Synonyms, Key Words, and Related Terms:
anti-phospholipid antibody syndrome, Hughes syndrome, Hughes' syndrome,
antiphospholipid syndrome, anti-phospholipid syndrome, APS, APLS, Sneddon
syndrome, Sneddon’s syndrome, thrombosis
AUTHOR INFORMATION |
Section 1 of 12
 |
Authored by Barry L
Myones, MD,
Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
at Houston; Associate Professor, Departments of Pediatrics & Immunology,
Pediatric Rheumatology Section, Baylor College
of Medicine
Coauthored by Deborah
McCurdy, MD, Director of Rheumatology, Department of Pediatric
Rheumatology, Children's Hospital of Orange County
Barry L Myones, MD, is a
member of the following medical societies: American Academy of
Pediatrics,
American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, American Heart
Association,
American Society for Microbiology, Clinical Immunology Society, and Texas Medical
Association
Edited by Terry Chin,
MD, Codirector of Cystic Fibrosis Center, Associate Professor,
Department of Pediatrics, Loma Linda University and Children's Hospital;
Mary L Windle, PharmD, Adjunct Assistant Professor, University
of Nebraska Medical Center College of Pharmacy; David Sherry,
MD, Director of Clinical Pediatric Rheumatology, Department of
Rheumatology, University of Washington Children's Hospital; Daniel
Rauch, MD, Program Director, Associate Professor, Department of
Pediatrics, Albert Einstein College of Medicine and Jacobi Medical Center; and
Norman T Ilowite, MD, Chief, Rheumatology Division, Schneider
Children's Hospital, Professor, Department of Pediatrics, Albert Einstein
College of Medicine
September 4 2002
INTRODUCTION |
Section 2 of 12
 |
Background:
Antiphospholipid (aPL) antibodies have been found in association with
clinical symptoms such as deep venous thrombosis, arterial occlusive events (eg,
stroke, myocardial infarction), and recurrent fetal loss and with vasospastic
phenomena such as migraine headache, Raynaud phenomenon, and transient ischemic
attack (TIA).
The terminology associated
with aPL antibodies has been fraught with misnomers. Conley and Hartmann’s
observation of prolongation of the prothrombin time (PT) in a series of patients
with systemic lupus erythematosus (SLE) later was termed the "lupus
anticoagulant" (LAC). This term is misleading for the following reasons:
- The LAC phenomenon can be
caused by any number of antibodies to the phospholipid template of the
coagulation cascade.
- These antibodies are
frequently found outside the clinical spectrum of SLE.
- Although these antibodies
are responsible for a prolongation of the activated partial thromboplastin time
in vitro, they are associated with a hypercoagulable state in
vivo.
In the early 1980s, Harris
identified anticardiolipin antibodies in a subset of these patients. Since that
time, it has been determined by doctor Graham Hughes that antibodies to phospholipids alone are
more often associated with infectious causes. In contrast, antibodies to
combinations of phospholipids and serum proteins (eg, b2-glycoprotein I [b2-GPI]
or prothrombin) are more likely associated with vasculopathic events of the
antiphospholipid syndrome (APS or APLS).
The occurrence of aPL
antibodies associated with vaso-occlusive events without any underlying disease
process is termed the primary antiphospholipid syndrome (PAPS). The presence of
aPL antibodies and a vaso-occlusive event superimposed on an underlying disease,
such as SLE or malignancy, is a secondary antiphospholipid syndrome.
Preliminary classification
criteria for "definite" Antiphospholipid Syndrome (APS or APLS) were proposed in a report from the Eighth International Symposium on Antiphospholipid Antibodies and published in
Arthritis and Rheumatism (Wilson, 1999).
The purpose of the report was
to define the essential features of Antiphospholipid Syndrome (APS or APLS) in order to facilitate studies of treatment and causation. These essential features of Antiphospholipid Syndrome (APS or APLS) would encompass the clinical and laboratory features that are most closely
associated with aPL in
prospective studies and based on the strongest experimental evidence. The hope
was to use the "cleanest" patient populations for basic research and clinical
treatment studies. These criteria were not meant to supplant the
physician's clinical judgment in making the diagnosis in any particular patient.
Features such as migraine headache, peripheral vasospasm, and thrombocytopenia,
while excluded from these published criteria, were argued at the Ninth
International Symposium on Antiphospholipid Antibodies to be valid and useful
clinical parameters in arriving at the diagnosis of Antiphospholipid Syndrome (APS or APLS) in the clinical setting.
Clinical criteria
- Vascular thrombosis - One or
more clinical episodes of arterial, venous, or small vessel thrombosis in any
tissue/organ confirmed by imaging/Doppler studies or histopathology (without
vessel inflammation)
- Pregnancy morbidity (normal
morphology)
- One or more unexplained
fetal deaths at more than 10 weeks of gestation
- One or more premature births
at less than 34 weeks of gestation because of severe preeclampsia or eclampsia
or placental insufficiency
- Three or more unexplained
consecutive spontaneous abortions at less than 10 weeks of gestation, excluding
maternal anatomic and/or hormonal abnormalities and paternal and/or maternal
chromosomal causes
Laboratory criteria
- Anticardiolipin (aCL)
antibody of the immunoglobulin G (IgG)/immunoglobulin M (IgM) isotype in
medium/high titer on 2 or more occasions at least 6 weeks apart (measured by a
b2-GPI–dependent enzyme-linked immunosorbent assay [ELISA]).
- Lupus anticoagulant on 2 or
more occasions at least 6 weeks apart according to the guidelines set forth by
the International Society of Thrombosis and Hemostasis (for
LAC/phospholipid-dependent antibodies).
- Prolonged
phospholipid-dependent coagulation (eg, activated partial thromboplastin time
[aPTT], Kaolin clotting time [KCT], dilute Russell viper venom test [DRVVT],
dilute PT)
- Failure to correct the
prolonged coagulation time by a mix with platelet poor plasma (PPP)
- Shortening or correction of
the prolonged coagulation time with excess phospholipid
- Exclusion of other
coagulopathies (eg, factor VIII inhibitor, heparin)
A patient must meet at
least one clinical and one laboratory criterion for a diagnosis of Antiphospholipid Syndrome (APS or APLS).
A postconference workshop was
held after the Ninth International Symposium on Phospholipid Antibodies during
which data were presented for modifying and expanding the above criteria, and a
decision was reached not to change the criteria for research studies pending
further validation studies. Future efforts, however, were to focus on guidelines
for the clinical diagnosis as distinct from classification of Antiphospholipid Syndrome (APS or APLS).
Pathophysiology:
The mechanism or mechanisms by which the antiphospholipid antibodies
interact with the coagulation cascade to produce clinical events are largely
speculative and have not been elucidated clearly. The presence of preexisting or
coincident vascular (endothelial) damage along with the identification of an aPL
antibody as requisites for the emergence of a thrombotic complication has been
coined the “two-hit” hypothesis.
- Possible mechanisms by which
aPL might induce thrombotic events include the following:
- aPL may combine with
platelet membrane phospholipids, resulting in increased platelet adhesion and
aggregation.
- aPL may combine with the
endothelial cell membrane phospholipids along with b2-GPI and induce endothelial
cell damage, impaired prostacyclin production, increased platelet adhesion, and
aggregation.
- Endothelial cell damage may
also result in decreased production of endothelium-derived relaxing factor and,
thus, increased vasospasm and ischemia.
- In the secondary Antiphospholipid Syndrome (SAPS or SAPLS), vascular endothelial cell damage has already occurred, enhancing the vascular
spasm/occlusion, ischemia/infarction, and reperfusion injury.
- b2-GPI may be bound up by
aPL and (1) prevented from covering up exposed procoagulant inner membrane
leaflet phospholipids or (2) blocked from inhibiting platelet prothrombinase
activity.
- aPL may interfere with the
interaction of coagulation protein C and coagulation protein S and, thus, affect
the formation of the APC coagulation control complex (activated protein C,
protein S, and factor V).
- Possible mechanisms by which
aPL might be generated include the following:
- Autoimmunity may be a
factor; a break in tolerance may lead to an "escaped clone."
- Closely related to the above
is the concept that aPL antibodies are a response to inner membrane leaflet
antigens (ie, phosphoserine) that are exposed in apoptotic blebs on cells not
eliminated from the circulation because of an overloaded or defective clearance
system.
- aPLs may also be
cross-reactive antibodies induced by exogenous antigens from infectious
organisms (eg, viral or bacterial).
Frequency:
- In the US:
aPL antibodies are reportedly present in 1-15% of the general
population (higher in elderly persons). The presence of these antibodies in
patients with SLE is reported to be as high as 70%; however, the frequency of Antiphospholipid Syndrome (APS or APLS) (ie, aPL antibodies plus a clinical event) is far less. In patients with SLE, a history of thrombosis was present in 61% of those with positive test
results for LAC, 52% who had positive anticardiolipin antibodies, and 24% who
had no aPL antibodies.
- Internationally:
No major differences have been noted. A large multicenter European SLE
registry suggests that 3-7% of patients with SLE and aPL are at risk for
new-onset thrombosis.
Mortality/Morbidity:
Mortality and morbidity are related to the clinical manifestations; an
increased incidence of the following is seen in young individuals:
- Cerebrovascular accident
(CVA, stroke)
- Myocardial infarction (MI)
- Endocarditis (may lead to
valvular replacement)
- Pulmonary emboli (may lead
to pulmonary hypertension)
- Deep vein thrombosis
(DVT)
- Fetal loss from second
trimester to the perinatal period, including intrauterine growth retardation
(IUGR), prematurity, and symptoms of toxemia
- Catastrophic APS
(Multisystem failure secondary to thrombosis/infarction may lead to death in 50%
of cases.)
Race:
Overall, no specific race predilection exists.
- Frequency in PAPS is skewed
by race predilection of risk factors for thrombosis and atherosclerotic
disease.
- Frequency in secondary Antiphospholipid Syndrome (SAPS or SAPLS) is skewed by race predilection for autoimmune diseases.
Sex:
- In secondary
Antiphospholipid Syndrome (SAPS or SAPLS), the frequency is skewed by the female predominance in autoimmune diseases (eg, SLE)
in general.
- In PAPS, the frequency is
skewed by the inclusion of pregnancy-related events in the classification
schema.
- In both Antiphospholipid Syndrome (APS or APLS) and PAPS, the frequency related to sex is equalized in young patients, especially prior to the
onset of puberty.
Age:
- Antiphospholipid Syndrome (APS or APLS) has been described in patients of all ages. The prenatal, perinatal, and neonatal periods can be
affected.
History: Vasospastic or
vaso-occlusive events can occur in any organ system; thus, a thorough history
should be taken, and an organ-specific review of systems should be performed. A
broad spectrum of involvement ranging from rapidly progressive to clinically
silent and indolent may be present.
- Head, ears, eyes, nose, and
throat
- Blurred or double
vision
- Visual disturbance ("wavy
lines," "flashing lights")
- Visual loss (field cuts,
total vision loss)
- Cardiorespiratory
- Chest pain
- Radiating arm
pain
- Shortness of
breath
- Gastrointestinal
- Abdominal pain
- Abdominal distension
(bloating)
- "Abdominal migraine"
- Emesis
- Peripheral vascular
- Leg pain
- Leg swelling
- Claudication
- Digital
ulcerations
- Leg ulcerations
- Cold-induced finger and/or
toe pain
- Musculoskeletal
- Bone pain
- Joint
pain
- Muscular pain
- Cutaneous
- Purpuric and/or petechial
rashes
- Persistent or transient lacy
rashes of livedo reticularis
- Dusky fingers and/or
toes
- Blanching of fingers and/or
toes
- Neurologic and
psychiatric
- Syncope
- Seizures
- Headache
(migraine)
- Paresthesias
- Paralysis
- Ascending
weakness
- Tremors
- Abnormal
movements
- Memory loss
- Problems with concentrating,
reading comprehension, calculations (change in school
performance)
- Endocrine - Weakness,
chronic fatigue, arthralgia, abdominal pain (Addisonian features)
- Genitourinary
- Hematuria
- Peripheral
edema
- Pregnancy-related history -
Not expected to be of frequent concern in the field of pediatrics but may be
significant in teenagers
- Family history - A strong
family history is more pertinent to most pediatric patients; it may be a clue to
identifying patients at risk.
- Family history of frequent
miscarriage, premature birth, IUGR, oligohydramnios, chorea gravidarum,
placental infarction, preeclampsia, toxemia of pregnancy, or neonatal
thromboembolism
- Family history of MI or
stroke in persons younger than 50 years
- Family history of DVT,
phlebitis, or pulmonary embolus
- Strong family history of
migraine, Raynaud phenomenon, or TIAs
- Medication history - Use of
oral contraceptives at the time of a clinical event
Physical:
Physical findings are specific to the affected organ and can involve
any organ system. Catastrophic antiphospholipid syndrome is a multisystem
failure secondary to thrombosis/infarction and has a picture of microangiopathy
on histology.
- Peripheral
vascular
- Point tenderness to
palpation of bone or joints (bone infarction)
- Pain on range of motion of
joints without arthritis (avascular necrosis)
- Limb swelling
(DVT)
- Muscular pain (circulatory problems or DVT)
- Peripheral edema (DVT, renal
vein thrombosis)
- Decreased capillary refill
(arterial thrombosis/vasospasm)
- Decreased pulses (arterial
thrombosis/vasospasm)
- Decreased perfusion
(arterial thrombosis/vasospasm)
- Gangrene (arterial
thrombosis/infarction)
- Pulmonary - Respiratory
distress, tachypnea (pulmonary embolism [PE], pulmonary
hypertension)
- Renal
- Hypertension (renal artery
thrombosis, intrarenal vascular lesions)
- Hematuria (renal vein
thrombosis)
- Cardiac
- Insufficiency murmur of
aortic, mitral valve (endocarditis)
- Chest pain, diaphoresis
(MI)
- Gastrointestinal
- Right upper quadrant
tenderness, hepatomegaly (Budd-Chiari syndrome, hepatic small vessel thrombosis,
hepatic infarction)
- Abdominal tenderness
(mesenteric artery thrombosis)
- Endocrine - Muscle weakness (including pain),
progressive stiffening of pelvic and thigh muscles with flexion contractures
associated with adrenal insufficiency (adrenal
infarction/hemorrhage)
- Ocular
- Retinal artery occlusion
- Retinal vein
thrombosis
- Skin manifestations
- Purpuric lesions
- Superficial
thrombophlebitis
- Vasospasm (ie, Raynaud
phenomenon) (see Image 3)
- Splinter hemorrhages
(periungual, subungual) (see Image 4)
- Peripheral infarctions
(digital pitting)
- Skin ulcerations (eg, leg
ulcers)
- Bruising (associated with
thrombocytopenia)
- Central or peripheral
nervous system abnormalities
- Paresthesia, polyneuritis or
mononeuritis multiplex (vasovasorum ischemia/infarction
- Paralysis, hyperreflexia,
weakness (transverse myelitis, Guillain-Barré syndrome)
- Movement disorders -
Choreiform tremors (cerebral, cerebellar, basal ganglia infarction)
- Multiple sclerosis–like
disorder
- Learning disability
- Short-term memory
loss
Causes: The
causes of antiphospholipid antibody syndrome are unknown (see Pathophysiology).
The association of thrombotic
events with preexisting or coincident vascular perturbation is emphasized by the
high incidence of Antiphospholipid Syndrome (APS or APLS) in the following:
- Vascular inflammation,
vasculitis
- Autoimmune disease (eg, SLE,
cryoglobulinemia)
- Infectious processes (eg,
hepatitis, parvovirus, syphilis)
- Malignancy (eg, carcinoma,
leukemia)
- Vascular trauma
- Postsurgery (eg,
cardiac)
- Drug-induced state (eg,
procainamide, phenytoin, hydralazine, chlorpromazine)
- Hemodialysis-associated
condition (increased aPL antibodies with time on dialysis)
- Cuprophane membrane
exposure
Adrenal
Insufficiency Antithrombin III
Deficiency Consumption
Coagulopathy Endocarditis,
Bacterial Hepatitis A
Hepatitis B Hepatitis C Mixed Connective Tissue Disease
Mononucleosis and Epstein-Barr Virus
Infection Myocardial
Infarction in Childhood Parvovirus B19
Infection Pulmonary
Infarction Rheumatic Fever
Rheumatic Heart Disease
Syphilis Systemic Lupus Erythematosus
Thrombasthenia Thromboembolism Tuberculosis Vasculitis and Thrombophlebitis
Other Problems to
be Considered:
Carcinoma Catastrophic
antiphospholipid syndrome Cerebrovascular disease Coagulation factor
deficiencies Coagulation factor inhibitors Disseminated intravascular
coagulation (DIC) Essential mixed cryoglobulinemia Factor V Leiden
mutation Fetal loss, recurrent Guillain-Barré
syndrome Hemodialysis Homocysteinemia Immune thrombocytopenic purpura
(ITP) Infectious processes Leukemia Libman-Sacks
endocarditis Lymphoma Malignancy Methylene tetrahydrofolate reductase
mutation (MTHFR) Multiple sclerosis Prothrombin 20210A
mutation Pulmonary embolus Reactive airway disease Sneddon
syndrome Stroke Thrombocytopenia
Lab Studies:
- Antiphospholipid antibody
assays - If the clinical features are suggestive of an aPL antibody syndrome, a
thorough search for the presence of at least one of these antibodies is
imperative. See the laboratory evaluation algorithm in Image 5.
- Evaluate for
anticardiolipin, antiphosphatidylethanolamine, antiphosphatidylinositol,
antiphosphatidylserine, antiphosphatidylglycerol, and antiphosphatidic acid.
These antibodies are primarily of the IgG and IgM isotypes, although evidence is
mounting for the clinical significance of immunoglobulin A (IgA) antibodies as
well.
- Lupus anticoagulant test: At
least 2 assays need to be performed, and at least one should contain a
phospholipid-dependent step. If results are positive for LAC, a 4:1
(patient-to-normal) plasma mix test should be performed to correct for any
coagulation factor deficiencies but not dilute out a low-titer aPL antibody.
- Dilute Russell viper venom
test (DRVVT)
- Hexagonal-phase LAC test
- Activated partial
thromboplastin time (aPTT)
- Platelet neutralization
procedure (PNP)
- Kaolin clotting time (KCT)
or the Kaolin clot inhibition test
- Dilute PT (dPT)
- Textarin time (TT)
- Taipan snake venom time
(TSVT)
- Venereal Disease Research
Laboratories (VDRL) test or rapid plasma reagin (RPR) test: Extracts of bovine
heart, which contain cardiolipin, are used in these tests. These assays for
syphilis may produce "false"-positive results if anticardiolipin antibodies are
present in the serum/plasma. VRDL and RPR tests are usually less sensitive than
direct antibody testing but have a rapid turn-around
time.
- Identification of
intrarenal, renal artery, or renal vein thrombosis
- Urine dipstick analysis for
hemoglobin or protein
- Urine microscopic
examination for the presence of red blood cells
- A 24-hour urine collection
for protein and creatinine clearance
- Identification of persistent
thrombocytopenia or evidence of hemolytic anemia
- Complete blood count (CBC)
with platelet count and a blood smear examination
- Lactic acid dehydrogenase
(LDH), bilirubin, haptoglobin
- Direct/indirect Coombs test
- Urine dipstick analysis for
hemoglobin
- Antiplatelet antibody (to
evaluate for associated autoimmune thrombocytopenic
purpura)
- Coexisting deficiencies of
the coagulation system
- Antibodies to coagulation
proteins, such as anti–factor II (prothrombin)
antibodies
- Coexisting genetic
polymorphisms
- Prothrombin gene mutation
20210A
- Methylene tetrahydrofolate
reductase (MTHFR) mutations (leading to hyperhomocysteinemia)
- The A677V (alanine to
valine) polymorphism is present in 50% of Caucasians (40% heterozygotes, 10%
homozygotes).
- Plasma homocysteine levels
should also be measured.
Imaging Studies:
- For venous thrombotic events
(eg, DVT)
- Venography
- Ventilation/perfusion scan
(to document pulmonary emboli)
- For arterial thrombotic
events (eg, cerebral vascular, cardiovascular, peripheral vascular
ischemia/occlusion)
- Computerized tomography
(CT)
- Magnetic resonance imaging
(MRI)
- Magnetic resonance
arteriography (MRA)
- For cardiac events
(including vegetative valvular lesions, eg, Libman-Sacks endocarditis)
- Two-dimensional
echocardiography
- Transesophageal
echocardiography
- Cardiac angiography by
catheterization
Procedures:
- Biopsy of a sample of the
affected organ system (eg, skin, kidney) may be necessary to establish the
vasculopathy/microangiopathic picture of Antiphospholipid Syndrome (APS or APLS) versus vasculitis.
Histologic Findings: This is a thrombotic
microangiopathic process characterized by a noninflammatory vasculopathy without
vasculitis. Fibrin thrombi are associated with fibrous intimal hyperplasia and
obstruction by recanalized intimal connective tissue. Renal lesions, in
particular, are characterized by fibrotic vascular occlusion with acute
thrombosis and vaso-oclusive lesions of the intrarenal vessels. Interstitial
fibrosis and tubular atrophy are also present. See histopathology Images 7-9.
Medical Care: The following
are potential therapeutic interventions for various patient care scenarios.
Classes of medications are suggested below, and specific drugs are covered in
Medication. See the therapeutic algorithm in
Image 5.
- The healthy asymptomatic
patient with no risk factors and a negative family history for arterial/venous
thrombosis or fetal loss: No treatment or specific follow-up care is
recommended.
- The asymptomatic patient
with a family history positive for arterial/venous thrombosis or fetal loss:
Many physicians use antiplatelet prophylaxis, such as aspirin; however, others
do not treat in the absence of other risk factors.
- Primary Antiphospholipid Syndrome (PAPS or PAPLS) with venous thrombosis: The initial treatment consists of heparin followed by coumadin or low molecular
weight (LMW) heparin. The highest risk for recurrence is in the first 6-12 weeks
postthrombosis, but many physicians treat for at least 6 months in the absence
of other risk factors. Some physicians advocate treatment for
life.
- PAPS with arterial
thrombosis/infarction: In the absence of other risk factors, many would treat
with antiplatelet therapy, but the use of anticoagulants is controversial. Some
have advocated anticoagulation for life, but the recent Antiphospholipid
Antibodies in Stroke Study (APASS) did not show a statistical difference between
the group treated only with aspirin versus the group treated with aspirin and
coumadin with regard to recurrence of stroke.
- Secondary APS with arterial
or venous thrombosis: The ongoing endothelial perturbation secondary to the
underlying vasculitis places these patients at continuous risk for recurrence.
Antiplatelet therapy (often with combinations of aspirin, hydroxychloroquine,
and pentoxifylline) plus anticoagulation (with coumadin or LMW heparin) is
indicated. If the patient has positive test results for LAC and any other risk
factors (eg, factor V Leiden mutation, prothrombin gene mutation, MTHFR mutation
[see Coexisting genetic
polymorphisms]),
anticoagulation may be necessary for life.
- Catastrophic
antiphospholipid syndrome
- Antiplatelet therapy,
anticoagulation, corticosteroids, and immunosuppression all have been used with
varied success; however, all should be considered in this potentially lethal
condition.
- Consider plasmapheresis in
cases of coagulopathy with an underlying vasculitis or in the catastrophic APS.
- Precautions include
worsening of the hypercoagulable state through the removal of coagulation
control proteins such as antithrombin III. This can be ameliorated by
replacement with fresh frozen plasma or concentrates instead of albumin.
- Some suggest the use of
intravenous immunoglobulin (IVIG) as final replacement after pheresis to
decrease B-cell immunoglobulin production.
Surgical Care:
- Insertion of venous
umbrella
- Organ-specific biopsy for
diagnostic purposes
- Central-line insertion for
vascular access (for medications or plasmapheresis)
- Cardiac valve replacement or
papillary muscle repair
Consultations:
Multiple consultations may be appropriate and are dependent on the
organ system involvement.
- Medical - Rheumatologist,
hematologist, cardiologist, neurologist, dermatologist,
ophthalmologist
- Surgical - Plastic surgeon
(for peripheral vascular insults/ulcerations), cardiovascular surgeon (for
valvular infarctions, papillary muscle rupture), vascular surgeon (for arterial
graft/bypass, thrombus removal)
Diet:
- Identification and
correction of folate deficiencies and/or elevated homocysteine levels
- Dietary supplementation with
folic acid, vitamin B-12, or both is indicated for patients with
hyperhomocysteinemia.
- Dietary manipulation is
indicated to decrease consumption of methionine-containing foods, which may
increase homocysteine levels in patients carrying mutations of the gene for
MTHFR.
- Dietary counseling for
patients on oral anticoagulant therapy
- Patients should maintain a
consistent diet of foods containing vitamin K. Foods rich in vitamin K include
asparagus, broccoli, brussel sprouts, cabbage, cauliflower, egg yolk, kale,
lettuce, liver and pâtés, potatoes, spinach, turnip greens, vegetable oils, and
watercress.
- Patients should avoid foods
that have anticoagulant properties. Herbs with anticoagulant properties include
dong quai (Angelica sinensis), fenugreek (Trigonella
foenum-graecum), feverfew (Tanacetum parthenium), garlic
(Allium sativum), ginger (Zingiber officinale), ginkgo
(Ginkgo biloba), and ginseng (Panax
ginseng).
- Dietary manipulation to
prevent obesity, hyperlipidemia, and hypertension, starting at a young age,
especially in patients with a family history of these problems
Activity:
- Physical activity: No
specific limitations on activity are needed for individuals with aPL antibodies
or Antiphospholipid Syndrome (APS or APLS) other than those imposed by residua from a thromboembolic event (eg, stroke, MI). However, certain restrictions are prudent for individuals who are
anticoagulated.
- Avoid contact sports and
high impact activities.
- Use protective headgear
(helmet) for sports (eg, bicycle riding, skating).
- Travel: Recent studies have
demonstrated Doppler evidence of DVT after prolonged air travel. These data have
stimulated discussion of possible prophylaxis for travelers with aPL
antibodies.
- Antiplatelet therapy for
asymptomatic individuals with aPL and additional risk factors for the duration
of any prolonged travel
- Anticoagulation with
LMW-heparin injections for the duration of air travel (or any travel in which
the individual is cramped and stationary) longer than 6 hours if the patient has
positive test results for LAC and additional risk
factors
Very
few studies have addressed the efficacy of any treatment protocol. Most are
small retrospective analyses or anecdotal reports. Many prospective studies have
included too few patients and have been hampered by a lack of homogeneity of
test groups. The Sapporo criteria were established, in part, to ensure a uniform
homogeneous test population in order to promote accurate prospective studies of
treatment protocols for patients with Antiphospholipid Syndrome (APS or APLS).
Drug Category:
Antiplatelet agents -- Aspirin inhibits prostaglandin synthesis,
preventing formation of platelet-aggregating thromboxane A2. It is
used in low doses to inhibit platelet aggregation and improve complications of
venous stases and thrombosis. However, doses as low as 5 mg/kg appear to
additionally inhibit prostacyclin, thus promoting a procoagulant state.
Ticlopidine does not inhibit cyclooxygenase and, in this way, differs from
aspirin. It inhibits the primary and secondary phase of aggregation induced by
adenosine 5’-diphosphate (ADP) and reduces platelet-derived growth factor.
Ticlopidine may also impair platelet adhesion, resulting in prolonged bleeding
time. Dipyridamole potentiates the inhibitory effects of aspirin on platelet
aggregation.
Drug
Name
|
Aspirin (Anacin, Ascriptin,
Bayer Aspirin, Bayer Buffered Aspirin) -- Used for antiplatelet effect. Inhibits
prostaglandin synthesis, preventing formation of platelet-aggregating
thromboxane A2. May be used in low
dose to inhibit platelet aggregation and improve complications of venous stases
and thrombosis.
|
Adult Dose
|
1-2 mg/kg/d PO for
antiplatelet effect
|
Pediatric
Dose
|
Limited comparative data
exist for effective antiplatelet dose in pediatrics; 1-2 mg/kg/d PO is a typical
dose
|
Contraindications
|
Documented hypersensitivity;
liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders,
asthma; because of association of aspirin with Reye syndrome, do not use in
children (<16 y) with influenzalike illnesses
|
Interactions
|
Effects may decrease with
antacids and urinary alkalinizers; corticosteroids decrease salicylate serum
levels; additive hypoprothrombinemic effects and increased bleeding time may
occur with coadministration of anticoagulants; may antagonize uricosuric effects
of probenecid and increase toxicity of phenytoin and valproic acid; doses >2
g/d may potentiate glucose lowering effect of sulfonylurea
drugs
|
Pregnancy
|
D - Unsafe in
pregnancy
|
Precautions
|
May cause transient decrease
in renal function and aggravate chronic kidney disease; avoid use in patients
with severe anemia, with history of blood coagulation defects, or taking
anticoagulants
|
Drug
Name
|
Ticlopidine (Ticlid) -- Used for livedoid vasculitis/thromboembolic
disorders. Second-line antiplatelet therapy for patients who cannot tolerate or
in whom aspirin therapy has failed. |
Adult
Dose |
250 mg PO bid |
Pediatric
Dose |
Not established |
Contraindications |
Documented hypersensitivity; neutropenia or thrombocytopenia, liver
damage, and active bleeding disorders |
Interactions |
Effects may decrease with coadministration of corticosteroids and
antacids; toxicity increases when taken concurrently with theophylline,
cimetidine, aspirin, or NSAIDs |
Pregnancy |
B - Usually safe but benefits must outweigh the risks. |
Precautions |
Discontinue if absolute neutrophil count decreases to
<1200/mm3 or if platelet count falls to
<80,000/mm3 |
Drug
Name
|
Dipyridamole (Persantine) -- Used for thromboembolic disorders to
complement usual aspirin or warfarin therapy. Platelet adhesion inhibitor that
possibly inhibits RBC uptake of adenosine, which is an inhibitor of platelet
reactivity. In addition, may inhibit phosphodiesterase activity, leading to
increased cyclic-3',5'-adenosine monophosphate within platelets and formation of
the potent platelet activator thromboxane A2. Used alone or in combination with low-dose aspirin therapy as
indicated above. Also used in combination with low-dose oral anticoagulant
therapy (with or without aspirin) in children with mechanical prosthetic heart
valves. |
Adult
Dose |
75-400 mg/d PO divided tid/qid |
Pediatric
Dose |
<12 years: 3-6 mg/kg/d PO divided tid >12 years: Administer
as in adults |
Contraindications |
Documented hypersensitivity |
Interactions |
Theophylline may decrease the hypotensive effects; antiplatelet activity
of dipyridamole may increase heparin toxicity |
Pregnancy |
B - Usually safe but benefits must outweigh the risks. |
Precautions |
Caution in hypotension; medication has peripheral vasodilating
effects |
Drug
Name
|
Heparin -- Used for thromboembolic disorders. Augments activity of
antithrombin III and prevents conversion of fibrinogen to fibrin. Does not
actively lyse, but is able to inhibit further thrombogenesis. Prevents
reaccumulation of clot after spontaneous fibrinolysis. Used as a continuous
infusion while initiating oral warfarin therapy. |
Adult
Dose |
Initial dose: 40-170 U/kg IV Maintenance infusion: 18 U/kg/h
IV Alternatively, 50 U/kg/h IV initially, followed by continuous infusion
of 15-25 U/kg/h, increase dose by 5 U/kg/h q4h prn using PTT results (PTT at 2
times baseline) |
Pediatric
Dose |
Initial dose: 50 U/kg IV Maintenance infusion: 15-25 U/kg/h
IV Increase dose by 2-4 U/kg/h q6-8h prn using PTT results (PTT at 2
times baseline) |
Contraindications |
Documented hypersensitivity; subacute bacterial endocarditis, active
bleeding, history of heparin-induced thrombocytopenia |
Interactions |
Digoxin, nicotine, tetracycline, and antihistamines may decrease effects;
NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase
heparin toxicity |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
In neonates, preservative-free heparin recommended to avoid possible
toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative;
caution in severe hypotension and shock; monitor for bleeding in peptic ulcer
disease, menstruation, increased capillary permeability, and when giving IM
injections |
Drug
Name
|
Enoxaparin (Lovenox) -- Used for thromboembolic disorders. Prevents DVT,
which may lead to PE in patients undergoing surgery who are at risk for
thromboembolic complications. Enhances inhibition of factor Xa
(preferentially) and thrombin (factor IIa) by increasing antithrombin III
activity. The ratio of antifactor Xa to antifactor IIa activity is approximately
4:1 (1:1 for unfractionated heparin) |
Adult
Dose |
Prophylaxis (average dose): 30 mg SC q12h Treatment (suggested
dose): 1 mg/kg/dose SC q12h |
Pediatric
Dose |
Not established; suggested dose for prophylaxis: <2 months:
0.75 mg/kg/dose SC q12h >2 months: 0.5 mg/kg/dose SC
q12h Suggested dose for treatment: <2 months: 1.5 mg/kg/dose SC
q12h >2 months: 1 mg/kg/dose SC q12h Adjust dose by monitoring
anti–factor Xa and aPTT |
Contraindications |
Documented hypersensitivity; major bleeding,
thrombocytopenia |
Interactions |
Platelet inhibitors or oral anticoagulants such as dipyridamole,
salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk
of bleeding |
Pregnancy |
B - Usually safe but benefits must outweigh the risks. |
Precautions |
If thromboembolic event occurs despite LMW-heparin prophylaxis,
discontinue drug and initiate alternate therapy; elevation of hepatic
transaminases may occur but is reversible; heparin-associated thrombocytopenia
may occur with fractionated LMW heparins; 1 mg of protamine sulfate reverses
effect of approximately 1 mg of enoxaparin if significant bleeding complications
develop |
Drug
Name
|
Warfarin (Coumadin) -- Used for thromboembolic disorders. Interferes with
hepatic synthesis of vitamin K–dependent coagulation factors. Used for
prophylaxis and treatment of venous thrombosis, pulmonary embolism, and
thromboembolic disorders. Adjust dose to maintain an INR in the range of
2.5-3.5. |
Adult
Dose |
5-15 mg/d PO qd for 2-5 d; adjust dose according to desired INR (range
2.5-3.5) |
Pediatric
Dose |
Administer weight-based dose of 0.05-0.34 mg/kg/d PO; adjust dose
according to desired INR (range 2.5-3.5) |
Contraindications |
Documented hypersensitivity; severe liver or kidney disease; open wounds
or GI ulcers |
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 Medications that may increase
anticoagulant effects of warfarin include oral antibiotics, phenylbutazone,
salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic
steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid,
sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram,
metronidazole, phenylbutazone, phenytoin, propoxyphene, gemfibrozil,
acetaminophen, and sulindac |
Pregnancy |
X - Contraindicated in pregnancy |
Precautions |
Do not switch brands after achieving therapeutic response; caution in
active tuberculosis or diabetes mellitus; patients with protein C or S
deficiency are at risk of developing skin necrosis; abrupt withdrawal of
warfarin may result in a thrombotic event |
Drug Category:
Immunomodulators -- Immune globulin is a purified preparation of gamma
globulin. It is derived from large pools of human plasma and is comprised of 4
subclasses of IgG antibodies, approximating the distribution of human serum.
IgA-depleted products are also low in the IgG4 component.
Drug
Name
|
Immune globulin intravenous (Sandoglobulin, Gammagard, Gamimune,
Gammar-P) -- Used for autoimmune diseases. Neutralizes circulating myelin
antibodies through antiidiotypic antibodies; down-regulates proinflammatory
cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses
inducer T and B cells and augments suppressor T cells; blocks complement
cascade; promotes remyelination; may increase CSF IgG (10%). |
Adult
Dose |
2 g/kg IV over 2-5 d |
Pediatric
Dose |
Not established Suggested dose: 1-2 g/kg IV over 2-5
d |
Contraindications |
Documented hypersensitivity; IgA deficiency; IgE/IgG anti-IgA
antibodies |
Interactions |
Globulin preparation may interfere with immune response to live virus
vaccine (MMR) and reduce efficacy (do not administer within 3 mo of
vaccine) |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Check serum IgA before IVIG (use IgA-depleted product, eg, Gammagard
S/D); infusions may increase serum viscosity and thromboembolic events;
infusions may increase risk of migraine attacks, aseptic meningitis (10%),
urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d) Increases
risk of renal tubular necrosis in elderly patients and in diabetes mellitus,
volume depletion, and preexisting kidney disease; lab result changes associated
with infusions include elevated antiviral or antibacterial antibody titers for 1
mo, 6-fold increase in ESR for 2-3 wk, and apparent
hyponatremia |
Drug Category: Vasodilators
-- These agents are used to lower elevated blood pressure, decrease vasospasm,
or prevent ischemia. Niacin is also used to decrease hyperlipidemia.
Drug
Name
|
Nitroglycerin ointment (Nitrol, Nitro-Bid) -- Causes relaxation of
vascular smooth muscle by stimulating intracellular cyclic guanosine
monophosphate production. The result is a decrease in blood
pressure. Onset of action for ointment is in 20-60 min. Duration of
effect is 2-12 h. |
Adult
Dose |
2% ointment (20 mg/g): Apply 1-2 inches topically to chest wall or
extremity with occlusive dressing, such as Tegaderm q8h Adjust dose for
clinical effect |
Pediatric
Dose |
2% ointment (20 mg/g): Apply 0.5-1 inch topically to chest wall or
extremity with occlusive dressing, such as Tegaderm q8h Adjust dose for
clinical effect |
Contraindications |
Documented hypersensitivity; severe anemia, shock, postural hypotension,
head trauma, closed-angle glaucoma, or cerebral hemorrhage |
Interactions |
Aspirin may increase serum nitrate concentrations; marked symptomatic
orthostatic hypotension may occur with coadministration of calcium channel
blockers (dose adjustment of either agent may be necessary) |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Caution in coronary artery disease and low systolic blood pressure; care
must be taken to avoid placing fingers in mouth or near
eyes |
Drug
Name
|
Niacin (Niacor, Niaspan, Nicotinex, Slo-Niacin) -- Also called nicotinic
acid or vitamin B-3. Component of 2 coenzymes necessary for tissue respiration,
lipid metabolism, and glycogenolysis; inhibits synthesis of VLDL. Used as a
dietary supplement and as adjunctive treatment of hyperlipidemias, peripheral
vascular disease, circulatory disorders, and treatment of pellagra. Onset
of action within 20 min (extended release within 1 h). Duration of effect 20-60
min (extended release 8-10 h). Half-life 45 min. |
Adult
Dose |
50-100 mg PO tid with an upward titration until desired effect is
obtained or until adverse effects are not tolerable (used in hyperlipidemia at a
dosage range of 1.5-6 g/d PO divided tid) Once dosage established,
sustained-release capsule or tablet can be used |
Pediatric
Dose |
Not established Suggested dose: Administer as in adults with
gradual upward titration |
Contraindications |
Documented hypersensitivity; severe hypotension; arterial hemorrhage;
active liver disease or unexplained, significant increases in AST and ALT; large
doses of niacin, especially when administered in a sustained-release form
(associated with severe hepatotoxicity); a definite and recent history of peptic
ulcer disease (can reactivate ulcers); GERD |
Interactions |
Cutaneous vasodilation may be a problem if high dose used with peripheral
dilators, such as nitroglycerin, or with adrenergic blocking
agents Taking aspirin 30-60 min before first dose of the day may help
alleviate prostaglandin-mediated adverse effects of niacin (ie, flushing,
itching, headache); clonidine may inhibit niacin-induced flushing May
decrease effect of oral hypoglycemic agents, may inhibit uricosuric effects of
sulfinpyrazone and probenecid, and may increase risk of myopathy with
lovastatin |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Caution in gallbladder disease or diabetes mellitus and in persons
predisposed to gout; monitor blood glucose; may elevate uric acid levels;
pregnancy category C when used at doses higher than RDA; some products may
contain tartrazine |
Drug Category: Drugs with effects
on vascular endothelium, platelets, red blood cells -- These drugs appear
to have multiple mechanisms in the prevention of thrombosis and vascular spasm.
The exact mechanisms are largely unexplained, but changes in red blood cell
rheology, inhibition of platelet adhesiveness/activation, inhibition of
TNF-alpha production, and decreases in neutrophil and endothelial cell
activation are some of the properties of these drugs.
Drug
Name
|
Pentoxifylline (Trental) -- Used for vascular disease. May alter rheology
of red blood cells, which, in turn, reduces blood viscosity. Improves peripheral
perfusion and vascular spasm in Raynaud phenomenon and
vasculopathy/vasculitis. Other effects include inhibition of platelet
adhesiveness/activation, inhibition of TNF-alpha production, and decrease in
neutrophil and endothelial cell activation. |
Adult
Dose |
400 mg PO tid pc; may reduce frequency to bid if GI or CNS adverse
effects occur |
Pediatric
Dose |
Not established Suggested doses: <25 kg: Not
established, doses of 20 mg/kg/d PO divided tid (and higher) have been used in
Kawasaki disease; doses of 30 mg/kg/d have been infused IV over 6-h periods in
preterm infants; doses of 40-60 mg/kg/d have been used in peripheral vascular
disease 25-40 kg: 400 mg PO bid >40 kg: 400 mg PO
tid Decrease dose frequency if GI or CNS adverse effects
occur |
Contraindications |
Documented hypersensitivity; cerebral and/or retinal
hemorrhage |
Interactions |
Coadministration with cimetidine or theophylline, increases effect/toxic
potential; pentoxifylline increases effect of antihypertensives |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Caution in renal impairment |
Drug
Name
|
Hydroxychloroquine (Plaquenil) -- Inhibits platelets, chemotaxis of
eosinophils, locomotion of neutrophils, and impairs complement-dependent
antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is
equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine
phosphate. |
Adult
Dose |
310 mg (base) PO qd or bid for several wk depending on response; 155-310
mg/d for prolonged maintenance therapy |
Pediatric
Dose |
3-5 mg base/kg/d PO qd or divided bid; not to exceed 7
mg/kg/d |
Contraindications |
Documented hypersensitivity; psoriasis; retinal and visual field changes
attributable to 4-aminoquinolones |
Interactions |
Serum levels increase with cimetidine; magnesium trisilicate may decrease
absorption |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria;
not recommended for long-term use in children (but has been used for long
courses in the treatment of JRA); perform periodic (6 mo) ophthalmologic
examinations especially for color and peripheral vision; test periodically for
muscle weakness |
Drug
Name
|
Cilostazol (Pletal) -- Affects vascular beds and cardiovascular function.
May improve blood flow by altering rheology of red blood cells. Produces
nonhomogenous dilation of vascular beds, with more dilation in femoral beds than
in vertebral, carotid, or superior mesenteric arteries. Cilostazol and
its metabolites are inhibitors of phosphodiesterase III and, as a result, cyclic
AMP is increased, which leads to inhibition of platelet aggregation and
vasodilation. |
Adult
Dose |
100 mg PO bid at least 30 min ac or 2 h pc Decrease to 50 mg bid
if coadministering drugs that inhibit clearance (see
interactions) |
Pediatric
Dose |
<12 years: Not established >12 years: Administer as in
adults |
Contraindications |
Documented hypersensitivity; CHF; coadministration with grapefruit
juice |
Interactions |
Inhibitors of CYP3A4 (eg, diltiazem, erythromycin, grapefruit juice,
itraconazole, ketoconazole, macrolide antibiotics) or CYP2C19 (eg, ketoconazole,
omeprazole) may increase levels |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Caution in renal impairment; do not prescribe or administer without
thoroughly reading complete prescribing
information |
Drug Category: Platelet count
enhancers -- These agents are used to augment platelet recovery.
Drug
Name
|
Vincristine (Oncovin, Vincasar PFS) -- Mechanism of action for treatment
of thrombocytopenia is uncertain. May involve a decrease in reticuloendothelial
cell function or an increase in platelet production. However, neither of these
mechanisms fully explains the effect in TTP and HUS. |
Adult
Dose |
0.4-1.4 mg/m2 IV; not to exceed 2
mg/dose IV push; repeat weekly prn for effect |
Pediatric
Dose |
1-2 mg/m2 IV; not to exceed 2
mg/dose IV push; repeat weekly prn for effect |
Contraindications |
Documented hypersensitivity; IT administration (may be
fatal) |
Interactions |
Acute pulmonary reaction may occur when taken concurrently with
mitomycin-C; asparaginase, CYP3A4 inhibitors (eg, itraconazole,
quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim,
filgrastim), and nifedipine increase toxicity; CYP3A4 inducers (eg,
carbamazepine, phenytoin, phenobarbital, rifampin) may decrease
effects |
Pregnancy |
D - Unsafe in pregnancy |
Precautions |
Caution in severe cardiopulmonary disease, hepatic impairment (adjust
dose), or preexisting neuromuscular dysfunction |
Drug
Name
|
Danazol (Danocrine) -- Synthetic steroid analog with strong
antigonadotropic activity (inhibits LH and FSH) and weak androgenic
action. Increases levels of C4 component of complement and reduces
attacks associated with angioedema. In hereditary angioedema, danazol increases
level of deficient C1 esterase inhibitor. |
Adult
Dose |
200-600 mg/d PO divided bid/tid Angioedema: 200 mg PO bid/tid;
after favorable response, decrease the dosage by 50% or less at intervals of 1-3
mo or longer if the frequency of attacks dictates; if an attack occurs, increase
the dosage by up to 200 mg/d |
Pediatric
Dose |
Not established |
Contraindications |
Documented hypersensitivity; seizure disorders; hepatic, renal, or
hepatic insufficiency; lactation; conditions influenced by edema; undiagnosed
genital bleeding; porphyria |
Interactions |
Decreases insulin requirements and increases effects of anticoagulants;
may increase carbamazepine levels |
Pregnancy |
X - Contraindicated in pregnancy |
Precautions |
Caution in seizure disorders and renal, hepatic, or cardiac
insufficiency |
Further Inpatient Care:
- Further inpatient care is
only on an as-needed basis for management of thrombotic events but may include
the following:
- Invasive procedures for
thrombolytic therapy
- Further inpatient care is
indicated if a catastrophic Antiphospholipid Syndrome (CAPS or CAPLS) occurs.
Further Outpatient
Care:
- Interval care includes the
following:
- History and physical
examination for signs and symptoms of thrombotic or vasospastic
events
- Laboratory testing for
monitoring anticoagulant therapy, aPL antibody testing, and, in the case of
secondary APS, underlying disease activity
- Imaging/Doppler studies for
follow-up of previous thrombotic process
- Dietary and lifestyle
counseling
In/Out Patient
Meds:
- Antiplatelet therapy, such
as aspirin, dipyridamole, hydroxychloroquine, ticlopidine, clopidogrel, or
combinations of these agents
- Vasodilator and/or
antiplatelet therapy, such as pentoxifylline or cilostazol
- Vasodilators, such as niacin
or topical nitroglycerin (nitropaste)
- Anticoagulation therapy,
such as warfarin, heparin, or LMW heparin
- Warfarin sensitivity is
conferred by the presence of a cytochrome oxidase P-450 mutation (CYP2C9) and
can be associated with severe bleeding (*3 isoleucine to leucine in 10% of
Caucasians; *4 asparagine to glutamine in 3% of
African-Americans).
- The presence of an aPL
antibody accentuates the prothrombotic state that exists when warfarin is
withdrawn (because of low protein C synthesis and the presence of plasminogen
activator inhibitors).
- Abrupt withdrawal of
warfarin by the physician or by the patient through noncompliance may result in
a thrombotic event.
- Coverage with LMW heparin
during the period of warfarin withdrawal (approximately 3-5 d until protein C
levels return to normal) may reduce this risk.
- The PT, standard partial
thromboplastin time (PTT), or both may be prolonged in the presence of an aPL
antibody, thus diminishing the accuracy of these assays in monitoring of the
effectiveness of anticoagulant therapy.
- The PT/INR assays are also
inaccurate in presence of the LAC and may provide results that vary according to
source of thromboplastin (manufacturer or lot to lot).
- Chromogenic factor X levels
and the prothrombin–proconvertin time more accurately reflect the level of
anticoagulation in patients with a LAC who are on warfarin therapy.
- The adequacy of therapy with
LMW heparin should be assessed with a plasma anti–factor Xa assay, which
measures the inactivation of factor Xa. Ideally, the sample should be drawn 3
hours postinjection, kept at 4°C, and processed as soon as
possible.
- Immunomodulators, such as
intravenous immunoglobulin
- Therapy for
thrombocytopenia, such as steroids, danazol, dapsone, IVIG, or
vincristine
- Dietary supplementation with
folic acid, vitamin B-12, or both for patients with hyperhomocysteinemia
- See Medication and the therapeutic algorithm in
Image 5.
Transfer:
- Patients with CNS,
cardiovascular, or peripheral vaso-occlusive events may need to be transferred
to facilities with appropriate support personnel, experience, and
equipment.
- Patients with catastrophic
APS require intensive care units, high-level supportive care, and multiple
consultative services.
Deterrence/Prevention:
- Adequate medical
therapy
- Patient education
- Monitoring for new
events
- Monitoring for drug adverse
effects and toxicity
Complications:
- Hemorrhage may occur as a
result of overaggressive therapy.
- Rethrombosis may occur as a
result of inadequate therapy.
- Catastrophic APS can lead to
death (50% mortality rate).
Prognosis:
- The long-term prognosis is
varied and dependent on the tissue damage incurred and organ system(s) affected.
Clinical manifestations that are associated with a worse prognosis include the
following:
- Neurologic involvement (eg,
CNS involvement, transverse myelopathy)
- Gangrene of the
extremities
Patient Education:
- Lifestyle counseling is
indicated to educate patients and their families about the risk factors that are
known to complicate the prognosis of patients with Antiphospholipid Syndrome (APS or APLS).
- Dietary manipulation is
recommended to prevent obesity, hyperlipidemia, and hypertension, starting at a
young age, especially in patients with a family history of these
problems.
- Dietary manipulation is
recommended to decrease consumption of methionine-containing foods that might
increase homocysteine levels in patients carrying mutations of the gene for
methylyene tetrahydrofolate reductase (MTHFR). Folate deficiencies need to be
identified and corrected in these patients to control homocysteine
levels.
- Counsel adolescents about
the potential risks of smoking tobacco in this setting. Provide smoking
cessation programs for patients who already have started
smoking.
- In patients with a secondary
APS, encourage compliance with medications for control of underlying disease
processes, such as vasculitis and SLE.
- Dietary counseling is
indicated for patients on oral anticoagulants.
- Maintenance of a consistent
diet of foods containing vitamin K
- Avoidance of foods and herbs
with anticoagulant properties
- Counsel patients regarding
the risks of oral contraceptive use and the need for alternative methods of
contraception.
Medical/Legal Pitfalls:
- Failure to recognize
symptoms of venous or arterial thrombosis/ischemia
- Failure to recognize
symptoms of inadequate therapy (rethrombosis) or therapy that is too aggressive
(bleeding)
- Failure to interpret
laboratory analyses correctly
- Overtreatment for the
presence of a positive antibody titer alone without clinical
symptoms
- Undertreatment when
laboratory test results are misinterpreted as negative in the presence of a
clinical event
Special Concerns:
- One should exercise
restraint in ordering aPL antibody testing in healthy, asymptomatic individuals
with no known additional risk factors. In general, these patients are not
treated because little direct evidence exists of increased risk of clinical
events. However, insurance carriers (eg, life insurers, long-term care insurers)
have scanned the literature and have subsequently assigned these individuals to
a higher risk category.
- Loss of transplanted organs
due to thrombosis occurs at a high rate in patients with preexisting aPL.
-
CME Question
1: Which of the following is not a test for the lupus anticoagulant?
A:
Activated partial thromboplastin time (aPTT) B: Dilute
Russell viper venom time (DRVVT) C: Kaolin clotting time
(KCT) D: Hexagonal-phase phospholipid test
E: Rapid plasma reagin (RPR)
The correct answer
is E: The RPR is an insensitive test for the antiphospholipid antibody and
is not a test for the lupus anticoagulant, which is a functional assay. This
test is a variation on the Venereal Disease Research Laboratories (VDRL) test,
which contains reagin (a cardiolipin-containing extract of bovine heart).
CME Question
2: Which of the following is not a factor when choosing therapy in the
face of an antiphospholipid antibody–associated event?
A: The
titer of the detected antiphospholipid antibody B: Arterial
versus venous thrombotic event and organ system affected C:
Presence of a cytochrome oxidase P-450 mutation (CYP2C9) D:
Availability of monitoring tests for anticoagulant therapy
E: Compliance and reliability of the patient and family
The correct answer is A: No relationship exists between antibody
titer and response to anticoagulation. Therapy for arterial events is weighted
heavily toward antiplatelet drugs with or without anticoagulation. Venous events
are primarily treated with anticoagulation. Myocardial infarction and stroke are
primarily treated with antiplatelet therapy, although concomitant
anticoagulation has been used. Antiplatelet therapy has been used to treat
migraine headache and Raynaud phenomenon but not thrombocytopenia. The presence
of a cytochrome oxidase P-450 mutation (resulting in warfarin sensitivity)
complicates warfarin therapy and has been associated with severe bleeding.
Therapy with low molecular weight (LMW) heparin is monitored by a factor Xa
inhibition assay, which is not always available with rapid turn-around
time. Compliance with lab testing and drug dosing is vital to most therapy,
but noncompliance is particularly dangerous with warfarin. The prothrombotic
state that exists when warfarin is withdrawn (because of low protein C synthesis
and the presence of plasminogen activator inhibitors) is accentuated in the
presence of an antiphospholipid antibody.
Pearl Question 1
(T/F): To secure a diagnosis of the antiphospholipid syndrome, a
patient must fulfill the strict ²Sapporo² criteria, which were published in
1999.
The correct answer is
False: The ²Sapporo² criteria were meant as guidelines for the establishment
of uniform populations for research studies. Only those features confirmed by
prospective studies were included in these guidelines. A clinical diagnosis of
antiphospholipid syndrome can be made using the original guidelines, which
include the vasospastic symptoms (eg, Raynaud phenomenon, migraine headache) and
thrombocytopenia, as well as tests for antiphospholipid antibodies other than
anticardiolipin immunoglobulin G (IgG)/immunoglobulin M (IgM) and the lupus
anticoagulant.
Pearl Question 2
(T/F): A prolonged activated partial thromboplastin time (aPTT) is
sufficient to fulfill criteria for presence of lupus anticoagulant.
The correct answer is
False: Coagulation factor deficiencies (genetic or consumptive) can prolong
the aPTT. A mix with normal plasma is necessary to confirm that the prolongation
is secondary to an antiphospholipid antibody. A 4:1 mix (patient-to-normal
plasma) is sufficient to correct for factor deficiencies; however, a 1:1 mix may
dilute out any low titer antiphospholipid antibodies. A phospholipid-dependent
absorption assay, such as the platelet neutralization procedure (PNP) or the
phosphoethanolamine-containing hexagonal-phase assay is necessary to
differentiate antiphospholipid antibodies from antibodies to coagulation
factors. The hexagonal-phase assay has a built-in 1:1 mix so that it corrects
for factor deficiencies but, because of the dilution, may be less sensitive to
low-level antiphospholipid antibodies.
Pearl Question 3
(T/F): A 14-year-old adolescent girl presents with a deep vein
thrombosis in the left lower extremity and symptoms of a pulmonary embolus. Test
results are negative for anticardiolipin antibody immunoglobulin G
(IgG)/immunoglobulin M (IgM), and a standard partial thromboplastin time (PTT)
is within reference range; therefore, a diagnosis of antiphospholipid syndrome
can be eliminated, and another cause must be sought.
The correct answer is
False: Up to two thirds of positive sera may be missed using anticardiolipin
IgG/IgM antibody test alone. The PTT is not a sensitive test (50-60%), and even
the most sensitive aPTT is at best 70% sensitive. At least 2 and perhaps 3
assays for lupus anticoagulant are necessary because of nonoverlapping
specificities of many of the assays. Some patients with previously documented
positive test results for antiphospholipid antibodies and lupus anticoagulants
will have negative test results immediately before and during a thrombotic event
(only to have positive results again later). Other causes for thrombosis should
be investigated, regardless of antiphospholipid antibody status. Coexistent
factor deficiencies (eg, protein S, protein C, antithrombin III) and gene
mutations (eg, factor V Leiden, prothrombin 20210A, methylene tetrahydrofolate
reductase [MTHFR]) are additional risk factors and should influence any
decisions on the choice of anticoagulants, duration of therapy, and lifestyle
counseling.
Pearl Question 4
(T/F): A child who had a single venous thrombotic event and was treated
with warfarin should be given anticoagulation therapy for as long as the child
has positive test results for lupus anticoagulant.
The correct answer is
False: Anticoagulants do not decrease the levels of antiphospholipid
antibodies (although with a decrease in antigenic stimulus, one may see lower
titers of antibody). The assays for lupus anticoagulant are affected by the
presence of warfarin (some more than others); thus, prolonged activated partial
thromboplastin time (aPTT) and positive hexagonal-phase or dilute Russell viper
venom time (DRVVT) assays do not reflect the patient`s antiphospholipid antibody
status. The decision to discontinue therapy is based on many factors and depends
on careful assessment of the etiology of the event. Risk factors, such as the
presence of an underlying disease process (eg, systemic lupus erythematosus
[SLE]), coagulation factor deficiencies, metabolic defects (eg,
homocysteinemia), and gene mutations (eg, factor V Leiden, prothrombin 20210A,
methylene tetrahydrofolate reductase) weigh heavily in the decision.
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