Antiphospholipid Syndrome

Article Last Updated: Aug 10, 2007

AUTHOR AND EDITOR INFORMATION

Author: Elise Belilos, MD, Section Head of Rheumatology, Division of Rheumatology, Allergy and
Immunology, Winthrop-University Hospital; Assistant Professor of Clinical Medicine, Department of
Internal Medicine, State University of New York at Stony Brook

Coauthor(s): Steven Carsons, MD, Chief, Division of Rheumatology, Allergy, and Immunology,
Professor of Medicine, Department of Internal Medicine, Winthrop University Hospital, State
University of New York at Stony Brook

Editors: Carlos J Lozada, MD, Director of Rheumatology Fellowship Program, Associate Professor,
Department of Medicine, Division of Rheumatology and Immunology, Jackson Memorial Medical
Center, University of Miami School of Medicine; Francisco Talavera, PharmD, PhD, Senior
Pharmacy Editor, eMedicine; Lawrence H Brent, MD, Associate Professor of Medicine, Thomas
Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology,
Albert Einstein Medical Center; Alex J Mechaber, MD, FACP, Assistant Dean for Medical
Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of
Miami Miller School of Medicine; Herbert S Diamond, MD, Professor of Medicine, Temple
University School of Medicine; Chairman, Department of Internal Medicine, Western Pennsylvania
Hospital

Synonim: Anticardiolipin antibody syndrome, aCL syndrome, lupus anticoagulant syndrome, LA

syndrome, SLE, systemic lupus erythematosus, rheumatic disease, arterial thrombosis, venous
thrombosis,

INTRODUCTION Antiphospholipid syndrome (APS) is a disorder characterized by recurrent

venous or arterial thrombosis and/or fetal losses associated with characteristic laboratory abnormalities,
such as persistently elevated levels of antibodies directed against membrane anionic phospholipids (ie,
anticardiolipin [aCL] antibody, antiphosphatidylserine) or their associated plasma proteins,
predominantly beta-2 glycoprotein I (apolipoprotein H), or evidence of a circulating anticoagulant.

Multiple terms for APS exist. Unfortunately, some synonyms can be confusing. Lupus anticoagulant
(LA) syndrome, for example, is misleading because patients with APS may not necessarily have
systemic lupus erythematosus (SLE) and LA is associated with thrombotic rather than hemorrhagic
complications. In an attempt to avoid further confusion, APS is currently the preferred term for the
clinical syndrome (as described below).

APS can occur in patients without evidence of any definable associated disease or in association with
SLE or another rheumatic or autoimmune disorder. Traditionally, this has been referred to as primary
or secondary APS, respectively, although, currently, the preferred terminology is APS with or without
associated rheumatic disease. Although antiphospholipid (aPL) antibodies are clinically linked to APS,
whether they are involved in the pathogenesis or are an epiphenomenon is unclear. (Up to 5% of
healthy individuals are known to have aPL antibodies.)

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Pathophysiology. In APS, the homeostatic regulation of blood coagulation is altered; however,
the mechanisms of thrombosis are not yet defined. One hypothesis postulates a defect in
cellular apoptosis, which exposes membrane phospholipids to the binding of various
plasma proteins, such as beta-2 glycoprotein I. Once bound, a phospholipid-protein
complex is formed and a neoepitope is uncovered, which subsequently becomes the target
of autoantibodies. Recent evidence suggests that oxidized beta-2 glycoprotein I is able to
bind to and activate dendritic cells in a manner similar to activation triggered by Toll-like
receptor 4 (TLR-4), which could amplify the production of autoantibodies.1

Other proposed mechanisms for the hypercoagulable effect of aPL antibodies, which may or may not
depend on beta-2 glycoprotein I, include the following:

• Production of antibodies against coagulation factors, including prothrombin, protein C, protein

S, and annexins
• Activation of platelets to enhance endothelial adherence
• Activation of vascular endothelium, which, in turn, facilitates the binding of platelets and
monocytes
• Reaction of antibodies to oxidized low-density lipoprotein, thus predisposing to atherosclerosis
and myocardial infarction (MI)

Complement activation has been increasingly recognized as a possible significant role in the
pathogenesis of APS. Emerging evidence from murine models suggests that APL-mediated
complement activation may be a primary event in pregnancy loss.2

Clinically, the series of events that leads to hypercoagulability and recurrent thrombosis can
affect virtually any organ system, including the following:

• Peripheral venous system (deep venous thrombosis [DVT])

• Central nervous system (cerebrovascular accident [CVA], sinus thrombosis)
• Hematologic (thrombocytopenia, hemolytic anemia)
• Obstetric (pregnancy loss, eclampsia)
• Pulmonary (pulmonary embolism [PE], pulmonary hypertension)
• Dermatologic (livedo reticularis, purpura, infarcts/ulceration)
• Cardiac (Libman-Sacks valvulopathy, MI)
• Ocular (amaurosis, retinal thrombosis)
• Adrenal (infarction/hemorrhage)
• Musculoskeletal (avascular necrosis of bone)

Frequency

United States The actual frequency of APS in the general population is unknown. One to 5% of
healthy individuals have aPL antibodies. aCL antibodies tend to be found more frequently in
elderly persons; thus, positive titer results should be interpreted with caution in this
population. aPL antibodies are found in approximately 30-40% of patients with SLE, but only
about 10% have APS.3 Approximately half of APS cases are not associated with another
rheumatic disease. In a study of 100 patients with confirmed venous thrombosis and no history
of SLE, aCL antibodies were found in 24% and LA in 4%.

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International

International frequency is probably similar to US frequency.

Mortality/Morbidity

• APS may contribute to an increased frequency of CVAs or MIs, especially in younger

individuals. CVAs may develop secondary to in situ thrombosis or embolization that originates
from the valvular lesions of Libman-Sacks (sterile) endocarditis, which may be seen in patients
with APS. Cardiac valvular disease may be severe enough to require valve replacement.
Recurrent pulmonary emboli or thrombosis can lead to life-threatening pulmonary
hypertension.
• Catastrophic APS (CAPS) is a rare, serious, and often fatal manifestation (mortality rate of
approximately 50%) characterized by multiorgan infarctions over a period of days to weeks.
• Late spontaneous fetal loss (second or third trimester) is common; however, it can occur at any
time during pregnancy. Recurrent early fetal loss (<10 weeks’ gestation) is also possible.

Sex

• A female predominance has been documented, particularly for secondary APS. This parallels
the association of APS with SLE and other connective-tissue diseases, which also have a female
predominance.

Age

• APS is more common in young to middle-aged adults; however, it also manifests in children
and elderly people. Disease onset has been reported in children as young as 8 months.

CLINICAL
History
Antiphospholipid syndrome (APS) is a heterogenous disorder in terms of clinical manifestations and
range of autoantibodies. In 2006, revised criteria for the diagnosis of APS were published in an
international consensus statement.4 At least one clinical criterion and one laboratory criterion
(discussed further in Lab Studies) must be present for a patient to be classified as having APS.

• The clinical criteria are as follows:

•
o Vascular thrombosis
o
 One or more clinical episodes of arterial, venous, or small-vessel thrombosis in
any tissue or organ confirmed by findings from imaging studies, Doppler studies,
or histopathology (see Histologic Findings).

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  Thrombosis may involve the cerebral vascular system, coronary arteries,
pulmonary system (emboli or thromboses), arterial or venous system in the
extremities, hepatic veins, renal veins, ocular arteries or veins, or adrenal glands.
Investigation is warranted if a history of DVT, PE, acute ischemia, MI, or CVA
(especially when recurrent) is present in a younger individual (males <55 y;
females <65 y) or in the absence of other risk factors.
o Pregnancy morbidity
o
 One or more late-term (>10 weeks’ gestation) spontaneous abortions
 One or more premature births of a morphologically healthy neonate at or before
34 weeks’ gestation because of severe preeclampsia or eclampsia or severe
placental insufficiency
 Three or more unexplained, consecutive, spontaneous abortions before 10
weeks’ gestation
• Laboratory criteria: Patients must have (1) medium to high levels of immunoglobulin G (IgG)
or immunoglobulin M (IgM) anticardiolipin (aCL), (2) anti–beta-2 glycoprotein I, or (3) LA on
at least 2 occasions at least 12 weeks apart. (See also Lab Studies.)

Other antiphospholipid (aPL)–associated clinical features recognized by the 2006 consensus statement
but not included in the criteria include cardiac valve disease, livedo reticularis, thrombocytopenia,
nephropathy, and neurologic manifestations.

Thus, history of any of the following should raise the examiner's suspicion for APS:

• Thrombosis (eg, DVT/PE, MI, transient ischemic attack [TIA], or CVA, especially if recurrent,
at an earlier age, or in the absence of other known risk factors)
• Miscarriage (especially late trimester or recurrent) or premature birth
• History of heart murmur or cardiac valvular vegetations
• History of hematologic abnormalities, such as thrombocytopenia or hemolytic anemia
• History of nephropathy
• Nonthrombotic neurologic symptoms, such as migraine headaches, chorea, seizures, transverse
myelitis, Guillain-Barré syndrome, or dementia (rare)
• Unexplained adrenal insufficiency
• Avascular necrosis of bone in the absence of other risk factors
• Pulmonary hypertension

Physical

• Cutaneous
•
o Livedo reticularis
o Superficial thrombophlebitis
o Leg ulcers
o Painful purpura
o Splinter hemorrhages
• Venous thrombosis
•
o Leg swelling (DVT)

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 o Ascites (Budd-Chiari syndrome)
o Tachypnea (PE)
o Peripheral edema (renal vein thrombosis)
o Abnormal funduscopic examination results (retinal vein thrombosis)
• Arterial thrombosis
•
o Abnormal neurologic examination results (eg, CVA)
o Digital ulcers
o Gangrene of distal extremities
o Signs of MI
o Heart murmur (frequently aortic) or mitral insufficiency (Libman-Sacks endocarditis)
o Abnormal funduscopic examination results (retinal artery occlusion)

Causes

APS is an autoimmune disorder of unknown cause. The search for possible triggers has uncovered a
wide array of associated autoimmune or rheumatic diseases, infections, and drugs that are associated
with the LA or aCL antibodies. These associations may ultimately provide a clue to the etiology of
APS. A considerable percentage of persons with certain autoimmune or rheumatic diseases also have
aPL antibodies. Note that these represent percentages of patients with aPL antibodies, rather than the
clinical syndrome of APS.

• Common autoimmune or rheumatic diseases and the percentage of affected patients with aPL
antibodies
•
o SLE - 25-50%
o Sjögren syndrome - 42%
o Rheumatoid arthritis - 33%
o Autoimmune thrombocytopenic purpura - 30%
o Autoimmune hemolytic anemia - Unknown
o Psoriatic arthritis - 28%
o Systemic sclerosis - 25%
o Mixed connective-tissue disease - 22%
o Polymyalgia rheumatica or giant cell arteritis - 20%
o Behçet syndrome - 20%
• Infections
•
o Syphilis
o Hepatitis C infection
o HIV infection
o Human T-cell lymphotrophic virus type 1 infection
o Malaria
o Bacterial septicemia
• Drugs
•
o Cardiac - Procainamide, quinidine, propranolol, hydralazine
o Neuroleptic or psychiatric - Phenytoin, chlorpromazine
o Other - Interferon alfa, quinine, amoxicillin
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 • Genetic predisposition
•
o Familial association: Relatives of persons with known APS are more likely to have aPL
antibodies. One study showed a 33% frequency.
o HLA associations: Recent studies have revealed an association between aCL antibody
and groups of individuals who carry certain HLA genes, including DRw53, DR7 (mostly
people of Hispanic origin), and DR4 (mostly whites).

DIFFERENTIALS
Disseminated Intravascular Coagulation
Infective Endocarditis
Thrombotic Thrombocytopenic Purpura

Other Problems to be Considered

Hypercoagulable state - Malignancy, oral contraceptive use and hormone replacement therapy,
homocystinemia, antithrombin III deficiency, protein C or S deficiency, factor V Leiden mutation,
prothrombin A20210 mutation, antiprothrombin antibodies
Atherosclerotic vascular disease, including multiple cholesterol emboli syndrome
Systemic necrotizing vasculitis

WORKUP

Lab Studies

The hallmark result from laboratory tests that defines antiphospholipid syndrome (APS) is the presence
of antiphospholipid (aPL) antibodies or abnormalities in phospholipid-dependent tests of
coagulation. In addition to the clinical criteria listed in History, at least one of the following laboratory
criteria is necessary for the classification of APS:

• Presence of LA in plasma on 2 or more occasions at least 12 weeks apart (see below)

• Presence of moderate to high levels of anticardiolipin (aCL) (IgG or IgM) in serum or plasma
(ie, >40 IgG phospholipid units (GPL)/mL or IgM phospholipid units (MPL)/mL or >99th
percentile) on 2 or more occasions at least 12 weeks apart
• Presence of moderate to high levels of anti–beta-2 glycoprotein I antibodies (IgG or IgM) in
serum or plasma (>99th percentile) on 2 or more occasions at least 12 weeks apart

aCL antibodies react primarily to membrane phospholipids, such as cardiolipin and phosphatidylserine.
Of the 3 known isotypes of aCL (ie, IgG, IgM, immunoglobulin A [IgA]), IgG correlates most strongly
with thrombotic events. Cardiolipin is the dominant antigen used in most serologic tests for syphilis;
consequently, these patients may have a false-positive test result for syphilis.

Recent literature suggests that an abnormal LA finding is the laboratory test result that confers the
strongest risk for thrombosis.5 LA is directed against plasma coagulation molecules. In vitro, this
interaction results in the paradoxical prolongation of clotting assays, such as activated partial

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thromboplastin time (aPTT), kaolin clotting time, and dilute Russell viper venom time (DRVVT). The
presence of LA is confirmed by mixing normal platelet-poor plasma with the patient's plasma. If a
clotting factor is deficient, the addition of normal plasma corrects the prolonged clotting time. If the
clotting time does not normalize during mixing studies, an inhibitor is present; the absence of a specific
clotting factor inhibitor confirms that a LA is present.

Patients with APS may have one or more abnormal results from these laboratory tests; the following
laboratory tests should be considered in a patient suspected of having APS:

• aCL antibodies (IgG, IgM)

• Anti–beta-2 glycoprotein I antibodies (IgG, IgM)
• Activated partial thromboplastin time (aPTT)
• LA tests such as DRVVT
• Serologic test for syphilis (false-positive result)
• CBC count (thrombocytopenia, hemolytic anemia)

Thrombocytopenia is fairly common in persons with APS (22% at presentation, 30% cumulatively) and
is therefore associated with paradoxical thrombosis. However, patients with platelet counts of less than
50,000/µL may have an increased risk of bleeding. Hemolytic anemia has been well described in
patients with APS and is associated with the presence of IgM aCL antibodies.

A low antinuclear antibody level may be present and does not necessarily imply coexisting SLE.

Additional antibodies directed against phospholipid/phospholipid-protein complexes that may be useful

in selected cases include the following:

• IgA aCL
• IgA beta-2 glycoprotein I
• anti-phosphatidylserine antibodies
• anti-phosphatidylethanolamine antibodies
• anti-prothrombin antibodies
• antibodies against the phosphatidylserine-prothrombin complex

Imaging Studies

• Imaging studies are helpful for confirming a thrombotic event. A good example is the use of CT
scanning or MRI of the brain (CVA), chest (PE), or abdomen (Budd-Chiari syndrome).
• Doppler ultrasound studies are recommended for possible detection of DVT.
• Two-dimensional echocardiography findings may demonstrate asymptomatic valve thickening,
vegetations, or valvular insufficiency; aortic or mitral insufficiency is the most common
valvular defect found in persons with Libman-Sacks endocarditis.

Procedures

• Individualize appropriate procedures to evaluate specific thrombotic events.

Histologic Findings

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Unlike inflammatory autoimmune diseases, histologic studies of skin or other involved tissue reveal a
noninflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic
vasculitis. Similarly, biopsy samples from affected kidneys demonstrate glomerular and small arterial
microthrombi.

TREATMENT

Medical Care

Patients with antiphospholipid syndrome (APS) may be evaluated in an outpatient setting. Inpatient
evaluation is required if the patient presents with a significant clinical event. Patients with CAPS
require intense observation and treatment, often in an intensive care unit.

In general, treatment regimens for APS must be individualized according to the patient's current
clinical status and history of thrombotic events. Asymptomatic individuals in whom blood test findings
are positive do not require specific treatment.

• Prophylactic therapy
•
o Eliminate other risk factors, such as oral contraceptives, smoking, hypertension, or
hyperlipidemia.
o Low-dose aspirin is used widely in this setting; however, the effectiveness of low-dose
aspirin as primary prevention for APS remains unproven. Clopidogrel has anecdotally
been reported to be helpful in persons with APS and may be useful in patients allergic to
aspirin.
o In patients with SLE, consider hydroxychloroquine, which may have intrinsic
antithrombotic properties.
o Consider the use of statins, especially in patients with hyperlipidemia.
• Thrombosis
•
o Perform full anticoagulation with intravenous or subcutaneous heparin followed by
warfarin therapy.
o Based on the most recent evidence, a reasonable target for the international normalized
ratio (INR) is 2.0-3.0 for venous thrombosis and 3.0 for arterial thrombosis. Patients
with recurrent thrombotic events, while well maintained on the above regimens, may
require an INR of 3.0-4.0. For severe or refractory cases, a combination of warfarin and
aspirin may be used. Treatment for significant thrombotic events in patients with APS is
generally lifelong.
• Obstetric considerations
•
o Patients with pregnancy loss receive a prophylactic dose of subcutaneous heparin
(preferably low–molecular-weight heparin [LMWH]) and low-dose aspirin. Therapy is
withheld at the time of delivery and is restarted after delivery, continuing for 6-12 weeks
postpartum. Most authors avoid warfarin (Coumadin) because it is contraindicated in
pregnancy.
o Patients with a history of thrombosis receive therapeutic doses of heparin during
pregnancy; long-term anticoagulation is then continued postpartum.

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 o Corticosteroids have not been proven effective for persons with primary APS, and they
have been shown to increase maternal morbidity and fetal prematurity rates.
o Breastfeeding women may use heparin and warfarin.
• CAPS
•
o These patients generally are very ill, often with active SLE.
o Treatment with intensive anticoagulation, plasma exchange, and corticosteroids appears
beneficial, but no controlled trials have been performed. Intravenous immunoglobulin
may be of some benefit and cyclophosphamide may be considered in selected cases,
especially in SLE-associated CAPS.

Surgical Care

Recurrent DVT may necessitate placement of an inferior vena cava filter.

Consultations

• Rheumatologist
• Hematologist
• Neurologist, cardiologist, pulmonologist, hepatologist, ophthalmologist (depending on clinical
presentation)
• Obstetrician with experience in high-risk pregnancies

Diet

• If warfarin therapy is instituted, instruct the patient to avoid excessive consumption of foods
that contain vitamin K.

Activity

• No specific limitations on activity are necessary.

• Individualize the activity according to the clinical setting.
• Instruct the patient to avoid sports with excessive contact if taking warfarin.
• Limit activity in patients with acute DVT.
• Instruct the patient to avoid prolonged immobilization.

MEDICATION
Therapeutic agents are based on anticoagulant properties, and benefits are weighed carefully against
their significant risks. Life-long treatment with warfarin (see Treatment) is standard for recurrent
thrombotic events.

For obstetric patients with antiphospholipid syndrome (APS) (see Obstetric considerations), the
standard therapy is subcutaneous LMWH and low-dose aspirin.

Heparin therapy may be administered in several regimens, as follows:

• Thrombotic events are initially treated with intravenous infusion of unfractionated heparin or
therapeutic doses of LMWH.

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 • Subcutaneous LMWH (enoxaparin [Lovenox]) may also be used for obstetric or thrombosis
prophylaxis. Lower doses (20-40 mg/d SC) are used to prevent fetal loss, while higher doses (1
mg/kg q12h or 1.5 mg/kg/d) are used for thrombosis prophylaxis in patients (pregnant or
nonpregnant) who have had prior thrombotic events.

Patients who require heparin administration throughout pregnancy should receive calcium and vitamin
D supplementation to help avoid heparin-induced osteoporosis. When monitoring heparin therapy, note
that the aPTT may be unreliable in the presence of circulating LA with a baseline elevated aPTT. In
this case, factor Xa may be helpful.

The antithrombotic properties of hydroxychloroquine have long been recognized and may be
considered in the prophylactic treatment of a patient with SLE and a positive antiphospholipid (aPL)
antibody test result. Case reports suggest that clopidogrel may be effective because of its antiplatelet
effect. Recently, statins have been suggested to have potential antithrombotic effects. In addition to full
anticoagulation, plasma exchange and corticosteroids are generally used in the treatment of CAPS.
Intravenous immunoglobulin or cyclophosphamide may also be considered in selected patients with
CAPS.

Drug Category: Anticoagulants

Standard therapy for thrombosis commonly consists of intravenous heparin followed by warfarin.
Treatment of a pregnant patient with a history of recurrent fetal loss is controversial but generally
includes subcutaneous heparin and aspirin.

Drug Name Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K–
dependent coagulation factors. Long-term warfarin is
Description DOC for APS in patients with recurrent thrombotic
events. Titrated dose suggested to maintain INR in
therapeutic range (see above).
Adult Dose Individualized to achieve target INR
Pediatric Dose Individualized to achieve target INR
Documented hypersensitivity; active bleeding or
hemorrhage; malignant hypertension; severe liver or
Contraindications
kidney disease; pregnancy; neurologic,
ophthalmologic, or traumatic surgery
Interactions Drugs that may decrease anticoagulant effects include
griseofulvin, carbamazepine, glutethimide, estrogens,
nafcillin, phenytoin, rifampin, barbiturates,
cholestyramine, colestipol, vitamin K, spironolactone,
oral contraceptives, and sucralfate
Drugs that may increase anticoagulant effects include
oral antibiotics, sulfonamides, chloral hydrate,
clofibrate, diazoxide, anabolic steroids, ketoconazole,
ethacrynic acid, miconazole, nalidixic acid,
sulfonylureas, allopurinol, chloramphenicol,
cimetidine, disulfiram, metronidazole,

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 phenylbutazone, phenytoin, propoxyphene,
gemfibrozil, and acetaminophen
Drugs that may enhance bleeding diathesis when
coadministered include aspirin, most NSAIDs (eg,
ibuprofen, indomethacin, naproxen), ticlopidine, and
clopidogrel
Pregnancy X - Contraindicated; benefit does not outweigh risk
Monitor PT and INR; hepatic or renal insufficiency;
elderly or debilitated patients or those prone to falls;
do not switch brands after achieving therapeutic
Precautions
response; caution in active tuberculosis or diabetes;
patients with protein C or S deficiency are at risk of
developing skin necrosis
Drug Name Enoxaparin (Lovenox)
LMWH. Most experience; other LMWH preparations
Description
available.
Low dose: 20-40 mg/d SC
High (adjusted dose): 1 mg/kg SC bid; alternatively,
Adult Dose
1.5 mg/kg SC qd
See above
Pediatric Dose Not established
Documented hypersensitivity; major bleeding;
Contraindications
thrombocytopenia (see information for heparin)
Drugs that inhibit platelet activation (eg, aspirin,
Interactions NSAIDs, dipyridamole, sulfinpyrazone, ticlopidine,
clopidogrel) may increase risk of bleeding
B - Fetal risk not confirmed in studies in humans but
Pregnancy
has been shown in some studies in animals
Monitor platelets, hematocrit, and stool for occult
blood; active or recent GI bleed or hemorrhagic CVA;
Precautions severe hypertension; recent brain, spinal, or eye
surgery; heparin-induced thrombocytopenia; heparin-
induced osteoporosis; elderly or debilitated patients
Drug Name Unfractionated heparin
Used in inpatient settings as continuous infusion
during conversion to warfarin therapy until a
therapeutic INR is achieved. May be administered SC
Description
as substitute for warfarin during attempted pregnancy
or for temporary anticoagulation during warfarin
loading in outpatient setting.
Adult Dose SC: 5000-10,000 U q12h
IV standard dosing
Initial: 5000 U
Maintenance: 1000-2000 U/h

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 Weight-based dosing
Initial: 80 U/kg IV
Maintenance: 18 U/kg/h IV
IV: Titrate infusion to aPTT; aPTT of 2-times baseline
is considered therapeutic (if baseline is within
reference range)
Pediatric Dose Use weight-based dosing as described for adults
Severe thrombocytopenia; uncontrollable active
bleeding; when monitoring is not possible;
Contraindications documented hypersensitivity; subacute bacterial
endocarditis; history of heparin-induced
thrombocytopenia
Digoxin, nicotine, tetracycline, and antihistamines may
decrease effects; aspirin, NSAIDs, ticlopidine,
Interactions
clopidogrel dextran, dipyridamole, sulfinpyrazone, and
hydroxychloroquine may increase toxicity
C - Fetal risk revealed in studies in animals but not
Pregnancy established or not studies in humans; may use if
benefits outweigh risk to fetus
Monitor platelets, hematocrit, and stool for occult
blood; active or recent GI bleed or hemorrhagic CVA;
severe hypertension; recent brain, spinal, or eye
surgery; heparin resistance; heparin-induced
Precautions osteoporosis; in neonates, preservative-free heparin is
recommended to avoid possible toxicity (gasping
syndrome) from benzyl alcohol, which is used as
preservative; caution in severe hypotension, shock, or
elderly or debilitated patients
Drug Name Aspirin (Anacin 81, Ascriptin, Bayer Aspirin)
Although not proven effective when used alone, most
clinicians use aspirin with SC heparin in pregnant
Description
patients with APS. Begin aspirin as soon as conception
is attempted.
Adult Dose 81 mg PO qd
Pediatric Dose Not established
Documented hypersensitivity; liver damage;
hypoprothrombinemia; vitamin K deficiency; bleeding
disorders; aspirin-sensitive asthma; because of
Contraindications
association of aspirin with Reye syndrome, do not use
in children (<16 y) with influenza or varicella
infections
Interactions Effects may decrease with antacids and urinary
alkalinizers; additive hypoprothrombinemic effects
and increased bleeding time may occur with
coadministration of anticoagulants; may antagonize

12
 uricosuric effects of probenecid and increase toxicity
of phenytoin and valproic acid; doses >2 g/d may
potentiate glucose-lowering effect of sulfonylurea
drugs
C - Fetal risk revealed in studies in animals but not
Pregnancy established or not studies in humans; may use if
benefits outweigh risk to fetus
May cause transient decrease in renal function and
aggravate chronic kidney disease; avoid use in patients
Precautions
with severe anemia, in those with a history of blood
coagulation defects, or those taking anticoagulants

Drug Category: Antimalarials

As prophylactic therapy, these agents may have an additional anticoagulant effect in patients with SLE.

Drug Name Hydroxychloroquine (Plaquenil)

Most common antimalarial used in APS, mostly
Description
because of excellent safety profile.
6-7 mg/kg/d; usually 200-400 mg/d PO qd or divided
Adult Dose
doses
Pediatric Dose 6-7 mg/kg/d PO
Documented hypersensitivity; retinal and visual-field
Contraindications
changes attributable to 4-aminoquinolones
Hepatotoxic or dermotoxic drugs may increase
Interactions toxicity; serum levels increase with cimetidine; choline
magnesium trisalicylate may decrease absorption
C - Fetal risk revealed in studies in animals but not
Pregnancy established or not studies in humans; may use if
benefits outweigh risk to fetus
Perform periodic ophthalmologic examinations (q6-
Precautions 12mo); hepatic disease, G-6-PD deficiency, psoriasis,
and porphyria

Drug Category: Immunosuppressive agents

Consider immunosuppressive agents in select cases (eg, refractory APS, CAPS).

Drug Name Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an
alkylating agent, mechanism of action of active
Description metabolites may involve cross-linking of DNA, which
may interfere with growth of normal and neoplastic
cells. Has not been shown to be effective in APS.

13
 0.5-1 g/m2 IVPB single dose
Adult Dose
2-3 mg/kg/d PO single morning dose
Pediatric Dose Dosing by weight; administer as in adults
Documented hypersensitivity; infection; severely
Contraindications
depressed bone marrow function; severe cytopenias
Allopurinol may increase risk of bleeding or infection
and enhance myelosuppressive effects; may potentiate
doxorubicin-induced cardiotoxicity; may reduce
digoxin serum levels and antimicrobial effects of
quinolones; chloramphenicol may increase half-life
while decreasing metabolite concentrations; may
Interactions
increase effect of anticoagulants; coadministration
with high doses of phenobarbital may increase rate of
metabolism and leukopenic activity; thiazide diuretics
may prolong cyclophosphamide-induced leukopenia
and neuromuscular blockade by inhibiting
cholinesterase activity
D - Fetal risk shown in humans; use only if benefits
Pregnancy
outweigh risk to fetus
Leukopenia and thrombocytopenia; monitor CBC and
platelet counts and perform urinalysis q1-2wk with
Precautions any change in dosing; perform urinalysis with
cytology q6-12mo after cessation of drug (especially
with PO regimen)

Drug Category: Corticosteroids

In selected cases with specific nonthrombotic autoimmune manifestations (eg, clinically significant
thrombocytopenia), corticosteroids may be considered.

Drug Name Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune
disorders. May decrease inflammation by reversing
Description
increased capillary permeability and suppressing PMN
activity. Useful in treating cytopenias.
Individualize dosing depending on clinical setting and
Adult Dose
specific manifestation being treated
Individualize dose as in adults; high dose is 1-2
Pediatric Dose
mg/kg/d PO
Documented hypersensitivity; no absolute
contraindications; use caution in severe bacterial, viral,
Contraindications
or fungal infection; active peptic ulcer disease;
uncontrolled diabetes mellitus
Interactions May cause water and salt retention, exacerbating
hypertension and increasing requirement for

14
 antihypertensive drugs in patients with hypertension;
may aggravate hyperglycemia, increasing requirement
for hypoglycemic agents in patients with diabetes;
metabolism may be increased by drugs that induce
hepatic microsomal enzymes, including phenytoin,
phenobarbital, carbamazepine, and rifampin, thus
increasing corticosteroid requirements
B - Fetal risk not confirmed in studies in humans but
Pregnancy
has been shown in some studies in animals
Toxicities include weight gain, dyspepsia, mood
changes, infection, peptic ulcer disease, hypertension,
diabetes mellitus, osteoporosis, avascular necrosis,
Precautions
cataracts, glaucoma, myopathy, and skin changes;
growth retardation in children; abrupt discontinuation
may result in adrenal crisis

Drug Category: Immunomodulatory therapy agents

These agents interfere with processes that promote immune reactions resulting from diverse stimuli.

Intravenous immune globulins, 5% (Gammagard,

Drug Name
Gamimune)
Following features may be relevant to efficacy:
neutralization of circulating myelin antibodies through
antiidiotypic antibodies, down-regulation of
proinflammatory cytokines (including IFN-gamma),
Description blockade of Fc receptors on macrophages, suppression
of helper/inducer T and B cells and augmentation of
suppressor T cells, blockade of the complement
cascade, promotion of remyelination, and 10%
increase in CSF IgG. May be effective in APS.
400 mg/kg/d IV for 5 d; alternatively, 1000 mg/kg/d
Adult Dose
for 1-2 consecutive days
Pediatric Dose Administer as in adults
Documented hypersensitivity; IgA deficiency; anti-
Contraindications
IgE/IgG antibodies
Interactions Live viral vaccines (MMR)
C - Fetal risk revealed in studies in animals but not
Pregnancy established or not studies in humans; may use if
benefits outweigh risk to fetus
Precautions Caution in IgA-deficient patients, may have severe
reactions; check serum IgA levels prior to use; may
increase serum viscosity and thromboembolic events;
adverse effects may include migraine attacks, 10%
increased risk of aseptic meningitis, and increased risk

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 of urticaria or pruritus or petechiae 2-5 d postinfusion
(may last as long as 1 mo); increased risk of renal
tubular necrosis in patients who are older, have
diabetes, are volume depleted, or have preexisting
kidney disease; can lead to changes in laboratory
values (eg, elevated antiviral or antibacterial antibody
titers for 1 mo, 6-fold increased ESR for 2-3 wk,
apparent hyponatremia)

FOLLOW-UP
Further Inpatient Care

• Intensive observation is warranted for patients with CAPS.

Further Outpatient Care

• Carefully monitor medication doses and the INR if applicable.

• Closely observe the patient for clinical events.
• Ensure the care of any underlying connective-tissue disease.

In/Out Patient Meds

• The suggested medications include heparin, warfarin, aspirin, and, in selected cases,
hydroxychloroquine, intravenous immunoglobulin, and corticosteroids.
• Corticosteroids are rarely used for the treatment of recurrent fetal loss because of the increased
risk of maternal morbidity. Generally, the use of corticosteroids is reserved for specific
nonthrombotic manifestations, such as associated thrombocytopenia, autoimmune hemolytic
anemia, or the treatment of an underlying connective-tissue disease.
• Prescribe antihypertensive drugs when necessary.
• Administer antihyperlipidemic agents including statins when appropriate.

Transfer

• When treating seriously ill patients with CAPS, transfer the patient to a setting where plasma
exchange can be performed or where intravenous immunoglobulin or cyclophosphamide can be
administered if needed.

Deterrence/Prevention

• Instruct the patient to avoid smoking.

• Inform the patient to avoid oral contraceptives or estrogen replacement therapy.
• Ensure that the patient avoids any prolonged immobilization.

Complications

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 • Permanent functional disability can occur at a relatively young age. This may include the
following:
•
o Cardiovascular accident
o MI
o Pulmonary hypertension
o Renal failure
o Death

No defined racial predominance for primary APS has been documented, although
SLE is more common in African American and Hispanic populations. Prognosis

• With appropriate medication and lifestyle modifications, most individuals with primary
antiphospholipid syndrome (APS) lead normal healthy lives. However, subsets of patients
continue to have thrombotic events despite aggressive therapies. In these patients and in patients
with CAPS, the disease course can be devastating, often leading to significant morbidity or
early death.
• Patients with secondary APS carry a similar prognosis; however, morbidity and mortality may
also be influenced by these patients' underlying autoimmune or rheumatic condition. In patients
with SLE and APS, antiphospholipid (aPL) antibodies have been associated with
neuropsychiatric disease and have been recognized as a major predictor of irreversible organ
damage.
• Women with aPL antibodies who experience recurrent miscarriages may have favorable
prognoses in subsequent pregnancies if treated with aspirin and heparin.

Patient Education

• Stress the importance of early recognition of a possible clinical event.

• Educate the patient about anticoagulation therapy.
• Discuss the importance of planned pregnancies so that long-term warfarin can be switched to
aspirin and heparin before pregnancy is attempted.
• For excellent patient education resources, visit eMedicine's Circulatory Problems Center. Also,
see eMedicine's patient education article Blood Clot in the Legs.

MISCELLANEOUS

Medical/Legal Pitfalls

• Failure to recognize antiphospholipid syndrome (APS) when suggested by history or clinical

examination findings, especially thrombosis in a relatively young individual
• Failure to warn female patients about potential complications with pregnancy
• Failure to discourage continuation of oral contraceptives or other estrogen preparations

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