Blood hypercoagulability as a risk factor for leg ulcers in sickle cell disease.

We found the article by Koshy et al,’ entitled “Leg Ulcers in Patients With Sickle Cell Disease” very interesting. However, we want to make some comments mainly addressed to the factors implicated in the development of leg ulcers in sickle cell disease that, in our opinion, bring insights into the pathogenic mechanism of this complication. Among the contributing factors, the authors refer to ‘‘. . . the vessel obstruction by sickled cells, increased venous and capillary pressure, secondary bacterial infection, and decreased oxygen-carrying capacity of blood . . . ,” but they make no mention of the possible pathogenic role played by hemostatic abnormalities. In this regard, there are interesting reports, in both sickle cell disease and thalassemia syndromes, of vaso-occlusive microthrombotic events that, related to blood hypercoagulability, are responsible for the end organ damage frequently observed in these disease^.^-^ In corroboration with this view, we recently found indirect evidence’ that the leg ulcers may also be considered as a clinical equivalent of an end organ damage related to an in vivo chronic activation of blood coagulation. Indeed, in some adult subjects with sickle cell disease/@-thalassemia, complaining for long time of refractory leg ulcers, we detected the presence of an acquired antithrombin 111 deficiency, related to a chronic thrombin activation as expressed by an increase of plasma levels of fibrinopeptide A, along with increase of thrombinantithrombin complex, D-dimer fragment, and fibrinogen/fibrin degradation products. When we corrected the antithrombin 111 deficiency state by human antithrombin I11 concentrate (ATIII; Immuno, Pisa, Italy) given in combination with subcutaneous calcium heparin (Calciparina; Italfarmaco, Milan, Italy), a complete healing of leg ulcers was observed after 6 weeks of treatment. It is also noteworthy that no recurrence of leg ulcers occurred in any of our patients at distance of 6 months from hATIII concentrate discontinuation. On the basis of what was reported above, it would be interesting to know whether hemostatic profile was also considered in Koshy et al’s’ cooperative study as among risk factors for leg ulcers, such as age, sex, type of sickle cell disease, hemoglobin level, fetal hemoglobin level, and body mass. This would be important for us because, contrary to Koshy et al’s patients, ours were all affected by sickle cell disease/@-thalassemia, and the spontaneous raising and maintenance of leg ulcers was independent of hemoglobin concentration or fetal hemoglobin levels. We emphasize here that in Sicily, the coinheritance of sickle cell disease and &thalassemia is much more frequent than the homozygous sickle cell disease. However, in our experience, the percent of patients with leg ulcers is comparable with that reported by Koshy et al.’ In conclusion, we believe that in hemoglobinopathic patients complaining of refractory leg ulcers and showing an acquired antithrombin I11 deficiency, replacement therapy with h-ATIII concentrate should be encouraged as an “aggressive treatment.”