Authors: Rita Baron-Faust,Jill Buyon
Any kind of abnormal blood clotting, whether in an artery or vein, and pregnancy losses that occur between the end of the first trimester to the middle of the second trimester should make a physician think of testing for antiphospholipid syndrome.
The presence of the
lupus anticoagulant (LAC)
,
anticardiolipin (aCL)
, and
β
2GPI antibodies
, together with clinical signs and symptoms, are the gold standard for diagnosing APS.
1
Under the most recent diagnostic criteria, you need a history of a clot, and the presence of an antiphospholipid antibody (seen in two lab tests at least 12 weeks apart) to be diagnosed with APS.
1
However, if you have antibodies but have never had a clot, your risk seems to increase along with the level of the antibody. So specific testing for one of these three antibodies (one of which includes a test to measure clotting times) is needed for a definitive diagnosis. Positive tests may help to predict which women are at risk for problems as well as for management of their treatment.
Antibodies are also called
immunoglobulins
. There are several categories of immunoglobulins—including
immunoglobulin G (IgG)
,
immunoglobulin M (IgM)
, and
immunoglobulin A (IgA)
. It’s important to know the subcategory (or
isotype
) that the antiphospholipid antibody belongs to (in the case of aCL and aβ2GPI) if you’re suspected of having APS, since the IgG isotype is
associated with a greater risk of blood clotting. So your blood tests will not only report the level of antibodies, but also their isotype.
According to revised diagnostic criteria for APS,
1
you need to have one or more of the following clinical signs, along with any of the three antiphospholipid antibodies (for aCL and aβ2GPI it can be either the IgG or IgM subtype):
In addition, these clinical signs may factor into a diagnosis:
According to the latest guidelines, APS is defined by the presence of one or more
antiphospholipid antibodies (aPLs)
detected at least 12 weeks apart, plus a history of thrombosis (arterial or venous) and/or pregnancy complications.
1
The rationale for repeated testing is that some harmless aPLs may be produced after an infection or as a reaction to medication and these would be expected to be only transient.
8
There are three important blood tests:
Anticardiolipin antibodies (aCLs)
are measured using a test called an
ELISA
(
enzyme-linked immunoabsorbent assay
), in which the clear part of the blood (
plasma
, devoid of cells such as white cells, red cells, or platelets) is analyzed for the presence of antibodies. An ELISA test is very sensitive and can detect even low levels (
titers
) of aCLs and other antibodies. The tests are reported as high titers (over 80 units), medium titers (20 to 80 units), or low titers (10 to 20 units); they also indicate whether the aCLs belong to the IgG subgroup. Generally, titers below 40 are not regarded as worrisome.
The
aCL antibodies
react with a specific type of phospholipid (called
cofactors
) in order to promote blood clots. A conventional ELISA test can detect whether aCLs react to
beta2 glycoprotein I
. Why have this additional test? For one thing, it can be more specific for APS than measuring the titer of aCLs. Studies have also shown that aCLs produced by infections don’t react with beta2 glycoprotein I and are less likely to cause clotting. Finding aCLs that react with this cofactor is considered to be a good predictor of clotting (thrombotic) events.
8
Beta2 glycoprotein I antibodies (anti-β2GPI)
can also be detected using an ELISA test. Finding specific antibodies to β2GPI may be a better predictor than ACL of a woman’s risk for clotting problems.
Lupus anticoagulant antibodies (LAC).
This test is an important marker for a high risk of blood clots and fetal loss. Tests to measure the presence of a so-called lupus anticoagulant include an
activated partial thromboplastin time (aPTT)
test, in which clot-promoting factors are added to a sample of blood plasma from a patient with suspected APS and to normal plasma, and the time both samples take to coagulate is compared. Remember, the name of this test is very misleading because a positive result doesn’t mean you are at risk for poor clotting—actually the opposite.
Recent research suggests that the type of aPL may indicate the risk for a vein or artery clot. One study found that the lupus anticoagulant and aCLs were associated with both venous and arterial thromboses, while β2GPI was strongly linked to arterial clots.
9
Laboratory tests
may also include assays for other, less common antiphospholipid antibodies (such as
phosphatidyl serine
); tests for deficiencies in
antithrombin
and in the clotting cofactors
protein C
and
protein S
(these protect against excessive clotting), and for
homocysteine
(a naturally occurring amino acid in the body that is harmful to blood vessels in high amounts and is also a risk factor for clots); and genetic tests for clotting disorders. A complete blood count (CBC) measures white and red blood cells, as well as platelets. The normal range for platelets is 150,000 to 450,000 per microliter (µL) of blood. A platelet count of less than 150,000 is considered to be thrombocytopenia (see
pages 363
to
364
) and may be present in patients with aPLs.
Magnetic resonance imaging (MRI)
may be done if it’s suspected that a woman has had strokes or mini-strokes. The damage from TIAs may be seen
as small white spots scattered around the brain. You may also need Doppler ultrasound of your legs to look for VTEs, and perhaps pulmonary scans.
Do female hormones play a role in APS? The answer is unclear.
“It probably has something to do with hormones, but it’s not as simple as ‘female hormones are bad, and male hormones are good.’ There’s a very complicated system of checks and balances in which hormones play an important role, and it looks as if people who get autoimmune diseases have a slightly different balance of hormones. But we don’t really understand these issues very well,” says Dr. Merrill.
Naturally occurring estrogens in the body help to keep blood vessels more supple and seem to prevent clogging and hardening of the arteries before menopause. On the other hand, it’s important to know that estrogen increases production of clotting factors in the liver; therefore, adding estrogen (whether in oral contraceptives or postmenopausal hormone therapy) can increase the risk of blood clots. Estrogen can also lower levels of
protein S
, an anticoagulant protein that may be abnormally low in APS.
“So it’s a question of balance, what other hormones are present or not present. We do not know that women with antiphospholipid antibodies should not take estrogen. The relationship of hormones to APS requires further study,” adds Dr. Merrill.
Elaine’s story continues:
You really need to take a careful family history. You can’t just ask about one disease—you throw out a name and people may not know what it is. Or someone would say, “What’s my thyroid got to do with anything? You have arthritis.” People don’t make the connections. I know I didn’t. And until I was diagnosed and had my daughter tested, because she kept having miscarriages, I never would have connected the dots. But it turns out that my mother had arthritis, colitis, thyroid disease, and terrible migraines and died of a stroke when she was 48. Her father and two of my uncles died of strokes. My eldest daughter has had several miscarriages, she has headaches, and she has Crohn’s disease. My other daughter has tested positive for aPLs. So autoimmunity runs in my family, but it never had a name.
Treatment for antiphospholipid syndrome usually involves measures to prevent blood clotting. This can include aspirin (which prevents platelets from clumping together) or anticoagulants like
heparin
or
warfarin
. The dose and length of treatment depends on whether you’ve had recurrent miscarriages and/or clots.
Corticosteroids and other drugs that dampen inflammation and immune system activity are not generally used in women with APS, since it’s not considered an inflammatory disease.
Immune thrombocytopenia
(see
page 369
) can occur in APS, and although it responds to steroids, it may be absolutely necessary to prevent bleeding when there is an extremely low platelet count; the coexisting tendency for bleeding due to low platelet counts and the tendency for abnormal clotting poses a major problem for women receiving anticoagulants. So treatment for women with both disorders can be a delicate balancing act.
Anticoagulant therapy
with
warfarin (Coumadin)
is prescribed if you have aPLs and have had any kind of clotting episode (including deep vein thromboses and transient ischemic attacks). If you haven’t had a clot and are asymptomatic, aspirin may be prescribed.
10
A newer anticlotting drug,
Xarelto
(Rivaroxaban), is used for prevention of venous thromboembolism (DVT and PE).
11
Treatment is usually prolonged, often lifelong, because the risk of recurrent vascular thromboses is so high. However, your level of anticoagulation will
need to be monitored carefully with regular blood tests to make sure that you’re not at risk for bleeding because your blood has been overtreated and does not clot at all.
Monitoring the level of anticoagulation
is based on a numerical system called the
international normalized ratio (INR)
. In the past, coagulation standards were set at each lab; the INR is a means of standardizing the coagulation assay. The INR measures the balance of bleeding to coagulation by measuring your actual clotting time against an expected or control time.
Your INR will be measured with daily blood tests when you’re first prescribed warfarin, until your doctor is sure clotting time is within a safe range. Blood tests will then be gradually reduced in frequency if your clotting time is stable.
The goal for APS patients with vascular thromboses is an INR between 2.0 and 3.0. At this range there’s a higher risk of bleeding complications, so careful monitoring is needed. (A slightly lower level of anticoagulation may be needed in women with both APS and thrombocytopenia.) In addition, other risk factors for thromboembolic events—including high blood pressure and high cholesterol—must be aggressively controlled.
12
Aspirin and heparin may be prescribed together or separately to prevent miscarriages in women with APS who have had recurrent pregnancy losses.
13
Women who have had recurrent early miscarriages, regardless of whether they have had a history of clotting episodes when not pregnant, are usually given injections of
low-molecular-weight heparin
twice a day, along with low-dose aspirin (81 mg).
Low-molecular-weight heparin is
fractionated
to include only smaller heparin molecules. Low-molecular weight heparin (
Lovenox
,
Fragmin
) is generally longer acting and carries less risk of bleeding than regular (or
unfractionated
heparin). This is given by injection.
Prophylactic (preventive) therapy
may be needed if you have antiphospholipid antibodies but no other clinical signs of APS, or if you do have APS and have experienced miscarriages but not thromboses, since there’s a risk for developing clots later on in life. The first step may be low-dose (81 mg) aspirin.
APS patients at high risk of clots should avoid sitting for long periods during lengthy air travel; this increases the risk of deep vein thromboses (dubbed “economy-class syndrome”).
Women with APS should avoid certain drugs that may increase their risk of clotting, including oral contraceptives and postmenopausal estrogen therapy (which increase production of clotting factors by the liver).
COX-2 inhibitors
(like
celecoxib
, see
pages 36
to
37
) prescribed for pain relief may have less anticlotting effects than aspirin, but there’s a possibility that they can also increase the risk of clots.
Careful planning for any surgical procedure in women with APS is essential because of bleeding concerns with anticoagulants. Surgery may also trigger
catastrophic antiphospholipid syndrome (CAPS)
and damage multiple organs.
14
Since CAPS can be fatal, it is treated aggressively with anticoagulants, corticosteroids, intravenous immunoglobulin, and/or plasmapheresis.
14
If you have antiphospholipid syndrome and aPLs, you will probably not have a problem getting pregnant, but you can lose the pregnancy—most commonly during the second trimester, but even in the first trimester.
The negative effects of APS on pregnancy may be due to abnormal function of the placenta. In normal pregnancies, the end portions of the spiral-shaped arteries that supply the placenta are open, and there’s no smooth muscle layer, so blood flows freely to the fetus. In women with APS, some researchers have found narrowing of these small arteries, with a thickened inner lining and deposits not unlike those in cardiovascular disease, so blood flow to the fetus can be impeded (
placental insufficiency
).
15
In addition, can be blood clots and even placental tissue death. Investigators are looking into the possible role of complement in damage to the placenta. Right now, the exact mechanism that causes poor functioning of the placenta in APS is not fully understood, so therapy to prevent pregnancy loss remains aimed at avoiding blood clots.
13
An estimated 10 to 15 percent of women who suffer recurrent miscarriages may actually have antiphospholipid syndrome.
2
“In women with clearly established APS, if the last pregnancy resulted in early loss, the chances of the next pregnancy also resulting in a loss are something around 70 to 80 percent, if you don’t treat with anticoagulants,” says Dr. Roubey. The treatment is generally a low dose of heparin and baby aspirin (see
page 359
). “There’s some evidence that if you just take the baby aspirin, you can get the success rate up to 40 percent or so. But with low-molecular weight heparin, you usually can maintain the pregnancy 70 or 80 percent of the time.”
If pregnancy loss occurs despite treatment with heparin, infusions of
intravenous gamma globulin (IVIG)
over a four- or five-day period may be a safe (but costly) alternative.
13
If you have APS you should not use estrogen therapy to treat menopausal symptoms because of the risk of blood clots. “Antiphospholipid antibodies give you one risk factor for clotting, and you don’t want to add another,” remarks Dr. Roubey.
Nonhormonal menopausal remedies might be helpful as long as they don’t promote clotting (as does evening primrose oil) or interfere with blood thinners and aspirin (as red clover/Promensil do).
Wild yams, which contain
diosgenin
(a precursor to natural progesterone (used by some drug companies to make prescription progestins), may also relieve hot flashes and other menopausal symptoms without promoting clotting. You should discuss any herbal or vitamin regimens with your doctor. (For details on nonhormonal menopausal remedies, see
page 54
.)
It’s also important to note that the risk of recurrent thromboses may increase with age, so anticoagulant therapy must be continued with careful monitoring.
In 1992, I noticed I was getting these fried-egg-sized bruises on my forearm. If I bit my tongue it would bleed for a long time. . . . I would also have very heavy periods. At the time, I was a systems analyst for a pharmaceutical company. My tongue kept bleeding, and I didn’t feel well. I went to a doctor, who eventually ran blood tests. My platelet count was around 6,000—there were virtually none in my blood. He told me I had a platelet disorder. He
wrote down the name of the disease. At the time, I didn’t even know what platelets were.J
OAN
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OUNG, FOUNDER AND FORMER PRESIDENT
,
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