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. Factor V Leiden is one of the inherited disorders that was only recently discovered, is widely prevalent and is becoming known to the general public. The following case is instructive.

A 26-year-old woman 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 evaluation revealed the heterozygous presence of the Factor V Leiden mutation. The homocysteine level was 12 mol/L (normal <9). The patient was then tested for the C677T methytetrahydrofolate reductase (MTHFR) mutation and was found to be heterozygous. 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.
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.

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. 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. A recent study has just reported that an inherited tendency to high levels of Factor XI is a newly identified thrombophilic abnormality.

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 and that some obstetrical disorders are mediated by thrombosis.

In a recent study of 119 women with a history of venous thromboembolism during pregnancy and the puerperium, the investigators 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. 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.

As a result, it has been recommended that all pregnant women with a personal or family history of venous thromboembolism should be screened for congenital thrombophilia. 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. Newly reported findings suggest that the pregnancy loss associated with thrombophilia can be prevented with enoxaparin (p<0.0001).

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. Epidemiological studies, combined with molecular biologic analysis, promise better understanding in the future.

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