Course Authors
Robert G. Lerner, M.D.
In the past three years, Dr. Lerner has served as a consultant for RPR, and has served on the Speakers' Bureau for Pharmacia & Upjohn.
This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.
Estimated course time: 1 hour(s).
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In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe the term "thrombophilia" and list the recently discovered thrombophilic mutations such as Factor V Leiden, Prothrombin G20210A and MTHFR
Discuss the increased risk of thrombosis for pregnant women with thrombophilia, and the risk of pregnancy loss and complications
Discuss the preliminary data supportive of enoxaparin to prevent pregnancy loss.
In recent years, several new inherited and acquired disorders that predispose to thrombosis have been discovered, and as a group they are sometimes called thrombophilia.(1) Factor V Leiden is one of the inherited disorders that was only recently discovered,(2) is widely prevalent and is becoming known to the general public. I found the following case to be instructive.
Case Report
A 26-year-old woman came directly to me as a hematologist asking to be tested for the Factor V Leiden mutation. She reported that she had experienced two first trimester spontaneous abortions and was trying to become pregnant. Her mother had, recently, experienced a deep vein thrombosis (DVT) and, as part of her medical evaluation, was found to have the Factor V Leiden mutation. In retrospect, the patient's maternal grandmother had suffered from recurrent DVT and a pulmonary embolus. Her maternal grandfather also had a history of a "blood clot" in his leg. The patient's siblings had already been tested: three siblings were found not to have Factor V Leiden; one brother, aged 32, was found to be heterozygous for the mutation and had no history of thromboembolic disease.
There were no abnormalities on physical examination.
Laboratory Findings
Laboratory evaluation revealed the heterozygous presence of the Factor V Leiden mutation. The homocysteine level was 12 mmol/L (normal <9). The patient was then tested for the C677T methylenetetrahydrofolate reductase (MTHFR) mutation and was found to be heterozygous. An elevated level of homocysteine is a known risk factor for vascular disease, both arterial and venous. Very marked elevations are seen in hereditary homocysteinuria, which is usually tested for at birth and becomes obvious in early childhood. However, MTHFR deficiency is much more prevalent and typically accounts for the mild elevation seen in this patient. There was no detectable lupus anticoagulant. Assays for Protein C, Protein S and antithrombin were all normal. The prothrombin G20210A mutation -- another cause of thrombosis -- was not present. Routine CBC and chemistries were normal.
Genetics, Diagnosis and Risk Factors
Advances in molecular biology have made the genetic diagnosis of thrombophilia relatively easy. Many of these molecular abnormalities are clearly associated with a clinical tendency to the development of thromboembolic disease when present in the homozygous state, but the clinical implications of heterozygous abnormalities or combinations of abnormalities are less clear-cut. Additionally, it has become apparent that the tendency to thrombosis is multifactorial. In addition to the hereditary component, there are acquired risk factors, such as recent surgery, immobilization, pregnancy and cancer. Changes in the blood, such as polycythemia, lupus anticoagulants and elevated levels of coagulation factors, may also be acquired risk factors.
Elevated levels of coagulation factors may also be hereditary. Indeed, the prothrombin G20210A mutation, referred to earlier, actually results in elevated levels of apparently normal prothrombin.(3),(4) There has been considerable confusion in the past about the implications of a single abnormality. This was, in part, due to the presence of other inherited abnormalities that were not known at the time.
Epidemiology
Careful epidemiology has allowed the advances in molecular biology to be paralleled by increased understanding of the risks for thrombosis. It has also resulted in an appreciation of how much we do not know about the prognosis of individuals with the various combinations of risk factors. Pregnancy is a well-known risk factor for thrombosis. Additionally, it is becoming apparent that a tendency to thrombosis is a risk factor for loss of pregnancies(5),(6) and that some obstetrical disorders are mediated by thrombosis.
Discussion
Some recent studies cast light on this evolving body of knowledge. Gerhardt et al reported a study of 119 women with a history of venous thromboembolism during pregnancy and the puerperium.(7) They measured the activity of antithrombin, protein C, protein S and lupus anticoagulant, and did genetic analysis for Factor V Leiden, prothrombin G20210A mutation and the MTHFR mutation. They calculated that the risk of thrombosis during pregnancy among carriers of Factor V Leiden was 0.2 percent, among carriers of the G20210A mutation, 0.5 percent and among carriers of both defects, 4.6 percent. This report was accompanied by an editorial in the New England Journal of Medicine recommending that all pregnant women with a personal or family history of venous thromboembolism should be screened for congenital thrombophilia.(8) The additional recommendation was made that women with a history of second trimester pregnancy loss, severe or recurrent preeclampsia or intrauterine growth restriction also be screened.
These recommendations are based upon accumulating information on the relationship between thrombophilia and pregnancy. This does not mean that random screening should be done on all women in early pregnancy. Indeed, McColl had previously estimated that the thrombotic risk for a woman during pregnancy or the puerperium with just the Factor V Leiden mutation was 1 in 400-500,(9) similar to the 0.2 per cent risk calculated by Gerhardt et al. Neither author suggests that this lends support to random screening. McColl also reported a retrospective analysis of the same population of 72,000 deliveries in which only 49 cases of superficial venous thrombosis developed in 47 women.(10) Twenty-four of these women were screened for Factor V Leiden and only one abnormality was found, indicating that thrombophilia may play only a minor role in the etiology of superficial venous thrombosis.
One of the most provocative new reports at the American Society of Hematology meeting in December 1999 suggested that the pregnancy loss associated with thrombophilia can be prevented with enoxaparin. Brenner et al(11) found combined thrombophilic defects in 21 per cent of women with multiple pregnancy loss, compared to 5.5 per cent in controls. They treated 61 subsequent pregnancies in 50 women with thrombophilia, and 46 of the 61 (75%) resulted in live birth. This compared to only 38/193 (20%) live births of untreated pregnancies in these women prior to the diagnosis of thrombophilia (p<0.0001).
In summary, this case broadens our understanding of the impact of thrombophilia on health. Our knowledge of thrombophilic disorders has now expanded beyond antithrombin deficiency. Only recently, more than 95% of venous thromboembolic events were without explanation, when screened for antithrombin, protein C and protein S deficiency. Now that screening for Factor V Leiden, the prothrombin G20210A mutation, homocysteine level and the presence of a lupus anticoagulant are included, greater than 40% of patients with thromboembolic events are found to have an associated thrombophilic abnormality. A recent study has just reported that an inherited tendency to high levels of Factor XI is a newly identified thrombophilic abnormality.(12) Epidemiological studies, combined with molecular biologic analysis, promise better understanding in the future.