Women who face a series of repeat miscarriages may be able to blame it on abnormal levels of two proteins in the body. Knowing this could help doctors predict who may be at risk for complications, explained a team of researchers at Yale University.1
Clotting Connection
The compounds in question are two anti-clotting proteins, designated as proteins Z and S. Anti-clotting proteins are substances in the blood designed to prevent abnormal clotting. When a person is deficient in anti-clotting proteins C and S, for example, it promotes the production of fibrin (FIH-brin), a protein that plays a key role in clot formation.2
According to a study published in March in Blackwell Publishing's Journal of Thrombosis and Haeomstasis, Michael Paidas, MD, and his colleagues write that lower levels of these anti-clotting factors early in pregnancy might act together with other genetic clotting tendencies to adversely affect pregnancy.
"Our findings will help clinicians determine early in pregnancy which women will have healthy pregnancies and which women will develop complications," explained Paidas, an associate professor of Obstetrics, Gynecology, and Reproductive Sciences at the Yale University School of Medicine.
Physicians could theoretically conduct certain tests to look for these proteins, and if positive, they could design treatment strategies aimed at subsequently preventing these complications, said Paidas and his colleagues at the Bio-Reference Laboratory in Elmwood Park, New Jersey.
Underlying Genetics
The tendency toward abnormal clotting in the blood revolves around a genetic mutation that is "fairly common" in the general population, Paidas told Priority Healthcare. The condition is known as thrombophilia.
Thrombophilia increases the risk of blood clot formation in the veins; in a few cases, the condition boosts the number of blood clots in both arteries and veins. Some of the disorders that cause thrombophilia are inherited, such as an abnormality in the prothrombin gene, a deficiency in certain anti-clotting proteins, or activated protein C resistance (Factor V Leiden mutation).2
Other disorders that cause thrombophilia are acquired after birth, such as disseminated intravascular coagulation, the presence of lupus "anticoagulant" and antiphospholipid (anticardiolipin) syndrome. These disorders increase the risk of clotting because blood-clotting factors are overactivated.2
Often, this condition occurs without symptoms, so medical experts have wondered if there was some biological indicator that would demonstrate that a person might be predisposed to this condition. They began answering this question by looking at thrombin, an enzyme that plays a role in blood clot formation. Digging deeper, they began focusing on the anti-clotting proteins in the blood.
Pregnancy Loss and Its Causes
Miscarriage is the most common type of pregnancy loss, occurring in 25% of all pregnancies, experts estimate. Most miscarriages occur during the first 13 weeks of pregnancy, and the causes vary. Most often, the cause cannot be identified; however, the most common cause is a chromosomal abnormality, meaning something went wrong with the baby's chromosomes. Usually, this was due to a faulty egg or sperm cell or due to a problem during the zygote's (early embryo) division process. Other causes of miscarriage:
• Hormonal problems, infections or health problems in the mother.
• Lifestyle factors like smoking, drug use, malnutrition or exposure to toxic substances.
• Improper embryo implantation in the uterus.
• Older age of the mother.
• Maternal trauma.3
Effect of Anti-Clotting Factors
There have been previous studies suggesting that lower levels of certain anti-clotting proteins may be linked to stroke, albeit it's controversial, Paidas explained.4 Other research has pointed to the possibility that reduced levels of these proteins may be associated with pregnancy loss.5
These findings formed the basis for the latest research. The study involved 103 women who had normal pregnancies. They were compared with 106 women diagnosed with certain pregnancy complications. An additional 20 women with thrombophilia, which affects about one-fifth of Caucasian women, were also included in the research.
Paidas and his team took blood samples from each patient during their first trimester of pregnancy and compared anti-clotting protein Z levels between the three groups. Additionally, tests for anti-clotting protein Z and free protein S antigen were taken during the second and third trimesters in 51 women who had adverse pregnancy outcomes and 51 equally matched women with no pregnancy complications.
A Possible Relationship
In the end, the researchers found that average first trimester levels of anti-clotting protein Z were significantly lower in the group of women who had had pregnancy complications, such as miscarriage, compared to those who had normal pregnancies. Even in those with known blood-clotting abnormalities, lower levels of anti-clotting proteins predicted a higher risk of complications. "Of those with known thrombophilia, those with adverse pregnancy outcomes had a tendency for lower protein Z levels compared to those thrombophilia women with normal pregnancy outcomes," wrote Paidas and his fellow investigators, though the differences in that group weren't significant. Those with thrombophilia who had experienced a pregnancy complication had the lowest levels of the anti-clotting protein, Paidas stated.
Additionally, when analyzing the results of tests on anti-clotting protein levels in women in their second and third trimesters, "there was a significant decrease in the protein Z levels in patients with abnormal pregnancy outcome compared to normal pregnancy outcome," the researchers reported. Protein S levels were also significantly lower in those who had pregnancy complications.
"In early pregnancy, patients with low levels of protein Z have a four-fold higher risk of pregnancy complications," Paidas said. "Based on our data, we speculate that protein S free antigen levels below 29% may be associated with clotting-related pregnancy complications."
The researchers hope their findings can be used to develop a comprehensive risk assessment to help women determine their individual risk for developing pregnancy complications.
More Questions to Pursue
While it's not yet known why lower levels of anti-clotting factors (which results in increased clotting) boost the risk of miscarriage and other pregnancy complications, it's thought they may have an adverse effect on the blood vessels that lie between the placenta and the uterus. "We're concerned that if there's excessive clotting there, it puts you at risk for excessive complications like abruption, which is what we call decidual hemorrhage," Paidas explained. "It's where the placenta prematurely separates from the uterus."
Blood clotting during pregnancy can also boost the risk of preeclampsia, a condition characterized by high blood pressure, high fluid retention (edema), and abnormally high protein levels (proteinuria). "To put it in perspective, preeclampsia is the leading cause of maternal death in underdeveloped countries, and it's the second leading cause in the developed world," Paidas said. "So, these are complications that are important to know about, not only for the fetus, but also for the mother."
1. Paidas MJ, Ku DH, Lee MJ et al. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications. J Thromb Haemost 2005 Mar;3(3):497-501.
2. Merck Manual. Thrombophilia. Available at: http://www.merck.com/mmhe/sec14/ch173/ch173g.html?qt=anti-clotting%20protein&alt=sh. Accessed July 12, 2005.
3. American Pregnancy Association. Miscarriage. Available at: http://www.americanpregnancy.org/pregnancyloss/miscarriage.htm. Accessed July 12, 2005.
4. Heeb MJ, Paganini-Hill A, Griffin JH, Fisher M. Low protein Z levels and risk of ischemic stroke: differences by diabetic status and gender. Blood Cells Mol Dis 2002 Sep-Oct;29(2):139-44.
5. Gris JC, Quere I, Dechaud H et al. High frequency of protein Z deficiency in patients with unexplained fetal loss. Blood 2002 Apr 1;99(7):2606-8.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
