Michael D. Lockshin, MD

Public and Patient Education Department Program, October 17 and 24, 2006
Michael D. Lockshin, MD

How many days before a colonoscopy procedure should a person with APS cease taking their prescribed 81mg of aspirin or other similar medications?
The amount of time before a procedure should be approximately 1 week for aspirin, clopidogrel (Plavix) or warfarin (Coumadin). For low molecular weight heparin you need 24 hours and for unfractionated heparin the patient should cease about eight hours before.

What are some symptoms a person with APS should worry about?
Visual changes, speech defect, sudden change of anything, persistently blue digit, unusual bruising or red spots on the skin.

If I have APS, is my immune system overactive or underactive?
There is a technical answer and a conventional answer to this question. The conventional answer is that the immune system is overactive and it produces an antibody that should not be there. The technical answer is that scientists are highly suspicious that the overactivity is an attempt by the body to compensate for an under active part of the immune system that we haven’t yet identified.

If you have lupus without APS, are you at risk for developing it later on? If you have APS without lupus, what are your chances for developing lupus?
In general, if both diseases appear, they do so at about the same time, so the answers to the questions are “no” and “very low,” respectively.

Is oral surgery safe for someone with APS?
In general, yes. But it depends on the specific details for the patient and for the oral surgery procedure. There may be specific precautions necessary, i.e., antibiotics, if heart valves are abnormal, or changes of anticoagulation medicine if the surgery is extensive.

Is a diagnosis of “sticky platelets” the same as APS?
The British, especially those associated with Graham Hughes’s group, use the term “sticky platelets” to describe APS. There are other causes of sticky platelets and I don’t think the term is very accurate, so I don’t use it myself.

How do I know if my doctor is prescribing the right medication for me?
That is always a tough question, because there’s a fair amount of variability in both patients and doctors. The best option is to get another opinion from someone who has a great deal of experience. This applies to any illness - not just antiphospholipid syndrome.

Why don’t doctors use a Greenfield filter as opposed to coumadin?
Greenfield filters are used on occasion when the indication is correct. Clots form on the filter and above it, so you still have to take anticoagulation medication. (For those who don’t know, a Greenfield filter is a sort of mesh that is placed in the big vein leading from the legs to prevent blood clots in the legs or pelvis from traveling to the lungs. It is sometimes used for a short period of time after surgery and then removed when the risk of clotting is over. For someone with APS, the risk of clotting is never over. A Greenfield filter is usually used when the clots in the lower extremities are very big and very threatening and/or have already traveled to the lungs.)

If a pregnant woman has APS and severe preclampsia, should heparin absolutely be used?
There is no history of clots or previous miscarriages.
There are not clear rules on this, but severe preclampsia is considered to be a manifestation of APS, and most physicians who treat APS do advise the use of heparin in this circumstance. There is an additional reason to do so; in the animal models of pregnancy complications heparin appears to be beneficial in ways that are not associated with clot prevention, so the theory is right.

How is preclampsia related to APS?
Early and severe preeclampsia occurs relatively commonly in women with APS whether or not they have had prior symptoms. There are a number of theories about the mechanism, but exactly how they are related biologically is not yet clear. Research in this area is very hot right now and we may have answers in the near future.

How common is it to have miscarriages, strokes, or a heart attack?
Each of these problems can be a manifestation of antiphospholipid syndrome. For one treated patient to have all three to occur would be uncommon, at least over a 10-year period. However, if you ask about these things happening over 30 or 40 years, then there are not really clear answers since we have only known about antiphospholipid syndrome (separate from lupus) for about 15 years.

Is rituximab effective for the kidney disease aspect of APS?
Rituximab is an experimental drug for antiphospholipid syndrome. We are asking this question right now in our current studies and hope to have an answer for this within a few years. At this moment the most honest answer is that we don’t know.

See the complete article on the Hospital for Special Surgery’s web site

Adapted from a talk at The SLE Workshop at Hospital for Special Surgery
Michael D. Lockshin, MD

A syndrome is a collection of events that constitute a specific illness. Antiphospholipid Antibody Syndrome (APS) includes a series of symptoms as follows:

Repeated clotting in veins (for example - a pulmonary embolus) or arteries (examples include a stoke, a blood clot in an arm or a leg, or a coronary).
Recurrent pregnancy loss, usually in mid to late pregnancy as opposed to early pregnancy.

An antibody test has to be strongly positive. Having a weak or trace positive test is fairly common in the general population and is not enough to diagnose the syndrome.
The above symptoms are specifically characteristic of APS. However, there are a lot of other symptoms that are also associated with APS. Such symptoms include skin changes and low platelets.

You may have heard different terms used when referring to tests for the antibody. The antiphospholipid antibody is the more general term. The anticardiolipin antibody refers to a type of phospholipid. Another test for the antibody is the Lupus Anticoagulant Test. These terms are all equivalent from the patient’s point of view. In other words, they all test for the same thing. The only difference is in the type of measurement.

In the 1900’s, certain people had false positive test results for syphilis. This was a curiosity without clinical importance at the time, but rediscovered in the 1940’s. By the 1950’s, it was foundthat this false positive syphilis test had something to do with lupus. Today, although known as a clue to diagnosis, a false positive syphilis test is not sufficient for a diagnosis of lupus or APS.

In the 1950’s and 1960’s it was realized that the antiphospholipid antibodies had something to do with blood clots. In 1983, Hughes, Gharavi, and Harris developed a simple test for the antibodies called an ELISA. Clinical descriptions of various things that happened to people who had this antibody were also noted. In 1985, descriptions of what happened in pregnancy for people with this antibody were also noted.

Up until 1989, it was thought that APS was a subset of lupus. However, enough cases were seen in which people had APS without having Lupus. It was decided that it should be categorized as a separate illness. Several names have been used to describe it. The most common name is PAPS (primary antiphospholipid syndrome). It is also sometimes called Hughes’ syndrome. In 1990, the B2-Glycoprotein 1 was discovered. The importance of this protein will be reviewed later.

See the complete article on the Hospital for Special Surgery’s website

About HSS’ SLE Workshop

posted 6/2/2004

Summary of a presentation given at The SLE Workshop, a free support and education group held monthly for people with lupus and their families/friends.

Grand Rounds
Michael D. Lockshin

I want to give you both an overview of the antiphospholipid antibody syndrome and update the audience on things that happened at the recent meeting in Tours, France, which gave some of the most current and up-to-date information on the syndrome. I am also going to give you some speculations about the future.

The basic definition of the syndrome has been around for more than a decade now and has consisted of recurrent thromboses, venous or arterial, recurrent pregnancy losses (I will have more to say about that in just a few minutes), the presence of an antibody, a diagnostic antibody within a family of antibodies, not a single antibody, and some people will add another major component which is the catastrophic vascular occlusion syndrome. The clinical manifestations can be very dramatic and they happen in young people. This is one of the first patients I ever saw here at this hospital, probably 20 years ago, before we had a diagnosis of the antiphospholipid syndrome. This is a young lady, 21 years old at the time, who had multiple cerebral infarcts and a known lupus anticoagulant. I have used the term here now, which we did not have then, of antiphospholipid antibody syndrome or PAPS. This also is a MRI, one of the earliest versions of the MRI, demonstrating diffuse white matter disease and infarctive disease in a 33-year-old man whose presenting manifestations were dementia and occipital blindness. This is a more common manifestation; this is a lady whom I saw just about two weeks ago, a 42-year-old woman who had multiple UBOs (or just diffuse areas of hyperintensity) scattered throughout her brain-you can see them along here or in contrast along here-and forgetful episodes with some hints of dementia but very little else as a manifesting symptom. You can also see abrupt and severe vascular occlusion. This was a spontaneous event in the lady who ended up developing gangrene of three of her extremities before the catastrophic syndrome was stopped by plasmapheresis, and who survived this event despite the severity of what happened.

The way in which I got into studying this syndrome was with the pregnancies. This again, is a relatively old slide, demonstrating in a patient population with lupus and primary antiphospholipid antibody syndrome alone, the risk to pregnancy of having the antibody going from no antibody present (under 16 IgG antiphospholipid antibody units) to high titer on the first blood test drawn during the index pregnancy. In the green bars are women who have not been pregnant before. The yellow bars are women who have had prior losses, and you can see that in this group of patients the history of a prior fetal loss and a high titer antibody gave an over 80% probability of losing the current pregnancy. There was stepwise increment from negative titers but it was also true that the history of a prior loss even in women who had negative antibody titers also predicted loss at about a 2:1 ratio, that is, a prior loss plus the high titer antibody. Predicted losses in a woman who had never been pregnant but who had high titer antibody had about a 40% probability of losing that pregnancy. I guess it does not show well on this slide, but one of the characteristics also is livedo reticularis. This, in a better projection, shows rather striking livedo. It is characteristic of many patients and is distinct from a more hard livedo, as you see, here referred to as livedo racemosa, a point made by Jean-Charles Piette from France, that is different and that occurs in patients with vasculitis. There is a good paper by him in the recent Journal of Autoimmunity that describes the differences between the two types of livedo that occur, the one with antiphospholipid antibody and the one with vasculitis. This is one of the severe manifestations occurring in a young woman with the catastrophic syndrome. Those of you who recognize the histology will recognize this as myocardium. This is a coronary artery that has completely occluded and was the cause of her death. Again, I do not remember her precise age, but she was in her thirties. You will note the characteristic pathology, which is a totally bland thrombus like this, with no signs of inflammation, no vasculitis whatsoever within the coronary vessels. This is another patient, a young man who was well known to many of the physicians here. This is his aortic valve, along here, with this huge excrescence that led to severe aortic insufficiency and eventual valve replacement in this man, and also, mitral valve replacement. This is another manifestation of the syndrome that occurs in patients who have had the disease for some period of time. In the catastrophic syndrome, a relatively rare but dramatic event that can occur is the sudden onset of adrenal failure associated with hemorrhage around the adrenal glands. The hemorrhage occurs after infarction of the adrenal glands and is the cause for sudden hypotension, severe nausea, and back pain in patients with the antiphospholipid antibody syndrome; this slide given to me by Ware Branch shows extensive hemorrhage around both adrenal glands. …

See the complete article on the Hospital for Special Surgery’s web site

Listen to the audio from the Hospital for Special Surgery’s web site 

Ask the Expert
Michael D. Lockshin

Currently, the recommendation for asymptomatic patients who have antiphospholipid antibody (regardless of titer) is that they not be treated. One retrospective study, conducted here at HSS, looked at women who had been identified because of fetal loss and were/were not treated with aspirin; the results suggested that aspirin protects against future clotting events[1]. The primary author, Doruk Erkan, MD, is now engaged in a prospective study through the national registry (APSCORE) to verify the findings.

I don’t believe that anyone would treat asymptomatic patients with warfarin or heparin. Michelle Petri, MD, of Johns Hopkins Medical Center, advises hydroxychloroquine[2].

With regard to the INR, the best information comes from the a double-blind, prospective study by Crowther in The New England Journal of Medicine in 2003, which stated that, for uncomplicated antiphospholipid syndrome patients who have not previously failed anticoagulation, an INR of 2.5 is as effective as are higher INRs[5]. This paper reduces a recommendation previously made by Khamashta in 1995 for an INR of greater than 3[3],and a subsequent update raising (without justification, in this reviewer’s mind) the recommended INR to 3.5[4]. In the Crowther study, the recommendation applied equally to patients with venous and with arterial clots.

Many authorities also prescribe a baby aspirin as well.

See the complete article on the Hospital for Special Surgery’s web site
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[1] Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum. 2001 Jun;44(6):1466-7.

[2] Petri M. Treatment of the antiphospholipid antibody syndrome: progress in the last five years? Curr Rheumatol Rep. 2000 Jun;2(3):256-61.

[3] Khamashta MA, Hughes GR. Antiphospholipid antibodies and antiphospholipid syndrome. Curr Opin Rheumatol. 1995 Sep;7(5):389-94. Review.

[4] Ruiz-Irastorza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrado MJ, Hughes GR. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med. 2002 May 27;162(10):1164-9.

[5] Crowther M A, Ginsberg J S, Julian J, Denburg J, Hirsh J, et al. A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome. New Engl J Med 2003 Sep 18; 349:1133-1138.

Ask the Expert
Michael D. Lockshin

The antiphospholipid syndrome (APS) causes excessive blood clotting, leading to strokes, heart attacks, and pulmonary emboli (clots in the lungs). It also causes pregnancies to fail, because of clots in the placenta.

While much is known about the syndrome, what actually triggers a clot at a specific time in an individual patient is unknown. Similarly, there are no definitive studies on the effect of herbals and other supplements on the initial occurrence of APS or on its worsening or improving when such supplements are taken. Indeed, with the large number of supplements available, the absence of standardization in their formulation and manufacture, and the differing doses with which they are used, the absence of such information is not very surprising.

Once a patient is diagnosed with APS, however, he or she is often prescribed warfarin (Coumadin) or a form of heparin (such as Lovenox or Fragmin) taken orally or injected daily to stop the abnormal clotting from recurring. In doses too high, the effect of these drugs is to cause hemorrhage. The body normally has redundant systems to prevent hemorrhage, so patients taking the appropriate dose of medicines that interfere with one type of clotting are still reasonably safe if, for example, they cut themselves because other ways to form clots are available. However, the dose must be constantly monitored to be certain that a patient is in a safe zone. That’s where taking herbal supplements may be dangerous.

According to a publicly available listing of drug interactions[1], the following is a minimum list of alternative medicines that interact with prescribed anticoagulants by increasing risk of bleeding: androgens, German chamomile, coQ10, danshen (red sage, saliva root), dong quai (Chinese angelica), evening primrose oil, fenugreek, feverfew, fish oils, flaxseed, garlic, ginger, ginko biloba, ginseng, grape seed, green tea, horse chestnut seed, milk thistle, quinine, red clover, red yeast, St. John’s wort, willow bark.

Other alternative therapies may increase the risk of clotting. Vitamin K counteracts Coumadin; vitamin preparations or diet supplements that include vitamin K increase the risk of clotting in patients taking Coumadin (but not in those using heparin or antiplatelet drugs like aspirin or Plavix).

Thus the major risk of herbals and other supplements to patients with antiphospholipid syndrome is interference with treatment rather than worsening the disease.

The same cannot be said for estrogen. Estrogen, in the form of postmenopausal treatment or oral contraception, including patches, increases a woman’s tendency to clot. Therefore, estrogen can provoke clotting in patients with APS, whether they are being treated with anticoagulants or not. Most specialists in the field advise against taking this hormone.

Progesterone, also used for contraception, amenorrhea, in some pregnancy situations, and in post-menopausal therapy, is probably safe for patients with APS. In fact, the literature on this topic is remarkably old and sparse[2], but information from the SELENA study of lupus patients may be available soon. Excessive clotting is a listed side-effect of drugs of the progesterone class.

Most experts in the field prefer that patients with APS use no estrogen or progesterone supplements until better information is available. In our small study of infertile women with APS undergoing artificial ovarian stimulation to achieve pregnancy, no APS-related complications of hormone treatment occurred[3].

Therefore, the take-home message is simple: both hormones and herbal and other dietary supplements may change one’s risk for clotting or, in some cases, bleeding. The best advice for APS patients is to use such products with extreme caution, if at all.

See the complete article on the Hospital for Special Surgery’s web site——————————————————————————–
[1] ePocrates RxPro, www.epocrates.com

[2] Comp PC, Zacur HA. Contraceptive choices in women with coagulation disorders. Am J Obstet Gynecol. 1993 Jun;168(6 Pt 2):1990-3.

[3] Guballa N, Sammaritano L, Schwartzman S, Buyon J, Lockshin MD. Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome. Arthritis Rheum. 2000 Mar;43(3):550-6.|

Interviews with Experts 

Select the audio version for Dr. Stephen Paget’s interview with Dr. Lockshin on the Hospital for Special Surgery’s web site