The review of the present clinical case has allowed us to observe that immobility due to COVID-19 confinement in a 23-year-old non-smoking female patient, heterozygous for the prothrombin gene G20210A, asymptomatic until the moment of immobility, and a user of hormonal contraception, are factors of risk significant enough to have triggered DVT / PE, up to three times, which highlights the multifactoriality of TED.
Thrombosis is a multifactorial entity that depends on genetic factors (such as the G20210A gene mutation in our case), and environmental factors (immobility and use of hormonal contraceptives) .
TED basically comprises two entities: a) DVT and b) PE; however, some authors consider c) thromboembolic cerebrovascular accident (CVA) as an entity of the same spectrum (TED). Many authors consider that PE is almost always secondary to DVT; therefore, they consider DVT / PE as a single entity . The importance of these considerations is highlighted, since the incidence of PE is not negligible. The incidence of PE of 1: 100 older adults has been described; 1: 1000 young adults and 1: 100,000 children .
Rudolf Virchow described as early as 1859 the pathogenic triad for thromboembolic disease, highlighting three factors: a) venous stasis (immobility); b) endothelial injury; c) hypercoagulability or thrombophilia .
Regarding the first element of Virchow's triad (venous stasis and immobility), although the tourist class syndrome was described in 1958 as a temporary cause of immobility and a risk factor for developing DVT, it had already been described in 1940 PE by prolonged sitting in bomb shelters during the London bombings; and later in 1950, PE was described after prolonged sitting on long car trips, at work, or in the theater . However, and despite the anecdotal of these publications, immobility is more frequent in bedridden patients, in casts, and even in paraplegics . Recently, in 2003 e-thrombosis was described and in 2013 gamer-thrombosis due to prolonged sitting in front of a computer while playing video games. In 2006, the presentation of TED was also described in patients who, after immobility due to an earthquake in Japan, lived by car for 4-5 days. It is considered that 10 hours of sitting / day and 2 hours without getting up / day are risk factors for developing thrombosis. In fact, it is postulated that the new triad: a) obesity; b) sedentary lifestyle and; c) use of video games could be the cause of thrombophilia in young people between the ages of 13 and 18. Finally, in 2020, confinement due to COVID-19 has been described as a cause of temporary immobility that may be a new risk factor for developing DVT / PE .
This agrees with Franch-Llasat et al, who consider that thrombosis in the time of COVID-19 can be considered a collateral effect of confinement. In addition, they argue that the main risk factor for developing PE is immobility. In fact, it reports an incidence of 4 cases of PE in patients in a 10-day period of confinement, compared with the presentation of 7 cases of PE presented in a year without confinement (2019) . They compared the cases with PE from 2020 and 2019, and found that the patients in confinement (2020) were younger, had fewer risk factors and only 15% had hereditary thromboembolic alterations (genetic factor). In fact, they suggest that up to 30% of PE are due to work or recreational immobility . They concluded that, in young patients, immobility from confinement due to COVID-19 was the most important risk factor for developing TED . This would explain the presentation of PE in the patient in our clinical case (immobility due to confinement).
It is known that in 50% of thrombotic events (TED, DVT / PE) the causal factor cannot be identified. The other 50%, transient or prolonged clinical or environmental factors have been detected that induce venous stasis, hypercoagulability and endothelial damage, as postulated by Virchow .
With regard to hypercoagulability or thrombophilia (second element of Virchow's triad), thrombophilia can be genetic or acquired. In the first place, Factor V Leiden has been described as a genetic factor; the G20210A prothrombin gene mutation in second place; and the mutation of the enzyme methylene-tetra-hydro-folate-reductase in third place [5, 6]. Anti-phospholipid syndrome, systemic lupus erythematosus, resistance to protein C, hyperhomocystinemia, sticky platelet syndrome, and cancer have been described as acquired factors .
The mutation of the prothrombin gene G20210A is associated with an increased risk of venous thrombosis. Poor et al, in 1996, was the first to describe that the transposition of Guanine by Adenosine at position 20210 caused an increase in plasma prothrombin levels in carriers of this mutation. In heterozygotes (G / A), the prothrombin level increased by 30%; while in homozygous (A / A), the levels increased by 70% . The inheritance of the G20210A mutation is autosomal dominant. Its prevalence is 1–3% in the general population, 6% in patients with DVT, and 10% in families with a history of thrombophilia . By race, the prevalence of the G20210A mutation in Caucasian Americans is 2%; while in African Americans, Asians, Africans and Native Americans it is 0.5% . This mutation increases the risk of developing TED by between 2 and 5 times, with the same behavior both by age and by sex .
With regard to endothelial injury / damage (third element of Virchow's triad), it has been reported that some drugs, including contraceptives, could inflame the intimal layer . Cabrera-Payne et al have observed that the conjunction of the G20210A gene mutation and the presence of use of hormonal contraception and / or pregnancy are sufficient risk factors for the presentation of DVT / PE . Del Valle-Rubido et al have described that the G20210A gene mutation associated with pregnancy / puerperium are sufficient risk factors for the presentation of postpartum ovarian venous thrombosis . This reinforces the point that hormonal changes (pregnancy / puerperium) constitute a risk factor for the presentation of TED. This is also in agreement with Cabrera-Payne et al, who argue that in women heterozygous for the G20210A gene mutation, exposure to hormonal contraceptives significantly increases the risk of developing DVT and cerebral thrombosis . Therefore, the thrombogenic effect of the mutated G20210A gene plus the appearance of modifiable risks such as the use of hormonal contraceptives, pregnancy or the puerperium, in addition to immobility (surgical or traumatic), could favor the presentation of thrombosis, as has occurred in the present clinical case .
Finally, the management of TED requires pharmacological and non-pharmacological measures. The use of strong compression stockings decreases post-phlebitic syndrome by 50%, which appears in up to 60% of cases with thrombosis . The mortality of PE is 30%, therefore, the use of effective pharmacological measures is required. Anticoagulation begins with low molecular weight heparin (LMWH) and then to add Acenocoumarol (Sintrom) until maintaining an INR (International Normalized Ratio) between 2 and 3. After an idiopathic episode and if treatment was maintained between 3 and 6 months, the recurrence rate per year is 5-10%. If there is a second episode of TED, the recurrence rate per year if anticoagulated for 6 months is 21%, while it will be 2.6% if anticoagulated indefinitely . Specialists suggest 6 months of anticoagulation after an idiopathic episode, one year after a second episode and anticoagulation for life if three episodes occur . This would explain in our clinical case the observed recurrence of up to three episodes in one year, which suggests that the patient probably has to be anticoagulated indefinitely, given the existing hypercoagulable state (G20210A gene mutation).
Cabrera-Payne et al have shown that the use of LMWH in addition to oral antiagregants (aspirin) is effective in the management of TED in pregnant patients with a G20210A gene mutation .