Thrombophilias

by Claudia Ravaldi

In recent weeks there has been much talk of maternal deaths in labor or after childbirth. In particular, the issue of thrombophilias was addressed, which has created a lot of noise in the newspapers: some doctors have in fact proposed a carpet screening of congenital and acquired thrombophilias as a possible prevention of these cases, saying that the tests are not carried out due to the high cost (up to 1000 euros for full exams).

This statement has sparked some controversy, a good number of articles edited by other experts in response, and has in any case allowed to open a debate on a topic unknown to most, often reserved for very few specialists, and still much debated today. Moreover, a theme that affects a non-negligible share of bereaved parents, and that therefore with CiaoLapo we felt the need to deal with one of our experts.

What science says, and what you need to know.

We asked Dr. Valentina Pontello to explain in detail what thrombophilias are, how they can be diagnosed, how they can be treated.

Doctor Pontello, what do you think of all the noise around the theme of thrombophilias?

Thrombophilias are a vast and complex topic, and to date, blanket screening is not feasible for various reasons, which go beyond the simple economic criterion, and which I will try to explain:

congenital and acquired thrombophilias are very common : the most frequent is factor V Leiden (factor V mutation), which can affect 5 to 8% of the Caucasian population, followed by factor II mutation (prothrombin) with 2% . Mutation involving antithrombin III deficiency is rarer (1 out of 630 subjects); protein S (0.2%), protein C (0.3%). These mutations are more common if investigated within families with established thrombophilia, i.e. with previous cases of deep vein thrombosis before age 40.

The mutation for the thermolabile variant of MTHFR (methylenetetrahydrofolate reductase), an enzyme involved in the metabolism of folic acid, is not considered at risk of thrombogenicity, unless this is severely deficient (mutation in homozygosity, i.e. in double copy) with consequent increase of plasma homocysteine. The heterozygous variant (only one mutated gene) is very common and can affect up to 25% of the general population.

With regard to acquired thrombophilias , the most common is the antiphospholipid antibody syndrome, diagnosed only when the presence of these antibodies is associated with previous thromboembolic events or previous adverse obstetric outcomes. In practice, antibodies are very frequent (up to 2-5% of the healthy population), and a single finding is not enough, but their presence must be confirmed by at least two blood dosages 12 weeks apart. .

Congenital and acquired thrombophilia factors are therefore very common, but only in a minority of cases they cause adverse events (deep vein thrombosis, thromboembolism, adverse obstetric outcomes). Indeed, thrombophilia is believed to be a multifactorial condition, in which individual mutated genes represent a susceptibility and not a direct cause of disease.

Why is carpet screening in the absence of sentinel elements not the right way to prevent?

We have to consider two aspects: the risk of false positives, and that, even more dangerous than false negatives.

if we carried out the carpet screening, at least 10% of all healthy people would test positive and would be treated with drugs for rare diseases that nevertheless would never develop ( false positives , excessive medicalization).

a negative screening, on the other hand, could represent false reassurance. (false negatives, i.e. untreated people who nevertheless should have received therapy). If we consider the adverse events (deep vein thrombosis, negative obstetric outcomes from placental pathology) more than half of the patients have normal blood tests. This is one of the reasons why literature studies do not find correlation (or give very discordant results) between adverse obstetric outcomes and thrombophilia.

This fact represents an obstacle to the indiscriminate use of antithrombotic therapy in pregnancy.

What are the cases in which screening should be performed?

Today it is well established that the woman with previous venous thrombosis, for example while taking the pill, should be treated with anticoagulants as soon as she is pregnant; however, it is less understandable for the non-specialist doctor that even those who have apparently normal tests should be treated.

Histological documentation of placental thrombosis after an adverse outcome (growth retardation, gestosis, placental abruption, second and third trimester abortions) is therefore essential. For this reason, the histological examination of the placenta must only be carried out by pathologists who are experts in the field, since it represents the only evidence of a thrombophilic defect, which in a large number of cases does not emerge from blood tests.

It is therefore necessary to be wary of very concise histological responses that do not report anomalies in the case in which the pathology has emerged clinically and dramatically (death in utero, severe growth retardation). In these cases, a normal placenta is practically never verifiable, if examined by an expert.

Are there any other risk factors for thrombophilia to be aware of?

Public attention should be stressed on general acquired thrombophilic factors : age, obesity, smoking, prolonged immobilization.

Before thinking about a blanket treatment for the entire thrombophilic population, the message should be conveyed that an incorrect diet and excessive weight gain in pregnancy, especially in an already obese patient, is an important risk factor for maternal thrombosis and placental and therefore adverse outcomes.

What are the antithrombotic therapies?

Aspirinette (100 mg acetylsalicylic acid) and low molecular weight heparin they are well-tolerated drugs, which can be taken for long periods without significant side effects (aspirinetta must in any case be suspended after 30-32 weeks due to the risk of closure of the Botallo duct, while heparin can be continued for the entire pregnancy).

These therapies have been shown to increase the rate of live births in polyabortivity due to antiphospholipid antibodies, but there are no reliable scientific data regarding their use for the prevention of late pregnancy complications (gestosis, growth retardation, stillbirth). However, being safe drugs, their clinical use is spreading in all those situations in which there have been previous complications related to the placenta in the second and third trimester.

To be effective, antithrombotic therapy it must be started in the first 6 weeks , but there can also be a benefit by the 18th, when the second phase of invasion of the placenta (“trophoblast”) into the maternal circulation occurs. It has no rationale in thrombophilic patients or non-use of preconceptional anticoagulant therapies.

Furthermore, it is good to remember that antithrombotic therapy is not a panacea : thrombophilic susceptibility is only one of the factors that leads to adverse outcomes, other elements are certainly involved, probably related to the functioning of the immune system, which in some cases is not possible. eliminate entirely.

Bibliography

Thrombophilia and Pregnancy Complications. Louise E. Simcox, Laura Ormesher, Clare Tower, Ian A. Greer. Int J Mol Sci. 2015 December; 16 (12): 28418-28428.

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