Systemic Antiphospholipid Antibody Syndrome, Antiphospholipid Antibody Syndrome, APS, APLS, Hughes Syndrome, Sticky Blood, Clotting Disorder, Stroke, TIA, PE, death

1st International Workshop of Anti-Phospholipid Syndrome (APS or APLS)

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October 12-13, 2001, Pleven, Bulgaria
Reported by Yehuda Shoenfeld , M.D.
published 21. November 2001

Bulgaria attracted worldwide attention when the king, who left Bulgaria when he was 9 years old, returned to his country. He was recently nominated Prime Minister, which gave great hope to Bulgaria, which has a population of 8.5 million. The hope and the enthusiasm also engulf the field of medicine.

The international meeting on Antiphospholipid Syndrome (APS or APLS) is the first to put Bulgarian medicine and science on the map. Five years ago, people in Bulgaria hardly related to Antiphospholipid Syndrome (APS or APLS). However, due to the efforts of Dr. Emiliana Konova and the groups around her, insight into the syndrome grew to entail diagnoses of many patients with many rare manifestations as well as developing novel therapies.

The meeting took place in Pleven, a city with a millennial history. Throughout the centuries, different cultures have thrived in the region – Prehistoric, Thracian and Roman, Byzantine, Slavonic, and Bulgarian. The battle on Pleven on December 10, 1878, was decisive for the outcome of the Russo-Turkish war.

Behind the meeting was the Highest Medical Institute (HMI) in Pleven which was founded in 1974, at first as a faculty of the Sofia Medical University. Today, HMI-Pleven is a separate medical school with its own curriculum developed under the requirements of the Ministry of Education and Science (MES). By 2001, 3738 Bulgarian and 307 foreign students from different countries have graduated from HMI-Pleven. In 1997, HMI-Pleven introduced a medical curriculum that was taught in English in compliance with state requirements. Now almost 150 students are enrolled in this curriculum.

Because the aim of the Antiphospholipid Syndrome (APS or APLS) meeting was to solve unanswered questions in Antiphospholipid Syndrome (APS or APLS), the summary of the conference will be by questions and answers.

WHAT PRECIPITATES CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME (APS or CAPS)?

Ron Asherson (South Africa), who published the first description of Catastrophic Antiphospholipd Syndrome (CAPS) in 50 patients delineated the diagnostic parameters as well as detailed clinical findings in 80 patients (the article will be published in Medicine). In this meta-analysis, Asherson et al found that in 35% of patients the precipitating factor was infection, which ranged from upper respiratory infections to leg ulcers and other septic conditions, such as urinary tract infections, and rare conditions, such as typhoid fever.

The second most frequent precipitating factor was trauma and invasive procedures (13%), ranging from needle-stick injury to angioplasty and other various major operations. An association with tumors was recorded in 8% of cases. Withdrawal of anticoagulant or low INR led to 8% of the cases of Catastrophic Antiphospholipid Syndrome (CAPS). An instructive association was noted with obstetric complications (6%) such as post-fetal loss or the HELPP syndrome. Others were associated with SLE "flares" (5%) or exposure to estrogen (3%).

Precipitating factors in 80 patients with catastrophic Antiphospholipid Syndrome (CAPS)

No.

(%)

Infections

12

(5)

Respiratory tract

6

(8)

Cutanous

5

(6)

Urinary tract

2

(3)

Spesis

1

(1)

Gastrointestinal

7

(9)

Other

10

(13)

Surgery, trauma, and invasive procedures

6

(8)

Neoplasia

6

(8)

Anticoagulation withdrawal/low INR

5

(6)

Obstetric complications

4

(5)

SLE flares

2

(3)

Oral contraceptives

28

(35)

No factor identified

Infectious Etiology of Antiphospholipid Syndrome (APS or APLS)

Yehuda Shoenfeld (Israel) expanded on the infectious etiology of Antiphospholipid Syndrome (APS or APLS), also acting as a specific trigger mechanism for Catastrophic Antiphospholipid Syndrome (CAPS). Originally, antiphospholipid antibodies (aPL) were reported in infectious conditions such as syphilis (for example, false-positive serologic test for syphilis), since then, aPL have been reported in a variety of infections from human imunno-deficiency virus (HIV) and to bacterial and even parasitic infestation (for example, malaria, leishmaniasis, and trypanosomiasis). Most of the infection related-aPL seems to be a non-pathogenic type, in that their binding to cardiolipin is not B2GPI dependent. Yet this classification is not necessarily clear-cut. Furthermore, it is not inconceivable that in susceptible subjects having the necessary HLA DR4 or DR7 or other genetic tendency the "non-pathogenic" infections induced anticardiolipin antibodies (aCL) will mutate and rearrange the amino acid at the CDR3 domain of the binding site determining the B2GPI dependency and the pathogenic nature of antibody.

Recent research from two groups supports the infectious origin of pathogenic aPL by immunization with foreign B2GPI or synthetic peptides representing the phospholipid-binding site of the B2GPI. These autoantibodies caused intrauterine fetal death and transverse myelopathy (due to spinal cord infraction in mice), and activated endothelial cells in vitro. This group (Gharavi et al) also demonstrated the induction of aPL in mice by immunization with phospholipid-binding viral peptides and observed their pathogenic effects. Recently, the same authors proved the pathogenic effects of aPL induced by immunization with human CMV-derived phospholipid-binding synthetic peptides. These research findings are compatible with CMV- and HIV-induced Antiphospholipid Syndrome (APS or APLS) in patients.

Shoenfeld et al complemented the relationship between infections and Antiphospholipid Syndrome (APS or APLS) by adding a series of additional studies. Employing a peptide phage display library, they identified three hexapeptides that reacted specifically with anti- B2GPI monoclonal antibodies. All three peptides inhibited the biologic function of the corresponding anti- B2GPI monoclonal antibodies and the in vitro endothelial cell activation and induction of experimental Antiphospholipid Syndrome (APS or APLS) in vivo. Using the Swiss protein database, they revealed a high degree of homology between the hexapeptides with different bacteria and viruses.

Naive mice were immunized with a panel of pathogenic particles, sharing the appropriate homology with peptides. All the immunized mice developed aPL. Mouse IgG, specific to relevant peptide (equivalent to B2GPI), was affinity purified from the immunized mice. These specific immunoglobulins were infused into BALB/c mice to study the development of associated clinical manifestations. Only the mice infused with mouse antibodies derived from mice immunized with Haemophilus influenzae or Neisseria gonorrhoeae, directed to the peptide TRLVYK, had the potential to induce clinical manifestations that resembled experimental Antiphospholipid Syndrome (APS or APLS). Shoenfeld hypothesized that the mechanism of pathogenic anti-B2GPI generation is induced by epitope mimicry, and Antiphospholipid Syndrome (APS or APLS) should be included in the group of infection-induced autoimmunity.

Several presenters stressed the infectious etiology of Antiphospholipid Syndrome (APS or APLS). M. Nikolova et al (Sofia, Bulgaria) found aCL in 11% and 5% of patients with infectious with chlamydia and mycoplasma, respectively. Some of the patients had Antiphospholipid Syndrome (APS or APSL) clinical manifestations. Lieva P. et al (Pleven, Bulgaria) reported an associated aCL with hepatitis A and B, while M. Daskolova (Pleven, Bulgaria) detailed a case of echinococcosis with aCL. WHAT ADDITIONAL FINDINGS CHARACTERIZE Antiphospholipid Syndrome (APS or APLS)?

Bone Marrow Necrosis

Ron Asherson (South Africa) reported the surprising frequency of cases of Antiphospholipid Syndrome (APS or APLS) with associated bone-marrow necrosis. As opposed to osteonecrosis – no fewer than 6 patients from his present series developed these complications. Bone-marrow necrosis is a relatively uncommon condition and is most frequently encountered in patients with lymphoma, neoplastic diseases (metastatic carcinoma, acute leukemia following radiotherapy or chemotherapy), sickle-cells disease, and severe bacterial infections (particularly septic shock). To this list Asherson has added catastrophic Antiphospholipid Syndrome (CAPS).

Bulvik et al in 1995 first report the association between Antiphospholipid Syndrome (APS) and bone-marrow necrosis in young pregnant patients who developed this complication on the third day post-cesarean section. The postpartum occurrence of these complications (2 days postpartum) had been noted some years before by Knickerbockers et al. Their patients had had a previous history of recurrent thrombophlebitis and three spontaneous abortions. Its assurance in pregnancy was reported by Paydas et al in 1997 in a 27-year-old pregnant woman with a history of 9 miscarriages, a cerebrovascular accident, and high titers of aPL.

Murphy et al in 1998 documented this complications associated with lymphoma and aPL. In the literature associated with Antiphospholipid Syndrome (APS or APLS), 9 patients have been reported tohave this complication, of whom 6 suffered catastrophic APS (CAPS). It is, therefore, among the less well-known manifestations of the aPL-associated complications occurring mainly in catastrophic APS patients for reasons unknown at the present time.

WHAT KIND OF PHOSPHOLIPID AND IG ISOTYPES ARE MEASURED FOR THE DIAGNOSIS OF ANTIPHOSPHOLIPID SYNDROME (APS or APLS)?

Sozos Loizou (U.K) in 1980 with G. Hughes and other colleagues published the first paper on a quantitative Elisa for measurements of aCL antibodies. Based on this extensive experience, they recommended a series of 6 phospholipids (CL, PS, PEA, PC, prothrombin, B2GPI) to detect autoantibodies. Loizou reported cases with a single unique anti-phospholipid and emphasized the importance of all 3 isotypes, i.e. IgM, anti-CL, and anti-PEA may specifically characterize patients with Antiphospholipid Syndrome (APS or APLS) associated with autoimmune hemolytic anemia. He also referred to the many cases with only IgA aCL.

WHAT IS THE EURO-PHOSPHOLIPID PROJECT?

Richard Cervera (Spain) explained that the aim of this "Euro-phospholipid project" is to evaluate prospectively the clinical and serologic manifestations and the evaluation of the Antiphospholipid Syndrome (APS or APLS) by means of a long-term follow-up study of a large cohort of European patients. The specific objectives of the project are: 1. To determine the incidence and characteristics of the different Antiphospholipid Syndrome (APS or APLS) clinical manifestations at the onset of disease and during follow-up.
2. To analyze the biologic and immunologic features of these patients and the relationship with their clinical manifestation in order to clearly define different subsets of the disease.
3. To determine the natural history, severity, and response to treatment of these Antiphospholipid Syndrome (APS) subsets.
4. To evaluate to morbidity of the different Antiphospholipid Syndrome (APS) subsets (including complications induced by the different treatment regimens of this condition).
5. To establish the mortality rate and the main causes of death in the European Antiphospholipid Syndrome (APS) population.

The final cohort includes 1,000 unselected patients with Antiphospholipd Syndrome (APS or APLS) attending 20 tertiary referral university centers from 13 countries (Spain, France, United Kingdom, Israel, Denmark, Hungary, Italy, Greece, The Netherlands, Germany, Bulgaria, Belgium, and Portugal). All fulfill the Consensus Criteria for the Antiphospholipid Syndrome (APS) [1]. Patients with both primary Antiphospholipid Syndrome (APS) and Antiphospholipid Syndrome (APS) associated with systemic lupus erythematosus (SLE) or other autoimmune diseases have been enrolled and they will be followed for 10 years.

Information on the progress of the study can be obtain at the website of the "European Forum of Antiphospholipid Antibodies" (www.med.ub.es/MIMMUN/FORUM/INDEX.HTM). Dr. Cervera detailed the findings in the first 1,000 patients with Antiphospholipd Syndrome (APS or APLS) (to be published in Arthritis & Rheumatism).

ARE THERE AGE DIFFERENCES IN THE APPEARANCE OF ANTIPHOSPHOLIPID SYNDROME (APS or APLS)?

The answer by Cervera analysis is YES. For instance, chorea is seen almost only in children.

CAN WE PREDICT CASES OF ANTIPHOSPHOLIPID SYNDROME (APS or APLS) THAT WILL EVOLVE TO SLE?

No definite criteria are currently available to predict such an evolvement (short follow-up of the disease). Yet, analyses of the 1,000 cases seems to indicate that high ANA, lymphopenia, anti-Sm, and arthritis can be used as predictive markers for such progression.

HOW DO ANTI-PHOSPHOLIPID ANTIBODIES AFFECT PLACENTAL FUNCTION?

Siohan Donohoe (UK) summarized the growing evidence that aPL affect pregnancy viability through a variety of mechanisms. However, the currently available laboratory parameters defining Antiphospholipid Syndrome (APS or APLS) give little indication of the obstetric risk of PET, intrauterine growth retardation (IUGR), or recurrent miscarriages. To date the best clinical indicator of obstetric outcome is the outcome of previous pregnancies, both with and without prophlyxis.

aPL may mediate placental dysfunction by disrupting endometrial and/or trophoblast function and promote procoagulant conditions [157]. Histologic and cell culture studies support a pathogenic role of aPL on the processes of implantation and invasion occurring in early pregnancy. Thrombosis is a relatively common feature of the placenta in women with Antiphospholipid Syndrome (APS or APLS) and is likely to contribute to the observed pathology, either as a cause or a consequence of placental dysfunction. A primary causative role for aPL-related thrombosis mediating miscarriage, pre-eclampsia, IUGR, fetal loss, and preterm delivery is in question. However, the unifying features of placental histology are fetal death, preterm birth, pre-eclampsia, and intrauterine growth restrictions. The latter include thrombosis, defective placentation, abnormal uteroplacental vascular conversion, and chronic inflammation, which provide insight into the etiology of the complications and suggest abnormal trophoblast invasion as a pathologic mechanism. In Antiphospholipid Syndrome (APS or APLS) as are for PET and IUGR, events occurring during early pregnancy are thought to determine pregnancy outcome. The level of disruption to these processes is likely to determine pregnancy outcome.

More recent placental research suggests that aPL restrict trophoblast invasion. As a result, the conversion of the spiral arteries to placid vessels, which allow increasing blood flow, is reduced. Furthermore, aPL have been associated with atherosclerosis, apoptosis, and endothelial activation, which combined with the procoagulant activity of these antibodies present the feto-maternal junction with a multiple hit. It is her hypothesis that the placenta has an inherent excess capacity and that the obstetric presentation in Antiphospholipid Syndrome (APS or APLS) reflects the degree of underlying physiologic feto-maternal functional compromise associated with heterogeneous aPL. This balance may be tipped sufficiently in favor of a successful pregnancy as a response to therapy.

WHAT IS THE PREVALENCE OF FACTOR LEIDEN AND 20210 6-A MUTATION OF PROTHROMBIN IN ANTIPHOSPHOLIPID SYNDROME (APS or APLS)?

Baleva Metal (Sofia, Bulgaria) analyzed the frequencies of factor Leiden and 20210 6-A mutation of prothrombin in 80 patients with Antiphospholipd Syndrome (APS or APLS) and healthy controls and could not find an increased prevalence compared with controls.

IS ANTIPHOSPHOLIPID SYNDROME (APS or APLS) A PURE ANTIBODY-MEDIATED DISEASE OR IS T CELL IMMUNITY ALSO INVOLVED?

D. Kyurkchiev et al (Sofia, Bulgaria) found in patients with high anti-CL titers T-cell reaction in vitro against 200 ug/mL B2GPI/CL complex, but no reaction against B2GPI alone. Their study confirms the immunogenic role of B2GPI in Antiphospholipd Syndrome (APS or APLS) and is supported by previous studies showing the transfer of experimental Antiphospholipd Syndrome (APS or APLS) by bone marrow T cells.

ARE PLATELETS ACTIVATED IN ANTIPHOSPHOLIPID SYNDROME (APS or APLS) OR ARE THEY AN INNOCENT BYSTANDER?

According to the new Sapporo Criteria for Antiphospholipd Syndrome (APS or APLS) diagnosis, the 40% occurrence of thrombocytopenia were not included. Tz Lukanov et al (Pleven, Bulgaria) employing flow cylometry revealed expression of CD3 and CD62 on platelets from 29 patients with Antiphospholipd Syndrome (APS or APLS). These data point to the existence of circulating activated platelets in Antiphospholipid Syndrome (APS or APLS). Many discussants raised the question whether thrombocytopenia should be incorporated again in the diagnostic criteria for Antiphospholipd Syndrome (APS or APLS).

CAN HEROIN ABUSE INDUCE aPL?

M. Nikolova et al (Sofia, Bulgaria) reported 4 heroin addicts (22 to 30 years old) with a mean duration of heroin abuse of 46 months (range, 6 to 96 months). All had aPL in addition to other antibodies (ANA). Yet one of them developed clinical findings of Antiphospholipd Syndrome (APS or APLS). The question of heroin being the inciting factor or the co-association with HCV or HIV was raised. The report draws attention to addicts with Antiphospholipid Syndrome (APS or APLS) manifestations.

ARE KIDNEYS INVOLVED IN ANTIPHOSPHOLIPID SYNDROME (APS or APLS)?

Previously kidney involvement in Antiphospholipd Syndrome (APS or APLS) was limited to cases with Antiphospholipid Syndrome (APS or APLS) secondary to SLE. More and more papers appearing recently indicate kidney involvement in Antiphospholipd Syndrome (APS or APLS). M. Nikolova (Sofia, Bulgaria) reported 48% prevalence of aCL in lupus nephritis. One third had clinical manifestations of Antiphospholipid Syndrome (APS or APLS). The presence of aCL with lupus nephritis did correlate with a specific histologic type.

IS ANTIPHOSPHOLIPID SYNDROME (APS or APLS) A GENETIC DISEASE?

K. Ongelova et al (Pleven, Bulgaria) described three generations of one family with multiple cases of Antiphospholipid Syndrome (APS or APLS). Other members were found to harbor only aCL. The asymptotic cases raised the question of therapy: should we follow these subjects with aCL or should we at least give them low dose aspirin? The discussant raised the legal issue of both options. The question of treating an asymptotic aCL-positive subject remains unanswered.

THE MOSAIC OF ANTIPHOSPHOLIPID SYNDROME (APS or APLS)

Additional interesting aspects of Antiphospholipid Syndrome (APS or APLS) raised by presenters included:

1. High titers of aCL in advanced coronary atherosclerosis (I. Stankulov).
2. The appearance of aCL often with myocardial infarction.
3. The 5% to 10% incidence of epilepsy in Antiphospholipid Syndrome (APS or APLS), related to the effect of aCL on the central nervous system.
4. The 29% of aCL positivity in sera of patients (I. Kokareshkov) with multiple sclerosis.

All the above indicates that indeed Antiphospholipd Syndrome (APS or APLS) is a multi-disciplinary disease.

CAN IVIG IMPROVE ANTIPHOSPHOLIPID SYNDROME (APS or APLS) PATIENTS?

There is a local institute in Sofia, Bulgaria, producing IVIG. This safe IVIG was given to a series of SLE patients whose disease was resistant to a conventional therapy. The condition of most patients improved. Another study included 19 women with a history of two or more consecutive recurrent pregnancy failures and presistantly positive tests for aCL. In two patients, IVIG (250 mg/kg in two infusions) was started within 2 weeks after attempted conception. Once conception was achieved, IVIG was continued in all patients on a monthly basis at the same dose through 23 to 36 weeks of gestation.

1) aCL were significantly suppressed after each IVIG infusion (p<0.01) for about 3 weeks;

2) platelets, autoantibodies, and activity index were decreased after each infusion (p<0.05) for 2 to 3 weeks;

3) platelet count rapidly increased at the 24 hours to normal levels for a period of 2 to 3 weeks (p<0.01).

Reproductive outcome: 19 pregnancies were reported; 17 delivered maturely, the infants were normal for gestational age. One woman had a missed abortion at 8 weeks of gestation and one at 13 weeks of gestation. The rate of successful deliveries was 89.5% (17 out of 19).

Conclusion: it seems that IVIG therapy is a therapeutic benefit for the feto-placental unit for women with a history of antiphospholipid-associated miscarriages. aPL lead to an early organ failure, defective placentation, and hypercoagulation. IVIG down regulates the levels of these autoantibodies. This therapy is immunomodulating, safe, and well tolerated.

R. Roussey et al (Chicago, USA) reported similar results in patients with recurrent pregnancy failure.

The unique observation in the Bulgarian experience with IVIG was that the IVIG was given in one-tenth of the dosage regularly reported to help in the literature. If approved in extended studies, this low dose of IVIG (150 to 250 mg/kg.B.W) may lower substantially the expenses associated with this therapy.

Yehuda Shoenfeld, M.D.
Department of Medicine 'B' and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-Aviv University, Israel

Correspondence to: Y. Shoenfeld, M.D., Department of Medicine 'B', Sheba Medical Center, Tel-Hashomer, 52621, Israel. Tel: 972-3-5302652.
Fax: 972-3-5352855. E-mail: shoenfel@post.tau.ac.il

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