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Dear Editor,
Thrombophilia is the tendency to form blood clots both in arteries and veins [1]. Inherited and
acquired high plasma homocysteine (HHcy) levels are judged as thrombophilic agents because can
induce both arterial and venous thrombosis [2-5]. But, the association of hHHcy with Venous
Thromboembolism (VTE) has been studied less extensively than that with arterial thrombosis. Some
causes are responsible for this, such as Endothelial Dysfunction (ED). Several mechanisms have been
suggested explaining HHcy-induced ED. Among these are included: nitric oxide (NO) inhibition due
to the suppression of NO. The inhibition is caused by Asymmetric-D-Methyl-Arginine (ADMA),
an endogenous inhibitor of nitric oxide synthase (NOS). ED is also dependent on the endothelin-1
induction, angiotensin II activation and oxidative stress [6]. Other factors involved in the induction
of arterial thrombosis are: impaired DNA methylation, vascular smooth muscle cells proliferation,
and platelet’s activation [7]. On the contrary, a direct correlation between HHcy and venous
thrombosis is substantially less known [8]. In this context, some AA. Reports show that HHcy
promotes venous thrombosis by disturbing the procoagulant-anticoagulant balance [9]. But, a
significant increase of VTE risk also happens in patients contemporary suffering of inherited HHcy
and factor V Leiden gene mutation. In addition, venous thrombosis can be evident when HHcy is
present in association with other thrombophilic factors, such as prothrombin G 20210A, protein C
deficiency, protein C deficiency or antithrombin deficiency [10].
On view of these evidences, to prevent both arterial and venous thrombosis in HHcy-patients, an
antiplatelet drug should be added to an anticoagulant compound. The combination of two
antithrombotics seems to be effective to antagonize the risk of arterial and venous thrombi formation,
even if this treatment increases the risk of major bleeding [11]. Antiplatelet therapy should consist of
Aspirin or Clopidogrel, whereas anticoagulant treatment will require an acecumarol. But,
conventional anticoagulants, such as acecumarol, also called Vitamin K Antagonists (VKAs), have
multiple negative effects as: delayed onset of action, need to coagulation monitoring performed
through the evaluation of International Normalized Ratio (INR), frequent dosage adjustments and
numerous drugs and foods interaction [12]. Thus, a combination of an antiplatelet drug with a DOAC
should be used in HHcy-patients. Specifically, likewise to the Cardiovascular OutcomMes for People
uSing Anticoagulation StrategieS (COMPASS) Study [13], Aspirin or Clopidogrel at full dosage +
half dose of a DOAC could be administered. The choice of DOACs, as above referred, added to an
antiplatelet treatment can be associated with risk of major bleeding. For this reason, DOAC should
be given at reduced dose.
Conclusively, HHcy is certainly associated with atherosclerosis, while its association with venous
thrombosis is controversial. On the contrary, its presence in association with factor V Leiden and/or
other coagulative factors could likely increase VTE [14]. In that case, the association of an antiplatelet
drug with reduced doses of DOAC seems to be an attractive and rational treatment to antagonize both
arterial and venous thromboembolism induced by HHcy. Interestedly, the supplementation with water
soluble vitamins (folate, Vit. B6, Vit. B12) reducing the high Hcy levels, can also decrease the severity
of HHcy-related thrombophilia [4, 15].
Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients
