Insight into Thrombophilia; DVTs, PEs and Coronary Artery Disease
by Beth A. Pletcher, MD, November 1999

Over the past several years there has been an outpouring of information on both inherited and acquired factors predisposing to thrombosis. In the process we have learned that these factors may not only contribute to the development of deep vein thrombosis and pulmonary embolism, but also to coronary artery disease and poor pregnancy outcome. This review will concentrate on the information affecting the general adult patient population and will not go into great depth regarding pregnancy or obstetric considerations since these are somewhat distinct and more complex. However, if you wish to review these issues as they apply to women who are or plan to become pregnant, there is a parallel article in this edition of the obstetric newsletter that you will find at the website www.genesatwork.org. Recognized factors that increase an individual's risk for having a thrombotic event include: immobilization with or without surgery, having a first or second degree relative with a history of DVT or PE, pregnancy and merely the process of aging. While many individuals with thromboses are not found to have an inherited or even an acquired deficiency, as many as 50% will demonstrate an abnormality if laboratory investigations are pursued. Identifying individuals at increased risk for thrombosis may allow clinicians the chance to intervene before an adverse event occurs or to prevent a future event, thereby reducing morbidity and mortality.

Risk Factors

Below are some clues that might increase one's suspicion about a possible identifiable thrombophilia factor that would suggest a need for laboratory testing prior to elective surgery, pregnancy or initiation of oral contraceptive therapy. In fact, a personal history of DVT or PE alone would be contraindications to use of oral contraceptives.

  • Family history of cardiovascular disease or myocardial infarction occurring at a young age

  • DVTs at a young age

  • Family history of maternal or paternal relatives with DVTs or "phlebitis"

  • Pulmonary embolism

  • Placental abruption

  • IUGR

  • Severe preeclampsia

Thrombophilic Factors

Below are some of the inherited and acquired factors that contribute to thrombophilia in both men and women.

A.Inherited Factors

  • The Factor V Leiden (FVL) mutation, present in 3-8% of the general population, leads to less than normal anticoagulant response to activated protein C resulting in an increased risk for venous thrombosis. Individuals with one copy of the FVL gene mutation (heterozygotes) have a seven fold increased risk for thrombosis compared to the general population whereas homozygotes have an eighty fold increase. It is found in 25% of individuals with postoperative DVTs or PEs, but unlike some of the other factors described below, does not seem to significantly contribute to risk for strokes or myocardial infarction. In one study, FVL was found in 20% of women with preeclampsia, placental abruption or stillbirth compared to 6% of controls. It is also found in as many as 50% of women with estrogen-related thrombosis.

  • The prothrombin II (PTII) mutation, present in 1-2% of the general population, is associated with as much as a four fold increase for cardiovascular disease which skyrockets to a twenty-five fold increase when combined with other risk factors such as smoking, obesity or diabetes. This mutation is found in about 6% of individuals with postoperative DVTs or PEs. It also confers a three fold increase in thrombotic events in pregnant women and is associated with an increased risk for placental abruption and IUGR.

  • A homozygous methylenetetrahydrofolate reductase (MTHFR) mutation, present in 1-4% of the general population, is associated with a three fold increased risk for DVT or PE, as well as preeclampsia and placental abruption. Of greatest concern are the cardiovascular risks associated with this condition with homozygosity for MTHFR found in 15% of individuals with myocardial infarction and up to 40% of individuals with nonspecific cardiovascular disease. Of greatest interest is the possibility of simple medical intervention with daily folic acid supplementation to reduce the risks for adverse events in patients with a "double dose" of the MTHFR mutation.

B.Acquired or Inherited Factors

  • Protein S deficiency (PSD)#, present in up to 2% of the general population, is found in approximately 15% of individuals with a DVT or PE and 6% of women with obstetrical complications including a relatively high risk for stillbirth. Although there are inherited causes of PSD, more often other factors result in PSD such as nephrotic syndrome, liver dysfunction, DIC, vitamin K deficiency, use of coumadin, use of L-asparaginase, inflammation, pregnancy and use of estrogens. Ironically, thrombosis itself may induce PSD.

  • Protein C deficiency (PCD)#, present in about 1.5% of the general population, is associated with a lower risk for obstetrical complications than PSD and is found in 3-5% of individuals with a DVT or PE. Furthermore, PCD combined with a FVL mutation is a relatively common cause of DVTs and show a higher risk for thrombosis compared to FVL alone.

  • Antithrombin III deficiency (ATIII)#, present in less than 0.5 % of the general population, as with PSD and PCD, may rarely result from mutational events and instead occurs more commonly in individuals with confounding medical conditions or in association with use of one of a number of medications. Interestingly, heparin and not coumadin use is associated with decreasing levels of ATIII. It is found in approximately 1-5% of individuals with a DVT or PE. Because of its relative rarity, actual risks for thrombotic events are difficult to estimate, but without question this entity contributes to thrombotic risks during pregnancy.

# Actual mutations in any of these genes, although less common than acquired deficiencies, greatly increase an individual's lifetime risk for thrombosis with an estimated 50% risk for a thrombotic event by age 40 and an 85% risk by age 50.

Evaluation

Since many individuals with inherited or acquired thrombotic factors never experience thrombotic complications and at least half of patients with such complications do not have any recognized laboratory abnormalities, it is important to consider who might benefit from screening and when testing should be done. For the inherited factors, timing of testing is not critical since they employ molecular technologies. However, for the other factors, it might be wise to wait until at least one month following an acute thrombotic event or obstetrical problem before doing assays for PSD, PCD or ATIII. Below is a list of circumstances where thrombophilia testing might be considered.

  • A patient with a personal or family history of DVT or PE

  • A patient with a personal or family history of early onset MI (<45 years)

  • A patient with a stoke at an early age (< 50 years) without other risk factors such as HTN

  • A patient with a prior pregnancy with severe preeclampsia, multiple late pregnancy losses of unknown etiology, prior placental abruption or prior pregnancy with unexplained IUGR

In general, for a high risk patient both molecular and non-molecular testing could be offered to carefully assess individual risks. Since one person may have two factors simultaneously that would greatly increase the risk for an adverse outcome, it is important to do a reasonable panel of tests rather than sequential or partial testing. Furthermore, for patients undergoing elective surgery who have a significant family or personal history, such testing could alter preoperative and postoperative management and perhaps avoid a complication that could prolong the length of stay and increase medical costs, not to mention decrease morbidity and mortality.

Because risks for thrombosis are increased somewhat in young women taking oral contraceptives and some women may actually carry more than one of these inherited thrombophilia factors, the question comes up as to the possible benefits of screening women prior to starting low dose oral contraceptives. There is no data at the present time to suggest a significant decrease in the morbidity or mortality in young women on birth control pills who have been screened for these thrombophilia factors. Furthermore, if women who test positive are denied access to these medications, there actually may be a higher rate of unwanted pregnancies and the concomitant risks that are inherent to pregnancy itself. That being said, it appears that these risk/benefit studies need to be done to answer these questions with certainty. Furthermore, before starting oral contraceptives, patients with a strong family history of DVT or PE need to be identified so that selective screening may be offered. Women who are found to carry two factors (such as FVL and PTII or FVL and PCD) should be strongly cautioned about use of these medications and may require careful evaluation and/or treatment before and during pregnancy. Over time we anticipate that these questions will be answered so that women may comfortably take oral contraceptive without unnecessary worry about potential thrombotic complications.

Testing Options

One way to examine the laboratory studies is to divide the tests into the molecular and non-molecular assays. Molecular testing can be done for the most common mutations associated with a heritable increased risk for thrombosis including: FVL heterozygotes, FVL homozygotes, PTII heterozygotes and MTHFR homozygotes. Assays for PSD, PCD and ATIII may also be done depending upon the clinical scenario with the caveat about not testing for these deficiencies too close to a thrombotic event that could result in a false positive test. Regardless of the availability of testing, it is clearly up to individual providers to decide which if any of these tests is indicated for a given patient. Since many thrombotic events are not related to any of the predisposing factors, and aging, trauma and prolonged bed rest alone may contribute more to thrombotic events than all of these factors combined, it is important to recognize when the history is significant enough to warrant screening. Surely over the next few years many more studies will be done to elucidate the actual risks and relative contributions of each of these factors in the genesis of thromboses and their relationship to untoward pregnancy outcome.

REFERENCES

  1. Bonnar, J. (1999). Can more be done in obstetric and gynecologic practice to reduce morbidity and mortality associated with venous thromboembolism? American Journal of Obstetrics and Gynecology, 180(4) : 784-791.
  2. Bucciarelli, P., et al. (1999). Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: A multicenter collaborative family study. Arteriosclerosis, Thrombosis and Vascular Biology, 19 : 1026-1033.
  3. Kupferminc, M. J., et al. (1999). Increased frequency of genetic thrombophilia in women with complications of pregnancy. New England Journal of Medicine, 340(1) : 9-13.
  4. Meinardi, J. R., et al. (1999). Increased risk for fetal loss in carriers of factor V Leiden mutation. Annals of Internal Medicine, 130(9): 736-739.
  5. Redondo, M., et al. (1999). Coagulation factors II, V, VII, and X, prothrombin gene 20210G to A transition, and factor V Leiden in coronary artery disease: High factor V clotting activity is an independent risk factor for myocardial infarction. Arteriosclerosis, Thrombosis and Vascular Biology,19 : 1020-1025.
  6. Sibai, B. M. (1999). Thrombophilias and adverse outcomes of pregnancy- What should a clinician do? New England Journal of Medicine , 340 (1): 50-51.