Thrombophilias or Clotting Disorders are an Inherited Condition that can Cause Recurrent Miscarriage
The word thrombophilia means tendency toward blood clot formation. As it turns out, the ability of our blood to flow through our vessels (a vitally important bodily function), results from a balance between clotting mechanisms on the one hand, and anticlotting mechanisms on the other.
Pregnancy in all individuals, is a condition which ’tilts the balance’ so to speak, in favor of clotting.
I have heard a reputable authority on this topic make the statement that it is surprising that during pregnancy, the person ‘does not become one large clot’. Now we each have an underlying genetic predisposition toward clot formation. Some people are more prone to develop clots and others less prone. It stands to reason, that the person with a greater genetic predisposition toward clot formation, will be more likely to form clots when pregnant, than the person with a lower genetic predisposition toward clot formation.
Through a series of blood tests, we can determine if a patient has thrombophilic tendencies and may benefit from the addition of aspirin or heparin/lovenox.
Thrombophilias are an inherited or acquired condition.
Thrombophilias are inherited or acquired conditions, which predispose an individual to thromboembolism (blood clots). This is due to an imbalance between certain blood clotting factors and anti-clotting proteins in the blood. As many as one in five people in the United States is a carrier of a type of thrombophilia. There is limited information in medicine today regarding the testing and treatment criteria of thrombophilias, but studies are emerging.
Although most women with thrombophilias have healthy pregnancies, thrombophilias can contribute to a number of pregnancy complications. These include recurrent first trimester pregnancy losses, second or third trimester stillbirths, placental abruption (when the placenta separates from the uterine wall before delivery), preeclampsia less than 37 weeks gestation (high blood pressure and presence of protein in the urine) and poor fetal growth. Several of these problems are believed to result from blood clots in placental blood vessels that lead to changes in the placenta and reduced blood flow to the fetus. As yet, no proven cause and effect relationship has been shown to exist between thrombophilias and failed embryo implantation, poor IVF outcome or very early pregnancy losses (chemical pregnancy).
As already mentioned, pregnant women in general are more likely than non pregnant women to develop venous thromboembolism (VTE), or development of a blood clot in a vein. This is due to the normal pregnancy-related changes in the blood clotting system in order to limit blood loss during labor and delivery. Pregnant women with a thrombophilia are at a higher risk of developing VTE. Studies suggest that more than half of pregnant women who develop a VTE have an underlying thrombophilia disorder.
Women with a personal or family history of blood clots, pulmonary embolism (blood clot in the lung), strokes, low platelet counts, a history of pregnancy complications including stillbirth, preterm preeclampsia, placental abruption, recurrent pregnancy loss or poor fetal growth due to undetermined causes should be considered for testing.The heritable thrombophilias are a group of genetic disorders of coagulation that result in an increased risk of thrombosis (clotting). Successful pregnancy requires the creation of the early placental circulation, the lifeline of nutrients, oxygenation and removal of wastes for the developing fetus. Thrombosis of the placental vessels in the setting of a genetic condition that predisposes to increased clot formation may result in serious problems for a pregnancy. These include first and second trimester miscarriages, growth restriction, preeclampsia and intrauterine fetal death in the third trimester.
This review will discuss the role of three of the genetic thrombophilias and discuss their possible role in recurrent miscarriages.
- Factor V Leiden mutation
- Prothrombin Gene Mutation
- MTHFR mutation
Factor V Leiden
Two Vitamin K-dependent clotting proteins, named Protein C and Protein 5 are located on blood platelets, and are therefore part of the normal coagulation mechanism. These proteins inactivate additional clotting factors, Factor V and Factor VIII, resulting in decreased clot formation, which is part of the body’s protective mechanism against excessive clot formation. A resistance to the activated form of Protein C due to a genetic mutation in Factor V, with subsequent amino acid change, is termed the Factor V Leiden mutation. This mutation is the most common genetic thrombophilia, with a prevalence of 3-5% of Caucasian women being heterozygous carriers. In addition to problems in pregnancy, this condition is felt to be the leading cause of clot formation in women who take oral contraceptive pills. This condition is found in approximately 60% of women with gestational (pregnancy-related) thrombosis. In addition, the factor V Leiden mutation has been demonstrated in between 15-30% of women with recurrent early miscarriages.
*The terms heterozygous (hetero-different) and homozygous (homo-same) are terms used in genetics. The human genome contains to copies of the information. If the copies are the same, they are homozygous; if the copies are different, they are heterozygous. For example, take a protein called A. The normal genome would code for the protein as AA. This is homozygous for the normal protein. If there is a variation of the protein called a, there are two possible ways to get the a. The genome could be Aa, which is called heterozygous or the genome could be aa, which is called homozygous.
Prothrombin (Factor II) 20210 Gene Mutation
Prothrombin is another clotting protein that is critical in the body’s formation and dissolution of clots. An amino acid change in this gene is associated with elevated levels of Prothrombin and subsequent increased clot formation in both the venous and arterial systems. Heteroygotes (one normal copy, one abnormal copy) for this gene has been identified in 2% of normal individuals and in 6% of individuals with Deep Venous Thrombosis (DVT). Several research studies have shown correlation between this condition and recurrent miscarriages. One study demonstrated that in women with recurrent miscarriages, the incidence of this mutation was approximately 8%, vs. 4% in controls.
Homocysteine is an amino acid that may accumulate in the body under certain conditions and cause enhanced clot formation via stimulated increase of certain clotting factors and stimulation of toxic free radicals. The metabolism of homocysteine is controlled by Folic Acid and Vitamin B-12, and dietary deficiencies of these substances may therefore contribute to enhanced levels of homocysteine in the blood (Hyperhomocystinemia). Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the metabolism of homocysteine, and deficiency of this enzyme may likewise cause enhanced accumulation of this amino acid. Two amino acid mutations in MTHFR, the C677T and the A1298C mutations, contribute to the potential for accumulation of homocysteine. The risks for elevated homocysteine are predominantly with the homozygous (two copies) state of each of these mutations, with the A1298 overall being less severe than the C677T mutation. Homozygosity for the C677T mutation can be found in up to 15% of otherwise normal individuals. Compound heterozygotes (one copy of each), may have similar risks as the homozygous C677T individuals. These mutations are extremely common, with approximately 20% of the general population heterozygous for one of the MTHFR variants. In addition to recurrent miscarriages, homozygous and compound heterozygous individuals are at risk for venous and arterial thrombosis, preeclampsia, placental abruption, decreased folate levels and fetal neural tube defects. Although some data is conflicting, studies with homozygous MTHFR and elevated homocysteine levels have demonstrated an approximate doubling of risk for spontaneous miscarriages. In addition, additional studies suggest that in women with at least two miscarriages, the incidence of MTHFR is 2-3 x that of women without history of miscarriages.
Combined Thrombophilic Defects
Combinations of genetic thrombophilias result in an increased risk of thrombosis and miscarriage, as well as other adverse pregnancy events. Certain combinations, such as the combination of Factor V Leiden and homozygous MTHFR, may be particularly severe. One study showed that the risk of still births in women with combined defects was 14 times that of controls without these mutations. Later pregnancy complications, including early onset preeclampsia, growth restriction and abruption are also dramatically increased in these individuals.
Genetic thrombophilias may play a significant role in the devastating problem of recurrent pregnancy loss. Appropriate diagnosis is critical in the process, to identify those individuals who require specific treatment. In our center, we believe that liberal use these treatment modalities are crucial to maximize early placental circulation, to decrease miscarriages, and to foster a healthy pregnancy and a healthy newborn. Patients with the inherited type of these disorders may benefit from genetic evaluation because of the possibility of passing these genes on to the offspring. In certain types of thrombophilias testing of family members may be necessary due to the inherited characteristic of these disorders and some patients may need life-long prophylaxis. A thorough consultation with the reproductive endocrinologist and geneticist is of utmost importance in the testing and treatment of these disorders.e)