Acquired Thrombophilia Antiphospholipid Antibody Syndrome Category 2 Immune Problems

• Introduction
• Incidence of Antiphospholipid Antibodies
• Diagnosis of Antiphospholipid Antibodies
• Placental Pathology
• References

Introduction 

Acquired thrombophilia, antiphospholipid antibodies (APAs) and the antiphospholipid antibody syndrome (APS) are autoimmune conditions characterized by the presence of certain clinical features and levels of circulating APAs. The six APAs that are important are

1. cardiolipin,
2. serine,
3. ethanolamine,
4. phosphatidic acid,
5. inositol, and
6. glycerol.

The types of antibodies that are tested are reported as titers, GPL units or borderline, positive or high positive. There are of three classes of antibodies:

1. IgM. This antibody circulates in the blood as opposed to the lymphatic system and the organs. As the immune problem strengthens or gets worse an additional antibody is formed.
   
   
2. IgG. This antibody also circulates in the blood but its main home is in the lymphatic system and the lymph nodes. As the immune problem strengthens and gets worse an additional antibody is formed.
   
   
3. IgA. This antibody lives in the organs and is often responsible for turning the serological test for syphilis falsely positive.

The presence of borderline levels by titer, GPL or borderline, positive or high positive testing to any one of the above is significant and requires preconception treatment during the cycle of conception.

The most specific clinical features or problems that a woman experiences are

1. thrombotic events,
2. blood clots (venous or arterial),
3. autoimmune thrombocytopenia (low platelet count), and
4. anemia (low red blood cell count).

The problems that are experienced with the pregnancies are

1. intrauterine fetal death,
2. intrauterine growth retardation,
3. low amniotic fluid volume,
4. sub chorionic hemorrhages,
5. toxemia of pregnancy,
6. the Hellp Syndrome, and
7. unexplained stillborn babies.

Certain criteria for APS were developed at a workshop at the 8^th International Symposium on Antiphospholipid Antibodies in Sapporo, Japan, on October 11, 1998 (see Table 1 below).

The six phospholipid molecules are components of every cell membrane. In the placenta they function in cytotrophoblast to syncytiotrophoblast formation. The cytotrophoblast are the first cells of the placenta that attach the pregnancy to the uterus. The glue that causes them to stick firmly to the lining of the uterus and then grow deeply into the uterus are phospholipid molecules. Every woman has them. Once these cells attach the baby to the uterus, they form a new cell called the syncytiotrophoblast, which is like a filter cell between the mother's blood and the baby's blood. This cell transports all the nourishment to the baby and removes the waste from the baby's blood so that the mother can eliminate it for her baby.

If there are antibodies to the phospholipids, then the woman's blood clots too fast, cutting off support to the baby; the cell is retarded in its development and the baby can "whither on the vine" and die. These antibodies also cause the embryo to attach too weakly to the uterus. Women with APAs belong to category 2 of immune disorders. This abnormality can be seen by doing immune pathology of the placental tissue paraffin blocks of the baby that died and miscarried.

Phospholipids are essential for trophoblast growth and development. APAs in the mother (IgM, IgG or IgA) retard and damage placental development, causing the baby to die; they are associated with a history of recurrent spontaneous abortion (RSA), endometriosis, infertility, IVF failure and implantation failure. APAs are very common in women with blood clots, autoimmune diseases and inherited Thrombophilia (see Thrombophilia: Inherited and Acquired). Their incidence and titers increase with each successive pregnancy loss when compared to controls. In addition to pregnancy loss, several obstetrical complications are associated with APAs, such as preeclampsia, fetal growth retardation in the second or early third trimester, abnormal fetal heart-rate tracing, abruption of the placenta, bleeding during pregnancy, subchorionic hemorrhages and preterm delivery. We have also found that women who are HLA DQ A1 4.1, and who gestate a fetus of the same phenotype, are at the risk to develop APAs to phospholipid molecules and lose their pregnancy despite of optimal therapy.

Each pregnancy that is lost makes the problem worse. A woman effectively vaccinates herself against a successful pregnancy. Many doctors are responsible for this because they tell the couple that nothing is wrong and simply try again. When a baby dies something is wrong; this is a common problem (category 2) in many women with miscarriages, infertility, IVF failure and implantation failure. It is important to know that it is not necessary to lose one baby after another just to qualify for testing and treatment.

Every woman has two DQ alpha numbers (DNA fingerprint); one from her mother, the other from her father. There are many DQ alpha numbers and crime labs use this blood test, or autorad, to identify who was at a crime scene. Couples who miscarry share DQ alpha numbers in common; the worst one to share is DQ alpha 4 or 4.1, often called 0501. Something about a pregnancy of this type causes the mother to make the antiphospholipid antibodies. DQ alpha testing of the mother and the baby is important in this regard and can be done from the paraffin blocks to know what the DNA fingerprint and the DQ alpha numbers of the baby were. (See document New Developments in the Evaluation of Immune Abnormalities in Couples with Recurrent Pregnancy Losses: Infertility and Miscarriages Following one Live-born Child.)

Fifty percent of women with APAs also have activated natural killer cells and elevated CD19+5+ B-1 cells. These are category 5 immune problems. Many doctors, when they find one problem, think that they have found the reason for the pregnancy losses. They treat the problem and the woman loses her baby again because the problem was not so simple. She was category 2 and needed aspirin and heparin, but her immune problems had progressed to category 5 and she also requires treatment for this.

Incidence of Antiphospholipid Antibodies 

Incidence of APAs in different patient populations:

1. Normal obstetrical patients (5.3% of 7,278 women);
2. Women with recurrent pregnancy losses (20-30% of 2,226 women);
3. Women with systemic lupus erythematosus or other autoimmune diseases (37% of 1579 women);
4. IVF patients (24%-60% of 3,343 women); and
5. IVF failure patients (even higher).

Diagnosis of Antiphospholipid Antibodies 

We recommend the following tests to diagnose if a woman has APAs:

1. Antibodies to six phospholipids of the IgM, IgG and IgA classes. Reported as
   • GPL units,
   • Titer (ie, 1:40, 1:80 etc), or
   • Borderline (1:40 to 1:100),
   • Positive (1:100 to 1:400),
   • High Positive (1:400 or higher).
2. Lupus anticoagulant antibody. This test is not used solely to diagnose lupus. The lupus anticoagulant antibody is an antiphospholipid antibody that makes blood clot too quickly and can cause problems during pregnancy.
3. Russel Viper Venom Time. This test measures whether blood clots too quickly.
4. Activated Partial Thromboplastin Time (APTT). This test measures whether blood clots too quickly.
5. Prothrombin Time (PT), Partial Prothrombin Time (PTT). These tests measure clotting time when a woman is on heparin. They do not measure the effect of low molecular weight heparin. The factor 10 A activity test does this.

Placental Pathology 

Thrombosis causes placental damage in women with positive APAs. Clotting in the placenta or the blood vessels to the uterus is a category 2 immune problem and can be diagnosed by doing immune pathology. Slides and paraffin blocks of the placenta are saved in the pathology department of the hospital that served the patient when the baby was lost. Couples are encouraged to ask pathologists to send these blocks to our office for immune pathology. (See The Importance of Pathological Evaluation of Pregnancies that Terminated in Spontaneous Miscarriage.)

Natural Killer Cells in the Uterus

Biopsies of the lining of the uterus (endometrium) on cycle day 26 of a normal cycle or of a failed IVF-ET cycle can also show this category 2 problem. The tissue is processed exactly like the tissue from a miscarriage. It is fixed in 10% formalin and sent in the liquid or send to the pathology department for processing into the paraffin blocks and then sent for immune pathology.

It is hoped that this simple description of the APAs will serve the consumer well. In our experience, many doctors who deal with reproductive health do not understand this problem or do not believe the problem is really important or even exists. They often criticize those who recommend testing and treatment and say until double blind studies are done they are not interested in talking to you. Double blind studies, meta analyses, and prospective controlled studies do exist. Demand of the doubting doctor articles and evidence that support his/her views. The references that follow are a few of these that support our view.

"Innovators are rarely received with joy."

"Established authorities launch into condemnation of newer truths."

"At every crossroads to the future, are a thousand self-appointed guardians of the past."

References 

The information contained in this article is not intended to be a medical diagnosis, treatment or medical advice in any way, as it is general information and cannot be relied on without consultation with your physician. It is not intended nor is it implied to be a substitute for profession medical advice. As medical information can change rapidly, we strongly encourage you to discuss all health matters and concerns with your physician before embarking on new diagnostic or treatment strategies.

Home  ·  Dr. Beer  ·  The Center  ·  Resources  ·  Calendar
My Account  ·  Glossary  ·  Search Tools  ·  Contact Us

Alan E. Beer Center for Reproductive Immunology & Genetics
15151 National Ave. #2; Los Gatos, CA 95032; Phone: (408) 356-9500; Fax: (408) 356-9509; E-mail: info@repro-med.net.
Date: 8-28-08, Time: 3:49 pm.

General Question? E-mail: info@repro-med.net.
© Copyright 2003-2008 Alan E. Beer, MD. All rights reserved.
Please read our privacy policy and legal disclaimer.
Site design by Loracs Creations Inc.