In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Abstract

Increased frequency of thromboembolic events has been recently observed in patients with beta-thalassemia major (TM). Platelet function anomalies including impaired aggregation, increased circulating aggregates, and our finding of shortened platelet survival indicate that platelets may be involved in the hypercoagulability in thalassemia. Consequently, we used a technique based on thin layer chromatography purification and enzyme immunoassay to measure urinary metabolites of thromboxane A2 (TXA2) and prostacyclin (PGI2) in nine splenectomized patients with beta-TM regularly transfused, five non- splenectomized patients with beta-thalassemia intermedia (TI), and 20 healthy individuals. A significant 4- to 10-fold increase was observed in the urinary excretion of 2,3-dinor-TXB2, 11-dehydro-TXB2 and 2,3- dinor-6-keto-PGF1 alpha in patients with TM and TI as compared with healthy controls. No significant differences were found in the concentrations of these metabolites between TM and TI patients. Six TM patients received a very low dose of aspirin (20 mg/day) for 7 days. A significant decrease was observed in the urinary concentrations of 2,3- dinor-TXB2 and 11-dehydro-TXB2 derived from platelets. However, the levels of urinary 2,3-dinor-6-keto-PGF1 alpha reflecting vascular production and TXB2 and 6-keto-PGF1 alpha originating from the kidney were not significantly changed. These results are consistent with those of increased in vivo production of TXA2 because of endogenous platelet activation.

The effects of vitamin E on platelet activity in β‐thalassaemia patients

“…An increase in platelet function and reduction in prostacyclin production by vascular cells has been shown in vitamin E-deficient animals (Karpen et al, 1981). Low vitamin E levels in thalassaemia (Rachmilwitz et al, 1979;Eldor et al, 1991;Chantharaksri et al, 1992;Livrea et al, 1996) might be one of the contributing factors in the hyperaggregability of platelets in b-thalassaemia/HbE disease.…”

“…adenosine diphosphate (ADP), adrenaline and collagen (Isarangkura et al, 1987;Chantharaksri et al, 1992). There is increased aggregation of circulating platelets, and evidence of increased in vivo platelet activation as shown by increased urinary excretion of the metabolite thromboxane-A 2 (TXA 2 ) (Eldor et al, 1991). Thus, abnor-mality of platelets might contribute to hypoxaemia in these patients.…”

Activated platelet‐derived microparticles in thalassaemia

“…The spleen, liver and lung are the three major organs that have been shown to clear MPs in an animal model, in which the injection of mouse or human RBC led to the generation and clearance of MPs (Bocci et al, 1980). It is also known that splenectomy in b-thalassaemia uncovers a population of RBCs with particularly severe abnormalities that would otherwise have been selectively removed by the spleen (Eldor et al, 1991;Eldor & Rachmilewitz, 2002). This can result in increased numbers of damaged RBCs showing anisocytosis and poikilocytosis that can, in turn, generate a large amount of MPs in the circulation.…”

In‐vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with β‐thalassaemia major

“…Thus, sickle RBC were shown to display a procoagulant effect in in-vitro assays and were thought to be operative in the induction of a hypercoagulable state (Middelkoop et al, 1988;Hermann & Devaux, 1990). Although occlusive vascular complications are frequent in sickle cell disease, the existence of a hypercoagulable state in thalassaemia major and intermedia was recognized only recently (Eldor et al, 1987(Eldor et al, , 1991Musumeci et al, 1987;Del Principe et al, 1993;Cappellini et al, 1995Cappellini et al, , 1996. Despite the fact that none of our TM or TI patients had an overt thrombotic event, a chronic hypercoagulable state was evident by the increased fraction of circulating platelets expressing activation dependent neoantigens, p-selectin (CD62p) and the lysosomal glycoprotein CD63.…”

“…Several platelet and coagulation anomalies, frequently observed in TM or thalassaemia intermedia (TI) patients, suggested the existence of a hypercoagulable state. These include changes in platelet aggregation (Eldor, 1978), shortened (by about 50%) mean platelet life-span (Eldor et al, 1989), increased urinary excretion of thromboxane (TX) A 2 metabolites (2,3-dinor-TXB 2 and 11-dehydro-TXB 2 ) (Eldor et al, 1991), enhanced expression of p-selectin (PADGEM/GMP 140) on intact thalassaemic platelets (Del Principe et al, 1993), elevated plasma levels of thrombin-antithrombin III (TAT) complexes and low plasma levels of the natural anticoagulants, protein C and protein S (Musumeci et al, 1987;Eldor et al, 1992;Cappellini et al, 1995).…”