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Hereditary Thrombophilia (Coagulation Factors)

General aspects
 Fig.1 – Formazione di un trombo sulla parete di un vaso sanguigno
 Fig.1 – Thrombi formation

The hereditary thrombophilia is a genetic predisposition to form thrombi (blood clots), that may cause of a venous or arterial thrombosis, a partial or total obstruction of the blood vessels that prevents the normal blood flow (Fig. 1). The thrombophilia takes on a particular importance in pregnancy because a placental thrombosis can cause some complications (fetal growth delay, placental detachment, etc.) until his spontaneous interruption.

Genetics aspects

The more involved genes to cause susceptibility (predisposition) to thrombotic events encode for coagulation factors, such as factor V and factor II (Prothrombin) directly involved in a blood coagulation process and the Methylentetrahydrofolate reductase (MTHFR) enzyme. In the population many coagulation defects occur in a heterozygous form, so the individuals are carriers of a mutation in one of two copies of the gene; they have on two chance to transmit the disease predisposition to their children, independently from sex. Individuals with both copies of the gene altered are called homozygous. DNA analysis identifies carrier individuals with a particular mutation, both heterozygotes which homozygotes.

Factor V

The factor V is a very important protein to promote the blood coagulation process. In individuals without a genetic mutations this process is regulate and it is successful. The DNA analysis makes it possible to highlight the presence of the R506Q or G1691A or Arg506GIn mutation, defined Leiden variant, which involves in a increased pro-coagulative activity of Factor V the risk of venous thrombosis development is increased: in heterozygous individuals, 3-8% of the population (2-3% in Italy) the risk is higher by 5-10 times; in homozygous individuals (frequency 1 on 5000, but changes widely among different populations) the risk is equal to 50-100 times. The risk of the thrombotic event is increased in the presence of other conditions like pregnancy (up to 50 times), oral contraceptives taking (30 times in heterozygous and hundred times in homozygous), surgical operations.

Factor II (Prothrombin)

The coagulation factor II or Prothrombin, thanks to the action of the V Factor is converted in thrombin which play a vital role in the clot formation. The DNA analysis for the II Factor allows the identification of the mutation G20210A responsible to an increase of the prothrombin levels (10-140%), and then of thrombin in plasma with an increased risk of thrombosis. Heterozygous individuals for the mutation have a 2-3% frequency in the population and an increased risk of 2-3 times compared with the average.
The thrombotic event is also promoted in the presence of other conditions such as oral contraceptives taking (from 15 to 30 times). The homozygous individuals for the mutation are rare.

Methylentetrahydrofolate reductase (MTHFR)

Methylentetrahydrofolate reductase (MTHFR) is a protein which, in contrast with the II and V factors, isn't directly involved in the blood coagulation process, but it is important in different metabolic reactions including the transformation of the homocysteine in the methionine amino acid. The DNA analysis allows to identify the C677T mutation in the MTHFR gene that causes a reduction of the protein activity of 50%; so it is minus efficient to convert the homocysteine in the methionine; this involves increased levels of homocysteine in the blood (homocysteine) and in the urine (homocystinuria). High plasma homocysteine levels are considered risk factors for the thrombosis development. In the population the frequency of heterozygotes for the mutation C677T is about the 45%, while that of homozygosites of little more than 10%. Recent studies point out
that homozygous individuals for the mutation have a venous thrombosis risk of 20% compared with normal homozygotes. In the MTHFR gene there is another mutation, known as A1298C which causes the reduction of the enzyme activity of 30% and if it is present individually seems to not affect the plasma homocysteine levels; in compound heterozygous C677T/A1298C the reduction of the enzyme activity is about of 60% and they have plasma homocysteine levels elevated. If heterozygous individuals for C677T the mutation is associated with variation of Leiden (factor V) or G20210A (factor II), it may further increase the risk of thrombotic events.

Genetic counseling

Tecnobios Eurogenlab Prenatal gives a genetic counseling service to inform patients and parents, in a clear terms about the disease, the risk of disease transmission within the family diagnosis and treatments.

Response times

The result of the DNA is generally available after 7 days from draw blood.

Analyzed material

DNA is extracted from blood lymphocytes in tubes with EDTA.

Sources sites
Malattie genetiche – Cao, Dalla Piccola, Notarangelo – Piccin (2004)
Rosendaal FR, Reitsma PH (2009). Genetics of VT- J. Thromb. Haemost. 7 Suppl 1: 301–4
Rosedaal FR (2005) Venous Thrombosis: The Role of Genes, Environment, and Behavior -Hematology Am. Soc. Hematol. Educ. Program
http://www.orpha.net