Yale Center for Hemostasis and Thrombosis in Women’s and Children’s Health

Michael J. Paidas, M.D., Associate Professor and Center Co-Director, Department of Obstetrics, Gynecology and Reproductive Sciences

Diana S. Beardsley, MD, PhD, Associate Professor and Center Co-Director, Department of Pediatrics

Pregnancy complications such as fetal loss, preeclampsia, intrauterine growth restriction and abruption collectively complicate approximately 8% of pregnancies. Epidemiologic data have suggested that the patients with a poor obstetrical history are at significantly increased risk of recurrence. Inherited thrombophilic conditions are increasingly being implicated in these pregnancy outcomes, yet paradoxically, the majority of patients harboring the most common mutations, such as Factor V Leiden and prothrombin gene mutation G20210A are asymptomatic. Identifying patients at increased risk would represent a significant advance. Recently, we have demonstrated that moderately levels of protein Z, a co-factor for protein Z dependent protease inhibitor of Factor Xa is associated with a fourfold increased risk of pregnancy complications, and may identify the select group of thrombophilic patients at high risk for subsequent pregnancy complications. This work complements a large, population based initiative evaluating the association between family history, obstetric events and genetic determinants in collaboration between University of Copenhagen, Celera Diagnostics, and our Center.

Plasma biomarkers are being evaluated in conjunction with a new Doppler ultrasound technique employing multigate spectral Doppler analysis to study velocity blood flow patterns in the uteroplacental circulation. This new technology is the result of collaboration between the Department of Engineering, University of Florence, University of Milan, Bicocca, and Yale. Presently, conventional uterine artery Doppler evaluation has been an insensitive tool in detecting pregnancies at risk for preeclampsia and fetal growth restriction. Our preliminary experience studying the fetal circulation documented the feasibility of this new approach and currently we are enrolling patients in a prospective study to determine the predictive value of this innovative Doppler modality, which can safely provide the most accurate description of blood velocity profiles in the uteroplacental circulation.

While anticoagulation and antiplatelet agents have helped improve pregnancy outcomes in patients with thrombotic related etiologies, a significant proportion of patients with immune related recurrent pregnancy loss still have unsuccessful pregnancies. We are currently participating in a prospective, randomized, double blinded, placebo controlled study to determine whether preconceptual administration of intravenous gamma-globulin (500mg/kg IVIG) and continuation through the first half of pregnancy will improve reproductive outcome in women who have had at least three consecutive fetal losses, but who have achieved at least one pregnancy beyond 20 wks. The rationale for this approach of passive immunotherapy is based upon the finding of activation of T-cells favoring a Th-1 response associated with pro-inflammatory cytokines, especially tumor necrosis factor alpha, interleulin-1 and interferon. Intravenous gamma-globulin infusion has been associated with a suppression of the number of CD 56+ and natural killer cells, and has shown promise in women with recurrent spontaneous abortion.

Inherited and acquired thrombophilic conditions are associated with enhanced thrombin generation and fibrin deposition which leads to uteroplacental thrombosis. A constellation of adverse pregnancy outcomes, namely second and third trimester fetal loss, preeclampsia and abruption are the clinical sequellae of this pathologic condition. Recurrence risks for each of these events vary widely, ranging from five to over sixty percent. Since there are agents, namely, aspirin and heparin that may reduce the chance of having an adverse pregnancy outcome, determining which group of patients is at higher risk for such untoward outcome would be beneficial.

Thrombophilia is a multigenic disorder. We have shown a thrombophilia dose dependent increase in coagulation activation marker levels as the number of thrombophilic conditions present increases (Table1). We have further demonstrated that women with thrombophilic conditions have elevated levels of Thrombus precursor Protein TM, soluble fibrin polymers and tumor necrosis factor alpha in the first trimester (Tables 2, 3). Potentially these and other components of the coagulation and inflammatory cascades will be helpful in identifying high risk patients, and provide a tool for monitoring preventive therapies. For example, deficiency of protein Z, a plasma protein which serves as a co-factor for a protease inhibitor for Factor Xa, has been reported recently to be associated with fetal loss.

Recently, we found that mean 1st trimester maternal plasma protein Z levels (ug/ml) are significantly lower among thrombophilic patients compared to pregnant controls with normal outcomes (2.0+/-0.9 vs. 2.2+/-0.8 p‹0.04), and that there is a trend toward thrombophilic patients and adverse pregnancy outcome having the lowest protein Z levels. A large multicenter clinical trial is necessary to determine the best course of treatment and detection of these thrombophilic conditions.

Since at least 10% of the population harbors a thrombophilic mutation, a significant number of women, approximately 400,000 women per year in the United States alone, are potentially at risk for pregnancy complications. Fortunately however, the majority of women will experience an uncomplicated outcome. The Center for Thrombosis and Hemostasis in Women’s Health is devoted to providing expert, coordinated care through a multidisciplinary approach to patients at risk for thrombosis related sequellae and bleeding disorders, including ITP, von Willebrand disease, Factor deficiencies, neonatal alloimmune thrombocytopenia, and other inherited disorders.

Other special circumstances, including postmenopausal women on estrogen replacement and women with malignancy are also appropriate candidates for referral given the increased thrombotic risk under these circumstances. Interested patients can participate in research studies and trials devoted to these topics.

A clinical care coordinator/ research nurse assists in patient education and enrollment. Faculty members of the department of Laboratory Medicine and division of Hematology are an integral component of the Center’s mission. Biweekly case presentation will highlight the most complex cases requiring an integrated approach to management. Educating medical students, residents, fellows, other faculty members and allied health professionals is an important goal of the Center. Teaching occurs in a variety of settings, including, direct patient care, formal rounds, conferences, and symposia, sponsored by the Center, and other organizations, such as the March of Dimes.