Michael D. Lockshin, MD

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. …

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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.