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Definition
The antiphospholipid syndrome is
defined as a clinical disorder with recurrent arterial and venous thrombotic events,
pregnancy wastage and/or thrombocytopenia in the presence of the lupus anticoagulant
and/or moderate to high positive anticardiolipin test. Both a primary form, in patients
without clinically or serologically evident autoimune disorders, and a secondary form,
usually in patients with systemic lupus erythematosus, are recognized. This separation is
solely for academical purposes.
Clinical Features:
A)Thrombosis
Thrombosis may be present in small, medium, or large venous or arterial sites. The
presentation is episodic and unpredictable. Venous thrombosis of a leg or arm, renal vein
thrombosis, the Budd-Chiari syndrome, pulmonary embolism, Addison’s disease, retinal
, sagital, pelvic, mesenteric, portal and axillary vein thrombosis have all been
described. When an arterial site is involved, the manifestations may vary between the
clinical features of a stroke or transient ischemic attack. When other arterial vascular
beds are affected, such as the retinal, coronary, brachial, mesenteric, renal
(interlobular arteries, arterioles and glomerular capillaries) and dermal arterioles, the
clinical presentations are directly related to involved site.
B)Pregnancy Loss
Some patients may present with recurrent pregnancy losses often, but not always, in late
second or third trimester of gestation. Both preeclampsia and intrauterine growth
retardation have been observed concomitantly. Patients who present a history of previous
pregnancy loss are subject to a new event more frequently.
C) Nervous System Disorders
Most neurologic abnormalities are consequent to cerebrovascular thrombosis which result in
reversible or fixed focal deficit. The neurological manifestations of the patient with
antiphospholipid antibody syndrome are much wider transient ischemic attacks, cerebral
infarcts and cerebral venous thrombosis. Other neuralgic presentations include epilepsy,
transverse myelopathy, Guillain-Barré syndrome and chorea.
D)Other Features
Association of antiphospholipid antibodies with renal vein thrombosis, Addison’s
disease, gut ischemia, Budd-Chiari syndrome, thrombocytopenia, autoimune hemolytic anemia,
idiopathic thrombocytopenic purpura, cardiac valve abnormalities (insufficiency mitral and
aortic) and Libman-Sacks endocarditis have all been described. Dermatologic manifestations
are extremely frequent. The most common of them is livedo reticularis while others such as
leg ulceration, distal cutaneous ischemia or necrosis, superficial thrombophlebitis,
blue-toe syndrome, splinter hemorrhage and porcelain-white scars are also seen.
Laboratory Diagnosis
A)Venereal Disease Research
Laboratory(V.D.R.L.)
This was the first test to detect an antiphospholipid antibody. Reviews of patients with
biologic false-positive test for syphilis, however, did not identify an increased risk of
thrombosis or fetal loss. Therefore, this test is not diagnostic and the biologic
false-positive test for syphilis is not even considered a strong associate of
antiphospholipid syndrome.
B)Lupus Anticoagulant (LA) :
The lupus anticoagulant is an immunoglobulin, either IgG or IgM, that prolongs clotting
time in vitro because they agglutinate phospholipids present in the plasma thereby
preventing their participation as cofactors in coagulation steps. Its in vitro action
appears to be the inhibition of the conversion of prothrombin to thrombin.
Since phospholipids are not very antigenic, the true antigen for the lupus anticoagulant
antibody probably includes a plasma protein. The heterogeneity of the lupus anticoagulant
can therefore be explained by the concept that the lupus anticoagulants are a family of
antiphospholipid-plasma antibodies, with subgroups defined by both the phospholipids and
plasma protein involved. Accordingly, no lupus anticoagulant test is 100% sensitive.
Therefore, the following criteria are required for a positive lupus anticoagulant test:
1-prolonged partial thromboplastin time, Russel Viper Venom time, or Kaolin clotting time;
2-failure to correct the test by mixing patient plasma with normal plasma (suggesting a
clotting inhibitor is present); 3-normalization of the test with freeze-thawed platelets,
or phospholipids.
C)Anticardiolipin Test (Acl) :
Realizing that cardiolipin was the major antigenic component of the false-positive test
for syphilis, a radioimmunoassay was created directed against this phospholipid. Over
time, an enzyme-linked assay (ELISA) replaced the radioimmunoassay. Cardiolipin, which is
found in the mitocondria is unlikely the antigen against which the antibody reacts in
vivo. Nevertheless, because antiphospholipid antibodies cross-react with other negatively
charged phospholipids, cardiolipin can serve as a representative antigen in the system.
Anticardiolipin antibody is one of the few autoantibodies that have assays which allows
the identification and quantification of specific isotypes (IgG, IgM and IgA).The IgG
isotype was the major predictor of thrombosis and pregnancy loss while the IgM class was
associated especially with hemolytic anemia in addition to thrombosis. Besides the
identification of different isotypes, the antibody titer seems an useful predictor of
pathogenicity (even though it is still not clear that quantity of antibody is the best or
the only one). The higher-titer of IgG anticardiolipin antibody (>40GPL) correlates
strongly with thrombosis and fetal loss. Most patients with antiphospholipid syndrome have
medium to high IgG anticardiolipin antibody levels with or without other isotypes.
D)Relationship of the LA and aCL :
Both lupus anticoagulant and anticardiolipin antibody are associated with each of the
clinical manifestations of the antiphospholipid syndrome. There are controversy between
the relation of aCL and LA, thus the test may be positive for one, negative for other, or
positive for all.
Differential Diagnosis
The differential diagnosis will vary
depending on the clinical manifestations. In cases in which thrombosis is the main
presentation, other procoagulation states - such as protein C, protein S or antithrombin
III deficiency, malignancy, oral contraceptives, nephrotic syndrome, polycytemia,
thrombocitosis, dysfibrinogemia, paroxysmal nocturnal hemoglobinuria, homocystinuria -
should be in mind and excluded. In the case of pregnancy loss, other mechanisms may be
responsible for the fetal loss. These include fetal chromossomal abnormalities, anatomic
anomalies of the maternal reproductive tract and others such as endocrine, infectious,
autoimmune, drug induced disorders.
Management
A)Thrombosis:
Acute management of arterial or venous thrombosis in patient with antiphospholipid
syndrome is no different from the treatment of other patients with similar complications.
Thus the patient should receive heparin (1000 units/h). Prophylactic oral anticoagulant is
advised following venous thrombosis for a prolonged period of time since patients with
antiphospholipid syndrome are prone to recurrent thrombosis. In patients with stroke or
other arterial thrombotic event, aspirin (80-100 mg/day), aspirin plus dipyridamole, or
oral anticoagulation have been used by various groups. When venous thrombosis occurs an
INR>3,5 should be achieved with warfarin. In cases in which thrombosis continues
despite adequate anticoagulation high doses of corticosteroids, initially, and
cyclophosphamide have been used in addition to anticoagulation.
B)Recurrent Pregnancy Losses:
Management of women during pregnancy is controversial. Subcutaneous heparin (5000-15000
units) twice daily prophylaxis is recommended for patients with antiphospholipid syndrome.
Some centers have reported successful pregnancy outcome with prednisone (20-60 mg/day) and
aspirin (80-100 mg/day). The essential is the frequent monitorization of the patient.
Another alternative management is immunoglobulin therapy (0.5 mg/kg/day) for 3-5 day each
month. The follow-up is multidisciplinary.
New Article:
Monitoring and Treatment
of Pregnant Women With the Antiphospholipid Antibody Syndrome
More info on Anti-phospholipids.
Press Releases
ANTIBODY ASSOCIATED WITH AUTOIMMUNE DISORDERS
FOUND TO "CLUSTER" IN FAMILIES
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Finding May Be First Step In Preventing
Premature Stroke, Heart Attack and Miscarriage
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An antibody traditionally associated with rheumatic autoimmune diseases such as
lupus, has been identified as a "common thread" in families where at least one
member suffers from an autoimmune disorder associated with high levels of the antibody.
The research, conducted by investigators at Yale University School of Medicine and
St. Mary's Hospital in Waterbury, Connecticut, was published in the November issue of the
American Journal of Medicine.
The antibody, known as the antiphospholipid antibody (APL), is one of a class of
antibodies referred to as auto-antibodies. Common to autoimmune diseases, auto-antibodies
are proteins produced by the body to attack itself, rather than invading viruses and
bacteria. APL is made to fight certain good body fats called lipids. When the level of APL
is high and these proteins float freely throughout the blood, a disease state occurs.
The antiphospholipid antibody syndrome (APS) is associated with recurrent clotting events
(thrombosis) including premature stroke, repeated miscarriages, phlebitis, venous
thrombosis (clot in the vein) and pulmonary thromboembolism (blockage of an artery found
in the lung due to a clot that has traveled from a vein). It is also associated with low
platelet or blood elements that prevent bleeding.
Recently, however, even more disease states have been linked with APL including
premature heart attack, migraine headaches, various cardiac valvular abnormalities, skin
lesions, diseases that mimic multiple sclerosis, vascular diseases of the eye that can
lead to visual loss and blindness, and early peripheral vascular disease that can result
in amputations of the extremities and digits.
The St. Mary's/Yale study looked at 23 individual family members with APS, 87 of
their blood relatives, 18 spouses and 37 controls. Overwhelmingly, it found clustering of
the APL antibody in families. Of the 87 blood relatives, some 50 - or nearly 60% - had
auto-antibodies, compared with only one spouse. Approximately 33 percent or one-third had
antiphospholipid antibodies, while another 37 percent had other auto-antibodies, such as
anti-nuclear antibodies. None of the controls tested positive.
The study also found that more relatives had suffered from one of the
manifestations of APS than did either the spouses or controls. Indeed, several relatives
were found to have either lupus (4) or lupus-like syndrome (4), premature stroke (2),
recurrent fetal loss (3), recurrent thrombosis (1) or thrombocytopenia (2).
"While the study is relatively small, it is supported by other previous
studies that suggest APL antibodies may actually be genetically transmitted from family
member to family member, from generation to generation," said Thomas Greco, M.D.,
assistant clinical professor of medicine, Yale University School of Medicine, and chief,
Section of Inflammatory Diseases, St. Mary's Hospital, who conducted the research, along
with Nahum Goldberg, M.D., and Ann Marie Kelly, M.D. "More important, the APL
antibody may be associated with one disease process in one family member and yet another
disease process in another family member," he added.
Collaborative studies looking into whether the various disease states may possibly
occur in increased frequency in family members who carry the proteins are currently being
planned by St. Mary's, Yale University, and Duke University School of Medicine. In
addition, other universities may participate in the joint research effort.
Previous independent research at Duke led by Michael Seldin, M.D., Ph.D., associate
professor, supports this new data. Dr. Seldin's team found strong evidence for genetic
transmission of APS in analyses of 12 different families. Preliminary modeling in these
studies has suggested the possibility that inheritance of this disease may be due to a
single dominant genetic defect with variability in disease penetrance. The workers in
collaboration with Dr. Greco and other centers have initiated a study of the gene patterns
in families with APL. It is hoped that this "gene hunting study" will ultimately
define the genetic defect(s) in this disease.
Recent data presented by French researchers at the October meeting of the American
College of Rheumatology also support the findings of Drs. Greco, Goldberg and Kelly. In a
study on families with antiphospholipid antibodies, many relatives were found to have
diseases related to these proteins as well as many other immunologic diseases, including
rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, crohn's disease,
multiple sclerosis, low platelets (ITP), thyroid disease and others.
Dr. Greco pointed out that while the prevalence of these proteins among the
patients nationwide is relatively low (between 1 and 2 percent), for given families it may
be very high - as high as one in every two family members. "If an APL inheritance
pattern can be firmly established in future studies, the good news is that we may be able
to prevent premature stroke, heart attack, recurrent miscarriage and the other
APL-associated diseases by performing simple and inexpensive tests and taking more
thorough family
histories," explained Dr. Greco. "It may be premature to say, but APL may end up
being one of the common threads that ties together all of the seemingly unrelated 80 known
autoimmune diseases," said Virginia T. Ladd, president of the American Autoimmune
Related Diseases Association (AARDA).
She said large studies of patients with neurologic autoimmune diseases such as
multiple sclerosis and myasthenia gravis, endocrine autoimmune diseases such as thyroid,
juvenile and type 1 diabetes, and rheumatic autoimmune diseases including rheumatoid
arthritis, lupus, scleroderma and Sjogren's syndrome, need to be conducted to confirm this
theory. "If it turns out that APL is a common factor in autoimmune diseases, then the
next step for researchers is to begin looking for an autoimmune gene."
According to AARDA, approximately 50 million Americans,(20 percent of the
population or one in five people) suffers from an autoimmune disease. Of these, the
majority are women; some estimates say that 75 percent of those affected - well over 30
million people - are women. Autoimmunity is the underlying cause of all autoimmune
diseases and the leading cause of chronic illness. While these illnesses cannot be cured,
they can be treated.
AARDA is the nation's only organization dedicated to raising awareness of the early
warning signs of autoimmune diseases, bringing a national focus to autoimmunity as a major
health issue, and promoting a collaborative effort among researchers to find a cure for
all autoimmune diseases.
Profiles - Families with APL
The Frey Family - Several years ago, Jennie Frey, one of the patients in Dr.
Greco's study, suffered severe headaches, arthralgia (joint pain) and tested positive for
the antiphospholipid antibody (APL). In her workup she was found to have multiple small
strokes on her MRI scan. While in care, her daughter was hospitalized and had a stroke.
Other physicians who had been caring for her discontinued her Coumadin after a year and
she had a second stroke. In Dr. Greco's first family study, he found that not only was
this daughter (age 31) suffering from the APL syndrome (APS), but that a second daughter
who had pregnancy loss has APLs. In addition, a third daughter also has auto-antibodies in
her serum.
The Santiago Family - Amarilis Santiago is a young woman who, in her teens,
developed ITP (the low platelet syndrome associated with APLs). She was treated for that
and then developed ischemia (gangrene) of her finger and toe. She then developed deep
venous thrombosis and phlebitis of her leg. Later, she had a major lung clot and recurrent
lung clots - despite aggressive therapy - and required a filter placed in her inferior
vena cava
to prevent further clotting and stroke, and further pulmonary emboli.
The Santiago family, like the Frey's, was one of the families in Dr. Greco's study.
Amarilis' mother, Mrs. Santiago, tested positive for APLs. She also has experienced joint
pain, myalgia, headaches, but has not yet had any major events.
Amarilis' brother has not been as lucky. In the early 90's, while at the Groton
Submarine base, he developed ITP (low platelet), the exact same disease process that
Amarilis had developed. He was sent to Bethesda Naval Hospital where he tested positive
for other auto-antibodies, and upon further evaluation was diagnosed with aplastic anemia.
After conferring with Dr. Greco about the other family members' medical history, a bone
marrow transplant was ruled out by the Bethesda physicians. Instead, they treated him with
high doses of corticosteroid and were able to reverse the aplastic anemia. While he
recovered from that, he has since developed other medical problems, including a lupus-like
illness.
The Morgan Family - Sister Morgan is a nun at the Abbey of Regina Laudis in
Waterbury, Connecticut. She was diagnosed with a multiple sclerosis-like illness. Because
of atypical presentations for her neurologic syndrome, she was evaluated by Dr. Greco and
found to have APLs antibodies (two types).
Multiple sclerosis-like illnesses have not been described in patients with APLs and work
is being done currently to further study this patient population. While not part of Dr.
Greco's study, his team has seen her father, who was suffering from weakness, joint pain
and swelling. At first, his platelet count, which normally is 150,000 to 250,000, was
1,000. He suffered from thrombocytopenia (low platelet count), a disease that is well
established as a primary marker for the APS. He also had APLs. Hence, both the daughter
and father had APLs and both had different disease processes. Mr. Morgan had numerous
hospitalizations over the next year. Over that period, a classic picture of APS, with
thrombocytopenia , positive lupus anticoagulant and anticardiolipin antibodies (two types
of APLs). He then developed a perforated nasal septum. Currently in Dr. Greco's care, he
is doing well on a therapy that includes cortisone therapy and cytoxic (anticancer)
agents.
The Berardi Family - Anthony Berardi is a husband and father and has been a patient
of Dr. Greco's for many years. He has had cutaneous skin lupus erythematosus and some
other features of systemic lupus erythematosus (SLE), but has been healthy enough to
maintain his job as an electrician. His daughter developed juvenile rheumatoid arthritis
and had been followed by Dr. Greco. She has also had pregnancy loss and has tested
positive for APLs.
Her gynecologist has been notified and she has been started on treatment with aspirin
therapy throughout the current pregnancy (standard therapy now for one pregnancy loss with
APL). Recently, Mr. Berardi developed dizzy spells, numbness of his face, and symptoms
suggestive of a transient ischemic episode (compromised blood flow to his brain). Based on
his daughter's history, he was tested for APLs recently and tested positive. He is being
treated with Coumadin in order to prevent further strokes. (The strokes have been
documented on MRIs). Another family member recently died with systemic lupus
erythematosus.
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