anticoagulants (LA) are a heterogeneous group of antibodies that cause a
variety of clinical and laboratory effects.
They affect 2-4% of the U.S. population, making familiarity with
them a necessity for the clinician.
Many LA are discovered accidentally such as when a prolonged
activated partial thromboplastin time (APTT) is found during a
pre-operative evaluation. Often,
there are no clinical consequences other than the need to explain the
reason for the long APTT. A
minority of patients with LA have a hypercoagulable state manifested by
recurrent thromboses, multiple spontaneous miscarriages, migraine
headaches, or stroke. Very
rarely, patients may have bleeding.
have traditionally been classified as anti-phospholipid antibodies, but
a more correct view is that they are antibodies directed against plasma
proteins, which also bind to phospholipid surfaces.
They are usually IgG, IgM, or mixtures of both, and frequently
interfere with standard phospholipid-dependent coagulation tests.
Importantly, the clotting test abnormalities caused by LA are in
vitro phenomena; the antiphospholipid antibodies of the LA react
with the phospholipid preparations used to initiate clotting reactions. In vivo clotting
factor activities are not diminished and, except in extremely rare cases
where there are specific antibodies directed against clotting factor II,
there is no danger of a bleeding diathesis.
It should also be recognized that most patients with LA do not
have lupus erythematosus or other systemic autoimmune disorders.
exact etiology of LA is unclear. These
antibodies are commonly found in asymptomatic elderly individuals.
Among patients with autoimmune disorders, those with SLE have the
highest incidence (20-45%). Patients
with HIV infection also have a high incidence of LA at some time in
their course. A number of
drugs, most notably, procainamide, hydralazine, isoniazid, dilantin,
phenothiazines, quinidine, and ACE inhibitors are known to induce LA. The majority of patients with drug-induced LA however, have
no systemic autoimmune disease or any other underlying disorder and have
no clinical manifestations.
only a minority of patients with LA present with recurrent episodes of
thrombosis, LA are one of the most common acquired predisposing causes
of thrombosis; they are associated with cerebral, deep venous, or renal
vein thromboses, as well pulmonary emboli or arterial occlusions,
particularly stroke. Depending
upon the population studied, the incidence of thrombotic complications
in patients with LA ranges from 5-20%.
Reports indicate that LA are found in 8-14% of patients with deep
venous thrombosis and approximately 1/3 of patients with stroke <50
years of age. There is also evidence that the type of recurrent thrombotic
event, venous or arterial, tends to be persistent over time in the same
anticoagulants and Pregnancy
have clearly been associated with an increased risk of fetal loss due to
pre-eclampsia, placental abruption, intrauterine growth retardation, and
stillbirth. Some evidence suggests that this may be due to antibodies
against the placental anticoagulant protein, annexin
infarction has been suggested as the cause of the failure to carry to
term but pathological analysis has not definitely supported this
anticoagulants and thrombocytopenia
immune type thrombocytopenia has been observed in a small percentage of
patients with LA; this may be due to reactions between antibodies and
platelet membrane-associated phospholipids.
single test is definitive for a lupus anticoagulant.
As a result, a variety of tests and testing algorithms are used
in an attempt to establish the diagnosis.
The typical screening test is a prolongation of the standard APTT
that fails to correct when the patient's plasma is mixed with normal
plasma. This suggests an
inhibitor since normal plasma usually corrects any factor deficiency.
However, this screening alone is inadequate to establish the
presence of a LA because many affected patients, especially pregnant
women, have normal APTT's. Conversely,
occasional patients with a prolonged APTT that does not correct may have
specific antibodies against individual clotting factors.
Thus, additional tests are needed both to establish and exclude
the presence of a lupus anticoagulant.
tests that aid in the recognition and confirmation of lupus
anticoagulants include tests for anticardiolipin and
antiphosphatidylserine antibodies, the tissue thromboplastin inhibition
index (TTI), the dilute Russell viper venom time (dRVV), the prothrombin
time (PT), the hexagonal lipid neutralization test, and testing for ß-2
glycoprotein I. Standard
clotting factor assays may also be performed; they can differentiate LA
from the more clinically dangerous specific antifactor antibodies such
as anti-factor VIII antibody.
of the foregoing tests either directly measure antiphospholipid
antibodies or manipulate the amount of active phospholipid available to
initiate the clotting cascade.
LA are found incidentally in asymptomatic patients, no therapy may be
necessary. In patients with
drug-induced LA, discontinuing the agent will usually cause any abnormal
clotting tests to revert to normal in 2-3 weeks.
thrombotic patients who need anticoagulation with heparin have long
APTT's due to a lupus anticoagulant, monitoring the heparin can be
accomplished by using the anti-factor Xa activity assay, which is
usually used for the monitoring of low molecular weight heparin.
Although the PT is less affected by LA than the APTT, the
chromogenic factor X assay may be used to determine the accuracy of the
INR in patients with LA.
studies of small groups of non-randomized patients suggest that a
combination of aspirin and prednisone or heparin alone may result in
successful term pregnancy in women with recurrent fetal loss.
However, no randomized study has established the usefulness of
may influence the recommendation for the duration or intensity of
anticoagulant therapy in patients with thrombotic events.
If a LA, present initially, persists after a standard course of
anticoagulation in a patient with thrombosis, continued anticoagulation
is usually recommended for at least three additional months when repeat
testing for the LA is again performed.
If the LA disappears, anticoagulation may be discontinued; if it
remains, indefinite anticoagulation is usually recommended because of a
high recurrent thrombotic risk.
intensity INR ranges of 2.5 to 3.5 have been shown to be beneficial in
patients with LA on oral anticoagulation, but the uses of the
chromogenic factor X assay to determine any possible interference of the
LA with the PT/INR may again provide more accurate dosing.
to suppress any undefined underlying autoimmune process with prednisone
in patients with LA to lower thrombotic risk has not been shown to be
effective and is currently not recommended.