Superficial vein thrombosis in non-varicose veins of the lower limbs and thrombophilia

Introduction

There has been an ongoing debate in this century, largely due to a need for cost reduction, as to whether complete thrombophilia screening should be conducted on individuals experiencing a first venous thrombotic event. We need to identify the clinical cases in which full screening is to little avail; it yields a low percentage of positive results as opposed to more frequent cases of secondary thrombophilia. This identification would be useful in determining the medical conditions which justify the high costs.

A distinction must be made between SVT in varicose veins, in which venous stasis appears to be the main element in the disease, and SVT in non-varicose veins. The latter form of SVT should prompt a search for the causes as the disorder is sometimes secondary to thrombophilia or cancer. ¹

The discovery over the years of numerous inherited and acquired thrombophilias has made this search for the causes, on the one hand, more precise and on the other, more complex.

Methods

The aim of this study is to investigate the prevalence of hereditary or acquired thrombophilia in a consecutive group of outpatients found to have an SVT.

From January 2004 to December 2014, 73 consecutive patients with SVT of the lower limbs (of which one was bilateral) came under our observation. All underwent a colour Doppler ultrasound (Toshiba) to confirm clinical diagnosis, determine the extent of the clot and diagnose a potential association with deep vein thrombosis (DVT). The examination was carried out on both limbs in all cases, and analysis of the deep venous system was extended from the leg veins to the inferior vena cava.

All the patients were tested for antithrombin, protein C and protein S deficiency, for APC resistance, lupus anticoagulant, anti-cardiolipin antibody, anti-beta-2 glycoprotein-1 antibodies, factor V Leiden mutation, prothrombin G20210A mutation and MTHFR C677T mutation as well as for homocysteine levels.

For the sake of thoroughness, a basic screening for occult tumours was performed at that time. In cases in which a tumour had previously been determined by an oncologist, that diagnosis was deferred to.

In addition, complete blood counts were performed. Chest X-rays, PSA for males, gynaecological check-ups, pap tests and mammograms for women were conducted and complete abdominal ultrasounds were performed to spot potential associated tumours.

Patients with connective tissue disease, occlusive arterial disease of the lower limbs, cirrhosis of the liver were excluded as were end-stage renal disease patients on haemodialysis and subjects with serious congestive heart failure and all patients treated with dicoumarols.

Patients' average age was 42 (16–82), of which 44 were males and 29 females.

Results

Among the 73 patients, the SVT involved the great saphenous vein in 58 cases (one was bilateral, another was associated with a small saphenous vein thrombosis), 10 involved the small saphenous vein, 14 were thromboses of tributary veins.

An association was found with a DVT in nine patients: one was femoral; one popliteal; one posterior tibial; six gastrocnemius veins, a percentage of 12.3.

In 26 patients, a condition had triggered the thrombosis (35%). These were due to: estrogen/progestin therapy in nine cases, pregnancy and post-partum state in four, recent surgery, where no antithrombotic prophylaxis was carried out in four, prolonged bed rest for acute illness in three, immobility owing to flights of over 6 h in three, lymphangitis in two and trauma in one (see Figure 1). Sixty patients completed the testing, while 13 dropped out. OPEN IN VIEWER

Thrombophilia was found in 46 patients (76%), no thrombophilia in 14 (24%), cancer was found in four of the latter (5.4% of the 60 patients studied, i.e. 28.5% of the patients without thrombophilia).

In patients found with thrombophilia, we noted the following: 31 factor V Leiden (51%), of which 14 were homozygous and 17 heterozygous; prothrombin G20210A mutations (3.3%), both were heterozygous; 23 MTHFR mutations (38.3%), of which 6 were homozygous and 17 heterozygous all with homocysteine levels above the normal cutoff; 5 antiphospholipid antibodies (APLA) (8.3%); 3 LAC; 1 anti-cardiolipin; 1 anti-beta-2 glycoprotein-1; 1 protein C deficit (1.6%); 1 protein S deficit (1.6%); 0 antithrombin deficit (0%) (see Figure 2). OPEN IN VIEWER

In the 46 patients with thrombophilia, 14 had an association of two or more thrombophilias (14/46, i.e. 30.4%). Two subjects had MTHFR + APLA (3.3%), 10 factor V Leiden + MTHFR (21.7%), one LAC + factor V Leiden + MTHFR (2.1%), one Factor V Leiden + prothrombin mutation + MTHFR (2.1%) (see Figure 3). OPEN IN VIEWER

Discussion

Our result of 76% of thrombophilia is rather high. Martinelli et al. ² found 21.7% of inherited thrombophilia. Milio et al.'s research^3,4 revealed 57.9% of inherited cases. In a recent work, Legnani et al. ⁵ observed 25.6% of thrombophilia, but the sample examined involved SVT on both varicose and non-varicose veins. Our study was conducted only on patients with SVT on non-varicose veins and the results are similar to the sub-group in Milio’s two works on patients with SVT in non-varicose veins. Milio et al. found a prevalence of 63.3% of inherited thrombophilia in the patients observed. The higher prevalence of thrombophilia found in our study might be justified by the fact that we also tested our patients for APLA.

The prevalence of factor V Leiden in our research is high (51.6%), nearing the upper limits of prevalence reported in the literature (26.3–60%); the prevalence of homozygous cases is high as well (45.1%). This is a difficult finding to explain in view of the fact that prevalence of factor V Leiden in the overall population of Lazio, where the research was conducted, is not reported in the literature. The prevalence of factor V Leiden in the overall population in Italy is approximately 4%.

The MTHFR mutation appeared in 38.3% of our study, 8 homozygous and 15 heterozygous, and fell within the limits reported in the literature.^3,6–8

Cancer was very rare in our observational study, a mere 5.4%. However, this may be due to the young age of our subjects and to the fact that all were outpatients, thus in good general condition.^8,9

This finding, however, was not the aim of our research.

The prevalence of DVT, 12.3%, is lower than that found in the literature,^8,9 but this too may be related to the recruitment of outpatients of a young age.

The limitation of our study is the restricted number of cases analysed, but SVT in non-varicose veins is not frequent and, in any case, the number of patients recruited is no lower than those recruited in previous research involving only patients with SVT in non-varicose veins. Nevertheless, research needs to be extended to include a higher number of cases.

Our study along with the literature, leads us to consider inherited or acquired thrombophilia as an event that is not rare and that should be taken into account when managing patients with SVT. In addition, we believe that a systematic search for thrombophilia in such patients may be useful as it might reveal a condition of increased thrombotic risk that could have repercussions during the course of patients’ lives.