plasminogen activator from plasminogen, is responsible for
fibrinolysis.

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454 Thornsberry, LoSicco, and English

Table I. Primary and secondary hypercoagulable


states
Primary (inherited)

Factor V Leiden mutation


Prothrombin G20210A
mutation
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Hyperhomocysteinemia
- Methyltetrahydrofolate
reductase deficiency
- Cystathioneb-synthase deficiency
Dysfibrinogenemia
Plasminogen deficiency
Elevated factor VIII, IX, or X
Low levels of tissue factor
pathway inhibitor

SEPTEMBER 2013

Table II. Risks factors for venous and arterial


thrombosis

Secondary (acquired)

Hospitalization
Surgery
Immobilization
Cancer/myeloproliferative
states
Pregnancy
Obesity

Venous thrombosis

Gene mutations:
Factor V Leiden mutation
Prothrombin G20210A
mutation

Deficiencies of anticoagulants
(inherited or acquired):
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Medications
Antiphospholipid antibody
syndrome
Acquired
hyperhomocysteinemia
Acquired antithrombin III
deficiency, protein C,
protein S deficiency

Purpura fulminans. PF (Fig 2) is a dermatologic


emergency and presents as multiple violaceous,
nonblanching retiform macules and skin necrosis.
Cutaneous findings can also include hemorrhagic
bullae. Noninfectious neonatal PF occurs secondary
to a congenital homozygous deficiency of protein C
or S.16 The most common infectious cause of PF is
meningococcemia and 15% to 25% of patients with
this infection develop PF.34 Neonatal PF has also
been reported with group B streptococcus infection.34 Acquired PF is secondary to DIC, sepsis,
trauma, malignancy, obstetric complications, hepatic
failure, or toxic or immunologic reactions.35 In DIC,
the consumption of clotting factors and platelets
leads to both thrombosis and hemorrhage. The
laboratory abnormalities of DIC include prolonged
prothrombin time and partial thromboplastin time,
thrombocytopenia, decreased fibrinogen, and increased fibrin split products, including D-dimer.
The treatment of DIC involves treating the underlying cause, and cautious use of anticoagulants and
blood products.
Thrombotic thrombocytopenic purpura. TTP
can be congenital, acquired, or idiopathic, and is
classically described by the pentad of fever, hemolytic anemia, thrombocytopenia, renal failure, and
neurologic symptoms. The pathogenesis for the majority of patients with acquired TTP involves deficiency of ADAMTS13, a metalloprotease responsible
for cleaving polymers of von Willebrand factor

Venous and arterial


thrombosis

Hyperhomocysteinemia
Methyltetrahydrofolate
reductase deficiency
Cystathione-b-synthase
deficiency
Acquired
hyperhomocysteinemia
Cancer/myeloproliferative
states

Secondary
hypercoagulable states:
Hospitalization
Surgery
Immobilization
Pregnancy

Obesity

Rare causes:
Dysfibrinogenemia
Plasminogen deficiency
Tissue factor pathway
inhibitor deficiency
Elevated levels of factor
VIII, IX, or X

Medications

Antiphospholipid
antibody syndrome

during thrombus formation.36,37 Decreased levels of


this enzyme lead to platelet accumulation and microthrombi. The congenital form is a result of a deficiency of ADAMTS13 whereas the acquired form is a
result of an IgG antibody to ADAMTS13. Idiopathic
TTP cannot be explained by ADAMS13 deficiency
and the cause remains unknown. The diagnosis of
TTP is based on the characteristic clinical findings.
Cases of suspected acquired TTP may be confirmed
by the presence of anti-ADAMTS13 antibodies. The
most common treatments for TTP include plasmapheresis and rituximab.37
Warfarin necrosis. Warfarin (Coumadin) necrosis can occur in patients with heterozygous protein C or S deficiency after starting the anticoagulant
warfarin.11 Warfarin, a vitamin-K antagonist, is used
for anticoagulation via inhibition of the vitamin
Kedependent coagulation factors, which include
FII, FVII, FIX, and FX, as well as proteins C and S.
Within 3 to 5 days of initiating warfarin, patients with
protein C or S deficiency are at risk for developing

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Table III. Laboratory tests for evaluation of hypercoagulable states


Laboratory evaluation of HS

Interpretation

Gene mutations:
Factor V Leiden
Prothrombin G20210A
MTHFR (677TT genotype) 1 homocysteine level

Presence of factor V Leiden or prothrombin gene mutation


increases risk of thrombosis
Presence of MTHFR gene mutation may be associated
with increased homocysteine level

APLAs:
Lupus anticoagulant panel
- Screening tests: PTT, PTT screen with different
reagent, dRVVT, hexagonal phospholipid screen
- Mixing studies: PTT mixing study, dRVVT
mixing study
- Confirmation tests: dRVVT confirmation,
hexagonal PL confirmation, platelet
neutralization procedure

Presence of APLA increases risk of thrombosis; APLA


must be identified on 2 occasions, at least 12 wk apart

Anticardiolipin antibody (IgG, IgA, IgM)


Anti-b2-glycoprotein I antibody (IgG, IgM)
Anticoagulant activity levels:
Antithrombin
Protein C
Protein S

Decreased activity of anticoagulant increases risk


of thrombosis

APLA, Antiphospholipid antibody; dRVVT, dilute Russell viper venom test; HS, hypercoagulable states; MTHFR, methyltetrahydrofolate
reductase; PL, phospholipid; PTT, partial thromboplastin time.

warfarin necrosis because of a temporary HS caused


by the inhibition of protein C and S. Treatment starts
with discontinuing warfarin and reversing its effects
with vitamin K and/or fresh frozen plasma.38
Heparin is often used for anticoagulation after the
warfarin is stopped, and this condition can be
prevented by starting heparin before starting warfarin treatment.38 Local wound care, debridement of
ulcers, mastectomy, and amputation may be necessary depending on the severity of the skin necrosis.38
Heparin-induced thrombotic thrombocytopenia. Heparin induced thrombocytopenia (HIT)
is caused by the formation of antibodies to the complex of platelet factor 4 and heparin.39 HIT usually
occurs 5 to 14 days after initiating heparin and
is characterized by a decrease in platelets to less
than 150,000, a 30% to 50% decrease in platelets
from baseline, or any evidence of thrombosis.40
Symptomatic HIT occurs in 1% to 5% of patients
receiving unfractionated heparin, LMWH, or fondaparinux.41,42 Of patients with HIT, 30% develop thrombosis, also known as heparin-induced thrombotic
thrombocytopenia, which has a mortality of 30% and
is complicated by loss of limb in 20% of patients.40
These patients are 4 times more likely to form venous
thrombosis than arterial thrombosis.40 The treatment
involves discontinuing all heparin products and using
an alternative anticoagulation therapy, such as a direct
thrombin inhibitor, followed by a transition to long-

term anticoagulation with a vitamin-K antagonist


(warfarin).40
Calciphylaxis. Calciphylaxis, also known as calcific uremic arteriolopathy, is characterized by purpura, skin necrosis, nonhealing ulcers, and
calcification of blood vessels. Calciphylaxis primarily
affects patients with end-stage renal disease on dialysis but can also occur in nonuremic patients. This
condition is associated with mortality as high as 80%
when lesions are ulcerated.43 The pathogenesis of this
disorder is poorly understood, although it has been
associated with HS, including protein C or S deficiency44-48 and APLS.49 In a review of reports of
protein C and protein S levels and calciphylaxis,
protein C was decreased in 38% of patients and
protein S was decreased in 43% of patients.44 A review
of 36 patients with nonuremic calciphylaxis revealed
protein C or S deficiency in 11% of the patients.50
These deficiencies occurred in the setting of hepatorenal syndrome,51 alcoholic cirrhosis,52 chemotherapy,53 and rheumatoid arthritis.54 Additional evidence
for the association with HS has been shown by the use
of LMWH46,55 and tissue plasminogen activator56 for
the treatment of calciphylaxis, although the treatment
remains controversial.
APLS and associated cutaneous findings
Antiphospholipid antibody syndrome. An
APLA is an acquired antibody against cell membrane

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Fig 2. Purpura fulminans (PF). A, Noninflammatory microvascular occlusion. B, PF manifesting as purpura and hemorrhagic bullae from Escherichia coli sepsis. (A, Hematoxylin-eosin
stain; original magnification: 310.)

phospholipids. The most common APLAs include


the lupus anticoagulant, anticardiolipin antibody,
and anti-b2-glycoprotein I antibody. There are several proposed mechanisms of thrombogenesis associated with APLAs, including the inhibition of the
activation of protein C and fibrinolysis, induction of
TF, and activation of platelets.57 The APLA must be
detected on 2 occasions (at least 12 weeks apart) to
diagnose the presence of an APLA.58
APLS is diagnosed by the presence of an APLA,
and a thrombotic event, such as VTE or miscarriage.58 Primary APLS occurs without an underlying
medical condition whereas secondary APLS is associated with underlying autoimmune conditions, infection, malignancy, or medications. The syndrome
can be associated with heart valve vegetations,
thrombocytopenia, nephropathy, and neurologic
complications, including transient ischemic attack
and stroke. The reported skin findings associated
with this condition include anetoderma (Fig 3, A),
livedo reticularis (LR) (Fig 3, B), chronic venous
ulcers, pseudovasculitis (Fig 3, C ), superficial thrombophlebitis, superficial skin bullae (Fig 3, D), infarcts
and distal gangrene, acrocyanosis, and relapsing
polychondritis.
Catastrophic APLS (Fig 4) is an accelerated form
of the disease that affects the small vessels of
multiple organs via acute thrombotic microangiopathy. Less than 1% of patients with APLS develop
catastrophic APLS.59 Diagnosis is made by the presence of an APLA, evidence of 3 or more affected
organs or systems within 1 week of onset of the
disease, and demonstration of histologic vessel occlusion of at least 1 organ.59 The differential diagnosis includes DIC, however, in catastrophic APLS,
the D-dimer is negative and there is a positive APLA.
The treatment options include unfractionated heparin, high-dose steroids, intravenous immunoglobulin, or plasmapheresis.

Anetoderma. Anetoderma, also called macular


atrophy, is an elastolytic disorder of unknown origin
characterized by localized areas of flaccid skin,
which can appear atrophic (Fig 3, A) or protuberant.
Histopathology shows a loss of dermal elastic fibers
with an elastin stain, such as the Verhoeff-van Gieson
stain. Primary anetoderma occurs in areas of skin
with no prior skin pathology, whereas secondary
anetoderma occurs in areas of skin with prior pathology, most commonly acne or varicella.60 Primary
anetoderma has been reported in association with
HIV, penicillamine use, and autoimmune diseases
including lupus and thyroiditis.61-63 Primary anetoderma has been reported as a specific skin manifestation for the underlying presence of an APLA.60,62-69
A study of 9 patients with primary anetoderma
revealed APLAs in all 9 patients, with 4 patients also
having APLS.70 A case report of anetoderma and
chronic lower leg ulceration has been reported in
association with decreased antithrombin III levels.71
Livedo reticularis. LR (Fig 3, B) is a blanching
erythematous to violaceous netlike vascular pattern
on the skin. Livedo racemosa is atypical LR that has
prominent asymmetry and breaks in the netlike
pattern. LR can be a normal physiologic finding
that resolves with warming, or it can be indicative of
an underlying HS. The 3 subtypes of LR not associated with systemic disease include: physiologic (cutis marmorata), primary, and idiopathic.72 A review72
of secondary LR describes the numerous associated
conditions, including the following HS: APLAs,73-75
APLS,76 protein C and S deficiency, antithrombin III
deficiency, DVT, DIC, and TTP. Other systemic
associations include systemic vasculitis, connective
tissue disease, emboli, vessel wall deposition, medications, infections, malignancy, neurologic disease,
and endocrine and nutritional diseases.72
Livedo vasculopathy. Livedo vasculopathy
(LV), also known as livedoid vasculopathy, atrophie

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Thornsberry, LoSicco, and English 457

Fig 3. Antiphospholipid antibody syndrome. A, Anetoderma. B, Livedo reticularis. C, Chronic


leg ulcer and pseudovasculitic lesions. D, Superficial skin bullae.

blanche, segmental hyalinizing vasculitis, PURPLE


(painful purpuric ulcers with reticular pattern of the
lower extremities), and LR with winter or summer
ulceration, is a chronic, painful, recurrent, and progressive skin disease often occurring on the lower
extremities (Fig 5).77 The lesions are varied, and may
consist of focal purpura with shallow ulcerations that
heal leaving atrophic, stellate, scarlike white plaques
stippled with telangiectasis and peripheral hyperpigmentation.78 There are many proposed mechanisms
of pathogenesis of LV, including venous flow abnormalities, vascular endothelial dysfunction, immune
complex deposition, and microthrombi of the dermal
vessels secondary to HS.79 The reported associated HS
include FV Leiden mutation,80-82 prothrombin gene
mutation,83,84 antithrombin III deficiency,85 protein C
deficiency,86,87 double heterozygous FV Leiden and
prothrombin mutations,88 APLAs,89,90 APLS,91 and
hyperhomocysteinemia.92-94
Chronic venous ulceration. Chronic venous
ulceration (CVU) often occurs in the setting of

chronic venous insufficiency, varicose veins, or


both. A prior DVT is a major risk factor for chronic
venous insufficiency. Studies have shown that patients with CVU and varicose veins have increased
rates of primary HS or the presence of an APLA.95 In a
study of 110 patients with CVU, approximately one
third of patients had an underlying primary HS,
compared with 1.8% of the control patients.95
Another study of 97 patients with CVU showed
41% of patients with a thrombophilic state.96
Superficial venous thrombosis. SVT, or superficial thrombophlebitis, presents as a swollen, red,
tender, cordlike area of inflammation along a superficial vein, most commonly in the lower extremities.
This was once considered a benign condition however it has recently been proven to be associated with
VTE in 20% to 30% of patients.97,98 An anatomic
communication between the superficial and deep
venous systems exists, which presents the potential
for the development of DVT by direct extension of
the clot into the deeper vasculature. In the POST

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Fig 4. Catastrophic antiphospholipid antibody (APLA) syndrome. A, Auricular and facial


purpura in critically ill patient with negative disseminated intravascular coagulation workup
and positive APLAs. B, Right shoulder purpura in same patient.

Fig 5. Atrophie blanche from livedo vasculopathy.

study, 25% of 844 patients with SVT also had DVT, PE,
or both.98 In the OPTIMEV study, 29% of 788 patients
had DVT.99 Varicose veins are present in 60% to 90%
of patients before developing SVT.100,101 The most
commonly affected vein is the great saphenous vein,
which accounts for 60% to 80% of SVT.101 This
condition is more common in women with an average age of onset at 60 years.101 When SVT is associated with varicose veins, it is less likely to be
complicated by extension into the deep venous
system.102 Superficial thrombophlebitis has been
found in association with anticardiolipin antibodies,
protein C or S deficiency, FV Leiden mutation,
prothrombin mutation, and antithrombin III deficiency.103-107 One study showed FV Leiden mutation
was present in 14.3% of patients presenting with
superficial thrombophebitis.106

THE USE OF ANTIPLATELET AND


ANTICOAGULANT THERAPY IN
DERMATOLOGY
The pharmacologic treatments available for VTE
include antiplatelet and anticoagulant medications
(Table IV) and thrombolytic agents. Embolectomy

may be performed to remove large thromboses and


inferior vena cava filters can be placed to help
prevent additional pulmonary emboli.
In dermatology, the most frequently reported use
of antiplatelet and anticoagulant medication is for the
treatment of LV. There have been reports of the use of
unfractionated heparin or LMWH, such as enoxaparin92,108,109 or dalteparin.109 Other reported treatments of LV include warfarin, aspirin, dipyridamole,
clopidogrel, ticlopidine, recombinant tissue plasminogen activator, and rivaroxaban.79,110 In a case report
of LV associated with a positive lupus anticoagulant
and methyltetrahydrofolate reductase mutation, the
patient achieved complete remission after treatment
with tinzaparin (LMWH) for 6 months.111 The use of
warfarin has been reported in patients with LV and FV
Leiden mutation,109,112,113 prothrombin mutation,84
and hyperhomocysteinemia.77 Recently, the oral
factor Xa inhibitor rivaroxaban was shown to decrease pain and ulceration in 3 patients with LV.110
In patients with CVU, there have been case
reports of the successful use of warfarin, LMWH
(enoxaparin or dalteparin), clopidogrel, and aspirin.
One case of anetoderma and chronic ulceration of
the lower leg associated with antithrombin III deficiency demonstrated resolution of ulceration with
enoxaparin followed by fondaparinux.71
The treatment of APLS with anticoagulation has
been shown to decrease recurrent thrombosis, however when the anticoagulation is stopped, the patient
is at an increased risk of thrombosis during the first 6
months after discontinuation of therapy.114 If APLS is
suspected, referral to a hematologist for anticoagulation recommendations is preferred for long-term
management.
In patients with an SVT of at least 5 cm in length,
recommended treatment includes a prophylactic

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VOLUME 69, NUMBER 3

Table IV. Antiplatelet and anticoagulant therapies


Mechanism of action

Antiplatelet medications
Aspirin
Clopidogrel
Ticlopidine
Prasugrel
Dipyridamole
Pentoxifylline

Anticoagulants
Unfractionated heparin
LMWH:
Enoxaparin
Dalteparin
Reviparin
Tinzaparin
Nadroparin
Parnaparin

Cyclo-oxygenase inhibitor
Adenosine diphosphate
receptor inhibitors
Adenosine deaminase
inhibitor
Phosphodiesterase
inhibitor

Potentiates action
of antithrombin III
Potentiates action
of antithrombin III

Direct thrombin inhibitor


Argatroban
Lepirudin
Bivalirudin
Desirudin
Antithrombin III
Fondaparinux
Factor Xa inhibitor
Idraparinux (in development)
Rivaroxaban (oral)
Warfarin (Coumadin)
Vitamin-K antagonist
LMWH, Low-molecular-weight heparin.

dose of fondaparinux (2.5 mg subcutaneously


daily).115 In the CALISTO study of 3002 patients
with SVT, fondaparinux was superior to placebo in
the prevention of VTE.115 Various doses and durations of LMWH have been reported with SVT. A
recent randomized, double-blind study of parnaparin determined that an intermediate dose of
parnaparin for 30 days was effective treatment for
at least 4-cm-long SVT.116 Nonsteroidal antiinflammatory medications have been the mainstay
of treatment, and although these medications reduce
the pain and recurrence of SVT, they do not decrease
the incidence of VTE.117 In a patient with a first
episode of DVT of the leg, the recommended treatment is warfarin for 3 months.118

CONCLUSION
Primary and secondary HS are associated with
cutaneous manifestations, including purpura, PF, LR,
LV (atrophie blanche), anetoderma, SVT, and
chronic venous ulcers. The dermatologist can

identify these abnormal findings and pursue a


workup for an underlying HS. The successful use
of numerous antiplatelet and anticoagulant medications have been reported in patients with HS and
skin manifestations, however, prospective studies
are still needed to determine the optimal treatment
for many of these conditions.
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