A chronic hypercoagulable state in patients with β‐thalassaemia major is already present in childhood

Abstract

Summary. A higher than normal incidence of thromboembolic events has been observed in adult patients with bthalassaemia major (TM) and certain haemostatic anomalies found in these patients suggest the existence of a chronic hypercoagulable state. Thalassaemic red blood cells (RBC) were demonstrated to facilitate thrombin formation due to altered asymmetry of the membrane phospholipids with enhanced exposure of phosphatidylserine. Since RBC anomalies exist in thalassaemia from the ®rst months of life, we studied markers of hypercoagulability and thrombophilia in 36 adult patients (range 19±38 years) and 26 children (range 2±18 years) with b-TM. All the patients were in steady state and none had experienced clinical signs or symptoms of thrombosis. Highly elevated urinary levels of 11-dehydro-thromboxane B 2 and signi®cantly elevated plasma levels of thrombin±antithrombin III (TAT) complexes were observed to the same extent in TM children and adults. The levels of factor II were decreased while factors V, VII X and plasminogen were within the normal range. The natural coagulation inhibitors, protein C (PC) and protein S (PS) were signi®cantly decreased in all TM patients investigated, regardless of age, but the PS binding protein (C4bBP) and antithrombin III levels were normal. The frequency of other thrombophilic mutations was not increased. Thus, a chronic hypercoagulable state already exists in thalassaemia in childhood and may contribute to the cardiac and pulmonary anomalies and the thrombotic events which occur later.

The hypercoagulable state in thalassemia

“…In a study by Eldor et al, 4 plasma prothrombin levels were significantly lower in adult patients (aged 19-30 years) with ␤-TM (68% Ϯ 11.5%) compared to age-matched healthy controls (86.1% Ϯ 12.3%), whereas the levels of factors V, VII, X, and plasminogen were similar. Similarly reduced levels of prothrombin (61.1% Ϯ 6.5%) were observed in a group of children, aged 2 to 18 years, with ␤-TM, suggesting that this anomaly is related to the thalassemia rather than to hepatic dysfunction due to hemosiderosis, which is a rare occurrence in children.…”

“…4,19,53,54 In Israeli patients mostly of Kurdish Jewish, Yemenite Jewish, or Arabic origin, protein C (antigen and activity) and free protein S were significantly decreased in both adults and children. 4 Mean protein C antigen levels were 51.2% Ϯ 11.2% in adult ␤-TM patients and 46% Ϯ 9.1% in ␤-TM children (aged 2-13 years); they were 94.1% Ϯ 21% in healthy individuals (P Ͻ .001). Similar values were obtained for protein C activity: 52.3% Ϯ 12.1% in ␤-TM adults, 48.8% Ϯ 14.7% in ␤-TM children, and 99.2% Ϯ 16.1% in healthy controls (P Ͻ .001).…”

“…Similarly reduced levels of prothrombin (61.1% Ϯ 6.5%) were observed in a group of children, aged 2 to 18 years, with ␤-TM, suggesting that this anomaly is related to the thalassemia rather than to hepatic dysfunction due to hemosiderosis, which is a rare occurrence in children. 4 Low levels of the coagulation inhibitors, protein C and protein S, have been observed in patients with ␤ thalassemia from a variety of ethnic backgrounds. 4,19,53,54 In Israeli patients mostly of Kurdish Jewish, Yemenite Jewish, or Arabic origin, protein C (antigen and activity) and free protein S were significantly decreased in both adults and children.…”

“…4 Low levels of the coagulation inhibitors, protein C and protein S, have been observed in patients with ␤ thalassemia from a variety of ethnic backgrounds. 4,19,53,54 In Israeli patients mostly of Kurdish Jewish, Yemenite Jewish, or Arabic origin, protein C (antigen and activity) and free protein S were significantly decreased in both adults and children. 4 Mean protein C antigen levels were 51.2% Ϯ 11.2% in adult ␤-TM patients and 46% Ϯ 9.1% in ␤-TM children (aged 2-13 years); they were 94.1% Ϯ 21% in healthy individuals (P Ͻ .001).…”

“…32 The results of this study are consistent with enhanced production of TXA 2 due to chronic endogenous platelet activation and reflect the increased concentrations of urinary thromboxane metabolites found in other diseases associated with in vivo platelet activation including unstable coronary disease, severe atherosclerosis, and type II diabetes mellitus. [33][34][35][36] In another more recent study, 4 urinary prostaglandin metabolites were determined in a group of 62 ␤-TM patients comprising 26 children (aged 2-18) and 36 adults. All the thalassemic children (including the youngest, aged 2-8 years) and the adults had highly elevated levels of the urinary prostaglandin metabolites, 11-dehydro-TXB 2 and 2,3-dinor-6-keto-PGF 1␣ .…”