Treatment of Antiphospholipid Antibody Syndrome

The spectrum of the antiphospholipid syndrome
allows for the stratification of risks and therapeutic
options. Among patients with antiphospholipid antibodies,
the risk of thrombosis at some future time
is moderate in women with pregnancy loss alone,
higher among those in whom thrombosis occurs,
and extremely high in patients with the rare but devastating
syndrome of rapidly progressive, multistage
vascular occlusion, known as catastrophic
antiphospholipid syndrome.


By contrast, asymptomatic
persons who are incidentally found to have
positive antibody tests are at the lowest risk for any
of these events. A high titer of auto antibodies, especially
lupus anticoagulant, increases the likelihood
of thrombosis, as do smoking, the use of oral
contraceptives, surgery, immobilization, pregnancy,
and heritable pro coagulant states. Another measure
of complexity is that patients with antiphospholipid
antibodies who do not have recurrent thrombosis
but who do have livedo reticularis, thrombocytopenia,
cardiac-valve vegetation, a multiple sclerosis–
like condition, or progressive cognitive dysfunction
do not fulfill the usual criteria for the diagnosis of the antiphospholipid syndrome. In these patients,
the risk of thrombosis, and hence the urgency of
treatment with an anticoagulant agent, is unknown.
Thrombosis and fetal loss can also be caused
by mutations involving factor V (factor V Leiden),
prothrombin, or methylenetetrahydrofolate reductase,
or by deficiencies of protein C, protein S, or antithrombin
III. Opinions differ, but the concomitant
presence of two or more prothrombotic risk
factors may increase the risk. Thus, a precise diagnosis
requires an expensive and inconvenient panel
of tests. Very few clinical clues differentiate the various
types of thrombophilia. Arthralgia, leukopenia,
thrombocytopenia, livedo reticularis, or a rheumatic
illness (or a family history of rheumatic illness) increases
the likelihood that the antiphospholipid
syndrome is the cause of a newly diagnosed thrombosis.
Two tests, a standardized enzyme-linked immunosorbent
assay for anticardiolipin antibodies
and a clotting test for lupus anticoagulant, readily
and inexpensively confirm or rule out the antiphospholipid
syndrome. Population studies usually identify
the antiphospholipid syndrome and factor V
Leiden as the most common causes of thrombophilia,
each accounting for about 20 percent of cases
of recurrent thrombosis among young patients.
Approximately 15 percent of women with recurrent
pregnancy loss have the antiphospholipid syndrome.
The antiphospholipid syndrome and the
genetic thrombophilias are proportionately less frequent
among persons 65 years of age or older, because
with increased age, atherosclerosis and cancer
are more frequent causes of thrombosis.
A heterogeneous clinical picture has led to discrepant
recommendations for treatment of the
antiphospholipid syndrome. Corticosteroids, prescribed
in the 1980s because of the association of
the syndrome with lupus, proved ineffective in preventing
pregnancy loss.
4
In pregnant women with
a history of recurrent fetal loss, low doses of unfractionated
heparin (5000 U administered subcutaneously
twice daily) are as effective, with respect to the
outcomes of pregnancy, as high doses (10,000 U or
more twice daily).
5
Patients with previous thrombosis
require high doses. Prospective dose-ranging
studies of warfarin for the treatment of thrombosis
in patients who are not pregnant have not
been done. A 1995 report of a retrospective study
concluded that anticoagulant therapy that results in
an international normalized ratio (INR) of 3.0 or
higher affords better protection against recurrence
than does less intense anticoagulant therapy.

Antiphospholipid Antibody Syndrome

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

ANTIPHOSPHOLIPID ANTIBODIES (APLA)-DEFINITIONS AND HISTORY

APLA are antibodies directed against certain phospholipids. There are found in variety of clinical situations. APLA are important to detect because in certain patients they are associated with a syndrome that includes a hypercoagulable state, thrombocytopenia, fetal loss, dementia, strokes, optic changes, Addison's disease, and skin rashes. APLA were first described by Conley in the 1950's when it was noted that patients with lupus often had prolonged activated partial thromboplastin times (APTT). Soon there after the associated with false positive VDRLs was noted. Despite the elevation of the aPTT it observed that these patients did not develop hemorrhagic complications unless they also had hypoprothrombinemia or thrombocytopenia. Bowie first described the association of APLA and thrombosis in 1964. Feinstein and Rapaport in an 1972 review called this phenomenon the "lupus anticoagulant". Harris, recognizing that cardiolipin is a major component of the VDRL test, developed and popularized the anticardiolipin (ACLA) antibody test in the mid-1980's. In the 1980's it become well recognized that patients did not have to have SLE to have symptomatic disease from APLA.

One major difficulty in studying APLA is that no one really knows what the underlying pathogenic mechanism is that leads to the clinical syndrome. This review will side-step this issue (best reviewed in the McNeil paper) and concentrate on clinical matters.

WHO GETS APLA?

About 30-50% of patients with SLE will have APLA. These antibodies can also be found in patients with other autoimmune diseases. Patients without lupus or other autoimmune disease can have symptomatic APLA ("Primary APLA syndrome"). Children will often develop transient APLA after viral infections. These often come to clinical attention during pre-operative evaluation for tonsillectomy. Up to 30% of patients with HIV infection will also develop APLA. The infection associated APLA are not associated with thrombosis. Medication may also induce APLA. Chlorpromazine is the most common but APLA have also been associated with procainamide, dilantin and quinidine. In screening studies of blood donors, up to 8% of normal people will have APLA. However the APLA in these people are usually low titer and most often occur in young women.

TESTS FOR ANTIPHOSPHOLIPID ANTIBODIES (APLA)

There are two main groups of tests for APLA's: testing for presence of antibodies to cardiolipin and the coagulation based tests for APLA.

Coagulation Based Tests: As you recall, APLA react with phospholipid. Phospholipids are used in coagulation tests to provide a surface for the coagulation reaction to occur. The basis for all these tests is that if there are antibodies binding to the phospholipid, it will interfere with the coagulation reaction and prolong the clotting time. Once an elevated aPTT is found one must verify it is due to an inhibitor by demonstrating it does not correct with a 50:50 mix. This is done by making a mixture of the patient's and normal pool plasma and performing a aPTT on it. Then the mixture is incubated for 30, 60 and 120 minutes and aPTT's are performed at various times. Each of the three major diagnostic considerations will perform differently on the 50:50 mix:

1. Factor Deficiency. aPTT will correct to normal at time 0 and stay in the normal range on each of the time points.

2. APLA. Does not correct to normal (may partially correct) at time 0 or any time point. May actually prolong further. (Lupus cofactor effect).

3. Factor Inhibitors. Corrects to normal at time 0 but then prolongs at next time points.

TIME (SECONDS) 0 30 60 120

NORMAL POOL 30 32 33 34

PATIENT'S 50 52 55 53

50:50-DEF(1) 30 32 33 34

50:50-APLA(2) 40 38 42 39

50:50-INHIB(3) 30 34 40 55

After one demonstrates the prolongation of the clotting time and establishes this is do to an inhibitor, then one needs to show its dependance on phospholipids. To do this one adds phospholipid derived from platelets or "hexagonal phase" phospholipids (named for the shape they assume in suspension). APLA bind avidly to both platelet and hexagonal phase" phospholipids. Thus addition of these lipids will correct the prolonged coagulation tests. Factor inhibitors will not correct with platelet phospholipids. To summarize, one screens for APLA with coagulation based tests to see if any test is prolonged. If one test is prolonged, then one uses a 50:50 mix to prove it an inhibitor. Then one uses platelet or hexagonal phospholipids to correct the abnormal clotting time.

aPTT. Only sensitive to 30% of APLA. One can increase sensitivity by using different reagents. Many patients with APLA will have normal aPTT and therefor one cannot exclude APLA by just doing a aPTT.

Dilute Russell Viper Venom Time (dRVVT). This test is very sensitive to any interference with phospholipid because it utilizes very little added phospholipid. It is performed by initiating the coagulation cascade with Russell Viper venom.

Kaolin clotting time. This test uses no added phospholipid and is the most sensitive test to APLA but is very technique demanding.

Platelet Neutralization Test. This test takes a reaction that is prolonged by plasma which does not correct with a 50:50 mix and adds extracts of platelet. If it corrects to normal this is very specific for APLA.

Hexagonal Phase Phospholipid. Same principles as the platelet neutralization test but used hexagonal phase phospholipids. Currently OHSU uses a testing system that corrects for anticoagulation and other factor deficiencies. Thus this is the only valid test for lupus inhibitors when patients are on anticoagulants.

Anticardiolipin Antibodies: This is an ELISA test for antibodies to cardiolipin. Therefore, unlike the coagulation based tests, it can be performed on plasma which has been anticoagulated. Tests results at OHSU is reported in standard deviation with >3SD abnormal. Tests are also reported as specific isotype (IgG, IgA, IgM). It is still debatable if specific isotypes are associated with different patterns of disease. The antibodies that react with cardiolipin are different ones then those which cause the lupus inhibitor effect. Only 60% of patients with APLA will have both ACLA and lupus inhibitors. Consequently one needs to assay for both in assessing patients for APLA. Recently is has been discovered that the ACLA actually react with a complex of a cardiolipin and protein known as beta-2-glycoprotein. ACLA tests utilizing this complex are being tested to see if they provide more clinical information then the routine APLA.