and Treatment of Pregnant Women With the Antiphospholipid Antibody Syndrome
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
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.
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
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.
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.
A)Venereal Disease Research
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
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.
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.
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.
and Treatment of Pregnant Women With the Antiphospholipid Antibody Syndrome
More info on Anti-phospholipids.
ANTIBODY ASSOCIATED WITH AUTOIMMUNE DISORDERS
FOUND TO "CLUSTER" IN FAMILIES
Finding May Be First Step In Preventing
Premature Stroke, Heart Attack and Miscarriage
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
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
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
"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
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
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
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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