The Lupus Book: A Guide for Patients and Their Families, Third Edition (30 page)

lupus anticoagulant. Very low platelet counts can result in serious internal bleeding and must be managed with steroids and other immunosuppressive therapies.

Lymph glands swell with active lupus, but this can be treated. The spleen

also enlarges when its filtering capacities are overwhelmed, but treatment can

resolve this problem as well.

21

Why Do Blood Clots Develop?

As many as one-third of all deaths due to complications from lupus arise from

blood-clotting abnormalities. The saga of how we came to see that patients with SLE were especially susceptible to blood clots is one of the more interesting

and convoluted tales in rheumatology. After 40 years of struggling with the

problem, rheumatologists finally realized that the solution lay in tying the knot right under our nose. Fortunately, rapid developments in this area over the last decade should greatly decrease complication and mortality rates in this group at risk.

LUPUS AND FALSE-POSITIVE SYPHILIS TESTS

In 1940, Dr. Harry Keil and his colleagues at Johns Hopkins linked 10 women

together with a very peculiar finding. They all had lupus and they all tested

positive for syphilis, but they did not have the venereal disease. Many of these tests were performed as part of routine premarital exams. I still remember several patients relating to me that in the 1940s and 1950s they were told they had

syphilis, even though they were virgins. Engagements were broken and mis-

understandings abounded. Further studies showed that up to 20 percent of all

lupus patients had a false-positive ‘‘Wassermann’’ test, as the syphilis test was called in those days. However, these patients with lupus had no unique or specific clinical features that differentiated them from others with the disease.

The Wassermann test relied upon
reagin
, an antibody found in syphilis patients. Further work showed that the antigen to which this antibody reacted was
cardiolipin
, a phosphorus-fat component of cell membranes called
phospholipid
.

WHAT IS THE LUPUS ANTICOAGULANT?

In 1948, another Johns Hopkins team led by Dr. C. Lockard Conley and his

colleagues reported that an antibody found in the blood of lupus patients pro-

longed phospholipid-dependent clotting tests. In time, it was called the
lupus
anticoagulant
. This term has turned out to be a misnomer, since—except in

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Where and How Can the Body Be Affected by Lupus?

unusual circumstances—it is associated with the formation of blood clots rather than increased bleeding. For years, no investigator linked patients with false-positive syphilis tests to those who had the lupus anticoagulant. It did not seem important, since these findings were considered laboratory curiosities and lupus patients were strange in any case. Little if any clinical relevance was attached to these oddities for some 35 years.

ANTIPHOSPHOLIPID ANTIBODIES COME OF AGE

In the early 1980s, a team of English investigators headed by Graham Hughes

began looking in earnest at antibodies to the troublesome phospholipid antigens.

Using newly available immunologic techniques, they identified several anti-

phospholipid antibodies that had important clinical implications. One of these

antibodies, the
anticardiolipin antibody
, was first correlated with an increased risk of
thromboses
, or blood clots. As the testing process was further refined, a myriad of clinical associations were confirmed.
Approximately one-third of all
lupus patients possess antiphospholipid antibodies, and one-third of these patients have complications as a result of this antibody
. Since several antiphospholipid antibodies are associated with blood clots, what was originally called the anticardiolipin syndrome is now termed the
antiphospholipid syndrome
.

WHAT IS THE ANTIPHOSPHOLIPID SYNDROME?

As mentioned above, many patients have antiphospholipid antibodies but only

a small proportion of these individuals have problems resulting from them. For

example, 10 to 30 percent of all patients with rheumatoid arthritis, scleroderma, and other forms of vasculitis have antiphospholipid antibodies, even though

clotting complications are extremely unusual. Further, many infectious diseases, particularly AIDS, are associated with these antibodies and never cause clotting problems. The reasons for this are twofold. First, lupus patients are uniquely

susceptible to the antiphospholipid syndrome because they have an additional

protein cofactor known as anti-β glycoprotein-1 that makes antiphospholipid

2

antibodies which promote clotting. Also, antiphospholipid antibodies are di-

rected against different
isotypes
, or types of immunoglobulins, against which the antibody is directed (Chapter 11). IgG anticardiolipin antibody, for example, is much more likely to lead to blood clots than IgM or IgA anticardiolipin

antibody. Higher amounts of antibody also increase the risk of clots.

The term
antiphospholipid syndrome
is applied to a group of clinical complications that result from antiphospholipid antibodies. The overwhelming ma-

jority of patients with this syndrome have lupus, but a very small percentage of otherwise healthy people have the antiphospholipid syndrome.

Why Do Blood Clots Develop?

[161]

WHAT IS THE IMPORTANCE OF

ANTIPHOSPHOLIPID ANTIBODIES?

Quite simply, antiphospholipid antibodies and the lupus anticoagulant can cause blood clots and blood clots are potentially serious. These clots can form anywhere in the body, especially in arteries or veins. If they appear in the brain, they can produce a stroke (Chapter 18). In Libman-Sacks endocarditis, the heart valves can become a source for infection and can produce emboli (traveling

blood clots) to the brain, which lead to strokes (Chapter 14). In the body’s

vascular system, phlebitis (inflammation of a vein) from a clot is not uncommon, especially in the calves of the legs. Sometimes leg clots can travel to the lungs and produce pulmonary emboli (Chapter 14). Multiple pulmonary emboli may

lead to pulmonary hypertension.

In our blood, antibodies to platelets or red blood cells can be closely asso-

ciated with antiphospholipid antibodies. Several serious conditions are associ-

ated with these antibodies including autoimmune hemolytic anemia and throm-

bocytopenia. Pregnant women with antiphospholipid antibodies can miscarry

and must be closely monitored (Chapter 30). Other conditions are also found in

this syndrome such as livedo reticularis of the skin (Chapter 12).

The risks of clotting are not necessarily related to disease activity and can

become troublesome when lupus is in remission. Table 21.1 summarizes these

findings and shows how antiphospholipid antibodies can be complicating factors

in lupus that relate to many different parts of the body.

Table 21.1.
Complications Caused by

Antiphospholipid Antibodies in Lupus

Obstetric

Fetal loss/miscarriages

Hematologic

Arterial and venous clots (thromboses)

Low platelet counts (autoimmune thrombocytopenia)

Anemia (autoimmune hemolytic anemia)

Neurologic

Strokes

Migraines

Transient ischemic attacks (TIAs, or stroke warnings)

Cardiologic

Libman-Sacks endocarditis

Pulmonary

Pulmonary emboli

Pulmonary hypertension

Dermatologic

Livedo reticularis

Ulcers and gangrene

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Where and How Can the Body Be Affected by Lupus?

WHY DOES ABNORMAL CLOTTING DEVELOP?

We still don’t know why antiphospholipid antibodies predispose patients to

blood clots. Several theories that are difficult to test have been put forward.

Current thinking suggests that these antibodies bind to platelets and activate

them. This combination increases the risk of forming clots. Or possibly anti-

phospholipid antibodies could bind to
endothelial cells
, the cells that line blood vessels, or inhibit the release of certain chemicals that dilate blood vessels.

Patients with lupus are prone to develop an acquired deficiency of several pro-

teins important in clotting. These include protein C, protein S, annexin V, Factor V Leiden mutation, and antithrombin 3. A lack of any of these proteins induces

what physicians call a
hypercoagulable state
, or a milieu where clotting risks are high.

A small percentage of patients with antiphospholipid antibodies are more

likely to experience bleeding than clotting. This group either has very low platelet counts—less than 30,000 per cubic millimeter (30,000/mm3); normal is more

than 150,000/mm3—or lacks a blood clotting factor called factor II (also known

as prothrombin).

WHAT IS THE RELATIONSHIP BETWEEN

ANTIPHOSPHOLIPID ANTIBODIES,

THE LUPUS ANTICOAGULANT,

AND FALSE-POSITIVE TESTS FOR SYPHILIS?

Since many patients with antiphospholipid antibodies feel well until they de-

velop a clot, it is frequently difficult to convey the complicated interactions between clotting factors and antibodies in a meaningful way. Figure 21.1 is

designed to help the reader visualize these interrelationships.

The majority of patients with the lupus anticoagulant also have positive tests

for antiphospholipid antibodies, and vice versa. As previously noted, many of

VDRL

Lupus

anticoagulant

Antiphospholipid

antibodies

(includes anticardiolipin antibody

and approximately eight others)

Fig. 21.1.
Relationships Between Various Methods for Detecting

Antiphospholipid Antibodies

Why Do Blood Clots Develop?

[163]

these individuals also have a false-positive syphilis test. The prevalence of the lupus anticoagulant depends on how the testing is performed. A
partial thromboplastin time
(PTT) measures how long it takes to activate the body’s intrinsic clotting cascade. Most lupus patients have normal PTTs when tested by conventional methods. However, the PTT can be modified by a variety of methods

that reduce the amount of phospholipid in the test clotting mixture. This brings out evidence of an antibody to the
prothrombin activator complex
, or clotting factors X and V (ten and five), which is an antiphospholipid antibody. It is

probably not the anticardiolipin antibody but is closely related. That’s why some patients with a positive anticardiolipin antibody can have a negative modified

PTT and others with a positive lupus anticoagulant test have negative anticar-

diolipin antibody testing.

Some of the names for lupus anticoagulant tests include the Russell viper

venom test, the RBNP, and the kaolin PTT. Ten percent of patients with SLE

have an abnormal conventional PTT and 30 percent a prolonged modified PTT.

Another 20 percent of lupus patients have a false-positive VDRL, which detects

antiphospholipid antibodies that are not usually associated with clotting prob-

lems.

WHAT TESTING SHOULD BE DONE

TO SCREEN FOR CLOTTING RISKS?

Most of my new lupus patients are screened for the lupus anticoagulant and

anticardiolipin antibody and have a syphilis serologic test performed. The cost of doing these three tests is less than $200, and they can be lifesaving. If these tests are negative or only borderline positive in patients with an abnormal clotting history, I measure protein C, protein S, anti-β glycoprotein-1, Factor V

2

Leiden mutation, and antithrombin 3 levels and look for the presence of other

antiphospholipid antibodies for which testing is now commercially available.

Anticardiolipin antibodies can appear and disappear as the disease waxes and

wanes. Steroids can decrease anticardiolipin levels or make them disappear al-

together. Some lupus patients have antiphospholipid antibodies present only

when they are pregnant. Other less common deficiencies of additional clotting

factors occasionally induce clots, and a hematology consultant may wish to test for these.

HOW SHOULD ANTIPHOSPHOLIPID ANTIBODIES

BE TREATED?

Management of the antiphospholipid syndrome is controversial. Its therapy is

not without side effects and only one-third of the patients with antiphospholipid antibodies ever experience a clinical problem. Over the years, my practice has

evolved guidelines that I have found useful.

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Where and How Can the Body Be Affected by Lupus?

My patients with a positive test for the lupus anticoagulant, or IgG isotype

(Ͼ25), IgM isotype (Ͼ50), anticardiolipin antibody are told to take one baby

aspirin a day. There is some preliminary evidence that this decreases the risk of thromboses. If a patient cannot tolerate even low-dose aspirin, all three antimalarial drugs used to treat SLE can prevent clots, so I prescribe one of them

(Chapter 27). Aspirin can be combined with antimalarial therapy. However,

patients who have had a thromboembolic event while taking aspirin or anti-

malarials require lifelong anticoagulation with warfarin (Coumadin).

The treatment of certain thromboembolic events requires hospitalization in

order to use intravenous heparinization (or occasionally streptokinase), which

dissolves the clots, followed by oral warfarin. The antiphospholipid syndrome

demands a higher dose of warfarin than that used in other diseases since we’re