Antiphospholipid Syndrome

Michael Emerson, M.D.

I. Definition A. Antiphospholipid syndrome (APS) is an autoimmune syndrome comprised of clinical features associated with measurable autoantibodies 1. Lupus anticoagulant 2. Anticardiolipin antibody 3. This autoantibody is associated with a false positive serologic test for syphilis B. The most specific clinical features of APS 1. Thrombosis a. b. Venous Arterial

Antiphospholipid syndrome was characterized in 1983 by Nigel Harris. He described it as an autoimmune syndrome with specific clinical features including thrombosis, fetal loss and thrombocytopenia in association with measurable autoantibodies. In particular, lupus anticoagulant, anticardiolipin antibody and a biological false positive serology for syphilis. Other things that we see in the antiphospholipid syndrome besides thrombosis, which can be either arterial or venous since it is based upon platelet aggregation, would include recurrent abortion, second trimester demise, thrombocytopenia and that is autoimmune mediated, but also fetal growth restriction, neonatal loss in cases in which patients are delivered for neonatal indications such as growth restriction or oligohydramnios, prematurity again for neonatal indications, migraine headaches and early onset preeclampsia. The frequency of these antiphospholipid antibodies in the general population. The incidence of lupus anticoagulant in the population is less than 1% and anticardiolipin antibody is about 2%. If we look at select populations, we see slightly different data. This is data where they looked at patients who were habitual aborters based upon three or more spontaneous abortions. They found that the incidence of lupus anticoagulant was 9% in the aborters, 11% for anticardiolipin antibody compared to 0 and 2.5%. Frequencies that were quite similar to what Lockwood had described for the control population. The number of patients screened were very small so these were not statistically significant but certainly suggest a trend. In a larger study from Italy, they looked at patients who had two or more habitual abortions with larger numbers and case control on patients. In the controls, they found again numbers very similar to what Lockwood had described, 0 and 3%. Whereas among the habitual aborters with two or more losses, 7% for lupus anticoagulant and 19% for anticardiolipin antibody. I think it suggests and is pretty much well accepted that indeed among this group, we see a higher frequency of these antibodies even though, far and away, the most common cause of early pregnancy loss is not antiphospholipid antibodies. What happens in vivo is that the antibodies bind to the platelets and bind to the vascular endothelium or at least this is what is thought to be the mechanism. The platelets then lead to platelet disruption which leads to thromboxane release. Thromboxane causes vasoconstriction and it causes platelet aggregation both of which promote thrombosis. When it binds to the endothelium, it decreases prostacyclin production. Normally prostacyclin would inhibit platelet aggregation, would cause vasodilatation and so it shifts the normal balance between these two in favor of the thromboxane and therefore in favor of thrombosis. Animal models have been established to look at this. This is the first introduction of the animal model using a murine model with Blank and his group at the University of Utah. What they did is they took patients serum that were lupus anticoagulant or anticardiolipin antibody positive, they extracted the IgG and they introduced into intraperitoneal injection into mice and compared it with injection of IgG that was anticardiolipin antibody negative. They had 100% fetal loss in those who were exposed to antiphospholipid antibodies and what they found was vascular necrosis in the decidua suggesting that IgG and fibrin were deposited within the placenta. Their conclusion was that the fetal loss was mediated by the IgG binding in the maternal decidua. Criticism of this might be that maybe it is not really the anticardiolipin antibody. Maybe it is something that coexists and the anticardiolipin antibody is merely a marker. To address this fact, this issue, Blank and his colleagues looked at, also in a murine model, monoclonal antibody for anticardiolipin antibody. They compared it to another monoclonal antibody as a control and then

2. Fetal loss 3. Autoimmune thrombocytopenia II. Antiphospholipids A. Lupus anticoagulant 1. History a. The presence of circulating anticoagulant in patients with systemic lupus erythematosus (SLE) was first observed in 1952 2. Definition a. Lupus-like anticoagulant (LA) is thought to be an immunoglobulin of the IgG or IgM class b. Its presence is suggested by in vitro interference with the activation of prothrombin activator complex (1) Prothrombin (2) Factors Xa and 5 (3) Calcium c. In vitro activation of this complex requires phospholipids, whereas in vivo phospholipids are not required (platelets present) d. LA interferes with the activation by binding phospholipids, and thereby inhibits the interaction between the phospholipids and this complex

e. "Lupus anticoagulant" is actually a misnomer, since patients with LA usually do not have bleeding tendencies, but rather a tendency toward thrombosis f. In addition, the majority of patients who have LA do not have SLE (1) Only 40% of LA-positive patients have SLE (2) Only 5-15% of SLE patients are LA-positive 3. Laboratory tests a. LA is associated with prolongation coagulation of

they also looked at purified bovine serum as a sham model. What they found was that in the anticardiolipin antibody exposed, there was a high degree of reabsorption. Placental weights and embryo weights were much less whereas in the control IgG or in the sham model, the outcomes were quite similar suggesting that indeed it is the anticardiolipin antibody. Although there could be other factors involved, it is the anticardiolipin antibody that seems to lead to this pregnancy loss. In light of the retrospective studies which suggested 90% incidence of pregnancy loss, the interpretation was, this antibody is not so bad. It only leads to 50% pregnancy loss. I guess it is a little bit the "halfempty or half-full". I would say it is not as bad as the retrospective data but it is still very different than what you would expect in the normal population. If you look at their group of 737 patients and you look at the ACA positive versus the ACA negative, you can see that the ACA positive performed more poorly. They had only 60% live birth rate, a higher incidence of spontaneous abortion, fetal death, neonatal death and higher incidence of fetal growth restriction compared to the ACA negative patients who had live birth rates, fetal growth restriction and loss pretty similar to what you would have expected in the general population. So yes, to have this antibody may not be as bad as the retrospective study suggested but it is still worse to have this antibody than to not have it. Our therapeutic options for antiphospholipid include low dose aspirin. The way it is thought that low dose aspirin works is that low dose aspirin inhibits the production of thromboxane without inhibiting the production of prostacyclin. Once in awhile, I will have a patient who says, "If that low dose aspirin does that much good, I will take higher doses of aspirin and I will just knock the thromboxane out of the water." The problem you have with higher doses of aspirin is that you inhibit both the production of thromboxane and prostacyclin. Aspirin has probably essentially no side effects to either the mother or the fetus. It is rather a quite benign form of therapy. Prednisone was utilized early on in therapy and it was thought that the prednisone led to inhibition in the production of the antibody as well as in inhibition of the binding of the antibody. Prednisone probably has few side effects as far as the fetus is concerned. It can be associated with serious side effects in the mother including osteoporosis and fractures, cataracts, stomach ulcers, adrenal insufficiency if stopped acutely. So it is not, by far, a benign therapy. Heparin is utilized as kind of a nonspecific blood thinner although recently it is suggested that it may actually inhibit binding on the platelets of these antibodies. Heparin has been utilized as either prophylactic or therapeutic dosages. It probably has few side effects to the fetus. It can be associated with bleeding and also with osteoporosis in the mother. IV gamma-globulin has been utilized primarily in case reports or in a very small series in patients who have failed other forms of therapy. It is a very expensive course of therapy. What we would normally utilize would be somewhere around $4000-$8000 per month depending on the cost in your pharmacy. It is thought to work by inhibiting the binding of the antibody. It is not exactly clear how it works. It probably has very few, if any, side effects to either the mother or the fetus but again it hasn't been utilized in large numbers of cases in pregnancies. If you look at the preterm delivery rate, much higher in the aspirin and prednisone group compared to the aspirin alone and this was primarily as a result of premature rupture of membranes and we also had a higher frequency of abruption although this was not statistically significant.

phospholipid-dependent including (1) Activated PTT (aPTT)

test,

(2) Tissue thromboplastin inhibition tests (3) Russell viper venom time (4) Kaolin clotting time b. The prolongation of these coagulation tests are not corrected by the addition of normal plasma (to rule out coagulation factor deficiency) c. The addition of phospholipid-rich plasma or platelets decreases the sensitivity of these tests and corrects the coagulation studies B. Anticardiolipin antibody 1. Cardiolipin is a phospholipid; anticardiolipin antibodies (IgG, IgM, IgA) bind negatively charged phospholipids, including cardiolipin. Anticardiolipin antibody is present in 20-30% of patients with SLE; however, the majority of patients with anticardiolipin antibodies do not have SLE 2. Laboratory tests a. The assay for anticardiolipin antibody (ACA) is a standardized immunoassay (enzyme-linked

immunosorbent assay), usually performed as an enzyme-linked immunoassay b. Standard sera are assigned numerical values, and results are reported and interpreted in a semiquantitative fashion as negative, low positive, medium positive, or high positive c. Laboratories performing anticardiolipin testing do not uniformly use well characterized assays or serum standards, factors important for reliable testing Ill. Complications Associated with APS A. Thrombosis: both arterial and venous, including stroke B. Pregnancy loss 1. Recurrent spontaneous abortion 2. Second or third trimester fetal demise C. D. E. F. Thrombocytopenia Fetal growth retardation Neonatal loss Prematurity

It led us to several conclusions. One is that a successful pregnancy outcome could be achieved with either group and there is no obvious advantage to the prednisone. There is at least the potential disadvantage of higher incidence of premature rupture of membranes, again, a finding that was observed in Cowchuck's study and the inherent side effects of immunosuppression associated with prednisone. Since this study, there have been two recently published reports in the last six months looking at aspirin alone versus aspirin and prednisone. In those two studies, the conclusion is that aspirin and heparin is better than aspirin and prednisone. But if you look critically at those studies, you see findings that are quite similar to our study and quite similar between these two studies of aspirin and heparin versus aspirin alone. The only difference between the two groups was the aspirin alone had a higher incidence of first trimester pregnancy loss. Beyond the first trimester there did not appear to be any advantage to aspirin and heparin versus aspirin alone in those two randomized trials. Conclusions. Who should be screened for these antibodies? These are the reasons that we would normally screen. Recurrent pregnancy loss. If somebody has one prior loss, I would not recommend screening them. I think your yield is too low and interpretation of the results may be more difficult. So anybody with repetitive first trimester or unexplained second or third trimester loss. History of thrombosis. False positive serology. Connective tissue disorders, although the frequency of these antiphospholipid antibodies are quite low in the general population, in patients with lupus, the incidence of anticardiolipin antibodies is about 30%, of lupus anticoagulant about 15%. In other connective tissue disorders, they are also increased. So anybody with these disorders, I would look for antiphospholipid antibodies. Somebody with a prolonged coagulation time that does not correct with added serum, you would want to screen. Second trimester preeclampsia or second trimester fetal growth restriction. Who should be treated? Recurrent pregnancy loss greater than two, second trimester loss, neonatal death associated with fetal growth restriction so that patient that had neonatal indications for delivery and may have had an intrauterine demise had intervention not been performed and patients with thrombosis. What is therapy? The most common form of therapy for this is aspirin and heparin. We would still consider aspirin as our first line therapy for these patients that we have listed here. The only indication that we would include heparin within there is these patients with thrombosis. So our normal therapy would be aspirin, followed by aspirin-heparin. We do not utilize aspirin and prednisone. The only reason that any of these patients would be on prednisone is if they were on prednisone for some other reason such as connective tissue disease like lupus. I think that we may find that there is a select group of patients who their primary risk factor may be early unexplained loss who may actually benefit from aspirin and heparin early on with potentially discontinuation of heparin after the first trimester. I think the next step, in again learning to walk after we have been running, is to go back and look at a randomized trial of aspirin and heparin in the first trimester and then after the first trimester, patients to be randomized to receive either aspirin alone or aspirin and heparin in an effort to try to reduce first trimester loss but also reduce the risks of maternal complications associated with heparin. Studies show that there was an advantage after the first trimester of aspirin and heparin compared to aspirin alone. Finally, what are the indications for aspirin alone. If a patient has antiphospholipid antibodies but has never been pregnant, I would only treat them with aspirin alone. If they had had one first trimester loss

G. Migraines H. IV. A. Pre-eclampsia (second trimester) Prevalence and Natural History Prevalence 1. Selected populations a. Autoimmune disorders (1) Among patients with SLE, 5-15% are LApositive and 20-30% are anticardiolipin antibody-positive (2) Patients with other autoimmune disorders have an increased incidence of these antiphospholipids, however, to a lesser degree than those with SLE b. Recurrent pregnancy loss: LA- and ACApositive in 5-10% of patients c. Single first trimester loss: prevalence of LA

and ACA similar to the general population 2. General population: LA-positive in 0.2-0.3% of pregnant population, whereas ACA-positive in 23% of pregnant population B. Natural history 1. Retrospective studies a. Results suggest likelihood of successful pregnancy outcome <20 % b. Study design limits reliability of results since patients are identified based upon poor reproductive histories 2. Prospective studies a. Successful pregnancy outcome in 50% of ACA-positive patients without therapy b. Frequency of preterm delivery, growth retardation, and neonatal loss increased V. A. Pathophysiology of APS Inhibition of prostacyclin (PGI2) production by endothelial cells and increased thromboxane release by platelets, resulting in thrombosis (arterial or venous, including placenta) B. Alternative theories 1. Decreased fibrinolytic activity (the result of inhibition of prekallikrein factor production) 2. Deficiency of protein C activity 3. Deficiency of protein S activity 4. Deficiency of antithrombin III activity C. Placental histology (necrotizing decidual

and for some reason they were screened, I would treat with aspirin alone. If their only risk factors are prior IUGR, early preeclampsia, I would treat them with aspirin alone and I would not treat them with aspirin and heparin. I include all patients here and again this is relevant to our experience. We consider aspirin alone as a reasonable option for all patients, not just the patients with these indications. When I say all patients, all patients who are antiphospholipid antibody positive.

vasculopathy) 1. Intimal thickening 2. Fibrinoid necrosis 3. Acute atherosis 4. Intraluminal thrombosis 5. Placental infarction VI. A. Therapy Therapeutic options

1. Aspirin (low dose, 75-100 mg per day): low-dose aspirin is thought to inhibit the production of thromboxane without inhibiting prostacyclin 2. Prednisone (10--60 mg per day): may reduce antibody production and activity 3. Heparin (prophylactic, 5,000-10,000 units per day, or therapeutic, 15,000-30,000 units per day): inhibits thrombosis 4. IV gamma-globulin: mode of action unclear, possibilities include feedback inhibition of antibody synthesis or reticuloendothelial Fc receptor blockade B. Side effects of therapy 1. Aspirin 2. Prednisone 3. Heparin 4. IV (-globulin C. Studies 1. Nonrandomized trials 2. Randomized trials D. Recommendations

VII. Antenatal Surveillance A. B. C. Modified bedrest Maternal assessment of fetal movement daily Serial ultrasound assessment of growth and amniotic fluid volume D. E. Serial Doppler velocimetry of the umbilical artery Nonstress testing weekly (initiate at 30-32 weeks gestation) F. Timing of delivery